Toronto, Ontario, February 19, 2007
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
PFIZER CANADA INC. and PFIZER INC.
and
PHARMASCIENCE INC.
REASONS FOR ORDER AND ORDER
[1] This is a motion brought under the provisions of section 6(5)(a) of the Patented Medicines (Notice of Compliance) Regulations SOR/93-133 as amended, SOR/2006-242 (NOC Regulations) requesting that this Court strike out in whole or in part these proceedings as they relate to Canadian Patent 2,355,493 (493 patent). For the Reasons that follow I find that the motion is allowed with costs.
[2] This is a motion brought under the provisions of section 6(5)(a) of the NOC Regulations in its form as amended October 5, 2006. They state:
“6(5) In a proceeding in respect of an application under subsection (1) the Court may, on a motion of a second person, dismiss the application in whole or in part
(a) in respect of those patents which are not eligible for inclusion on the register.”
[3] These provisions differ from section 6(5)(a) as it read prior to November 2006, in that the application may now be dismissed “in whole or in part” and subsection (a) previously read:
“(a) if the Court is satisfied that the patents at issue are not eligible for inclusion on the register or…”
[4] Counsel for the Applicants Pfizer et al. has advised this Court that for purposes of these proceedings (not just this motion) taken against Cobalt and Pharmascience, they intend to assert only claim 22 of the 493 patent. Thus the issues for consideration on this motion are:
1. What is the standard to be applied by the Court in assessing matters before it on a motion under section 6(5)(a) of the NOC Regulations; and
2. Is that which is claimed in claim 22 of the 493 patent eligible for inclusion on the register?
1. Standard
[5] There has been no reported judicial consideration as to the standard to be applied to a motion brought under section 6(5)(a) of the NOC Regulations as they stand post October 5, 2006. That section as it previously stood was the subject of some consideration by this Court and the Federal Court of Appeal.
[6] The Federal Court of Appeal in Apotex Inc. v. Canada (Minister of National Health and Welfare) (2000), 3 C.P.R (4th) 1, per Rothstein JA (as he then was) provided guidance as to the general purpose of section 6(5)(a). The purpose of that provision is to provide to the generics an opportunity to dismiss the application because it is based on an ineligible patent included in the Register. At that time the Court of Appeal commented that this solution was not perfect as the application would only be dismissed if all patents were ineligible. That problem has been solved by the October 5, 2006, amendments which provides for dismissal in whole or in part. Rothstein, JA said at paragraphs 22 to 24:
22 Our second reason for not interfering with the discretion exercised by the Minister in this case relates to the scheme of the Regulations themselves. The Regulations expressly provide a process by which generic manufacturers may obtain relief in the event they are prejudiced by reason of ineligible patents being included on the Register. Subsection 6(1) and paragraph 6(5)(a) provide in relevant part:
…
23 It is apparent that in enacting paragraph 6(5)(a) of the Regulations, the Governor in Council was aware of, and allowed for, the possibility that ineligible patents may find their way onto the Register and may not be readily capable of being deleted under subsection 3(1). Paragraph 6(5)(a) provides generic drug manufacturers with the opportunity, if and when prohibition proceedings are commenced by a patent holder in respect of a Notice of Allegation served by the generic, to apply to the Court to dismiss the prohibition application because it is based on an ineligible patent included on the Register.
24 This form of relief may not be a perfect solution for the generic manufacturers because, as appellants' counsel pointed out, the prohibition application will only be dismissed if all the patents at issue are not eligible for inclusion on the Register and because the proceeding does not provide for a court order requiring the Minister to purge the Register of ineligible patents. However, the remedy provided by paragraph 6(5)(a) does directly address the problem of a generic manufacturer having to compare its product with the drug of a patent holder whose drug is based on an ineligible patent. It provides a judicial forum in which the eligibility of the specific patent or patents at issue can be decided by the Court after hearing from the patent holder and the generic competitor.
[7] The Federal Court of Appeal did not address the standard to be applied by the Court in considering a section 6(5)(a) motion.
[8] Section 6(5)(a) was considered by Gauthier, J. of this Court in Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health) (2003), 20 C.P.R. (4th) 180. She said at paragraphs 9 to 15 of her Reasons:
9 Before addressing the main issues raised by Genpharm's motion, it is also important to note that there has been no decision made pursuant to paragraph 6(5)(a) of the NOC Regulations since the provision was added in 1998 and the parties disagree on the standard or test to be applied in assessing the merits of this motion.
10 Paragraph 6(5) of the NOC Regulations reads as follows:
…
11 In Bayer Inc. v. Apotex Inc. (1999), 85 C.P.R. (3d) 334, Justice Joyal on a motion to dismiss under paragraph 6(5)(b) of the NOC Regulations held that such motion should be granted only where the Notice of Application is clearly improper and bereft of any possibility of success. He agreed with the arguments presented to him that paragraph 6(5)(b) simply gives the Court explicit jurisdiction to consider motions to dismiss where earlier the Court had to rely on its own rules to do so. Thus, the restrictive standard enunciated in Hunt v. Carey Canada Inc., [1990] 2 S.C.R. 959 at 980, should apply.
12 Procter argues that the reasoning adopted in Bayer applies when dealing with a motion under paragraph 6(5)(a) while Genpharm submits that the purpose of this provision is to get rid of groundless notices of application and there is thus no reason to adopt such a restrictive approach.
13 The parties said little more to support their respective position.
14 The administrative scheme set out in sections 5 and 6 of the NOC Regulations is intended to apply only where a notice of compliance is filed in respect of a drug that can be compared with another drug for which a patent was properly included in a patent list on the Register. Thus, a motion to strike a notice of application filed under subsection 6(1) based on the fact that the only patent currently on the Register should not be there, is or is akin to a motion to strike out the proceeding on the basis that there is no reasonable cause of action.
15 It is settled law that if this interpretation is correct, the restrictive standard set out in Hunt, supra, should apply. Genpharm would thus have to prove that it is plain and obvious that the '376 Patent was not eligible for inclusion in the Register.
[9] Justice Russell of this Court in Glaxo Smith Kline Inc. v. Apotex Inc. (2003), 29 C.P.R. (4th) 350 reviewed the decisions of Rothstein, JA and Gauthier, J. above. He concluded that Gauthier, J. did not have the benefit of a full argument on the point, and in particular, did not have Rothstein, JA’s reasons before her. Russell, J. concluded that the issue as to which standard applies under section 6(5)(a) remained to be determined. He said at paragraphs 18 to 21 of his Reasons:
18 It is clear from these passages that Gauthier J. did not have the benefit of full argument on this issue and was not asked to consider the general rationale for subsection 6(5)(a) enunciated by Rothstein J.A. in Apotex, supra. This being the case, Gauthier J.'s decision cannot be considered as strong authority on this point and, in any event, Gauthier J. went on to decide that the relevant standard to be applied under subsection 6(5)(a) was not determinative in Procter, supra, because the Court "would have reached the same conclusion even if it had not applied [the restrictive standard]."
19 The judgment of Rothstein J.A. in Apotex, supra, does not specifically state what standard should be applied in applications under subsection 6(5)(a), but, rather than characterizing such an application as being analogous to a motion to strike on the basis that there is no reasonable cause of action, it concludes that such an application "provides a judicial forum in which the eligibility of the specific patent or patents at issue can be decided by the Court after hearing from the patent holder and the generic competitor."
20 If the court is not being asked to decide that there are no reasonable grounds for GSK's section 6(1) application, but is merely examining eligibility after hearing from the parties, there is no justification, as far as Apotex is concerned, for applying the restrictive Hunt, supra, "plain and obvious" test under subsection 6(5)(a).
21 In my opinion, the issue of which standard applies under 6(5)(a) still remains to be determined. In the case before me, the matter is not determinative because, even if I apply the less restrictive standard that is urged upon me by Apotex, I cannot, for reasons that follow, allow this application.
[10] Prothonotary Morneau, in a decision made very shortly after that of Russell, J. and apparently without having had that decision placed before him, or the earlier decisions of Gauthier, J. or Rothstein, JA., said at paragraphs 12 and 13 of H. Lundbeck A/S v. Canada (Minister of Health), 2003 FC 1333:
12 Pharmascience's motion to dismiss asks the Court to consider the dismissal under both paragraphs of subsection 6(5) of the Regulations.
13 In regard to the burden of proof that Pharmascience must meet on this motion, it is essentially similar to the one that a defendant must meet when it seeks to have a statement of claim struck out under Rule 221 of the Federal Court Rules, 1998.
[11] In Sanofi-Aventis Inc. v. Novopharm Ltd. 2006 FC 1547, I held that with respect to section 6(5)(b) but not section 6(5)(a) that the standards used by the Court in considering motions to strike under Rule 221 should be applied and that an application should only be struck out where it was “plain and obvious” that it could not succeed, citing Hunt v. Carey Inc., [1990] 2 S.C.R. 959 I said at paragraph 11:
11 Taking section 6(5)(b) on an equal footing with old Rule 419 or present Rule 221 we must start with the well entrenched proposition as stated by the Supreme Court in Hunt v. Carey Canada Inc., [1990] 2 S.C.R. 959 that a party should not be driven from the judgment seat at an early stage before trial unless it is "plain and obvious" that the matter cannot succeed. In dealing with an application not an action, the Federal Court of Appeal in Norton v. Via Rail Canada (2005), 255 D.L.R. (4th) 311, at paragraph 15, states that striking out an application before hearing is an extraordinary remedy, granted only in narrowly defined circumstances. Finally, another classic decision of this Court should be cited, Creaghan Estate v. The Queen, [1972] F.C.J. No. 60, 1972 FC 732 at 736:
(3) Finally, in my view, a statement of claim should not be ordered to be struck out on the ground that it is vexatious, frivolous or an abuse of the process of the Court, for the sole reason that in the opinion of the presiding judge, plaintiff's action should be dismissed. In my opinion, a presiding judge should not make such an order unless it be obvious that the plaintiff's action is so clearly futile that it has not the slightest chance of succeeding, whoever the judge may be before whom the case could be tried. It is only in such a situation that the plaintiff should be deprived of the opportunity of having "his day in Court".
and at paragraph 22:
22 A motion to dismiss should not be used as a vehicle to resolve important, controversial points of law. This is particularly so in an area which the law is currently evolving (Daniels v. Canada, [2002] 4 F.C. 550). For this reason I will not dismiss the proceeding in respect of the '089 and '948 patent on this ground.
[12] The “plain and obvious” test was considered at length by the Supreme Court of Canada in Hunt v. Carey Inc., [1990] 2 S.C.R. 959 where Rule 19(24)(a) of the British Columbia Rules of Court were at issue. That Rule said:
“19(24) At any stage of a proceeding the Court may order to be struck out or amended the whole or any part of an endorsement, pleading, petition or other document on the ground that
(a) it discloses no reasonable claim or defence as the case may be…”
[13] The Supreme Court, per Wilson, J. concluded at page 980 of her reasons:
Thus, the test in Canada governing the application of provisions like Rule 19(24)(a) of the British Columbia Rules of Court is the same as the one that governs an application under R.S.C. O. 18, r. 19: assuming that the facts as stated in the statement of claim can be proved, is it “plain and obvious” that the plaintiff’s statement of claim discloses no reasonable cause of action? As in England, if there is a chance that the plaintiff might succeed, then the plaintiff should not be “driven from the judgment seat”. Neither the length and complexity of the issues, the novelty of the cause of action, nor the potential for the defendant to present a strong defence should prevent the plaintiff from proceeding with his or her case. Only if the action is certain to fail because it contains a radical defect ranking with the others listed in Rule 19(24) of the British Columbia Rules of Court should the relevant portions of a plaintiff’s statement of claim be struck out under Rule 1((24)(a).
[14] The application of the “plain and obvious” test by the Supreme Court in Hunt v. Carey Inc., supra, indicates that novel points of law which do not amount to an abuse of process, should not be struck out. A party should be allowed to make complete submission as to what the evidence at trial establishes. At page 988 Wilson, J. for the Court says:
The difficulty I have, however, is that in this appeal we are asked to consider whether the allegations of conspiracy should be struck from the plaintiff’s statement of claim, now whether the plaintiff will be successful in convincing a court that the tort of conspiracy should extend to cover the facts of this case. In other words, the question before us is simply whether it is “plain and obvious” that the statement of claim contains a radical defect.
It is plain and obvious that allowing this action to proceed amounts to an abuse of process? I do not think so. While there has clearly been judicial reluctance to extend the scope of the tort beyond the commercial context, I do not think this court has ever suggested that the tort could not have application in other contexts.
and at pages 989-990:
The issues that will arise at the trial of the plaintiff’s action in conspiracy will unquestionably be difficult. The plaintiff may have to make complex submissions about whether the evidence establishes that the defendants conspired either with a view to causing him harm or in circumstances where they should have known that their actions would cause him harm. He may well have to make novel arguments concerning whether it is enough that the defendants knew or ought to have known that a class of which the plaintiff was a member would suffer harm. The trial judge might conclude, as some of the defendants have submitted, that the plaintiff should have sued the defendants as joint tortfeasors rather than alleging the tort of conspiracy. But this Court’s statements in Inuit Tapirisat of Canada and Operation Dismantle Inc., as well as decisions such as Dyson and Drummond-Jackson, make clear that none of these considerations may be taken into account on an application brought under Rule 19(24) of the British Columbia Rules of Court.
[15] The balance that a Court must consider in this matter concerning section 6(5)(a) of the NOC Regulations is whether, on the one hand, an application should continue where at least one of the patents should not have been on the register in the first place. It would be a waste of judicial resources and those of the parties to do so. On the other hand, a party should not be deprived of its opportunity to make full argument based on all the evidence that would ultimately be before the Court. This latter point is tempered however in cases such as this where the application is to proceed in a summary fashion based on affidavit evidence and written transcripts of cross-examination alone and, at the end of the day, a decision has no binding effect should the parties proceed to an ordinary infringement and validity action.
[16] Taking these matters into consideration I find that a section 6(5)(a) motion should be considered on the basis that if a determination can be made based on law and the application of uncontroverted relevant evidence or admissions or plain and obvious findings on the evidence, then the Court should proceed to make a determination. Section 6(5)(a) must have a purpose that is not trivial. However, if the Court finds itself determining the matter on disputed relevant evidence or having to weight the merits of competing expert opinion, the matter should be left to the hearing at trial. It is difficult to sum this up as simply “plain and obvious”, it goes beyond that, but where the law can be applied to admissions and relevant evidence that is quite reasonably found to be undisputed or “plain and obvious” then the Court has a duty to make a determination.
2. Is the ‘493 Patent Claim 22, properly included on the Register?
a) The Issue
[17] The question is whether the ‘493 patent, and in particular claim 22, was properly listed having regard to the notice of compliance granted to the Applicant Pfizer Canada Inc. for NORVASC.
[18] By reason of the chemistry involved, Pfizer states the issue as: is a patent claiming a single medicine (one enantiomer of a racemate) eligible to be listed on the patent register against a drug containing that medicine plus an additional medicine (the racemate, that is, both enantiomers).
[19] The Court must consider first what the “medicine” is having regard to the NOC Regulations as they existed as of the time of listing, that is, pre-October 5, 2006. The medicine is described in Pfizer’s notice of compliance simply as “amlodipine besylate”.
[20] Section 4(1) of the NOC Regulations provides that:
“4(1) A person who files, or who has filed a submission for, or has been issued, a notice of compliance in respect of a drug that contains a medicine may submit to the Minister a patent list certified in accordance with subsection (7) in respect of the drug.”
A “medicine” is defined in section 2 of the NOC Regulations as:
“a substance intended or capable of being used for the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or symptoms thereof;”
[21] A “drug” is not defined in the NOC Regulations, however, the Federal Court of Appeal in Eli Lilly Canada Inc. v. Canada (Minister of Health), [2003] 3 FC 140 at paragraph 18 has stated that it has the same meaning as that found in the Food and Drug Regulations, namely that a “drug” includes any substance or mixture of substances manufactured, used or represented for use in the diagnosis, treatment, mitigation or prevention of disease, disorder, abnormal physical state, or the symptoms thereof, in human beings or animals.
[22] In Eli Lilly, supra, the Federal Court of Appeal reasoned that once any drug which contained the medicine in question had been issued a notice of compliance, any patent which claimed that medicine, even if the medicine of the notice of compliance needed to be combined with another chemical to make it useful and as claimed in the patent was not combined in that way, could be placed on the patent list contemplated by section 4(1) of the NOC Regulations. Sharlow, JA., for the Court said at paragraphs 20 to 29:
20 The Minister's task is facilitated by the form of the patent list. A separate patent list is submitted for each drug product. The form requires the following information about the drug: the name of the medicine in the drug, the brand name, the drug identification number set out on the notice of compliance, the intended use (human or veterinary), the route of administration, the pharmaceutical dosage form, and the dosage. There follows a section in which the patents sought to be included on the patent register are listed by patent number, date of grant and expiration date. Each patent is marked by a code indicating the status of the applicant as owner, exclusive licensee, or person with the consent of the owner. The remainder of the form identifies the person submitting the patent list and gives an address for service. The form also includes the required certification.
21 Subsection 3(3) is intended to ensure that the Minister does not give effect to a patent list submitted in relation to a particular drug product until a notice of compliance has been issued for that product. In this case it is common ground that the requirements of subsection 3(3) are met.
22 Subsection 4(1) tells the Minister who is entitled to file a patent list. That entitlement is given to a person who files or has filed a new drug submission to obtain a notice of compliance in respect of a "drug that contains a medicine", or a person who has been issued a notice of compliance in respect of a "drug that contains a medicine".
23 In the context of this case, it is common ground that Tazidime is a drug containing ceftazidime, and that Tazidime is a drug in respect of which Eli Lilly has been issued a notice of compliance. There was some dispute in the court below as to whether ceftazidime is a medicine.
24 The evidence is that ceftazidime is an antibiotic. Amorphous lactose has no medicinal qualities but prevents ceftazidime from degrading to toxicity. A formulation of ceftazidime and amorphous lactose that is the subject of one of the claims of the 969 patent would be considered to be a "medicine" as that term is defined in section 2 of the PMNOC Regulations: Hoffmann-La Roche Ltd. v. Canada (Minister of National Health and Welfare) (1995), 62 C.P.R. (3d) 58 (F.C.T.D.), affirmed (1996), 67 C.P.R. (3d) 25 (F.C.A.). However, it seems to me that ceftazidime alone also meets the definition of "medicine".
25 The Judge reasoned that, because ceftazidime by itself is toxic, it is not intended to be used for the treatment of a disease or disorder, and is not capable of being so used. I must respectfully disagree with that conclusion. An antibiotic does not cease to be an antibiotic merely because it cannot function safely in the human body until it is combined with a substance that prevents it from degrading to toxicity. It would follow that for the purposes of the PMNOC Regulations, ceftazidime is a medicine whether or not it is formulated with amorphous lactose.
26 It would also follow, paraphrasing the words of subsection 4(1), that because Eli Lilly has been issued a notice of compliance in respect of a drug, Tazidime, that contains a medicine, ceftazidime, Eli Lilly is permitted to submit a patent list in respect of the drug Tazidime. However, subsection 4(1) does not specify what patents Eli Lilly is entitled to include on the patent list. That question is determined on the basis of paragraphs 4(2)(b) and 4(7)(b).
27 Pursuant to paragraph 4(2)(b), the patent list submitted in respect of Tazidime may include any patent that contains "a claim for the medicine itself". The word "medicine" in paragraph 4(2)(b) must have the same meaning in that provision as it does in subsection 4(1). If that is so, then in the case of a patent list submitted for Tazidime, any patent that contains a claim for ceftazidime itself, or that contains a claim for a formulation in which ceftazidime is the active medicinal ingredient, is within the scope of paragraph 4(2)(b).
28 I need not analyze the requirements of paragraph 4(7)(b) in any detail. I understand that counsel for the Minister has not taken the position that the 969 patent is not "relevant to the dosage form, strength and route of administration" of Tazidime.
29 Based on the foregoing ordinary and grammatical reading of the PMNOC Regulations, the 969 patent should be eligible for inclusion on the patent lists for Tazidime. That is the interpretation that should be adopted unless the words of the PMNOC Regulations can reasonably bear a different meaning that would accord better with the purpose of the PMNOC Regulations.
[23] This reasoning may be tempered by the reasoning of the Supreme Court of Canada in its recent decision in AstraZeneca Canada Inc. v. Canada (Minister of Health), 2006 SCC 49. However, in view of my conclusions herein, I do not need to consider that issue.
b) The Notice of Compliance
[24] The notice of compliance is that granted to Pfizer Canada Inc. dated 1997-08-01, which is a supplemental notice respecting an earlier notice, for a prescription pharmaceutical branded as NORVASC provided in tablet form for oral administration of 5 mg; 10 mg and 25 mg. per tablet. The therapeutic class is described as “antihypertensive – antianginal agent”. Only one medicinal ingredient is named, it is:
“amlodipine besylate”
[25] Pfizer Canada Inc. makes available a product monograph respecting NORVASC first prepared June 23, 1992 and revised June 8, 2005. In that monograph the following pharmaceutical information is provided:
[26] The undisputed evidence is that amlodipine besylate is what is known as a racemate or racemic composition, that is, it can be described in two dimensions by a molecular depiction as shown in the product monograph but in three dimensions it consists of equal amounts of two such molecular structures. In three dimensions these two structures are twisted one way or the other. They are mirror images of each other. Sometimes a description is given that one is the right hand and the other is the left hand. Chemists call these structures enantiomers and describe their orientation by means of symbols such as (+) or (-) and R or S or a combination of those symbols. In this case it is undisputed that amlodipine besylate is, and at all material times was known to be, a racemate which comprised R(+) and S(-) enantiomers in equal amounts.
[27] The activity of enantiomers generally speaking from a pharmacological point of view, is undisputed. In this regard, I quote from the affidavit of one of Pfizer’s witnesses, Wasley, at paragraphs 42 to 44:
42. As noted above, enantiomers arise where a molecule contains one or more asymmetric carbon atoms. Enantiomers have identical physical and chemical properties except that they rotate the plane of polarized light in opposite directions (otherwise known as “optical rotation”) and their pharmacological properties are often different. By “pharmacological properties”, I mean the activity of a compound in a biological system, whether in vitro or in vivo.
43. Enantiomers can frequently, although not invariably, display markedly different biochemical and pharmacological effects. For example, administration of the enantiomers of a potent dopamine D-2 receptor agonist was found to give rise to mutual antagonism in which the two enantiomers each partially or completely inhibited the effects of the other. This supported the use of the separate enantiomers instead of the racemate.
44. In very few cases, the pharmacological differences between enantiomers are not “active versus inactive” or “active versus undesirably active”, but rather are cases of one enantiomer having desirable activity and the other enantiomer having a different desirable activity. Such is the case with amlodipine besylate.
[28] The notice of compliance for NORVASC lists “amlopidine besylate” as a single medicine, it does not state that it is a racemate or that there are R(+) or S(-) enantiomers of that compound. There is nothing on the record to show that any medicine has been described in any notice of compliance granted to anyone in terms of its component enantiomers. The record does indicate that notices of compliance have been granted where medicines contain two different compositions are listed in which case each composition is stated separately for example a drug called ADVAIR contains two medicinal ingredients salmeterol xinafoate and fluticasone propionate.
c) The 493 Patent
[29] At this point the ‘493 patent and claim 22 of that patent must be considered. It is undisputed that as of the earliest date set out in the patent, the priority date of August 23, 2000, NORVASC was a known drug containing as a medicine amlodipine besylate, a known racemate.
[30] The Supreme Court of Canada has, in Whirlpool Corp v. Camco Inc., [2000] 2 S.C.R. 1067, provided substantial guidance as to how a patent is to be considered in circumstances such as these. The construction of a patent, including its claims, is a task to be undertaken by the Court prior to consideration of issues such as infringement and validity (Whirlpool paragraphs 42 and 43). A purposive construction is to be given to the claims giving effect to their meaning as understood in view of the whole of the disclosure and the claims (Whirlpool paragraph 49(g)).
[31] A “dictionary” approach is to be avoided, a claim is not to be interpreted through the eyes of a grammarian or etymologist, (Whirlpool paragraphs 51 to 53).
[32] The Supreme Court made it clear that construction is for the Court and not for experts called by the parties. It stated in paragraph 57 of Whirlpool that the role of the expert was not to interpret the patent claims but to put the trial judge in a position of being able to do so in a knowledgeable way.
[33] It is apparent that in any seriously contested patent matter the parties will marshal experts on one side and the other, whose views as to construction of the claims will differ, favouring one party or the other. The Court will seek assistance from experts when needed to explain terms not readily apparent and to provide background, where needed, as to the concepts to be considered in the patent. In the final analysis however construction is a matter for the court alone, taking into consideration the whole of the description and claims and avoiding a strict “dictionary” approach to a claim.
[34] On this basis the ‘493 patent, including in particular claim 22, is construed.
[35] The title of the patent is telling, it says, “Therapeutic Compositions Comprising Excess Enantiomer”, thus the reader is told to expect a composition that is therapeutic and contains an excess of one enantiomer over another.
[36] Page 1 begins with a general description of the invention saying that the invention is concerned with pharmaceutical composition containing a “mixture of amlodipine enantiomers”.
The present invention is concerned with pharmaceutical compositions comprising a mixture of amlodipine enantiomers, which compositions have both anti-hypertensive and additional cardiovascular properties derived respectively from their calcium channel-blocking activity and their ability to release vascular nitric oxide (NO).
[37] The next paragraph on page 1 sets out what is undisputed between the parties. Amlodipine is a known medicine, a racemate, specifically as a besylate salt:
Amlodipine is a well-known calcium channel-blocking agent which is used in the treatment of hypertension and angina. Amlodipine is a dihydropyridine with an asymmetric centre at the 4-position; presently, amlodipine is only approved for administration in the form of the racemate, specifically that of the besylate salt.
[38] The next two paragraphs at page 1 state that the enantiomers of the racemate have been isolated and identified as R(+) and S(-) configurations and that specific medicinal properties reside in each. The S(-) has the known channel blocking actively of the racemate, the R(+) inhibits certain vascular smooth muscle migration.
The individual enantiomers of amlodipine have been isolated (J Med Chem 29 1696 (1986), Arrowsmith et al) and identified as R(+) and S(-) (J Med Chem 35 3341-3344 (1992), Goldmann et al). The calcium channel-blocking activity of the racemate has been found to reside largely, but not exclusively, in the S(-) enantiomer (J Cardiovasc Pharmacol 12 (Supp 6) S144, J W Rigby et al).
European Patent No. 0754043 describes the surprising ability of the R(+) enantiomer of amlodipine to inhibit PDGF-induced vascular smooth muscle cell migration using an in vitro system which effect may prove to be useful in the treatment of conditions such as atherosclerosis, restenosis after angioplasty and endometriosis.
[39] Then, at the bottom of page 1, is the disclosure of the invention. The R(+) enantiomer has another property, it releases NO (nitric oxide) having therapeutic effects:
It has now been found that the R(+) enantiomer of amlodipine has another unexpected property, specifically the ability to release NO, a potent vasodilator and inhibitor of platelet aggregation and the active species in nitroglycerin (Kidney International 49 S2-S5 (1996), Ignarro), from endothelial and vascular smooth muscle cells (hereinafter referred to as “vascular NO”).
[40] The next paragraph at the top of page 2 is extremely important. It advises that the racemate should not be used as it places an “artificial limit” on the amount of R(+) enantiomer that can be used for therapeutic effect:
When amlodipine is administered as the racemate, the NO-induced cardiovascular effects of the R(+) enantiomer are largely ‘masked’ by the potent anti-hypertensive effects of the S(-) enantiomer. Furthermore, the amount of racemate which may safely be administered is limited by the hypotensive activity of the S(-) enantiomer which, in excess of about 0.5 mg/kg, can give rise to adverse effects such as a marked and sustained fall in blood pressure and reduced coronary blood flow. The R(+) enantiomer, on the other hand, is expected to provide beneficial cardiovascular effects at concentrations far exceeding those at which the S(-) enantiomer begins to produce unwanted effects. Thus using the racemate of amlodipine places an artificial limit on the amount of R(+) enantiomer which may be administered and deprives the patient of the full cardiovascular benefits of said enantiomer.
[41] The next paragraph at page 2 articulates the problem that the patent seeks to address, getting the right balance between the amount of S(-) enantiomer and the R(+) enantiomer so as to achieve appropriate therapeutic benefits from each:
The problem which the present invention seeks to address is to provide amlodipine compositions comprising sufficient S(-) enantiomer to achieve the desired anti-hypertensive and anti-anginal effects while also comprising sufficient R(+) enantiomer to maximise the beneficial NO-induced cardiovascular effects of the latter. That is, to improve blood flow to vital organs such as heart, kidney and brain by vasodilation and inhibition of platelet aggregation without affecting normal haemodynamics.
[42] Other benefits are then canvassed before the patent turns to a brief discussion as to certain studies that revealed properties of the S(-) and R(+) enantiomer. The two concluding paragraphs at page 3 discuss results from these studies as to the release of NO by the R(+) enantiomer and concludes that if the racemate is administered so as to get optimum S(-) therapeutic effect, there is a failure to provide sufficient R(+) enantiomer for optimum NO release.
As indicated, maximum NO release as measured by nitrite production was observed at a free concentration of R(+) enantiomer of 109M or 0.4 ng/ml; this figure corresponds to a plasma protein-bound concentration of about 30 ng/ml, that is, some 5x the optimum plasma concentration for the S(-) enantiomer (Amer J Cardiol 73 A10-A17 (1994), D N Abernethy et al).
It follows that amlodipine racemate administered for optimum anti-hypertensive effect of the S(-) enantiomer fails to provide sufficient R(+) enantiomer for optimum NO release.
[43] Applicants’ counsel seized on the word “optimum” to launch an argument that, by implication, a sub-optimum release using the racemate is still contemplated. This cannot be so in view of the clear statements in the first paragraph at page 2 previously discussed that the benefits of the R(+) enantiomer are “largely masked” in the racemate, that the amount of racemate that would have to be administered would give rise to adverse effects and thus an artificial limit is imposed on the amount to be administered which would deprive a patient of the full benefits. In other words, don’t use the racemate alone if you want the NO effects of the R(+) enantiomer.
[44] This position is further supported at page 4 and over to page 5 of the patent where, after disclosure of some testing, the reader in told that the ratio of S(-) to R(+) is important since the presence of S(-) inhibits R(+); the R(+) must always exceed the S(-).
It follows that the dose of amlodipine racemate administered for optimum anti-hypertensive effect of the S(-) enantiomer limits the amount of R(+) enantiomer available for additional protection of the heart from hypoxic damage.
According to the present invention, therefore, there are provided compositions of amlodipine wherein the amount of S(-) enantiomer present is in the range 1.25mg to 5mg and the ratio of R(+) enantiomer: S(-) enantiomer exceeds the 1:1 ratio found in the racemate. In order to achieve the desired combination of anti-hypertensive and NO-induced cardiovascular effects, the compositions of the invention typically contain a ratio of R(+) enantiomers S(-) enantiomer in the range 2:1 to 8:1, ideally about 5:1.
[45] Then, at the first full paragraph of page 5 there is a statement critical to the understanding of claim 22, page 5 says that the invention also contemplates compositions comprising R(+) alone:
It is also within the scope of the present invention that said compositions may exclusively comprise the R(+) enantiomer when only those cardiovascular effects associated with elevated levels of vascular NO are required, for example, in the treatment of endothelial dysfunction arising from ischaemia and reperfusion of the heart.
[46] Then the patent speaks about combining the R(+) enantiomer with other things, not S(-), not the racemate, but other drugs such as an ACG inhibitor or a PDE5 inhibitor.
It may also be useful to combine the R(+) enantiomer with a cardiovascular drug of alternative mechanism, for example, an ACE inhibitor, such as ramaprilat or quinapril, to provide an additive or synergistic effect.
…
A similar synergy in NO effect might be expected for the R(+) enantiomer of amlodipine in combination with PDE5 inhibitor which combination is likely to potentiate the responses to released NO. A particularly preferred PDE5 inhibitor for use in such a combination might be sildenatil.
[47] The patent then discusses how to prepare the R(+) and S(-) enantiomers and at page 6 gives three ways of preparing enriched mixtures namely (1) combining appropriate amounts of R(+) and S(-); (2) adding R(+) to the racemate; or (3) preparing mixed crystals each containing the required ratio of R(+) and S(-).
The enriched enantiomer mixtures of the present invention may be prepared by (i) combining appropriate amounts of the two enantiomers, (ii) adding an appropriate amount of ‘excess’ R(+) enantiomer to amlodipine racemate, or (iii) preparing ‘mixed’ crystals each containing the required ratio of R(+) and S(-) enantiomers. When preparing enriched mixtures in accordance with these methods, it is within the scope of the invention to combine two free bases, a free base and a salt, or two salts. Furthermore, when combining two salts, the salt of one enantiomer may be combined with the enantiomer or racemate of the same or a different salt.
[48] Nowhere in the patent is it stated or suggested that the racemate alone will provide therapeutic amounts of NO. In fact, as discussed previously, the paragraph at the top of page 2 warns against such use.
[49] Critical to an understanding of the issue in this case is how enantiomers are derived from racemates. The patent at pages 5 and 6 describe this process. The racemate is, in effect, chemically broken apart into what are called diastereoisomers. These diastereoisomers are separated and then regenerated to create the enantiomers. It says:
The R(+) and S(-) enantiomers used in preparing the compositions of the invention may be prepared by chiral synthesis from a suitable optically pure precursor or obtained from amlodiine racemate by any conventional technique, for example, by chromatographic resolution using a ‘chiral’ column or by the preparation of diastereoisomers, separation thereof and regeneration of the desired enantiomer.
Specifically, diastereoisomers may be obtained by reaction of the racemate which a suitably optically active acid or base. The diasteroisomers are then separated, for example, by chromatography or fractional crystallisation, and the desired enantiomer regenerated by treatment with an appropriate base or acid. The other enantiomer may be obtained from the racemate in a similar manner or worked up from the liquors of the first separation.
[50] A detailed description of the process is given in Examples 1 and 2 at pages 10 to 12.
[51] The rest of the patent describes other matters such as how the enantiomers may be formed into tablets or other forms of administration and how they may be administered.
[52] There are 32 claims in the patent. No claim is directed to the racemate alone. Claims 1 through 21 and 24 to 28 are directly or indirectly directed to a composition of R(+) and
S(-) enantiomers with R(+) being present in excess of 1:1 and up to 10:1. Claim 5 and dependent claims are directed to achieving this ratio by mixing R(+) and S(-) crystals. Claim 8 and in particular claim 9 are directed to achieving this ratio by mixing R(+) crystals with a mixture of R(+) and S(-) crystals including mixing R(+) with the racemate. Claim 9 is the only claim using the word racemate or racemic and it is in a context where extra R(+) is added. Claims 29 and 31 and their dependant claims are directed to a mixture of R(+) enantiomers and another medicine such as an ACE or PDE5 inhibitor. Thus the claims recognize when a mixture occurs, R(+) can be mixed with a racemate, or such things as ACE or PDE5 inhibitors.
[53] No claim says that the R(+) as found in a racemate is itself sufficient. Even its broadest claim, claim 1, demands a ratio greater than 1:1 of R(+) to S(-) (keeping in mind that the racemate is 1:1).
[54] To return to the construction of claim 22 which says:
The R(+) enantiomer of amlodipine or a pharmaceutically acceptable salt thereof for use in the treatment of a condition for which a vascular NO-release agent is indicated.
and having in mind that principles expressed by the Supreme Court in Whirlpool, surpra, it is plain and obvious that claim 22 does not refer to the racemate. Considering claim 22 in light of the description and the rest of the claims, as is required by Whirlpool, it is plain and obvious that what is claimed in claim 22 is a composition that comprises essentially only the R(+) enantiomer and that it is therapeutically effective in treating a condition in which NO-release is indicated. The patent expressly teaches away from the use of the racemate for treatment of a condition in which NO-release is indicated.
d) Does the 493 Patent Claim the “Medicine” of the NOC
[55] From the foregoing analysis it can be seen that whereas the uncontradicted evidence shows that the notice of compliance for NORVASC is directed to the racemate, claim 22 is directed to one of the enantiomers contained in the racemate, the R(+) enantiomer.
[56] Pfizer characterizes the racemate as being composed of two medicines, the R(+) enantiomers and the S(-) enantiomer. It says that the law states that where a notice of compliance relates to two medicines a patent relating to one of those medicines can be listed under the provisions of section 4(1) of the NOC Regulations.
[57] In support of this proposition, Pfizer relies on the decision of the Federal Court of Appeal in Eli Lilly, supra, and in particular paragraphs 23 to 27 which I repeat:
23 In the context of this case, it is common ground that Tazidime is a drug containing ceftazidime, and that Tazidime is a drug in respect of which Eli Lilly has been issued a notice of compliance. There was some dispute in the court below as to whether ceftazidime is a medicine.
24 The evidence is that ceftazidime is an antibiotic. Amorphous lactose has no medicinal qualities but prevents ceftazidime from degrading to toxicity. A [page155] formulation of ceftazidime and amorphous lactose that is the subject of one of the claims of the '969 patent would be considered to be a "medicine" as that term is defined in section 2 of the PM(NOC) Regulations: Hoffmann-La Roche Ltd. v. Canada (Minister of National Health and Welfare) (1995), 62 C.P.R. (3d) 58 (F.C.T.D.); affirmed (1996), 67 C.P.R. (3d) 25 (F.C.A.). However, it seems to me that ceftazidime alone also meets the definition of "medicine".
25 The Judge reasoned that, because ceftazidime by itself is toxic, it is not intended to be used for the treatment of a disease or disorder, and is not capable of being so used. I must respectfully disagree with that conclusion. An antibiotic does not cease to be an antibiotic merely because it cannot function safely in the human body until it is combined with a substance that prevents it from degrading to toxicity. It would follow that for the purposes of the PM(NOC) Regulations, ceftazidime is a medicine whether or not it is formulated with amorphous lactose.
26 It would also follow, paraphrasing the words of subsection 4(1), that because Eli Lilly has been issued a notice of compliance in respect of a drug, Tazidime, that contains a medicine, ceftazidime, Eli Lilly is permitted to submit a patent list in respect of the drug Tazidime. However, subsection 4(1) does not specify what patents Eli Lilly is entitled to include on the patent list. That question is determined on the basis of paragraphs 4(2)(b) and 4(7)(b).
27 Pursuant to paragraph 4(2)(b), the patent list submitted in respect of Tazidime may include any patent that contains "a claim for the medicine itself". The word "medicine" in paragraph 4(2)(b) must have the same meaning in that provision as it does in subsection 4(1). If that is so, then in the case of a patent list submitted for Tazidime, any patent that contains a claim for ceftazidime itself, or that contains a claim for a formulation in which ceftazidime is the active medicinal ingredient, is within the scope of paragraph 4(2)(b).
[58] In that case the drug for which a notice of compliance had been granted was Tazidime. That drug included an active ingredient ceftazidime which required another substance, amorphous lactose, to render it sufficiently less toxic so that it could be administered safely. The question which the Court of Appeal answered in the affirmative, was whether a patent directed to the active ingredient alone, ceftazidime, could be listed. As Sharlow, JA. For the Court said in paragraph 25:
“An antibiotic does not cease to be an antibiotic merely because it cannot function safely in the human body until it is combined with a substance that prevents it from degrading to toxicity. It would follow that for purposes of the PMNOC Regulations, ceftozidime is a medicine whether or not it is formulated with amorphous lactose.
[59] It is wrong to conclude that the Federal Court has said that where the notice of compliance covers a combination, a patent directed to one of its components may be listed. In Eli Lilly, supra, there was always only one medicine, ceftazidime, the other compound was not a medicine but rather an ingredient that rendered the medicine less toxic. The medicine always was only ceftazidime.
[60] Here the notice of compliance is for the racemate, amlopidine besylate. It is not simply a mixture of two enantiomers. To achieve those enantiomers the racemate must be chemically broken apart, the resulting pieces are isolated then reconstituted as enantiomers. It is a substantial chemical reworking of the molecules.
[61] The notice of compliance itself speaks only of a single medical ingredient, amlodipine besylate, it does not speak of something made of two components. It is simply wrong to consider amlodipine besylate as a medicine comprising two medicines.
[62] Even if amlodipine besylate were to be considered to be two medicines it would not satisfy the Eli Lilly circumstances since in Eli Lilly there was only one medicine which in the notice of compliance form had been rendered less toxic not by another medicine but a compound having no medical effect of its own; it simply made the medicine less toxic.
[63] Therefore, it is clear that the “medicine” of the notice of compliance the racemate amlodipine besylate is not the R(+) enantiomer of claim 22 of the 493 patent.
In Conclusion
[64] The analysis as to “medicine” has been conducted based on the patent itself, its description and claims, and uncontradicted evidence. There is no serious controversy as to the law. While the analysis has been lengthy for clarity purposes the result is plain and obvious, the 493 patent should not be listed under the provisions of section 4(1) of the NOC Regulations as against the notice of compliance in question.
[65] As a result the motion will be allowed, striking out these proceedings as they relate to the 493 patent with costs to the moving party.
ORDER
FOR THE REASONS PROVIDED HEREIN:
THIS COURT ORDERS that:
1. The motion is allowed;
2. These proceedings as they relate to Canadian Patent No. 2,355,493 are struck out; and
3. The moving party, Pharmascience Inc., is entitled to its costs.
FEDERAL COURT
NAMES OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-899-06
STYLE OF CAUSE: PFIZER CANADA INC. and
PFIZER INC.
Applicants
and
THE MINISTER OF HEALTH and
PHARMASCIENCE INC.
PLACE OF HEARING: TORONTO, ONTARIO
DATE OF HEARING: FEBRUARY 13, 2007
REASONS FOR
ORDER AND ORDER: HUGHES, J.
DATED: FEBRUARY 19, 2007
APPEARANCES:
|
Kamleh Nicola Jana Stettner |
FOR THE APPLICANTS |
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|
|
|
Carol Hitchman Olga Kalinina |
FOR THE RESPONDENT, PHARMASCIENCE |
SOLICITORS OF RECORD:
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TORYS, LLP Toronto, Ontario |
FOR THE APPLICANTS |
|
|
|
|
HITCHMAN & SPRIGINGS Toronto, Ontario |
FOR THE RESPONDENT, PHARMASCIENCE |