Eli Lilly Canada Inc. v. Novopharm Limited

Eli Lilly Canada Inc. v. Novopharm Limited
Court (s) Database
Federal Court Decisions
Date
2008-03-19
Neutral citation
2009 FC 235
File numbers
T-1562-07
Notes
Digest
Decision Content
Date: 20090319
Docket: T-1562-07
Citation: 2009 FC 235
Ottawa, Ontario, March 19, 2009
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
ELI LILLY CANADA INC.
Applicant
and
NOVOPHARM LIMITED and
THE MINISTER OF HEALTH
Respondents
and
ELI LILLY AND COMPANY
Respondent/Patentee
REASONS FOR JUDGMENT
[1] This is a proceeding brought under the provisions of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended (NOC Regulations). The Applicant is seeking to prohibit the Minister of Health from issuing a Notice of Compliance to the Respondent Novopharm Limited for a generic version of the Applicant’s raloxifene hydrochloride medicine until the expiry of Canadian Letters Patent No. 2,250,191 (the ’191 patent).
[2] In a related proceeding heard at the same time (T-1561-07) the Applicant is seeking to prohibit the Minister from issuing a Notice of Compliance to Novopharm Limited in respect of its generic version of the same drug until the expiry of Canadian Patent 2,150,399 (the ’399 patent).
[3] A third proceeding between these parties respecting the same medicine, Court file No. T-1563-07 has been adjourned sine die by an Order of Prothonotary Tabib dated January 6, 2009 and is not of any relevance to this present proceeding. I am told that this proceeding relates to Canadian patent No. 2,101,356 which was the subject of my decision in another matter cited as 2008 FC 142 and is currently under appeal.
[4] For the Reasons that follow, I find that this application is dismissed with costs to Novopharm. These Reasons were released on a confidential basis to the parties on March 4, 2009. An opportunity was given to the parties to indicate whether any changes should be made to the public version now released. They indicated that no changes were required. I have made small spelling corrections at paragraphs 22 and 25.
THE PARTIES
[5] The Applicant Eli Lilly Canada Inc. (Lilly Canada) has received from the Minister of Health (Minister) a Notice of Compliance respecting a medicine containing raloxifene hydrochloride in 60 mg tablet form which medicine the Applicant markets in Canada under the brand name EVISTA under Drug Identification Number (DIN) 02239028. This medicine is used in the treatment and prevention of osteoporosis. The NOC Regulations refer to this party as the “first person”.
[6] The Respondent Novopharm Limited (Novopharm) sent a Notice of Allegation to Lilly Canada stating that it intends to market a generic version of such 60 mg tablets containing raloxifene hydrochloride and is seeking to obtain a Notice of Compliance from the Minister to do so by filing an Abbreviated New Drug Submission (ANDS) in which Lilly Canada’s product has been referenced. The NOC Regulations refer to this party as the “second person”.
[7] The Respondent Minister is charged with administering the NOC Regulations and issuing Notice of Compliance where appropriate.
[8] The Respondent Eli Lilly and Company Limited (Lilly US) is the patentee of the ’399 patent and has been made a party to these proceedings in accordance with section 6(4) of the NOC Regulations.
THE PATENT AT ISSUE
[9] At issue is Canadian Letters Patent No. 2,250,191 (the ’191 patent). The application for that patent was filed with the Canadian Patent Office under the provisions of the Patent Co-Operation Treaty (PCT) effective March 10, 1997. Thus the patent is governed by the provisions of the Patent Act, R.S.C. 1985, c. P-4, as they stand following amendments made after October 1, 1989. These provisions may be referred to as the new Patent Act.
[10] The application for the ’191 patent was laid open for public inspection on October 2, 1997. This becomes an important date in construing the patent. The application for the patent claims priority from applications filed in the United States Patent Office on March 26, 1996 and April 4, 1996. The ’191 patent will expire 20 years from the date of filing the application in Canada, that is, March 20, 2017. The ’191 patent was issued and granted on October 15, 2005. That date is not particularly important in these proceedings save to indicate that the patent has been issued and granted.
[11] In general, and subject to discussion later, the patent is directed to particle size of a compound known as raloxifene and its salts such as raloxifene hydrochloride (HCl). These compounds are directed, among other things, to the treatment of osteoporosis. Well chosen particle size is said to benefit both bioavailability and control of the manufacturing process.
THE EVIDENCE
[12] The evidence in this proceeding was provided, as is usual in applications before this Court, by way of affidavits, exhibits to affidavits, transcripts of cross-examination and exhibits to those cross-examinations. A Protective Order was granted in this proceeding on October 15, 2007. I have issued a further Order as to certain of the evidence that is to be maintained as confidential.
[13] The Applicant filed the affidavit evidence of the following witnesses:
· Rubina Luebke, a Regulatory Affairs Associate at the Applicant’s company. She provided information as to approval of the Applicant’s EVISTA product and exhibited certain product information submitted by the Applicant to Health Canada.
· Dr. Robert O. Williams III, professor of Pharmaceutics at the College of Pharmacy at the University of Texas. He claimed expertise in formulation development optimization and delivery of small organic compounds, peptides and proteins by a variety of technologies. He gave evidence directed to validity.
· Dianne Azzarello, pharmacist, experienced in the preparation and filing of new drug submissions. She formed her own company and deals in the filing of New Drug Submissions and Abbreviated New Drug Submissions with Health Canada. She provided comments as to portions of Novopharm’s Notice of Allegation and the Applicant’s New Drug Submission for its EVISTA product.
· Mark Feldstein, an American attorney admitted to practice before the US Patent and Trademark Office, employed by the Washington law firm Fennegan Henderson. That firm represents the Respondent Lilly US in litigation in the United States Courts against a company known as Teva. Teva is said to supply Novopharm with product samples of which were produced in the context of the US litigation. Feldstein gave evidence in this regard.
· Amy Ganden, Assistant Laboratory Manager of Particle Technology Labs Ltd. (PTL). This lab analysed samples provided by Feldstein. She provided a report as to the results.
· Dr. David E. Bugay, Managing Director of Aptuit Consulting. He specializes in the analysis of materials in the solid state, particularly pharmaceutical drug substances and dosage forms. He gave evidence on the infringement issue in his affidavit in chief. He provided a further affidavit in reply addressing matters raised by Novopharm’s witness Biggs on the infringement issue.
[14] Each of Williams, Ganden and Bugay were cross-examined.
[15] The Respondent Novopharm filed affidavits from the following witnesses:
· A. Louise McLean, a law clerk in the offices of Novopharm’s solicitors. She provided a copy of the Notice of Allegation and copies of the documents referenced in that Notice. She provided a second affidavit respecting the delivery of certain Teva samples.
· Dr. (Professor) Isador Kanfer, a professor at the Faculty of Rhodes University, South Africa, author and editor of texts related to drugs, all of which include the areas of bioavailability, dissolution and absorption of drugs. He addressed issues of validity.
· Mali Kadosh Project Manager of Teva, Israel. He testified as to the dispatch of certain samples to Ms. McLean aforesaid.
· Shirley Zhao, analytical chemist at Dalton Pharma Services. She testified as to the analysis of certain samples provided by Ms. McLean aforesaid.
· Dr. (Professor) Simon Biggs, professor of particle science and engineering at the University of Leeds, U.K. His work includes particle size measurement, characterization and analysis. He gave evidence as to the infringement issue. Biggs provided a further affidavit in sur-reply.
[16] Each of Kanfer, Zhao and Biggs was cross-examined.
[17] The Minister did not file any evidence and did not participate actively in this proceeding. Lilly US did not participate actively in this proceeding. I assume that its interests were looked after by Lilly Canada.
[18] I endorse the sentiments expressed by Harrington J. of this Court in Lundbeck Canada Inc. v. Canada (Minister of Health), 2009 FC 146 at paragraph 74, where he wrote that we really do not have evidence by way of actual persons or even “talking heads” in proceedings such as this: we simply have words on pieces of paper. Other than in the most exceptional cases, a Court is not in a position to come to any conclusions as to whether certain witnesses were evasive, or acted as advocates or acted in other ways urged by counsel so as to encourage the Court to take a dim view as to demeanour of any other party’s witnesses. I add my voice to those crying in the wilderness for improvements in the process.
ISSUES
[19] There are two issues raised in this proceeding: validity and infringement of the ’191 patent. As to validity there are two grounds raised:
a. Obviousness; and
b. Lack of utility
[20] A third ground raised by Novopharm as to validity was double patenting. Its counsel advised at the hearing that this ground was dropped.
[21] Novopharm has also alleged that its product will not infringe the claims of the ’191 patent. On this issue certain evidence has been provided that will remain confidential. It was conceded by all Counsel at the hearing that Lilly Canada’s product came within the parameters of at least some of the claims of the ’191 patent. It was also conceded by all Counsel at the hearing that claim 7, which deals with a particular use of the product, is not of concern in these proceedings.
BURDEN OF PROOF
[22] The issue as to who bears the burden of proof in NOC proceedings, where the issue of validity of a patent or infringement of a patent is an issue that I had throught had been put to rest. Nonetheless the parties in such proceedings continue to argue the point. It seems that my recent decision in Brystol-Myers Squibb Canada Co. v. Apotex Inc., 2009 FC 137 has given fresh ammunition to those continually wishing to stir the pot in this regard. Let me state emphatically that I did not intend in Brystol-Myers to say or apply any burden different than I had stated in previous decisions.
[23] To be perfectly clear, when I comes to the burden as to invalidity I canvassed the law, in particular recent Federal Court of Appeal decisions, in Pfizer Canada Inc. v. Canada (Minister of Health), (20008), 69 C.P.R. (4th) 191, 2008 FC 11 and concluded at paragraph 32:
32 I do not view the reasoning of the two panels of the Federal Court of Appeal to be in substantial disagreement. Justice Mosley of this Court reconciled these decisions in his Reasons in Pfizer Canada Inc. v. Apotex Inc., [2007] F.C.J. No. 1271, 2007 FC 971 at paragraphs 44 to 51. What is required, when issues of validity of a patent are raised:
1. The second person, in its Notice of Allegation may raise one or more grounds for alleging invalidity;
2. The first person may in its Notice of Application filed with the Court join issue on any one or more of those grounds;
3. The second person may lead evidence in the Court proceeding to support the grounds upon which issue has been joined;
4. The first person may, at its peril, rely simply upon the presumption of validity afforded by the Patent Act or, more prudently, adduce its own evidence as to the grounds of invalidity put in issue.
5. The Court will weigh the evidence; if the first person relies only on the presumption, the Court will nonetheless weigh the strength of the evidence led by the second person. If that evidence is weak or irrelevant the presumption will prevail. If both parties lead evidence, the Court will weigh all the evidence and determine the matter on the usual civil balance.
6. If the evidence weighed in step 5 is evenly balanced (a rare event), the Applicant (first person) will have failed to prove that the allegation of invalidity is not justified and will not be entitled to the Order of prohibition that it seeks.
[24] I stated the matter more succinctly in Pfizer Canada Inc. v. Canada (Minister of Health), 2008 FC 500 at paragraph 12:
12 Here the only issue is validity. Pharmascience has raised three arguments in that respect. Each of Pfizer and Pharmascience have led evidence and made submissions as to those matters. At the end of the day, I must decide the matter on the balance of probabilities on the evidence that I have and the law as it presently stands. If, on the evidence, I find that the matter is evenly balanced, I must conclude that Pfizer has not demonstrated that Pharmascience's allegation is not justified.
[25] The above cases state correctly in my view, the state of the law as to the burden in NOC proceedings as to invalidity.
[26] Turning to infringement the law is well settled that where a generic has alleged non-infringement, the statements that it makes in that regard in its Notice of Allegation are presumed to be true. The Applicant (first party) bears the burden of proof, on the balance of probabilities, to satisfy the Court that the allegations of non-infringement are not justified; merely to raise the possibility of infringement is insufficient. The Federal Court of Appeal made these points quite clearly in its recent decision in Novopharm Limited v. Pfizer Canada Inc. (2005), 42 C.P.R. (4th) 97, 2005 FCA 270 at paragraphs 19, 20 and 24:
19 In Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1995), 64 C.P.R. (3d) 450 (F.C.A.), Hugessen J.A. addressed the evidentiary burden placed on a generic under the Regulations. He adopted the reasons of the trial judge who described this burden as follows:
... the grounds that the patentee has for challenging the generic's notice of allegation should be advanced in the originating notice of motion filed pursuant to s. 6(1) of the Regulations. ... The generic may then be informed as to what vexes the patentee and why a prohibition order barring entry should be issued. Initially, i.e., before the Minister, the generic has raised the issue of non-infringement. At this stage, before the court, the generic now has the opportunity to file evidence supporting its detailed statement. In essence, this is the evidential burden on a respondent.
(see Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1995), 60 C.P.R. (3d) 328 at 339-40 (F.C.T.D.), per Wetston J.)
20 In my view, this statement remains good law. Where, as here, the NOA is found to be adequate, the legal burden remains squarely on Pfizer to prove, on a balance of probabilities, that the allegations in the NOA are unjustified. Novopharm has no evidential burden to support the allegations in its NOA and detailed statement (see AB Hassle 2 at paragraph 35). Therefore, Novopharm need only file evidence supporting its detailed statement to counter evidence, if any, submitted by Pfizer in the course of the prohibition proceedings.
…
24 For whatever reason, Pfizer relies solely on Dr. Munson's speculations in this proceeding. The law is well settled that in order to satisfy the legal burden placed on it under section 6 proceedings, it is insufficient for Pfizer to merely raise the possibility of infringement (see Glaxo Group Ltd. v. Canada (Minister of National Health and Welfare) (1998), 80 C.P.R. (3d) 424 (F.C.T.D.) at paragraph 9). In relying solely on Dr. Munson's evidence, Pfizer has failed to satisfy its legal burden of proving that Novopharm's NOA is not justified.
CONSTRUCTION OF THE CLAIMS
[27] The Supreme Court of Canada has instructed that the Court must first construe the claims at issue before moving to consideration of issues such as validity and infringement of those claims, the purpose in doing so is to identify what it is in the claims that the inventor considered to be essential. This construction is to be conducted in a purposive manner so as to endeavour to be fair to both the patentee and the public of the decision of Binnie J. for the Court in Whirlpool Inc. v. Camco Inc., [2000] 2 S.C.R. 1067:
43 The first step in a patent suit is therefore to construe the claims. Claims construction is antecedent to consideration of both validity and infringement issues.
…
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.
[28] The relevant date for construction of the ’191 patent, being a “new” Patent Act patent, is the date of its publication, October 2, 1997. Construction is to be undertaken by the Court, viewing the claims as of that date through the eyes of a person skilled in the art, assisted if needed by expert evidence as to the meaning of special terms and the knowledge that such a person would bring to bear. Regard is to be given to the whole of the disclosure of the patent and the claims. Again, there are many authorities stating such propositions. One is the Federal Court of Appeal, Sharlow JA. in Novopharm Ltd. v. Janssen-Ortho Inc., 2007 FCA 217 at paragraph 4. (It is to be noted that the patent there was an old Act patent therefore the date for consideration was different.):
4 In any case in which the validity or infringement of a patent claim is in issue, it is necessary to construe the claim: Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 at paragraph 43. The relevant date for the construction of the 080 patent is the date of its issuance, June 23, 1992. The patent must be understood as being addressed to a person skilled in the art, taking into consideration the knowledge that such a person is expected to possess on that date. The construction of a patent claim is a task for the Court and must be based on the whole of the disclosure and the claim, assisted by expert evidence as to the meaning of certain terms and the knowledge that a person skilled in the art is expected to possess on the relevant date.
PERSON SKILLED IN THE ART
[29] The parties spent little time in argument defining the person or persons who represented those skilled in the art to whom the ’191 patent was addressed. Novopharm, through its witness Dr. Kanfer at paragraph 18 of his affidavit stated that such a person was:
“…a person with a degree in science, focused on the physical sciences and preferably in the field of pharmacy, with at least several years experience in pharmaceutical formulation in an academic or industry setting.”
[30] Applicant’s counsel in oral argument accepted that definition. I accept it as well.
THE ’191 PATENT-DESCRIPTION
[31] The ’191 patent begins at page 1 in stating that the invention is directed to a particle size range of a class of pharmaceutical compounds known as benzothiophenes, which size range enhances bioavailability and allows control during manufacturing:
This invention relates to the fields of pharmaceutical and organic chemistry and provides a benzothiophene compound, in particulate form, which is useful for the treatment of various medical indications, including osteoporosis and lipid lowering. More particularly, the benzothiophene is of a particle size range which allows enhanced bioavailability and control during the manufacturing process.
[32] Later on page 1 and over to page 2, the patent restricts the discussion to one benzothiophene, raloxifene, useful in treating osteoporosis, but states that raloxifene has solubility problems that affect both its bioavailability and manufacturing:
The advancement of raloxifene has been somewhat hampered by its physical characteristics, both as to bioavailability and in manufacturing. For example, it is generally insoluble, and this can adversely affect the bioavailability. Clearly, any improvement in the physical characteristics of raloxifene, would potentially offer a more beneficial therapy and enhanced manufacturing capability.
[33] At page 2 a general description of the invention of the patent is given. Raloxifene is depicted in its chemical diagrammatic form:
This invention provides a compound of formula I
and pharmaceutically acceptable salts and solvates thereof, characterized in that the compound in its particulate form, said particles having a mean particle size of less than about 25 microns, and preferably between about 5 and about 20 microns.
[34] Thus the invention is stated to be the provision of raloxifene in particulate size less than about 25 microns and preferably between about 5 and about 20 microns. Further statements are made as to at least 90% of the particles being less than 50 microns, preferably less than 35 microns. It is pointed out that this raloxifene can be formulated with pharmaceutical compounds for treatment of osteoporosis and other conditions.
[35] The benefits of bringing the particle sizes within the specified narrow range are said to be in respect of dissolution, bioavailability and improved manufacturing capabilities. At pages 2 and 3 the patent says:
It has now been found that by processing compounds of formula I, to bring their particle sizes within a specified narrow range, pharmaceutical compositions may be prepared which exhibit for their active ingredient both a consistent in vitro dissolution profile and in vivo bioavailability. In addition to bringing about these desired dissolution/bioavailability characteristics, the control of particle size to narrow range has also resulted in significant improvements in manufacturing capabilities.
[36] The particle size and range is again set out at page 3:
The mean particle size of compounds of formula I, as set out by the invention, is less than about 25 microns, preferably between about 5 and about 20 microns. Further, the invention encompasses formula I compounds with at least 90% of the particles having a particle size of less than about 50 microns, preferably less than about 35 microns. More preferably, the mean particle size range is between about 5 and about 20 microns, with at least 90% of the particles having a size of less than about 35 microns.
[37] Pages 4 and 5 of the patent discuss conventional wisdom, that poor solubility can be improved by reducing particle size but reduced particle size gives rise to manufacturing problems such as heating of the ingredients and caking in the machinery. There must be a compromise between the two:
Often, compounds which have poor solubility profiles can have their bioavailability enhanced by increasing the surface area of the formulated particles. The surface area generally increases per unit volume as the particle size decreases. Various techniques for grinding or milling a drug substance are well known in the art…very finely divided material presents difficulties and cost in capsule filling or tablet preparation, because the material will not flow, but becomes caked in finishing machinery. Such finishing difficulties generate non-homogeneity in the final product, which is not acceptable for a drug substance. Additionally, the milling process physically generates heat and pressure on the material, such conditions lead to chemical degradation of the compound, thus such milling techniques are usually kept to a minimum.
Therefore, there is always dynamic between the properties which yield the maximum bioavailability (particle surface area) are the practical limits of manufacture. The point of compromise which marks this “best solution” is unique to each situation and unique as to its determination.
[38] At page 5 the patent tells the reader that, in the raw state, raloxifene has a broad size distribution with a volume diameter of about 110-200 microns. That size is measured by a Horiba LA900 device. At page 7 the particle size measurement technique is more fully described in respect of raloxifene whose particle size has been reduced:
The particle size of the reduced raloxifene HCl was measured as follows. The laser scattering particle sizes distribution analysis was effected on a small sample of the reduced material which is suspended in approximately 180 ml of dispersant solution. Sample is added to the dispersant until an acceptable level of laser light obscuration achieved at which point the particle sizes distribution is measured. Prior to the sample suspension the dispersant solution was prepared by adding 20 drops of Coulter 1A dispersant to a saturated aqueous solution of raloxifene HCl. The dispersant solution was filtered through a 0.2 micron microporous membrane filter to provide the necessary particle-free suspending dispersant.
Within five minutes of the preparation of the dispersion, triplicate particle size measurements were performed.
[39] At page 8 there begins a discussion as to the rate of dissolution of raloxifene and its absorption into the gastrointestinal tract, thus the effect upon bioavailability:
Given the low solubility, the rate at which the dosage form dissolves in the gastrointestinal tract can potentially impact the rate and extent of absorption of the active compound. Two related physical properties of the bulk drug which can alter the dissolution rate of the dosage form are particle size and surface area.
[40] There follows at pages 9 to 12 a description of in vitro and in vivo testing of raloxifene of various particle sizes obtained through recrystallization (said to be a control batch), micronizing and two forms of milling. As stated at page 9:
To ascertain the effect of particle size/surface area of raloxifene HCl on in vitro dissolution, lots with varying particle size distribution were obtained via recrystallization and further modified through various milling technologies.
[41] Tables showing the surface area and particle size and rate of dissolution of the samples are provided as Tabs 1, 2 and 3. At page 11, the patent postulates that the surface area of the particles as measured by a certain technique does not predict its dissolution:
It is postulated that the surface area as measured by nitrogen adsorption for the various types of milled raloxifene does not predict the effective surface area accessible to the dissolution medium.
[42] At page 12 the patent states that, as a result, a decision was made to pursue particle size as a parameter for drug performance:
Based upon these findings, the decision was made to pursue particle size distribution as a control parameter to ensure consistent performance of the drug product with regards to release of the drug component.
[43] A study was conducted, as set out in pages 12 to 15 of the patent, where it states that monkeys were fed from two batches of raloxifene, one with a mean particle size of 48.1 microns (Lot 5A) and one with a mean particle size of 9.0 microns (Lot 5B).
[44] At page 15 the patent states that particle size is critical and that the study confirms that in vitro testing can confirm the in vivo absorption:
This data is further evidence of the critical nature of the particle sizes distribution on its impact on bioavailability. The study also confirms the discriminating ability of the in vitro dissolution method and its relationship to in vivo absorption. Once again, the differences observed in the in vitro dissolution profiles translated into in vivo absorption differences.
[45] Based on this work, certain particle size specifications were established and work was undertaken to justify the range established. At page 15 and at page 17 the reader was told that bulk lots of raloxifene were milled and formulated into tablets which were then studied:
Based upon the above work and physical property data generated, a particle size specification was established. The invention provides that the mean particle sizes, as determined by laser light diffraction, should be less than about 25 microns. In addition, 90% of the particles by volume should be under 50 microns, which allows for characterization of the distribution. Preferably, the size between about 5 and about 20 microns, and 90% of the particles have a size of less than about 35 microns. To justify this range, bulk lots were produced by pin milling and samples of the available extremes were manufactures into formulated tablets and in vitro dissolution testing. In one study, six bulk lots of raloxifene hydrochloride (ca. 1 kg) were received and manufactured into formulated 60 mg raloxifene HCl tablets representative of the tablets being utilized in Phase III clinical testing.
…
Another similar study was performed with 7 different particle size distribution of bulk drug, with each again being formulated into 60 mg tablets.
[46] Data respecting these studies is presented, including tables. A conclusion is set out at page 18. This conclusion, the Applicant argues, is the inventive step of the patent: namely, that within the stated particle size range, the in vivo absorption/bioavailability characteristics are surprisingly consistent:
Given the relationship shown between in vitro dissolution and in vivo absorption, it follows that the particle size distribution range claimed in this patent will provide surprisingly consistent in vivo absorption/bioavailability characteristics.
[47] There follows at pages 18 and 19 a discussion as to particle sizes and manufacturing. Too fine a particle size results in poor flow and poor control of the process. Thus the particle size constraints of the patent result in more amenable processing. At page 19:
Too fine a granulation distribution can lead to poor granulation flow and poor control of individual table weight during the compression step. Thus the narrow particle size constraints previously mentioned have also resulted in making the process more amenable to automation by reducing the variations in water required during the granulation step and producing dry milled granules of the appropriate distribution to prevent the rejection of tablets during compression due to unacceptable tablet weight.
[48] From page 19 to page 36 various formulas for manufacturing tablets containing raloxifene are provided together with the added ingredients (excipients). The patent ends with 8 claims.
THE CLAIMS OF THE ’191 PATENT
[49] The 8 claims of the ’191 patent are as follows:
1. A compound of formula I
and pharmaceutically acceptable salts thereof, characterized in that
the compound is in particulate form, said particles having a mean
particle size of less than 25 microns, at least 90% of said
particles have a size of less than 50 microns.
2. The compound of claim 1 wherein said particles have a
mean particle size of between 5 and 20 microns.
3. The compound of claim 1 or 2 wherein at least 90% of said
particles have a size of less than 35 microns.
4. A pharmaceutical composition comprising or formulated
using a compound according to any one of claim 1, 2 or 3, or a
pharmaceutically acceptable salt thereof, in combination with one or
more pharmaceutically acceptable carrier, diluent or excipient.
5. A compound of any one of claim 1, 2 or 3 which is non-
solvated crystalline 6-hydroxy-2- (4-hydroxy-phenyl) -3-[4-(2-
piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride.
6. The use of a compound of claim 5 or a pharmaceutically
acceptable salt thereof for inhibiting osteoporosis in a person in
need thereof.
7. The use of a compound of claim 5 or a pharmaceutically
acceptable salt thereof for preventing breast cancer in a woman in
need thereof.
8. A pharmaceutical composition comprising or formulated
using the compound of claim 5 and one or more pharmaceutically
acceptable carrier, diluent or excipient.
[50] The compound as depicted in Formula I of claim 1 is the same as that as written in claim 5 and can be simply stated as raloxifene. The pharmaceutically acceptable salt can be described for the purposes of this proceeding as hydrochloride. Thus the claims can be more briefly be rewritten as:
a. Raloxifene hydrochloride in particulate form having a mean particle size of less than 25 microns, at least 90% of which particles have a size less than 50 microns.
b. As per claim 1 with a mean particle size of between 5 and 20 microns.
c. As per claims 1 and 2 in which 90% of the particle size is less than 35 microns.
d. A pharmaceutical composition using the compound of any of claims 1, 2 or 3.
e. A compound of any of claims 1, 2 or 3 comprising raloxifene hydrochloride.
f. Use of the claim 5 compound to inhibit osteoporosis.
g. (Not at issue). Use of the compound in preventing breast cancer.
h. A pharmaceutical composition of claim 5.
[51] The parties are agreed as to the essential elements of the claims and that for purposes of these proceedings, we need only to look at claims 1, 2 and 3. The essential elements of those claims are:
Claim 1: -Raloxifene hydrochloride
i. in particulate form
ii. such particles having a mean particle size of less than 25 microns, at least 90% of which particles have a size of less than 50 microns
Claim 2: The compound of claim 1 where the mean particle size is between 5 and 20 microns.
Claim 3: The compound of claim 1 and 2 wherein at least 90% of the particles have a size of less than 35 microns.
INFRINGEMENT
[52] It is agreed that, for purposes of considering Novopharm’s allegations as to non-infringement, only claim 1 needs to be considered. It is assumed that Novopharm will be formulating its raloxifene hydrochloride into pharmaceutical compositions for use directed to osteoporosis. The only issue is as to the particle size of the raloxifene hydrochloride. The broadest parameters for particle size are those found in claim 1 which requires the particle size to be less than about 25 microns, and at least 90% of the particles to have a size of less than 50 microns.
[53] Novopharm’s Notice of Allegations at pages 36 and 37 addresses its non-infringement allegation and states, inter alia:
Novopharm’s Tablets will not infringe any of the claims of the ’191 Patent. Novopharm’s Tablets will not contain raloxifene or a pharmaceutically acceptable salt thereof with a particle sizes of less than about 25 microns, and at least 90% of the particles having a size of less than 50 microns, as claimed and required in the ’191 Patent. The particles of raloxifene that Novopharm will use and incorporate into its Novopharm Tablets will have a mean particle size significantly greater than 25 microns, and the raloxifene (or a pharmaceutically acceptable salt thereof) particles used by Novopharm will not have at least 90% of the particles with a sizes of less than 50 microns.
[54] Novopharm relies on two things in support of its allegation. First, the information that it supplied to Health Canada in support of its own Abbrieviated New Drug Submission (ANDS). Second it relied on testing conducted by an outside laboratory known as Dalton and its employee Ms. Zhao who provided an affidavit and was cross-examined. Comments were provided thereon by Novopharm’s expert Dr. Biggs.
[55] The Applicant relied on testing of samples provided by Teva, an organization related to Novopharm, in the context of certain United States litigation. It was agreed by the parties that the results of such testing may be introduced into this proceeding as if the samples had been provided by Novopharm in the context of these proceedings. The testing was conducted by an outside laboratory, PTL, under the supervision of Ms. Ganden, who provided an affidavit and was cross-examined in these proceedings. The Applicant’s expert, Dr. Bugay, commented on this testing and the results.
[56] Each of Drs. Biggs and Bugay also provided comments as to the testing done by the other parties and conclusions that might be drawn as to the evidence of each other.
[57] I have no reason to doubt that all of the testing was performed as reported and that the results were accurately reported. I also have no reason to be critical of the evidence given by any of Ganden, Zhao, Biggs or Bugay or their independence or credibility.
[58] The critical issue is directed to how the particle size of the raloxifene is measured. I accept the evidence of Dr. Bugay in cross-examination found at pages 40 to 42 of the transcript, pages 1569 to 1570 of the Record, that in measuring particle size one must be careful not to cause the particles to dissolve, to be sure that the particles are not agglomerated, and to ensure that particles are not fractured during the course of measurement. I also accept the evidence of Zhao at paragraph 6 of her affidavit that bubbles in the sample may cause problems with measurement.
[59] The information given in the ‘191 patent as to how measurements of particle size were made is set out at pages 5 and 7:
The efficiency of the milling is checked by sampling using a Horiba LA900 Laser Scattering Particle Size Distribution Analyzer and the final particle size is checked in a similar manner.
…
The particle size of the reduced raloxifene HCl was measured as follows. The laser scattering particle size distribution analysis was effected on a small sample of the reduced material which is suspended in approximately 180 ml of dispersant solution. Sample is added to the dispersant until an acceptable level of laser light obscuration achieved at which point the particle size distribution is measured. Prior to the sample suspension the dispersant solution was prepared by adding 20 drops of Coulter 1A dispersant to a saturated aqueous solution of raloxifene HCl. The dispersant solution was filtered through a 0.2 micron microporous membrane filter to provide the necessary particle-free suspending dispersant.
Within five minutes of the preparation of the dispersion, triplicate particle size measurements were performed. Triplicate measurements are effected as a minimum check a) to produce more reliable measurements and b) to check the equivalent sampling of the suspended material has been reproducible i.e., the suspension has not settled.
The results were automatically recorded and displayed graphically to give a frequency percentage vs. undersize and a cumulative percentage vs. undersize characteristics curves for the sample.
[60] It appears that in the testing provided to the Court a device known as a Malvern Mastersizer was used rather than a Horiba LA900 but Counsel for the parties were agreed that these devices may be considered as equivalent for the purposes of this proceeding.
[61] Two matters should be noted in respect of the procedure for particle size measurement set out in the ’191 patent. First, a dispersant identified as Coulter 1A was used. Second, the procedure is silent as to agglomeration and if any were noticed, how, if at all, it is to be dealt with. It is noted that measurements are taken within five minutes of treating the sample with the dispersant.
[62] I accept the evidence of the Applicant’s expert Dr. Bugay as to the manner in which a sample would be prepared and handled as set out in paragraph 27 of his affidavit:
27. It is important to note that all particle size measurements are designed to measure representative samples of the individual fine particles of the material of interest as opposed to clumps of those particles such as aggregates or agglomerates. Consequently, regardless of the measuring apparatus used, the accuracy of a particle size measurement is highly dependent on ensuring that the measured material is in fine particles and not clumps. This is achieved through proper sample preparation and handling which include: (1) de-aggregating the original sample such that the individual fine particles are being measured; (2) selecting the medium to suspe