Date: 20031024
Docket: T-1755-01
Citation: 2003 FC 1248
BETWEEN:
GLAXOSMITHKLINE INC. and
SMITHKLINE BEECHAM P.L.C.
Applicants
and
GENPHARM INC. and
THE MINISTER OF HEALTH
Respondent
REASONS FOR ORDER
(Confidential Reasons for Order issued on October 3, 2003)
HENEGHAN J.
INTRODUCTION
[1] Glaxosmithkline Inc. and Smithkline Beecham P.L.C. ("GSK" or the "Applicants") seek an order pursuant to section 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the "NOC Regulations"), prohibiting the Minister of Health from issuing a Notice of Compliance ("NOC") pursuant to section C.08.0904 of the Food and Drug Regulations, C.R.C. 1985, c. 870 to Genpharm Inc. ("Genpharm" or the "Respondent") until after the expiry of Canadian letters patent 1,287,060 (the " '060 patent"). Genpharm seeks the issuance of a NOC relative to its tablets of paroxetine hydrochloride ("paroxetine HCL") in strengths of 10 mg, 20 mg and 30 mg.
THE PATENT
[2] The '060 patent, entitled "Crystalline Paroxetine HCL", was filed in the Canadian Patent Office on October 23, 1986. The patent claims priority from applications filed in the British Patent Office on October 25, 1985. The '060 patent was issued by the Canadian Patent Office on July 30, 1991. Since the patent was filed in Canada prior to October 1, 1989, the provisions of the Patent Act, R.S.C. 1985, c. P-4 then in effect, apply.
[3] The '060 patent relates to crystalline paroxetine hydrochloride hemihydrate, and the processes for its preparation and use as a therapeutic agent in a pharmaceutically acceptable form. In this application, GSK has taken issue only with claim 10 of that patent. Claim 10 is a composition of matter claim and reads:
10 Crystalline paroxetine hydrochloride hemihydrate
[4] The '060 patent has received prior consideration by this Court: see the decision of Justice McGillis in Smithkline Beecham Inc. v. Apotex Inc. (1999), 1 C.P.R. (4th) 99 (F.C.T.D.), affirmed (2001), 267 N.R. 101 (F.C.A.). More recently, the '060 patent was discussed in Glaxosmithkline Inc. and Smithkline Beecham P.L.C. v. Apotex Inc. and The Minister of Health, 2003 FCT 687, although the latter case dealt primarily with another patent owned by GSK, that is Canadian letters patent 2,214,575 (the " '575 patent"). This proceeding originally included the '575 patent and Canadian letters patent 2,178,637 (the " '637 patent"). GSK withdrew its application related to these two other patents at the commencement of the hearing, at least in part due to the decision Glaxosmithkline v. Apotex, supra, 2003 FCT 687, released the day before the hearing in this proceeding took place.
PAROXETINE HCL
[5] Paroxetine HCL is a serotonin reuptake inhibitor and is used in the treatment of depression and anxiety. The original patent that first disclosed the medicine paroxetine was U.S. Patent, No. 4,007,196 (the '196 U.S. patent"); that patent was issued on February 8, 1977 to a Danish company called Ferrosan. This patent disclosed a class of compounds that were 5-hydroxtryptamine (5-HT) inhibitors with a therapeutic use as anti-depressants.
[6] Two articles, written by Ferrosan's employees, Lund et al, and published in 1979 and 1982, described paroxetine hydrochloride as a new drug known to have an anti-depressant effect. These articles are attached as Exhibits to the affidavit of Dr. Story, filed in the Applicants' Application Record.
[7] In a subsequent article published in 1988, "Solid-state forms of paroxetine hydrochloride", Buxton et al. described two different forms of paroxetine in solid form:
Paroxetine HCL exists in two solid state forms, differentiated by their degree of hydration. Form I is a non-hygroscopic hemihydrate and is thermodynamically the more stable. Form II is a hygroscopic anhydrate the moisture content of which is controlled by the prevailing humidity. Form II converts to Form I, if seed crystals of Form I are present, when exposed to humid conditions or if subjected to compression.
[8] The chemical compound at issue in this proceeding is in a solid, "crystalline" form. When water is incorporated into the crystalline, it is called a "hydrate". When the ratio of number of molecules of water to the compound is 1:1, the compound is called a "monohydrate". When the ratio is 0.5:1, it is called a "hemihydrate". When no water is present as part of the crystalline structure, the compound is called an "anhydrate". Therefore, crystalline paroxetine hydrochloride hemihydrate refers to a solid crystalline form of paroxetine hydrochloride where there is a half mole of bound water for each mole of paroxetine hydrochloride as a structural part of its crystal lattice. While the anhydrate form has no bound water as part of its crystalline structure, it is hygroscopic, meaning that it has a propensity to attract moisture. The environment in which the anhydrate form of the compound is kept, therefore, can affect the moisture content of the compound. The difference between the anhydrate and hemihydrate forms of paroxetine HCL was discussed by Justice McGillis in Smithkline Beecham Inc. v. Apotex Inc., supra at paragraph 13.
[9] This description says that there is a difference in the crystalline forms of anhydrate and hemihydrate. It has been suggested that this difference is due to the dominance of a more stable form, the hemihydrate, over the less stable form, the anhydrate. This dominance has been said, in this proceeding, to give rise to the phenomenon of "disappearing crystal forms". One explanation tendered for that phenomenon is "seeding", that is the proliferation in the environment of seeds of a given crystalline form.
[10] "Seeding" can be deliberate; that is following the deliberate introduction of seeds of the crystalline form which is sought to be made into the system where the crystallization is occurring. Unintentional seeding occurs when the seeds of a particular crystalline form exist in the environment and contaminate the molecular structure, converting it to the crystalline form of the seeds. The concept of "seeding" is relevant to this proceeding since Genpharm's ability to create an anhydrate form of paroxetine HCL is a critical issue.
THE NOTICE OF ALLEGATION ("NOA")
[11] By letter dated August 17, 2001, Genpharm served a Notice of Allegation ("NOA"), upon GSK regarding the patents pursuant to section 5 of the NOC Regulations. Genpharm alleged that six patents listed by GSK with the Minister are invalid and four will not be infringed by Genpharm's product.
[12] In the NOA, Genpharm stated that it seeks to market tablets for oral administration containing paroxetine HCL in 10, 20 and 30 mg strengths. Genpharm attached two detailed statements to the NOA, one dealing with the '060 patent and the other dealing with the '637 and '575 patents. These attachments set out, in detail, the basis for the allegations contained in the NOA.
[13] Genpharm identifies its intended product as a solvated form of paroxetine hydrochloride anhydrate. Genpharm's tablets are manufactured in Australia using paroxetine HCL anhydrate as the active ingredient. This is mixed with other non-drug components of the formulation, collectively known as "excipients", using a dry compression process.
[14] Genpharm claims that its product will contain anhydrate rather than a hemihydrate form of paroxetine HCL.
[15] On October 4, 2001, the Applicants filed their application with this court for an order pursuant to section 55.2(4) of the Patent Act, R.S.C. 1985, c. P-4 (the "Act") and section 6 of the NOC Regulations prohibiting the Minister from issuing a NOC to the Respondent. In response to Genpharm's NOA, GSK claims that the '060 patent is valid and will be infringed by Genpharm's product.
EXPERT EVIDENCE
[16] Both GSK and Genpharm submitted affidavit evidence, including expert evidence, in support of their respective positions. GSK filed the affidavits from the following experts: Victor W. Jacewicz, John E. Richardson, Kurt Justin Baldwin, Thomas M. Niemczyk, Stephen Byrn and Gerald Brenner.
[17] Genpharm filed the affidavits of the following experts: Michael Story, Antony Godwin, James Durig, Dennis V. Stynes, and Elias Ndzie.
[18] GSK conducted tests of Genpharm's product, specifically of 50 mg of the bulk material manufactured in Australia, non-commercial tablets in strengths of 10 mg, 20 mg and 30 mg, and of the commercial tablets in the 20 mg strength.
[19] The bulk material was tested by Dr. Thomas Niemczyk, an expert in analytical chemistry. He used a technique called partial least squares ("PLS") and analysed infrared spectroscopic data. He concluded that the bulk material contained a detectable amount of hemihydrate, sufficient to cause seeding. In his affidavit, he said:
From my report attached as Exhibit "B", it is clear that Genpharm's bulk material contains some crystalline paroxetine hydrochloride hemihydrate as claimed in claim 10 of the '060 Patent and as described in Figure 2 of the '060 Patent. My experiments showed that crystalline paroxetine hydrochloride hemihydrate is present in the sample of Genpharm's bulk material at a level of 0.18 " 0.08% (0.08 is the standard deviation of five repeat determinations).[1]
[20] Dr. Baldwin, an analytical chemist and expert in spectroscopy, analysed samples of both the non-commercial and commercial tablets. He understood that the non-commercial tablets were quantitatively and qualitatively the same as the commercial tablets. He used the technique of Raman microscopy. He described this as a way of identifying molecular materials by reference to the vibration frequencies of molecules. He characterized this as a sensitive technique for detecting the drug within pharmaceutical tablets because there is usually a stronger Raman signal for the drug than for the typical excipients surrounding it. Identification of molecular material is made by comparing the Raman spectrum with the respective spectra recorded from already characterized and referenced molecular material.
[21] He determined that for the 10 mg non-commercial tablets, between 0.86% and 17.59% showed a "fingerprint" for paroxetine hydrochloride hemihydrate. He found a fingerprint for combined paroxetine hydrochloride hemihydrate and paroxetine hydrochloride anhydrate of between 0.86% and 21.76% in the 10 mg tablets he tested. He did not find any paroxetine hydrochloride hemihydrate in the 20 mg and 30 mg non-commercial tablets.
[22] Dr. Baldwin found paroxetine hydrochloride hemihydrate in all of the 20 mg commercial tablets tested. The amounts varied between 1.00% and 28.57% for paroxetine hydrochloride hemihydrate, and between 3.48% and 48.39% for paroxetine hydrochloride hemihydrate and paroxetine hydrochloride anhydrate.
[23] Dr. Byrn is an expert in solid state chemistry, including crystal chemistry, pharmaceutical chemistry and process, polymorphis and analytical techniques. He reviewed the reports and affidavits of Dr. Niemczyk and Dr. Baldwin who had tested the Genpharm bulk material and tablets, respectively. Dr. Byrn addressed the issue of invalidity of the '060 patent on the basis of obviousness and commented on certain publications relied on by Genpharm in that regard. He concluded that the testing techniques employed by Dr. Niemczyk and Dr. Baldwin were appropriate analytical tools.
[24] Dr. Byrn concluded that a partial presence of crystalline paroxetine hydrochloride hemihydrate in the Genpharm materials, that is the bulk material and tablets, was consistent with the phenomenon of seeding and conversion. Seeding is related to conversion of anhydrate to hemihydrate. He said that any amount present is capable of acting as a seed to promote the growth of crystals of paroxetine hydrochloride hemihydrate.
[25] Dr. Byrn dismissed the argument of invalidity on the basis of anticipation and found that prior to the first preparation of hemihydrate, a person making paroxetine hydrochloride would have produced an anhydrate or amorphous form of paroxetine hydrochloride. That is in contrast with developments after the discovery of the hemihydrate form since that later form affected the ability of the anhydrate to convert. He concluded that the '196 patent and the Lund articles did not teach the making of crystalline paroxetine hydrochloride hemihydrate.
[26] Dr. Jacewicz is a synthetic chemist employed by GSK. He has been involved as a chemist, in developing the crystallization of paroxetine hydrochloride. He addressed the issue of seeding and stated that he believed it was "extremely improbable, if not impossible" to recreate some crystalline forms due to the presence of widespread seeding.
[27] Dr. John Richardson, one of the named inventors of the '060 patent, filed an affidavit in which he described the discovery of the crystalline paroxetine hydrochloride hemihydrate in mid-December 1984. At the time, Dr. Richardson and others were preparing batches of paroxetine hydrochloride. The first 22 batches were of paroxetine hydrochloride anhydrate but batch 23 unexpectedly revealed the crystal form of the hemihydrate. This new form was found to be stable and non-hygroscopic, with a consistent water content. Subsequently, Dr. Richardson and other scientists with GSK were unable to produce the hygroscopic anhydrate since the process would only yield crystalline paroxetine hydrochloride hemihydrate.
[28] Dr. Brenner, an organic chemist with particular experience with crystalline and polymorph forms of compounds, was asked to provide an opinion about the allegations of invalidity raised by Genpharm relative to the '060 patent. In that report, he reviewed certain material including the decision of Justice McGillis in Smithkline Beecham Inc. v. Apotex, supra, the affidavits of Dr. Richardson, Dr. Jacewicz, Dr. Niemczyk and Dr. Baldwin, and Genpharm's formulation process. He commented on seeding and conversion. He interpreted claim 10 of the patent as follows:
In light of the above, I interpret Claim 10 to include crystalline paroxetine hydrochloride hemihydrate made by any process, including but not limited to, crystallization or recrystallization, with or without seeding, unintentional or otherwise, and conversion from paroxetine hydrochloride anhydrate with pressure or over time.
[29] He expressed the opinion that the '060 patent was valid, notwithstanding the '196 patent and the two Lund articles. He also concluded that the '060 patent would be infringed by Genpharm's product, on the basis that there is sufficient water in the Genpharm bulk material to permit conversion of approximately 86% of that material to crystalline paroxetine hydrochloride hemihydrate. He concluded, based on the testing done by Drs. Niemczyk and Baldwin, that Genpharm's product would infringe the '060 patent because "some" crystalline paroxetine hydrochloride hemihydrate was detected in the bulk material, as well as the non-commercial and commercial tablets.
[30] He dismissed the experiments conducted by Genpharm as set out in a document called "Investigations", dated March 29, 2001, primarily on the basis that these tests were conducted after the appearance of the new polymorph, that is the crystalline paroxetine hydrochloride hemihydrate because the new more stable polymorph, by the process of seeding, would negatively affect the ability to successfully make the older, less stable polymorph, that is the anhydrate of paroxetine hydrochloride. Dr. Brenner commented upon the opportunity for the likelihood of conversion of Genpharm's bulk material to crystalline paroxetine hydrochloride hemihydrate.
[31] Genpharm responded to the expert evidence tendered by GSK with parallel experts. In response to Dr. Niemczyk and Dr. Baldwin, it filed the affidavit of Dr. Durig, an analytical chemist with experience in infrared and Raman spectroscopy. He was asked to comment on the three tests described in the '060 patent as characterizing the paroxetine hydrochloride hemihydrate and their use at the date when the '060 patent was issued, that is July 30, 1991. As well, he commented on the technique of Raman microscopy and described it as a laboratory tool, rather than an analytical tool. He said it is less sensitive than infrared.
[32] Dr. Durig also reviewed the Drug Master File ("DMF") for paroxetine HCL anhydrate which he understood to be the raw material for the Genpharm products. He expressed the opinion that the Genpharm raw material, according to the charts in the DMF, is not paroxetine hydrochloride hemihydrate and further, that there is no evidence that the raw material contains paroxetine hydrochloride hemihydrate.
[33] Dr. Durig referred to testing of the Genpharm raw material according to all three methods described in the '060 patent, that is infrared spectroscopy, Differentiated Scanning Caliometry ("DSC") and x-ray diffraction. These results are included in Genpharm's DMF. He compared the results in the DMF with the data for the same tests according to the '060 patent and found differences between the Genpharm raw material and the material described in the '060 patent. He described the difference, in relation to the DSC, as "substantial", and in respect of the x-ray diffraction, as "huge". He concluded, on the basis of the differences noted when the methods of the '060 patent were employed on the Genpharm raw material, that the raw material being analysed was not the same as the material described in the patent.
[34] Dr. Durig also commented on the affidavits of Dr. Niemczyk and Dr. Baldwin. In the case of Dr. Niemczyk, he criticized his choice of analytical tool, that is the PLS type of infrared analysis. He said it was not suitable for micro-analysis, that is less than 1%, where there are large variants in the sample. He also criticized the conclusions of Dr. Niemczyk as to the amount of paroxetine hydrochloride hemihydrate present in the Genpharm bulk material, that is 0.18% "0.11%. Dr. Durig expressed other criticisms of Dr. Niemczyk's methodology and conclusions.
[35] Dr. Durig similarly criticized the choice of analysis made by Dr. Baldwin, that is the Raman microscopy. He says this method is not identified in the '060 patent as a means for identifying paroxetine hydrochloride hemihydrate. He also notes the difference in the results found by Dr. Baldwin in his analysis of the tablets, when some paroxetine hydrochloride hemihydrate was detected in the 10 mg non-commercial tablets, none in the 20 mg and 30 mg non-commercial tablets, and "some" in all of the 20 mg commercial tablets. Dr. Durig says these results are so different from the test results found by Dr. Niemczyk in his analysis of the bulk material that procedures of neither expert are reliable.
[36] Dr. Stynes, a chemist with expertise in organic chemistry and crystalline forms, addressed the issue of disappearing crystal forms and commented on GSK's evidence in that regard, particularly the affidavits of Dr. Jacewicz, Dr. Richardson and Dr. Brenner. He dismissed the theory of disappearing polymorphs saying that there was no scientific basis in theory or practice for that proposition. In particular, he commented on a prior publication by Dr. Jacewicz in which the author "debunked" the theory of disappearing polymorphs. Dr. Stynes also expressed the opinion that it is still possible to create the previously existing form, that is the anhydrate form of paroxetine hydrochloride and if it is not, that is due to the activities of GSK who have contaminated the environment with the hemihydrate, apparently without the possibility of containment.
[37] Dr. Story is a chemist and currently a consultant to the pharmaceutical industry. He prepared the Detailed Statement concerning the '060 patent that is attached to Genpharm's NOA. He expressed the opinion that claim 10 of the patent was anticipated by the prior art, specifically the '196 patent and the two Lund articles. He concluded that, for this reason, the '060 patent is invalid.
[38] Dr. Story also commented on the evidence of Dr. Byrn, Dr. Brenner, Dr. Jacewicz and Dr. Richardson relative to the '060 patent. He disagreed with their conclusions, especially the conclusion as to the "disappearance" of the anhydrate form.
ISSUES
1. Is the NOA deficient?
2. How should claim 10 of the '060 patent be construed?
3. Is Genpharm's allegation that the '060 patent is invalid, justified?
A) Obviousness
B) Anticipation
4. Is Genpharm's allegation that its product will not infringe the '060 patent, justified?
NATURE OF THIS PROCEEDING
[39] This application seeks to prohibit the issuance of a NOC to the Respondent for its product which contains crystalline paroxetine hydrochloride anyhydrate. The Applicants challenge the Respondent's NOA on the grounds that the allegations of invalidity and non-infringement of the '060 patent are not justified.
[40] A NOC grants marketing approval for drugs in Canada. It is issued by the Federal Government, indicating that all requirements have been met pursuant to the Food and Drug Regulations for the protection of public health and safety. The NOC Regulations authorize owners of existing patents for pharmaceutical products to file a "patent list" relative to those products for which they hold a NOC. The NOC Regulations refer to the person filing such a list as the "first person". In this case, the Applicants are the "first person".
[41] The framework of the NOC Regulations allows generic drug manufactures to rely on prior approval of related pharmaceutical products in applying for marketing approval of their generic form of the products. Manufacturers who produce the same drug may file application for a NOC that refers to and relies on the fact that prior approval has been granted for the brand- name version of the drug. Such a manufacturer is known to as the "second person" and that is the Respondent's status.
[42] The NOC Regulations prohibit the Minister of Health from issuing a NOC until all relevant product and use patents in the earlier approved medicine, as described in the patent list, have expired. Consequently, a second person must either wait until patent expiry before receiving a NOC or it may submit a NOA to the Minister with its new drug submission.
[43] The NOC Regulations require service of the NOA upon the first person. Section 5 sets out the grounds upon which an NOA is to be based. Briefly, the NOA must assert either that the first person is not the patentee, that the patent is expired or invalid, or that it would not be infringed if a NOC were issued.
[44] Following service of the NOA, the Minister may issue a NOC to the second person, unless the first person avails of its right, pursuant to section 6(1) of the NOC Regulations, to seek an order from the Federal Court of Canada prohibiting the Minister from issuing the NOC. Any such step must be taken by the first person within 45 days after receipt of the NOA and once such a proceeding is commenced, the issuance of a NOC to the second person is stayed for a maximum period of twenty-four months.
[45] Before addressing the specific aspects of this case, I will briefly address the jurisprudence applicable to the burden of proof and the question that must be answered in a NOC proceeding. It is well-established that the burden of proving that the second person's, that is, Genpharm's, allegations are not justified is on the person seeking the prohibition order, GSK. GSK must establish, on a balance of probabilities, that Genpharm's allegations are not justified. Genpharm must put its allegations "in play" through its NOA. However, once that has been done, GSK bears the burden of proving that such allegations are not justified, on a balance of probabilities: see Eli Lilly Co. v. Nu-Pharm Inc. (1996), 69 C.P.R. (3d) 1 (F.C.A.), Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) and SmithKline Beecham Pharma Inc. v. Apotex Inc., [2001] 4 F.C. 518 (T.D.), aff'd (2002), 291 N.R. 168 (F.C.A.).
[46] Second, the Court must determine whether Genpharm's allegations of invalidity and non-infringement are justified or not. In Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.), the Federal Court of Appeal commented upon the standard to be applied in this type of proceeding, at page 216:
..these proceedings are not actions for determining validity or infringement: rather they are proceedings to determine whether the Minister may issue a notice of compliance. That decision must turn on whether there are allegations by the generic company sufficiently substantiated to support a conclusion for administrative purposes (the issue of a notice of compliance) that the applicant's patent would not be infringed if the generic's product is put on the market....
SUFFICIENCY OF THE NOA
[47] Sections 5(1) and 5(3)(a) of the NOC Regulations provide as follows:
| 5. (1) Where a person files or has filed a submission for a notice of compliance in respect of a drug and compares that drug with, or makes reference to, another drug for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics and that other drug has been marketed in Canada pursuant to a notice of compliance issued to a first person and in respect of which a patent list has been submitted, the person shall, in the submission, with respect to each patent on the register in respect of the other drug, (a) state that the person accepts that the notice of compliance will not issue until the patent expires; or (b) allege that (I) the statement made by the first person pursuant to paragraph 4(2)(c) is false, (ii) the patent has expired, (iii) the patent is not valid, or (iv) 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 that person of the drug for which the submission for the notice of compliance is filed. ... |
|
5. (1) Lorsqu'une personne dépose ou a déposé une demande d'avis de conformité pour une drogue et la compare, ou fait référence, à une autre drogue pour en démontrer la bioéquivalence d'après les caractéristiques pharmaceutiques et, le cas échéant, les caractéristiques en matière de biodisponibilité, cette autre drogue ayant été commercialisée au Canada aux termes d'un avis de conformité délivré à la première personne et à l'égard de laquelle une liste de brevets a été soumise, elle doit inclure dans la demande, à l'égard de chaque brevet inscrit au registre qui se rapporte à cette autre drogue : a) soit une déclaration portant qu'elle accepte que l'avis de conformité ne sera pas délivré avant l'expiration du brevet; b) soit une allégation portant que, selon le cas : (I) la déclaration faite par la première personne aux termes de l'alinéa 4(2)c) est fausse, (ii) le brevet est expiré, (iii) le brevet n'est pas valide, (iv) aucune revendication pour le médicament en soi ni aucune revendication pour l'utilisation du médicament ne seraient contrefaites advenant l'utilisation, la fabrication, la construction ou la vente par elle de la drogue faisant l'objet de la demande d'avis de conformité. ... |
| 5(3) Where a person makes an allegation pursuant to paragraph (1)(b) or (1.1)(b) or subsection (2), the person shall (a) provide a detailed statement of the legal and factual basis for the allegation; ... |
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5(3) Lorsqu'une personne fait une allégation visée aux alinéas (1)b) ou (1.1)b) ou au paragraphe (2), elle doit : a) fournir un énoncé détaillé du droit et des faits sur lesquels elle se fonde; ... |
[48] Does Genpharm's NOA comply with this requirement of the NOC Regulations, by setting out the legal and factual basis for its allegations of invalidity and non-infringement?
[49] The Federal Court of Appeal in AB Hassle v. Canada (Minister of National Heath and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.), stated at paragraph 23:
The respondent suggests that the list of prior art in the detailed statement was not intended to be exhaustive, hence the presence of the word "including", so that the way was left open to add to that list in the section 6 proceeding. I am of the view, however, that paragraph 5(3)(a) does not contemplate such possibility. The intent appears to be that the entire factual basis be set forth in the statement rather than be revealed piecemeal when some need happens to arise in a section 6 proceeding. This Court has cautioned persons in the position of the respondent that they assume a risk that a particular allegation may not be in compliance with the Regulations and that the deficiency cannot be cured by the Court in a section 6 proceeding....
[50] The Applicants, relying on AB Hassle, supra, as well as Hoffman-La Roche Ltd. et al. v. Apotext Inc. et al. (1997), 72 C.P.R. (3d) 480 (F.C.T.D.), aff'd (1998), 82 C.P.R. (3d) 284 (F.C.A.) say that the Respondent failed to include certain issues in the NOA, that are now raised in legal argument. Consequently, GSK argues that Genpharm should not be permitted to allege that new pieces of prior art, not mentioned in its NOA, invalidate the '060 Patent. GSK also argues that the NOA is deficient in not mentioning the sections of the legislation upon which Genpharm intended to rely.
[51] The Respondent argues that the NOA, including the detailed statement pertaining to the claims in the '060 patent, is not insufficient in the sense that GSK is not left unaware of the real grounds of the Respondent's allegations that the patent would not be infringed and that the patent is invalid. The Respondent relies on the case of Merck Frosst Canada Inc. et al. v. Minister of Health et al. (2000), 8 C.P.R. (4th) 87 (F.C.T.D.), aff'd (2001), 12 C.P.R. (4th) 447 (F.C.A.). In that case Justice Muldoon stated as follows at paragraph 10:
In response to the applicants' charge, counsel for Alcon pointed to several allegations of fact in the NOA which, he alleged, could ground a claim of non-infringement, if assumed to be true. In particular, he pointed to the following allegations: that Alcon's product contains xanthan gum, that xanthan gum does not undergo a liquid-to-gel phase transition in situ, that any gelation does not occur due to the presence of ions and that the applicants have admitted the second alleged fact. As the applicants submit, these allegations are not fraught with precision. They do, however, suit the purposes of paragraph 5(1) (a) of the Regulations. This is because they support, assuming them to be true, Alcon's claim of non-infringement. They also define the issues or the arena in which the applicants would have to fight Alcon's claim of non-infringement if they were so to choose. The claim of non-infringement, in other words, is not a mere bald assertion.
[52] The Respondent argues that once an Applicant makes arguments in a NOC proceeding, the Respondent must be allowed to file responding evidence. The evidence which the Applicants maintain is new evidence that should not be permitted should therefore be seen as evidence filed in response to the Applicants' evidence and argument. This was recognized by Justice Muldoon in Merck Frosst, supra, at paragraph 11.
[53] After a review of the NOA, which includes a detailed statement written by Dr. Story, I conclude that the NOA sufficiently sets out the factual and legal basis for the Respondent's allegations.
[54] The Detailed Statement filed by the Respondent clearly raises allegations of invalidity on the grounds of anticipation and novelty, in relation to claim 10. The Detailed Statement refers to three pieces of prior art in relation to the allegation of anticipation. The Detailed Statement refers to the same three pieces of prior art and two other U.S. patents in relation to the allegation of obviousness.
[55] As well, the Detailed Statement raises the issue of non-infringement. Although there is no specific reference to the argument about the applicability of the maxim de minimus in assessing the question of infringement, in my opinion that argument is inherent in the general allegation of non-infringement. Indeed, the Applicants have argued that any infringement is prohibited and they are not caught by surprise by the refinement represented by the de minimus argument.
[56] The Applicants devoted much argument to the alleged failure of the Respondent to address section 27(1)(a) of the pre-1989 Act. The Applicants advanced submissions to deal with this statutory provision.
[57] The Detailed Statement clearly sets forth the section 27(1) grounds for alleged anticipation of claim 10 as follows:
To determine whether an invention is novel one must ask the following questions:
a) Was the invention known or used by another, before the date that the named inventors made their invention? The date is presumably, for lack of other evidence, the Priority Date, October 25, 1985.
b) Was the invention described in any other patent or publication printed in Canada or any other country more than two years before filing of the patent application that is before October 23, 1984?
c) Was the invention used publicly or sold in Canada more than two years before the date of application, that is before October 23, 1984?
With regard to the question (b) above, in order for an invention to be anticipated by a prior published document all its essential features must be disclosed in a single document.
[58] The fact that the Detailed Statement does not specifically mention "section 27(1)" is not fatal. This criticism about the sufficiency of the NOA fails.
[59] Accordingly, I find that the NOA, including the Detailed Statement, meets the test for sufficiency as described in the relevant jurisprudence. The affidavit evidence filed by the Respondent was responding to the evidence and argument filed by the Applicants. As held in Merck Frosst, supra, this must be permitted to allow for the adversarial process to function properly.
CONSTRUCTION OF CLAIM 10 OF THE '060 PATENT
[60] The first step in determining whether Genpharm's allegations of non-infringement and invalidity are justified is to construe the disputed claim of the '060 patent. As held by the Supreme Court of Canada in Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 and Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024, the patent claim is to be construed in a "purposive" way and the Court must look at the entire specification of the patent in order to understand the words as stated in a disputed claim.
[61] At page 1098 of Whirlpool, supra, Justice Binnie for the Supreme Court of Canada stated as follows:
I have already given my reasons for concluding that to the extent the appellants are arguing for a simple "dictionary" approach to construction of the '803 claims, it must be rejected. In Western Electric Co. v. Baldwin International Radio of Canada, [1934] S.C.R. 570, the Court cited earlier authority dealing with the word "conduit" as used in a patent claim. Duff C.J. at p. 572 accepted the proposition that "[y]ou are not to look into the dictionary to see what 'conduit' means, but you are to look at the specification in order to see the sense in which the patentees have used it". In Consolboard, supra, as mentioned, Dickson J. considered that the whole of the specification (including the disclosure and the claims) should be looked at "to ascertain the nature of the invention" (p. 520). To the same effect is the statement of Taschereau J. in Metalliflex Ltd. v. Rodi & Wienenberger Aktiengesellschaft, [1961] S.C.R. 117, at p. 122:
The claims, of course, must be construed with reference to the entire specifications, and the latter may therefore be considered in order to assist in apprehending and construing a claim, but the patentee may not be allowed to expand his monopoly specifically expressed in the claims "by borrowing this or that gloss from other parts of the specifications".
More recently, Hayhurst, supra, at p. 190, cautioned that "[t]erms must be read in context, and it is therefore unsafe in many instances to conclude that a term is plain and unambiguous without a careful review of the specification". In my view, it was perfectly permissible for the trial judge to look at the rest of the specification, including the drawing, to understand what was meant by the word "vane" in the claims, but not to enlarge or contract the scope of the claim as written and thus understood.
[62] The Applicants say that pursuant to Beecham Canada Ltd. v. Procter & Gamble Co. (1982), 61 C.P.R. (2d) 1 (F.C.A.), the meaning of claim 10 of the '060 patent is clear and unambiguous and therefore, there is no need to refer to the disclosure of the patent in order for this Court to construe the claim. In that case, Urie J.A. stated as follows at page 9:
From these general propositions it is next necessary to recall that the claims define the scope of the monopoly and may be read with the disclosure in the earlier part of the specification "in order to understand what the former says": see Noranda Mines Ltd. v. Minerals Separation North American Corp. (1949), 12 C.P.R. 99, [1950] S.C.R. 36 at p. 56, 9 Fox Pat. C. 165 [affirmed 15 C.P.R. 133, 12 Fox Pat. C. 123]. That this is the proper method to be used in construing claims is apparent from the following passage in the well-known case of Electric and Musicial Industries, Ltd. et al. v. Lissen, Ltd. et al. (1939), 56 R.P.C. 23, wherein Lord Russell of Killowen at pp. 41-2 had this to say:
But I know of no canon or principle which will justify one in departing from the unambiguous and grammatical meaning of a claim and narrowing or extending its scope by reading into it words which are not in it; or which will justify one in using stray phrases in the body of a Specification for the purpose of narrowing or widening the boundaries of the monopoly fixed by the plain words of a claim.
[63] The Applicants also rely on Whirlpool, supra, and argue that it supports their submission that claim 10 is unambiguous and the specification of the patent should not be looked at to "enlarge or contract the scope of the claim".
[64] The Respondent argues that claim 10 must be read in the context of the entire patent specification and the most recent Supreme Court of Canada jurisprudence supports this approach. If GSK's submission is accepted, the Respondent says that this would mean that claim 10 of the '060 patent would apply to any minute quantity of crystalline paroxetine hydrochloride hemihydrate found in anything, anywhere, at any time.
[65] The Respondent also argues that construing claim 10 by reference to the specification of the patent results in the conclusion that "crystalline paroxetine hydrochloride hemihydrate", as defined by claim 10, can only encompass such substance that can be found through the detection techniques that existed as of July 1991, the date the Canadian patent was granted. Otherwise, if the Applicants can rely on other testing techniques that are not mentioned in the patent specification, they are effectively relying on after-acquired knowledge to expand the scope of the patent.
[66] In construing the claim in issue, the Court must identify the essential elements of that claim. Again I refer to Whirlpool, supra, where Justice Binnie stated at paragraph 45:
The key to purposive construction is therefore the identification by the court, with the assistance of the skilled reader, of the particular words or phrases in the claims that describe what the inventor considered to be the "essential" elements of his invention...
[67] In the present case, that task is challenging since the claim contains only four words and reads as follows: "crystalline paroxetine hydrochloride hemihydrate". The determination of the essential elements of the claim is to be done on the basis of the common knowledge of the worker skilled in the art at the time the patent was issued, that is July 1991. The evidence provided by the experts for each side as persons skilled in the art is to be considered in construing the patent. From the expert evidence, I am satisfied that a worker skilled in the art in 1991 would have knowledge of Buxton's description of the hemihydrate and anhydrate forms of crystalline paroxetine hydrochloride and the benefits of the hemihydrate form over the anhydrate.
[68] In addition to identifying the essential elements of the claim, the current jurisprudence requires that the Court take a purposive approach. This means that regard can be had to the entirety of the patent, including the disclosure. Pages 2 and 3 of the patent describe its purpose in the following terms:
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 a stable and non-hygroscopic. It is characterized by an X-ray powder diffractogram as shown in the accompanying drawing (Fig. 1). A typical Nujol infra-red spectrum (Fig. 2) and DSC profile (prepared using a 2.26 mg sample in a sealed container (Fig. 3) is also shown. Under extreme dessication conditions the bound water may be removed to give an anhydrous form, but on rehydration it rapidly reforms the hemihydrate.
The patent also deals with methods of formulating the crystalline paroxetine hydrochloride hemihydrate but those claims are not in issue in the present proceeding.
[69] This description includes reference to three specific methods by which the patent is characterized. The Respondent argues in the present proceeding that these detection methods are essential to the correct construction of the patent and that they are the only detection means that should be used in construing the patent and in determining infringement. The Respondent relies on Free World Trust, supra, and Whirlpool, supra, as authority for the proposition that after acquired knowledge, such as detection methods not mentioned in the patent, cannot be used to expand the scope of the monopoly granted by the patent.
[70] This is a novel argument but is unsupported by any Canadian jurisprudence. In my opinion, the caveat expressed by the Court in Free World Trust, supra, and Whirlpool, supra, that there should be no reliance upon knowledge acquired after the date of issuance of a patent in construing patent claims, does not support the argument that only the detection methods named in a patent can be used for the purpose of construing the claims of a patent. In the absence of Canadian jurisprudence to support this argument, I decline to accept it. I am not prepared to find that the construction of claim 10 is defined by the detection methods named in the disclosure statement.
[71] In Free World Trust, supra, the Supreme Court of Canada described the nature of a patent in terms of an agreement between the state and the inventor. At page 1035, the Court said as follows:
Patent protection rests on the concept of a bargain between the inventor and the public. In return for disclosure of the invention to the public, the inventor acquires for a limited time the exclusive right to exploit it. It was ever thus. Even before the Statute of Monopolies (1623), the Crown rewarded an inventor with a limited monopoly in exchange for public disclosure of "a new invention and a new trade within the kingdom ... or if a man hath made a new discovery of any thing": Clothworkers of Ipswich Case (1653), Godb. 252, 78 E.R. 147, at p. 148, where the court went on to say that the effect of an unjustified monopoly was "to take away free-trade, which is the birthright of every subject". ...
[72] That monopoly, however, is not open-ended. The purposive approach to construction must refer to the actual words used, identify the essential elements of the invention and consider the purpose for which the patent was granted in the first place. According to the extracts from the disclosure quoted above, this compound of paroxetine hydrochloride hemihydrate in crystalline form displayed better handling qualities than the previously known form of paroxetine hydrochloride. The hemihydrate is described as being stable and non-hygroscopic. According to the literature cited by the parties, it is less hygroscopic than the anhydrate form.
[73] The interpretation of claim 10, on a purposive approach, cannot be so broadly interpreted as to overstep the stated purpose of the patent. In broad terms, the Applicants argue that the four words of claim 10 mean any amount of crystalline paroxetine hydrochloride hemihydrate found anywhere, in any quantity, for any reason. On the other hand, the Respondent argues that the words in claim 10 mean crystalline paroxetine hydrochloride hemihydrate found in a pharmaceutically acceptable product in sufficient quantity so as to improve its handling quality during manufacture. In my opinion, the Applicants are advocating an extremely literal approach, while the Respondent is presenting a functional approach. I do not accept the submissions made by the Applicants because that argument effectively overreaches the monopoly for which the patent was granted.
[74] The interpretation urged by the Applicants would lead to a result that is inimical to the stated purpose of the patent, that is to improve the handling properties of a manufactured drug product that includes paroxetine hydrochloride as the active ingredient. It is not sensible to interpret the claim as covering minuscule and minute amounts of crystalline paroxetine hydrochloride hemihydrate which, according to the expert evidence, is now extremely widespread since the discovery of the product in 1984, due to the prevalent use of the drug and the factors of seeding and conversion.
[75] The purpose of the invention noted in claim 10 is to use the noted compound as the active ingredient in medicine for the treatment of depression and anxiety, and to use this particular form of paroxetine hydrochloride, that is the hemihydrate as opposed to the anhydrate, because it makes manufacture easier. Claim 10 means crystalline paroxetine hydrochloride hemihydrate when it is found in a drug in sufficient quantity that it improves the handling properties of such drug during manufacture.
VALIDITY OF THE '060 PATENT
OBVIOUSNESS
[76] The Respondent argues that the patent is invalid on two grounds: obviousness and anticipation. The Applicants contest the allegation of lack of novelty, or obviousness, raised by the Respondent. The Respondent relies on five pieces of prior art in relation to its allegation of invalidity of the '060 patent on the ground of obviousness. The prior art consists of the '196 patent, the two Lund articles, the U.S. Patent 4,248,876 (the "U.S. '876 patent") and U.S. Patent 4,032,642 (the "U.S. '642 patent").
[77] The Applicants argue that the Respondent fails to meet the test for lack of novelty, as set out in Beloit, supra. They say that these articles and patents do not help the Respondent to show lack of novelty or obviousness of claim 10; the closest that the Respondent can show is paroxetine hydrochloride in solution.
[78] The Federal Court of Appeal in Tye-Sil Corp. et al. v. Diversified Products Corp. (1991), 35 C.P.R. (3d) 350 (F.C.A.), described the requirement that an invention not be obvious at page 365:
There is no specific section in the Patent Act relating to the requirement for inventiveness or inventive ingenuity, but it has been held and is no longer questioned that by use of the words "invention" and "inventor" throughout the Act, inventiveness or inventive ingenuity is required to obtain a valid patent. ...
[79] The test for obviousness is stated in Beloit, supra, at page 294, as follows:
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
[80] In assessing the allegation of obviousness, the Court must look at all the cited prior art, together. The Applicants argue relying on the evidence of Dr. Byrn and Dr. Brenner, that this prior art does not suggest the existence of the crystalline paroxetine hydrochloride hemihydrate. In his affidavit, Dr. Byrn says as follows:
To me, the development of the new hemihydrate polymorph would have been a completely unexpected result. Invention of a new polymorph is an uncertain science with no predictability. Further, extensive experimentation would not necessarily result in finding all the polymorphs or even multiple polymorphs. The preparation and identification of polymorphs is both complicated and fraught with uncertainty. It is impossible to predict in advance the results of crystallization experimentation. Even today, one cannot predict with certainty that multiple polymorphs of a given compound even exist. This was certainly at least as true in 1984.
Further, it was totally unpredictable that the hemihydrate form would be stable and non-hygroscopic and therefore exhibit better handling properties than that anhydrate form.
...
Genpharm's thesis and its reliance on the '876 Patent and the '642 Patent referred to on page 39 of its report, appear to be based on a presumption that if the hemihydrate form of a piperidine hydrochloride is known to exist, that all piperidine hydrochlorides would exist in a hemihydrate form. This is simply false. The ability to predict polymorphs or hemihydrate forms of any compound are usually unique to that compound.
[81] Dr. Brenner acknowledges that the '876 and '642 patents relate to piperidines, including a piperdine ring structure and that paroxetine is such a compound. However, he concludes that a person skilled in the art, prior to December 1984, would not be able to predict that a given polymorph would exist. Once a new polymorph appears and once seeding has occurred, the old process will yield the new product. A person skilled in the art would not consider any of the art cited, that is the '196, the two Lund articles, the '876 and the '642 patents in terms of obviousness.
[82] The Respondent, relying on Dr. Story and Dr. Stynes, takes a different approach. Dr. Story, in the Detailed Statement, makes the following statement:
Claim 10 is invalid through lack of inventive step in view of disclosure of preparation of crystalline hydrochloride hemihydrates of piperidines.
He then refers to the U.S. Patent '876 and U.S. Patent '642. In his affidavit, he says that the '196 patent fully discloses the hemihydrate, to a person skilled in the art who was knowledgeable about the preparation of a salt of paroxetine, that is paroxetine hydrochloride.
[83] As a further attack on the validity of claim 10 of the '060 patent, the Respondent argues that no patent is to be granted for a mere "discovery" alone where such discovery was something yet unseen, however, it was nonetheless, to a skilled worker with the cumulative state of chemical knowledge existing at the time of the invention, known that producing the hemihydrate was "worth a try". In support of this argument, Genpharm relies on Farbwerke Hoechst A/G v. Halocarbon (Ontario) Ltd., [1979] 2 SCR 929 at 944-946 and Fabwerke Hoechst A/G v. Halocarbon (Ont.) Ltd. (1983), 74 CPR (2d) 95 (F.C.T.D.) at 99, where the case was returned to Trial Division for determination on the issue of obviousness.
[84] The Applicants, on the other hand, say that claim 10 of the '060 patent is valid, and does not lack inventiveness due to the fact that it was discovered, empirically, through investigations that yielded a surprise development, namely, the discovery and detection of the hemihydrate form of crystalline paroxetine hemihydrate in the 23rd batch of Richardson's preparation in mid-December 1984. GSK discovered that this hemihydrate form had more commercially beneficial properties than the previously known anhydrate form. The Applicants argue that despite the fact that this discovery came as a surprise, the person who invented it is still entitled to a valid patent, provided the discovery is unobvious and useful.
[85] In my opinion, the Fabwerke, supra, case does not support the Respondent on this point. At pages 944-945, the Supreme Court of Canada stated as follows:
...In my view, the true doctrine was clearly stated by the Privy Council in Pope Appliance Corporation v. Spanish River Pulp and Paper Mills, [1929] A.C. 269, where Viscount Dunedin Said (at pp. 280-1):
... After all, what is invention? It is finding out something which has not been found out be other people. This Pope in the present patent did. He found out that the paper would so stick, and the practical problem was solved. The learned judges below say that all this might have been done by any one who experiment with "doctors" and air blasts already known. That is that some one else might have hit upon the invention. There are many instances in various branches of science of independent investigators making the same discovery. That does not prevent the one who first applies and gets a patent from having a good patent...
[86] In my opinion, the evidence of the state of the knowledge at the date of invention, that is the discovery of the hemihydrate form and the fact that it had beneficial properties for the manufacture of crystalline paroxetine hydrochloride, does not indicate that others skilled in the art would have known the way in which to create, notice and document the benefits of the hemihydrate form. It is true that it may have existed prior to the Richardson's 23rd batch, however, the fact remains that no one, up until that point, had detected and described such a compound. Therefore, the fact that it was discovered accidentally is of no consequence to the nature of the invention's ingenuity.
[87] As noted above, the test for obviousness is stringent. It requires the capable but non-imaginative skilled person to look at the common knowledge in the art at the date of the invention and immediately, without inventive ingenuity, reach the described invention. In my opinion, the cited art here does not meet that test. I conclude that the Respondent has not established the invalidity of the claim on the basis of obviousness.
ANTICIPATION
[88] Turning now to the issue of anticipation, the Respondent says that crystalline paroxetine hydrochloride hemihydrate is anticipated by the '196 patent and two articles co-authored by Lund and others, the first in 1979 and the second in 1982.
[89] The Applicants say that neither the '196 patent nor the Lund articles, considered separately, meet the legal test for anticipation set out by the Federal Court of Appeal in Beloit Canada Ltd. v. Valmet Oy (1986), 8 C.P.R. (3d) 289 (F.C.A.). The Applicants submit that the '196 patent and the Lund articles provide only general teaching about paroxetine hydrochloride, rather than teaching the crystalline form, or specifically the hemihydrate.
[90] The Respondent argues that the '196 patent and the two Lund articles disclose crystalline paroxetine hydrochloride hemihydrate. In this regard the Respondent relies on the report prepared by Dr. Story. That report is the detailed statement attached to the NOA.
[91] The Applicants also argue that the Respondent has not demonstrated that the cited prior art anticipates, pursuant to section 27(1)( b) of the Act. Only patents issued on or before October 23, 1984 or printed articles published before October 23, 1984 fall within section 27(1)(b). The '060 patent application was filed in the Canadian Patent Office on October 23, 1986.
[92] The Applicants rely on Beloit, supra, where the Court determined that the test for anticipation is met when the prior publication contains so clear a direction that a skilled person reading and following it would be led to the claimed invention in every case. The Applicants also rely on Reeves Brothers Inc. v. Toronto Quilting and Embroidery Ltd. (1978), 43 C.P.R. (2d) 145 (F.C.T.D.) and Consolboard v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 where the Courts identified several factors that must exist in order to support a finding of invalidity on the grounds of anticipation. The test for anticipation was defined by the Federal Court of Appeal in Beloit, supra, as follows at page 294:
It will be recalled that anticipation, or lack of novelty, asserts that the invention has been made known to the public prior to the relevant time. The inquiry is directed to the very invention in suit and not, as in the case of obviousness, to the state of the art and to common general knowledge. Also...anticipation must be found in a specific patent or other published document; it is not enough to pick bits and pieces from a variety of prior publications and to meld them together so as to come up with the claimed invention. One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention. Where, as here, the invention consists of a combination of several known elements, any publication which does not teach the combination of all the elements claimed cannot possibly be anticipatory.
This test for anticipation was cited with approval by the Supreme Court of Canada in Free World Trust, supra at para. 26.
[93] In the present case, does the prior art referred to by Genpharm contain so clear a direction that a skilled person reading and following it would be lead to the claimed invention in every case?
[94] The Applicants here argue that the three items of prior art relied on by the Respondent to support its claim of invalidity on the basis of anticipation, that is the '196 patent, a 1979 article by Lund J. et al, and a 1982 article by Lund J. et al, do not meet the test. These documents do not disclose solid paroxetine hydrochloride, a crystalline form of paroxetine HCL, or the hemihydrate or anhydrate crystalline forms. In particular, the '196 patent does not disclose paroxetine hydrochloride in any form and in this regard, the Applicants refer to the affidavit evidence of Dr. Byrn and Dr. Brenner and the cross-examination of Dr. Story.
[95] As for the two Lund articles, considered separately, the Applicants say that they do not disclose a solid form of paroxetine hydrochloride nor do they disclose information as to the formulating process that could have been followed. Again, the Applicants rely on the evidence of Dr. Byrn and Dr. Brenner and the cross-examination of Dr. Story, an expert for the Respondent.
[96] As noted above, the test for anticipation requires the Court to consider independently each item of prior art cited by the Respondent. In this case, the Respondent must establish that at least one of the articles of prior art would have contained "so clear a direction that a skilled person" would inevitably find the invention.
[97] Sections 27(1) and 61(1) of the Act are relevant to the issue of anticipation and provide:
| 27. (1) Subject to this section, any inventor or legal representative of an inventor of an invention that was(a) not known or used by any other person before he invented it, (b) not described in any patent or in any publication printed in Canada or in any other country more than two years before presentation of the petition hereunder mentioned, and (c) not in public use or on sale in Canada for more than two years prior to his application in Canada, may, on presentation to the Commissioner of a petition setting out the facts, in this Act termed the filing of the application, and on compliance with all other requirements of this Act, obtain a patent granting to him an exclusive property in the invention. |
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27. (1) Sous reserve des autres dispositions du present article, l'auteur de toute invention ou le representant legal de l'auteur d'une invention peut, sur presentation au commissaire d'une petition exposant les faits, appelee dans la presente loi le "depot de la demande", et en se conformant a toutes les autres prescriptions de la presente loi, obtenir un brevet qui lui accorde l'exclusive propriete d'une invention qui n'etait pas : a) connue ou utilisee par une autre personne avant que lui-meme l'ait faite; b) decrite dans un brevet ou dans une publication imprimee au Canada ou dans tout autre pays plus de deux ans avant la presentation de la petition ci-apres mentionnee; c) en usage public ou en vente au Canada plus de deux ans avant le depot de sa demande au Canada.
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| 61. (1) No patent or claim in a patent shall be declared invalid or void on the ground that, before the invention therein defined was made by the inventor by whom the patent was applied for, it had already been known or used by some other person, unless it is established that (a) that other person had, before the date of the application for the patent, disclosed or used the invention in such manner that it had become available to the public; (b) that other person had, before the issue of the patent, made an application for patent in Canada on which conflict proceedings should have been directed; or (c) that other person had at any time made an application in Canada which, by virtue of section 28, had the same force and effect as if it had been filed in Canada before the issue of the patent and on which conflict proceedings should properly have been directed had it been so filed.
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61. (1) Aucun brevet ou aucune revendication dans un brevet ne peut etre declare invalide ou nul pour la raison que l'invention qui y est decrite etait deja connue ou exploitee par une autre personne avant d'etre faite par l'inventeur qui en a demande le brevet, a moins qu'il ne soit etabli que, selon le cas : a) cette autre personne avait, avant la date de la demande du brevet, divulgue ou exploite l'invention de telle maniere qu'elle etait devenue accessible au public; b) cette autre personne avait, avant la delivrance du brevet, fait une demande pour obtenir au Canada un brevet qui aurait du donner lieu a des procedures en cas de conflit; c) cette autre personne avait a quelque epoque fait au Canada une demande ayant, en vertu de l'article 28, la meme force et le meme effet que si elle avait ete enregistree au Canada avant la delivrance du brevet et pour laquelle des procedures en cas de conflit auraient du etre regulierement prises si elle avait ete ainsi enregistree. |
[98] The Respondent argues that the English cases of Merrell Dow Pharmaceuticals Inc. v. H.N. Norton & Co. Ltd., [1996] R.P.C. 76 (HL) and Evans Medical Ltd's Patent, [1998] R.P.C. 517 (UK Pat. Crt.), support his position that as long at the public knows of the existence of a product prior to a patent claim, knowledge of its actual composition is immaterial, in order to satisfy the "available to the public" requirement of section 61(1)(a) of Canada's Act.
[99] The Applicants disagree with this proposition, stating that the requirements of section 27(1)(a) and 61(1)(a), mean that claim 10 must have been known or used before the application date of the patent in a manner that it had become "available to the public". The Applicants argue that the purported prior knowledge or use claimed by the Respondent was not "available to the public" prior to the application date of the patent.
[100] In my opinion, the Respondent's argument that claim 10 is anticipated because of section 27(1)(a) of the Act, that is that the invention was "known or used' by another person before the priority date, fails because such knowledge or use must have been "available to the public", pursuant to section 61(1)(a) of the Act. I do not accept the argument that as long as the public is aware of the existence of the end "product", then knowledge of the product's composition is immaterial. In the Merrell Dow, supra, case, the House of Lords based its reasoning on this point on a case of a patent for chicken soup concentrate, where a previously existing recipe in a cookbook disclosed the same process for producing the concentrate, just in non-technical terms. It was held that since this recipe which "inevitably" produced the substance that was the subject-matter of the concentrate patent, the patent was invalid, as being anticipated through knowledge already available to the public.
[101] The present case is different from the situation outlined in Merrell Dow, supra. While there was some literature about paroxetine hydrochloride available to the public prior to 1984, such literature did not, in my view, "inevitably" lead to the invention of crystalline paroxetine hydrochloride hemihydrate. Secondly, this authority comes from the English courts, and while useful to this Court, is by no means binding as precedent.
[102] Further, as pointed out in the Evans Medical, supra, case, the Court in Merrell Dow, in fact pointed out that the reasoning advocated by the Respondent on this point is an exception to the general rule that "in most cases knowledge of the products's chemical composition will be necessary to enable the public to work the invention" (para. 30 of Evans Medical).
[103] I turn now to anticipation based on section 27(1)(b) of the Act. In particular the '196 patent cited by Genpharm as prior art. Particulars of the alleged anticipation in relation to the '196 patent are set out in Dr. Story's affidavit at paragraphs 69 and 71 as follows:
As more fully explained in my Hemihydrate Report pages 18-20, the chemist would have known from his/her experience that when an acid salt of a basic drug was required for pharmaceutical formulation, the hydrochloride salt of paroxetine was generally preferred for therapeutic use because of its physiological acceptability. The chemist would have known from the Lund articles that the hydrochloride salt of paroxetine in solution had already been tested on humans.
...
The chemist would have known from the '196 Patent how to prepare paroxetine. The chemist would have been taught by Example 1 of the '196 Patent ('196 Example 1) how to prepare a salt of paroxetine, ie, paroxetine hydrochloride. As explained more fully in my Hemihydrate Report pages 10-13, and as proved by the 2001 Investigations, which I am informed are the subject of another affidavit in these proceedings, '196 Example 1, teaches a chemist how to prepare crystalline paroxetine hydrochloride hemihydrate. The Investigations followed the procedure described in '196 Example 1, lines 38 - 45. They showed that the solid form produced by the chemist following '196 Example 1 and using paroxetine base instead of methyl-paroxetine, would have been crystalline paroxetine hydrochloride hemihydrate.
[104] The 2001 investigations referred to above were performed by Dr. Ndzie in March 2001. Dr. Ndzie states in his affidavit that he essentially followed example 1 of the '196 patent, using paroxetine free base instead of n-methyl paroxetine free base. He describes his results as producing a solid form from the '196 process that was found to be consistent with paroxetine hydrochloride hemihydrate. Dr. Ndzie compared infrared spectra for the precipitates that he generated, with the infrared spectra for paroxetine hydrochloride hemihydrate as shown in figure 2 of the '060 patent and found that the spectra of the solids generated in his investigations were consistent with the infrared spectra for the '060 patent. He concluded that the precipitates that he had generated according to the '196 patent were crystalline paroxetine hydrochloride hemihydrate.
[105] Dr. Byrn and Dr. Brenner disputed the argument that '196 anticipated claim 10. Dr. Byrn commented, at paragraph 98 of his affidavit, that the Respondent used paroxetine instead of n-methyl paroxetine. He says that in the early 1980's, example 1when performed using paroxetine, produced anhydrous paroxetine hydrochloride. However, following the invention of the hemihydrate in 1984, Dr. Byrn opined that it would be impossible to reproduce the anhydrate form of paroxetine hydrochloride due to seeding.
[106] Dr. Brenner also commented on the investigation conducted by Dr. Ndzie. He commented on the replication of example 1 of the '196 patent and notes that Dr. Ndzie used paroxetine freebase instead of n-methyl paroxetine. He said that Dr. Ndzie "generally" followed example 1. Further, he said he was not surprised that Dr. Ndzie obtained the results he did, following the invention of hemihydrate and the effect of unintentional seeding. At paragraph 84 of his affidavit, he said as follows:
Certain experiments were done by Genpharm and ae set out in a document called "Investigations", which is dated March 29, 2001. These experiments were done after the new polymorph, namely crystalline paroxetine hydrochloride hemihydrate, appeared. Therefore, it is not surprising that Genpharm obtained the results it did, namely synthesis of the more stable newly appeared polymorph. This does not mean that this would have been the result had these experiments been conducted prior to December of 1984. Indeed, they cannot be reflective of the results which would have been obtained at that time, because crystalline paroxetine hydrochloride hemihydrate did not yet exist. In my experience, assuming that Genpharm's experiment would hae yielded a crystalline form of paroxetine hydrochloride if conducted prior to the first synthesis of crystalline paroxetine hydrochloride hemihydrate, these experiments likely would have yielded the hygroscopic anhydrate of paroxetine hydrochloride that GSK had worked with prior to December of 1984.
[107] Dr. Byrn and Dr. Brenner criticize both the attempt by the Respondent to replicate example 1 of the '196 patent and the use of paroxetine freebase, instead of n-methyl paroxetine, in that attempt. Dr. Story, in the Detailed Statement, comments on this use of paroxetine freebase in the following terms:
As to step 2 of claim 1, the precipitating out of the crystalline hemihydrate, Genpharm conducted five experiments, attached as Exhibit 1, to determine whether the method of example 1 of the '196 patent, for converting the base (N-methyl-paroxetine) to the hydrochloride form, would give crystalline paroxetine hydrochloride hemihydrate if paroxetine free base was used instead of N-methyl-paroxetine. This work was reported by Merck Generics Raw Material Support Group on March 29, 2001, and is titled "Attorney Client Privileged Work Product, Investigations" (referred hereafter as "Investigations"). This work consisted of five trials in which paroxetine free base was converted to its hydrochloride salt according to the method of example 1 of US patent 4,007,196 (column 6, lines 38-45). The paroxetine free base was first dissolved in diethyl ether and dried with anhydrous magnesium sulphate. The ether was then evaporated and an oily residue was obtained.
...
The white solid products from all five trials were dried and characterised by IR as paroxetine hydrochloride hemihydrate. The white solid was found to consist of needle-like crystals when examined by microscope. These trials showed that by using paroxetine free base in place of N-methyl-paroxetine, which was used in example 1 of US patent 4,007,196, the product would have been paroxetine hydrochloride hemihydrate (claim 10). To a person of ordinary skill in the art, the '196 patent discloses the use of paroxetine free base in place of N-methyl-paroxetine if the desired product is paroxetine hydrochloride. As has been shown in the above-described trials, the precipitated product obtained by following the patent is then crystalline paroxetine hydrochloride hemihydrate (claim 10).
...
The disclosures and claims of the'196 patent are therefore prior art which would disclose preparation of a solution of paroxetine hydrochloride and the ready crystallisation of the salts of the paroxetine family of compounds. This patent discloses claims 1, 2, 9 and 10 of the Hemihydrate Patent.
[108] In my opinion, this explanation does not respond to the question raised by the Applicants about the propriety of using paroxetine freebase, rather than n-methyl paroxetine. The remaining objection made by the Applicants relates to the alleged impossibility of making a hemihydrate-free product, following example 1 of '196, after 1984. The Applicants here rely on the evidence of Dr. Byrn and Dr. Brenner who speak about the effect of unintentional seeding, after 1984. The seeds would not allow anyone to make anything other than hemihydrate.
[109] I find that the Applicants' objection on this point is supported by the evidence. The reliability of Dr. Ndzie's investigations is put into question, due to the existence of the hemihydrate form in his laboratory on the date he conducted the investigations. This appears from the cross-examination on his affidavit:
BY MR. CREBER:
Q. I just want to get some dates right, because you actually have two investigations in your affidavit. You have one that was an attempt to do some investigations related to the 196 patent and you also did some stress studies; correct?
A. Yes.
Q. As I understand your reports, in particular Exhibit B and Exhibit F, the first report you did in time was Exhibit F. Is that correct? That was done on March 15th 2001; or at least commenced on that date? It is paragraph 13 of your affidavit.
A. Yes.
Q. Then it was two weeks later that you did the investigations that are Exhibit B to your affidavit?
A. Yes
Q. In Exhibit F, you did some studies on both paroxetine hydrochloride hemihydrate and paroxetine hydrochloride anhydrate?
A. Yes.
Q. Therefore, on March 29th 2001, when you replicated the experiments or carried out the investigations related to the 196 patent, you had previously had in the same lab some paroxetine hydrochloride hemihydrate?
A. Yes.
Q. Was that material still present in the lab on March 29th 2001?
A. Yes.
[110] There is a dispute among the witnesses for the parties as to the inevitability of seeding and its effect upon the reproduction of the "old" form of paroxetine hydrochloride. The Applicants rely on the theory of "disappearing polymorphs" to say that the production of anhydrate is impossible, due to the invention of the more stable hemihydrate. The Respondent, relying on Dr. Stynes and Dr. Story, argues that there is no basis for this theory.
[111] There is evidence submitted by the Respondent that the "old" anhydrate form can still be produced. In this regard, I refer to the experiments conducted by Dr. Godwin using the Great Britain patent application 8526407 (the " '407 application") the priority application for the '060 patent, and certain patents obtained by the Applicants themselves for the anhydrate form. These patents, referred to as the "Forms Patents", in Dr. Story's affidavit, were obtained by the Applicants subsequent to the issuance of the '060 patent. At paragraph 87 of his affidavit, Dr. Story makes the following blunt statement:
The myth that has been created by the Applicants regarding disappearing polymorphs, and the claimed inability to produce the 'old anhydrate' since the alleged invention of the hemihydrate, has been disproved by the '407 Application, the Goodwin Experiments, the Repeated Experiments and the Forms Patents.
[112] The materials referred to by Dr. Story in this paragraph are not prior art but are relied upon to answer the Applicants' argument that following the invention of hemihydrate in 1984, it was impossible to create the anhydrate form of paroxetine hydrochloride.
[113] In my opinion, the Respondent has adduced sufficient evidence to show that it is not impossible to reproduce the anhydrate form, to cast doubt on the position advanced by the Applicants in that regard.
[114] I turn now to the first Lund article. The Applicants acknowledge that this article discloses paroxetine hydrochloride in solution, but no more. The Respondent argues that it discloses the dissolution of a solid form and invites the inference that this solid is crystalline paroxetine hydrochloride hemihydrate.
[115] The parties advance the same arguments relative to the second Lund article.
[116] I am not persuaded on the basis of the text of the first Lund article that it meets the test in Beloit, supra. There is nothing more than the disclosure of a form of paroxetine hydrochloride in water. There is no teaching that the disclosed form was a solid, or that the paroxetine hydrochloride hemihydrate form existed.
[117] As for the second Lund article, I see no teaching there that discloses the dissolution of a solid form of paroxetine hydrochloride.
[118] In conclusion, I accept the arguments of the Applicants concerning the two Lund articles, as failing to meet the test for anticipation. Secondly, for the reasons outlined above, I am not satisfied that Dr. Ndzie's testing reliably demonstrated that the '196 patent anticipates claim 10 of the '060 patent.
INFRINGEMENT
[119] The remaining issue is infringement. The Applicants argue that any evidence of hemihydrate in the Respondent's product, regardless of intention or reasonable efforts to avoid it, constitutes infringement of the '060 patent. They refer to the evidence obtained from testing the Genpharm bulk material, commercial tablets from Australia and non-commercial Canadian tablets.
[120] The Applicants argue that the testing conducted by various experts of the Respondent's bulk material, non-commercial tablets and commercial tablets shows varying degrees of hemihydrate. A low level of hemihydrate of 0.18% was found in the bulk material. That material was tested by Dr. Niemcyzk, using a mathematical technique of PLS. Dr. Baldwin conducted Raman spectroscopy, a form of infrared testing, on the non-commercial tablets in strengths of 10 mg, 20 mg and 30 mg. He did not find any hemihydrate in the 20 and 30 tablets but did find some in the 10 mg tablets.
[121] As well, the 20 mg commercial tablets were tested by Dr. Baldwin. He found some hemihydrate, in varying percentages. According to the Applicants, Dr. Baldwin conducted a semi-quantitative test which shows the presence of hemihydrate. This contradicts the position asserted by the Respondent in its NOA where it said that its product did not contain any hemihydrate.
[122] The Applicants also refer to the evidence obtained in the cross-examination of the expert witnesses for the Respondent, including Dr. Durig. Dr. Durig was a parallel witness to Dr. Baldwin. In cross-examination, he admitted that the bulk material showed some low levels of hemihydrate. There was "some" hemihydrate in the non-commercial tablets and a larger amount in the commercial tablets.
[123] The Applicants criticized the testing technique used by Dr. Durig. They say that he used a technique that would make it difficult to find hemihydrate. As well, he used a technique that failed to solve the problem of extracting the excipients surrounding the paroxetine. He did not run his own spectra of the Genpharm product but reviewed and commented on IR spectra from the Genpharm drug master file. In contrast, the Applicant's expert, Dr. Baldwin followed a technique that allowed him to separate the excipients from the paroxetine and obtained a better result.
[124] The Applicants also take issue with the evidence of Dr. Stynes, a counterpart to Dr. Byrn. Dr. Stynes is an expert in solid state chemistry. The Applicants argue that Dr. Stynes, in cross-examination, resiled from an opinion expressed in his affidavit concerning the concept of "disappearing polymorphs". Dr. Stynes expressed the opinion, in his affidavit, that there is no foundation, in theory or in practice, for this proposition. According to the Applicants, in cross-examination, Dr. Stynes distinguished between widespread seeding and disappearing polymorphs.
[125] The Applicants say that Dr. Stynes found hemihydrate in the Respondent's product. The Applicants say that this is a manifestation of widespread seeding. In such circumstances, it is difficult to avoid conversion. The evidence, according to the Applicants, is that the Respondent's product contains some hemihydrate seeds. In theory, there will be more.
[126] The Respondent acknowledges that the testing carried out by the Applicants shows the presence of hemihydrate in its product. However, it argues that the Applicants, by employing testing methods not mentioned in the patent, are improperly attempting to extend the scope of the patent, contrary to the law. The Respondent notes that when its product is tested by the methods in the patent, no hemihydrate is found.
[127] Furthermore, the Respondent argues that there is no evidence that the hemihydrate as "discovered" in 1984, was free of seeds. If the current production of anhydrate is impossible due to seeding, then it is due to the action of the Applicants who have made the seeds available. In this regard, the Respondent refers to the evidence of Dr. Stynes.
[128] The Respondent also argues that a finding that its product infringes the Applicants' patent, when only minute traces are detected using methods not identified in the patent and when the Applicants themselves have contributed to the ubiquity of hemihydrate through widespread seeding is unfair. The Respondent's position, simply stated, is that its product, IPA solvate, does not infringe having regard to the proper construction of the patent, including the disclosure.
[129] The bulk material was tested by Dr. Niemczyk by the mathematical technique of PLS. He determined that the bulk material contained a detectable amount of hemihydrate that was sufficient to cause seeding. The amount detected was small, that is 0.18% " 0.08%. The PLS technique is not mentioned in the '060 patent.
[130] Dr. Baldwin used Raman spectroscopy to test the tablets, both the Australian commercial tablets and the Canadian non-commercial tablets. He tested the Australian tablets in dosage strengths of 20 mg; the Canadian non-commercial tablets in strengths of 10 mg, 20 mg and 30 mg. He detected a "fingerprint" for paroxetine hydrochloride taken at the done-waist of the commercial tablet between 1% and 20.5%. He found a fingerprint of between 3.48% and 48.39% that showed both paroxetine hydrochloride hemihydrate and paroxetine hydrochloride anhydrate. These "fingerprints" are not the measure of the quantity of the hemihydrate in the tablets.
[131] As for the non-commercial tablets, Dr. Baldwin detected a "fingerprint" of paroxetine hydrochloride at the done-waist of the 10 mg tablets. Between 0.86% and 17.59% of the points showed the paroxetine hydrochloride. Between 0.86% and 21.76% of the points for the 10 mg non-commercial tablets showed a fingerprint for both paroxetine hydrochloride hemihydrate and for paroxetine hydrochloride anhydrate. No paroxetine hydrochloride was detected in the 20 mg and 30 mg non-commercial tablets, although Dr. Baldwin expressed the opinion that "this result does not preclude some paroxetine hemihydrate existing in the tablets at points other than those tested".
[132] The technique employed by Dr. Baldwin, that is Raman spectroscopy, is not mentioned in the '060 patent. The Applicants chose to employ this technique and the PLS technique on their own. They did not conduct any testing of the Respondent's bulk material commercial tablets and non-commercial tablets according to the tests identified in the '060 patent. Those were the techniques used by the Respondent.
[133] Dr. Durig examined the DMF for the Respondent's material and concluded that the product did not infringe according to the detection methods in the '060 patent. He reviewed the IR spectra for Genpharm's raw material and compared it with the IR spectra for the '060 patent, and concluded that the Genpharm IR spectra did not show any hemihydrate. He also reviewed the DSC for the '060 patent and compared it with the DSC for Genpharm's raw material and concluded that they were different. Finally, he reviewed the x-ray diffractogram for figure 1 of the '060 patent and compared it with the x-ray diffractogram for the Genpharm raw material and concluded that a "huge" difference existed.
[134] He compared the IR spectra for the Canadian non-commercial tablets with the infrared spectra provided for the '060 patent figure 2 and concluded from his review of the spectra, that the Canadian tablets do not contain paroxetine hydrochloride hemihydrate. Further, he noted that the spectra for the Canadian tablets show bands that are not characteristic of the hemihydrate shown at figure 2 of the '060 patent.
[135] Dr. Durig criticized the technique used by the witness for the Applicants in their tests of the Respondent's raw material and the Canadian non-commercial tablets. He said that the PLS type of infrared analysis chosen by Dr. Niemczyk is not appropriate for micro-analysis, that is less than 1%, where there are "large variations in the contents of the sample". Among other things, he said that the infrared analysis generated by PLS cannot be compared with the infrared spectra shown as figure 2 to the '060 patent because "the PLS method does not generate a spectra as contemplated" by the '060 patent.
[136] Dr. Durig also criticizes the testing performed by Dr. Baldwin. He questions his choice of Raman spectroscopy which is not mentioned in the '060 patent. According to Dr. Durig, this type of spectroscopy is "rarely used to identify impurities in a compound as it is not sensitive enough for that purpose".
[137] Dr. Durig comments on the lack of explanation from Dr. Baldwin as to his preparation of the samples he tested and an apparent lack of steps taken to protect the tablets from contamination by heat or moisture in the environment. Dr. Durig says that these deficiencies cast doubt on the reliability of Dr. Baldwin's testing.
[138] As well, Dr. Durig addresses the discrepancies in the results obtained by Dr. Baldwin relative to the Canadian non-commercial tablets where no "fingerprints" of paroxetine hydrochloride hemihydrate were found in the 20 mg and 30 mg dosage strengths, but traces were found in the 10 mg strength. Dr. Durig refers to Dr. Niemczyk's evidence that he detected 0.18% " 0.11% in the bulk material. Dr. Durig says that the difference in those results are so great as to cast doubt on the reliability of the procedures used by both Dr. Baldwin and Dr. Niemczyk.
[139] Criticism of the techniques used by Dr. Niemczyk and Dr. Baldwin is not limited to the Respondent's witnesses. Dr. Brenner, an expert engaged on behalf of the Applicants, also undermines these tests and results. At paragraph 44 of his affidavit, Dr. Brenner made the following statement:
The fact that increasing amounts of crystalline paroxetine hydrochloride hemihydrate are observed in the Genpharm materials as one progresses through the process (in other words, there are relatively low amounts of crystalline paroxetine hydrochloride hemihydrate in the bulk, somewhat more in the non-commercial tablets, and even more in the commercial tablets said to be quantitatively and qualitatively the same as those that Genpharm will bring to market) is not unexpected and is consistent with all of the above.
[140] This statement is made without qualification and suggests that Dr. Brenner is relying on the cumulative effect of the testing conducted by Dr. Niemczyk and Dr. Baldwin. However, upon cross-examination in relation to this statement, Dr. Brenner starts importing limitations to this statement. He says that the results of these tests cannot be compared. At pages 80 and 82 of his cross-examination, the following answers were given:
We've talked about the 30 milligram tablets as the noncommercial tablets.
A. Okay.
Q. Now, I want to talk about the 20 milligram tablets.
A. Okay.
Q. Will you agree with me that Dr. Baldwin's data shows no hemihydrate in the 20 milligram tablets as compared to Dr. Niemczyk's data, which shows .18 percent hemihydrate in the raw material; is that correct?
Is that a correct statement of the data?
A. No, that's incorrect.
Q. What did I say wrong?
A. What you said wrong, is that you're bridging Dr. Niemczyk's and Dr. Baldwin's data, and attempting to say they're inconsistent. And you're making an inappropriate bridging, because you're bridging a lot that was not used in making the 20 or 30 milligram tablets.
You have, you know, that's an erroneous attempt to bridge those two events. It's scientifically not correct.
Q. Well, then why did you do it in Paragraph 44?
Why are you connecting the two?
You tell us in Paragraph 44, that there are increasing amounts of crystalline paroxetine hemihydrate going from the bulk to the noncommercial to the commercial.
And if it's not proper to make that comparison, then why did you do it?
A. Okay. I went through the arguments I used, you know, to make that bridging. Which is a little different than your bridging which is attempting to say, you know, Dr. Niemczyk's results are inconsistent with the 20 and the 30 milligram tablets.
Q. I'm saying Dr. Niemczyk's results are inconsistent with what you say the data shows.
A. Okay.
[141] A further line of inquiry was undertaken concerning the results obtained from Dr. Baldwin that showed hemihydrate only in the 10 mg dosage strength:
Can you tell me how much more there is in the noncommercial tablets than there is in the bulk?
A. Okay. One of the issues we discussed before we broke, was the fact that the - that only one potency of the noncommercial tablet showed hemihydrate.
Q. Yes.
A. The ten. And the 20 and the 30 didn't.
Q. Yes.
A. And in writing up 44, that was a dilemma to me because, you know, how could the bulk have and the tablets not.
Q. Yes.
A. I was trying to come up with some kind of explanation that - I can't explain 20 and 30 milligrams in light of the bulk and the ten milligrams.
If I had a bulk with zero hemihydrate, I could explain all the data based on my experience with low potency tablets versus high tablets.
But the fact that the bulk did have hemihydrate, there's no - the only explanation I could comp [sic] up with for 20 and 30 milligrams, was that different bulks were used to make the ten, 20 and the 30. Or maybe the same bulk was used to make the 20 and the 30, and a different bulk was used to make the ten.
That's the only explanation I could come up.
Q. If in fact they are the same bulks, then you have no explanation; is that correct?
A. If the same bulk was used to make all three, I have no explanation.
[142] Dr Brenner went on to suggest that the bulk from which the 10 mg tablets were made "might be representative" of the bulk analyzed by Dr. Niemczyk.
[143] The Applicants rely heavily on the closing comment made by Justice McGillis in Smithkline v. Apotex, supra, in finding, in that case, that the second person's product did not infringe. She said that if there was future conversion of the second person's anhydrate to hemihydrate "in whole or in part", the second person would face "very grave" consequences. Contrary to the submissions of the Applicants, this decision is not binding upon me, as this point was not addressed by the Federal Court of Appeal in its affirmation of Justice McGillis' decision.
[144] I note that the decision of Justice McGillis was based upon her finding that the evidence submitted raised "no more than a possibility" of infringement. Similarly, I have identified problems with the reliability of the evidence submitted here by the Applicants covering the testing that was conducted on their behalf, in an effort to show infringement by the Respondent. I am not questioning the choice of detection methods but rather, the credibility of the results obtained in light of the weaknesses revealed in the cross-examination of some of the Applicants' witnesses. I am not satisfied that an adequate explanation has been given for the discrepancies arising from the tests carried out by Dr. Baldwin. There is no evidence that Dr. Baldwin attempted to repeat his tests to rule out the possibility that his results were in error.
[145] As well, there is no adequate explanation for the difference in the results obtained by Dr. Niemczyk and Dr. Baldwin.
[146] It is curious that the refinements on the evidence of the analyses conducted by Dr. Niemczyk and Dr. Baldwin are raised by Dr. Brenner, an expert on behalf of the Applicants, only during cross-examination. According to his affidavit, Dr. Brenner had reviewed the affidavits of Dr. Niemczyk and Dr. Baldwin, in considering his response to the Respondent's allegation of non-infringement of claim 10 of the '060 patent. In my opinion, the failure of Dr. Brenner to refer to the limitations of the analyses of the bulk material and the tablets, both commercial and non-commercial, until his cross-examination, raises questions about the credibility of Dr. Brenner's opinion and the reliability of the tests.
[147] Dr. Brenner is an important witness for the Applicants. He is attempting, at a late stage, to reconcile the apparent differences in the GSK test results. Dr. Durig similarly questioned the discrepancies in the results and said the differences in the results of the tests put in question the reliability of those tests.
[148] The burden lies on the Applicants to show the Respondent's product infringes claim 10 of the patent. The Applicants rely on the testing of the bulk material and certain tablets. However, in my opinion, doubt has been case on the reliability of that testing. In those circumstances, I conclude that the Applicants have failed to establish infringement by the Respondent, on a balance of probabilities. It is unnecessary for me to address the other arguments raised by the Respondent concerning infringement.
CONCLUSION
[149] In conclusion, I find that the Applicants have shown that the allegations of invalidity made by the Respondent of claim 10 of the '060 patent, are not justified. However, the Applicants have failed to show, on the balance of probabilities, that the Respondent's allegation of non-infringement is not justified. Accordingly, the Applicants' application for an Order of Prohibition relating to the '060 patent is dismissed with costs to the Respondent.
[150] At the commencement of the hearing of this application, counsel for the Respondent asked for the opportunity to be heard with respect to costs relating to the other two patents, that is the '575 patent and the '637 patent, upon which the Applicants did not proceed. Accordingly, I reserve concerning the issue of those costs, unless the parties otherwise agree. In the absence of agreement, the Respondent may make submissions concerning the costs upon ten (10) days notice to the Applicants, thereafter the Applicants shall respond within ten (10) days and the Respondent shall file its reply within five (5) days of receipt of submissions from the Applicants.
(Sgd.) "Elizabeth Heneghan"
J.F.C.
VANCOUVER, BRITISH COLUMBIA
October 24, 2003
FEDERAL COURT OF CANADA
TRIAL DIVISION
NAMES OF COUNSEL AND SOLICITORS OF RECORD
COURT FILE NO.: T-1755-01
STYLE OF CAUSE: GLAXOSMITHKLINE INC. ET AL v. GENPHARM INC. ET AL
PLACE OF HEARING: Ottawa, Ontario
DATES OF HEARING: June 2 and 3, 2003
REASONS FOR ORDER AND ORDER: The Honourable Madam Justice Heneghan
DATED: Confidential Reasons for Order filed October 3, 2003 and public Reasons for Order filed October 24, 2003
APPEARANCES:
Anthony Creber
James E. Mills for the Applicants
Roger Hughes, Q.C.
Barbara Murchie for the Respondent, Genpharm Inc.
SOLICITORS OF RECORD:
Gowling Lafleur Henderson LLP
2600 -160 Elgin Street
Ottawa, Ontario K1P 1C3 for the Applicants
Sim, Hughes, Ashton & McKay
6th Floor, 330 University Ave.
Toronto, Ontario M5G 1R7 for the Respondent, Genpharm Inc.
[1] In Dr. Niemczyk's report, attached as Exhibit "B" to his affidavit, he writes in the "Results" section that 0.18"0.11% of crystalline paroxetine hydrochloride hemihydrate was found in Genpharm's bulk material.