Docket: T-2021-10 TEVA CANADA LIMITED Plaintiff (Defendant by Counterclaim) v. NOVARTIS, 2013 FC 141

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 compounds. Over the next year, further testing demonstrated that CGP 57148 was the molecule of greatest interest. CGP 57148 – now known as imatinib –entered clinical trials in 1998 (Van Etten Report, TX 37 at para 156).

Imatinib was eventually granted an NOC/c by Health Canada, which allows for promising, breakthrough therapies to be approved quickly (Anne Bowes, 2AT238-243). [ 71 ] Imatinib has revolutionized the treatment of CML. Before imatinib became available, patients receiving the best available treatment had a mean survival rate ranging from 42 to 98 months. However, once imatinib entered the market, “[w]hat once was a death sentence has now become a manageable chronic illness with overall survival rates equal to the general population” (Van Etten Report, TX 37, paras 155-157).

It is not an exaggeration to say that the work done by the Ciba-Geigy scientists changed the lives of patients living with CML; with imatinib, such patients can lead almost normal lives while living with a disease that would otherwise have been a death sentence. V. Burden [ 72 ] In these proceedings, the Plaintiffs bear the burden of establishing, on a balance of probabilities, any facts which render the '203 Patent invalid, keeping in mind the presumption of validity ( Eli Lilly and Co v Apotex Inc , 2009 FC 991 at paras 348-349 , 370, 80

CPR (4th) 1 [Cefaclor], aff’d 2010 FCA 240, 90 CPR (4th) 327). Upon the issuance of a patent, the patent as a whole is presumed to bevalid, absent evidence to the contrary (Section 43(2) of the Patent Act; see for example Abbott Laboratories v Canada (Minister ofHealth), 2007 FC 455 at para 90, [2008] 2 FCR 636, aff’d 2008 FCA 44, 68 CPR (4th) 167; Windsurfing Int’l Inc v EntreprisesHermano Ltée (1982), (FCA), 69 CPR (2d) 176 at 181-182, [1982] FCJ No 1144 (TD)).

Once the party attacking thepatent has adduced evidence to rebut the presumption, the Court must evaluate the evidence on a balance of probabilities (Rubbermaid(Canada) Ltd v Tucker Plastic Products Ltd (1972), 8 CPR (2d) 6 at 13-14, [1972] FCJ No 1003 (TD)). VI. Claims Construction A. Principles of Claims Construction [73] The first step in a patent suit is to construe the claims, in accordance with principles that are well established in thejurisprudence (see, for example, Whirlpool Corp v Camco Inc, 2000 SCC 67, [2000] 2 S.C.R. 1067 [Whirlpool]).

This jurisprudenceteaches that claims are to be interpreted in a purposive way in order "to achieve fairness and predictability and to define the limits of themonopoly" (Dimplex North America Ltd v CFM Corp, 2006 FC 586 at para 49, 54 CPR (4th) 435 [Dimplex], aff'd 2007 FCA 278, 60CPR (4th) 277). As cautioned, over and over, by the jurisprudence, construction of the claims must be approached with a mind willing tounderstand. For example, Justice Binnie in Whirlpool, above at paragraph 49(

c) stated the following: The orthodox rule is that a patent "must be read by a mind willing to understand, not by a mind desirous of misunderstanding", per ChittyJ. in Lister v. Norton Brothers and Co. (1886), 3 R.P.C. 199 (Ch. D.) at p. 203.

A "mind willing to understand" necessarily pays closeattention to the purpose and intent of the author. [74] Similar caution can be seen in the comments of Justice Dickson in Consolboard Inc v MacMillan Bloedel (Sask.) Ltd, (SCC), [1981] 1 SCR 504 at 520, 122 DLR (3d) 203 [Consolboard]: There is no occasion for being too astute or technical in the matter of objections to either title or specification for, as Duff C.J.C. said,giving the judgment of the Court in Western Electric Company, Incorporated, and Northern Electric Company v.

Baldwin InternationalRadio of Canada, [ (SCC), [1934] S.C.R. 570], at p. 574, "where the language of the specification, upon a reasonableview of it, can be so read as to afford the inventor protection for that which he has actually in good faith invented, the court, as a rule,will endeavour to give effect to that construction". Sir George Jessel spoke to like effect at a much earlier date in Hinks & Son v. SafetyLighting Company, [(1876), 4 Ch. D. 607].

He said the patent should be approached "with a judicial anxiety to support a really usefulinvention". [Emphasis added.] [75] Construction of the claims is a matter for the court to decide. The court is called on to determine, on an objective basis, what ahypothetical skilled person would have understood the claims to mean (Whirlpool, above at paras 45, 53).

Where a patent is of a highlytechnical nature, the person skilled in the art will be someone possessing a high degree of expert scientific knowledge in the particularfield of art to which the patent relates (Aventis Pharma Inc v Apotex Inc, 2005 FC 1283 at para 64, 278 FTR 1 [Ramipril II (FC)]; ApotexInc v Syntex Pharmaceuticals International Ltd et al (1999), (FC), 166 FTR 161 at para 38, [1999] FCJ No 548 (TD)). [76] I wish to emphasize that the claims – and not the disclosure – are the essence of a patent and it is the claims that must beinterpreted.

While the specification, as a whole, will describe the invention, the scope of the monopoly is defined by the claims (seeAmfac Foods Inc v Irving Pulp & Paper, Ltd (1986), 12 CPR (3d) 193 at 198, 72 NR 290 (FCA); CH Boehringer Sohn v Bell-Craig Ltd(1962), (CA EXC), 39 CPR 201 at 243, 1962 Ex CR 201, aff’d (SCC), [1963] SCR 410, 41 DLR (2d)611).

As stated by Justice Binnie in Whirlpool, above at paragraph 45: The key to purposive construction is therefore the identification by the court, with the assistance of the skilled reader, of the particularwords or phrases in the claims that describe what the inventor considered to be the "essential" elements of his invention. [Emphasisadded.] [77] However, where necessary, the court may have resort to the disclosure to assist in the exercise (Eli Lilly Canada Inc v ApotexInc, 2008 FC 142 at para 25, 63 CPR (4th) 406, aff’d 2009 FCA 97, 78 CPR (4th) 388; Eli Lilly Canada Inc. v.

Novopharm Ltd., 2007FC 596 at para 103, 58 CPR (4th) 214). Stated differently, the Court should construe the claims in light of the description in thespecification, assisted by experts as to the meaning of technical terms if such terms cannot be understood by the Court from reading thespecification (Shire Biochem Inc v Canada (Minister of Health), 2008 FC 538 at para 22, 328 FTR 123; Whirlpool, above at para 45). [78] With these overarching principles in mind, I turn to the patent in question.

B. The hypothetical skilled person [ 79 ] As noted, claims must be construed from the view of a hypothetical skilled person. Thus, as a preliminary matter, I must define what attributes would be held by our hypothetical skilled person or person of ordinary skill in the art. [ 80 ] Apotex submits that I should accept the description of Dr.

Rönnstrand, from his expert report (TX 13, para 19), to define our skilled person: [T]he 203 Patent is addressed to persons having a graduate level degree in pharmacology, biology, biochemistry, medicinal chemistry, organic chemistry, pharmaceutical sciences, or a closely related field.

These persons would also have at least two to three years of experience in applications related to the development of therapies for the treatment of conditions or diseases, for example tumours, that respond to inhibition of protein kinases, including experience employing various in vitro and in vivo assays. [ 81 ] Novartis does not disagree but notes the emphasis placed on the knowledge of organic and medicinal chemistry by Dr.

Wuest in his report (TX 53, para 17). [ 82 ] As is often the case, the notional skilled person will likely consist of a team of people with a combination of the skills identified by the experts. Moreover, although the person of ordinary skill in the art will not be an “expert”, in the sense used by the Court, the '203 Patent requires a person with considerable expertise in the areas of organic and medicinal chemistry, as also noted by Dr. Heathcock (T938; Heathcock Report, TX 22, para 23), as well as Dr. Heldin (T2624; Heldin Report, TX 71, para 27). C.

The Patent Specification [ 83 ] A patent normally consists of two separate sections – the disclosure or description of the invention followed by the claims. Together, the disclosure and the claims make up the specification of the patent ( see Consolboard , above at 520). [ 84 ] Even though the task at hand is to construe the claims of the '203 Patent, I begin with a study of the '203 Patent disclosure. This study will help situate not only the proper construction of the claims but will assist in the later discussion of: (

a) the utility of the claims where the “promise” of the patent will need to be ascertained; and (

b) the sufficiency of the '203 Patent where the nature of the invention must be determined. [ 85 ] The importance of the chemistry component of the '203 Patent is reflected in its title, “PYRIMIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF”.

The first paragraph of the disclosure is far more descriptive: The invention relates to N-phenyl-2-pyrimidine-amine derivatives, to processes for the preparation thereof, to medicaments comprising those compounds, and to the use thereof in the preparation of pharmaceutical compositions for the therapeutic treatment of warm-blooded animals. [ 86 ] This four-fold description is reflected in the claims where: • Claims 1 to 39 are claims to compounds; • Claims 40 to 43 are claims to “pharmaceutical compositions” (medicaments); • Claim 44 is a claim to the process for making the claimed compounds; and

• Claims 45 to 48 claim particular uses of the compounds. [ 87 ] Following these introductory comments, the patent sets out the chemical structure of formula I compounds: [ 88 ] The following four pages of the patent describe the various possible substituents for R 1 to R 8 . [ 89 ] At page 5 of the disclosure, the patent begins to describe and delineate the invention, beginning with the important therapeutic use to which the compounds may be put: The compounds of formula I have valuable pharmacological properties and can be used, for example, as anti-tumoral drugs and drugs against atherosclerosis. [ 90 ] An overview of the knowledge in the field is then set out describing the operation of phosphorylation of proteins and the role of kinases.

Kinases of particular relevance are “the serine/threonine kinases [including] protein kinase C and the tyrosine kinases [including] the PDGF (platelet-derived growth factor)-receptor tyrosine kinase”. These particular enzymes are referred to as PKC and PDGF-R. [ 91 ] The disclosure then turns to a more detailed description of the compounds, beginning with a subset of formula I compounds referred to at trial (although not in the '203 Patent) as the Group 1 compounds.

As set out in the disclosure (sixth full paragraph, p. 5), “[t]he compounds of formula I wherein R 4 and R 8 are hydrogen selectively inhibit the enzyme [PKC]” (emphasis added). [ 92 ] This is the first use in the '203 Patent of the terms “selectively” and “inhibit”, terms which would have been well known to persons of ordinary skill in the art. [ 93 ] The following several paragraphs of the disclosure (from page 5 to 7) appear to relate exclusively to the Group 1 compounds (from page 5 to 7).

Some expansion of the notion of selective inhibition and potential use of the Group 1 compounds because of the function of PKC, the enzyme that they selectively inhibit, is provided. [ 94 ] The inventor first explains the in vitro testing of the Group 1 compounds using PKC from pig brain. No specific compounds are mentioned although it is reasonable to assume that the illustrative Group 1 examples at pages 25 to 35 were those compounds tested (Dr. Rönnstrand, 4T733-734). The testing results are given as a range of IC 50 values.

There was inhibition of PKC “at a concentration of IC 50 of as low as approximately from 0.1 to 10 µmol/litre, especially approximately from 0.05 to 5 µmol/litre”. With respect to the inhibition of other enzymes (with some examples disclosed), the compounds inhibited those other enzymes “only at a far higher concentration, for example 100 times higher”.

This difference, in the statement of the inventor, “is an indication of the selectivity of the compounds of formula I”. [ 95 ] In the following paragraph the inventor ascribes certain properties to the Group 1 compounds, which properties flow from the inhibiting activity of the compounds: Owing to their inhibiting activity towards [PKC] , the [Group 1 compounds] . . . can be used as tumour-inhibiting, immunomodulating and anti-bacterial active ingredients and, further, as drugs against atherosclerosis, the immunodeficiency disorder AIDS, and diseases of the cardiovascular system and the central nervous system. [Emphasis added.]

[ 96 ] In the third full paragraph at page 6, further testing is described. The inventor describes the test carried out to assess the inhibiting action of the Group 1 compounds on the growth of human T24 bladder carcinoma cells. Using the testing methodology described in the disclosure, the inventor reports that the IC 50 values determined are “from 0.1 to 10 µmol/litre”. Again, the patent provides only a range of IC 50 values. [ 97 ] This

section of the disclosure is completed with another paragraph extolling the therapeutic possibilities for the Group 1 compounds, which flow again from their inhibitory properties: Owing to the properties described , the [Group 1 compounds] can be used especially as tumour-inhibiting active ingredients, for example for the treatment of tumours of the bladder.

In addition, they are suitable for the further applications mentioned above for [PKC]-modulators and can be used especially in the treatment of diseases that respond to inhibition of [PKC]. [Emphasis added.] [ 98 ] The disclosure then turns its attention to two further subsets of formula I; these compounds are referred to in the trial (although not in the patent) as Group 1A and Group 2 compounds.

In a somewhat muddy single paragraph, the inventor sets out the following descriptions of the two subsets: Some of the compounds of formula I wherein R 4 and R 8 are hydrogen inhibit not only [PKC] but, at a concentration IC 50 as low as approximately 0.01 to 5 µmol/litre, especially approximately from 0.05 to 1 µmol/litre, also certain tyrosine kinases, such as especially PDGF-receptor kinase or abl-kinase, for example v-abl-kinase.

Compounds of formula I wherein at least one of the radicals R 4 and R 8 is other than hydrogen and is, for example, lower alkyl, such as methyl, are especially selective for the above-mentioned PDGF-receptor and abl-tyrosine kinases and inhibit [PKC] virtually not at all. [ 99 ] The first sentence of this paragraph describes the Group 1A compounds. These compounds are said to inhibit PKC, as well as PDGF-R or v-ABL kinases. The inhibition is apparently evidenced from the range of IC 50 values provided.

Although unstated, the experts appeared to agree that the range set out applied to both PDGF-R and ABL inhibition for the Group 1A compounds. [ 100 ] The second sentence of this paragraph is the first description of the compounds that became, in the years subsequent to the filing of the '203 Patent application, the most valuable compounds of the patent. These compounds were referred to during the trial as the Group 2 compounds, one of which is imatinib. According to the patent disclosure, the Group 2 compounds inhibit PDGF-R and ABL kinases but do not inhibit PKC.

The key construction issue raised by the wording of this paragraph is whether the inventor is telling us that the inhibition of both PDGF-R and ABL are disclosed (the Plaintiffs’ position) or that the inhibition of either PDGF-R or ABL is disclosed (Novartis’s position).

This issue is discussed below. [ 101 ] This paragraph is followed with a short description of the role of PDGF in “normal growth and pathological cell proliferation, such as in carcinogenesis and disorders of the smooth muscle cells of blood vessels, for example in atherosclerosis and thrombosis”. [ 102 ] At page 8 of the patent, the first full paragraph describes three types of testing to determine the PDGF-R inhibition characteristics of certain of the formula I compounds. Although the paragraph does not set out which of the particular subsets of compounds were tested in which experiments, Dr.

Rönnstrand agreed that the compounds tested were those outlined in the examples (4T733-734). The three types of tests were as follows: 1. The cell free inhibition of PDGF-R kinase activity in vitro “is measured in PDGF receptor immunocomplexes of BALB/c 3T3 cells”, using known methods.

The disclosure observes that “the compounds of formula I described in detail above [presumably, the Group 2 compounds although this is not expressly set out] exhibit “PDGF-dependent cell-free receptor phosphorylation at concentrations of from 0.005 to 5 µmol/litre, especially from 0.01 to 1.0, more especially from 0.01 to 0.1 µmol/litre.” 2. The next portion of the paragraph describes a method of detecting inhibition of PDGF-R in the intact cell through the use of the Western Blot Analysis.

The formula I compounds “described in detail above” inhibit the tyrosine kinase activity of the PDGF receptor at concentrations of from 0.005 to 5 µmol/litre, especially from 0.01 to 1.0 and more especially from 0.01 to 0.1 µmol/litre”. 3. Lastly, the disclosure states that “[a]t concentrations below 1.0 µmol/litre, these compounds also inhibit the cell growth of a PDGF-dependent cell line, namely BALB/c 3T3 mouse fibroblasts”.

[ 103 ] The next paragraph contains the only specific mention of testing of inhibition of v-ABL kinase. It states that: The above-mentioned inhibition of v-abl-tyrosine kinase is determined in accordance with the methods of N. Lydon et al . . . and J.F. Geissler et al . . . In those methods [Val 5 ]-angiotensin II and [γ- 32 P] ATP are used as substrates. [ 104 ] No results are provided in this paragraph. The statement is simply made that the “above-mentioned inhibition” of v-ABL kinase is determined in accordance with methods contained in published literature and names the compounds used as substrates.

This gives rise to an area of disagreement between the parties. Novartis submits that this paragraph should be read as including the test results set out in the earlier paragraph; the Plaintiffs argue that no test results are provided for the inhibitory ability of the Group 2 compounds against v-ABL kinase. Although this issue is not directly relevant to claims construction, it is relevant to the issue of sufficiency of disclosure.

I address this issue below. [ 105 ] Finally (p. 8, third and fourth full paragraphs), the patent sets out that: Owing to the properties described , compounds of formula I can be used not only as tumour-inhibiting active ingredients but also as drugs against non-malignant proliferative diseases . . . [Emphasis added.] [ 106 ] The experts agree that this paragraph likely is a reference to just the Group 2 compounds (see for example, Dr. Rönnstrand’s direct examination, 3T437-438) The experts disagree, however, on the meaning of the phrase “can be used”.

This question is at the crux of the disagreement between the parties on both the “promise” of the '203 Patent and the nature of the invention. [ 107 ] The disclosure continues for several pages with a description of preferred embodiments (pages 9-12), a description of the process for preparing the compounds (pages 12-25) and descriptions of 32 examples that “illustrate the invention” (pages 25-35). Of particular relevance, Example 21 (page 31) is imatinib. [ 108 ] The balance of the specification consists of the 48 claims.

Broadly speaking, the claims are divided into four categories, directly matching the initial paragraph of the disclosure: • Claims 1-39 claim compounds, with Claims 1 to 8 consisting of compounds described in terms of their possible chemical substitutions for R 1 to R 8 in formula I and Claims 9-39 consisting of individual compounds, all of which fall within one or more of Claims 1 to 8; • Claims 40-43 cover pharmaceutical compositions for particular treatments; • Claim 44 is a claim to the process for preparation of the compounds of formula I; • Claims 45-48 are claims to the use of the compounds according to any one of claims 1 to 39 for the preparation of a pharmaceutical composition for use in the treatment of atherosclerosis (Claim 45), use in the chemotherapy of tumours (Claim 46), chemotherapy treatment of tumours (Claim 47) and treatment of atherosclerosis (Claim 48). [ 109 ] Based on the many possible chemical substitutions at R 1 to R 8 , the class of compounds covered by Claim 1 is exceedingly large, as acknowledged by the experts, likely extending to billions of compounds. [ 110 ] The claims which follow begin to narrow the selection.

Claims 5 and 7 are of particular interest: 5. A compound of formula I according to claim 1, wherein R 1 is pyridyl or N-oxido-pyridyl each of which is bonded at a carbon atom, R 2 and R 3 are each hydrogen,

R 4 is hydrogen or lower alkyl, R 5 is hydrogen, lower alkyl or trifluoromethyl, R 6 is hydrogen, R 7 is nitro, fluoro-substituted lower alkoxy or a radical of formula II wherein R 9 is hydrogen, X is oxo N is the number 0 and R 10 is pyridyl bonded at a carbon atom, phenyl that is unsubstituted or substituted by halogen, cyano, lower alkoxy, carboxy, lower alkyl or by 4-methyl-piperazinyl-methyl, or C 5 -C 7 alkyl, thienyl, 2-naphthyl or cyclohexyl, and R 8 is hydrogen. or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group. 7.

A compound according to any one of claims 1 to 5 of formula I, wherein at least one of the radicals R 4 and R 8 is lower alkyl, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group. [ 111 ] Claim 7 encompasses only compounds from Group 2 because, as stated by Dr.

Rönnstrand (TX 13, para 109): at least one of the chemical groups substituted at positions R 4 and R 8 must be a lower alkyl group and, therefore, Group 1 compounds are excluded because they are required to have only hydrogen atoms at positions R 4 and R 8 . [ 112 ] The experts agree that Claims 9-27 and 34-39 cover compounds that are within Group 1. They also agree that the compounds of Claims 28-33 belong to Group 2 and Claim 29 is to the compound imatinib. [ 113 ] The “use” claims – Claims 45 to 48 all refer to the “use of a compound of formula I according to any one of claims 1 to 39” (emphasis added).

One example of how the compound claims should be read together with the use claims is that Claim 29 together with Claim 46 means a claim to imatinib when used in the chemotherapy of tumours. The experts acknowledge that the use of imatinib to treat CML is a use that would be considered the “chemotherapy of tumours”. [ 114 ] One very important point of agreement among the experts was that a person of ordinary skill in the art would be able to recognize that the '203 Patent includes compounds within two classes – Group 1 and Group 2.

There was some lack of clarity about Group 1A compounds; no expert identified any Group 1A compounds in the examples or the specific claims of the patent. However, the '203 Patent clearly delineates which of the examples and specifically-claimed compounds belong to Group 1 and which to Group 2. Further, the skilled person would also know the key attributes of each of these two groups or sub-classes. Specifically, the Group 1 compounds selectively inhibit PKC.

Subject to the dispute surrounding the meaning of “and”, the Group 2 compounds selectively inhibit PDGF-R and ABL, but not PKC. [ 115 ] The submissions of the parties raise serious issues of construction of the '203 Patent. [ 116 ] The first question has been referred to as the “and/or” issue. Should the '203 Patent – and Claim 46 in particular – be read such that every one of the claimed Group 2 compounds is capable of treating both tumours which are driven by PDGF-R and tumours driven by ABL kinases?

Or, is the more appropriate construction one where each of the Group 2 compounds may treat either a PDGF-R driven tumour or an ABL-driven tumour? [ 117 ] The second issue relates to the meaning of “can be used” as presented in the disclosure. [ 118 ] Finally, in this section, I will address the question of whether the '203 Patent discloses any data or test results for ABL kinase inhibition by the Group 2 compounds.

[ 119 ] Another broad area of concern relates to the intent or breadth of the '203 Patent. In language useful for an analysis of the utility of the patent, what is the “promise” of the '203 Patent? In a similar vein, the question relevant to an examination of the sufficiency of the disclosure is this: what is the nature of the invention? These two questions will be dealt with in the applicable sections of these reasons. D.

The “and/or” Question [ 120 ] A central construction question is whether Claim 46 should be construed to mean that every Group 2 compound is a selective inhibitor of both PDGF-R and ABL kinases. Or, is the more reasonable construction one where each of the Group 2 compounds is a selective inhibitor of either PDGF-R or ABL? Claim 46 is a claim to: 46.

A use of a compound of formula I according to any one of claims 1 to 39 or a pharmaceutically acceptable salt of said compound having at least one salt-forming group for the preparation of a pharmaceutical composition for use in the chemotherapy of tumours. [ 121 ] The Plaintiffs submit that the proper construction of Claim 46 is that each of the Group 2 compounds is useful in the treatment of both PDGF-R and ABL-driven tumours.

The term “tumours” is not defined in the claims; the reader must turn to the disclosure to assist. [ 122 ] The paragraph that appears to address this issue is at page 7 of the disclosure: Some of the compounds of formula I wherein R 4 and R 8 are hydrogen inhibit not only protein kinase C but, at a concentration IC 50 as low as approximately from 0.01 to 5 μ mol/litre, especially approximately from 0.05 to 1 μ mol/litre, also certain tyrosine kinases, such as especially PDGF-receptor kinase or abl-kinase, for example v-abl-kinase.

Compounds of formula I wherein at least one of the radicals R 4 and R 8 is other than hydrogen and is, for example, lower alkyl, such as methyl, are especially selective for the above-mentioned PDGF-receptor and abl-tyrosine kinases and inhibit protein kinase C virtually not at all. [ 123 ] All of the experts agree that the first sentence of this paragraph refers to a separate group of compounds referred to as the Group 1A compounds.

The Group 1A compounds are described with these words: [The Group 1A compounds] inhibit not only protein kinase C but . . . also certain tyrosine kinases, such as especially PDGF-receptor kinase or abl-kinase . . . [Emphasis added.] [ 124 ] This same paragraph continues with a sentence referring to the Group 2 compounds: [Group 2 compounds] are especially selective for the above-mentioned PDGF-receptor and abl-tyrosine kinases and inhibit kinase C virtually not at all. [Emphasis added.] [ 125 ] The Plaintiffs submit that the inventor chose to use the word “or” to describe the function of the Group 1A compounds.

Reading this sentence in association with Claim 46, a reader would understand that some Group 1A compounds would be useful to treat tumours driven by PDGF-R, while others could treat ABL kinase-driven tumours. [ 126 ] In contrast, the Plaintiffs assert that, by choosing the word “and” in association with the Group 2 compounds, the inventor leads the notional reader to understand that every one of the Group 2 compounds would be useful for treatment of tumours associated with either PDGF-R or ABL kinases.

It follows, in the view of the Plaintiffs, that the word “tumours” in Claim 46 means that any compound of Group 2 can treat both PDGF-R and ABL-driven tumours. Thus, they argue that a Group 2 compound that inhibits PDGF-R but not ABL does not meet the promise of the patent that the compounds would be useful for “the chemotherapy of tumours”. [ 127 ] Dr.

Rönnstrand, with no reasoning or analysis, adopts the “and” construction (TX 13, para 79): In my opinion, the person skilled in the art would have understood the above passage from the 203 Patent to say that the compounds of Group 2 inhibit both the PDGF-R and Abl protein kinases, but do not inhibit appreciably PKC (or at all). In other words, the compounds of Group 2 are said to have activity against each of PDGF-R and Abl protein kinases, but exhibit no inhibition of PKC.

[ 128 ] The English word “and” is notoriously ambiguous. I do not need an expert in medicinal chemistry to tell me that the word “and” takes its meaning from its context. The problem with the

interpretation put forward by the Plaintiffs and Dr. Rönnstrand is that it fails to consider the context of the entire paragraph in which the “and” reference is placed. The first part of the paragraph speaks to the inhibitory qualities of Group 1A compounds. As I read the second part of the paragraph, containing the explicit reference to the Group 2 compounds, it is specifically outlining the selectivity of these particular compounds. It incorporates by reference and builds on the first part of the paragraph.

In other words, the inventor is telling the reader that these Group 2 compounds have the same characteristics of the Group 1A compounds, but they are more selective because they do not inhibit PKC. The words “the above-mentioned PDGF-receptor and abl-tyrosine kinases” must be linked to the first sentence that speaks of PDGF-R and ABL in disjunctive terms. Read as a whole, this paragraph supports a reasonable

interpretation that the Group 2 compounds may be inhibitors of either PDGF-R or ABL kinases. [ 129 ] This construction also is consistent with the known science of tumours in 1993. As explained by Dr. Van Etten in his Expert Report (TX 37, para 111): I would read the Patent as relating to either PDGF-R or ABL-kinase tumours. In 1993 it was known that tumours associated with activated PDGF-R or with activated ABL kinase are distinct. That is, there are no examples either in 1993 or today of tumours that are associated with activation of both kinases. [ 130 ] This statement makes sense.

Knowing this information in 1993, a person of ordinary skill in the art would, in my view, conclude that the '203 Patent discloses that the treatment attributes of Group 2 compounds relate to either PDGF-R or ABL-kinase tumours. [ 131 ] The Plaintiffs assert that Dr. Heldin, during his cross examination, agreed that the patent promises therapeutic treatment of PDGF-R-related tumours and ABL-related tumours (14T2740-2743). In describing the properties of Group 2 compounds, one may state that they inhibit PDGF-R and ABL kinases, as Dr. Heldin did during his testimony.

However, these comments did not, in my view, address the controversy over the use of the word “and”. Dr. Heldin’s point, given the context, appears to be that use of a Group 2 compound according to Claim 46 can relate to the treatment of two types of tumours – those associated with PDGF-R and those associated with ABL kinase. It is a huge and contrived step to interpret a statement such as this as an opinion that a Group 2 compound that inhibits PDGF-R but not ABL does not meet the promise of the patent that the compounds would be useful for “the chemotherapy of tumours”, especially since Dr.

Heldin clearly took the opposite position in his report (TX 71, para 114). The Plaintiffs have taken Dr. Heldin’s general remarks out of context. [ 132 ] In support of their position on this issue, the Plaintiffs refer to my decision in Schering-Plough Canada Inc v Pharmascience Inc, 2009 FC 1128 , 81 CPR (4th) 9 [ Desloratadine (FC) ] in which case I had the occasion to review the meaning of the word “or” in a patent. [ 133 ] Claim 1 of the patent under consideration in Desloratadine (FC) , above at paragraph 76, was a claim to “a pharmaceutical composition”.

Claim 9 of the patent was to: The pharmaceutical composition of claim 1 wherein the composition is present in one of tablet or capsule form. [ 134 ] The applicant in that case, Schering-Plough Canada Inc (Schering-Plough), submitted that Claim 9 defined the subject matter of the invention in the alternative – that the claim described the invention as being in one of tablet or capsule form (para 89). Thus, Schering-Plough argued, even if I were to find that the capsule form of the compound was anticipated by the prior art, the tablet form of the drug could be treated as a separate claim and upheld.

I did not accept this argument and found all of Claim 9 to be invalid for anticipation. [ 135 ] The

interpretation that I applied in Desloratadine (FC) to Claim 9 is, in the view of the Plaintiffs, consistent with the construction that they promote for the word “tumours” in Claim 46 and the use of the word “and” in the disclosure. [ 136 ] A key factor to the meaning that I ascribed to the phrase “tablet or capsule” in that case is found at paragraph 78 of Desloratadine (FC) , where I stated the following: Claim 9 captures either tablet or capsule forms of the “pharmaceutical composition of claim 1”.

No expert appears to dispute that conclusion . [Emphasis added.] [ 137 ] The flaw in the Plaintiffs’ reliance on Desloratadine (FC) is that no expert, in that case, provided any contrary meaning of the phrase “tablet or capsule”. In contrast, before me in this case, I have opposing views from Dr. Van Etten and Dr. Rönnstrand. Unlike

Desloratadine (FC) , in this case, I must consider the alternative construction. The conclusion that I reached in Desloratadine (FC) , involving a different patent and different issues and with no dispute from the experts on the meaning of the term, cannot be said to provide me with a meaningful precedent. [ 138 ] In

summary on this issue, I conclude that it is not a reasonable construction of the '203 Patent to conclude that the word “tumours” in Claim 46 means that any compound of Group 2 can treat both PDGF-R and ABL-driven tumours. Rather, the meaning to be ascribed to Claim 46 of the '203 Patent is that a Group 2 compound may be useful to treat either PDGF-R or ABL tumours. E. Meaning of “can be used” [ 139 ] The next disagreement between the parties revolves around the words “can be used” as seen in several places in the disclosure. [ 140 ] The '203 Patent makes extensive reference to the intended use of the compounds.

The first of these references is at page 5, fourth full paragraph, where the author states: The compounds of formula I have valuable pharmacological properties and can be used, for example, as anti-tumoral drugs and as drugs against atherosclerosis . [ 141 ] A second reference is contained on page 6, second full paragraph, where the uses of the Group 1 compounds are described as follows: Owing to their inhibiting activity towards protein kinase C, the compounds of formula I ... can be used as tumour-inhibiting . . .ingredients ... [ 142 ] A similar statement is made with respect to the Group 2 compounds (third full paragraph, p. 8). [ 143 ] Does the use of the word “can” when referring to the therapeutic use of the compounds mean that the compounds are guaranteed to treat the described medical conditions?

This appears to be the position of the Plaintiffs. As presented in oral argument (15T2970): [R]eally the debate between the parties is whether "can be used" means "might be used" or "potential for use." My friend's position is that is what someone takes from the words "can be used.” We submit that the words "can be used" connote a radically different meaning to "might be used" or have "potential for use. [ 144 ] The experts were in disagreement on this question. In his report and throughout his oral testimony, Dr. Rönnstrand promoted a meaning of the word “can” to mean a certainty. In contrast, Drs.

Van Etten and Heldin took a position that the skilled person would understand the words of the patent to mean something less than certainty. For example, in his report (TX 71, para 129), Dr. Heldin stated that “compounds such as imatinib have the potential to be useful in treatment of tumours or atherosclerosis” (emphasis added).

In final argument, the Plaintiffs wrote that: The words “might” and “potential” were repeatedly injected into Novartis’ experts’ construction of the patent, notwithstanding that those words are never used in the patent in the manner suggested by Novartis’ experts. [ 145 ] The first argument of the Plaintiffs is that the words used by the author of the patent are “can be used” and not “the potential to be used”. That is correct. However, it is not determinative. [ 146 ] In the Canadian Oxford Dictionary , 2d ed, sub verbo “can”, the word “can” has at least two meanings.

It can mean “be able to”; this would support the position of the Plaintiffs. However, it can also mean “be potentially capable of”; this accords with the view of Novartis. To establish a purposive meaning for the phrase “can be used”, we need to look to the context and subject matter of the '203 Patent.

[ 147 ] The Plaintiffs rely on the decision of my colleague, Justice Boivin, in Apotex Inc v Sanofi-Aventis , 2011 FC 1486 , 101 CPR (4th) 1 [ Clopidogrel ] , where Justice Boivin was faced with a similar question of

interpretation of the words “can be usefully administered in the treatment and prevention of platelet disorders” in the patent at issue.

While acknowledging that the words did not make reference to a guaranteed treatment in humans, he concluded that: [T]he reference at page 21 of the '777 Patent that 'the medicine of the invention can be usefully administered in the treatment and prevention of platelet disorders due to extracorporeal blood circuits or the consequence of complications in atheroma' confirms that clopidogrel on account of its properties, whilst not a guarantee, promises more than potential: it can be used in the treatment of certain human thrombotic diseases." [emphasis in original] [ 148 ] Absent the entire record before Justice Boivin in Clopidogrel , I cannot have a full understanding of how he came to this finding or what he meant by “more than potential”.

However, I observe that he rejected any argument of a “guarantee” and, from the emphasis he added to his conclusion, that he was focussed on the words “used” and “human”. In sum, I do not take this citation as an authority that is either contrary to my conclusion on this question or binding on me. [ 149 ] In the context of the '203 Patent and the world of cancer research, the word “can” does not conve

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