Eli Lilly Canada Inc. v. Novopharm Limited

Eli Lilly Canada Inc. v. Novopharm Limited
Court (s) Database
Federal Court Decisions
Date
2009-03-23
Neutral citation
2009 FC 301
File numbers
T-1561-07
Decision Content
Date: 20090323
Docket: T-1561-07
Citation: 2009 FC 301
Ottawa, Ontario, March 23, 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 AND 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. 2,158,399 (the ’399 patent).
[2] In a related proceeding heard at the same time (T-1562-07) 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 2,250,191 (the ’191 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 informed that this proceeding relates to Canadian Patent No. 2,101,356 which was the subject of my decision cited as 2008 FC 142 and is currently under appeal.
[4] For the reasons that follow, I find that the application is dismissed with costs payable by the Applicant to Novopharm.
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. This party is referred to as the “first person” under the NOC Regulations.
[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. This party is referred to as the “second person” under the NOC Regulations.
[7] The Respondent Minister is charged with administering the NOC Regulations and issuing a Notice of Compliance where appropriate.
[8] The Respondent Eli Lilly and Company (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. 2,158,399 (the ’399 patent). The application for that patent was filed with the Canadian Patent Office on September 15, 1995, 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 October 1, 1989. These provisions may be referred to as the new Patent Act.
[10] The application for the ’399 patent was laid open for public inspection on March 20, 1996. 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 September 19, 1994 and April 26, 1995. The ’399 patent will expire 20 years from the date of filing the application in Canada, that is, on September 15, 2015. The ’399 patent was issued and granted on March 20, 2001. That date is not particularly important in these proceedings save to indicate that the patent has been issued and granted.
[11] At page 1 the patent states in the opening paragraph that it is directed to what is described as a novel, non-solvated crystalline form of a class of chemicals described by a written formula:
This invention is directed to a novel pharmaceutical product. More particularly, the invention is directed to a novel, non-solvated, crystalline form of a 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy) benzoyl] benzo[b]thiophene.
[12] In particular the patent deals with a particular member of that class identified by the formula set out in the second paragraph of page 1:
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride
[13] Fortunately, the patent at the same page, as well as the parties, have used the name raloxifene hydrochloride or raloxifene HCl in place of the written formula. I will also do so.
THE EVIDENCE
[14] 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 however, given that the issues are reduced from those set out in the Notice of Allegation, only the issue of validity is now before the Court thus no part of the evidence as to that issue remains confidential.
[15] The Applicant filed affidavits from the following witnesses :
· Dr. Joel Bernstein, a full professor of chemistry at Ben-Gurion University of Negev, Beer Sheva, Israel. He claims expertise in the areas of polymorphism, crystallography and organic solid state chemistry.
· Nancy Gallagher, a law clerk employed by the Applicant’s law firm. She provided copies of the Notice of Allegation, the patent at issue, certain prior art references and the Notice of Application. None of these documents are contested.
· Dr. Leonard J. Chyall, a research investigator, currently a principal in the consulting division of Aptuit, an independent research laboratory. He attempted to reproduce Examples 16 and 18 of United States Patent No. 4,418,068 (the ’068 patent) and reviewed the work of Dr. Ferrari, one of Novopharm’s witnesses. This affidavit was filed in reply.
[16] Drs. Bernstein and Chyall were cross-examined. Their claim to be experts was not contested; however Novopharm took issue with the claimed area of expertise of Dr. Bernstein.
[17] The Respondent Novopharm filed affidavits from the following witnesses:
· Dr. Massimo Ferrari, director of Research and Development at Erregierre S.P.A. an Italian pharmaceutical manufacturer. He presented evidence as to his synthesis of a chemical compound said to be in accordance with Examples 16 and 18 of the ’068 patent. This evidence, according to Novopharm’s Counsel’s submission at the hearing, was presented as factual evidence. Dr. Ferrari also presented evidence in sur-reply to Dr. Chyall which was submitted as expert evidence. His sur-reply affidavit also contained evidence as to further experiments conducted by Dr. Ferrari which evidence was struck out by an Order of the Prothonotary. However remaining in evidence is some discussion as to those experiments by Dr. Chyall and Dr. Stradi in their cross-examinations.
· Dr. (Professor) Riccardo Stradi, a professor in the Department of Organic Chemistry, Faculty of Pharmacy at the University of Milan, Italy. He conducted X-Ray Powder Diffraction (XRPD) analysis on samples of material produced by Dr. Ferrari. This evidence was tendered as expert evidence.
· Dr. (Professor) Thomas T. Tidwell, a professor emeritus at the University of Toronto, Department of Chemistry. He claimed expertise in the area of synthesis, purification analysis and structural indentification of organic compounds. He reviewed the patent at issue, the prior art including the ’068 patent and a Jones article and the evidence of Dr. Bernstein.
· A. Louise McLean, a law clerk in Novopharm’s law firm’s offices. She provided copies of the Notice of Allegation and the prior art referred to therein. This evidence is not contested.
[18] Each of Drs. Ferrari, Stradi and Tidwell were cross-examined.
[19] The Minister did not file any evidence nor 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.
[20] 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.
MOTION TO STRIKE
[21] At the outset of the hearing Lilly Canada brought a motion requesting that the Court strike out the first affidavit of Dr. Massimo Ferrari, the sur-reply affidavit of Dr. Ferrari including Exhibits A and B, and the affidavit of Mr. Riccardo Stradi including Exhibits A, B, C and D, all of which had been submitted by Novopharm together with the transcripts of the cross-examinations of Drs.Ferrari and Stradi and, as Applicant’s counsel agreed at the hearing, also including the Applicant’s own evidence comprising the affidavit of Dr. Chyall and the transcript of his cross-examination. I did not grant the motion, all this evidence shall remain in the Record, subject to weight.
[22] The basis for the motion was twofold:
a. The cross-examination of Dr. Ferrari showed that Novopharm and a related company Teva, were clients of the company that he works for, Erregierre, thus, it was argued, he was likely to be biased; and
b. The experiments performed by Dr. Ferrari were irrelevant and in any event the results were questionable.
[23] I rejected both grounds of argument. First, as to the allegation of bias. This allegation is based on answers to two questions put to Dr. Ferrari on cross-examination as follows:
Q. The company that you work for, Erregierre, they are the supplier of Novopharm in Canada, is that correct?
A. I do not deal with the commercial activity of the company and therefore I cannot give you a definite answer. But as far as I know, Novopharm is one of our clients.
Q. And Teva as well?
A. Yes.
[24] This exchange cannot be said to give rise to any question of bias sufficient to exclude Dr. Ferrari’s evidence. At best it shows that he works for a company that has, among its clients, Novopharm and Teva. We don’t know if the product at issue is involved, whether the clients are major or trivial, nor whether the clients were in any position to exert influence over Dr. Ferrari or the experiments performed by him. The Court will exercise caution in looking at Dr. Ferrari’s evidence, but, without more, that caution would be the same as looking at the evidence of any outside expert that the Court knows full well is being compensated by the party tendering his or her evidence.
[25] Secondly as to the soundness of the evidence, that is a matter to be considered in the context of all the evidence in the proceeding. I was not persuaded that the experiments conducted were so unsound as to be removed from the Record. The evidence shall remain, subject to weight.
ISSUES
[26] The issues in this proceeding relate to validity of the claims of the ’399 patent having regard to:
a. Anticipation
b. Obviousness
The Respondent Novopharm had also raised a mixed question of validity and infringement on the basis of what is known as the Gillette Defence. At the outset of the hearing Novopharm’s Counsel advised that this matter was withdrawn.
BURDEN OF PROOF
[27] The issue as to who bears the burden of proof in NOC proceedings, as to validity of a patent or infringement of a patent, is an issue that I had thought 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.
[28] To be perfectly clear, when it 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.
[29] 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.
[30] The above cases state correctly, in my view, the law as to the burden in NOC proceedings as to invalidity.
[31] 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 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 PATENT-GENERALLY
[32] Before embarking upon a consideration as to validity of the patent, the Court is required to construe the patent and its claims. Construction of this patent, which is a “new” Patent Act patent, is done as of the date of its publication, March 20, 1996 through the eyes of a person skilled in the art, taking into consideration the knowledge that such a person would possess as of that date. Construction must take into consideration the whole of the patent, its disclosure and claims. Expert assistance, where needed, may be provided to provide the meaning of certain terms and the knowledge that a person skilled in the art would have had as of that date. As Sharlow JA. for the Federal Court of Appeal panel said in Novopharm Limited v. Janssen-Ortho Inc. (2007), 59 C.P.R. (4th) 116, 2007 FCA 217 wrote at paragraph 4:
Construction of Claim 4
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.
[33] She was speaking of an “old” Patent Act patent which is to be construed as of the date of its grant but otherwise her words are equally appropriate to a “new” Patent Act patent.
PERSON SKILLED IN THE ART
[34] The parties did not devote any significant attention either in written or oral argument to defining the notional person or persons skilled in the art to whom the patent is said to be directed.
[35] Assistance can be de derived from the first page of the ’399 patent itself which states that the invention is directed to a novel pharmaceutical product namely a non-solvated crystal of a compound known as raloxifene which is produced by the use of a hitherto unknown synthetic process. It says:
This invention is directed to a novel pharmaceutical product. More particularly, the invention is directed to a novel, non-solvated, crystalline form of a 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy) benzoyl] benzo[b]thiophene.
…
In accordance with the present invention, the Applicants have now discovered that a novel, non-solvated crystalline form of raloxifene can be produced, free of, for example, chlorobenzene and aluminium contaminants, by the use of a hitherto unknown synthetic process.
[36] Thus one would expect that a person skilled in the art would be familiar with crystalline forms of pharmaceutical products such as raloxifene and known processes as to how they might be produced.
[37] The Applicant’s expert, Dr. Bernstein defined a person skilled in the art in paragraph 27 of his Affidavit as follows:
As the subject matter of the claims in question relates to a new crystal form of raloxifene hydrochloride, I would consider a person skilled in the art to be a person with at least a Bachelor of Science in chemistry and at least a couple years experience working or conducting research in the drug development process with some exposure to polymorphic compounds and their characterization.
[38] Novopharm’s expert, Dr. Tidwell described a person skilled in the art in paragraph 11 of his Affidavit:
11. In my opinion, the 399 Patent is directed to a person with a degree in organic chemistry and a minimum of several years experience in the synthesis of organic chemical compounds, including drug molecules. This person would be familiar with, and experience in, the area of synthesis, crystallization and purification of drug molecules and would understand the role of XRPD in distinguishing crystalline structures from one another. I will refer to such a person as the “person skilled in the art”.
[39] There is little difference between the two experts except that Dr. Tidwell also states that the person skilled in the art should have some reasonable knowledge as to synthesis of organic compounds. I agree. It must be recognized that the person skilled in the art, must know not only about crystal forms but also how to produce them.
CONSTRUCTION OF THE ’399 PATENT-SPECIFICALLY
[40] The introductory paragraph of the ’399 patent at page 1 states that the invention is directed to what it describes as a novel pharmaceutical product, a non-solvated, crystalline form of raloxifene:
This invention is directed to a novel pharmaceutical product. More particularly, the invention is directed to a novel, non-solvated, crystalline form of a 2-aryl-6-hydroxy-3[4-(2-aminoethoxy) benzoyl] benzo[b]thiophene.
[41] Following this paragraph, at page 1 of the ’399 patent is an acknowledgement that raloxifene hydrochloride is a previously known pharmaceutical agent. Reference is made to U.S. Patent No. 4,418,068 (the ’068 patent) and what has become known in these proceedings as the “Jones Article” in this regard. The ’068 patent and Jones Article are important in discussing the validity questions. The ’399 patent states that the compound is difficult to purify, it contains solvent and other contamination and has an unpleasant odor:
U.S. Patent No. 4,418,068 describes 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride, known as raloxifene hydrochloride, which has shown particular promise as a pharmaceutically-active agent. Unfortunately, this compound has proven extremely difficult to purify. Particular problems have arisen due to solvent contamination. For instance, the process described in the Journal of Medicinal Chemistry, 27(8), 1057-1066 (1984), for synthesizing raloxifene suffered from the serious shortcoming that it produced a solvated compound contaminated with chlorobenzene, a known cancinogen. Further, other processes described in the literature utilized a classical aluminum chloride-catalyzed Friedel-Crafts acylation. The product of these processes contain aluminum contaminants and various thioester by-products, which are difficult to remove. Also the product of these literature processes has an unpleasant residual thiol or sulphide odor.
[42] Next, and still at page 1, the “discovery” made by the named inventors is concisely described: it is that a novel, non-solvated crystalline form of raloxifene can be produced free of certain contaminants, by what is described as a hitherto unknown process:
In accordance with the present invention, the Applicants have now discovered that a novel, non-solvated crystalline form of raloxifene can be produced, free of, for example, chlorobenzene and aluminum contaminants, by the use of a hitherto unknown synthetic process.
[43] The “new process” is described at pages 6 and 7 of the patent in saying that “…(t)he new process eliminates the use of aluminum and the odorous mercaptans and sulfides”.
[44] The novel crystal form of the alleged invention is identified beginning at the bottom of page 1 of the ’399 patent over the middle of page 3, by two columns of numbers produced by the X-Ray diffraction (XRPD) technique (Table 1). The experts are agreed that such numbers called a “pattern” represent a “fingerprint” which is unique to this particular crystal form of raloxifene hydrochloride. For instance another crystal form of that compound will have a different “fingerprint” or “pattern”. I will not reproduce the column of numbers here.
[45] What is important to note is that the patent does not ascribe any particular reason why the so-called novel crystal form is any better than any other form, no particular advantage as to the form is described no unique feature is given. It seems just to have that form and nothing more.
[46] At pages 3 and 4 of the patent, the reader is told that this new form should be at least 95% raloxifene hydrochloride, preferably 98% or 99%, and “substantially free” from chlorobenzene, aluminium salts and organoaluminum impurities, and substantially odor free. Each of these characteristics are defined as to what constitutes “substantially free” in respect of each unwanted impurity. It says:
Preferably, in the new, non-solvated form of raloxifene hydrochloride, the amount of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride present in the crystalline material is at least 95% by weight (w/w), preferably at least 98%, more preferably at least 99%. More particularly, this preferred form is substantially free from chlorobenzene. Further, this preferred form is also substantially free from aluminum salts or organoaluminum impurities. Also, this preferred form is substantially odor free.
The term “substantially free from chlorobenzene”, as used herein in reference to the non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride, represents a compound containing less than 5% of chlorobenzene calculated on a weight basis (w/w). Preferably, the amount of chlorobenzene is less than 2%, more preferably less than 1%. Most preferably, the amount of chlorobenzene in the non-solvated crystalline material is less than 0.6%.
The term “substantially free from aluminum salts or organoaluminum impurities”, as used herein in reference to the non-solvated crystalline describes 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride, represents a crystalline compound containing less than 5% of aluminum salts or organoaluminum impurities calculated on a weight basis (w/w). Representative aluminum salts include, but are not limited to, aluminum hydroxide, aluminum oxides, and hydrated forms thereof. Representative organoaluminum impurities include, but are not limited to, aluminum alkoxides, aluminum(III) complexed to the formula I or IV compounds, and thioaluminates. Preferably, the amount of aluminum salts or organoaluminum impurities is less than 2%, more preferably less than 1%.
The term “substantially odor free”, as used herein in reference to the non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride, represents a compound containing less than 3% of mercaptan or sulfide impurities. Preferably, the amount of mercaptan or sulfide impurities is less than 2%, more preferably less than 1%. Representative mercaptan or sulfide impurities include, but are not limited to, C1-C6 alkylthiols and methyl C1-C6 alkyl sulfides.
[47] The resulting product, the patent says at page 4 is more pure than the material produced by previous processes described in the literature and that it is free of aluminum and chlorinated aliphatic solvents and aromatic solvents and therefore is preferred for use in making pharmaceutical compositions:
The non-solvated crystalline material is more pure than the material produced by the processes described in the literature. The present material is free from aluminum impurities, as well as, chlorinated aliphatic hydrocarbon solvents and aromatic solvents. The non-solvated crystalline form is particularly preferred for use in the manufacture of pharmaceutical compositions.
[48] The statement that the product is free of aluminum and chlorinated aliphatic hydrocarbon solvents and aromatic solvents is at odds with the statements at pages 3 and 4 of the patent to the effect that the product is only “substantially free” of such impurities, with less than 2% and preferably less than 1% of such impurities. It is as if someone at a later time in drafting the patent had decided to hedge their bets. The new process is said not to use aluminum or the aromatic solvents at all. Why they should be said to appear in the final product is a question that the patent does not answer.
[49] Beginning at the bottom of page 4 of the ’399 patent to the end of the description at page 25 is a description of the process to make this purer form of the product and several Examples in that regard are given. It is important to note that at pages 15 and 16 there is provided Table 2 which are two columns of numbers comprising an X-ray Diffraction “pattern” for a crystal form of raloxifene hydrochloride which is different from that shown in Table 1 at pages 2 and 3 of the patent. This different form is called Form I at page 15 but the parties are agreed that this is a misnomer and should be Form II. In the Examples provided Example 2, 3 and 6 are said to be directed to Form I (Table 1) and Example 4 is said to be directed to Form II (Table 2). The parties are agreed however that Example 3 is really directed to Form II (Table 2) and that the reference is that Example to Form I is incorrect.
[50] In the claims, only Form I (Table 1) is claimed. The claims are directed only to “non-solvated” crystalline raloxifene hydrochloride. Any other form mentioned in the description of the patent, such as Form II is solvated. Solvated means that a measured quantity of the solvent used in the process from which the crystal is produced remains bound within the molecular lattice structure of the crystal itself.
THE CLAIMS OF THE ’399 PATENT
[51] The ’399 patent contains 8 claims. Claims 1 to 5 are directed to Form I non-solvated crystalline raloxifene hydrochloride. Claim 6 is directed to a pharmaceutical formulation containing such material. Claim 7 is directed to use of such material as a pharmaceutical.
[52] The claims (omitting the page and a half of X-Ray pattern data) are:
1. Non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride exhibiting substantially the following X-ray diffraction pattern obtained with copper radiation:
[Table 1]
…
2. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride of Claim 1 wherein the amount of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride present is at least 95% by weight.
3. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride of any one of Claims 1 and 2 which is substantially free from chlorobenzene.
4. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride of any one of Claims 1, 2 and 3 which is substantially free from aluminum salts or organoaluminum impurities.
5. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride of any one of claims 1-4 which is substantially odor free.
6. A pharmaceutical formulation comprising the crystalline compound as claimed in any one of Claims 1 to 5 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
7. The crystalline compound as claimed in any one of Claims 1 to 5 for use as a pharmaceutical.
[53] The chemical formula can be replaced with the words raloxifene hydrochloride such that the claims read:
1. Non-solvated crystalline raloxifene hydrochloride exhibiting substantially the following X-ray diffraction patterns obtained with copper radiation:
[Table 1]
2. The crystalline raloxifene hydrochloride of claim 1 wherein the amount of raloxifene hydrochloride present is at leaset 95% by weight.
3. The crystalline raloxifene hydrochloride of any one of Claims 1 and 2 which is substantially free from chlorobenzene.
4. The crystalline raloxifene hydrochloride of any one of Claims 1, 2 and 3 which is substantially free from aluminum salts or organoaluminum impurities.
5. The crystalline raloxifene hydrochloride of any of claims 1-4 which is substantially odor free.
6. A pharmaceutical formulation comprising the crystalline compound in any one of Claims 1 to 5 and one or more pharmaceutically acceptable carriers, diluents, or excipients.
7. The crystalline compound in any of claims 1 to 5 for use as a pharmaceutical.
[54] The Court must construe these claims having in mind what a person skilled in the art would understand them to mean and having regard to the disclosure. As to the disclosure I have particular regard to those portions set out earlier in these reasons as to what is meant by “substantially free” of various substances and odors.
[55] While I am not bound by their construction, I also have had regard to the meaning given to these claims by the Applicant’s expert Dr. Bernstein at paragraphs 28 to 37 of his affidavit and Novopharm’s expert Dr. Tidwell at paragraphs 45 to 52 of his affidavit.
[56] I find, as a matter of construction of the claims of the ’399 patent, that the essential elements of each claim are:
· Claim 1: a form of raloxifene hydrochloride having the following characteristics:
- it is crystalline
- it is non-solvated
- it exhibits the particular x-ray diffraction pattern as set out in Table 1
It need not be pure.
· Claim 2: The form of raloxifene hydrochloride of claim 1 that is at least 95% pure.
· Claim 3: The form of raloxifene hydrochloride of claims 1 or 2 which contains less than 5% by weight of chlorobenzene.
· Claim 4: The form of raloxifene hydrochloride of claims 1, 2 or 3 which contains less than 5% by weight of aluminium salts or organoaluminium impurities.
· Claim 5: The form of raloxifene hydrochloride of claims 1, 2, 3 or 4 which is substantially odor free in that it contain less than 3% by weight or mercaptan or sulphide impurities.
· Claim 6: A pharmaceutical formulation containing the form of raloxifene hydrochloride of any of claim 1 through 5.
· Claim 7: The form of raloxifene hydrochloride of any of claims 1 through 5 used as a pharmaceutical composition.
[57] Nowhere in the ’399 patent or in the evidence has there been shown to exist any form of raloxifene hydrochloride that is both crystalline and non-solvated that has an x-ray diffraction pattern other than Table 1. There are solvated crystalline forms having other patterns, but no non-solvated form has been shown to exist that has an x-ray diffraction pattern other than that of Table 1. The experts have said either in their affidavits or in cross-examination that there is a theoretical possibility that a form that is crystalline and non-solvated having a different x-ray diffraction pattern may in the future be found or created. The fact remains that at present the only known form of raloxifene hydrochloride that is both crystalline and non-solvated is that having the pattern or “fingerprint” of Table 1.
PRIOR ART
[58] The challenges to validity of the ’399 patent are two fold, anticipation and obviousness. As stated in many decision of the Courts such as the Federal Court of Appeal in Imperial Tobacco Ltd. v. Rothmans Benson & Hedges Inc. (1993), 47 C.P.R. (3d) 188 per Desjardins JA. at pages 197 to 199, as well as the recent Supreme Court of Canada decision in Apotex Inc. v. Sanofi-Synthelabo Canada Inc. 2008 SCC 61, anticipation and obviousness are related concepts in that they both require an examination of the prior art, but that prior art must be treated differently. Anticipation or lack of novelty requires the Court to examine whether the claimed invention has already been disclosed to the public by a single disclosure in such a way as to enable it to be put into practice. Obviousness (or lack of invention) requires that the Court consider a number of disclosures that would have been known to or found by a person skilled in the art to determine whether an inventive step has been made.
[59] In the present proceeding, Novopharm relies upon two pieces of prior art: United States Patent No. 4,418,068 (’068 patent) which was referred to at page 1 of the ’399 patent at issue and an article by Jones et al., also referenced at page 1 of the ’399 patent as published in the Journal of Medicinal Chemistry 2718), 1057-1066 (1984) which is the Jones Article. Both pieces of prior art were published sufficiently early so as to be applicable from a date point of view. It is acknowledged that the Jones who is an author of the article is also the named inventor of the ’068 patent.
[60] The ’068 patent was granted to the Respondent Lilly US naming Jones as an inventor. Jones and the other authors of the Jones Article appear from what is said at the first page of that article to be members of the research laboratory of Lilly US..
THE ’068 PATENT
[61] The ’068 patent, as acknowledged at page 1 of the ’399 patent, discloses raloxifene hydrochloride that is said to show promise as a pharmaceutically – active agent. The ’068 patent discloses how to make a number of compounds including raloxifene hydrochloride. Examples 16 and 18 are of particular interest in this regard. Example 16 discloses how to make a crude raloxifene hydrochloride and Example 18 discloses how to purify it:
EXAMPLE 16
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene hydrochloride. A mixture of 1.5 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 20ml. of chlorobenzene, 3ml. of thionyl chloride and 2 drops of dimethylformamide was stirred at 75o-79o for 2 hours, to prepare the corresponding acid chloride. Vacuum was then applied, and the temperature dropped to 65o. Distillation was continued until the pot temperature was 90o. Twenty ml. of additional chlorobenzene was added, and the mixture was redistilled to a pot temperature of 90o, and was then cooled. To the mixture was added 15ml. of dichloromethane, 1.35g. of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]-thiophene, 5 g. of aluminum chloride and 15 ml. of additional dichloromethane. The mixture was stirred at 27o-29o for 90 minutes, and then 1.6 ml. of ethanethiol was added. The mixture was stirred with cooling to maintain it at or below 35o. After 30 minutes, the mixture was worked up as described in Example 8 above, except that only 18 ml. of tetrahydrofuran and of water were used, to obtain 2.6 g. of the crude desired produ