Date : 19990420
Docket : T-2660-96
| IN THE MATTER OF an application for an Order pursuant to Section 6 of the Patented medicines (Notice of Compliance) Regulations and Section 55.2(4) of the Patent Act |
|
OTTAWA, ONTARIO, TUESDAY, THIS 20TH DAY OF APRIL, 1999
BEFORE: THE HONOURABLE MADAME JUSTICE McGILLIS
BETWEEN:
SMITHKLINE BEECHAM INC.
and BEECHAM GROUP p.l.c.
Applicants
- and -
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
JUDGMENT
The application is dismissed with costs.
The following documents shall remain subject to the confidentiality order:
| i) affidavit of Alan Frank Barnes sworn October 22, 1997; |
| a) exhibit B-1: Report from Dr. Apperley "A Solid-State NMR Investigation of Tableted Paroxetine"; |
| ii) affidavit of Neal Ward #2 sworn October 22, 1997; |
| a) exhibit A-1: IR Spectrum at time of synthesis; |
| b) exhibit A-2: IR Spectrum of SB internal reference standard; |
| c) exhibit B: IR Spectrum of stored sample; |
| iii) affidavit of David Charles Apperley sworn October 22, 1997; |
| a) exhibit A-1: Report of Dr. Apperley "A Solid-State NMR Investigation of Tableted Paroxetine; |
| iv) affidavit of David Philip Elder sworn October 22, 1997; |
| v) affidavit of Neal Ward #1 sworn October 22, 1997; |
| a) exhibit W-1: IR Spectrum of Batch NW50910-015D1 |
| IR Spectrum of SB internal reference standard |
| IR Spectrum from Brantford Chemicals Inc. DMF; |
| vi) affidavit of Neal Ward #3 sworn October 22, 1997; |
| a) exhibit 1: Comments on open part of Canadian Drug Master File on Paroxetine Hydrochloride (anhydrous); |
| vii) affidavit of Jan Sedgeworth No. 2 sworn October 23, 1997; |
| viii) cross-examination of Brian John Russell held March 12, 1998; |
| ix) further cross-examination of Brian Russell held November 19, 1998; |
| x) cross-examination of Alan Frank Barnes held March 12, 1998; |
| xi) further cross-examination of Alan Frank Barnes held November 19, 1998; |
| a) exhibit 1: written answers from the cross-exam of Alan Frank Barnes; |
| b) exhibit 2: minutes of Paroxetine Form/Monograph Meeting No. 1 Held at Tonbridge on Thursday 13th October 1994; |
| xii) cross-examination of Neal Ward held March 12, 1998; |
| xiii) further cross-examination of Neal Ward held November 19, 1998; |
| a) exhibit 1: written answers to cross-examination held March 12, 1998; |
| xiv) cross-examination of David Charles Apperley held March 12, 1998; |
| xv) further cross-examination of David Charles Apperley held November 19, 1998; |
| a) exhibit 2: written answers to cross-examination of David Charles Apperly held March 12, 1998; |
| b) exhibit 3: letter dated January 10, 1994 from Dr. D.C. Apperley to Mr. A. Barnes and Report entitled "A Solid-State NMR Investigation of Polymorphic Contamination in Paroxetine Hydrochloride"; |
| c) exhibit 4: letter dated May 16, 1994 from A. F. Barnes to Dr. Apperley; |
| d) exhibit 5: letter dated June 3, 1994 from D.C. Apperley to Dr. A.F. Barnes; |
| xvi) cross-examination of David Philip Elder held March 12, 1998; |
| xvii) further cross-examination of David Elder held November 19, 1998; |
| xviii) cross-examination of Jan Sedgeworth held April 6, 1998; |
| xix) written answers of Neal Ward to cross-examination held March 12, 1998; |
| xx) written answers of Neal Ward to cross-examination held November 19, 1998; |
| xxi) written answers of David Charles Apperley to cross-examination held March 12, 1998; |
| xxii) written answers of David Charles Apperly to cross-examination held November 19, 1998; |
| xxiii) written answers of Alan Frank Barnes to cross-examination held March 12, 1998; |
| xxiv) written answers of Alan Frank Barnes to cross-examination held November 19, 1998; |
| xxv) written answers of Brian Russell to cross-examination held November 19, 1998; |
| xxvi) memorandum of fact and law of the applicants; |
| xxvii) exhibit #1 to the cross-examination of Jan Sedgeworth; |
| xxviii) exhibit #2 to the cross-examination of Jan Sedgeworth; and, |
| xxix) memorandum of fact and law of Apotex. |
Date : 19990420
Docket: T-2660-96
| IN THE MATTER OF an application for an Order pursuant to Section 6 of the Patented medicines (Notice of Compliance) Regulations and Section 55.2(4) of the Patent Act |
|
BETWEEN:
SMITHKLINE BEECHAM INC.
and BEECHAM GROUP p.l.c.
Applicants
- and -
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT
McGILLIS J.
INTRODUCTION
[1] The applicants SmithKline Beecham Pharma Inc. and Beecham Group p.l.c. ("SmithKline") have brought an application under the provisions of the Patented Medicines (Notice of Compliance) Regulations ("Regulations"), SOR/93-133, as amended SOR/98-166, for an order prohibiting the Minister of Health ("Minister") from issuing a notice of compliance to Apotex Inc. ("Apotex") for its paroxetine hydrochloride tablets until the expiry of Canadian Letters Patent No. 1,287,060 ("'060 patent").
FACTS
[2] The application for the '060 patent was filed on October 23, 1986, claiming a priority date in the United Kingdom of October 25, 1985. The '060 patent issued on July 30, 1991. The invention in the '060 patent generally relates to the novel compound "...crystalline paroxetine hydrochloride hemihydrate, processes for its preparation, compositions containing the same and its therapeutic use".
[3] At the priority date of the '060 patent, paroxetine and paroxetine hydrochloride were both old substances. The '060 patent cited U.S. Patent No. 4,007,196 which issued on February 8, 1977 ("U.S. Patent"). The U.S. Patent disclosed a class of compounds that were 5-HT inhibitors with a therapeutic use as anti-depressants. In Canada, paroxetine and its salts were covered by Canadian Letters Patent No. 1,038,390. That patent issued on September 12, 1978 and expired on September 12, 1995.
[4] In describing its invention, the '060 patent discloses as follows:
| In general, the hydrochloride salt of a basic compound is preferred for therapeutic use because of its physiological acceptability. |
|
| However for commercial use it is also important that the solid product should have good handling qualities. |
|
| We have found that amorphous paroxetine hydrochloride is a hygroscopic solid of poor handling qualities. |
|
| It has now been discovered that paroxetine hydrochloride can be produced in crystalline form in a manner reproducible on a commercial scale. |
|
| The present invention provides crystalline paroxetine hydrochloride hemihydrate as a novel material, in particular in pharmaceutically acceptable form. |
|
Paroxetine hydrochloride hemihydrate is stable and non-hygroscopic.
[5] The invention in the '060 patent therefore provides for crystalline paroxetine hydrochloride hemihydrate ("hemihydrate") in a pharmaceutically acceptable form. The invention also provides a process for producing hemihydrate. In a preferred aspect, the invention provides hemihydrate in substantially pure form. In a further aspect of the invention, hemihydrate can be obtained by compressing crystalline paroxetine hydrochloride anhydrate ("anhydrate"). The invention also provides a pharmaceutical composition comprising hemihydrate and a pharmaceutically acceptable carrier.
[6] The '060 patent has ten claims. Claims 1 to 6 are claims for processes only, and not for the medicine itself or the use of the medicine. Claims 7 and 8 are claims for intermediates that may be used for the production of the medicine, and are not claims for the medicine itself. Claim 9 claims the use of hemihydrate for the manufacture of a medicament for use in the treatment of depression. Claim 10 claims the product hemihydrate. Accordingly, the embodiments of the invention in which SmithKline claims an exclusive property or privilege are processes to make pure hemihydrate, the product hemihydrate and the use of that product for the manufacture of a medicine for use in the treatment of depression.
[7] SmithKline sells hemihydrate in Canada under the trade-mark PAXIL. Hemihydrate is a serotonin reuptake inhibitor and is used to treat depression.
[8] On April 7, 1993, SmithKline filed four patent lists, pursuant to the Regulations, in connection with 10 mg, 20 mg, 30 mg and 50 mg tablets of the medicine paroxetine. SmithKline listed the '060 patent on all four of the patent lists.
[9] By letter dated October 15, 1996, Apotex provided a notice of allegation under paragraph 5(3)(b) of the Regulations. The notice of allegation stated as follows:
| We will be submitting to the Federal Minister of Health a New Drug Submission for tablets containing the medicine paroxetine hydrochloride. It is our position that manufacture and sale of our product will not infringe any relevant patent. The Patented Medicines (Notice of Compliance) Regulations require that we serve on you a Notice of Allegation so as to be able to include a copy of same and proof of service in our submission. |
|
| Accordingly, this is a Notice of Allegation pursuant to Section 5(3)(b) of the said Regulations. With respect to patents 1287060, 1290340 and 1310649 we allege that no claim for the medicine itself and no claim for the use of the medicine, would be infringed by the making, constructing, using or selling by Apotex Inc. of tablets containing the medicine paroxetine hydrochloride. The legal and factual basis for the aforesaid allegation is as follows. |
|
| None of the aforesaid patents contains any claim for the medicine itself or the use of the medicine, paroxetine hydrochloride. Furthermore, with respect to any claims that might be considered to be claims for a medicine, even if not the medicine, the product sold by us will not be within the scope of any such claims. |
|
| Specifically, with respect to patent 1287060: |
|
| i) claims 1 to 6 inclusive are claims for processes only, and not for the medicine itself or the use of the medicine. |
|
| ii) claims 7 to 8 are claims for intermediates which may be used for the production of the medicine, but are not claims for the medicine itself. |
|
| iii) claims 9 and 10 relate only to crystalline paroxetine hydrochloride hemihydrate, which is not the same compound as the medicine, paroxetine hydrochloride. |
|
| iv) In any event, the tablets to be made and sold by Apotex Inc. will not be made using crystalline paroxetine hydrochloride hemihydrate, but will be made using the medicine paroxetine hydrochloride. |
|
| Specifically with respect to patents 1290340 and 1310649, these patents have claims only for processes and intermediates that may be useful to make the medicine, and such claims are not claims for the medicine itself or the use of the medicine. |
|
[10] The allegation made by Apotex rests solely on non-infringement.
[11] On December 4, 1996, SmithKline instituted its application for an order prohibiting the Minister from issuing a notice of compliance to Apotex.
[12] In support of its application for prohibition, SmithKline filed affidavit evidence, including affidavits from David Philip Elder, Neal Ward, Alan Frank Barnes, David Charles Apperley, Brian Russell and Jan Sedgeworth. In response, Apotex filed affidavit evidence, including an affidavit from Srebri Petrov. Apotex also, through its solicitors, sent to SmithKline's solicitors a copy of the Drug Master File of its supplier of paroxetine hydrochloride, as well as a "copy of the relevant portion of the New Drug Submission". SmithKline's affiants had access to the Drug Master File and the New Drug Submission prior to preparing their affidavits.
[13] As appears from the '060 patent, hemihydrate is a novel form of paroxetine hydrochloride and is reproducible on a commercial scale. Hemihydrate is one crystalline form of paroxetine hydrochloride; the other crystalline form is anhydrate. However, hemihydrate and anhydrate have different crystalline structures and a different degree of hydration. Hemihydrate has a half mole of strongly bound water as a structural part of its crystal lattice. In contrast, anhydrate has no strongly bound or structural water in its crystal lattice, but it may contain a variable amount of loosely held water. Indeed, anhydrate is hygroscopic, in that it has a propensity to attract moisture. In that sense, the prevailing humidity conditions may affect or control the moisture content of anhydrate.
[14] To date, regulatory approval has only been given in Canada and throughout the world for the sale of paroxetine hydrochloride in its hemihydrate form.
[15] In support of its application for prohibition, SmithKline relied on, among other things, two experiments conducted by it or on its behalf to support its assertion that the conversion of anhydrate to hemihydrate would result in the infringement of the '060 patent by Apotex. The question of the conversion of anhydrate to hemihydrate is therefore central to the case.
[16] The first experiment was conducted by David Charles Apperley, a chemical scientist with the University of Durham Industrial Research Laboratories in England. In the early 1990's, Dr. Apperley collaborated with Alan Frank Barnes, a chemist employed by SmithKline, to determine whether the anhydrate and hemihydrate forms of paroxetine hydrochloride could be differentiated by solid state nuclear magnetic resonance ("NMR") spectroscopy. By examining the solid state NMR spectrum of anhydrate and hemihydrate, certain differences were observed. As a result, by early 1995, the NMR technique was routinely used by SmithKline to identify the anhydrate and hemihydrate forms of paroxetine hydrochloride "...in a series of powder blends of the drug substance in tablet excipients".
[17] Between January 1994 and January 1996, Mr. Neal Ward, a chemist at SmithKline, prepared a number of batches of anhydrate "as reference materials or for investigational purposes". He stored samples of those batches of anhydrate in sealed glass containers at 20C in the dark, and also retained more than one sample from some of the batches.
[18] In February 1995, Dr. David Philip Elder of SmithKline supervised the manufacture of tablets of paroxetine hydrochloride consisting of anhydrate and/or hemihydrate in various ratios. The anhydrate used in preparing the tablets came from batch NW50910-015D1 prepared by Mr. Ward in January 1995, while the hemihydrate was as described in the '060 patent. All excipients in the tablets came from commercial suppliers. The constituents of the tableted formulations were as follows:
| Constituent Batch Master Formula Actual Batch |
| Quantity (mg/tablet) Quantity (g) |
| Paroxetine HCI 11.44 17.163 |
| Dibasic Calcium Phosphate E00160 158.84 238.30 |
Dihydrate (Encompress)
| Sodium Starch Glycollate 5028878 2.97 4.45 |
(Explotab)
| Magnesium Stearate 5014544 1.75 2.63 |
[19] Dr. Elder prepared the following tablets and sent them to Mr. Barnes:
| 1. Tablets made from paroxetine hydrochloride 100% of which was in the hemihydrate form. |
|
| 2. Tablets made from paroxetine hydrochloride 100% of which was in the anhydrate form. |
|
| 3. Tablets made from paroxetine hydrochloride anhydrate and paroxetine hydrochloride hemihydrate in the ratio of 95% by weight respectively. |
|
| 4. Tablets made from paroxetine hydrochloride anhydrate and paroxetine hydrochloride hemihydrate in the ratio of 90% and 10% by weight respectively. |
|
| 5. Tablets made from paroxetine hydrochloride anhydrate and paroxetine hydrochloride hemihydrate in the ratio of 75% and 25% by weight respectively |
|
[20] Dr. Elder prepared the anhydrate tablets in the controlled humidity environment of the manufacturing area at SmithKline, and took no special precautions in relation to the humidity, moisture and temperature of the area. He used the same machines that are used by SmithKline for tableting hemihydrate. The constituents in the tablets were the same as those in SmithKline's commercial formulation. He described the level of moisture in the excipients used in formulating the tablets as "very low". However, in cross-examination, he admitted that the main excipient in the anhydrate tablets was dibasic calcium phosphate dihydrate which contains crystalline hydrated water. It was used as a filler or a diluent in the formulation, and was the largest single component of the anhydrate tablets, comprising 158.84 mg of the 175 mg tablet. Dr. Elder did not try to tablet the anhydrate with an excipient that was anhydrous or that contained no water. The choice of the formulation, including the excipient dibasic calcium phosphate dihydrate, was dictated solely by SmithKline's commercial formulation. Dr. Elder did not know what compression level was applied in making the tablets, but used the same level for all of the tablets. Dr. Elder accepted the hypothetical premise that anhydrate could be tableted without converting to hemihydrate if there was no water or humidity present in the tableting process. However, he maintained that it would not be "practically attainable". In making the tablets, Dr. Elder took no steps to try to avoid the conversion of anhydrate to hemihydrate; he simply ran the commercial tableting process.
[21] On February 22, 1995, Mr. Barnes sent Dr. Apperley the tablets formulated by Dr. Elder and the corresponding untableted powder blends, and instructed him to investigate the "...anhydrate:hemihydrate ratios in the tableted product using solid state NMR". Mr. Barnes kept the tablets and the powder blends at ambient conditions with no special precautions. He sent the materials to Dr. Apperley by courier.
[22] Dr. Apperley conducted his experiment and, in March 1995, determined that "...in those tablets tested the ratio of hemihydrate:anhydrate had apparently increased relative to the expected ratio". In short, Dr. Apperley concluded that anhydrate had converted to hemihydrate "...as a result of the tableting process". In order to demonstrate that the sample preparation and the measuring system had not influenced the result, Dr. Apperley measured the hemihydrate level in a sample of the powder blend which had initially contained exclusively anhydrate. In that sample, no hemihydrate was detected. He also took a tablet containing exclusively anhydrate and ran the NMR experiment at -20C in order to eliminate the possibility that conversion had occurred due to sample heating, and determined that the percentage of anhydrate at -20C was the same as at 25C. Dr. Apperley performed his experiment at ambient conditions in the laboratory, and took no special precautions in relation to storage of the materials, temperature or humidity. Mr. Barnes agreed with and adopted the conclusions reached by Dr. Apperley.
[23] The second experiment was conducted by Mr. Neal Ward, a chemist at SmithKline. In October 1997, Mr. Ward was asked "...to consider whether paroxetine hydrochloride anhydrate with a melting point of about 120C is likely to convert to hemihydrate under normal storage conditions for pharmaceutical products, i.e. ambient temperature (about 20C) in sealed glass containers and in the dark" .
[24] On October 1, 1997, Mr. Ward re-examined all of his stored batches of anhydrate by infrared analysis using the Nujol mull technique. He found evidence of conversion from anhydrate to hemihydrate in eleven out of the sixteen samples. From the eleven samples indicating conversion, two had "completely or almost completely" converted to hemihydrate, four were partially converted and five "showed evidence of conversion". He summarized his data as follows:
TABLE
| Batch number Date of preparation Comments on IR |
| NW34922-171C January 31, 1994 Partial convertion to hemihydrate |
| NW50910-015D1/1 January 26, 1995 Some hemihydrate present |
| NW50910-015D1/2 January 26, 1995 Some hemihydrate present |
| NW50910-015D1/3 January 26, 1995 Partial conversion to hemihydrate |
| NW50910-016B February 22, 1995 Some hemihydrate present |
| NW50910-030B/1 February 24, 1995 Partial conversion to hemihydrate |
| NW50910-030B/2 February 24, 1995 Nearly complete conversion to hemihydrate |
| NW50910-033B March 3, 1995 Complete conversion to hemihydrate |
| NW50910-036C March 9, 1995 Some hemihydrate present |
| NW50910-036D1 March 13, 1995 Unchanged |
| NW50910-037A March 8, 1995 Some hemihydrate present |
| NW50910-043D March 13, 1995 Unchanged |
| NW50910-052A March 16, 1995 Unchanged |
| NW50910-060A March 28, 1995 Some hemihydrate present |
| NW50910-159A November 23, 1995 Unchanged |
| NW50910-179C January 19, 1996 Unchanged |
[25] With respect to the five samples that remained completely unchanged at the date of the experiment, Mr. Ward opined that these samples "...would over time convert in part or in whole to the hemihydrate". However, those five samples had remained unchanged for periods ranging from two years to over two and a half years.
[26] Mr. Ward also noted that internal records in SmithKline indicated that, on September 24, 1996, seven samples of anhydrate, prepared two to three months earlier, were tested. Two of the five samples showed the presence of hemihydrate. However, data on two of the other five samples were not available.
[27] Mr. Ward explained the theory of anhydrate conversion, noting that anhydrate is thermodynamically less stable than hemihydrate at normal temperatures. He further stated as follows:
| It therefore follows on theoretical grounds that all samples of the anhydrate will tend to transform into the hemihydrate. While the science of thermodynamics is clear about the theoretical inevitability of transformation of the anhydrate to the hemihydrate, it does not address the question of whether a suitable mechanism is available for the transformation, or whether the transformation will take place on a reasonable time-scale. I have considerable recent experience of working with the anhydrate and have found that such a transformation does indeed occur in real samples of the anhydrate over a time-scale of several months to years, indicating that there is a suitable mechanism available at present for the transformation to take place. |
|
[28] In summary, Mr. Ward expressed the opinion that "...a proportion of samples of [anhydrate] prepared today will convert to [hemihydrate] over a time scale of several months to years, and that all such samples of the anhydrate will convert to hemihydrate over time". He further stated that his opinion "...applies equally to bulk material and to material that has been formulated into a conventional pharmaceutical composition".
[29] In an unrelated matter, Mr. Ward also noted that the IR spectrum of a batch of anhydrate prepared in January 1995 conformed to a SmithKline internal reference IR spectrum of anhydrate, as well as to the IR spectrum of the material described as anhydrate in the Drug Master File of Apotex's supplier. In other words, he confirmed that the material described in the Drug Master File was anhydrate.
[30] Srebri Petrov, a research associate in the Department of Chemistry at the University of Toronto, reviewed for Apotex the affidavit evidence of Mr. Ward, Mr. Barnes and Dr. Apperley. Following his review of their procedures and conclusions, he saw "...no reason to disagree with their conclusions inasmuch as they state that: 1. the anhydrate form will convert to the hemihydrate over time; 2. the anhydrate form is converted to the hemihydrate form as a result of the tableting process." He further indicated that "[t]heir affidavits will confirm to a skilled chemist and reiterate the conclusions reached by Dr. Buxton, one of the inventors (of the '060 patent) in his paper entitled 'Solid-state forms of paroxetine hydrochloride'...". The paper was appended as an exhibit to Mr. Petrov's affidavit. The paper was authored by P. Christopher Buxton and Ian R. Lynch, who are two of the inventors of the '060 patent, and John M. Roe. In that paper, the authors conclude, among other things, that anhydrate will convert to hemihydrate "...when exposed to humid conditions or if subjected to compression".
[31] During the course of the hearing, counsel for SmithKline agreed as a fact, for the purposes of the present proceeding, that the drug referred to in the Drug Master File of Apotex's supplier was anhydrate.
ISSUES
[32] The principal questions to be determined on this application are as follows:
| i) whether Apotex's notice of allegation is ambiguous and contains insufficient facts to justify its allegation of non-infringement; and, |
|
| ii) whether SmithKline has discharged its burden of establishing that Apotex's allegation of non-infringement is not justified. |
|
ANALYSIS
i) notice of allegation
[33] Counsel for SmithKline submitted that the notice of allegation is ambiguous and contains insufficient facts to justify the allegation of non-infringement. I agree that there is some ambiguity in the notice of allegation, given the absence of any specific reference to anhydrate. However, the notice of allegation specifically alleges that "...no claim for the medicine itself and no claim for the use of the medicine would be infringed by the making, constructing, using or selling by Apotex Inc. of tablets containing the medicine paroxetine hydrochloride". Furthermore, the legal and factual basis for the allegation indicates, among other things, that "...the tablets to be made and sold by Apotex Inc. will not be made using crystalline paroxetine hydrochloride hemihydrate, but will be made using the medicine paroxetine hydrochloride." I am satisfied that the notice of allegation, when considered in its totality, alleges that Apotex would not infringe the '060 patent by making, constructing, using or selling tablets containing hemihydrate. I am further satisfied that such an allegation is not insufficient, in that it constitutes a specific factual allegation of non-infringement [See Glaxo Group Ltd. v. Canada (1998), 80 C.P.R. (3d) 424 at 426 (F.C.T.D.)].
ii) is Apotex's allegation of non-infringement not justified
[34] Counsel for SmithKline submitted that, in making its tablets, Apotex could not avoid infringing the '060 patent in that anhydrate converts to hemihydrate over time and in the tableting process. He therefore submitted that, as a result of the conversion, Apotex will be making hemihydrate either directly or indirectly by making its anhydrate tablets, and it will therefore infringe claim 10 of the '060 patent.
[35] The question of whether SmithKline has met its burden of proof by establishing, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified, depends on an analysis of the facts concerning the conversion of anhydrate to hemihydrate. Indeed, absent any conversion, Apotex's anhydrate tablets would clearly not fall within the claims of the '060 patent.
[36] The facts concerning the two main experiments conducted in relation to the conversion of anhydrate to hemihydrate must therefore be considered.
[37] In the Apperley experiment, the tablets used were prepared by Dr. Elder according to SmithKline's commercial formulation. Each tablet contained approximately 90 per cent of the excipient dibasic calcium phosphate dihydrate, which contains water. No efforts were made to create or use an excipient that was anhydrous or contained no water, despite the fact that water or humidity was a known factor affecting the stability of anhydrate and its conversion to hemihydrate. In my opinion, the Apperley experiment is of limited probative value on the facts of this case, given that 90 per cent of the composition of the tablets was an excipient containing water, a substance directly affecting the conversion of anhydrate to hemihydrate. The conclusions reached by Dr. Apperley are therefore entitled to little, if any, weight in the context of the present case.
[38] In the Ward experiment, approximately 30 per cent (5 out of 16) of the samples analysed by Mr. Ward did not convert from anhydrate to hemihydrate and, indeed, were completely unchanged between the dates of their preparation and the experiment, namely for periods of time ranging from two to two and a half years. In discussing the theory of anhydrate conversion, Mr. Ward stated that, although science recognized the "theoretical inevitability" of anhydrate conversion to hemihydrate, it did not address "...whether the transformation will take place on a reasonable time-scale". In dealing with the question of the time frame, Mr. Ward expressed the opinion, based on his experiment, that a "proportion" of anhydrate samples would convert to hemihydrate "within several months to years", and that "all such samples will convert to hemihydrate over time". He did not specify or quantify in any manner what he meant by the phrase "over time". However, the phrase "over time" must be considered in the context that 30 per cent of the samples tested by him had not converted at all in the two years prior to the date of the experiment. Furthermore, Mr. Ward provided no information concerning the conditions under which his anhydrate batches were prepared. Finally, he took no special precautions in relation to storage, temperature or humidity.
[39] Apotex has alleged in its notice of allegation that its tablets will not infringe the '060 patent. That allegation is presumed to be true, "...except to the extent that the contrary has been shown..." by SmithKline. [See Merck Frosst Canada Inc. v. Canada (1994), 55 C.P.R. (3d) 302 at 319 (F.C.A.)]. In my opinion, the evidence adduced by SmithKline, including the two experiments, raises no more than a possibility of infringement by Apotex, and does not establish, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified. I am also satisifed that the evidence of Apotex's witness Mr. Petrov does not advance the case for SmithKline, as suggested by its counsel. In my opinion, Mr. Petrov simply confirmed that he agreed with the conclusions of Dr. Apperley and Mr. Ward in the context of the experiments conducted by them.
[40] I have therefore concluded that Apotex should not be prevented from taking its anhydrate tablets to market on the basis of a potential conversion to hemihydrate at some undisclosed and imprecise time in the future. In the event that Apotex's anhydrate tablets do convert to hemihydrate, in whole or in part, it will face "very grave" consequences at that point in time. [See Hoffman-LaRoche Ltd. v. Canada (Minister of National Health and Welfare) (1996), 70 C.P.R. (3d) 206 at 213 (F.C.A.); Zeneca Pharma Inc. v. Canada (Minister of National Health and Welfare) (1996), 69 C.P.R. (3d) 451 at 452 (F.C.A.)].
[41] Given my conclusion in this matter, it is unnecessary for me to consider all of the other issues raised by counsel.
DECISION
| [42] The application is dismissed with costs. |
| _________________________ |
OTTAWA
April 20, 1999
Date : 19990420
Docket : T-2230-97
| IN THE MATTER OF an application for an Order pursuant to Section 6 of the Patented medicines (Notice of Compliance) Regulations and Section 55.2(4) of the Patent Act |
|
OTTAWA, ONTARIO, TUESDAY, THIS 20TH DAY OF APRIL, 1999
BEFORE: THE HONOURABLE MADAME JUSTICE McGILLIS
BETWEEN:
SMITHKLINE BEECHAM INC.
and BEECHAM GROUP p.l.c.
Applicants
- and -
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
JUDGMENT
For the reasons delivered in file T-2660-96, the application is dismissed with costs.
OTTAWA
- ) 1.