Vancouver, British Columbia, July 18, 2006
PRESENT: The Honourable Justice Johanne Gauthier
BETWEEN:
SANOFI-AVENTIS DEUTSCHLAND GmbH
and
THE MINISTER OF HEALTH
REASONS FOR ORDER AND ORDER
[1] Aventis Pharma Inc. and Sanofi-Aventis Deutschland GmbH (collectively Aventis) seek a declaration that Pharmascience's letter dated July 12, 2004 (the NOA) is not a notice of allegation and detailed statement as contemplated by the Patented Medicines (Notice of Compliance Regulations) (the Regulations) and, in the alternative, an order prohibiting the Minister of Health from issuing a Notice of Compliance (NOC) to Pharmascience in respect of ramipril oral capsules of 2.5 mg, 5 mg and 10 mg until after the expiration of Canadian Patent 2,055,948 (the '948 Patent).
[2] This application was heard together with a similar application by Aventis in file T-836-04. Thus, the present reasons must be read with the reasons for order issued in that file which contain my analysis of the common issues. Here, the Court will only address the facts, the evidence and the issues that are unique to this application.
[3] It is undisputed that the claims of the '948 Patent are limited to the use of compounds including ramipril in combination with a calcium antagonist to prevent and treat proteinuria. This is a condition in which an excessive amount of protein is present in the urine. It is often a hallmark of kidney damage. Although hypertension is one of the causes of proteinuria, it is common to have patients with proteinuria who do not suffer from hypertension.
[4] As in T-836-04, the parties have agreed that this proceeding only involves the allegation of non-infringement and, more particularly, the non-infringement of the use claims. Thus, the most relevant portions of Pharmascience's NOA are:
5. Such claims would not be infringed by the making, constructing, using or selling by Pharmascience of the drug for which the submission for the Notice of Compliance has been filed. In particular, the Pharmascience products containing Ramipril for which a Notice of Compliance is sought will only be made, constructed, used, promoted for use and sold by Pharmascience for the treatment of hypertension and will not be made, constructed, used, promoted for use, or sold for Pharmsascience for use in a combination with calcium antagonists in the prevention and therapy of proteinuria.
(...)
20. The Pharmascience products for which a Notice of Compliance is sought are capsules containing Ramipril for the treatment of hypertension. These products will not be made or sold for use in a combination with calcium antagonists in the prevention and therapy of proteinuria.
21. In particular, the product monograph will list only treatment of hypertension in the "Indications and Uses" section and will not list the combination uses claimed in the 948 Patent, the Notice of Compliance is not being sought for such combination uses, and the marketing of the product by Pharmascience will not include any reference to such combination uses. The reader is directed to the Pharmascience product monograph provided to Aventis in Court file no. T-482-03 under a confidentiality order dated June 16, 2003, referred to in the Notice of Allegation included herewith.
[5] In this case, Aventis filed an affidavit from Franca Macino, its Director of Regulatory Affairs, who put in evidence the '948 Patent, the NOA and Health Canada's document "Guidance for Industry: Product Monograph", effective October 1, 2004.
[6] It also relies on the affidavit of Dr. Andrew Steele, a nephrologist who was a research resident at the Royal College of Physicians and Surgeons Clinical Investigator Program and practiced at St. Michael's Hospital. He is now a staff nephrologist at Lakeridge Health in Oshawa.
I accept that Dr. Steele is an expert in the field of nephrology, particularly acquainted with the treatment of proteinuria (his patient load constitutes 75% of patients suffering from that disease).
I feel that he is qualified to give an opinion on his practice as well as the prescribing methods of other nephrologists in Ontario.
[7] Finally, Aventis relies on an affidavit from Barbara Marie Berry, the pharmacist who swore an affidavit in T-836-04 on essentially the same issues.
[8] Pharmascience did not file any affidavit from a nephrologist or a doctor. It relies on two affidavits, one by Mr. Neirinck, Pharmascience's Vice-President of Scientific Affairs. He also repeats many of the things he said in his affidavit in file T-836-04. Notably, he reiterates his pledge that Pharmascience's application for listing on provincial formularies will be based on approval for its product's use in the treatment of hypertension. This same limitation will apply to Pharmascience's product monograph and its promotional material. Mr. Neirinck adds that Pharmascience is also willing to include in a new product announcement, to be sent to all pharmacies and hospitals, a statement of the indication for which it has received its NOC and a statement that its ramipril has not yet been approved for use with a calcium antagonist in the treatment of proteinuria.
[9] Mr. Neirinck also comments on the evidence of Dr. Steele particularly his statement that 75% of his patient load suffers from proteinuria. Mr. Neirinck indicates that, according to the reports of Intercontinental Medical Statistics Canada (IMS), it appears that between October 2003 and September 2004, only 1% of the total prescriptions written for ramipril involved proteinuria, whereas 65% of the total prescriptions related to the treatment of essential hypertension.
[10] Finally, Pharmascience filed another affidavit from Mr. Nefski. As in file T-836-04, his opinion is based on the assumption that Pharmascience would obtain a limited interchangeability listing in Ontario. He also comments on Pharmascience's undertaking to amend its product monograph and to send a notice to the pharmacists and the hospitals stating that its ramipril product has not yet been approved for use with a calcium antagonist for the prevention and treatment of proteinuria.
[11] Once again, the affiants were cross-examined.
[12] Aventis raises the same issues as in T-836-04 with some variants. It says that the NOA is deficient and that, even if it is found adequate, the Court should not consider the additional undertakings made by Pharmascience with respect to its willingness to seek a limited interchangeability listing, or to send the above-mentioned notice to health professionals. For Aventis, these undertakings constitute an attempt to expand the factual basis set out in the NOA.
[13] Aventis also submits that Pharmascience's allegation of non-infringement is not justified. In addition to its argument that patients will inevitably infringe the '948 Patent, Aventis states that Pharmascience's product monograph contains a reference to the article of Tom P. Mills, "Ramipril: a review of the new ACE inhibitor" (1992) 88: 9 Journal of the Arkansas Medical Society 437 (the Mills reference). This document mentions the treatment of proteinuria and will, allegedly, encourage patent infringement by patients. Aventis finds the same encouragement in other passages of Pharmascience's product monograph.
[14] Aventis also objects to the evidence of Mr. Neirinck based on the IMS Report appended to his affidavit. Among other things, it indicates that this report was provided to Mr. Neirinck by someone else at Pharmascience. It is essentially hearsay. Aventis says that the Court should give it little or no weight because the affiant had no knowledge of how this information was assembled, particularly of how information that was obtained through sampling could be extrapolated to draw conclusions with regard to all prescriptions in Canada. Obviously, Pharmascience presented arguments to the contrary.
[15] The Court does not need to deal with this objection because it is clear that even 1% of the number of prescriptions of the popular ramipril drug represents a significant amount of prescriptions. The Court is satisfied that this issue has no real impact on the assessment of the evidence with respect to the probability of infringement by patients. Like Pharmascience's argument with respect to restrictive construction[1] of the claims, it would only affect the number of potential infringing uses.
[16] On the main issues, Pharmascience took essentially the same positions as in file T-836-04.
Analysis
[17] Essentially, the Court has applied the same principles it describes in its reasons in file
T-836-04.
a. Is the NOA deficient?
[18] For the reasons expressed in file T-836-04, the Court is satisfied that the NOA is adequate.
b. Is the allegation of non-infringement justified?
[19] Reference should be made to my reasons in file T-836-04, which deal with the proper interpretation of sub-paragraph 5.1 (b) iv) of the Regulations, as recently construed by the Federal Court of Appeal in Pharmascience Inc. v. Sanofi-Aventis Canada Inc. et al., 2006 FCA 229, [2006] F.C.J. No. 980, as well as my conclusion that infringement by patients would not be sufficient to decide that Pharmascience's allegation of non-infringement is unjustified.
[20] As I did in T-836-04, I will nevertheless assess the evidence presented in that respect.
[21] As I explained in T-836-04, the Court agrees that Pharmascience cannot rely on its undertaking to amend its product monograph or to send a notice to the health professionals warning them of its limited NOC and of the fact that it would seek a limited interchangeability listing. This would, in my view, improperly expand the factual basis described in its NOA.
[22] However, for the same reason given in the file T-836-04, I have nonetheless considered the evidence of Mr. Nefski in assessing the weight to be given Ms. Berry's evidence.
[23] With respect to the proposed amendment to the product monograph and the notice to be circulated to health professionals, the Court notes that Aventis took the position that these measures would have little, if any, impact on the ultimate use of Pharmascience's product by patients in the prevention or treatment of proteinuria.
[24] Ms. Berry's evidence is clearly to the effect that it is an economic reality that, in the regulatory environment applicable in Manitoba (Mr. Nefski testified to the same effect in respect of Ontario), the choice of the drug dispensed to a patient by a pharmacist is dictated by the drug's inclusion in the provincial formulary.
[25] The Court is satisfied that it is highly probable that Pharmascience's product would be listed without limitation or restriction in Ontario and Manitoba.
[26] Given that prescriptions expressly marked "with no substitution" are rare, it is evident that, even if the Court considered only Mr. Steele's own patients who suffer from proteinuria and not from hypertension, it is highly probable that patients will use Pharmascience's product in combination with a calcium antagonist for the new use claimed in the '948 Patent.
[27] That said, the Court will turn to Aventis' allegation that Pharmascience's actions appear to encourage or incite such infringement.
[28] As mentioned, Aventis claims that the Mills reference discusses the treatment of proteinuria. It refers to the following statement at the end of the first page:
... In patients with glomerulonephritis and nephrotic syndrome, low doses of Ramipril (1.25 mg or 2.5 mg every two days) administered for 24 weeks significantly reduced proteinuria and blood pressure without further deterioration in renal function.
[29] This sentence must be read in context. It is quite clear that the main purpose of the Mills reference is to discuss the effectiveness of ramipril in treating hypertension. Although proteinuria is mentioned, the article warns that any conclusions regarding the treatment of renovascular diseases are subject to further studies. The article does not discuss the specific treatment that is the subject of the '948 Patent, i.e. the use of ramipril in combination with a calcium antagonist. Furthermore, Aventis did not provide evidence explaining how anyone would be able to conclude from the Mills reference that ramipril should be employed with a calcium antagonist to treat proteinuria.
[30] As for the actual text of Pharmascience's product monograph, Aventis claims that it implicitly encourages the use of ramipril in combination with a calcium antagonist as claimed in the '948 Patent. It points out that the "Indications and Clinical Uses" section of the product monograph includes a warning that "[t]he safety and efficacy of concurrent use of ramipril with antihypertensive agents other than thiazide diuretics have not been established". Aventis takes this to be an implicit suggestion that calcium antagonists, although not tested by Pharmascience, can interact effectively with ramipril.
[31] Aventis sees the same hidden suggestion to use calcium antagonists in the statement on page 21 of the product monograph that "[t]he dosage of other antihypertensive agents being used with pms-RAMIPRIL may need to be adjusted".
[32] Aventis also notes that Pharmascience produces a calcium antagonist, know as pms-verapamil, and that the latter's product monograph discusses the possibility of using it in combination with ACE-inhibitors, a category which would include ramipril. It takes all this as an indication that Pharmascience intends people to use pms-ramipril in a manner which infringes the '948 Patent.
[33] The allegations with regard to the content of the product monographs for pms-ramipril and pms-verapamil do not stand up to scrutiny. The product monograph for pms-verapamil states at page 8 that:
pms-VERAPAMIL SR (verapamil hydrochloride) is indicated in the treatment of mild to moderate essential hypertension. pms-VERAPAMIL SR should normally be used in those patients in whom treatment with diuretics or beta blockers has been associated with unacceptable adverse effects.
(...)
Concomitant use of pms-VERAPAMIL SR with a diuretic or an angiotensin converting enzyme inhibitor has been shown to be compatible and to have additive blood pressure lowering effects.
[34] Clearly, pms-verapamil does not refer to the new use claimed in the '948 Patent, since it only refers to the combining of ACE-inhibitors with calcium antagonists as an improved method of lowering blood pressure (old use). Approval for pms-ramipril would not change the fact that pms-verapamil is not intended for use in treating proteinuria. In fact, on page 12 of the product monograph of pms-verapamil, it is stated that "verapamil should be used with caution in patients with impaired renal function." As pointed out by Pharmascience, if anything this is a disincentive to the use of pms-verapamil in the treatment of proteinuria.
[35] With regard to the language quoted by the applicant from the product monograph of pms-ramipril, it is difficult to see how such vague references to the use of ramipril in conjunction with other "hypertensive agents" could ever lead a person to conclude that pms-ramipril can be combined with a calcium antagonist for the treatment of proteinuria.
[36] Finally, as mentioned in my reasons in T-836-04, there is little evidence that doctors and pharmacists or hospitals consult the generic product monograph when they already know the brand name product well, or that they request and review the articles referred to therein.
[37] Here again, having considered all of the evidence put forth, the Court cannot conclude that Aventis has established that Pharmascience's allegation of non-infringement is not justified. Aventis' allegation that Pharmascience would be infringing by inducement or procurement is simply not supported by the evidence. (Valmet Oy v. BeloitCanadaLtd.) (1988), 20 C.P.R. (3d) 1 (F.C.A.).
[38] The application is therefore dismissed with costs which should be assessed on the basis of Column III of Tariff B.
ORDER
THIS COURT ORDERS that:
The application is dismissed with costs to be assessed on the basis of Column III of Tariff B.
FEDERAL COURT
NAME OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-1602-04
STYLE OF CAUSE: AVENTIS PHARMA INC. et al.
v. PHARMASCIENCE INC. et al.
PLACE OF HEARING: Toronto, Ontario
DATES OF HEARING: May 2, 3 and 4, 2006
REASONS FOR ORDER AND ORDER: GAUTHIER J.
DATED: July 18, 2006
APPEARANCES:
Gunars A. Gaikas
J. Sheldon Hamilton FOR THE APPLICANTS
Donald H. MacOdrum
Mark S. Mitchell FOR THE RESPONDENTS
SOLICITORS OF RECORD:
SMART & BIGGAR FOR THE APPLICANTS
Toronto, Ontario
LANG MITCHENER LLP FOR THE RESPONDENTS
Toronto, Ontario Pharmascience Inc. et al.
John H. Sims, Q.C. FOR THE RESPONDENT
Deputy Attorney General of Canada The Minister of Health
Ottawa, Ontario
[1] In this case, considering that hypertension is not the most common cause of proteinuria, their argument has even less impact than in T-836-04.