GlaxoSmithKline Inc. v. Pharmascience Inc.

GlaxoSmithKline Inc. v. Pharmascience Inc.
Court (s) Database
Federal Court Decisions
Date
2011-03-01
Neutral citation
2011 FC 239
File numbers
T-1687-09
Decision Content
Federal Court
Cour fédérale
Date: 20110301
Docket: T-1687-09
Citation: 2011 FC 239
Toronto, Ontario, March 1, 2011
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
GLAXOSMITHKLINE INC. and
BEECHAM GROUP p.l.c.
Applicants
and
PHARMASCIENCE INC. and
THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT AND JUDGMENT
[1] This is an application for prohibition brought under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended (NOC Regulations). The medicine at issue is rosiglitazone, a derivative of a class of compounds known as thiazolidinediones (TZD). It is used to treat diabetes. The Applicant GlaxoSmithKline Inc. (GSK) sells a rosiglitazone drug under the brand name AVANDIA. The Respondent Pharmascience Inc. wishes to sell a generic version of that drug in Canada. The Applicants seek an order prohibiting the Respondent Minister of Health from issuing a Notice of Compliance to Pharmascience which would otherwise permit it to sell that generic version in Canada until the expiry of Canadian Patent No. 1,328,452.
[2] For the reasons that follow, I find that the application is allowed with costs to the Applicants. The Minister is prohibited from issuing a Notice of Compliance to Pharmascience until after the expiry of Canadian Letters Patent No. 1,328, 452 on April 12, 2011.
INDEXING
[3] For convenience, the matters considered in these Reasons can be found at the following paragraphs:
THE PARTIES ………………………………………paras 4 to 7
CANADIAN PATENT NO. 1,328,452 …………….paras 8 to 25
EVIDENCE ………………………………………….paras 26 to 30
BACKGROUND – DIABETES ………………………….. para 31
THE DEVELOPMENT OF THE INVENTION …………para 32
ISSUES ………………………………………………paras 33 to 36
NOC PROCEEDINGS ……………………………...paras 37 to 42
BURDEN OF PROOF……………………………….paras 43 to 44
PERSON OF ORDINARY SKILL IN THE ART
(POSITA) ……………………………………………paras 45 to 52
CLAIM 41 – CONSTRUCTION …………………..paras 53 to 58
OBVIOUSNESS …………………………………….paras 59 to 76
INSUFFICIENCY – UTILITY – LACK OF SOUND PREDICTION ………………………………………paras 77 to 94
IS THE SPECIFICATION “SUFFICIENT” ENOUGH TO SUPPORT THE “PROMISED” UTILITY ………..paras 95 to 98
a)Pharmascience’s Allegations in a Nutshell. ...paras 80 & 81
b)GSK’s Position in a Nutshell ……………………...para 82
c)Jurisprudence as to Reading a Specification ..paras 83 to 85
d)Construing Page 1 of the ‘452 Patent ………paras 90 to 94
WHAT WAS THE MOUSE TEST THAT BEECHAM
DID ………………………………………………….paras 99 to 118
CONCLUSIONS AND COSTS ………………….paras 119 to 121
JUDGMENT………………………………………………………..
THE PARTIES
[4] The Applicant GlaxoSmithKline Inc. (GSK) is called a “first person” in the NOC Regulations. It has received approval, in the form of a Notice of Compliance, from the Minister of Health to sell a drug in Canada containing rosiglitazone as its active ingredient for use as an adjunct to diet and exercise to reduce insulin resistance and improve glycemic control in patients with type 2 diabetes mellitus. It sells such a drug in different strength tablets containing 1.0 mg, 2.0 mg, 4.0 mg and 8.0 mg rosiglitazone, under the brand name AVANDIA.
[5] The other Applicant is Beecham Group p.l.c. of the United Kingdom (Beecham). Canadian Patent No. 1,328,452 was issued and granted to Beecham on April 12, 1994. It has been joined as a party as required by subsection 6(4) of the NOC Regulations. Given that there is no evidence to the contrary, Beecham remains the owner of that patent.
[6] The Respondent Pharmascience Inc. is a generic drug company with offices in Montreal. It is called a “second person” in the NOC Regulations. It delivered a letter dated August 24, 2009, referred to as a Notice of Allegations under the NOC Regulations, to GSK stating that it was seeking approval from the Minister of Health to market a generic version of GSK’s rosiglitazone drug in Canada in the same strengths in tablet form, for the same uses. Pharmascience alleged that the relevant claims of Canadian Patent No. 1,328,452 were invalid, and because they were invalid, would not be infringed by Pharmascience’s generic version.
[7] The Respondent Minister of Health is responsible for approving drugs such as that at issue here for sale in Canada by way of issuing Notices of Compliance to drug companies under the NOC Regulations. The Minister had notice of these proceedings but did not actively participate.
CANADIAN PATENT NO. 1,328,452
[8] At issue is one patent, Canadian Patent No. 1,328,452 (the ‘452 Patent). The application for that patent was filed with the Canadian Patent Office on September 2, 1988, which is before October 1, 1989. This means that the provisions of the “old” Patent Act, RSC 1985, c. P- 4 pertaining to patents maturing from applications filed before October 1, 1989, apply to the ‘452 Patent.
[9] Among the matters pertinent to the ‘452 Patent under the provisions of the “old” Patent Act are:
a. It endures for a term of seventeen (17) years from the date it was granted. The patent was granted April 12, 1994; therefore, its term will expire April 12, 2011.
b. The patent and its claims are to be construed as of the date of publication, which in the case of an “old” Patent Act patent is the date of grant, here April 12, 1994, (see Whirlpool Corp. v. Camco Inc., [ 2000 ] 2 S.C.R. 1067 at para. 55).
c. Novelty has not been pursued in these proceedings; however, it is to be considered having regard to certain kinds of publications and uses earlier than two years before the Canadian filing date that is, before September 2, 1986.
d. Obviousness, which is an issue in these proceedings, is to be considered as of the “date of invention”. That date may be proved in evidence. Unless otherwise provided, it is presumed to be the Canadian filing date, here September 2, 1988. In the present case, the ‘452 Patent claims “priority” from three applications filed in the British Patent Office on September 4, 1987, November 30, 1987 and February 4, 1988. These applications were not properly put in evidence. If those applications were put in evidence, and if they are shown to disclose the same invention as claimed in the claims at issue of the ‘452 Patent, then the relevant one or more of those applications can be said to support a date of invention as of their filing date in the British Patent Office.
[10] In the present case, the Applicants are relying only on one claim of the ‘452 Patent, claim 41. That claim is directed to a specific compound which is set out in a chemical form, but may simply be called rosiglitazone. Claim 41 reads as follows:
41. A compound according to claim 1 being
5-(4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-
2,4-thiazolidinedione; or a tautomeric form thereof
and/or a pharmaceutically acceptable salt thereof
and/or a pharmaceutically acceptable solvate thereof.
The specification begins at page 1 with a general description as to the invention:
NOVEL COMPOUNDS
This invention relates to certain substantial thiazolidinedione derivatives, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
[11] In the next paragraph the ‘452 Patent acknowledges certain prior art relating to TZDs including a number of published European patent applications and a scientific article (referred to as “Sohda II” in this proceeding) all relating to TZD derivatives:
European Patent Applications, Publication Numbers 0008203, 0139421, 0155845, 0177353, 0193256, 0207581 and 0208420 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity. Chem. Pharm. Bull 30 (10) 3580-3600 also relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities.
[12] Pharmascience relies on many of these patent applications, as well as Sohda II and a related article in the same scientific publication (referred to as Sohda I in these proceedings) as “prior art” for the purpose of arguing obviousness. The named inventor of the ‘452 Patent, Richard M. Hindley, gave evidence in these proceedings and acknowledged that Sohda I and Sohda II were not only known to him, but formed part of the basis for his research leading to rosiglitazone. (Hindley affidavit paras 9-11). Hindley also acknowledged that at least some of these European patent applications became known to him during the course of his research. (Hindley affidavit paras 28-30). All of this “prior art” originates from a Japanese pharmaceutical company, Takeda.
[13] The next two paragraphs provide the basis for much of the argument in these proceedings, namely, what, if anything, is the “promise” of the patent, and has it been fulfilled:
It has now surprisingly been discovered that certain novel substituted- thiazolidinedione derivatives show improved blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes.
These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia, hypertension, cardiovascular disease and certain eating disorders.
[14] The specification, beginning at the bottom of page 1 to the first two lines at page 8 of the ‘452 Patent describes the compounds encompassed in the patent, their structure and substituent parts. The number is vast. I will not repeat this section in detail. Rosiglitazone is not specifically mentioned until Example 30 of the ‘452 Patent, which occurs much later.
[15] The specification of the ‘452 Patent beginning at page 8, line 5, through to page 18, line 28, describes processes by which the compounds may be prepared.
[16] Beginning at line 30 of page 18 of the ‘452 Patent and over to page 19, line 20, a number of uses for the compounds are described. In general, the uses are therapeutic properties including treatment of hyperglycaemia, hyperlipidaemia, hypertension, cardiovascular disease, and certain eating disorders.
[17] From line 22, page 19, to the end of page 22, the method of administration, the formulation and dosages of the medicine are described.
[18] At page 21 the patent describes the invention as further providing a method of treatment and/or prophylaxis of a number of human and non-human conditions:
The present invention further provides a method for the treatment and/or prophylaxis of hyperglycaemia in a human or non-human mammal which comprises administering an effective, non-toxic, amount of a compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycaemic human or non-human mammal in need thereof.
The present invention further provides a method for the treatment of hyperlipidaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, to a hyperlipidaemic human or non-human mammal in need thereof.
[19] From page 23 to page 79, a number of preparations and examples are provided. Of importance here is Example 30, found at page 78, which is the only Example which specifically discloses rosiglitazone:
EXAMPLE 30
5-(4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl)-2,4-thiazolidinedione
The title compound (m.p. 153-5°C; MeOH) was obtained from 5-(4-[ 2-(N-methyl-N-(2-pyridyl)amino)ethoxyl ]-benzylidene)-2,4-thiazolidinedione by a similar procedure to that described in Example 1.
1H NMR & (DMSO – d6)
2.9-3.4 (2H, complex); 3.1 (3H, s); 3.9 (2H, t); 4.15 (2H, t); 4.8 (1H, complex); 6.5-6.85 (2H, complex); 6.8 (2H, d); 7.2 (2H, d); 7.5 (1H, complex); 8.1 (1H, d); 12.05 (1H, broad s, exchanges with D20).
[20] The procedure found in Example 1, as referred to in Example 30, appears at pages 51 and 52 of the ‘452 Patent as follows:
5-(4-[2-(N-Methyl-N-(2-benzothiazolyl)amino)ethoxy]benzylidene)-2,4-thiazolidinedione (2g) in dry 1,4-dioxan (70ml) was reduced under hydrogen in the presence of 10% palladium on charcoal (3g) at ambient temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through diatomaceous earth, the filter pad was washed exhaustively with dioxan and the combined filtrates were evaporated to dryness under vacuum. The title compound (m.p. 167-8ºC) was obtained after crystallisation from methanol.
[21] The only test data provided in the ‘452 Patent is set out at pages 80 and 81. It describes a test in which obese (also referred to as ob/ob) mice were fed a powdered diet into which were incorporated compounds of the kind set out in some of the Examples of the patent. It is to be noted that the compound of Example 30, rosiglitazone, is not among the compounds tested:
DEMONSTRATION OF EFFICACY OF COMPOUNDS
Obese Mice, Oral Glucose Tolerance Test.
C57bl/6 obese (ob/ob) mice were fed on powdered oxoid diet. After at least one week, the mice continued on a powered oxoid diet or were fed powdered oxoid diet containing the test compound. After 8 days on the supplemented diet all of the mice were fasted for 5 hours prior to receiving an oral load of glucose (3 g/kg). Blood samples for glucose analysis were taken 0, 45, 90 and 135 minutes after glucose administration and the results appear below as the percentage reduction in area under the blood glucose curve where test compound treated groups are compared with the control groups. 7 mice were used for each treatment.
LEVEL IN DIET % REDUCTION IN
(μmol kg—1 of AREA UNDER
DIET BLOOD GLUCOSE
EXAMPLE NO: CURVE
_____________ _____________ ________________
1 100 51
2 300 30
3 10 39
4 300 30
5 100 40
7 50 47
9 100 58
11 100 34
13 100 37
15 100 39
17 100 34
19 30 22
21 30 33
24 30 15
25 30 19
27 300 56
29 300 32
Toxicology
No toxicology effects were indicated for any of the compounds of the invention in any of the abovementioned tests.
[22] The claims of the ‘452 Patent begin at page 82. In all, there are 49 claims. Claims 1 to 42 are directed to compounds. Claims 43 and 46 are directed to a pharmaceutical composition containing the compound(s). Claims 44, 45, 47 and 48 are directed to an “effective amount” of the compound(s) for treatment. Claim 49 is directed to a process for preparing the compound(s).
[23] Claim 1, which is referred to in claim 41, refers to a vast number of compounds (of which rosiglitazone is one although not specifically mentioned) with reference to a general structure. I will repeat only the opening portion as the balance of the claim describes the various substituents that can be used:
1. A compound of formula (I):
or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof; wherein:
[24] Claims 1 and 41 refer to a “tautomeric form” of the compound. No issue was made of in this proceeding as to what a tautomeric form was. For convenience the parties have agreed on the definition of a tautomer as found in Wikipedia as follows (omitting the pictorial representations):
Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. It is common that this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. The concept of tautomerizations is called tautomerism. Because of the rapid interconversion, chemical structures which are tautomers of each other are generally considered to be the same chemical compound. Tautomerism is a special case of structural isomerism and can play an important role in non-canonical base pairing in DNA and especially RNA molecules.
[25] Claims 1 and 41 also both use the words “pharmaceutically acceptable”, which are defined at pages 19 and 20 of the ‘452 Patent as follows:
As used herein the term ‘pharmaceutically acceptable’ embraces compounds, compositions and ingredients for both human and veterinary use: for example the term ‘pharmaceutically acceptable salt’ embraces a veterinarily acceptable salt.
EVIDENCE
[26] As is usual in applications of this kind, the evidence was provided in the form of affidavits, transcripts of cross-examinations and related exhibits. No live witnesses appeared before the Court. At one time, there was a Confidentiality Order in place; however, at the request of the parties, that Order was set aside by my Order dated January 11, 2011. Some of the material may still bear a caption to the effect that it is confidential, but that is no longer the case.
[27] The Applicants provided the affidavit evidence of the following witnesses:
i. Carolyn Ann Lister, an employee of GSK (a term I use to include its predecessors as well) at the relevant time, in particular, 1988. She received diplomas in biological science and was employed to organize and manage in vivo testing at these predecessors. She testified as to the testing of compounds including rosiglitazone in ob/ob mice.
ii. Professor Clifford Bailey, of Birmingham, UK. He is the Head of Biomedical Research, including Diabetic Research; and Professor of Clinical Science at Aston University, Birmingham, UK. His mandate, as stated at paragraph 12 of his affidavit, was to provide scientific and historical content to research relating to abnormal glucose metabolism and diabetes prior to September 2, 1988 and to comment on certain aspects of the ‘452 Patent as they relate to the use of animal models in diabetes research and data GSK had generated on rosiglitazone prior to September 2, 1988.
iii. Richard M. Hindley, of Surrey UK. He is the named inventor of the ‘452 Patent. He worked as a chemist in a variety of industries. He joined a predecessor of GSK in 1968. Most of his career was focused on the synthesis of potential new drugs. He testified as to the research and development leading up to the ‘452 Patent.
iv. Dr. Peter Jurs, of Pennsylvania, USA. He received a PhD in chemistry in 1969 and spent much of his career in academia, research and consulting. Before his retirement in 2005, he was Professor of Chemistry at Penn State University. He is now a Professor Emeritus at that University. His mandate, as stated at paragraph 8 of his affidavit, was to provide an opinion on the subject of lipophilicity as it relates to the allegation of obviousness and generally as to the subject of lipophilicity.
v. Professor Peter Wipf, of Pennsylvania, USA. He received a PhD in chemistry in 1987 and has spent most of his career in academia, research and consulting. He is currently a Distinguished University Professor of Chemistry at the University of Pittsburgh. He was asked to provide a background as to organic chemistry and to address a number of questions as set out at paragraph 11 of his affidavit:
Questions addressed
11. I have been asked to provide my opinion on the following questions:
(a) Who is the person of ordinary skill in the art to whom the 452 patent is directed?
(b) What does claim 41 of the 452 Patent claim?
(c) Is the invention of claim 41 of the 452 Patent obvious in light of the prior art?
(d) Does the disclosure of the 452 Patent enable a person of ordinary skill in the art to synthesize rosiglitazone?
vi. Christine Ingham, law clerk with the Applicants’ firm of solicitors. Her affidavit served to put in the Record, as exhibits, a number of documents. This affidavit and the authenticity of these documents are not controversial.
[28] The evidence of Bailey, Jurs and Wipf was tendered as expert evidence. No objection was taken by Pharmascience to this evidence being received by this Court as expert evidence. Each of Lister, Bailey, Hindley, Jurs and Wipf was cross-examined by Counsel for Pharmascience. Ingham was not cross-examined.
[29] The Respondent Pharmascience provided the affidavit evidence of the following witnesses:
1. Dr. Jonathan S. Dordick, of Schenectady, New York. He received a PhD in Biochemical Engineering in 1986. He has spent most of his career in academia, research and consulting. He is currently the Howard P. Isermann Professor in the Department of Chemical and Biological Engineering, with a joint appointment in the Department of Biology and Biomedical Engineering at Rensselaer Polytechnic Institute, Troy, NY. He was asked to review a number of documents and to answer certain questions as set out in paragraph 22 of his affidavit:
22. I have been asked to review Canadian Patent No. 1,328,452 (“’452 Patent”) and answer the following questions:
(1) Who is the “person skilled in the art” to whom the ‘452 Patent is addressed?
(2) Is there sufficient information in the patent for a person skilled in the art to understand what the invention is; and is there sufficient information for a person skilled in the art to understand that rosiglitazone will be an effective compound for use or potential use in humans?
(3) What is the promised utility of the patent? Is there sufficient information in the affidavit of Ms. Lister to show that rosiglitazone has the promised utility and if not, is there sound scientific prediction based on the information in the patent that rosiglitazone will have the promised utility?
(4) If Dr. Bailey is correct at paragraph 41 that “improved blood glucose lowering activity” simply means that when these TZD derivatives are administered to animals there is an improvement in the blood glucose levels of the animals, then is rosiglitazone obvious?
2. Dr. Barry L. Posner, of Montreal, Quebec. He is a medical doctor and currently a Professor of Medicine and Director of Polypeptide Hormone Laboratory at McGill University. He claims expertise in Endocrinology and Diabetology, as well as the mechanism of hormone and drug action. He was given a number of documents to review and was asked to answer certain questions as set out in paragraph 19 of his affidavit:
19. I have been asked to review Canadian Patent No. 1,328,452 and answer the following questions:
i. Who is the “person skilled in the art” to whom the ‘452 Patent is addressed?
ii. Is there sufficient information in the patent for a person skilled in the art to understand what the invention is; and is there sufficient information for a person skilled in the art to understand that rosiglitazone will be an effective compound for use or potential use in humans?
iii. What is the promised utility of the patent? Is there sufficient information in the affidavit of Ms. Lister to show that rosiglitazone has the promised utility and if not, is there a sound scientific prediction based on the information in the patent that rosiglitazone will have the promised utility?
iv. If I accept Dr. Bailey’s evidence that all thiazolidinedione derivative compounds would be useful as blood glucose lowering agents and useful in the treatment of diabetes, is it be obvious that rosiglitazone (which is such a compound) would have the same usefulness?
3. Dr. Brian Rodrigues, of Vancouver, British Columbia. He received his PhD in Pharmaceutical Sciences in 1989 and spent most of his career in academia. He is also a Director of the Canadian Diabetes Association. He is currently Professor of Pharmacology and Toxicology at the University of British Columbia. He was asked to review a number of documents and provide an opinion as set out in paragraph 12 of his affidavit:
12. The solicitors for Pharmascience have asked me to review the documents in the above paragraph of my affidavit and to provide my opinion with respect to the issues set out in the Notice of Allegation. Specifically, the solicitors for Pharmascience have asked me to provide my opinion with respect to the following issues:
(a) Sufficiency of Specification: is the data disclosed in the ‘452 Patent sufficient for a person skilled in the art to understand what the invention is?
(b) Utility/Sound Prediction what is the promise of the ‘452 Patent and does Rosiglitazone have the utility as promised in the patent? Does the additional information provided by GSK establish the utility of rosiglitazone as promised in the patent? And if not, is there a sound scientific prediction found in the patent to support the utility of rosiglitazone?;
(c) Obviousness: If I accept Dr. Bailey’s evidence that all thiazolidinedione derivative compounds would be useful as blood glucose lowering agents and useful in the treatment of diabetes, would is it be [sic] obvious that rosiglitazone (which is such a compound) would have the same usefulness?
4. Professor Alexander M. Klibanov, of Boston, USA. He received his PhD in Chemical Enzymology in 1974. He has spent most of his career in academia, research and consulting. He reviewed the ‘452 Patent and the evidence of Hindley, Lister and Wipf and provided his opinion in respect thereof.
[30] The evidence of each of Dordick, Posner, Rodriguez and Klibanov was put forward by Pharmascience as expert evidence without objection by GSK to this evidence being received by this Court as such. Each was cross-examined by Counsel for GSK.
BACKGROUND - DIABETES
[31] The ‘452 Patent is, in large measure, directed to compounds said to be useful in the treatment of conditions related to the level of glucose in the bloodstream of a human body. Of these, diabetes is common. GSK has provided evidence from Dr. Bailey in this regard. Pharmascience’s Counsel has advised the Court, by letter dated December 30, 2010, that paragraphs
11 – 18 of Dr. Bailey’s affidavit can be accepted by the Court as agreed upon background. Dr. Bailey says at paragraphs 13 to 18:
Scientific Background
13. Since the 452 Patent discloses and claims compounds of potential use in diseases associated with abnormal glucose metabolism, including diabetes, it is appropriate to begin with a brief introduction of the basic principles of glucose metabolism and diabetes. The basic principles discussed below would have been known to a person of ordinary skill in the art (defined below) as of September 2, 1988 and the same basic principles are known today.
Glucose Metabolism
14. Glucose is a sugar that provides energy to all of the cells in the body. The cells take in glucose from the blood and break it down for energy. The glucose in the blood comes from food. When food is eaten, glucose is absorbed from the intestines and distributed by the bloodstream to all of the cells in the body. In normal, healthy individuals, the level of glucose in the blood is regulated. The body tries to maintain a balance between the amount of glucose available in the bloodstream and its clearance from the bloodstream. In a situation when there is an oversupply of glucose, the body stores the excess glucose in the liver and muscles by making glycogen (long chains of glucose). When there is a short supply of glucose, the body mobilizes glucose from stored glycogen and/or makes glucose from other sources.
15. To maintain a constant blood glucose level the body depends on certain simultaneously ongoing processes that must occur in a coordinated fashion. After the ingestion of food, the body stimulates secretion of insulin, a hormone that is produced in the pancreas. Insulin is made and secreted by the beta cells (β-cells) of the pancreatic islets, small islands of endocrine cells in the pancreas. Insulin is required by almost all of the body’s cells, but its major targets are liver cells, fat cells and muscle cells. The combination of hyperinsulinaemia (i.e., high insulin levels in the blood) and hyperglycaemia (i.e., high glucose levels in the blood) promote glucose uptake by peripheral tissues (primarily muscle) and suppress glucose production in the liver. As such, insulin stores nutrients after the ingestion of food by reducing the concentrations of glucose in the bloodstream and maintains a steady blood glucose concentration in the body. Defects at the level of the β -cell, muscle or liver can lead to the development of glucose intolerance or overt diabetes.
Diabetes
16. Diabetes is a disease that affects the body’s ability to use glucose. It is classified into two main types: Type 1 and Type 2. Type 1 (also called juvenile diabetes or insulin- dependent diabetes) is caused by a lack of insulin. This type is found in five to ten percent of diabetics and usually emerges in children or adolescents. In these individuals, the β -cells of the pancreatic islets are destroyed either by the person’s own immune system, genetic or environmental factors. As a result, these patients have abnormal levels of glucose and little or no insulin in their blood.
17. Type 2 diabetes (also called adult-onset diabetes or non-insulin-dependent diabetes) occurs through two primary defects. In some patients the primary defect starts at the level of the β -cell and manifests itself as an impairment in insulin secretion. These individuals are represented by lean diabetic patients. In other patients the primary defect starts as an impairment in tissue (muscle and liver) sensitivity to insulin (insulin resistance). These individuals are represented by obese diabetic patients. However, both defects initiate the development of Type 2 diabetes and lead to the development of glucose intolerance. Type 2 diabetes occurs in 90 to 95 percent of diabetics and usually occurs in adults over the age of 40, emerging most often between the ages of 50 and 60.
Insulin resistance
18. Insulin resistance is a cardinal feature of Type 2 diabetes. It is defined as a “reduced biological response to physiological amount of insulin.” It causes high blood glucose levels during fasting and after a meal (reduced glucose tolerance). Since the body does not respond to insulin, the cells do not take up glucose from the bloodstream, which causes high blood glucose levels. Because cells have no glucose coming into them from the blood, the body “thinks” that it is starving and triggers a number of events. It triggers certain hormones to act on liver and muscles to breakdown stored glycogen and release glucose into the blood. This further raises blood glucose levels.
THE DEVELOPMENT OF THE INVENTION
[32] The Court has been provided with the evidence of Richard M. Hindley, the person named as the inventor of the ‘452 Patent and of Carolyn Ann Lister, the person at GSK responsible for testing compounds such as rosiglitazone in mice. Taking their evidence including their affidavits, cross-examination transcripts, and exhibits (in particular Exhibit X to Hindley’s affidavit a scientific paper naming Hindley and Lister as authors, called the Cantello paper in these proceedings, and Exhibit C to Hindly’s affidavit, a useful chart) the development of the “invention” of the ‘452 Patent can be outlined as follows:
a. 1968 after working elsewhere as a chemist, Hindley joined Beecham as a research chemist.
b. 1981 Hindley was assigned to work on a diabetes research program at Beecham, Cantello was his supervisor. Lister performed or supervised many of the animal tests on compounds made.
c. 1982 Hindley became aware of the Sohda I and Sohda II papers published by Takeda. They disclosed what Hindley described at paragraph 10 of his affidavit as interesting preliminary results concerning TZD. He considered this to be a starting point for his research.
d. 1983 a course of experimental research was established using one of the TZD compounds disclosed in Sohda II as a reference, ciglitazone (AD-3878).
e. By summer 1988, Hindley and his colleagues had made and tested approximately 129 compounds. Some with more blood glucose level reducing activity than ciglitazone, some less.
f. During the period from 1983 to 1988 Hindley and his colleagues became aware of some of the European Patent Applications published by Takeda as listed in the ‘452 Patent, including applications 0155845 (EP845) and 0177353 (EP353). These applications were used to direct the areas of research conducted by Hindley.
g. By August 1, 1988 Hindley had synthesized the compound he called HG 49653 and which we now know as rosiglitazone. Details of this compound, its structure and method of synthesis were provided to Beecham’s patent agent and now appear in Example 30 of the ‘452 Patent.
h. August, 1988 a sample of rosiglitazone was provided to Lister’s group for testing.
i. In mid August 1988 Lister’s group subjected the rosiglitazone compound as well as another compound to testing in mice. The nature of the test is essentially as described for other compounds at page 80 of the ‘452 Patent. A group of mice called a “control” group were fed only normal feed without any additives. Another group were fed with food including a dosage of the compound to be tested. Only a single dosage level was tested for rosiglitazone. After a period of eight days each group of mice were fasted for five hours; blood samples were then withdrawn from each group over intervals; the glucose levels measured and the results from each group compared. Normally the test would comprise feeding at two different dosage levels but apparently for constraints of space, only one dosage level was used for the rosiglitazone test. The other compound was tested at two levels. The result achieved for rosiglitazone using an area under a curve (not shown), as calculated by computer, showed a 42% reduction of blood-glucose level which is said to be near the top level of what could be expected.
j. The mice results arrived too late to be given to the Beecham patent department.
k. September 2, 1988 the application for the ‘452 Patent was filed in Canada.
l. Work continued, further compounds were developed.
m. April 12, 1994 the ‘452 Patent was issued.
n. Late 1994 the work of Hindley and Lister was published in the form of the Cantello paper.
o. 1999 rositiglazone, along with another TZD derivative proglitazone ,was approved for sale as a diabetic treatment in the United States and elsewhere. At the same time a previously approved TZD derivative, troglitazone was removed from the market because of toxic effects on the liver (Posner, Exhibit D).
p. the Posner affidavit also provides evidence that, in the mid 2000’s and onward, concerns have arisen that rosiglitazone may have a detrimental effect on persons with heart conditions. In some countries the drug has been withdrawn. Elsewhere, such as Canada, its use has been restricted. (Posner affidavit paragraphs 56 and 57, Exhibits F and G).
ISSUES
[33] The primary issue is whether the Applicants have demonstrated, in accordance with subsection 6(2) of the NOC Regulations, that none of the allegations made by the Respondent Pharmascience in its Notice of Allegation are justified. Those allegations were directed to the validity of certain of the claims of the ‘452 Patent. Other claims were said to be irrelevant to the proceedings. The claims at issue have been reduced to one: claim 41.
[34] There is no issue as to infringement, Pharmascience’s allegation in that respect rests on its allegations as to invalidity; hence, it is alleged, no valid claim is infringed.
[35] As to invalidity of claim 41 of the ‘452 Patent, Pharmascience, at paragraph 53 of its Notice of Allegation, alleged invalidity on the following grounds:
a. Obviousness;
b. Insufficient Disclosure;
c. Lack of Utility;
d. Lack of Sound Prediction; and
e. Claims Broader than the Invention Made or Disclosed
[36] In its Memorandum, Pharmascience reduced these issues to three:
1. Inutility (in this regard Pharmascience’s Counsel made it clear that it was not arguing that the description in the patent was insufficient as far as the making of the compound is concerned);
2. Sufficiency; and
3. Obviousness.
NOC PROCEEDINGS
[37] The NOC Regulations are unique. They are based on the United States Hatch-Waxman Act (Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No 98-47, 98 Stat. 1586) and were introduced in 1993 to replace the previous compulsory licence scheme pertaining to drug patents in Canada. There is no question that they were imperfectly drafted, that they have been imperfectly amended and imperfectly interpreted by the Courts.
[38] The NOC Regulations identify two groups of persons, a “first person”, commonly called the “brand”, who is the person owning or licensed under a patent and who has received permission to sell a drug somehow relating to that patent in Canada (section 4(1)). A “second person”, commonly called a “generic” is a drug company wanting to take advantage of much of the material submitted by the first person in order to obtain approval itself to sell the drug. The second person must notify the first person providing particulars of its application to secure approval and to state that the patent will not be infringed or is invalid or that the second person will wait for the patent to expire. That notification takes the form of a “Notice of Allegation” (NOA).
[39] That Notice of Allegation (NOA) is required by subsection 5(3)(b)(ii) of the NOC Regulations to include “a detailed statement of the legal and factual basis for the allegations”. In the present case, the allegations made are that certain claims of the ‘452 Patent, now restricted to claim 41, are invalid for a number of reasons. When the NOC Regulations were introduced in 1993, a Notice of Allegation took the form of a simple letter, only a few pages long, in which very generalized statements were made. Matters have evolved. Typical of a current style NOA is that filed in this case which is 50 pages long, containing 173 paragraphs drafted as if it were a legal memorandum of law and fact.
[40] Without comment as to whether they are right or wrong as a matter of “fairness”, certain principles have emerged as a result of judicial interpretation as to an NOA, including:
i. The NOA cannot be amended once legal proceedings have commenced except that certain allegations made can be omitted or no longer relied upon (e.g. Hoffmann-La Roche Ltd v. Canada (Minister of National Health and Welfare) (1996), 70 C.P.R. (3d) 1, (FCA); Bayer A/G v. Novopharm Ltd. (2006), 48 C.P.R. (4th) 46 (FC) at paras 72 to 84).
ii. The Notice of Allegation must be sufficient so as to make the “first person” fully aware of the grounds raised as to invalidity or non-infringement (Mayne Pharma (Canada) Inc. v. Aventis Pharma Inc. (2005), 38 C.P.R. (4th) 1 (FCA), at paras. 19-21).
iii. A second person cannot, in proceedings taken in Court, present argument and evidence relating to an issue that is outside the scope of its NOA (e.g. Ratiopharm Inc. v. Canada (Minister of Health) (2007), 58 C.P.R. (4th) 97 (FCA), at para. 25.
iv. The second party may not shift ground or raise a new ground during the legal proceedings that has not been raised in its NOA (Pfizer Canada Inc. v. Canada (Minister of Health) (2006), 54 C.P.R. (4th) 279 (FC), at paras 70 – 71).
[41] In the Court proceedings, a first person is required to demonstrate, in accordance with subsection 6(2) of the NOC Regulations, that “none of those allegations is justified”. Thus, the object of the proceedings is to look at the allegations, consider the evidence, apply the law, and determine whether an allegation made in the NOA is justified. Such a determination, for instance, whether an allegation as to invalidity is justified or not, does not preclude that issue from being litigated in an ordinary action respecting the patent, in other words, there is no res judicata (Aventis Pharma Inc. v. Apotex Inc. (2006), 46 C.P.R. (4th) 401(FCA), at para. 7).
[42] Therefore, the purpose of the present proceeding is to look at what Pharmascience has alleged in its NOC as to the validity of claim 41 of the ‘452 Patent and to determine if the allegations are “justified”.
BURDEN OF PROOF
[43] O’Reilly J of this Court has summarized the question of burden of proof where the issue is invalidity in Pfizer Cana