Teva Canada Limited v. Novartis AG

Teva Canada Limited v. Novartis AG
Court (s) Database
Federal Court Decisions
Date
2013-02-19
Neutral citation
2013 FC 141
File numbers
T-2010-10, T-833-11
Notes
Digest
Decision Content
Date: 20130219
Docket: T‑2021‑10
Docket: T‑833‑11
Citation: 2013 FC 141
BETWEEN:
Docket: T‑2021‑10
TEVA CANADA LIMITED
Plaintiff
(Defendant by Counterclaim)
and
NOVARTIS AG
Defendant
(Plaintiff by Counterclaim)
Docket: T‑833‑11
BETWEEN:
APOTEX INC.
Plaintiff
(Defendant by Counterclaim)
and
NOVARTIS AG
Defendant
(Plaintiff by Counterclaim)
PUBLIC REASONS FOR JUDGMENT
(Confidential Reasons for Judgment issued February 8, 2013)
SNIDER J.
I. Introduction
A. Overview
[1] Novartis AG (Novartis) is the recorded owner of Canadian Patent No. 2,093,203 (the '203 Patent), a patent applied for on April 1, 1993, granted to Novartis on November 26, 2002, and which will expire on April 1, 2013. Novartis Pharmaceuticals Canada Inc. (Novartis Canada), a related corporate entity, sells a drug in Canada with the trademark of GLEEVEC, which is best known as a highly effective drug for the treatment of chronic myeloid leukemia (CML). The active ingredient in GLEEVEC is imatinib mesylate. Imatinib and its salt, imatinib mesylate, are compounds included in the '203 Patent.
[2] Teva Canada Limited (Teva) wishes to sell a generic version of imatinib. On December 3, 2010, Teva commenced an action against Novartis, seeking a declaration under s. 60(1) of the Patent Act, RSC 1985, c P‑4 (Patent Act) that certain of the claims of the '203 Patent are invalid (the Teva Impeachment Action; Court File No. T‑2021‑10).
[3] Apotex Inc. (Apotex) also is planning to sell a generic version of imatinib. On May 13, 2011, Apotex commenced an action against Novartis, seeking a declaration under s. 60(1) of the Patent Act that the '203 Patent and each of its claims are invalid (the Apotex Impeachment Action; Court File No. T‑833‑11).
[4] Each of Teva and Apotex has also taken steps to obtain regulatory approval for the sale of imatinib. Specifically, each company has: (a) applied to the Minister of Health (the Minister) for a Notice of Compliance (NOC) in respect of orally administered 100 mg and 400 mg tablets containing imatinib, pursuant to the Patented Medicines (Notice of Compliance) Regulations, SOR/93‑133 (the PM (NOC) Regulations or Regulations); and, (b) served Novartis Canada with a Notice of Allegation (NOA) with respect to the '203 Patent, in which Teva or Apotex, as applicable, alleges that all or certain claims of the '203 Patent are invalid.
[5] In response to each of the NOAs, Novartis Canada filed a Notice of Application requesting that the Court: (a) declare the NOA to be a nullity; or (b) issue an Order of Prohibition in accordance with s. 6(1) of the PM (NOC) Regulations preventing the Minister of Health from authorizing the second person to market imatinib until the expiry of the '203 Patent (the Teva Prohibition Application in Court File No. T‑679‑11 and the Apotex Prohibition Application in Court File No. T‑599‑11).
[6] Pursuant to the Order of Prothonotary Tabib dated May 30, 2011, the Teva Impeachment Action, the Apotex Impeachment Action, the Teva Prohibition Application and the Apotex Prohibition Application were consolidated. All four matters were dealt with in the course of 14 days of evidence and five days of argument.
[7] These Reasons for Judgment address the issues raised by the Teva and Apotex Impeachment Actions. In these reasons, Teva and Apotex are referred to as the Plaintiffs, except where the context requires separate identification. The Prohibition Applications are jointly dealt within a separate set of Reasons for Judgment and Judgment:
(a) 2013 FC 142 (the Apotex Prohibition Application in Court File No. T-599-11); and
(b) 2013 FC 142 (the Teva Prohibition Application in Court file No. T-679-11.
B. Summary of Issues and Conclusions
[8] In bringing the impeachment actions, the Plaintiffs acknowledge that imatinib is an “extraordinary drug that offers extraordinary therapeutic benefits to those who are suffering from an insidious disease” (final written argument para 2). Neither of the Plaintiffs argues that imatinib, as of the relevant date, was not novel or was obvious. The arguments of the Plaintiffs rest primarily on their assertion that, as of April 1, 1993 (the Canadian filing date), the utility of imatinib and the other compounds of the '203 Patent had not been established. The Plaintiffs also assert that the '203 Patent fails to meet the disclosure requirements set out in s. 27(3) of the Patent Act.
[9] In its counterclaim, Novartis seeks a declaration that the '203 Patent is valid and asks that the Court order Apotex to deliver up all bulk imatinib in its possession.
[10] Thus, the key issues to be addressed are as follows:
1. Is the '203 Patent invalid because, as of April 1, 1993, the inventor, Dr. Jürg Zimmermann, had not satisfied the requirement that the compounds included in the claims of the '203 Patent have utility;
• By demonstrating that the compounds would work as promised; or
• On the basis that he could not soundly predict that the compounds would work as promised?
2. Does the specification of the '203 Patent “correctly and fully describe the invention and its operation or use as contemplated by the inventor”, as required by s. 27(3) of the Patent Act?
3. If the '203 Patent is valid, do the quantities of bulk imatinib in the possession of Apotex infringe the '203 Patent; or, do these quantities fall with the regulatory or experimental use exemption of s. 55.2 (1) and (6) of the Patent Act?
[11] For the reasons set out in the following, I have concluded that:
1. As of April 1, 1993, the utility of Claims 5, 7, 29, 44 and 46 of the '203 Patent had been demonstrated or could soundly be predicted;
2. The '203 Patent meets the disclosure requirement of s. 27(3) of the Patent Act; and
3. Apotex need not deliver up the bulk imatinib in its possession.
II. Contents
[12] To assist the reader, I am including an outline of these reasons. The paragraph number for the beginning of each noted section is set out below:
I. Introduction.................................................................................. [1]
A. Overview........................................................................... [1]
B. Summary of Issues and Conclusions ................................ [8]
II. Contents...................................................................................... [12]
III. Witnesses..................................................................................... [13]
A. Plaintiffs’ Fact Witnesses ............................................... [14]
B. Plaintiffs’ Experts........................................................... [18]
C. Novartis’s Fact Witnesses............................................... [22]
D. Novartis’s Experts........................................................... [26]
E. Complaints by the Plaintiffs about
Drs. Heldin and Van Etten ............................................ [32]
IV. Background to the '203 Patent.................................................... [45]
A. Protein Kinases................................................................ [48]
B. Selective Kinase Inhibitors.............................................. [61]
C. The Protein Kinase Group at Ciba-Geigy....................... [63]
V. Burden............................................................................................... [72]
VI. Claims Construction.................................................................... [73]
A. Principles of Claims Construction .................................. [73]
B. The Hypothetical Skilled Person..................................... [79]
C. The Patent Specification................................................. [83]
D. The “and/or” Question.................................................. [120]
E. Meaning of “can be used”............................................. [139]
F. Disclosure of ABL Data .............................................. [152]
G. Conclusion on Construction ......................................... [158]
VII. Utility: Principles and Promise.................................................. [159]
A. Principles ...................................................................... [159]
B. The Promise of the '203 Patent..................................... [169]
VIII. Utility of the Compound Claims............................................... [200]
A. Demonstrated Utility of the Compound Claims........... [200]
B. Utility of Claims 1, 2, 3, 4, 5 and 7............................... [248]
C. Conclusion on the Utility of the Compound Claims..... [264]
IX. Utility of the Use Claims.......................................................... [266]
A. Factual Basis................................................................. [271]
B. Articulable Line of Reasoning ..................................... [291]
C. Disclosure ..................................................................... [317]
D. Conclusion on Sound Prediction of the Use Claims..... [334]
X. Sufficiency or Adequacy of the Disclosure ............................. [336]
A. Introduction ................................................................. [336]
B. Teachings from Sildenafil (SCC).................................. [340]
C. Nature of the Invention................................................. [346]
D. Practising the Invention ............................................... [356]
E. Conclusion on Sufficiency............................................ [387]
XI. Apotex Infringement ................................................................ [388]
XII. Conclusion................................................................................. [402]
III. Witnesses
[13] During the 14‑day evidentiary phase of the trial, I heard from a number of fact and expert witnesses. Teva and Apotex jointly presented expert witnesses and presented individual fact witnesses. In the following, I will provide a brief overview of the expert and fact witnesses who appeared and the areas to which they testified. For the expert witnesses, I have set out a very short description of their education and experience in the areas for which this court found each of them to be qualified. More detailed references to the evidence of both fact and expert witnesses are contained in the appropriate sections of these reasons or, where necessary, in the reasons in the Prohibition Applications.
A. Plaintiffs’ Fact Witnesses
[14] Teva presented Dr. Brian Des Islet, the Executive Director of Scientific Affairs at Teva, to testify on the actions of Teva (or its predecessor, ratiopharm) with respect to its abbreviated new drug submissions (ANDS) submitted to Health Canada and its decision to proceed with both an NOA under the PM (NOC) Regulations and the Teva Impeachment Action.
[15] Apotex put forward a number of fact witnesses. Dr. Bernard Sherman, the founder and current Chairman of Apotex, testified with respect to two different matters. First, he spoke on matters generally related to Apotex’s corporate strategy and specifically concerning Apotex’s decision to pursue both a NOA under the PM (NOC) Regulations and the Apotex Impeachment Action. Dr. Sherman also addressed the factual matters related to Apotex’s claim of regulatory and experimental use exemptions to infringement.
[16] A number of other Apotex witnesses testified on the matters related to the experimental and regulatory exemption; they were:
• Mr. Donald Barber, Formulation Development Manager at Apotex;
• Ms. Galina Ayyoubi, Associate Director of Quality Assurance and Process in the Quality Assurance Department at Apotex;
• Mr. Gordon Fahner, Vice President of Business Operations and Finance at Apotex; and
• Ms. Bernice Tao, Director of Global Regulatory Operations at Apotex, responsible for regulatory filings in Canada, the United States, the European Union and Australia.
[17] The Plaintiffs jointly presented Ms. Anne Bowes, Director of the Office of Submissions and Intellectual Property within the Therapeutic Products Directorate of Health Canada to testify about Health Canada’s regulatory requirements for drug approvals.
B. Plaintiffs’ Experts
[18] Dr. Lars Rönnstrand, Professor of Molecular Medicine, Lund University, Sweden was retained by counsel for the Plaintiffs. He was qualified as an expert in the areas of:
• Protein kinases and their role in normal and abnormal cellular functioning;
• Protein kinase inhibitors as potential therapeutic agents to treat hyperproliferative diseases, including tumours; and
• The design, analysis and understanding of in vitro and in vivo assays used to evaluate protein kinase inhibitors as potential therapeutic agents to treat hyperproliferative diseases, including tumours.
[19] Dr. Rönnstrand opined on the utility of the invention disclosed by the '203 Patent, as well as whether utility could be soundly predicted. He reviewed the scientific literature as of the filing date with respect to the kinases described in the patent and whether or not there was a conclusive link to the pathologies noted in the specification. Dr. Rönnstrand also critiqued the tests disclosed in the '203 Patent as well as those later revealed by Novartis.
[20] Dr. Clayton Heathcock is a chemist with over 50 years of academic experience in organic chemistry and medicinal chemistry. He is currently Professor Emeritus at the University of California at Berkeley. From 2005 to 2008, he also held the position of Chief Scientist of the Berkeley branch of the California Institute for Quantitative Biosciences. Dr. Heathcock was qualified as an expert in synthetic organic chemistry and medicinal chemistry, including understanding and analyzing synthetic processes for making organic compounds intended to be used as pharmaceutical products and structure activity relationships (SARs) of organic compounds intended to be used as pharmaceutical products.
[21] Dr. Heathcock opined on the utility of the invention disclosed by the '203 Patent, as well as whether utility could be soundly predicted. In particular, Dr. Heathcock commented on the processes to prepare the claimed compounds as well as their structures and chemical properties.
C. Novartis’s Fact Witnesses
[22] Novartis called three fact witnesses to speak to the discovery and development of the compounds of the '203 Patent at Ciba‑Geigy Limited (Ciba‑Geigy), predecessor in interest to Novartis.
[23] Dr. Nicholas Lydon, who holds a Ph.D. in biochemistry, worked at Ciba‑Geigy from 1985 to 1997. During that time, he established the protein kinase research group at Ciba‑Geigy. During his testimony, Dr. Lydon discussed the targets of the protein kinase group and how the group pursued its research goals. Dr. Lydon testified about decision‑making processes designed to determine which molecules were assessed and promoted. He presented annual reports, progress reports and other documentation produced by the protein kinase group in the course of its work. He also explained the role of different individuals in the protein kinase group and how external collaborators, such as Dr. Brian Druker, became involved.
[24] Dr. Jürg Zimmermann, a medicinal chemist, is the inventor named in the '203 Patent. He described his role in the chemistry laboratory of the protein kinase group at Ciba‑Geigy, explaining how molecules were made, screened, and optimized to be selective and potent inhibitors. Dr. Zimmermann discussed his path to the invention that became the subject of the '203 Patent.
[25] Dr. Doriano Fabbro joined Ciba‑Geigy in 1991 and worked in the protein kinase group, developing assays and inhibitors relating to protein kinase C (PKC). Dr. Fabbro provided the reasons why PKC was interesting to researchers in the context of cancer and multi‑drug resistance at the filing date. He also explained some of the testing of the compounds of interest.
D. Novartis’s Experts
[26] Dr. Richard Van Etten is the Chief of the Division of Hematology/Oncology and an attending physician on the bone marrow transplant and hematologic malignancies service and haematology/oncology consult service at Tufts Medical Centre, Boston Massachusetts. He is also the current Director of the Tufts Cancer Centre. In addition to being a practising physician, Dr. Van Etten holds a Ph.D. in Biophysics. Dr. Van Etten was qualified to give expert testimony as a medical doctor and a research scientist in the following areas:
• Mechanisms of cell growth and cell signalling, and the importance of tyrosine kinases in these cellular functions;
• Cancer cells, including the role of oncogenes and tumour suppressing genes in cancer cells;
• Protein kinases, including PKC, PDGF‑R and ABL kinases, and their known association with certain cancers (including chronic myeloid leukemia (CML)) and other proliferative disorders as of April 1, 1993;
• Methods used for the treatment of cancer and theories relating to potentially new cancer treatments, including methods and theories relating to CML, as of April 1, 1993;
• The relevance of kinase selectivity in identifying compounds for the potential use as protein kinase inhibitors;
• In vitro tests used to identify compounds that may be effective as selective protein kinase inhibitors, including anti‑proliferation, cell‑free and whole cell tests that may be performed on various kinases;
• The use of in vivo testing used to evaluate the efficacy of protein kinase inhibitors; and
• Gleevec and its impact on the prognosis of patients diagnosed with CML.
[27] Dr. Van Etten reviewed the '203 Patent and opined on the patent’s promise and the utility of the patent claims. He summarized the state of the art with respect to PKC, PDGF‑R and ABL kinases at the filing date and the extent to which these kinases were implicated in cancer pathology. He commented on the testing performed by Novartis, what conclusions may be drawn from that testing and which testing methods were available at the filing date.
[28] Dr. James Wuest, who holds a Ph.D. in organic chemistry, is a Professor of Chemistry at Université de Montréal. Dr. Wuest was qualified to give opinion evidence with respect to synthetic organic chemistry, including SAR analyses and extrapolation of these SAR analyses to medicinal chemistry issues.
[29] Dr. Wuest testified about the organic chemistry and utility of the process Claim 44 and the compound claims. He described the three different processes encompassed by Claim 44 and the extent to which these processes and the reactions inherent in them were known at the time of filing. Dr. Wuest opined on the compounds made and tested by Novartis, and whether they were representative of particular claims, focussing on Claim 7 read with Claim 5.
[30] Dr. Carl‑Henrik Heldin is the Director of the Ludwig Institute for Cancer Research in Uppsala, Sweden. Dr. Heldin was qualified to give opinion evidence relating to:
• Protein kinases and their role in normal and abnormal cellular functioning;
• Protein kinase inhibitors, including as potential therapeutic agents, for the use in disorders associated with kinase dysregulation, including tumours and atherosclerosis; and
• Design and analysis of in vitro and in vivo experiments used to evaluate protein kinase inhibitors including as potential therapeutic agents for use in disorders associated with kinase dysregulation, such as tumours and atherosclerosis.
[31] Dr. Heldin testified about the state of art in 1993, the studies conducted by Novartis and whether the invention disclosed in the patent had utility. Dr. Heldin explained the tests performed on various compounds of formula I and what conclusions may be drawn from those results. Dr. Heldin focussed on Claim 29, Claim 46 dependent on Claim 29 and Claim 7 dependent on Claim 5.
E. Complaints by the Plaintiffs about Drs. Heldin and Van Etten
[32] The Plaintiffs, in final argument, were generally critical of the testimony of Drs. Van Etten and Heldin and requested that I give diminished weight to their evidence. I do not agree that the evidence of these experts is tainted as posited by the Plaintiffs. The criticisms relate to small portions of the evidence and do not affect the great assistance that both experts provided during this trial to my understanding of the subject matter of the '203 Patent.
[33] With respect to Dr. Van Etten, the main complaint of the Plaintiffs is that he did not construe the patent through the eyes of a person of ordinary skill in the art; rather, they submit that he reviewed everything as a “stone cold expert” in the field. In support for this position, they
refer to the following exchange (9T1741‑1742) where I had engaged Dr. Van Etten in a discussion of the person of ordinary skill in the art:
MADAM JUSTICE SNIDER: During your testimony, you referred a lot to what you had done and the state of the art in 1993, and you were fortunate enough to be very active in that area. Would you consider yourself to be a person of ordinary skill in the art?
THE WITNESS: I'm not sure what that actually means in the legal sense. I consider myself, if I can use the slang, to be a stone cold expert in this whole area. My entire career depended on it. I was right in the middle, in the thick of all of this, in this particular area around ABL and inhibitors and mouse models, so I think I'm pretty knowledgeable.
[34] I am not sure what a “stone cold expert” is. I assume that Dr. Van Etten was telling me that he had much more expertise than the “ordinary” skilled person. And, of course, in assisting the court, a “stone cold expert” is necessary to deal with the complex scientific concepts involved. However, I do not, as do the Plaintiffs, take this to be an admission that Dr. Van Etten did not provide me with his opinion of what a person of ordinary skill in the art would have known as of the relevant date.
[35] Dr. Van Etten did make some references to his understanding of the state of the art as of April 1, 1993 which raise a little concern. Specifically, in response to a question during examination in chief, Dr. Van Etten stated (8T1554) that he was asked “if a person skilled in the art such as myself could have a reasonable inference as to the utility” (emphasis added). Later in the same examination, Dr. Van Etten stated (8T1555) that “It's really about whether an expert in cancer biology at the time would have been able to reasonably infer, given the evidence, that PDGF and it's receptor were involved in certain types of cancer” (emphasis added). These comments must be read in context. Having read the transcript in its entirety and his report, I am satisfied that, despite the first statement, Dr. Van Etten was well aware of the task of patent construction and the difference between an expert such as himself and the person of ordinary skill in the art. With respect to the second comment about the “expert in cancer biology”, I observe that the notional skilled person, in this case and as discussed below, will have considerable expertise in medicinal chemistry. A person with such expertise may well be referred to as an “expert”.
[36] The other reason provided by the Plaintiffs is that Dr. Van Etten acted as an advocate for Novartis contrary to the role of an expert and contrary to the declaration made in accordance with Rule 52.2(1)(c) of the Federal Courts Rules, SOR/98‑106. This submission is often made by a party when an expert provides an opinion that does not agree with its expert or its position on the evidence. The argument may, in some cases, have substance. In this case, it does not. Dr. Van Etten, even in the examples cited by the Plaintiffs, was responding honestly and openly to questions posed to him. He did not blindly adhere to an opinion without merit. Rather than advocating for Novartis, I saw Dr. Van Etten as an advocate for his expert opinion; I see no problem with such advocacy.
[37] In addition to arguing that Dr. Heldin was an advocate for Novartis – an argument that I reject for the same reasons as expressed with respect to Dr. Van Etten – the Plaintiffs submit that Dr. Heldin provided his opinion without seeing or requesting to see all of the relevant documents.
[38] It is true that Dr. Heldin was not provided with Novartis Production Document 250 (ND250), which describes an experiment conducted by the Ciba‑Geigy researchers. Maybe he should have been given this document – particularly since it was referred to by Dr. Rönnstrand in his report. However, in my opinion, this oversight is not sufficient reason to discount the entire testimony of Dr. Heldin. The alleged importance of ND250, and the results of a “failed” experiment on one of the compounds of the '203 Patent, is much exaggerated. The mere fact that Dr. Rönnstrand felt that this experiment was relevant does not necessarily make it so. This question is discussed in greater detail below.
[39] A similar argument is made by the Plaintiffs about certain summary internal Ciba‑Geigy reports (ND151 and ND153) that were not provided to Dr. Heldin. Both of these reports were prepared after April 1, 1993. It is not at all strange that they were not provided to Dr. Heldin for preparation of his expert report where he was asked to form opinions as of April 1, 1993.
[40] In any event, during his oral testimony, Dr. Heldin provided clear responses to the questions posed to him on the “missing documents”.
[41] I am not prepared to discount the helpful opinions of Dr. Heldin on all issues because he was not given three documents which are of questionable relevance to the issues before me.
[42] The Plaintiffs assert that the testimony of Drs. Van Etten and Heldin is similar to that of Dr. Bartlett, whose testimony was assigned less weight in Sanofi‑Aventis Canada Inc v Apotex Inc, 2009 FC 676 at paras 126‑131, 77 CPR (4th) 99 [Ramipril I (FC)], aff’d 2011 FCA 300, 97 CPR (4th) 415 (15T2881‑2886). Although some of the statements by Novartis’s experts in this case may be superficially similar to Dr. Bartlett’s, the context in which these opinions were presented demonstrates that Ramipril I (FC) and Dr. Bartlett’s evidence presented very different circumstances.
[43] In Ramipri I (FC), the patent, the expert evidence, the relevant knowledge of the skilled person and the factual circumstances were very different. On this basis alone, it is difficult to compare Dr. Bartlett’s testimony to that of Dr. Van Etten and Dr. Heldin in a meaningful way. For example, the history of ACE inhibitors and their clinical use was significant at the time the inventors filed the ramipril patent (Ramipril I (FC), above at paras 53‑62). By contrast, the use of selective protein kinase inhibitors to treat hyperproliferative disorders was in its infancy at the filing date of the '203 Patent.
[44] Further, the concern with Dr. Bartlett’s testimony in Ramipril was not confined to his interpretive approach to the promise of the patent; another significant problem that troubled the Court in Ramipril I (FC) was Dr. Bartlett’s inconsistent testimony in the Ramipril trial as compared to his evidence in Laboratoires Servier v Apotex Inc, 2008 FC 825, 67 CPR (4th) 241 [Perindopril], aff’d 2009 FCA 222, 75 CPR (4th) 443. In the Perindopril trial, Dr. Bartlett opined that other patents in the field promised both an anti‑hypertensive effect as well as ACE inhibition, while in the Ramipril trial, Dr. Bartlett significantly qualified this statement, referring to potential ACE inhibition only (Ramipril I (FC), above at paras 129‑130). This significant discrepancy was an important reason why the Court questioned Dr. Bartlett’s objectiveness and gave his evidence less weight. The Plaintiffs have not demonstrated any reason rising to this level of significance why Dr. Van Etten and Dr. Heldin did not testify objectively.
IV. Background to the '203 Patent
[45] The '203 Patent and this trial involved a considerable amount of evidence related to medicinal chemistry and other branches of related science. In this section of the reasons, I have attempted to provide a brief overview of the complex scientific concepts involved and the history of the '203 Patent.
[46] This case requires some knowledge of certain human genes and protein kinases. I adopt the Human Genome Organisation (HUGO) nomenclature used in the scientific community to refer to genes and proteins, as explained by Dr. Van Etten and Dr. Rönnstrand. Names of human genes are capitalized and italicized, while names of proteins are capitalized but not italicized.
[47] Key concepts relate to certain protein kinases and the ways in which they may be uncoupled from the systems that regulate them, leading to diseases of uncontrolled cell division such as cancer. All of the experts who testified were extremely helpful in establishing a base level of information and knowledge around which I could frame this decision. At this stage, there was no disagreement among the experts.
A. Protein Kinases
(1) Protein Kinases, Cell Signalling and Cell Proliferation
[48] Enzymes catalyze chemical reactions between particular molecules, facilitating these reactions and allowing them to proceed. Protein kinases catalyze the covalent attachment of a phosphate group from ATP to a protein, a reaction known as phosphorylation. Kinases may be located in the interior of the cell in the cytosol or they may span the cell membrane. There are two groups of kinases of interest in these actions:
• One group of kinases, including PKC, phosphorylate serine and threonine amino acids.
• A second group of kinases, including platelet-derived growth factor receptor kinase (PDGF‑R kinase) and Abelson kinase (ABL kinase), phosphorylate tyrosine amino acids.
[49] Protein kinases play an important role in cell signalling through appropriate regulation of their activity. Kinases are generally present in a cell in their inactive state and have low levels of catalytic activity. However, they may become active upon receiving a particular signal, which causes them to phosphorylate other proteins, changing the behaviour of these phosphorylated proteins. These proteins may interact differently with other proteins, relocate to another part of the cell or, if the phosphorylated protein is itself an enzyme, its catalytic activity may increase or decrease.
[50] The response of a protein kinase to a stimulus may lead to changes in the cell as a whole through a signalling cascade. The signal that a kinase transmits through phosphorylation of a protein may be relayed from one molecule to another in a linear fashion or a branching fashion, allowing for regulation of multiple cellular processes. For example, when PDGF‑R kinase is activated by a growth factor, it can phosphorylate proteins in the RAS family. RAS proteins activate a serine/threonine kinase called RAF, which activates another kinase called MEK, which in turn will activate MAP kinase. MAP kinase will activate a number of proteins, including transcription factors, which bind to particular regions of DNA and affect the expression of certain genes, such as c‑FOS.
[51] Cell signalling initiated by protein kinases may eventually lead to changes in overall cell behaviour. For example, cells may mature into a specialized cell type, a process known as differentiation. They may also divide, a process referred to as cell proliferation. Protein kinases may also promote attachment or detachment of the cell to its surrounding environment as well as cell survival or cell death.
[52] Genes encoding proteins involved in cell signalling, including tyrosine kinases, may become mutated, leading to dysregulation of cell proliferation and associated diseases. In the context of cancer, oncogenes cause cells to behave in ways that are similar to cancer cells, often because they produce signalling proteins that have increased activity.
(2) ABL Kinase and Chronic Myeloid Leukemia
[53] ABL kinase is a tyrosine kinase located in the cytosol. ABL kinase plays a role in cell signalling and is expressed in many cells of the body. The gene encoding this kinase, known as c‑ABL, is located on chromosome 9. A similar gene to c‑ABL, known as v‑ABL, is the oncogene contained in the Abelson murine leukemia virus that causes mice to suffer from leukemia.
[54] A mutated form of c‑ABL, known as BCR‑ABL, is linked to a human form of cancer known as chronic myeloid leukemia or CML. CML is a form of cancer characterized by excessive proliferation of neutrophils, cells in the body that form part of the immune response, as well as their precursors. As the disease progresses, these cells accumulate in the blood and in the spleen. Eventually, a patient’s normal mature blood cell production becomes affected which eventually causes death.
[55] As of April 1, 1993, there were three possible treatments for CML:
• Myelosuppressive drugs which could interfere with the proliferation of blood cells in the bone marrow, offering, however, little beyond palliative therapy;
• Interferon‑alfa, to which few patients responded and which was highly toxic; and
• Stem cell transplantation, which was successful in only 65% of patients and which, due to its toxicity, was not available to many patients.
[56] There is a well‑established connection between BCR‑ABL kinase and CML. In 1960, Nowell and Hungerford observed that CML patients possessed a particularly small version of chromosome 22, known as the Philadelphia chromosome (Ph chromosome) (PC Nowell and PA Hungerford, “A minute chromosome in human chronic granulocytic leukemia”, 132 Science 1497). It was later discovered that the Ph chromosome is created from an exchange of genetic material between chromosomes 9 and 22, which forms the fusion gene, BCR‑ABL. This fusion gene codes for the fusion protein, BCR‑ABL. Researchers discovered that BCR‑ABL is a tyrosine kinase that is constitutively active, meaning that it has abnormally high activity compared to the normal ABL kinase.
[57] The relationship of BCR‑ABL to CML is important in the context of imatinib and this trial. A more detailed description of this link and the other literature and knowledge in the public domain up to the filing of the '203 Patent is found later in these reasons.
(3) PDGF‑R Kinase
[58] PDGF‑R kinase is a transmembrane tyrosine kinase that is mainly found in connective tissue cells such as fibroblasts, smooth muscle cells, pericytes close to the capillaries and the glial cells of the nervous system. When platelet derived growth factor (PDGF) binds to the extracellular receptor on PDGF‑R, this leads to the formation of a signalling complex; two adjacent PDGF‑R molecules come together, they phosphorylate each other and they both become activated. This creates sites where other signalling proteins may attach.
[59] Researchers had investigated the connection between PDGF‑R and cancer, as well as PDGF‑R and atherosclerosis prior to April 1, 1993, as explained in further detail later in these reasons.
(4) PKC
[60] PKC is a family of serine/threonine kinases, comprised of a number of PKC isozymes. These kinases are located in the cytosol of almost every cell in the body, where they regulate many processes including cell proliferation and survival. There are three distinct subgroups of PKC isozymes, which differ based on what substances they require for activation and in their biological activity. As of April 1, 1993, researchers had investigated the link between PKC and cancer, as well as PKC and multi‑drug resistance.
B. Selective Kinase Inhibitors
[61] The essence of the ‘203 Patent is selective inhibition of particular protein kinases. If the activity of a protein kinase is somehow “blocked” by a compound, referred to as an inhibitor, the protein kinase cannot transmit signals to the nucleus of the cell to cause cell growth and proliferation.
[62] If a kinase inhibitor interferes with several protein kinases, it would disrupt many normal physiological processes. This in turn would cause unnecessary and unwanted side effects and toxicity. However, if a kinase inhibitor is selective for one kinase or a small subset of kinases, it would be a much better drug candidate with the potential for treatment.
C. The Protein Kinase Group at Ciba‑Geigy
[63] The compounds of the '203 Patent were developed in the laboratories of Ciba‑Geigy. Three witnesses who were important players in the development of the compounds of the '203 Patent at Ciba‑Geigy testified in this trial ‑ Dr. Lydon, Dr. Fabbro and the named inventor, Dr. Zimmermann. Each is an impressive scientist who testified in a straight‑forward, credible manner.
[64] Dr. Lydon told the story of how, in 1985, he and Dr. Alex Matter started the protein kinase group (referred to as the PK Group) at Ciba‑Geigy. This group focussed on the role of protein kinases, the “molecular switches” of cell signalling, and the development of inhibitors to treat diseases when these “switches” became dysregulated (10T1956). A group of researchers worked on PKC and another group worked on four tyrosine kinases of interest: epidermal growth factor receptor (EGF‑R) kinase, c‑erb B2 kinase, PDGF‑R kinase and ABL kinase. Much of the early work was done to establish the project, including the development of tools and assays as well as the isolation of target enzymes. Once this was accomplished, the focus of the project became the synthesis of reference compounds, identification of lead molecules which had activity against the target enzymes and optimization of these molecules to improve selectivity and potency as well as physical and chemical properties.
[65] Dr. Zimmermann, the named inventor of the '203 Patent and a medicinal chemist, began his work on the protein kinase project as an investigator in the PK Group (12T2272‑2274, 2287‑2290). He told the story of the development of the claimed compounds from certain starting compounds.
[66] The PK Group began with a number of reference compounds, which became the “starting point” for their research (12T2288). Of critical importance, a compound known as staurosporine came to the attention of the group in 1986. As described by Dr. Fabbro (12T2459), the interest in this compound came from its properties as a protein kinase inhibitor; unfortunately, staurosporine was not selective. The chemists at Ciba‑Geigy modified the structure of the molecule to increase potency and selectivity. These modifications led to the compounds that became the subject matter of the '203 Patent.
[67] In April 1992, when the PK Group had developed inhibitors of PKC, they decided to file a patent (12T2306‑2308). This patent relating to the PKC inhibitors was filed in Switzerland and it is the priority application to which the '203 Patent refers.
[68] Two important discoveries occurred in the year between the filing of the priority application and the Canadian patent. The first important breakthrough occurred when the chemists created molecules that could inhibit PDGF‑R kinase and ABL kinase in addition to PKC (12T2290‑2293). These compounds contained an NHCO phenyl group, which led to activity against these two additional kinases. A second important discovery was the creation of a molecule selective for PDGF‑R and ABL kinase, which did not inhibit PKC (12T2293‑2308). These molecules contained a “flag methyl group” (12T2294) which accounted for their selectivity. The PK Group continued to optimize this new class of inhibitors, adding a piperazine group to improve solubility.
[69] On April 1, 1993, the PK Group filed a patent application in Canada; this became the '203 Patent issued November 26, 2002 . In this patent application, and in others filed around this time in other countries, Dr. Zimmermann referred to the PKC inhibitors as well as the activity of the new compounds against ABL kinase and PDGF‑R kinase (12T2308‑2309).
[70] After April 1, 1993, Ciba‑Geigy proceeded to focus primarily on the compounds that came to be known as the Group 2 comp