Date: 20051011
Docket: T-1851-03
Citation: 2005 FC 1381
BETWEEN:
AVENTIS PHARMA INC. and
AVENTIS PHARMA DEUTSCHLAND GmbH
Applicants
and
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR AN ORDER ISSUED ON OCTOBER 6, 2005
SIMPSON J.
[1] This application (the "Application") is for an order under subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the "Regulations") prohibiting the Minister of Health from issuing a Notice of Compliance ("NOC") to Apotex Inc. ("Apotex") for Apo-Ramipril, until after the expiry of Canadian Patent No. 1246457 for the drug Ramipril. This patent, (the "457 Patent"), expires on December 13, 2005.
[2] The Applicants also seek a declaration that Apotex' letter dated August 20, 2003 is not a Notice of Allegation as contemplated by the Regulations.
[3] Altace is the brand name for the Applicants' Ramipril. At present, it is the only Ramipril on the market. Its product monograph shows that it is approved by the Minister of Health (the "Minister") for the treatment of heart failure and hypertension.
[4] Although Altace is approved for the treatment of hypertension, this treatment is not a patented use. The 457 Patent only covers the use of Ramipril in the treatment of heart failure. This case deals with whether Apotex has filed a notice of allegation which satisfies the Court, on a balance of probabilities, that Apotex' manufacture and sale of Apo-Ramipril for the treatment of hypertension will not infringe the claims for the 457 Patent which are limited to compositions for treating heart failure.
TWO PRELIMINARY ISSUES
6. Which Product Monograph is relevant on this Application?
[5] Paragraph 5(3)(a) of the Regulations provides that a party filing a notice of allegation is to "provide a detailed statement of the legal and factual basis for the allegation".
[6] The Notice of Allegation is dated August 20, 2003 (the "NOA"). It incorporates a Product Monograph for Apo-Ramipril dated July 25, 2003 (the "First PM"). The First PM was the foundation for the allegation of non-infringement and was included with the Abbreviated New Drug Submission ("ANDS") which Apotex sent to the Minister. The ANDS compared Apo-Ramipril to the Applicants' Ramipril. On that basis, the Minister was asked to issue a Notice of Compliance for Apo-Ramipril.
[7] In its NOA, Apotex included the following comment about the First PM:
We enclose herewith our draft Product Monograph as presently included in our ANDS. Although we believe it clear beyond doubt that the proposed indications are limited to hypertension and do not include treatment of cardiac insufficiency, if you have any basis to disagree, please promptly advise us and we will consider any proposed revision to satisfy you as to non-infringement.
[my emphasis]
[8] The Applicants did not respond to Apotex' offer to suggest revisions. Instead, they brought this application in which they disputed certain passages in the First PM (the "Disputed Passages"). However, before cross-examinations were held on the affidavits filed for this application, Apotex filed a revised Product Monograph dated February 2004 (the "Second PM") as exhibit "A" to the affidavit of John Hems of February 19, 2004. It dealt with the Applicants' concerns about the Disputed Passages by deleting all but one.
[9] Apotex says that it is the Second PM which is relevant on this application. It says that a product monograph is not final until the Minister issues an NOC and that the NOA made it clear that the First PM was subject to revision. To underscore these submissions, Apotex points to subsection 6(7) of the Regulations which permits a patentee to bring a motion for an order requiring a generic company to produce, during a subsection 6(1) proceeding, a document showing any changes made to any portions of the submission for an NOC. Apotex says that this shows that revisions to a product monograph are contemplated. While this is undoubtedly true as part of the approval process, it does not mean, in my view, that Apotex is entitled to amend its NOA without consent or leave during proceedings under subsection 6(1) of the Regulations.
[10] Apotex also points out that, although in AstraZeneca AB and AstraZeneca Canada Inc. v. Apotex Inc. and the Minister of Health, 2004 FC 71 at paragraphs 29, 40 and 41, O'Keefe, J. refused to consider a revised product monograph, he did so only because the proceedings had advanced beyond cross-examinations on the affidavit evidence. Apotex notes that Justice O'Keefe did not say that a revised PM could never be considered.
[11] On the other hand, the Applicants say that only the First PM is relevant. They say that the time limits applicable to applications under section 6 of the Regulations are tight and that they must have certainty about the content of a notice of allegation. They also note that there were no unexpected new facts which justified the Second PM. To this submission, Apotex responds by saying that, when faced with the Second PM, counsel for the Applicants could have moved for leave to file further evidence.
[12] The Federal Court of Appeal has noted that applications under section 6 of the Regulations are to be conducted on an expeditious basis (see AB Hassle v. Canada(Minister of National Health and Welfare)(2000), 7 C.P.R. (4th) 272 (F.C.A.) at paragraph 27). The Court of Appeal has also emphasized that the detailed statement in a notice of allegation serves to inform a potential applicant of the reasons for non-infringement so that a decision can be made about whether to seek a prohibition order (see paragraphs 17, 19 and 21). These conclusions suggest that a notice of allegation is intended to be a comprehensive and final document not, as was the case here, an offer to open negotiations.
[13] In my view, a party filing a notice of allegation is obliged to put its full and best case forward. It does not accord with the time limits in the Regulations or with the purpose of a notice of allegation to accept the Second PM as part of the record in the circumstances of this case. Accordingly, the First PM will be the only product monograph considered in this application.
6. Is Limited Interchangeability at issue on this Application?
[14] Interchangeability is a policy which is applied in the administration of provincial drug distribution programs. For these programs, provinces generate lists of drugs known as formularies. There is an approval process for the placement of drugs on formularies which is undertaken after an NOC is issued. Once a drug is on a provincial formulary, governments will reimburse a pharmacy for the drug when it is dispensed to approved patients. However, if both a generic and an innovator version of a drug are listed on the formulary, a pharmacy will only be reimbursed if the generic is dispensed.
[15] When applied to this case, interchangeability means that if Altace were prescribed for heart failure, and if Apo-Ramipril and Altace were both on a formulary, a pharmacist would fill the prescription by dispensing Apo-Ramipril. This substitution would occur unless a patient requested Altace or a doctor ordered "no substitutions". When dispensing Apo-Ramipril for heart failure, a pharmacist would be infringing the 457 Patent, but would be unaware of the infringement because, although he would know that Altace had been prescribed, he would not know that heart failure was being treated unless he made inquiries. Accordingly, interchangeability will lead to systemic third party infringement.
[16] To address this problem and avoid infringement, Apotex proposed a theory of non-infringement known as limited interchangeability. It was suggested for the first time during its cross-examination of the Applicants' witnesses on their affidavits that interchangeability could be limited so that pharmacists would only be reimbursed if they could show that Apo-Ramipril had been dispensed for the treatment of hypertension. This requirement would mean that pharmacists would need to ask patients and/or their doctors why Altace had been prescribed. The evidence shows that limited interchangeability has only been implemented on one occasion and only in one province. It was tried in Ontario in connection with a drug called certraline. Apotex, nevertheless, asks the Court to assume that Apo-Ramipril will only be approved for provincial formularies on the basis of limited interchangeability.
[17] The Applicants say that limited interchangeability should not be considered on this application because it is neither mentioned in the NOA, nor in the Apotex affidavit evidence, because listing on formularies is a future matter which will not be considered until after an NOC is issued and because limited interchangeability is not an accepted concept.
[18] In Aventis Pharma Inc. and Aventis Pharma Deutschland GmbH v. Pharmasicence Inc. and the Minister of Health and Schering Corporation, 2005 FC 340 at paragraphs 35 and 36, Madam Justice Snider concluded that, if Pharmascience had wanted to raise limited interchangeability, it should have included it in its NOA and she did not consider the submission even though (unlike the present case) the topic had been addressed in the respondents' affidavits.
[19] I agree with Justice Snider. In my view, to comply with the requirement for a detailed statement found in paragraph 5(3)(a) of the Regulations, the NOA must clearly set out all the reasons why the second person alleges it will not infringe. Since limited interchangeability was not mentioned in the NOA, it is not relevant on this Application.
AGREED MATTERS
[20] The parties have agreed that the validity of the 457 Patent is not an issue. They have also agreed that Altace and Apo-Ramipril are therapeutically equivalent and that both drugs are therefore capable of treating hypertension and heart failure.
THE NOA
[21] The relevant text of the NOA reads as follows:
This is a Notice of Allegation, pursuant to the Patented Medicines (Notice of Compliance) Regulations with respect to Canadian Patent Nos 1246457 (the '457 Patent).
We have filed with the Minister of Health a submission for ramipril capsules for oral administration in strengths of 1.25, 2.5 and 5 and 10 mg.
We allege that no claim for the medicine itself and no claim for the use of the medicines will be infringed by our making, constructing, using or selling of said capsules.
The factual and legal basis for this allegation is as follows:
All claims for '457 Patent are limited to compositions for treating cardiac insufficiency.
There will be no infringement of the '457 Patent, as our capsules will be made, construed, used and sold only for the treatment of hypertension. We will not make, construct, use or sell capsules for treating cardiac insufficiency.
More particularly, we undertake that we will ensure that in our Product Monograph, issued by the Minister along with the Notice of Compliance, the only indication will be for the treatment of hypertension and any indication for the treatment of cardiac insufficiency will be excluded.
We enclose herewith our draft Product Monograph as presently included in our ANDS. Although we believe it clear beyond doubt that the proposed indications are limited to hypertension and do not include treatment of cardiac insufficiency, if you have any basis to disagree, please promptly advise us and we will consider any proposed revision to satisfy you as to non-infringement.
THE ISSUES
[22] The broad issue is whether the allegations of non-infringement in the NOA are justified or, put another way, whether the allegations are credible. To deal with this issue, the following underlying questions must be addressed:
(i) What is the test for infringement?
(ii) Is the test met in this case?
(iii) Does the First PM suggest that Apo-Ramipril may be used to treat heart failure?
6. The Test for Infringement
[23] The Federal Court of Appeal dealt with the test for infringement twice in 2002. See Procter & Gamble Pharmaceuticals Canada Inc. v. Canada(Minister of Health), [2003] 1 F.C. 402, 2002 FCA 290 ("P & G") (this case is sometimes referred to as Genpharm Inc. v. The Minister of Health and Procter & Gamble Pharmaceuticals (Canada) Inc.) andAB Hassle v. Canada (Minister of National Health and Welfare (2003), 298 N.R. 323, 2002 FCA 421 ("Hassle").
[24] In P & G, the Court was persuaded that Genpharm Inc.'s own conduct meant that infringement would be inevitable. For example, Genpharm intended to manufacture the drug in a dosage that was only needed for the patented use and it proposed a style of packaging that was only useful if a patient was taking the drug for the patented use. As well, the "Warning" and "Precaution" sections of the product monograph appeared to suggest that the generic drug would be prescribed for the patented use.
[25] In the Hassle case, the product monograph was not in evidence. However, the Court accepted that it would not refer to the patented use. Nevertheless, the applicants submitted that infringement was inevitable because doctors, pharmacists and patients would all know that the generic drug was therapeutically equivalent and less expensive. Accordingly, they said that the generic drug would be prescribed and dispensed for the patented use instead of the patented drug.
[26] However, the applicants' evidence in Hassle was problematic for two reasons. First, it focused on a "likelihood" of infringement by third parties which was beyond Apotex' control and, second, the Court concluded that the applicants' witnesses lacked independence and expertise.
[27] The first affiant was employed by the Applicant and was neither a physician nor a pharmacist. Her opinions about the practices of those professionals were therefore not accepted and the self-serving nature of her evidence was noted. The second affiant was a pharmacist but she provided opinions about doctors' prescribing practices. Her evidence was not accepted because she was not a physician. The third affiant was a physician but the Court decided that he was not qualified to talk generally about physicians' practices.
[28] Although it discounted the Applicants' affidavit evidence, the Court did address their submissions about infringement. It concluded that the existence of a "likelihood" that a patient would consume a generic product for a patented use, could not be a basis for refusing to approve the sale of the generic drug. The Court said, at paragraph 57, that refusing approval on this basis:
. . . would prevent new uses from being approved for existing drugs because there is always the possibility that someone somewhere will use the drug for the prohibited, patented purpose. This would result in a real injustice: since a generic company cannot possibly control how everyone in the world uses its product, the prevention of the generic from marketing the product would further fortify and artificially extend the monopoly held by the patent holders. The patent holder would, therefore, effectively control not just the new uses for the old compound, but the compound itself, even though the compound itself is not protected by the patent in the first place. The patent holders, as a result, would obtain a benefit they were not meant to have. In the end, society would be deprived of the benefit of new methods of using existing pharmaceutical medicines at a lower cost.
[29] In paragraph 59, the Court concluded that an applicant bears the onus of showing that future infringement "will" occur. However the test does not, in my view, require the Applicants to show that Apotex will be the infringing party. Proof on a balance of probabilities that third parties will infringe would satisfy the test.
6. Is the Test for Infringement Met in this Case?
[30] Dr. Gilles Dagenais is a cardiologist who swore an affidavit on the Applicants' behalf. His lengthy curriculum vitae shows, inter alia, that:
• He has been a practicing cardiologist since 1965 and presently practices at the Quebec Heart Institute.
• He was a Fellow in cardiology at JohnsHopkins Hospital from 1967 to 1969.
• He was a full professor of Medicine at Laval University from 1983 until 1991.
• He was a professor and chairman of the Department of Medicine, University of Montreal from 1991 to 1999.
• He has played a leadership role in professional organizations and has regularly associated with other Cardiologists in his work on grant, peer review and editorial committees, and in the course of scientific studies.
[31] I accept that Dr. Dagenais is an expert cardiologist and is in a position to comment on the views and practices of members of his profession.
[32] Mr. Adam Pignataro is a pharmacist and he swore an affidavit dated December 8, 2003. His affidavit says:
I have been licensed to practice as a pharmacist in the Province of Ontario since 1977 and have practiced pharmacy in Ontario since then. I currently practice in a retail setting, at Pascoe's Pharmacy (which I own), in the City of Mississauga. I have expertise working with other pharmacists. As a result of my experience, training and position, I have knowledge of the matters referred to herein.
[33] I have concluded that Mr. Pignataro is not qualified to speak about the practices of pharmacists generally, but can speak about the law and regulatory environment that applies to him, and by necessary inference to other Ontario pharmacists. I have, however, not accepted his evidence about physicians' prescribing practices because it is my conclusion that he is not qualified to provide such evidence.
[34] That said, I accept that his evidence shows that:
• Ontario law requires pharmacists to dispense the lowest cost generic drug in inventory unless they are otherwise directed by a doctor or a patient
• his pharmacy typically receives no information about the condition being treated when a drug is prescribed
• Apo-Ramipril will be dispensed at his pharmacy for heart failure "if there are physicians in Canada who are prescribing ramipril for such use"
[35] Dr. Dagenais' evidence clearly demonstrated that Ramipril (Altace) is widely prescribed in the treatment of heart failure. The Applicants submit that infringement by third parties will occur in two possible circumstances. First, doctors will prescribe Apo-Ramipril to treat heart failure because it is less expensive than, and therapeutically equivalent to, Altace. Second, pharmacists will dispense Apo-Ramipril when Altace is prescribed for the treatment of heart failure.
[36] Dr. Dagenais' affidavit did not address the first possibility. He did not offer an opinion about whether doctors would be aware that Apo-Ramipril was only approved to treat hypertension and, if they were aware, whether they would nevertheless prescribe it to treat heart failure.
[37] However, this first possibility was partially addressed on cross-examination. Dr. Dagenais spoke about a hypothetical patient who was already taking Apo-Ramipril when he arrived at the Heart Institute. In that context, he said that, if Apo-Ramipril were only approved for hypertension, he would not prescribe it for heart failure. Then he spoke generally and said that other doctors would most likely prescribe in the same manner. Unfortunately, this evidence did not clearly address the significant question which was whether doctors would prescribe Apo-Ramipril for heart failure if it had not been approved for that use.
[38] However, in re-examination, Dr. Dagenais said clearly that doctors were not necessarily required to prescribe based on the indications in a product monograph. In other words, even if Apo-Ramipril were only approved to treat hypertension, doctors could prescribe it to treat heart failure. However, he did not indicate what doctors would generally do. All Dr. Dagenais said was that he personally would "take note" of the fact that Apo-Ramipril was not approved for heart failure.
[39] There was, in the end, no clear evidence to show whether doctors would prescribe Apo-Ramipril for heart failure even though it was not approved for that indication. I have, therefore, not been persuaded by the Applicants' first submission that inevitable infringement will occur because doctors will write prescriptions for Apo-Ramipril to treat heart failure.
[40] The next question is whether infringement will occur because doctors will prescribe Altace for heart failure and pharmacists will substitute Apo-Ramipril when filling the prescriptions. This will happen, according to Mr. Pignataro's evidence, because pharmacists, at least in Ontario, are obliged to supply the least costly version of a drug unless directed otherwise by a "no substitution" order on a prescription.
[41] The Applicants say, based on Dr. Dagenais' evidence, that prescribing doctors do not indicate the patient's ailment on the prescription form. They add that the evidence of Dr. Dagenais and Mr. Pignataro shows that, when pharmacists are presented with a prescription for Altace which has been written to treat heart failure, they will inevitably dispense Apo-Ramipril.
[42] This submission leads to an inquiry about whether a pharmacist would ask about the condition being treated by a prescribed drug. In this regard, Mr. Pignataro's affidavit says:
In respect of such prescriptions which come to my attention. I am typically not advised either by the physician or by the patient why the particular patient has been prescribed ramipril. In addition, I have no particular reason for seeking to know why a particular patient has been prescribed ramipril. Even if I was interested in determining the use intended, I have no authority to compel disclosure of such information from either the physician or the patient. Furthermore, it is my experience that a physician and patient will not necessarily volunteer such information.
[43] This evidence demonstrates that Mr. Pignataro usually has no reason to inquire about the reason a prescription has been written, that he and other pharmacists in Ontario have no legal authority to compel patients or doctors to provide the reason for a prescription and that physicians may or may not disclose the information. On this point, Dr. Dagenais said in his affidavit that he would typically not reveal the indication to a pharmacist. However, he gave no evidence about general professional practice in this regard.
[44] Apotex submits that, if pharmacists were advised that Apo-Ramipril was not approved for heart failure, pharmacists would ask doctors about the reason for the prescription and would not dispense Apo-Ramipril for heart failure. In this regard, Apotex was assisted by Mr. Pignataro's admission that he would not dispense Apo-Ramipril if a doctor advised him that it was being prescribed for an indication that was not approved. However, Apotex' submission is otherwise speculative. There is no evidence to suggest how or whether pharmacists would ever be advised that Apo-Ramipril was only approved to treat hypertension and there is no evidence about how pharmacists generally would dispense if they had that information.
[45] Based on the Applicants' evidence, I have concluded that Altace will be prescribed for heart failure and that those prescriptions will not show why it was prescribed. Since pharmacists (at least in Ontario) will be obliged by law to dispense Apo-Ramipril unless directed otherwise by the doctor or patient, it is, in my view, inevitable that Apo-Ramipril will be dispensed for heart failure.
6. Does the First PM Suggest that Apo-Ramipril may be used to treat heart failure?
[46] The Applicants' evidence on this topic was provided by Dr. Dagenais and Franca Mancino.
[47] Franca Mancino is the Director, Regulatory Affairs and Pharmacovigilance at Aventis Pharma Inc. She has been employed in regulatory affairs for ten years and has a Masters degree in Genetics. Her duties include the preparation of product monographs.
[48] I have been asked to disregard her evidence as self-serving or assign it little weight because she is employed by an Applicant company. However, if her opinions are confined to her area of expertise, which is regulations and product monographs, I see no reason to discount her evidence simply because she is an applicant's employee. In any event, regarding the Disputed Passages in the First PM, her evidence is substantially the same as that of Dr. Dagenais.
[49] Dr. Dagenais was asked to provide an opinion about whether the First PM "... would suggest to a cardiologist or similar medical person that Apo-Ramipril is suitable for the treatment of cardiac insufficiency and therefore would be prescribed for that indication."
[50] The parties disagree about what portions of the First PM are relevant. Apotex says that the Court should only consider the section of the First PM entitled "Indications and Use" because it is the only section that Doctors normally read. On the other hand, the Applicants say that, even though the section of the First PM entitled "Indications and Clinical Use" provides that Apo-Ramipril is indicated for the treatment of hypertension, the Disputed Passages in other parts of the First PM suggest that Apo-Ramipril may be used in the treatment of heart failure.
[51] In my view, the Court is looking at the text of the First PM to determine whether Apotex' allegation of non-infringement is credible. In P & G, the Federal Court of Appeal looked at the Warnings and Precautions sections of the product monograph and reached a negative conclusion about Genpharm's allegation of non-infringement (see paragraphs 31 (3 and 4) and 40).
[52] Because the Court of Appeal considered the entire product monograph in P & G, because the focus of this inquiry is Apotex' credibility, not simply what interests a doctor, and because the entire First PM may be used for promotional purposes, I will consider the Disputed Passages.
THE DISPUTED PASSAGES
6. - Warnings - Hypotension
[53] At page 10 of the First PM, under the above heading, the text reads:
In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been associated with oliguria, and/or progressive azotemia, and rarely, with acute renal failure and/or death.
[54] The parties agree that Altace and Apo-Ramipril are ACE inhibitors.
[55] The Applicants say, and I accept, that this passage suggests that patients with severe congestive heart failure may be treated with Apo-Ramipril and, if that treatment is given, certain side effects may be observed. In my view, this warning is only relevant if Apo-Ramipril is used to treat congestive heart failure, which is the patented use.
[56] Apotex submits that co-morbidity explains the inclusion of this text and the other Disputed Passages. It says that, because a patient could experience both hypertension and heart failure, the Disputed Passages are reasonable and necessary and should not be interpreted as suggesting infringement. In his cross-examination, Dr. Dagenais acknowledged that hypertension and heart failure are often suffered at the same time. However, in my view, if the real purpose of the Disputed Passages is to address co-morbidity then they should clearly state that objective in terms that make it clear that Apo-Ramipril is not approved to treat heart failure.
6. Precautions - Renal Impairment
[57] At page 13 of the First PM, the document states:
In patients whose renal function may depend on the activity of the rennin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
[58] Again, the Applicants say, and I agree, that this passage suggests that agents that inhibit the rennin-angiotensin-aldosterone system may be used to treat patients with severe congestive heart failure and that this treatment may cause problems. In my view, this warning only makes sense if patients with heart failure are going to be treated with Apo-Ramipril.
3. - Dosage and Administration - Treatment Following Acute Myocardial Infarction
[59] At page 28 of the First PM, the test read:
Dosage of Apo-Ramipril must be individualized. Initiation of therapy requires consideration of concomitant medication and baseline blood pressure and should be instituted under close medical supervision, usually in a hospital, three to ten days following an acute myorcardial infraction in haemodynamically stable patients with clinical signs of heart failure.
The recommended initial dosage of Apo-Ramipril is 2.5 mg given twice a day (b.i.d.), one in the morning and one in the evening. If tolerated, and depending on the patient's response, dosage may be increased by doubling at intervals of one to three days. The maximum daily dose of Apo-Ramipril should not exceed 5 mg twice daily (b.i.d.).
[60] Dr. Dagenais says that this passage discusses the use of Apo-Ramipril in patients who have suffered an acute myocardial infarction (a heart attack) with signs of heart failure. I agree that the passage clearly discusses the use of Apo-Ramipril for the treatment of heart failure.
[61] Dr. Dagenais also observes that the recommended dosage for Apo-Ramipril in the second paragraph is the one used to treat heart failure. This indicates that Apotex is suggesting the use of Apo-Ramipril for heart failure.
4. - Dosage and Administration- use in renal impairment
[62] At page 29 of the First PM says:
Insufficient data is available concerning the use of ramipril following acute myocardial infarction in patients with heart failure and severe renal failure (see ACTION & CLINICAL PHARMACOLOGY - Pharmacokinetics & Metabolism, PRECAUTIONS - Renal Impairment).
Recommended initial dose: 2.5 mg of APO-RAMIPRIL once daily. Depending on the tolerability, the dose is gradually increased. It is recommended to double the dose after one week of treatment and - after another three weeks - to increase it to 10 mg. Usual maintenance dose: 10 mg of APO-RAMIPRIL daily (see ACTION AND CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS).
[63] Dr. Dagenais observes that this reference to the lack of availability of data regarding the use of ramipril to treat heart failure would be read to include Apo-Ramipril as a treatment for heart failure. I accept his evidence.
5. - Information for Patients - Following a Recent Heart Attack
[64] At page 35 the First PM says:
APO-RAMIPRIL has been shown to improve survival and reduce hospitalizations in patients recovering from recent heart attacks.
If you have developed heart failure after a heart attack, you may have to limit your physical activities. Before you begin exercising, be sure to consult with your doctor.
When initiating therapy in patients with heart failure after a heart attack, APO-RAMIPRIL is usually given twice a day, in the morning and in the evening. Take your medication as instructed by your Doctor.
[65] Dr. Dagenais observes, and I agree, that these passages indicate that Apo-Ramipril is to be used to treat heart failure.
6. - References
[66] At page 45, the First PM lists references. Objection is taken to references 4 and 10.
[67] Reference 4 is entitled "The Acute Infarction Ramipril Efficacy (AIRE) Study: Rationale, Design, Organization, and Outcome Definitions" studied the effect of administering ramipril to heart victims with early clinical evidence of heart failure. The authors note in the summary.
. . . We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.
[68] Reference 10 is entitled "Ramipril: A review of the New ACE Inhibitor", the author notes at page 439:
The acute hemodynamic effects of Ramipril have been examined in patients with congestive heart failure demonstrating significant reductions in mean arterial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure and peripheral vascular resistance, and a significant increase in cardiac output. The results of this study therefore suggests that Ramipril administered once daily produces sustained hemodynamic changes in patients with severe congestive heart failure which are comparable to those produced by Captopril administered three times daily.
[69] With regard to these references, Dr. Dagenais says, and I accept, that, in the context of the First PM, they suggest that Apo-Ramipril can be used to treat heart failure.
CONCLUSIONS
[70] In my view, the Applicants have demonstrated that infringement will occur and also that the Disputed Passages in the First PM show that the allegations of non-infringement in the NOA are not credible.
[71] Accordingly, on October 6, 2005 an order was made under subsection 6(1) of the Regulations.
[72] As noted above, the Applicants asked for a declaration that Apotex' letter dated August 20, 2003 is not a notice of allegation as contemplated by the Regulations. The order issued on October 6, 2005 also granted the declaratory relief for the reasons discussed in paragraphs 5 to 13 herein.
"Sandra J. Simpson"
Ottawa, Ontario
October 11, 2005
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