BETWEEN:
ASTRAZENECA AB and ASTRAZENECA CANADA INC.
and
APOTEX INC. and THE MINISTER OF HEALTH
REASONS FOR ORDER
[Confidential Reasons for Order issued on January 4, 2006]
[1] Are the applicants, AstraZeneca AB and AstraZeneca Canada Inc. (collectively Astra), entitled to an order prohibiting the Minister of Health (the Minister) from issuing a notice of compliance (NOC) to the respondent, Apotex Inc. (Apotex), with respect to 10mg and 20 mg magnesium omeprazole tablets until after the expiration of Canadian Letters Patent No. 2,186,037 (the '037 patent)? I conclude that the answer is "no".
BACKGROUND
[2] The '037 patent is listed by AstraZeneca Canada Inc. on the Patent Register in respect of omeprazole (which includes magnesium omeprazole) tablets 10 mg and 20 mg (manufactured as LOSEC) and used to treat gastric and duodenal ulcers. AstraZeneca AB is the owner of the patent. On March 25, 2003, pursuant to the provisions of the Patented Medicines (Notice of Compliance Regulations (the Regulations), Apotex informed Astra that Apotex had filed with the Minister a submission for a NOC for magnesium omeprazole tablets for oral administration in strengths of 10 mg and 20 mg. Apotex alleges non-infringement and invalidity of the '037 patent. Astra, by notice of application dated May 13, 2003, seeks a declaration that the Apotex letter of March 25th is not a NOA and Detailed Statement as contemplated by the Regulations and an order prohibiting the Minister from issuing a NOC to Apotex in respect of its 10 and 20 mg magnesium omeprazole tablets until after the expiration of the '037 patent. The Minister administers the Regulations and did not file submissions or participate in the hearing of this application.
THE PATENT
[3] The application that resulted in the '037 patent was filed on February 9, 1996, and claims a priority filing date of February 9, 1995. It was published on August 15, 1996, and the patent issued on April 16, 2002. The patent refers to new pharmaceutical formulations, comprising acid labile heterocyclic compounds with gastric inhibitory effect, referred to in the patent as proton pump inhibitors.
[4] The disclosure reveals that proton pump inhibitors are susceptible to degradation/ transformation in acidic reacting and neutral media. The proton pump inhibitor (PPI) in an oral solid dosage form must be protected from contact with the acidic reacting gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH (the measure of degree of acidity or alkalinity of a substance in water measured on a scale of 1-14 with 7 being neutral) is less acidic, neutral, or alkaline and where rapid absorption of the pharmaceutically active substance (the PPI) can occur. A pharmaceutical dosage form of these proton pump inhibitors is best protected from contact with acidic gastric juice by an enteric coating layer. The disclosure states that there must be a separating layer between the enteric coating and the ingredients in the tablet's core. The '037 patent purports to provide a new pharmaceutical formulation and process for the manufacture of such tablets, namely, the separating layer is formed in situ (formed as the result of a reaction between the enteric coating polymer and the tablet's core). An in situ separating layer can be contrasted with a separating layer that is put in place as a distinct step in the manufacturing process. The '037 patent purports to simplify the manufacturing process by removing the additional step, that being the application of a layer.
[5] The patent has 61 claims. Claim 1 and its dependent claims 2 through 22 and 27 to 29 are claims for the medicine or for the use of the medicine. Claim 1 and claims 2 to 19, 21, 22 and 27 to 29, which depend from claim 1, include an omeprazole dosage form within their scope. Claims 30 to 56 are process claims. Claims 57 to 59 are claims to the use of the pharmaceutical dosage form defined in any one of claims 1 to 29. Claim 60 is a claim to a commercial package comprising the pharmaceutical dosage form defined in any one of claims 1 to 29. Claim 61 is a claim to an oral pharmaceutical dosage form prepared by a process defined in any one of claims 30 to 56. The parties agree, for all intents and purposes, that it is claim 1 of the '037 patent that is relevant and, at the hearing, only claim 1 was addressed. Claim 1 describes an oral pharmaceutical dosage form in the following terms:
1. An oral pharmaceutical dosage form comprising:
(a) a core material that contains a proton pump inhibitor and an alkaline
reacting compound;
(b) an enteric coating layer comprising an enteric coating polymer; and
(c) a water soluble separating layer that is formed in situ as a water soluble
salt between the core material and the enteric coating layer by a reaction
between the enteric coating polymer and the alkaline reacting compound.
THE NATURE OF THE PROCEEDING
[6] As earlier noted, this proceeding is brought under the Regulations, the history and scheme of which are well known. Briefly, when a second person (usually a generic manufacturer) seeks marketing approval (a NOC) for a drug, by comparing its drug to the drug of a first person (an innovator) for the purpose of demonstrating bioequivalence, the generic will be required to address patents listed on the patent register by a first person. The generic or second person may do so by making an allegation of invalidity, non-infringement, or both. The issues of validity and non-infringement between the innovator and the generic originate with a NOA served on the first person by the second person setting out the second person's allegations, including a statement of the legal and factual basis for the allegation. Following receipt of a NOA, a first person may apply to the court for an order prohibiting the Minister from issuing a NOC until after the expiration of one or more of the patents. If the Court finds that none of the generic's allegations is justified, the Court shall grant an order of prohibition.
[7] Apotex, the generic drug producer or second person, under section 5 of the Regulations, provided its NOA to Astra regarding the '037 patent that Astra has listed under the provisions of section 4 of the Regulations. Astra's application, in response to the Apotex NOA, is brought under section 6 of the Regulations.
[8] Section 6 proceedings are not to be likened to actions for determining validity or infringement. They are proceedings in judicial review, to be held expeditiously, aimed at determining whether the Minister is free to issue the requested NOC. Their scope is confined to administrative purposes: Apotex Inc. v. Canada(Minister of National Health and Welfare) (1997), 76 C.P.R. (3d) 1 (F.C.A.). The determination must turn on whether there are allegations by the second person sufficiently substantiated to support a conclusion for administrative purposes (the issue of a NOC) that an applicant's patent would not be infringed if the second person's product is put on the market: Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.).
[9] The Regulations allow a Court to determine summarily, on the basis of the evidence adduced, whether the allegations are justified. If a full trial of validity or infringement 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.); SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001), 14 C.P.R. (4th) 76 (F.C.T.D.) aff'd. (2002), 21 C.P.R. (4th) 129 (F.C.A.); Novartis A.G. v. Apotex Inc. (2002), 22 C.P.R. (4th) 450 (F.C.A.). By merely commencing the proceeding, the applicant obtains what is tantamount to an interlocutory injunction without having satisfied any of the criteria a court would require before enjoining issuance of a NOC: Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare), [1998] 2 S.C.R. 193; Bristol-Myers Squibb Canada Inc. v. Canada (Attorney General) (2001), 11 C.P.R. (4th) 539 (F.C.A.). The statutory stay in this proceeding has been extended to February 11, 2006.
PRELIMINARY MATTERS
[10] There are grounds delineated in the NOA that were not pursued at the hearing. Specifically, Apotex did not advance its argument in relation to Canadian Patent No. 2,166,794 (the '794 patent) nor did it maintain its position that the '037 patent was ineligible for listing. Astra did not formally abandon its request for a declaration that Apotex's letter of March 25, 2003 "is not a Notice of Allegation and Detailed Statement as contemplated by the Regulations", but it made no submissions, written or oral, in this regard. Astra withdrew its argument of judicial estoppel in relation to the issue of anticipation. Consequently, I will not be dealing with these matters and no further reference will be made to them.
[11] Astra argued, both in its written submission and in oral argument, but did not plead, reliance on the doctrine of issue estoppel. After hearing from both parties, I invited Astra to consider (prior to its reply) whether it wished to abandon its position. It did not. I will therefore address this question.
[12] Astra argues that Apotex is estopped from relitigating certain factual matters in respect of its tablet formulation. It claims that the three requirements for issue estoppel, as set out by the Supreme Court of Canada in Danyluk v. Ainsworth Technologies, [2001] 2 S.C.R. 460 at 476, are met in this case. First, it points to the decision of the Federal Court of Appeal in AB Hassle v. Apotex Inc. (2003), 29 C.P.R. (4th) 23 (F.C.A.) and asserts that certain facts fundamental to the conclusion that Apotex's tablet infringes claim 1 of Canadian Patent No. 1,292,693 (the '693 patent) have been implicitly determined by the Court of Appeal. Astra contends that, in Apotex's appeal (premised on the construction of claim 1), Apotex accepted that its tablets would infringe if the subcoating of claim 1 of the '693 patent covers material between the core and enteric outer layer formed in situ from a reaction between components of the core and the enteric coating outer layer. The Court rejected Apotex's construction arguments and concluded that claim 1 of the '693 patent describes "a pharmaceutical preparation which, in its finished product form, contains a subcoating or separating layer between the core and enteric coating, however the subcoating or separating layer is formed".
[13] The second and third requirements have also been met, according to Astra, because the Court of Appeal decision is a final decision and the parties there included Astra and Apotex. Accordingly, issue estoppel applies and bars Apotex from disputing that its tablets have a separating layer that is sufficiently thick and complete to function to provide the requisite stability for the tablet and the layer cannot be comprised primarily of omeprazole or degraded omeprazole (as argued by Apotex's expert Dr. Cima). Since Apotex is precluded from relitigating the question of the nature of its tablets relevant to infringement of claim 1 of the '693 patent and since the completeness and thickness of the separating layer/subcoat are features common to claim 1 of both the '693 and '037 patents, Astra says that this is dispositive of Apotex's allegation of non-infringement herein.
[14] At the hearing, Astra expanded on its written arguments, stating that the same parties and the same tablets are involved. The only distinguishing factor is that a different patent is at issue. Astra notes that the purpose behind issue estoppel is to protect a party from being vexed more than once in relation to the same matter. The doctrine exists to preclude multiplicity of litigation and favours finality.
[15] Pointing to this Court's reasons in AB Hassle v. Apotex Inc. (2005), 38 C.P.R. (4th) 216 (F.C.), Astra says that this matter deals with factual matters that were either raised or could have been raised in the context of the '693 patent and that the Court of Appeal's decision has effectively determined the matter. Apotex led evidence before the applications judge with respect to the '693 patent, in relation to matters of continuity and thickness of the subcoating. The Apotex NOA was found to be inadequate. But, the same evidentiary record was in existence when the case went on appeal. It was the Court of Appeal that provided the basis for Astra to argue issue estoppel because, although it was not convinced that there was a deficiency in the Apotex NOA, the Court upheld the order of prohibition.
[16] Relying on Amgen Inc. v. Genetics Institute Inc. 40 USPQ2d, a decision of the United States Court of Appeals Federal Circuit, Astra says that the doctrine can be applied to different patents. In sum, Astra contends that it "shouldn't mean that we should duke it out again, because it's the same tablets, the same parties. Different patent doesn't matter."
[17] In relation to not having pleaded its reliance on the doctrine, Astra insists that this is a "technical point" and that to deny Astra its opportunity to rely on issue estoppel is to prefer form over substance. Jurisprudence that precludes an argument because it has not been pleaded deals with "true judicial review" and this is "not true judicial review, we're creating a record, and so it's really distinguishable". Moreover, Astra couldn't have raised this issue at the time the matter was initiated because the Court of Appeal decision was not available. Astra claims that this is a point of law and is not a matter of evidence. The intervening decision of the Court of Appeal has changed the law. Apotex is not prejudiced because the matter was raised in Astra's memorandum of law and Apotex has had its opportunity to respond.
[18] I reject Astra's argument that the requirement in Rule 301(e) can be characterized as a technical argument that elevates form over substance. The rule mandates that an application is to be commenced by a notice of application that must set out a complete and concise statement of the grounds intended to be argued. I also reject the submission that the jurisprudence does not evince the application of the rule to proceedings brought under the Regulations. In this respect, I refer specifically to Pharmacia Inc. et al. v. Minister of National Health and Welfare et al. (1995), 60 C.P.R. (3d) 328 (F.C.T.D.) at pp. 339, 340 aff'd. (1995), 64 C.P.R. (3d) 450 (F.C.A.) at paragraph 1. See also: Bayer AG et al. v. Apotex Inc. et al. (2003), 29 C.P.R. (4th) 143 (F.C.) and Pfizer Canada Inc. and Pfizer Inc. v. Apotex Inc. and the Minister of Health, 2005 FC 1421.
[19] If the intervening decision of the Court of Appeal crystallized Astra's issue estoppel argument, as alleged, Astra could have utilized Rule 75 which provides that the Court may on motion, at any time, allow a party to amend a document, on such terms as will protect the rights of all parties. Rule 75 applies to all proceedings. An application is a proceeding (see: Rules 61 and 300). Indeed, Astra was aware of Rule 75 for it utilized it in Court File No. T-1747-00, a matter that concerned the same tablets and the same parties, in its application for an order of prohibition under the Regulations. As for the timing, as Mr. Radomski notes, the Federal Court of Appeal's decision was issued on November 3, 2003. The evidence in this matter was far from complete at that time. Dr. Lindquist's (Astra's expert witness) second affidavit was not sworn until April 15, 2004. Apotex filed four affidavits after that date and Dr. Lindquist's third affidavit was not sworn until September 24, 2004. At no point, did Astra seek to amend its notice of application.
[20] It appears rather anomalous that Astra should point to what Apotex did or ought to have done in relation to the '693 patent and, in the same breath, request that I ignore its own failure to have regard to the Rules and the requirements contained therein.
[21] I note that the United States authority, relied upon by Astra, dealt with two patents where the specifications were identical. One patent was a continuation of the other and the subject matter was the same. That is not the situation here. The "invention" of the '693 patent is different than that disclosed in the '037 patent. Claim 1 of the '693 patent is not the same as Claim 1 in the '037 patent. The question regarding the allegation of non-infringement of the '037 patent has not been determined.
[22] For the foregoing reasons, I conclude that it is not open to Astra to advance issue estoppel, for the first time, in its memorandum of fact and law. Even if it were otherwise, it would not be open to it to expand on the contents of its memorandum during the course of its oral argument. Finally, there has been no previous determination in relation to the '037 patent.
THE BURDEN OF PROOF
[23] After hearing argument relating to the burden of proof, I articulated my understanding of the law as set out in a plethora of authorities beginning with Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) and culminating with Genpharm Inc. v. Procter & Gamble Pharmaceuticals Canada, Inc. et al. (2004), 37 C.P.R. (4th) 289 (F.C.A.). Counsel for both parties were satisfied that I had accurately summarized the law. Succinctly stated, the respondent Apotex's allegations of non-infringement are presumed to be true and the applicant Astra bears the legal burden of establishing, on a balance of probabilities, that none of Apotex's allegations are justified. In relation to validity, Astra may rely on the presumption of validity and Apotex must then meet an evidentiary burden to rebut the presumption. The legal burden remains with Astra throughout.
THE WITNESSES
[24] Astra relies on the evidence of the following witnesses:
(1) Mr. Peder Oxhammar, Senior Legal Counsel in GI Patent Litigation at AstraZeneca AB in Sweden, swore an affidavit on June 23, 2003, stating that Astra had no knowledge or access to knowledge regarding the contents or existence of the new drug submission (NDS) referred to by Apotex in its NOA. He is not being put forward as an expert and he was not cross-examined.
(2) Ms. Karen Burke, Vice-President of Regulatory Affairs at AstraZeneca Canada Inc., swore an affidavit on June 24, 2003, stating that Astra received Apotex's NOA and that Astra had no knowledge of the NDS referred to by Apotex in that NOA. She is not being put forward as an expert and she was not cross-examined.
(3) Ms. Jacinta M. De Abreu, a law clerk in the Toronto offices of Smart & Biggar (Astra's solicitors), swore an affidavit on June 27, 2003, wherein she provided a copy of Apotex's memorandum of fact and law in Court File No. T-1747-00.
(4) Dr. Jörgen Lindquist, a research scientist specializing in analytical chemistry and an employee of AstraZeneca AB, holds a Ph.D. in analytical chemistry from the University of Uppsala in Sweden. Until 1975, he was an associate professor of analytical chemistry at that university. He affirmed an affidavit on June 24, 2003, stating that he could determine whether an in situ separating layer existed in the Apotex tablets if he were to be provided with samples. He affirmed a second affidavit on April 15, 2004 (Lindquist 2) describing analytical tests he performed on samples of the Apotex tablets sent to him in order to determine the existence and composition of an in situ separating layer. He affirmed a third affidavit on September 24, 2004 (Lindquist 3) responding to the affidavits of Drs. Cima and Sodhi. Dr. Lindquist was cross-examined.
(5) Dr. John Elvan Rees, a former professor of pharmacy practice and pharmaceutics, holds a Ph.D. from the School of Pharmacy, University of London, for research on tablet manufacture. He has published extensively on pharmaceutical formulation, including articles on film-coating. He is an expert in pharmaceutical formulation including the coating of these formulations. He is currently a pharmaceutical industry consultant for matters relating to medicine design, pharmaceutical technology, and pharmacy practice research. He swore an affidavit on June 26, 2003, wherein he provided evidence with regard to the construction of the '037 patent and the validity of its claims. Dr. Rees was cross-examined.
[25] Apotex relies on the evidence of the following individuals:
(1) Dr. Harold B. Hopfenberg is the Camille Dreyfus Professor of Chemical Engineering and Director Emeritus of the Kenan Institute for Engineering, Technology and Science at North Carolina State University. He holds a Ph.D. in chemical engineering from the Massachusetts Institute of Technology. He has conducted research on surface, colloid and polymer science with a special emphasis on transport phenomena in coatings, membranes and films applied to pharmaceutical formulations and controlled drug delivery systems for human and veterinary medicine. He has served on a number of editorial advisory boards for scientific journals. He swore an affidavit on August 21, 2003, wherein he provided his opinion with regard to the construction of the '037 patent and the validity of its claims. He was cross-examined.
(2) Dr. Michael J. Cima, a professor of materials science and engineering at the Massachusetts Institute of Technology (MIT), holds a Ph.D. in chemical engineering from the University of California at Berkeley. He was elected a fellow of the American Ceramics Society in 1997 and was recently awarded the Sumitomo Industries Chair at MIT. His research interests include: powder processing; ceramics processing; drying; novel powder forming methods; slurry and ink formulation; pharmaceutical formulation; ceramic thin films; and ceramics manufacturing. He swore his first affidavit on August 22, 2003 and described his conclusions regarding tests that he conducted on samples of the Apotex tablets. He swore a second affidavit on July 19, 2004, responding to Lindquist 2. Dr. Cima was cross-examined.
(3) Mr. Francis Ng-Chen-Hin is employed in the office of Ivor M. Hughes, counsel to Apotex. He is not being offered as an expert. On August 25, 2003, he swore his first affidavit and stated that he forwarded documents to Drs. Signorio and Hopfenberg. His second affidavit, sworn July 19, 2004, described the contents of a delivery he received from Apotex and states that he forwarded the contents onto Dr. Sodhi. He was cross-examined.
(4) Dr. Bernard Sherman is the Chair of Apotex and is intimately involved with the development of Apotex's omeprazole magnesium tablets. He is not being put forward as an expert. In his affidavit, affirmed on August 25, 2003, he testified that he provided samples of tablets and documents to Ivor Hughes. In a second affidavit, affirmed July 14, 2004, he stated that he supplied samples of ingredients contained in the enteric coating of the Apotex tablets. Dr. Sherman was cross-examined.
(5) Dr. Charles A. Signorio is the President of Emerson Resources and C.S. Associates, companies that provide consulting services to the pharmaceutical industry on issues of coating formulations. He holds a Ph.D. in organic chemistry from the University of Pennsylvania and, for 30 years, he was employed by Colorcon Inc., one of the leading companies specializing in pharmaceutical coatings. He is the holder of 17 patents, the majority of which relate to pharmaceutical coatings. On August 25, 2003, he swore an affidavit in which he provided evidence regarding the construction of the '037 patent and deposed that he prepared slides and samples for testing. Dr. Signorio was cross-examined.
(6) Mr. Samuel Tekie, a professional engineer and a scientific technical researcher at the firm of Apotex's counsel, is not offered as an expert. In an affidavit sworn on August 25, 2003, he provided evidence regarding a literature search he conducted that resulted in the compilation of the documents listed within a number of Canadian and United States patents relevant to this matter. He was cross-examined.
(7) Ms. Nicole Roth, an employee of Goodmans LLP (solicitors for Apotex), swore an affidavit on August 25, 2003 and exhibited documents that were filed in Court File No. T-1747-00, including an affidavit sworn by Dr. Rees on October 20, 2000 and written representations made by Apotex dated November 6, 2000. She was not cross-examined.
(8) Dr. Rana N.S. Sodhi is the Director of Scientific Operations for Surface Interface Ontario, a laboratory established within the Department of Chemical Engineering and Applied Chemistry at the University of Toronto. Dr. Sodhi holds a Ph.D. in electron microscopy from the University of British Columbia and is an expert in the application of surface analytical techniques to a wide variety of different materials including polymers, pharmaceuticals, metals, ceramics and semi-conductors. On July 19, 2004, he swore an affidavit responding to Lindquist 2. Dr. Sodhi was cross-examined.
ISSUES
[26] The issues and the subsidiary issues flowing from those issues, as identified in the memoranda of fact and law, can be framed as follows:
(1) Has Astra established that Apotex's allegation of non-infringement is not justified?
(a) Do the Apotex tablets contain an alkaline reacting compound (ARC)?
(b) Do the Apotex tablets contain an in situ separating layer or subcoating?
(2) Has Apotex led evidence that is sufficient to displace the statutory presumption of validity and if so, has Astra established that Apotex's allegation of invalidity is not justified?
(a) Gillette Defence
(b) Anticipation
(c) Double Patenting
(d) Insufficiency of Specification and Ambiguity
(e) Insufficiency of Specification and Inutility
INFRINGEMENT
[27] Apotex's complete NOA is attached to these reasons as Schedule "A". The pertinent provisions in relation to claim 1 are set out below.
Claim 1 will not be infringed since our formulation will not contain an
alkaline reacting compound, as discussed above, within the meaning of
the '037 Patent.
Additionally, our product will contain a core material, which does not
contain an alkaline reacting compound, together with an enteric coating
disposed on the core material. Accordingly, claim 1 will not be infringed
since our formulation will not contain a water soluble separating layer,
because claim 1 requires that the water soluble separating layer be formed
in situ as a water soluble salt by a reaction between the enteric coating
polymer and the alkaline reacting compound. This cannot occur in our
product since it will not have an alkaline reacting compound.
Thirdly, as discussed above, the water soluble separating layer within
the meaning of claim 1 must completely coat the core material and be
of sufficient thickness which would allow it to function as a separating
layer which provides the requisite stability required for an oral dosage
formulation of a proton pump inhibitor which comprises a separating
or subcoating layer between the enteric coating and the core material.
Any material formed between our core material and the enteric coating
layer will not completely coat the core material and be of sufficient
thickness as to allow it to function as aforesaid.
Do the Apotex tablets contain an ARC?
[28] Before turning to the arguments of the parties, since this issue turns on the construction of claim 1, it is useful, again, to reproduce that claim.
1. An oral pharmaceutical dosage form comprising:
(a) a core material that contains a proton pump inhibitor and an alkaline
reacting compound;
(b) an enteric coating layer comprising an enteric coating polymer; and
(c) a water soluble separating layer that is formed in situ as a water soluble
salt between the core material and the enteric coating layer by a reaction
between the enteric coating polymer and the alkaline reacting compound.
[29] The first paragraph from the excerpt of Apotex's NOA reproduced above makes reference to a previous discussion in the NOA. The gravamen of that discussion is as follows:
The disclosure of the '037 patent makes it very clear that the phrase "proton pump inhibitor" includes both omeprazole and its base addition salt, such as magnesium omeprazole. The disclosure also makes clear that the phrase "alkaline reacting compound" cannot mean any substance which is a proton pump inhibitor. For example, omeprazole or magnesium omeprazole is not an "alkaline reacting compound" within the meaning of the patent.
Additionally, the phrase "alkaline reacting compound" cannot mean any constituent or excipient whose function in the formulation is other than as an "alkaline reacting compound". For instance, substances in the formulation which function as a lubricant, dye or disintegrant cannot be an "alkaline reacting compound".
[30] There is some, but not much, common ground. There is no debate that the proton pump inhibitor (PPI) includes both omeprazole and its base addition salts such as magnesium omeprazole. Thus, magnesium omeprazole is a PPI. There is also no dispute that the magnesium salt of omeprazole is alkaline. The crux of the argument between the parties is Apotex's assertion that the alkaline reacting compound (ARC) in Claim 1(a) cannot mean any substance that is a PPI and Astra's view to the contrary. The evidence that is pertinent to this issue is comprised of the affidavits and cross-examinations of Dr. Rees (for Astra) and Drs. Hopfenberg and Signorio (for Apotex).
The Arguments
[31] Astra submits that Apotex's construction of the '037 patent is incorrect. Astra maintains that the PPI can also be used to fulfill the role of the ARC. When read in its ordinary and grammatical context, claim 1 does not preclude the PPI and the ARC from being the same substance. The disclosure of the '037 patent contains a clear definition for the term "alkaline reacting compound" and, according to Astra, it was accepted by Apotex's witnesses that magnesium omeprazole can act as an ARC. Since the '037 patent imposes no other requirement or limitation in defining ARC (other than "a substance in the position to form a water soluble salt with an enteric coating polymer"), Astra alleges that Apotex's argument is tantamount to asking the Court to read in additional requirements that are not present on a fair reading of the claim. Specifically, Astra contends that the Apotex construction requires the addition of words in claim 1(a) to say "core material that contains a proton pump inhibitor and an alkaline reacting compound which must be different from the proton pump inhibitor".
[32] Astra asserts that it is well-known and common formulation practice that some ingredients are designed to serve more than one purpose and it is desirable, whenever feasible, to use as few ingredients as possible in a formulation in the interests of keeping it as simple as possible. Astra adds that the '037 patent provides no teaching to the effect that the ARC cannot be an excipient or constituent that serves more than one function.
[33] Moreover, notes Astra, Apotex's construction relies extensively upon examples in the disclosure when the disclosure specifically states that the scope of the invention is not limited by examples. Additionally, Dr. Signorio relied heavily (in cross-examination) on the patent's abstract. Subsection 79(1) of the Patent Rules, SOR/96-423 provides that the abstract "cannot be taken into account for the purpose of interpreting the scope of protection sought or obtained" in the patent.
[34] Apotex argues that the grammatical structure of claim 1, namely the use of the conjunctive word "and" makes it clear to an ordinary person skilled in the art that the PPI and the ARC are two separate components. To accept Astra's construction requires the insertion of a further definition regarding the PPI, specifically the insertion of the words "a proton pump inhibitor including an alkaline reacting compound", "a proton pump inhibitor without an alkaline reacting compound plus an alkaline reacting compound" or both.
[35] Also, says Apotex, component (c) of claim 1, which requires an in situ separating layer formed from a "reaction between the core material and the enteric coating layer by a reaction between the enteric coating layer and the ARC" supports the Apotex construction. Various references in the disclosure, which refer to the PPI "mixed with" the ARC also indicate that the ARC and PPI are distinct ingredients (affidavits of Drs. Hopfenberg and Signorio: applicant's record, volume 2, tab 7, pp. 197 and 199-201 and volume 3, tab 11, pp. 670-672).
[36] Further, the disclosure of the '037 patent teaches that it is the ARC that is involved in a reaction with the enteric coating polymer to form an in situ separating layer, the purpose of which is to protect the active medicinal ingredient (in this case the magnesium omeprazole) from degradation. Thus, Apotex asserts, to use the PPI (the active medicinal ingredient) as a reactant in a chemical reaction with the enteric coating polymer is antithetical to the intended purpose of the separating layer (affidavit of Dr. Hopfenberg, applicant's record, volume 2, tab 7, p. 204).
Analysis
[37] As noted, the determination of this issue turns on the construction of claim 1. One of the most recent pronouncements of the Federal Court of Appeal on the issue of claims construction is contained in Novartis Pharmaceuticals Canada Inc. v. RhoxalPharma Inc. (2005), 38 C.P.R. (4th) 193 (F.C.A.). Madam Justice Desjardins, for the majority[1], discusses the question at paragraphs 45 through 52 as follows:
¶ 45 Expert evidence, although essential to the construction of a claim, does not govern the construction of a claim. Claims construction is a question of law for the judge who is even entitled to adopt a construction of the claims that differs from that put forward by the parties (Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067, 9 C.P.R. (4th) 129, 194 D.L.R. (4th) 193, at para. 61 (Whirlpool); Canamould Extrusions Ltd. v. Driangle Inc. (2004), 237 D.L.R. [page207] (4th) 157, 30 C.P.R. (4th) 129 (F.C.A.), at para. 3, per Stone J.A.; Nekoosa Packaging Corp. v. AMCA International Ltd. (1994), 172 N.R. 387, 56 C.P.R. (3d) 470 (F.C.A.), at paras. 12, 13 and 14, per Robertson J.A.).
¶ 46 Whirlpool in particular (see also Free World Trust v. Electro Santé Inc., [2000] 2 S.C.R. 1024, 9 C.P.R. (4th) 168, 194 D.L.R. (4th) 232, at paras. 28 and 44) teaches us the principles of patent claims construction.
¶ 47 At para. 42 and 43 of Whirlpool, Binnie J. states:
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[42] The content of a patent specification is regulated by s. 34 of the Patent Act. The first part is a "disclosure" in which the patentee must describe the invention "with sufficiently complete and accurate details as will enable a workman, skilled in the art to which the invention relates, to construct or use that invention when the period of the monopoly has expired": Consolboard Inc. v. MacMillan Bloedel (Sask.) Ltd., [1981] 1 S.C.R. 504, at p. 517. The disclosure is the quid provided by the inventor in exchange for the quo of a 17-year (now 20-year) monopoly on the exploitation of the invention. The monopoly is enforceable by an array of statutory and equitable remedies and it is therefore important for the public to know what is prohibited and where they may safely go while the patent is still in existence. The public notice function is performed by the claims that conclude the specification and must state "distinctly and in explicit terms the things or combinations that the applicant regards as new and in which he claims an exclusive property or privilege" (s. 34(2))". An inventor is not obliged to claim a monopoly on everything new, ingenious and useful disclosed in the specification. The usual rule is that what is not claimed is considered disclaimed. |
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[43] The first step in a patent suit is therefore to construe the claims. ... [My emphasis.]
¶ 48 Binnie J. confirmed that the purposive approach developed in Catnic Components Ltd. v. Hill and Smith Ltd., [1982] R.P.C. 183 (H.L.), and adopted by this Court in Eli Lilly & Co. v. O'Hara Manufacturing Ltd. (1989), 26 C.P.R. (3d) 1 (F.C.A.), was the proper approach to claims construction.
¶ 49 "The key to a purposive construction ....", Binnie J. wrote at para. 45, "... is therefore the identification by the Court, with the assistance of the skilled reader, of the particular words or phrases in the claims that describe what the inventor considered to be the "essential elements" of his invention".
¶ 50 Binnie J. wrote further at para. 49(e) that when a patent is issued, it is an enactment within the definition of "regulation" in subsection 2(1) of the Interpretation Act, R.S.C. 1985, c. I-21, and, [page208] as such, according to section 12 of the Interpretation Act, it must be given an interpretation "as best ensures the attainment of its objects".
¶ 51 Binnie J. rejected the dictionary approach. He wrote that we must look at the whole of the specification (including the disclosure and the claims) "to ascertain the nature of the invention" (see para. 52 of Whirlpool).
¶ 52 He further added, at para. 53:
¶ ...53 However, the patent specification is not addressed to grammarians, etymologists or to the public generally, but to skilled individuals sufficiently versed in the art to which the patent relates to enable them on a technical level to appreciate the nature and description of the invention: H. G. Fox, The Canadian Law and Practice Relating to Letters Patent for Inventions (4th ed. 1969), at p. 185. The court, writes Dr. Fox, at p. 203, must place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and the manufacture at the time, and making itself acquainted with the technical meaning in that art or manufacture that any particular word or words may have. [My emphasis.]
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[38] However, the patent's disclosure cannot be used to impose limitations on the claims where no such limitations exist on a fair reading: Dableh v. Ontario Hydro (1996), 68 C.P.R. (3d) 129 (F.C.A.). Here, claim 1 provides that the product is comprised of three elements:
(a) a core;
(b) an enteric coating layer; and
(c) a water soluble separating layer between the core material and the enteric coating layer.
[39] Each of these elements has limitations. In the case of (a), the core must contain a PPI and an ARC. For (b), the enteric coating layer is comprised of an enteric coating polymer. Element (c) contains the most significant limitation in that it is not just any water soluble separating layer between the core and the enteric coating. It is a water soluble separating layer that is formed in situ as a water soluble salt between the core material and the enteric coating layer by a reaction between the enteric coating polymer and the alkaline reacting compound. Thus, there is a process limitation contained in claim 1. The meaning that is ascribed to the ARC is of significant import.
[40] Astra claims that a skilled formulator would interpret magnesium omeprazole as including both a PPI and ARC. Thus, without further ado, magnesium omeprazole is a core material that contains a PPI and an ARC within the meaning of claim 1(a) of the '037 patent. With respect, I do not think that it is that simple.
[41] Astra's argument, while referring to the skilled person, does not point to any evidence, other than that derived on cross-examination, to support its statement. Evidence obtained during cross-examination must be examined in the context in which it was given to ensure that the specific "admissions" being relied upon do, in fact, constitute statements of the nature for which they are being offered. Answers provided in the abstract do little to assist. Each of the experts who opined on the construction of claim 1 referred to the disclosure. None contended that a person skilled in the art would be aware, or would assume, simply by reading claim 1, that magnesium omeprazole is both a PPI and an ARC.
[42] Astra's expert witness, Dr. Rees, in his affidavit, turns to the disclosure of the '037 patent to enable him to provide evidence as to what the skilled person would take from the patent and more specifically its claims. The only basis that Astra provides to support its "ordinary and grammatical" argument is that the words used in claim 1(a) do not preclude the PPI and the ARC from being the same substance. While that may be true, in my view, it does not, in and of itself, yield a conclusion that the skilled person would assume that magnesium omeprazole necessarily constitutes the PPI and the ARC specified in claim 1(a).
[43] When regard is had to the disclosure portion of the '037 patent specification, it is readily apparent that the use of a subcoat or sublayer was known. The "invention" relates to a new method for the manufacture of the formulation and the use of the new formulation in medicine. It simplifies the preparation of the separating layer or subcoat because, rather than applying the layer, it is formed by way of in situ reaction. The subcoat requires but a single step and it occurs as a result of the application of the enteric coating. In short, the '037 patent addresses a different way of constructing a formulation of omeprazole with a PPI, an ARC, an enteric coating and a sublayer. It is, as earlier noted, a product patent with a process limitation.
[44] Aside from the PPI, there is no suggestion that anything else contained in Apotex's formulation is an ARC.
[45] There are a number of indications that the PPI and the ARC are intended to be regarded as distinct components. At line 8 on page 7, the disclosure states that the proton pump inhibitors are usually stabilized in mixtures with alkaline reacting compounds. Beginning at line 30 on page 9, the description is one that specifically includes magnesium omeprazole as the proton pump inhibitor in the core. Nonetheless, it refers to the fact that the tablets are also comprised of one or more alkaline reacting compounds. See also: page 12 beginning at line 6 and page 13 beginning at line 3.
[46] Additionally, examples in the disclosure that are comprised of magnesium omeprazole (rather than omeprazole) provide for an ARC other than the PPI. While I agree that the patent expressly states that the examples are not intended to limit the scope of the invention, those to which I refer are consistent with the notion of the PPI and ARC being discrete substances. Astra's argument that the PPI has the "characteristics" of both a PPI and an ARC is not persuasive because claim 1, in my view, does not speak of characteristics. Equally unpersuasive is Astra's comment that the PPI is "in a position to form a water soluble salt with an enteric coating polymer" and it therefore "fits the definition". As with cross-examination responses, regard must be had to context and, in this instance, the disclosure is referring to the core material.
[47] At the end of the day, it seems to me that the word "and", as used in claim 1 of the '037 patent, is intended to be conjunctive. I agree that the claim does not preclude the PPI and ARC from being the same substance. However, the inquiry is to ascertain what the claim says, not what it fails to say. I recognize that the experts for both parties agree that a skilled formulator would endeavour to use as few ingredients as possible in order to keep a formulation as simple as possible. They also agree that it is possible, all things being equal, for an ingredient to serve more than one function in a formulation.
[48] If the PPI and the ARC were intended to be a single substance, would that, too, not make the invention more efficient? It would eliminate not only the need for the application of a sublayer; it would eliminate the need for two substances in the core.
[49] Dr. Hopfenberg's opinion, that it is antithetical to the purpose of the in situ separating layer - to protect the active medicinal ingredient from degradation by reaction with the enteric coating polymer - to form the same layer through a reaction between the magnesium omeprazole, acting both as an ARC and the active medicinal ingredient (PPI), and the enteric coating, is persuasive. It does not make any sense to me that the PPI would be exposed to the enteric coating for the purpose of protecting it.
[50] I have searched for evidence that responds to Dr. Hopfenberg's position. Dr. Rees does say, on cross-examination, that a limited amount of omeprazole in the sublayer would not affect discolouration or degradation of the tablet. That said, it is not clear to me how degradation of the magnesium omeprazole would be limited in the absence of an ARC, nor is it clear why an in situ sublayer would then be required to protect that active ingredient if exposing the magnesium omeprazole directly to the enteric coating would not cause degradation.
[51] Given the very purpose of the new manufacturing process that the '037 patent purports to cover, it appears to me, that the ARC and the PPI referred to in claim 1 of the '037 patent are discrete components. Such a construction is sympathetic to the accomplishment of the inventor's purpose, expressed or implicit, in the text of the claims and it does not require that anything be read in. If the inventor has misspoken or otherwise created an unnecessary or troublesome limitation in the claims, it is a self-inflicted wound. The public is entitled to rely on the words used, provided that the words used are interpreted fairly and knowledgeably: Whirlpool and Free World Trust.
[52] It is not disputed that the Apotex tablets do not contain an ARC that is separate and distinct from the magnesium omeprazole PPI. If I am correct in my construction of claim 1, it is dispositive of the application. Apotex's tablets cannot infringe claim 1 because the tablets do not contain both a PPI and an ARC. However, patent construction is a matter of law. In the event that I am wrong, I will, alternatively, consider the issues with respect to the other allegation of non-infringement.
Do the Apotex tablets contain an in situ separating layer or subcoat?
[53] In examining this issue, I proceed on the basis that I have erred in construing claim 1 of the '037 patent and that Astra's construction is the proper one.
[54] In its NOA, Apotex alleges that its tablets do not contain a water soluble separating layer formed in situ as a water soluble salt by a reaction between the enteric coating polymer and an alkaline reacting compound in the core. It says that any material formed in its tablets between the core and the enteric coating does not completely coat the core material and/or is of insufficient thickness so as to allow the material to function as a separating layer that provides the stability required for the formulation.
[55] The arguments are lengthy and complex. However, they are what they are, and I believe that, for purposes of clarity and coherence in the analysis, it is essential to set them forth, as succinctly as I am able. The evidence that is most pertinent to this issue is comprised of the affidavits and cross-examinations of Dr. Lindquist (Lindquist 2 and Lindquist 3) for Astra, and Drs. Cima (Cima 1 and Cima 2) and Sodhi, for Apotex.
[56] Before delineating the arguments, it is useful to set out some definitions regarding certain terms and processes that will be referenced. These definitions are derived from the evidence and the written or oral submissions of counsel. No exception was taken to any part of the definitions so provided.
Acid - compounds which have the propensity to donate a proton (a hydrogen ion) and which will react with basic compounds (e.g. enteric coating);
Base - compounds which have the propensity to accept a proton (a hydrogen ion) and which will react with acidic compounds (e.g. magnesium of omeprazole);
Salt - compounds which are the product of a reaction between an acid and a base;
Polymer - class of chemical compounds the members of which consist of long, chemical molecules of repeating units;
Enteric coating (including Eudragit and Eudragit L30D) - polymeric material that acts as a coating designed to withstand (not dissolve in) an acidic environment such as the stomach but will dissolve in a more alkaline (basic) environment such as the intestines; comprised of polymeric backbone upon which carboxylic functional groups (COOH) are attached; acidic material;
Carboxylic Functional Group - a subclass of acidic compounds that contain as part of their structure the carboxylic group ( - COOH);
Neutralization - the process of reacting an acid with a base;
Inert - nonreactive material;
Neutralized enteric coating polymer - the product of a reaction between the enteric coating and a sufficient amount of base material such that each of the carboxylic functional groups are neutralized;
Fluorescence microscopy - involves the use of certain wavelengths of light to cause excitation and fluorescence in chemical materials. It is a microscopic technique whereby a sample material is exposed to ultraviolet light. The ultraviolet light is then removed for observation as to whether the sample fluoresces. Relative changes in the intensity of the fluorescence are associated with changes in the underlying chemical composition of the material. The technique assists a skilled analyst to distinguish between different materials;
Acetone wash - intended to remove soluble material (such as an enteric coating) while leaving insoluble material (such as the alleged salt of the enteric coating) intact; based upon principles of relative solubility;
FT-IR (Fournier Transform Infrared) - a vibrational spectroscopy technique used to help characterize the presence or absence of certain function groups in a sample; certain functional groups will absorb certain frequencies of light at certain regions in IR spectra. The IR spectrum of a compound is like a fingerprint and by comparing the spectrum of a sample to spectra for known compounds, a skilled analyst should be able to identify or characterize the compounds on the surface of the sample;
Raman Spectroscopy - a vibrational spectroscopy analytical method that is similar to IR spectroscopy. Raman utilizes a focused laser at a spot on the surface of a sample. The spectral content of the scattered light is analysed. The spectra yield a fingerprint of the material much the same as the IR although the intensity of the bands need not be the same. Its principle advantage is that the laser light can be precisely focused to specific locations with conventional optics. It can be used to detect compositional variations across the sample;
TOF-SIMS (Time-of-Flight Secondary-Ion-Mass-Spectrometry) - an analytical technique for determining the presence of different constituents on a surface. The methodology involves exposing the surface material to sudden force and the fragmentation pattern created provides information about the surface material. An ion beam is used to remove small numbers of atoms from the outermost atomic layer of the surface. A short pulse of primary ions strikes the surface and the secondary ions produced in the sputtering process are extracted from the sample surface and into a time-of-flight mass spectrometer. The mass of the secondary ions is determined (the secondary ions include whole molecules and molecular fragments). The pattern of fragments is like a fingerprint.
The Arguments
[57] Astra first argues that Apotex's non-infringement argument is based on an assertion that its tablets are not stable because the separating material formed in its tablets does not completely coat the omeprazole core and is not of sufficient thickness. This position, according to Astra, is completely frivolous since the Minister would not approve tablets that are not stable.
[58] Astra maintains that the Apotex tablets contain a layer, approximately 3 microns in thickness, between the enteric coating and the core. It states that the layer is continuous and separates the core from the enteric coating, that it dissolves in water, and that it contains a salt of magnesium and the enteric coating polymer. Its position is premised on a battery of tests conducted by its expert, Dr. Lindquist.
[59] Dr. Lindquist first used fluorescence microscopy (with an excitation wavelength of 395-440 nm) and observed a bright layer between the enteric coating and the core around the whole of the Apotex tablet. Dr. Lindquist explained that a continuous layer may have small pinholes or bubbles that can appear as shadows in the images of the sample, but he explained them away as being insignificant (cross-examination, volume 17, tab 28, pages 4487-4488). He also stated that he took eight pictures at random places on the Apotex tablet and that all showed a fluorescent layer (as before at p. 4475).
[60] Next, Dr. Lindquist conducted further tests in an effort to determine the composition of the separating layer. He used an acetone wash to strip away the enteric coat. He concluded, based on this method, that the enteric coating polymer, Eudragit (used in the Apotex tablets), was soluble in acetone (affidavit, volume 13, tab 15, p. 3473) and that, after the acetone wash, he observed a shiny, foil-like surface (cross-examination, volume 18, tab 28, p. 4533) that convinced him that there was a layer that remained after the enteric coating was washed off. Dr. Lindquist explained that it was therefore not necessary for him to confirm that the fluorescent layer was present after the Apotex tablet was washed in acetone (as before at p. 4534).
[61] After washing the Apotex tablet in acetone, Dr. Lindquist purported to analyse the composition of the separating layer using an infrared spectrometer (FT-IR and ATR) at different positions. He concluded that the results from these tests were consistent with the presence of a fluorescent layer between the enteric coating and the core in the Apotex tablets, since the salt of the enteric coating is fluorescent. He also concluded, from obtaining the same spectra when he washed the tablets in acetone for varying amounts of time, that the separating layer is insoluble in water (as before at pp. 4460-4464).
[62] Dr. Lindquist also conducted Time of Flight Secondary Ion Mass Spectrometry (TOF-SIMS) tests on the acetone-washed Apotex tablets to determine the constituents of the separating layer. He observed that there was no evidence of magnesium omeprazole or neutral omeprazole on the tested surface, that much talc remained on the tested surface, and that there were high areas of magnesium not associated with talc, which suggested that the observed subcoating contained the salt of magnesium and the enteric coating polymer.
[63] Astra posits the following explanations and counter-arguments for the problems proposed by Apotex with regard to Dr. Lindquist's experiments:
· that acetone washing itself could cause salt formation - Astra says that this is merely speculation. It claims that even when the surface of the subcoat is exposed by other methods, such as pulling away the enteric coating or microtoming to the surface of the subcoating, a salt of the enteric coating polymer was detected;
· that the IR analysis does not actually conclude that there is salt formation as the observations appear to be based on noise as opposed to true signals. Astra states that, in all of Dr. Lindquist's spectra, including where noise was reduced, there was increased relative absorption in the characteristic salt region when compared to the carbonyl peaks in another region, which should decrease upon salt formation. This, according to Astra, confirms the presence of the salt of the enteric coating polymer;
· that the salt of the Eudragit enteric coating polymer does not fluoresce - Astra maintains that its evidence that suggests that the salt of Eudragit does fluoresce has not been challenged. It contends that Dr. Cima's results to the contrary only suggest, at best, that at the excitation wavelength and exposure time he employed, the fluorescence of salt of Eudragit may not be detectable.
[64] Further, Astra suggests a number of different problems with the experiments conducted and the results achieved by Drs. Cima and Sodhi (the Apotex experts who tested the tablets).
[65] First, in relation to Dr. Cima, Astra states that he had not conducted any tests for determining the presence or composition of an in situ layer before his involvement in this matter. Dr. Cima observed a fluorescent layer between the coating and the core, but did not provide any evidence with regard to the continuity or the thickness of his layer. Astra claims that Dr. Cima examined the fluorescence of Eudragit films doped with magnesium hydroxide and compared these to placebos that did not contain omeprazole in order to determine whether the layer he observed was the magnesium salt of the Eudragit coating (affidavit, volume 3, tab 8, pp. 516-517). Astra notes that Dr. Cima admitted that the degradation products he identified were for neutral omeprazole, rather than magnesium omeprazole, and that the specific degradation products were not listed in the Phamacoepia entry for sodium omeprazole (cross-examination, volume 19, tab 30, pages 4836-4838), another alkaline salt of omeprazole.
[66] Additionally, Astra points to a number of problems with regard to the results of Dr. Cima's infrared spectroscopy. (Dr. Cima conducted an infrared spectroscopy analysis before and after he washed the Apotex tablet in acetone. He observed that there was an absence of any relevant difference between the FT-IR spectra before and after and concluded that the evidence does not suggest the presence of a separating layer). Astra says that the significance of Dr. Cima's results are unclear in the face of his admission that his acetone washing protocol did not remove all of the enteric coating, thus making it unlikely that he was actually testing the subcoat (cross-examination, volume 3, tab 8, pp. 522-523). Next, it claims that, even if Dr. Cima's results had some relevance, it is not clear what may be taken from them, since Dr. Cima himself seems to take different interpretations of his own results, suggesting at one point that the peaks had gone away (as before at p. 4828), and at another point suggesting that the band does not appear at all (as before at p. 4829).
[67] Astra also takes issue with Dr. Cima's Raman spectroscopy results. (Dr. Cima used Raman spectroscopy to try to determine whether omeprazole could definitively be detected in the interface between the enteric coating and the core). Astra contends that the significance of this experiment is unclear given the uncertainty in location of the interface that was examined by Dr. Cima. He estimated that the interface is 115 microns from the tablet's surface by visual inspection, while the interface detected and examined in the Raman spectroscopy was 5 to 15 microns towards the centre of the tablet. The interface is estimated (by Dr. Lindquist) to be approximately 3 microns thick, thus the thickness cannot account for the discrepancy between Dr. Cima's estimation and what was actually observed. Astra claims that there were no reference spectra provided for the degradation products Dr. Cima is said to have detected. Additionally, Dr. Cima admitted that the Raman signal can change shape and position depending on the local environment (as before, pp. 4866-4875), thus the data may simply reflect changes in the environment rather than the presence of degraded omeprazole.
[68] Last, Astra points to Dr. Cima's observation that there is a significant amount of degraded omeprazole in the separating layer. Dr. Lindquist has shown that a significant amount of degraded omeprazole would not fluoresce and that magnesium omeprazole is only weakly fluorescent. Consequently, Astra claims that Dr. Cima cannot be correct if he is suggesting that the fluorescent layer contains nothing more than magnesium omeprazole or degraded magnesium omeprazole.
[69] Regarding Dr. Sodhi, Astra notes that he, too, has never conducted tests like TOF-SIMS or analysed an enterically coated dosage form prior to his involvement in this proceeding (cross-examination, volume 18, tab 27, p. 4364). More importantly, Dr. Sodhi did not analyse the surface of the subcoating. Instead, he bisected the Apotex tablet using a blade to study its cross-section. Astra states that this technique is inadequate for obtaining a flat surface and that such an uncontrolled and violent technique resulted in a rough, smeared surface so as to yield meaningless images that are not capable of providing any evidence as to the contents of the separating layer (Sodhi affidavit, volume 14, tab 19, p. 3806; Lindquist 3, volume 14, tab 20, pp. 3875-3877).
[70] Apotex, at the outset, impugns the trustworthiness of Dr. Lindquist as an expert witness, pointing out that: he is a long-time employee and shareholder of Astra; the vast majority of his work consists of litigation support such that he is acting more as an advocate than an objective witness; Astra chose not to bring evidence of any independent analysis; group meetings were held to help Dr. Lindquist prepare for his testing; he intentionally destroyed his relevant notes; he failed to carry out all of his planned experiments; he is only trained as an electrochemist; and the scientific community has not accepted his acetone wash method.
[71] Moreover, according to Apotex, Dr. Lindquist's tests are so flawed that they do not satisfy Astra's burden of proving that the Apotex tablets contain an in situ separating layer with the characteristics of inertness, continuity, and water solubility, as required by claim 1(c) of the '037 patent. The Apotex assault on Dr. Lindquist's experiments and results has two fronts. Apotex levies attacks regarding the experiments and then with respect to the findings in relation thereto.
[72] Apotex claims that Dr. Lindquist's fluorescence microscopy is flawed because he failed to examine the entire region and he limited his testing to eight discrete points on the interface (subcoat) region. Second, he failed to magnify the observed breaks in the interface region in order to further inspect them. Third, by suggesting that the observed pinholes are not significant, Dr. Lindquist overstepped his expertise in that the question of whether the breaks are significant relates to stability or inertness, matters beyond his qualifications and upon which he is not qualified as a formulator to testify. Thus, Dr. Lindquist's opinion with regard to the significance of the breaks in the interface region should not be given any weight.
[73] Dr. Lindquist's acetone wash method, in Apotex's view, is also seriously flawed. First, he did not re-test the washed tablet to see if it fluoresced. Hence, there is no way to determine whether his acetone wash method washed off the fluorescent layer he observed with the fluorescence microscopy (cross-examination, volume 18, tab 28, p. 4533). Second, the procedure is based on the assumption that the enteric coating is soluble in acetone while the interface region is not. However, Dr. Lindquist acknowledged that certain insoluble excipients present in the enteric coating of the tablet ought to be removed by acetone wash (as before at p. 4523). Consequently, the procedure changed the composition of the exposed surface. Third, Dr. Lindquist conceded that the acetone wash will dissolve any omeprazole at the interfacial region. This is problematic given the Apotex evidence that the fluorescent region is actually comprised of omeprazole. Finally, Dr. Lindquist employed no precautions to ensure that the acetone wash did not cause a reaction (as before at pp. 4510-4511 and 4521). A reaction could occur if Astra's experts are correct in their theory that, in order to generate an in situ layer, an alkaline core, an acidic enteric coating and a solvent are needed.
[74] Apotex asserts that the two additional tests (microtoming the tablets and examining the underside of the enteric coating polymer), performed by Dr. Lindquist in order to compensate for the problems with his acetone wash method, are also inherently flawed. First, Dr. Lindquist did not perform fluorescence microscopy on the microtomed tablet when he ran the infrared spectrometer on the cross-section of the tablet. Consequently, there is no evidence to suggest that Dr. Lindquist was actually testing any fluorescent material when he ran the FT-IR spectra. Second, he failed to perform a TOF-SIMS analysis on the microtomed tablet to determine what type of salt he was allegedly observing, thereby rendering the testing incomplete and inconclusive. Third, his attempt to peel away the enteric coating polymer to examine its underside revealed that, in a number of areas, enteric coating polymer came into direct contact with the alkaline omeprazole core. Thus, any possible interface region that was examined could not have been continuous.
[75] Apotex further advances several deficiencies in relation to Dr. Lindquist's infrared spectroscopy experiments (FT-IR):
· his only reference is to a 1960 publication which refers to carboxylic ions in general, rather than to an enteric coating polymer or to the Eudragit coating that is used in the Apotex tablets, or to magnesium salts;
· he provided no explanation for his failure to run a reference spectrum, for a salt of the enteric coating, which would either confirm or deny the existence of that substance on the acetone washed tablet (as before at p. 4565). Moreover, he conceded that it would be most important and most reliable to do it; he had already been criticized for not doing it after he was given an opportunity; he could easily have run the spectrum because he had made the salt of the enteric coating polymer; and he admitted that it would have taken only one day;
· he failed to consider that his FT-IR results demonstrate that the presence of a salt of a carboxylic acid could be explained by the presence of sodium CMC (another salt of a carboxylic acid) which is expected to be in the interface region because it is an excipient present in the Apotex enteric coating (as before at pp. 4537-4541). He did not run a reference for CMC, which could have confirmed or eliminated the possibility of its presence. Therefore, he is not able to distinguish between a carboxylic acid associated with the salt of the enteric coating (a magnesium salt) and a carboxylic acid associated with sodium CMC (a sodium salt). The presence of sodium on the surface of the acetone washed tablet was corroborated by Dr. Lindquist's own TOF-SIMS analysis (as before at pp. 4579-4580);
· he failed to eliminate magnesium stearate as a possible alternative (another salt of a carboxylic acid that is expected to be at the interface region because it is contained in the Apotex magnesium omeprazole core (as before at pp. 4577);
· he provided only a small portion of the FT-IR spectrum that he observed from the acetone-washed tablet. His incomplete graph cannot support his conclusion that the interface region is a salt of the enteric coating nor can it eliminate the possibility that the FT-IR absorbance he observed could have been due to sodium CMC (as before at pp. 4541-4542);
· he conceded that the area he analysed using the FT-IR is but a tiny percentage of the entire surface (as before at p. 4575).
[76] Furthermore, according to Apotex, there are a number of problems with the logic Dr. Lindquist used to draw his conclusions with respect to his TOF-SIMS analysis. Dr. Lindquist concluded that the signals he observed were for magnesium, not associated with talc (from the enteric coating) or with omeprazole (from the core), at the surface of the washed tablet. He did not offer any direct evidence from the TOF-SIMS analysis that there is a magnesium salt of the enteric coating polymer on the surface after the acetone wash was performed. He simply deduced that the magnesium present must be a magnesium salt of the enteric coating polymer (as before at pp. 4576-4577). Apotex claims that the problem with this logic is that Dr. Lindquist totally ignored the possibility that the magnesium he found could be another type of magnesium (such as magnesium stearate or degraded products of the magnesium omeprazole core), expected to be at the interface region because they are found in the core of the tablets. Moreover, Dr. Lindquist conceded that, with TOF-SIMS, he only analysed a minute portion of the surface of the washed tablet and he, therefore, cannot rely on TOF-SIMS to conclude that whatever he measured represents the entire surface (as before at pp. 4586-4587).
[77] Apotex further contends that Dr. Lindquist's tests show that the interface region in the Apotex tablets is acidic and not inert. Thus, it does not meet the specification of claim 1 of the '037 patent. Astra has argued that a reaction occurs, between the acidic enteric coating and the alkaline magnesium omeprazole core, forming a salt of the enteric coating polymer. According to Astra, the enteric coating polymer is in an inert state thereby satisfying the patent claim that there be a "dosage form" comprising a "separate layer". Apotex explains that, in order to be inert, all of the carboxylic acid functional groups in the enteric coating must have been completely converted to their carboxylic salt forms. Dr. Lindquist's evidence points to the presence of material that is substantially in acidic form. His testing established that only material that is substantially acidic fluoresces, and long before the material approaches completely neutral form, it stops fluorescing.
[78] Apotex notes that Dr. Lindquist admitted that if the enteric coating and magnesium omeprazole reacted as to form a fully-neutralized salt of the enteric coating polymer, the material would not fluoresce. However, in his tests, the tested interface region did fluoresce. Thus, it must be that the interface region is substantially and predominantly acidic in form and not inert so as to fall within the '037 patent claim. In fact, Dr. Lindquist admitted that he was not able to say with certainty that the enteric coating was fully neutralized and thus inert. He also admitted that, absent certain calibration testing that he did not conduct, he was not in a position to make a determination with regard to the degree of salt formation of the polymer (as before at pp. 4706-4708).
[79] Dr. Lindquist's tests also show that the Apotex tablet's core comes into direct contact with the enteric coating and thus cannot be continuous. He attempted to examine the core side (the underside) of the enteric coating tablet, by peeling away the enteric coating from the core, then subsequently examining the picture of the underside of the enteric coating. He stated that the white areas (part of the core) are "in direct contact with the enteric coating" (Lindquist 3, volume 14, tab 20, p. 3881).
[80] Finally, Apotex alleges that there is no evidence in the record to show that its tablets contain a "water soluble separating layer". It says that Astra's only evidence on this point was that Dr. Lindquist dropped the acetone-washed tablet into pure water and found that it broke up. From this, he concluded that the separating layer that he purported to observe "dissolves or quickly disintegrates in water" (Lindquist 2, volume 13, tab 15 p. 3744). However, Dr. Hopfenberg explained that "water soluble" is different than "disintegrating in water" (affidavit, volume 2, tab 7, pp. 204-205). Apotex contends that this was conceded by Astra's expert, Dr. Rees, on cross-examination, when he acknowledged that disintegrating in water does not satisfy the water solubility requirement in claim 1 of the '037 patent.
[81] In sum, Apotex asserts that, to meet the specifications of claim 1 of the '037 patent, the separating layer must be continuous, water soluble and inert. Any separating layer that may be found in its tablet meets none of these requirements.
Analysis
[82] There are some facts that are not in dispute. They are as follows:
· the core of the Apotex tablet contains magnesium omeprazole;
· Apotex uses Eudragit L30D-55 as its enteric coating polymer;
· the Eudragit material contains what is known as carboxylic acid groups (carbon, two oxygen and hydrogen);
· enteric coating material is soluble in acetone.
[83] It is the separating layer that is the crux of the dispute. Throughout this analysis, the words separating layer, subcoat, subcoating, and interface region are used interchangeably and all refer to what is described in claim 1 of the '037 patent as the separating layer.
[84] It is also common ground that the experimental techniques used by the various experts are designed to:
(1) detect the separating layer;
(2) expose the separating layer; and
(3) characterize the separating layer.
[85] The parties have competing theories in relation to the separating layer. Astra claims that the Apotex tablet contains a water soluble separating layer, between the core and the enteric coating of the tablet, that is a salt of the enteric coating polymer. Apotex says that any material, between the core and the enteric coating of its tablet, is degraded omeprazole, or omeprazole, and is not continuous, inert, water soluble, or a salt of the enteric coating.
[86] In view of the arguments, it is useful to review the sequence of the expert evidence as well as the contents of that evidence, as I understand it. The first skeletal affidavit of Dr. Lindquist, on behalf of Astra, stated that he could determine whether an in situ separating layer existed in the Apotex tablet if he were to be provided with samples.
[87] The first expert affidavit evidence emanated from Dr. Cima (Apotex's witness). Dr. Cima was provided with: samples of the Apotex tablet; glass slides containing Eudragit L30D-55 doped with various alkaline reacting compounds; and glass slides containing Eudragit L30D-55 without any type of alkaline reacting compound (placebos).
[88] Dr. Cima tested using fluorescence microscopy and FT-IR. First, he attempted to ascertain whether there was a layer between the enteric coating and core of the Apotex tablets. He detected a fluorescent band. He then set out to determine whether a salt of the enteric coating would fluoresce. He tested the placebo formulations (containing no omeprazole) and conclusively found that none of the placebos exhibited any trace of fluorescence. He determined that the fluorescence was caused by the presence of omeprazole. He then tested the fluorescent characterization of several glass slides coated with pure Eudragit L30D-55 enteric coating polymer file and various types of alkaline reacting compounds. None of the files showed any signs of fluorescence. Dr. Cima again concluded that omeprazole was causing the fluorescence. He initially used an FT-IR excitation wavelength of 450-480 nm with an imaging filter of 520+ nm. The use of shorter wavelengths of 330-380 nm and an imagery filter of 420+ nm also demonstrated fluorescence. Dr. Cima stated that all observations from the tablets and slides support the conclusion that the fluorescent band between the enteric coating and the core is the result of a degradation of omeprazole and not a reaction, between alkaline constituents of the core and coating, resulting in the formation of a salt of the enteric coating polymer. He noted that decomposition does not necessarily include decomposition only at the time of manufacture as very little may occur at that time. Rather, the decomposition occurs over weeks, months and years.
[89] Dr. Lindquist (Lindquist 2), for Astra, employed techniques of tablet bisection, acetone wash, FT-IR, water wash, and TOF-SIMS. To bisect the Apotex tablet, it was cut in the middle and the exposed surface was shaved with a microtome. The "acetone wash" entailed washing the Apotex tablet in an acetone and water solution for 7 to 8 minutes until the enteric coating dissolved. Then, the excess acetone was removed and the tablet was rinsed, in the case of the short wash, for a few minutes and, in the case of the long wash, for one hour.
[90] The exposed surface of the bisected tablet was subjected to fluorescence microscopy and the edge of the tablet (including the coating) was photographed at 8 positions to show the interface at excitation wavelengths of 395-440 nm. Dr. Lindquist observed a continuous bright layer around the entire tablet. Using FT-IR on the acetone-washed tablets and comparing sample spectra to reference spectra, he observed (with respect to the washed tablets) peaks from Eudragit L30D and talc. The spectra from the tablet surfaces (before and after the wash) indicated that the enteric coating material closest to the core had changed to something insoluble in acetone; and a salt formation typical of a carboxylate salt was evident in the 1540-1610 cm-1 region. Dr. Lindquist placed an acetone-washed tablet in pure water and observed that it quickly started to disintegrate.
[91] For TOF-SIMS, the long wash tablet was used. Dr. Lindquist observed dominant peaks (in the spectrum of the tablet surface) of magnesium and silicon (the major peaks of talc), but found no evidence for magnesium omeprazole or neutral omeprazole. He determined that much talc remained on the surface of the long acetone-washed tablet and this was consistent with the formation of an acetone-insoluble subcoating between the enteric coat and the active core. The presence of magnesium between the talc particles suggested that the subcoating is a magnesium salt. His opinion was that "there is a subcoating or layer of approximately 3 Fm (microns) in thickness between the enteric coating and the core region of the sample tablets". He concluded as follows:
The subcoating or layer is continuous and separates the tablet core from the enteric coating. The subcoating or layer dissolves or quickly disintegrates in water. The subcoating or layer contains a salt of magnesium and enteric coating polymer.
[92] Dr. Cima (Cima 2) voiced a number of concerns regarding Dr. Lindquist's methodology, most notably, the failure to offer any explanation regarding the chemical constituents of the layer observed by fluorescence microscopy given Dr. Cima's previous determination that the magnesium salt of the enteric coating material is not fluorescent.
[93] Dr. Cima also took issue with the protocol used for Dr. Lindquist's removal of the enteric coating, specifically, the lack of controls to ensure that the chosen method did not generate the observed reaction. Additionally, Dr. Cima questioned Dr. Lindquist's interpretation of the FT-IR data. He noted the ambiguity in Dr. Lindquist's interpretation and found that, in any event, it was incorrect. Dr. Cima discussed the deficiencies arising from both the washed and unwashed tablets and claimed that Dr. Lindquist's deformation invalidated the measurements because they should be obtained only from undisturbed surfaces. Dr. Cima concluded that the peaks observed by Dr. Lindquist are not true signals and that the overall increase in absorbance is the result of differences in baseline or background spectrum. Even if true, there is no explanation for the fact that each of the four spectra, from the same tablet, is different and distinguishable.
[94] Dr. Cima utilized Raman spectroscopy and FT-IR to precisely focus the laser light to specific locations for the purpose of detecting compositional variations across the sample. He identified bands for magnesium omeprazole, lactose, and microcrystalline cellulose and plotted the intensities. The lactose and microcrystalline cellulose peaks clearly changed intensity in the region of the core-coating interface. The signal from magnesium omeprazole was observed to exist within the coating with its largest magnitude near the core interface.
[95] In the end, Dr. Cima disagreed with Dr. Lindquist's methodology and with his conclusions. Dr. Cima reiterated his previous conclusion that the fluorescence present at the core-enteric interfacing is not a salt of the enteric coating polymer and he remained steadfast in his opinion that the fluorescence showed the presence of omeprazole or degraded omeprazole.
[96] Dr. Sodhi (for Apotex) employed TOF-SIMS on a tablet that was bisected with a sharp scalpel blade in an effort to ascertain whether a layer containing magnesium existed at the interface region. He, too, criticized Dr. Lindquist's acetone-wash methodology for lack of proper controls. Dr. Sodhi responded to Dr. Lindquist's finding of magnesium not associated with talc or omeprazole and determined that the species pervaded the entire enteric coating region and not just the interface. Dr. Sodhi concluded that the magnesium species was referable to magnesium impurities within the talc.
[97] Dr. Lindquist's (Lindquist 3) final affidavit is comprised of a lengthy critique of Dr. Cima's methodology. Dr. Lindquist claimed that Dr. Cima's test results do not support the conclusion that the fluorescence observed by Dr. Lindquist is not a salt of the enteric coating polymer. He further claimed that Dr. Cima's conclusion that the fluorescent layer is comprised of magnesium omeprazole or degraded magnesium omeprazole is incorrect.
[98] In relation to Dr. Sodhi, Dr. Lindquist described Dr. Sodhi's method of bisection as an "uncontrolled and violent technique" that "does not result in a smooth, unsmeared bisected surface". He determined that Dr. Sodhi's analysis was so poorly prepared that the results are "useless" and "cannot be relied upon for any conclusions". Dr. Lindquist concluded that Dr. Sodhi's experiments were not capable of providing the evidence or results claimed by Dr. Sodhi.
[99] Dr. Lindquist then responded by conducting further experiments. He prepared a salt of the enteric coating for the purpose of testing fluorescence and took fluorescent images of the films at different excitation wavelengths. He determined that the magnesium salt of Eudragit strongly fluoresces and that plain Eudragit fluoresces with much lower intensity (at the same wavelength). Next, he degraded magnesium omeprazole by preparing 0.002 mole-percent film and 8 mole-percent film. The small concentration (0.002 mole-percent) showed fluorescence, but the higher concentration (8 mole-percent) did not. Dr. Lindquist thus concluded that degraded magnesium omeprazole, when present in any significant concentration, does not fluorescence. Consequently, the fluorescent layer that he had previously observed could not contain a significant amount of degraded omeprazole.
[100] Under visible light, Dr. Lindquist observed that the 8 mole-percent concentration exhibited the characteristic black appearance of degraded magnesium omeprazole.
[101] Next, Dr. Lindquist microtomed an Apotex tablet and obtained FT-IR spectra at three different areas of the exposed subcoating material. He increased the number of spectral scans averaged for each spectrum from 32 to 128 and discerned increased relative absorbance in the spectra, which he felt confirmed the presence of a salt of the enteric coating polymer.
[102] Finally, Dr. Lindquist peeled the coating from the Apotex tablet and obtained six reference spectra from the core side of the sample. He concluded that a salt of the enteric coating material was present in the core.
[103] It is within this context, in the face of competing and contradictory expert evidence, with the limited benefit of the transcripts of the cross-examinations upon those affidavits, that the Court is called upon to determine this matter. I confess, at this point, that I am uncertain as to the proper characterization of the fluorescence in the Apotex tablet. However, on the basis of the evidence before me, I am not persuaded, on a balance of probabilities, that the allegation of non-infringement is not justified. It bears repeating that, at the end of the day, the determinative question is whether Astra has met its burden to establish that Apotex's allegation of non-infringement is not justified. That is what this is about. It is not a trial with respect to infringement. Before turning to the reasons as to why Astra has failed to so persuade me, there are two points to be addressed.
[104] The first point is Astra's submission in relation to the Apotex NOA. Astra contends that the allegation of non-infringement amounts to nothing more than a contention relating to the construction of claim 1 of the '037 patent. All allegations, according to Astra, lead back to the construction issue. Relying on AB Hassle v. Canada(Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.) and Merck Frosst Canada Inc. v. Canada(Minister of Health) (2001), 12 C.P.R. (4th) 447 (F.C.A.), Astra argues that the allegation strictly frames the issues in the proceeding and it may not be amended or expanded by the generic during the proceeding.
[105] I reject Astra's argument in this respect. The NOA, after setting out the construction issue, specifically states:
...[T]he water soluble separating layer within the meaning of claim 1 must completely coat the core material and be of a sufficient thickness which would allow it to function as a separating layer which provides the requisite stability required for an oral dosage formulation of a proton pump inhibitor which comprises a separating layer or subcoating layer between the enteric coating and the core material. Any material formed between our core material and the enteric coating layer will not completely coat the core material and be of sufficient thickness to allow it to function as aforesaid. (my emphasis)
[106] The detailed statement of the bases of an allegation must be sufficiently complete to enable a patentee to make an informed decision as to whether to respond to the allegation by instituting proceedings for an order of prohibition: AstraZeneca AB v. Apotex Inc. (2005), 335 N.R. 1 (F.C.A.). Astra does not suggest that it did not know the case it had to meet and it does not, nor could it, suggest that it was prevented from tendering evidence to respond to Apotex's position. In my view, the NOA defined the legal and factual basis for Apotex's allegation of non-infringement. Its contents are presumed to be true unless Astra, on a balance of probabilities, establishes otherwise.
[107] I do agree with Astra that the word "inert" does not appear in the NOA. Notwithstanding, I attach no particular significance to Apotex's use of the word "inert" in its argument. Apotex has maintained, from the outset, that its tablet does not have material, between the enteric coating and the core, that meets the requirements of claim 1 of the '037 patent. Continuity and thickness are specifically itemized in its NOA. It was Astra that alleged that the Apotex subcoating is comprised of a salt of the enteric coating polymer. Apotex denies that this is so. Since a salt, by its nature, is the neutralized product of the reaction between its alkaline and acidic constituents, it is inert. Apotex's use of the word "inert" may well be superfluous but, in essence, it is a short hand way of stating that any layer that may exist in its tablet is not a salt of the enteric coating polymer as Astra claims it to be.
[108] The second point relates to the submissions regarding the expert witnesses. Apotex impugns the credibility of Dr. Lindquist's evidence on the basis that: he is a life-long employee and shareholder of Astra; the vast majority of his work consists of litigation support and his role is closer to that of an advocate than to that of an independent witness; group meetings were convened to assist him in preparing for his testing; he intentionally destroyed relevant notes; he failed to carry out all of his planned experiments; he is trained only as an electrochemist; the scientific community has not accepted his acetone-wash method; and Astra chose to rely on his evidence without the benefit of independent analysis.
[109] Astra responds by noting that Dr. Lindquist was accepted as having impressive qualifications in AB Hassle v. Canada(Minister of National Health and Welfare) (2000), 10 C.P.R. (4th) 38 (F.C.T.D.), aff'd. (2002), 18 C.P.R. (4th) 558 (F.C.A.). Moreover, simply being an employee is not sufficient reason to discount an individual's evidence: Aventis Pharma Inc. v. Apotex Inc., 2005 FC 1381. Astra also asserts that Dr. Cima, prior to his involvement in this case, had not conducted any tests for determining the presence or composition of an in situ layer. Dr. Cima's qualifications were not otherwise questioned. In relation to Dr. Sodhi, Astra submits that he had never previously conducted TOF-SIMS analysis of an enterically coated dosage form. Astra does not suggest that Dr. Sodhi is not an expert in TOF-SIMS analysis or that he was not qualified to conduct TOF-SIMS analysis of the Apotex tablet.
[110] The fact that Dr. Lindquist's evidence was accepted in another case is irrelevant. The record that was before Madam Justice Tremblay-Lamer in AB Hassle, above, is not the same record as that which is before me. Each case turns on the record that is before the Court in relation to the specific matter. The employee referred to in Aventis, above, was not of the variety that Dr. Lindquist is, nor was the employee's evidence of the nature of Dr. Lindquist's evidence.
[111] Given my determination, regarding the allegation of non-infringement, nothing ultimately turns on this issue and I need not specifically rule on it. Some of the factors that Apotex notes, in relation to Dr. Lindquist, I have considered in the context of my analysis. Those considerations will be discussed as they arise. Beyond that, I make no determination as to the propriety of Astra's use of Dr. Lindquist's evidence although I regard it as curious, given the admonition of the Court of Appeal in AB Hassle v. Canada (Minister of National Health and Welfare) (2002), 22 C.P.R. (4th) 1 (F.C.A.), that Astra would choose to rely solely on it with respect to the issue of non-infringement.
[112] Turning to Astra's failure to satisfy me, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified, I do not intend to engage in a microscopic dissection of the various criticisms levelled by each of the parties regarding the experimental techniques employed by the other's expert. Rather, I will focus on what I consider to be the central factors that lead to my conclusion. I have not considered submissions made at the hearing that were not contained in the written memoranda of fact and law.
[113] Overall, I find the evidence of Dr. Lindquist to be suspect. I accept the evidence of Drs. Cima and Sodhi that the acetone-wash procedure employed by Dr. Lindquist lacked a variety of appropriate controls. This is problematic because the majority of Dr. Lindquist's testing was conducted on tablets that had been acetone washed. Particularly troublesome is Dr. Lindquist's knowledge of Dr. Cima's conclusion (that any layer in the Apotex tablet is comprised of omeprazole or degraded omeprazole) coupled with Dr. Lindquist's awareness that the acetone- wash procedure could dissolve omeprazole.
[114] Astra claims that Dr. Lindquist's FT-IR results were consistent at the end of the day when, in his final set of tests, he did not use the acetone-wash procedure. This is only partially correct. Dr. Lindquist did not repeat the TOF-SIMS in his final round of testing. Therefore, his TOF-SIMS results are based on the testing of samples that had been subjected to the acetone-wash. The FT-IR tests stood to identify the existence of a salt of a carboxylic acid. The TOF-SIMS was required to ascertain the nature of the carboxylate salt, i.e. whether it was a salt of the enteric coating.
[115] Astra also claims that since Dr. Cima tried an acetone-wash procedure, Dr. Lindquist cannot be faulted for having done likewise. The distinction that I see is, unlike Dr. Lindquist, Dr. Cima readily acknowledged the deficiencies associated with the procedure and determined that the testing of the acetone-washed tablets did not yield satisfactory results.
[116] I have serious reservations about the continuity of the material between the enteric coating and the core of the Apotex tablet. Leaving aside that Dr. Lindquist did not photograph the entire surface (for fluorescence microscopy), he tested only approximately .01% of the tablet's surface (FT-IR) and he conceded that there were "minor" breaks in the material that he considered to be insignificant, when he peeled off the enteric coating from the core to study the composition of the subcoat, he expected that the sublayer would be found on the underside of the peeled-away outer coating. The large white patches shown on Exhibit "F" to his third affidavit were acknowledged by him, on cross-examination, to be comprised of core material. He also acknowledged the existence of white crystals around his tested area and the fact that those crystals "would be in direct contact with the enteric coating". I fail to see how the core could be in direct contact with the underside of the enteric coating if a continuous subcoat separated them. Astra has not provided any explanation in this respect other than to say that the peeling method "was not perfect".
[117] As noted, the objective of the FT-IR is to ascertain the existence of a carboxylate salt. Further identification of the carboxylate salt as a magnesium salt is determined by TOF-SIMS. Dr. Lindquist's TOF-SIMS test was not conducted in his final round of tests. Consequently, it bears repeating that this analytical technique was performed only on tablets subjected to the acetone-wash procedure. There is no explanation or reference providing any reason why Dr. Lindquist failed to repeat TOF-SIMS when he abandoned the acetone wash.
[118] On the original TOF-SIMS, Dr. Lindquist failed to have regard to any magnesium species in the Apotex tablet other than talc. He did identify areas where talc and magnesium were present and he further identified areas where magnesium was present without talc. However, he made no attempt to identify or discount the presence of magnesium stearate or degraded magnesium omeprazole. Moreover, his evidence as to the presence of a magnesium salt, per se, is equivocal at best. He states that "[t]he presence of Mg. between talc particles suggests that the subcoating is a magnesium salt". He then, without having excluded origin alternatives, concluded that the magnesium salt is the magnesium salt of the enteric coating.
[119] In relation to the last round of FT-IR, Dr. Lindquist conceded, on cross-examination, that if one were to compare "apples to apples", a reference spectra for the salt of the Apotex enteric coating would be used for comparison purposes. Despite having made a salt of the enteric coating, Dr. Lindquist did not do a spectra. He acknowledged that he had intended to do so.
[120] I also harbour a number of concerns with respect to the presentation of Dr. Lindquist's evidence. He never did address the results of Dr. Cima's tests on the placebos; he presented photographic images in a manner that was not helpful (Exhibit "A" to Lindquist 3); he failed to provide specific evidence that his test results were consistent for each of the samples that he obtained (acetone-washed tablet, microtomed tablet and peeled tablet); and he intentionally rinsed all notes and testing records from his computer.
[121] Finally, I find Apotex's theory regarding Dr. Lindquist's "degradation of omeprazole" experiment equally as plausible as the theory advanced by Astra. Dr. Lindquist introduced magnesium omeprazole into the Eudragit film to degrade the omeprazole. Apotex claims that Dr. Lindquist was putting an acid with a base and making a salt. The carboxylic acid functional groups (in the enteric coating) create a reaction when they are brought into contact with basic material. The extent of the reaction is referred to as mole percent. When all of the active material is reacted, or fully neutralized, 100 mole percent is achieved.
[122] In the case of magnesium and carboxylic functional groups, one magnesium ion reacts with two -hydrogens so that only 50 magnesium ions are required to obtain 100 mole percent. Dr. Lindquist reacted magnesium omeprazole with Eudragit at .002 mole percent (a more active area with less neutralization) and at 8 mole percent (a less active area with greater neutralization). In short, at 8 mole percent, one is closer to the making of a salt.
[123] Astra claims that Apotex's subcoating is a salt of the enteric coating. When regard is had to Dr. Lindquist's results, there is fluorescence at .002 mole percent, but the fluorescence is lost as greater neutrality is achieved. Fully neutralized material would therefore not fluoresce. The upshot of the Apotex theory is that Dr. Lindquist, by his testing, has established that a salt of the enteric coating will not fluoresce (cross-examination of Dr. Lindquist, applicant's record, volume XVIII, tab 29, pp. 4643-4651). Since both Dr. Lindquist and Dr. Cima identified fluorescent material in the interface region of the Apotex tablet, on the Apotex theory, that material cannot be a salt of the enteric coating polymer because the salt does not fluoresce. Astra has no response other than to say that the experiment was one dealing with the degradation of omeprazole.
[124] I reiterate what I said earlier. In the end, the onus is on Astra to establish that Apotex's allegation of non-infringement is not justified. For the foregoing reasons, it has not met that onus.
[125] Either of my alternative findings is sufficient to dispose of the application. It is therefore not necessary to deal with the allegation of invalidity and I decline to do so. The application will be dismissed and an order will so provide.
COSTS
[126] Counsel addressed the issue of costs at the conclusion of the hearing. I am not persuaded by Astra's submissions that the costs award should be "tweaked" or that adjustments downward from previous awards in similar matters are warranted. Having considered the submissions of counsel and the pertinent factors in Rule 400(3), I award costs to Apotex Inc. to be assessed at the upper end of column 3 of Tariff B. The assessment officer will be directed to assess second counsel fees for attendance at the cross-examinations and the hearing, as well as reasonable disbursements with respect to their attendance. Double-dipping, if it arises, is not to be permitted.
"Carolyn Layden-Stevenson"
Judge
SCHEDULE "A"
to the
Reasons for order dated January 18, 2006
[Confidential Reasons for Order issued January 4, 2006]
rendered by the Hon. Madam Justice Carolyn Layden-Stevenson
in
ASTRAZENECA AB and ASTRAZENECA CANADA INC.
and
APOTEX INC. and THE MINISTER OF HEALTH
A APOTEX INC. T-766-03
CANADA'S PHARMACEUTICAL_ COMPANY SOCIETE PHARMACEUTIQUE ENTIÈREMENT CANADIENNE
March 25, 2003
AstraZeneca Canada Inc. 1004 Middlegate Road Mississauga, Ontario
L4Y 1M4
Dear Sirs:
This is a Notice of Allegation pursuant to the Patented Medicines (Notice of Compliance) Regulations (the "Regulations") with respect to Canadian Patent No. 2,186,037 (the "037 Patent").
We have filed with the Minister of Health a Submission for a Notice of Compliance for magnesium omeprazole tablets for oral administration in strengths of 10 mg and 20 mg.
The '037 Patent contains 61 claims.
Claims 20, 23, 24, 25, 26, and claim 61, as it depends on each of claims 49, 52 and 53, do not include within their scope the medicine omeprazole or its pharmaceutically acceptable salts, and are irrelevant under the Regulations since none of these claims is a claim for the medicine itself or a claim for the use of the medicine.
Claims 30 to 56, inclusive, are process claims and are irrelevant under the Regulations since none of these claims is a claim for the medicine itself or a claim for the use of the medicine.
Claim 60 is a commercial package claim and is irrelevant under the Regulations since this claim is not a claim for the medicine itself or a claim for the use of the medicine.
With respect to the remainder of the claims, 1 to 19, inclusive, and 21, 22, 27, 28, 29, 57, 58, 59 and 61, as well as claim 60 if it is held to be a claim for the medicine itself or a claim for the use of the medicine (hereinafter referred to as the "claims in issue"), we allege that no claim for the medicine itself and no claim for the use of the medicine would be infringed by the making, constructing, using or selling by us of the said tablets.
We further allege that each of the claims in issue of the '037 Patent is invalid.
The legal and factual basis for the aforesaid allegation is as follows. The '037 Patent
The '037 Patent, entitled "New Pharmaceutical Formulation and Process", relates to a pharmaceutical formulation containing a proton pump inhibitor, which includes the compounds omeprazole and magnesium omeprazole, intended for oral use and to the use of these formulations in the treatment of gastric acid related diseases.
The formulation of the '037 Patent is described as comprising three components:
(1) a core material that contains a proton pump inhibitor and an alkaline reacting compound;
(2) an enteric coating layer comprising an enteric coating polymer; and
(3) a water soluble separating layer that is formed in situ as a water soluble salt between the core material and the enteric coating layer as a reaction between the enteric coating polymer and the alkaline reacting compound.
The essence of the alleged invention in the '037 Patent is the development of a formulation which purports to solve a manufacturing problem associated with the coating processes of prior art proton pump inhibitor oral dosage enteric coated formulations which comprised a water soluble separating layer (also known as a subcoating layer), which had been placed there as a result of a distinct subcoating step, situated between the enteric coating layer and the core material, which comprised a proton pump inhibitor and an alkaline reacting compound. The '037 Patent admits that the problem which it seeks to address is a simplification of the preparation of such formulations which previously involved at least two separate coating steps - one for the water soluble separating layer and another for the enteric coating layer.
The '037 Patent does not purport that its formulations have equal or improved storage stability or gastric acid resistance in comparison to the aforementioned prior art formulations, nor does the '037 Patent provide any information relating to the stability of such formulations. The only advantage taught by the '037 Patent is the simplification of the coating processes.
Each of the claims in issue of the '037 Patent contains among its essential elements, the following essential elements:
(2) 
an enteric coating layer comprising an enteric coating polymer; and
(3) a water soluble separating layer that is formed in situ as a water soluble salt between the core material and the enteric coating layer as a reaction between the enteric coating polymer and the alkaline reacting compound.
The disclosure of the '037 Patent makes it very clear that the phrase "proton pump inhibitor" includes both omeprazole and its base addition salts, such as magnesium omeprazole. The disclosure also makes clear that the phrase "alkaline reacting compound" cannot mean any substance which is a proton pump inhibitor. For example, omeprazole or magnesium omeprazole is not an "alkaline reacting compound" within the meaning of the patent.
Additionally, the phrase "alkaline reacting compound" cannot mean any constituent or excipient whose function in the formulation is other than as an "alkaline reacting compound". Constituents or excipients which have been referred to within the disclosure of the '037 Patent as serving a function other than as an "alkaline reacting compound" within a formulation cannot be construed to be an "alkaline reacting compound". For instance, substances in the formulation which function as a lubricant, dye or disintegrant cannot be an "alkaline reacting compound".
The "water soluble separating layer" must be a layer which does not contain a proton pump inhibitor or form as a result of a reaction, directly or indirectly, with the proton pump inhibitor.
Additionally, the "water soluble separating layer" must completely coat the core material and be of a sufficient thickness which would allow it to function as a separating layer which provides the requisite stability required for an oral dosage formulation of a proton pump inhibitor which comprises a separating or subcoating layer between the enteric coating and the core material.
Furthermore, the "water soluble separating layer" must dissolve, as opposed to disintegrate, in aqueous solutions.
Non-infringement Claims 1 to 29
Each of claims 2 to 19, inclusive, of the '037 Patent is dependent on claim 1. We allege that we will not infringe any of these claims since we will not infringe claim 1.
Claim 1 will not be infringed since our formulation will not contain an alkaline reacting compound, as discussed above, within the meaning of the '037 Patent.
Additionally, our product will contain a core material, which does not contain an alkaline reacting compound, together with an enteric coating disposed on the core material. Accordingly, claim 1 will not be infringed since our formulation will not contain a water soluble separating layer, because claim 1 requires that the water soluble separating layer be formed in situ as a water soluble salt by a reaction between the enteric coating polymer and the alkaline reacting compound. This cannot occur in our product since it will not have an alkaline reacting compound.
Thirdly, as discussed above, the water soluble separating layer within the meaning of claim 1 must completely coat the core material and be of a sufficient thickness which would allow it to function as a separating layer which provides the requisite stability required for an oral dosage formulation of a proton pump inhibitor which comprises a separating or subcoating layer between the enteric coating and the core material. Any material formed between our core material and the enteric coating layer will not completely coat the core material and be of sufficient thickness to allow it to function as aforesaid.
We further allege additional bases of non-infringement with respect to the following claims.
With respect to claim 3, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an alkaline organic substance, a hydroxide of an alkali metal, an alkaline ammonium salt or an alkaline salt of phosphoric acid, carbonic acid or silicic acid.
With respect to claim 4, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is a hydroxide of an alkali metal, an alkaline ammonium salt or an alkaline salt of phosphoric acid, carbonic acid or silicic acid.
With respect to claim 5, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an alkaline reacting organic substance.
With respect to claim 6, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an amino acid or salt thereof, an alkaline amine or derivative thereof, or an alkaline salt of a weak organic acid.
With respect to claim 7, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an alkaline amine or derivative thereof.
With respect to claim 8, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is Nmethyl-D-glucamine or tromethamine.
With respect to claim 9, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an amino acid.
With respect to claim 10, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is lysine, arginine, ornithine or histidine.
With respect to claim 11, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of more than 0.1 mmol/g of dry ingredients in the alkaline containing part of the core material.
With respect to claim 12, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of more than 0.3 mmol/g of dry ingredients in the alkaline containing part of the core material.
With respect to claim 13, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of not more than 15 mmol/g of dry ingredients in the alkaline containing part of the core.
With respect to claim 14, we further allege that we will not infringe this claim since our formulation does not include more than one alkaline reacting compound in the core material.
With respect to claim 15, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is a hydroxypropyl cellulose derivative.
With respect to claim 16, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is hydroxylpropyl methylcellulose phthalate.
With respect to claim 17, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is hydroxylpropyl methylcellulose acetate succinate.
With respect to claim 22, we further allege that we will not infringe this claim since our formulation does not include a pure enantiomer of omeprazole or an alkaline salt thereof.
With respect to claim 27, we further allege that we will not infringe this claim since our formulation does not include a core material which is individual pellets intended for capsule formulation or a tableted multiple unit dosage form.
With respect to claim 29, we further allege that we will not infringe this claim since our formulation does not include individually enteric coated pellets which are compressed into a tableted multiple unit dosage form.
Claims 30 to 56, 61
Claim 30 will not be infringed since our formulation will not contain an alkaline reacting compound, as discussed above, within the meaning of the '037 Patent.
Additionally, our product will contain a core material, which does not contain an alkaline reacting compound, together with an enteric coating disposed on the core material. Accordingly, claim 30 will not be infringed since our formulation will not contain a water soluble separating layer, because claim 30 requires that the water soluble separating layer be formed in situ as a water soluble salt by a reaction between the enteric coating polymer and the alkaline reacting compound. This cannot occur in our product since it will not have an alkaline reacting compound.
Thirdly, as discussed above, the water soluble separating layer within the meaning of claim 30 must completely coat the core material and be of a sufficient thickness which would allow it to function as a separating layer which provides the requisite stability required for an oral dosage formulation of a proton pump inhibitor which comprises a separating or subcoating layer between the enteric coating and the core material. Any material formed between our core material and the enteric coating layer will not completely coat the core material and be of sufficient thickness to allow it to function as aforesaid.
Each of claims 31 to 56 is dependent on claim 30. We allege that we will not infringe any of these claims since we will not infringe claim 30.
We further allege additional bases of non-infringement with respect to the following claims.
With respect to claim 32, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an alkaline organic substance, a hydroxide of an alkali metal, an alkaline ammonium salt or an alkaline salt of phosphoric acid, carbonic acid or silicic acid.
With respect to claim 33, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is a hydroxide of an alkali metal, an alkaline ammonium salt or an alkaline salt of phosphoric acid, carbonic acid or silicic acid.
With respect to claim 34, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an alkaline reacting organic substance.
With respect to claim 35, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an amino acid or salt thereof, an alkaline amine or derivative thereof, or an alkaline salt of a weak organic acid_
With respect to claim 36, we further allege that we will not infringe this claim since our formulation does not include an alkaline 'reacting compound which is an alkaline.amine or derivative thereof.
With respect to claim 37, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is Nmethyl-D-glucamine or tromethamine.
With respect to claim 38, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is an amino acid.
With respect to claim 39, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is lysine, arginine, ornithine or histidine.
With respect to claim 40, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of more than 0.1 mmol/g of dry ingredients in the alkaline containing part of the core material.
With respect to claim 41, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of more than 0.3 mmol/g of dry ingredients in the alkaline containing part of the core material.
With respect to claim 42, we further allege that we will not infringe this claim since our formulation does not include an alkaline reacting compound which is present in a concentration of not more than 15 mmol/g of dry ingredients in the alkaline containing part of the core material.
With respect to claim 43, we further allege that we will not infringe this claim since our formulation does not include more than one alkaline reacting compound in the core material.
With respect to claim 44, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is a hydroxypropyl cellulose derivative.
With respect to claim 45, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is hydroxylpropyl methylcellulose phthalate.
With respect to claim 46, we further allege that we will not infringe this claim since our formulation does not include an enteric coating polymer which is hydroxylpropyl methylcellulose acetate succinate.
With respect to claim 51, we further allege that we will not infringe this claim since our formulation does not include a pure enantiomer of omeprazole or an alkaline salt thereof.
With respect to claim 54, we further allege that we will not infringe this claim since our formulation does not include a core material which is individual pellets intended for capsule formulation or a tableted multiple unit dosage form.
With respect to claim 56, we further allege that we will not infringe this claim since our formulation does not include individually enteric coated pellets which are compressed into a tableted multiple unit dosage form.
Gillette Defence
(i) Non-infringement
More particularly, our formulation of magnesium omeprazole tablets is taught in European Patent Application No. 124,495, published on November 7, 1984, wherein at pages 5 to 8 and at Example 12 of this Application, formulations containing a base addition salt of omeprazole (including magnesium omeprazole) are disclosed. Included within the aforementioned disclosure are references to enteric coated tablet formulations wherein the tablets are coated with an enteric coating which protects the active compound from degradation. Our formulation is in accordance with the aforementioned teachings of European Patent Application No. 124,495.
In addition, you have asserted, as detailed more particularly below, that the claims of Canadian Patent Nos. 1,292,693 and 1,306,891 extend to a formulation of magnesium omeprazole tablets comprising: a tablet core containing magnesium omeprazole; an in situ subcoating; and an outer enteric coating, and that our formulation falls within the formulation claims of these patents. While we have disputed that this is so, in the event you are correct (which is denied), then there can clearly be no infringement of the '037 Patent.
Should you assert that any of the claims in issue of the '037 Patent are infringed, we allege that the claims are invalid based upon what has become known in Canadian law as the Gillette Defence, as discussed below.
(ii) Invalidity
If you assert that any of the claims of the '037 Patent are infringed by our formulation by reason of the fact that our formulation allegedly contains an alkaline reacting compound and/or a water soluble separating layer that is formed in situ as a water soluble salt between the core material and the enteric coating layer as a reaction between the enteric coating polymer and the alkaline reacting compound, and said alkaline reacting compound and/or water soluble separating layer are within the meaning of the of the claims of the '037 Patent, then we allege that the claims must be invalid in accordance with the principles set out in the decision of the House of Lords in Gillette Safety Razor Company v. Anglo-American Trading Company Ltd., (1913) R.P.C. 465, and the decision of J.K. Smit & Sons, Inc. v. Richard S. McClintock [1940] SCR 279.
Our formulation is within the prior art as disclosed by the teachings of European Patent Application No. 124, 495, published on November 7, 1984, as discussed above. Further, the use of such a formulation to treat gastrointestinal disease is also in accordance with the teachings disclosed within European Patent Application No. 124,495.
If our formulation contains an alkaline reacting compound and/or a water soluble separating layer within the meaning of the '037 Patent, then the enteric coated formulations within the European Patent Application No. 124,495 would also contain such an alkaline reacting compound and/or a water soluble separating layer, and thus any allegedly infringed claims must be invalid.
In addition, you have asserted, as detailed more particularly below, that the claims of Canadian Patent Nos. 1,292,693 and 1,306,891 extend to a formulation of magnesium omeprazole tablets comprising: a tablet core containing magnesium omeprazole; an in situ subcoating; and an outer enteric coating, and that our formulation falls within the formulation claims of these patents. While we have disputed that this is so, in the event you are correct (which is denied), then the claims of the '037 Patent must be invalid.
Invalidity
Anticipation - Canadian Patent No. 1,292,693
We allege that each of the claims in issue of the '037 Patent is anticipated by Canadian Patent No. 1,292,693 (the '693 Patent), published on December 3, 1991.
The essence of the alleged invention in the '693 Patent is the development of a formulation which purports to solve the problem of the prior art formulations which comprised an alkaline core containing omeprazole or an alkaline salt of omeprazole, and an enteric coating disposed on the core that led to degradation. The alleged solution to the problem is asserted in the '693 Patent to be the separation from .contact of the core and the enteric coating by application of a water soluble separating layer (also referred to as a subcoating layer) within the meaning of the patent.
The '693 Patent also disclosed, but not as part of its invention, formulations of omeprazole which comprised an alkaline core material which contained omeprazole, or an alkaline salt of omeprazole, plus an alkaline reacting compound, and an enteric coating disposed onto said core material.
The alkaline reacting compounds disclosed within the '693 Patent are the same or equivalent to the "alkaline reacting compounds" disclosed and claimed by the '037 Patent. Additionally, disclosed within the '693 Patent was the inclusion of an alkaline reacting compound within the core material in a concentration of more than 0.1 mmol/g and 0.3 mmol/g, and not more than 15 mmol/g, of dry ingredients in the alkaline containing part of the core material.
The enteric coating polymers disclosed within the '693 Patent are the same or equivalent to the enteric coating polymers disclosed and claimed by the '037 Patent. Also disclosed within the '693 Patent was the application of these enteric coating polymers using water based polymer dispersions.
The '693 Patent also disclosed the use of an omeprazole formulation for manufacturing a medicament useful in the treatment of gastric acid related disease, the use of an omeprazole formulation for treating a gastric acid related disease, an oral pharmaceutical dosage form for treating gastric acid related disease and a commercial package comprising an oral pharmaceutical dosage form of omeprazole together with instructions for its use in treating gastric acid related disease.
As a result, the person skilled in the art, aware of the teachings of the '693 Patent would, when following the disclosure of the '693 Patent for the preparation of an omeprazole formulation which did not contain a separating layer which had been placed there as a result of a distinct subcoating step, by applying a water based dispersion of an enteric coating polymer onto a core material which contained omeprazole, or an alkaline salt of omeprazole, plus an alkaline reacting compound, cause a reaction to occur between the enteric coating polymer and the alkaline reacting compound which results in the formation of a water soluble separating layer which is a salt of the enteric coating polymer. The resulting formulations and their use would fall within the scope of the claims of the '037 Patent.
Furthermore, if the '693 Patent is construed in a manner in which the claims include an oral dosage formulation which comprises as its subcoating or separating layer a salt of an enteric coating polymer which is formed in situ as a reaction between the enteric coating polymer and the alkaline core, as you have asserted in Federal Court File Nos. T-366-98, T-1747-00 and T-878-02, then the claims of the '037 Patent must be anticipated. We will rely on the decisions and materials contained within these court files. Particularly, in Court File No. T-36698, we rely on the decision reported at (2000), 18 C.P.R. (4th) 558, and in Court File No. T-1747-00, we rely on decision of Kelen J. dated September 4, 2002.
Anticipation - United States Patent No. 4,786,505
In addition, we allege that each of the claims in issue of the '037 Patent is anticipated by United States Patent No. 4,786,505 (the "'505 Patent"), entitled "Pharmaceutical Preparation for Oral Use", published on November 22, 1988. The '505 Patent is the corresponding United States Patent to the '693 Patent. Thus, on the same basis as set out above with respect to the '693 Patent, the resulting formulations and their use would fall within the scope of the claims of the '037 Patent.
Likewise, if the '505 Patent is construed in a manner in which the claims include an oral dosage formulation which comprises as its subcoating or separating layer a salt of an enteric coating polymer which is formed in situ as a reaction between the enteric coating polymer and the alkaline core, as you have asserted in Astra Aktiebolag, et al v. Andrx Pharmaceuticals, Inc. et al (referenced as "In re OMEPRAZOLE PATENT LITIGATION) which was before the United States District Court, Southern District of New York, then the claims of the '037 Patent must be anticipated. We will rely on the decisions and materials contained within this court file.
Anticipation - Canadian Patent No. 1,302,891
In addition, we also allege that each of the claims in issue of the '037 Patent is anticipated by Canadian Patent No. 1,302,891 (the "'891 Patent"), entitled "Pharmaceutical Formulations of Acid Labile Substances for Oral Use", published on June 9, 1992. The '891 Patent contains similar teachings, as set out above, as disclosed within the '693 Patent, however, the disclosure of the '891 Patent is not limited to the proton pump inhibitor omeprazole. Thus, on the same basis as set out above with respect to the '693 Patent, and noting that the '891 Patent is not limited to the proton pump inhibitor omeprazole, the resulting formulations and their use would fall within the scope of the claims of the '037 Patent.
Likewise, if the '891 Patent is construed in a manner in which the claims include an oral dosage formulation which comprises as its subcoating or separating layer a salt of an enteric coating polymer which is formed in situ as a reaction between the enteric coating polymer and the alkaline core, as you have asserted in Federal Court File Nos. T-366-98, T-1747-00 and T-878-02, then the claims of the '037 Patent must be anticipated. We will rely on the decisions and materials contained within these court files. Particularly, in Court File No. 1-366-98, we rely on the decision reported at (2000), 18 C.P.R. (4th) 558, and in Court File No. T-1747-00, we rely on decision of Kelen J. dated September 4, 2002.
Anticipation - United States Patent No. 4,853,230
In addition, we also allege that each of the claims in issue of the '037 Patent is anticipated by United States Patent No. 4,853,230 (the "'230 Patent"), entitled "Pharmaceutical Formulations of Acid Labile Substances for Oral Use", published on August 1, 1989. The '230 Patent is the corresponding United States Patent to the '891 Patent. Thus, on the same basis as set out above with respect to the '891 Patent, the resulting formulations and their use would fall within the scope of the claims of the '037 Patent.
Likewise, if the '230 Patent is construed in a manner in which the claims include an oral dosage formulation which comprises as its subcoating or separating layer a salt of an enteric coating polymer which is formed in situ as a reaction between the enteric coating polymer and the alkaline core, as you have asserted in Astra Aktiebolag, et al v. Andrx Pharmaceuticals, Inc. et a! (referenced as "In re OMEPRAZOLE PATENT LITIGATION) which was before the United States District Court, Southern District of New York, then the claims of the '037 Patent must be anticipated. We will rely on the decisions and materials contained within this court file.
Anticipation - Canadian Patent No. 2,166,794
Furthermore, we also allege that each of the claims in issue of the '037 Patent is anticipated by Canadian Patent No. 2,166,794 (the "'794 Patent"), published on January 19, 1995, entitled "Magnesium Omeprazole".
The essence of the alleged invention in the '794 Patent is a novel physical form of magnesium omeprazole which is described and characterized as having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction. The '794 Patent discloses the inclusion of such a compound within pharmaceutical oral dosage formulations and the use of such formulations for the treatment of gastric acid related disease.
A person skilled in the art reading the '794 Patent would be aware, as part of his common knowledge and skill in the art, of European Patent Application No. 124,495 and of the '693, '505, '891 and '230 Patents.
European Patent Application No. 124,495 discloses a pharmaceutical oral dosage formulation of omeprazole wherein an enteric coating has been directly applied, onto a core material comprising magnesium omeprazole. The '693 and '891 Patents additionally discloses formulations wherein an enteric coating has been directly applied onto a core material comprising magnesium omeprazole and an alkaline reacting compound.
As a result, the person skilled in the art, aware of the teachings of European Patent Application No. 124,495 and the '693, '505, '891 and '230 Patents, would when preparing a magnesium omeprazole formulation which did not contain a separating layer which had been placed there as a result of a distinct subcoating step, by applying a water based dispersion of an enteric coating polymer onto a core material which contained magnesium omeprazole and an alkaline reacting compound, cause a reaction to occur between the enteric coating polymer and the alkaline reacting compound which results in the formation of a water soluble separating layer which is a salt of the enteric coating polymer. The resulting
formulations and their use would fall within the scope of the claims of the '037 Patent.
Ambiguity and Anticipation
Each of the claims in issue, with the exception of claim 61, is invalid on the basis of ambiguity since claim 1 is open to two possible interpretations. In addition, each of the possible interpretations would lead to the subject matter of the claim being invalid on the basis of anticipation.
In the first interpretation, the claim is for a pharmaceutical oral dosage formulation without limiting the scope of the claim to the process of forming the water soluble separating layer in situ by a reaction between the enteric coating polymer and the alkaline reacting compound. The claim would be to a pharmaceutical oral dosage form comprising:
(a) a core material that contains a proton pump inhibitor and an alkaline reacting compound;
(b) an enteric coating layer comprising an enteric coating polymer; and
(c) a water soluble separating layer that is the appropriate salt of the enteric coating polymer.
Under this interpretation the claim, and the dependent claims, would be invalid, as having been anticipated by each of the '693, '505, '891, '230 and '794 Patents, as discussed above.
Under the second possible interpretation, claim 1 is for a pharmaceutical oral dosage formulation wherein the scope of the claim is limited to the specific process of forming the water soluble separating layer in situ by a reaction between the enteric coating polymer and the alkaline reacting compound. The claim would therefore be a product-by-process type claim.
Under this interpretation the claim, and the dependent claims, would be invalid, as having been anticipated by each of the '693, '505, '891, '230 and '794 Patents, as discussed above, in accordance with the principles set out in F. Hoffmann-La Roche & Co. Ltd. v. Commissioner of Patents, [1955] SCR 416. An old substance such as the formulation under consideration cannot be reclaimed notwithstanding that the old formulation is claimed in a process dependent fashion.
processes of any of claims 30 to 56. This claim would therefore be a product-byprocess type claim, and as such, would be invalid as having been anticipated by each of the '693, '505, '891, '230 and '794 Patents, as discussed above, in accordance with the principles set out in F. Hoffmann-La Roche & Co. Ltd. v. Commissioner of Patents, [19551 SCR 416. An old substance such as the formulation under consideration cannot be reclaimed notwithstanding that the old formulation is claimed in a process dependant fashion.
Double Patenting
As noted. above, you have asserted in Federal Court File Nos. T-366-98, T-174700 and T-878-02, that the claims of the '693 and '891 Patents include within their scope enterically coated omeprazole oral dosage formulations which comprise an in situ subcoating or "separating layer", said in situ subcoating being the salt of the enteric coating polymer and arising as a result of a reaction between the enteric coating polymer and the alkaline core. Additionally, you have asserted that the claims of Canadian Patent No. 2,166,483, entitled "New Pharmaceutical Formulation", filed in Canada on July 8, 1994, include within their scope enterically coated magnesium omeprazole oral dosage formulations which comprise an in situ subcoating or "separating layer", said in situ subcoating being the salt of the enteric coating polymer and arising as a result of a reaction between the enteric coating polymer and the alkaline core. Based on such a construction, the claims in issue of the '037 Patent are invalid on the basis of same invention and obviousness type double patenting. We will rely on the decisions and materials contained within these court files. Particularly, in Court File No. T-366-98, we rely on the decision reported at (2000), 18 C.P.R. (4th) 558, and in Court File No. T-1747-00, we rely on decision of Kelen J. dated September 4, 2002.
Insufficiency of Specification and Ambiguity
We further allege that each of the claims in issue is invalid on the basis of subsection 34(2) of the Patent Act in that the claims of the '037 Patent do not state distinctly and in explicit terms the things or combinations that the applicant regards as new and in which he claims an exclusive property or privilege since the claims do not allow the person skilled in the art to ascertain with some measure of exactness the boundaries of the exclusive privilege upon which they may not trespass during the exercise of the grant since the practice of the prior art (application of an enteric coating directly onto a core material which comprises a proton pump inhibitor and an alkaline reacting compound) can create a "separating layer" in situ. The claims in issue are therefore insufficient and ambiguous.
Insufficiency of Specification and Inutility
We further allege that each of the claims in issue of the '037 Patent is invalid on the basis that the '037 Patent does not meet the requirements of section 34 of the Patent Act in that the patent disclosure does not correctly and fully describe the invention, set out clearly in such full, clear and concise and exact terms as to enable any person skilled in the art to make or construct the formulations covered by the claims in issue.
Each of these claims includes within its scope formulations which include amounts and types of alkaline reacting compounds and enteric coating polymers which will not form an in situ "separating layer" when following the directions of the '037 Patent. Exemplary of these inoperable embodiments are formulations which use a poorly soluble or insoluble in water alkaline reacting compound, such as the magnesium and calcium containing alkaline reacting compounds disclosed within the '037 Patent and aluminum hydroxide. The claims in issue are therefore insufficient and lack utility.
Additionally, we allege that those claims in issue which include as the separating layer, as discussed above, a sodium, magnesium, calcium or aluminum salt of an enteric coating polymer, including a salt of a methacrylic acid co-polymer, would not possess the requisite stability required for an oral dosage formulation of a proton pump inhibitor which comprises a separating or subcoating layer between the enteric coating and the core material. These claims are therefore insufficient and lack utility.
Ineligible for listing on the Patent Register
The '037 Patent was and is ineligible for listing under the Regulations.
Subsections 4(4) and 4(6) of the Regulations provide that a patent may be listed only if the patent application date precedes the date of filing of the submission for the notice of compliance.
The '037 Patent was filed in Canadaon February 9, 1996. AstraZenenca obtained its first approval to sell its omeprazole magnesium tablets in Canada prior to February 9, 1996 and, accordingly, the submission for a Notice of Compliance for magnesium omeprazole tablets was filed prior to February 9, 1996.
Thus, listing is precluded by subsections 4(4) and 4(6) of the Regulations. Moreover, the case law makes it clear that the subsequent filing of another submission for a further notice of compliance for the same product does not give a further opportunity to list the patent.
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In the alternative if the '037 is properly listed in relation to a subsequent supplemental submission, then the listing must relate only to the product as approved by such subsequent submission, to which Apotex made no comparison or reference.
Yours very truly, APOTEX INC.
Bernard C. Sherman, Ph.D.,P.Eng. Chairman and C.E.O.
FEDERAL COURT
NAME OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-766-03
STYLE OF CAUSE: ASTRAZENECA AB ET AL.
v.
APOTEX INC. ET AL.
PLACE OF HEARING: Vancouver, B.C.
DATES OF HEARING: November 15, 16, 17, 18, 22, 2005
REASONS FOR ORDER BY: Layden-Stevenson J.
[Confidential Reasons for Order issued on January 4, 2006]
APPEARANCES:
| Mr. Gunars A. Gaikis Ms. Yoon Kang
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| Mr. Harry Radomski Mr. Andrew R. Brodkin Mr. Rick Tuzi |
SOLICITORS OF RECORD:
| Smart & Biggar Barristers and Solicitors Toronto, Ontario
|
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| Goodmans LLP Barristers and Solicitors Toronto, Ontario
|