Astrazeneca Canada Inc. v. Mylan Pharmaceuticals ULC

Astrazeneca Canada Inc. v. Mylan Pharmaceuticals ULC
Court (s) Database
Federal Court Decisions
Date
2011-08-29
Neutral citation
2011 FC 1023
File numbers
T-1473-09
Decision Content
Federal Court
Cour fédérale
Date: 20110829
Docket: T-1473-09
Citation: 2011 FC 1023
Ottawa, Ontario, August 29, 2011
PRESENT: The Honourable Mr. Justice Rennie
BETWEEN:
ASTRAZENECA CANADA INC. and ASTRAZENECA UK LIMITED
Applicants
and
MYLAN PHARMACEUTICALS ULC and THE MINISTER OF HEALTH
Respondents
REASONS FOR JUDGMENT AND JUDGMENT
TABLE OF CONTENTS
Page No.
OVERVIEW... 1
THE PARTIES. 1
ESTROGEN-DEPENDENT BREAST CANCER.. 2
Aromatase. 3
Aromatase inhibitors. 3
Aminoglutethimide (AG) – The First Generation Aromatase Inhibitor 4
DEVELOPMENTS AT ICI 4
Testing on Anastrozole. 6
THE PATENT. 7
ISSUES. 10
EVIDENCE. 10
The Utility Experts. 11
The Obviousness Experts. 13
AstraZeneca’s Attack on Dr. Redden’s Credentials. 16
NOC PROCEEDINGS. 18
BURDEN OF PROOF. 19
ASTRAZENECA’S MOTION TO STRIKE. 20
PERSON OF ORDINARY SKILL IN THE ART. 23
CONSTRUCTION OF THE CLAIMS. 24
UTILITY.. 25
Requirement for Utility. 25
The Promise of the Patent 26
Does the Patent Promise Therapeutic Utility?. 28
The Expert Evidence. 29
Analysis. 30
Situating the Patent in the Scientific Context 31
Situating the Patent in the Jurisprudence. 32
Does the Patent Promise Fewer Side Effects than AG?. 34
The Expert Evidence. 35
Analysis. 37
Reading the Promise in the Context of the Patent as a Whole. 41
Conclusion on the Promise of the Patent 42
Was the Utility Demonstrated?. 42
Expert Evidence. 43
The AR1 Test 43
The OI2 and OI3 Test 44
Analysis. 45
Is the 420 Patent Disclosure Sufficient?. 48
Are Therapeutic Utility and Fewer Side Effects Demonstrated or Soundly Predicted?. 52
OBVIOUSNESS. 54
Common General Knowledge: The Structural Diversity of Inhibitors. 56
Mylan’s Obviousness Argument 57
AstraZeneca’s Obviousness Argument 59
Analysis of Expert Evidence. 60
Conclusions on Obviousness. 63
CONCLUSIONS AND COSTS. 63
JUDGMENT. 65
OVERVIEW
[1] This application for prohibition is brought under the Patented Medicines (Notice of Compliance) Regulations SOR/93-133, as amended (NOC Regulations). The medicine at issue is a compound known as anastrozole. The applicant AstraZeneca Canada Inc. (AstraZeneca) has approval from the Respondent Minister of Health to sell in Canada 1 mg anastrozole tablets, which are sold under the brand name ARIMIDEX®. This drug is used in the treatment of cancer, particularly post-menopausal breast cancer.
[2] The respondent Mylan Pharmaceuticals ULC (Mylan) has sought approval from the Minister in the form of a Notice of Compliance (NOC) to sell a generic version of that drug in Canada. Mylan alleges that AstraZeneca’s patent is invalid for lack of utility and obviousness, so that a generic version of ARIMIDEX should be allowed on the market before the expiration of AstraZeneca’s patent.
[3] For the reasons that follow, the application is allowed, and the Minister is prohibited from issuing a Notice of Compliance to Mylan until after the expiry of Canadian Patent 1,337,420 (the 420 Patent).
THE PARTIES
[4] The Applicant AstraZeneca is referred to as the “first person” in the NOC Regulations.
[5] The patent at issue is currently owned by AstraZeneca, but the testing and development was done by Imperial Chemical Industries PLC (ICI), a predecessor to the applicant AstraZeneca UK Limited.
[6] Mylan is the “second person” referred to in the NOC Regulations, and as noted above seeks approval from the Minister to sell a generic version of anastrozole.
[7] The Respondent Minister of Health is responsible for approving drugs for sale in Canada, by way of issuing a Notice of Compliance under the NOC Regulations. The Minister had notice of these proceedings but did not participate.
ESTROGEN-DEPENDENT BREAST CANCER
[8] Breast cancer is the most common cancer in women. By the early 1980s, it was well known that approximately one-third of breast cancers need estrogen to grow. Breast cancer was therefore treated by surgically or medicinally reducing estrogen levels. Surgical techniques involved removing glands or ovaries responsible for estrogen production. Medical techniques involved treatment with anti-estrogen drugs, some of which have been in use for over 30 years.
[9] By the early 1980s, it was also understood that the inhibition of a number of enzymes involved in the synthesis of estrogen would result in reduced estrogen levels, and would therefore be useful in the treatment of breast cancer.
Aromatase
[10] Aromatase is an enzyme responsible for converting testosterone to estrogen. Steroid hormones such as testosterone, are composed of four fused rings. Aromatase converts one of the rings (ring A) on androgens, resulting in the formation of estrogens.
[11] This conversion process is called aromatization. In one of the steps of conversion, the enzyme aromatase transforms one of the rings in the testosterone molecule (ring A) to a state known as an aromatic state, through the processes of oxidation.
[12] It was known in the early 1980s that preventing aromatization of ring A would prevent the formation of estrogen. Estrogens are the only steroid hormones that have an aromatic ring A.
Aromatase inhibitors
[13] An aromatase inhibitor is a chemical molecule that interferes with the aromatizing function of the aromatase enzyme, or more colloquially, the conversion of testosterone into estrogen. Aromatase inhibitors block the conversion of androgens to estrogens, thus decreasing the availability of circulating estrogens.
[14] Various cancers, including breast cancer, depend on steroid hormones that have an aromatic ring A for their growth. These cancers can be treated by surgically removing the source of the ring A aromatized steroid hormones, or by preventing the production of ring A aromatized steroid hormones by administering a chemical compound that inhibits aromatization.
Aminoglutethimide (AG) – The First Generation Aromatase Inhibitor
[15] Aminoglutethimide (AG) was the first aromatase inhibitor to be widely used in breast cancer patients. AG was an effective aromatase inhibitor, but it also inhibited enzymes involved in the production of cortisol, which is a steroid hormone essential for regulating organ function. Cortisol is essential to the body’s stress response, and reduced cortisol levels can be a life-threatening condition. Patients taking AG had to be administered hydrocortisone to avoid the serious side effects caused by cortisol deficiency. AG was thus known as a “dirty drug”, since it was not sufficiently selective in the enzymes it inhibited. In addition to the cortisol problem, side effects included nausea, lethargy, ataxia, rash and abnormal blood conditions.
DEVELOPMENTS AT ICI
[16] Because of the problematic and potentially life threatening side-effects, AG was viewed as a prototype aromatase inhibitor in the 1980s. Many research groups were actively attempting to develop more selective aromatase inhibitors. There was a race between pharmaceutical companies and academic research groups to identify such inhibitors.
[17] In 1984, formestane was a second generation aromatase inhibitor, used to treat breast cancer patients. It was the first inhibitor that specifically targeted the aromatase enzyme.
[18] In 1986, Ciba-Geigy disclosed fadrozole, a third generation aromatase inhibitor said to be a more potent aromatase inhibitor than AG, with reduced toxicity. The problem with fadrozole was that it inhibited mineralocorticoid, which could result in increased sodium retention in the body and hypertension.
[19] ICI began intensifying its research into aromatase inhibitors around 1985. ICI had a research group working on the development of agents for the control of fertility in humans and domestic animals, and treatment of hormone dependent tumours. ICI synthesized more than one thousand compounds as potential aromatase inhibitors.
[20] Anastrozole, the compound at issue, was first synthesized around August, 1986. Initially treated as a backup compound, anastrozole became the preferred candidate for clinical development when ICI discovered its lead compound could not be used in humans. The structure of anastrozole can be shown as follows:
[21] Because it was known that AG inhibited the production of cortisol, and fadrozole inhibited the production of mineralocorticoid, ICI’s testing of anastrozole focused on its potency as an aromatase inhibitor, and its selectivity, in terms of its ability to inhibit only the targeted enzyme, without affecting other enzymes. Anastrozole was specifically tested for its ability to inhibit aromatase, and whether it also inhibited the production of cortisol and mineralocorticoid, the two main problems with AG and fadrozole.
Testing on Anastrozole
[22] By June 1988, ICI had carried out seven different tests on anastrozole:
· Human placental aromatase in vitro (AR1) – a screening test to measure inhibition of aromatase activity.
· Ovulation inhibition in rats in vivo, dosed at days 2 or 3 of oestrous cycle (OI2 and OI3) – to provide further evidence of inhibition of aromatase activity, but in an in vivo setting. An in vitro compound does not automatically result in in vivo activity.
· Male side effects in rats in vivo (MSE) – to determine whether the compound had the same side effect as AG, inhibition of cortisol synthesis.
· Placental enlargement in rats in vivo (PE9) – another measure of aromatase inhibition in vivo.
· 11-hydroxylase inhibition in guinea pig, dog and cow in vitro – This measured inhibition of 11β-hydroxylase (another enzyme involved in the synthesis of cortisol), to assess selectivity in comparison with fadrozole.
· Concurrent inhibition of 11- and 18- hydroxylation: effects on sodium and potassium excretion in rats - to assess the selectivity of the tested compounds in comparison with fadrozole, which inhibits hydroxylation at both sites.
· Male pig-tailed monkey in vivo – measures potency and selectivity in vivo in monkeys.
[23] According to AstraZeneca’s expert, Dr. Dowsett, AstraZeneca was granted permission by the U.S. Food and Drug Administration and the European Medicines Agency to initiate the first phase III trial based on clear, reliable and consistent results from the phase I trials around 1995. That is, no phase II tumor response data was required.
[24] Anastrozole has proven to be a highly potent aromatase inhibitor and estrogen suppressor. Anastrozole is also highly selective, and has no impact on adrenal steroids at doses up to ten times than those used clinically. It is an effective and well-tolerated treatment for patients with estrogen dependent breast cancer.
[25] According to Dr. Dowsett, at least until 2008, anastrozole was the most widely used aromatase inhibitor in the world, although the particular aromatase inhibitor to be used is a matter of clinical preference.
THE PATENT
[26] This case concerns Canadian Patent No. 1,337,420 (the 420 Patent). The patent was filed on June 15, 1988, claiming priority from a U.K. application filed on June 16, 1987. This is an “Old Act” patent. That is, the application was filed before October 1, 1989, and is therefore governed by the provisions of the “old” Patent Act, RSC 1985, c P-4.
[27] The patent issued on October 24, 1995, and expires on October 24, 2012.
[28] The 420 Patent is titled “(Substituted-aralkyl) Heterocyclic Compounds”. The inventors are listed as Philip Neil Edwards and Michael Stewart Large, both of the UK neither of whom gave evidence in this proceeding.
[29] Only claims 13, 14 and 15 of the 420 Patent are at issue in this proceeding.
[30] Claim 13 reads as follows:
The compound 2,2’ –[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di (2-methylpropiononitrile).
[31] This chemical formula is referred to by the parties simply as anastrozole. Thus, claim 13 specifically claims the compound anastrozole. According to AstraZeneca, no other compound is individually claimed in the 420 Patent.
[32] Claim 14 claims a pharmaceutical or veterinary composition, which comprises an effective amount of anastrozole:
A pharmaceutical or veterinary composition which comprises an effective amount of the compound 2,2’-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile) together with a pharmaceutically or vetrinarily acceptable diluents or carrier.
[33] Claim 15 claims the use of anastrozole as an aromatase inhibitor:
The use of the compound 2,2’-[5-(1H-1, 2, 4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile) as an inhibitor of the enzyme aromatase.
[34] Claim 16 claims a commercial package containing anastrozole as an active pharmaceutical ingredient for use as an aromatase inhibitor.
[35] The specification of the patent begins at page 1, with the following opening line:
This invention relates to (substituted-aralkyl) – heterocyclic compounds, and in particular relates to such compounds which are useful as inhibitors of the enzyme aromatase.
[36] The specification continues in the next paragraph:
Aromatase in an enzyme which effects aromatization of ring A in the metabolic formation of various steroid hormones. Various cancers, for example breast cancer, are dependent upon circulating steroid hormones which have an aromatic ring A. Such cancers can be treated by removing the source of ring A aromatized steroid hormones, for example by the combination of oophorectomy and adrenalectomy. An alternative way of obtaining the same effect is by administering a chemical compound which inhibits the aromatization of the steroid ring A, and the compounds of the invention are useful for this purpose.
A variety of compounds possessing aromatase inhibitory activity is known, of which the most important clinically is aminogluthethimide. Aminogluthethimide, however, has the drawback that it affects other aspects of steroid metabolism, with the consequence that its use is often associated with undesirable side-effects. It is a particular object of the present invention to provide aromatase inhibitory compounds with fewer undesirable side effects than aminogluthethimide.
[37] This part of the specification tells the reader that the invention contains a compound that is useful for inhibiting the aromatization of the steroid ring A, and that such compounds have applications in the treatment of estrogen-dependent cancers.
[38] The patent goes on to identify preferred compounds and particular preferred compounds of the invention at pages 5 and 6. Anastrozole is one of the five particularly preferred compounds. Example 1 sets out a process for synthesizing anastrozole.
[39] At page 11, the specification repeats the statement that “the compounds of the formula 1 are useful as aromatase inhibitors”, and that aromatase inhibition has been demonstrated through two tests. The specification goes on to describe the AR1 in vitro test and the OI2 and OI3 in vivo tests. The results of these tests are provided at page 13:
In the above tests, the compounds of formula 1 are active at less than 10 μg/ml (in vitro), and the preferred compounds of the formula 1 are active at below 0.1 μg/ml (in vitro) and 1.0 mg/kg (in vivo), and no indication of any toxicity has been seen at these doses.
[40] These are the only two tests referred to in the patent. The patent does not disclose the other five tests ICI conducted on anastrozole.
ISSUES
[41] This proceeding concerns whether Mylan’s allegations of invalidity regarding claims 13 to 15 of the 420 Patent are justified on any of the bases set out in the Notice of Allegation. Generally, the parties have raised the following four issues:
a. What is the promise of the 420 Patent?
b. Had the inventors demonstrated the promised utility by the Canadian filing date?
c. Had the inventors soundly predicted the promised utility of the 420 Patent by the Canadian filing date?
d. Was anastrozole obvious?
EVIDENCE
[42] Each party provided affidavit evidence from two experts, one dealing primarily with utility, and one dealing primarily with obviousness.
[43] The only other material witness was Dr. Michael Dukes. He is a former senior scientist at ICI and later at AstraZeneca, and was responsible for biological testing in the aromatase inhibition project. He provided fact evidence regarding the development and testing of anastrozole by ICI.
The Utility Experts
[44] AstraZeneca’s utility expert is Dr. Mitchell Dowsett. He is a professor of biochemical endocrinology Head of the Academic Department of Biochemistry at the Royal Marsden Hospital and the Institute of Cancer Research. He is also a professor of Translational Research in the Breakthrough Breast Cancer Centre at the Institute of Cancer Research. He holds a Ph.D. in pathology from the Institute of Cancer Research at the London University. His research has focused almost exclusively on breast cancer, and predominantly on hormonal aspects of the disease. He has been involved in the development of aromatase inhibitors for the last 30 years, and his research team has participated in a large number of drug development trials, with particular emphasis on aromatase inhibitors.
[45] Dr. Dowsett was asked by counsel for AstraZeneca to answer the following questions:
a. What was the understanding with respect to aromatase inhibitors as of June 16, 1987 and/or June 15, 1988?
b. Who is the person skilled in the art (the skilled person, or POSITA) to whom the 420 Patent is directed?
c. What is taught by the 420 Patent?
d. What is shown by the testing of anastrozole reviewed in the affidavit of Dr. Michael Dukes?
[46] Dr. Dowsett’s evidence is confidential.
[47] Mylan’s utility expert is R. Charles Coombes. He is a medical doctor, an oncologist and a professor of medical oncology. He holds a Ph.D. and an M.D from the University of London. His Ph.D. work was on endocrine aspects of cancer, including ectopic secretions of hormones by cancer. From 1980-1987, Dr. Coombes was involved in developing aromatase inhibitors, and worked alongside a medicinal chemist. He is currently the Head of the Department of Cancer Medicine at the Imperial College School of Medicine.
[48] Dr. Coombes was asked by counsel for Mylan to provide his opinion and commentary on the following questions:
a. Who is the person skilled in the art to whom the 420 Patent is directed?
b. How would a person skilled in the art have understood the claims of the 420 Patent at June 16, 1987, the priority date, June 15, 1988, the Canadian filing date, and October 15, 1995, the issue date of the 420 Patent?
c. What is the promised utility of the 420 Patent?
d. Does the 420 Patent contain information that demonstrates its promised utility by either June 16, 1987 or June 15, 1988?
e. As of either June 16, 1987 or June 15, 1988, is there a factual basis and sound line of reasoning disclosed in the 420 Patent to support a sound prediction of the promised utility of the 420 Patent?
f. Does any information provided by AstraZeneca demonstrate the promised utility of the 420 Patent?
g. Was there described and supported in the 420 Patent any peculiar or unexpected property of anastrozole that conferred a surprising advantage over the prior art aromatase inhibitors?
[49] Dr. Coombes’s evidence is confidential.
[50] Both experts were cross-examined. Neither party raised any challenges to the experts credentials. Both Dr. Coombes and Dr. Dowsett are recognized experts in the field. In fact, they shared the same lab for about a year while completing their Ph.D. work, and have published journal articles together.
The Obviousness Experts
[51] AstraZeneca’s expert on obviousness is Rolf W. Hartmann. He is a professor of pharmaceutical and medicinal chemistry at Saarland University, Saarbrucken, Germany. He holds a Ph.D. in pharmaceutical chemistry, and his thesis concerned the design, synthesis, biological evaluation and mode of action of novel antiestrogens with structures different from the drug tamoxifen. Dr. Hartmann’s work involved synthesizing and testing aromatase inhibitors in the 1980s. In 1987, Dr. Hartmann received a ‘Habilitation’, which is awarded for independent scholarly research undertaken at the post-doctoral or professorial level, for his thesis entitled “Establishment of a Test System and Development of New Mammary Tumor Inhibiting Aromatase Inhibitors”. Dr. Hartmann states that he has closely followed the literature on aromatase inhibitors for virtually his entire career, and has been active in research on aromatase inhibitors since 1983. He is a tenured professor and continues to direct an active research program involving drug design and development.
[52] Counsel for AstraZeneca asked Dr. Hartmann the following questions:
a. Describe the qualifications of the person of ordinary skill in the art to whom the 420 Patent is directed.
b. Provide an overview on the background to the 420 Patent and the state of the art of aromatase inhibitors as of June 1987 and June 1988.
c. Review the 420 Patent and comment on the invention that is disclosed and claimed in claims 13 through 16.
d. Answer the following questions on ‘obviousness’ related to the 420 Patent, having regard to a letter from Mylan dated June 21, 2009 and the documents listed in the letter:
i. What is the relevant common knowledge of the skilled person?
ii. What would the skilled person have considered to be the invention disclosed and claimed in claims 13 to 16 of the 420 Patent?
iii. Identify the differences between the prior art listed in the letter and the invention disclosed from part (b) above?
iv. Without any knowledge of the invention from part (b) above and considering the prior art, do the differences constitute steps that would have been obvious to the skilled person? In addressing this question, counsel have asked me to consider the following factors?
1. Would it be self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to the skilled person?
2. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials to be carried out or would the experimentation be prolonged and arduous such that the trials would not be considered routine?
3. Is there a motive provided in the prior art to find the solution the 420 Patent addresses?
4. What is the course of conduct which was followed which culminated in the making of the invention?
5. Was it obvious to try the invention of claims 13-16 of the 420 Patent?
e. Comment on the testing reported in the affidavit of Dr. Michael Dukes and what it demonstrates.
f. Comment on the affidavits of Dr. R. Charles Coombes and Dr. Peter Redden.
[53] Only a small portion of Dr. Hartmann’s affidavit is confidential.
[54] Mylan’s obviousness expert is Peter Redden. He is a synthetic chemist who holds a Ph.D. in organic chemistry from Dalhousie University. His early work related to the preparation of naphthalene derivatives. From 1999 to 2003, he was a senior scientist in medicinal chemistry, where he directed a drug development team. The focus of this work was on identifying anti-estrogen compounds for the treatment of breast cancer and other cancers, and osteoporosis. From 2003-2008, he was a principal scientist in medicinal chemistry, overseeing drug development teams identifying potential therapeutic agents for cardiovascular indications, anemia, inflammation and Alzheimer’s disease. From 2003-2005 his research specifically focused on identifying therapeutic agents for the treatment of breast cancer. Since 2008, he has worked as a consultant in synthetic and medicinal chemistry, for various biotechnology companies and contract research organizations.
[55] Dr. Redden was asked the following questions by counsel for Mylan:
a. Who is the person skilled in the art to whom the 420 Patent is directed?
b. How would a person skilled in the art have understood the claims of the 420 Patent on October 24, 1995?
c. What is the inventive concept of the 420 Patent?
d. What was the state of the art as of June 1987?
e. Is there a difference between the state of the art in June 1987 and the inventive concept described in the 420 Patent and if so, what is it?
f. Taking into account the prior art and the common general knowledge held by the skilled person prior to June 16, 1987, would the skilled person have been able to come to the claimed invention without undue burden or any degree of invention, conducting no more than routine trials?
[56] Dr. Redden’s evidence is not confidential.
AstraZeneca’s Attack on Dr. Redden’s Credentials
[57] AstraZeneca takes issue with Dr. Redden’s qualification as an expert. In AstraZeneca’s view, Dr. Redden is not qualified to provide an expert opinion. AstraZeneca argues that he was not a skilled person at the relevant date, and that he simply does not have sufficient knowledge of the art. Dr. Redden first learned about significant aspects of the art on reading Dr. Hartmann’s affidavit. He did not previously know about Type 1 and Type 2 inhibitors. He obtained the prior art from counsel for Mylan. The parties agree that Dr. Redden does not have any experience synthesizing aromatase inhibitors, although he does have experience synthesizing anti-estrogen compounds.
[58] Mylan agrees that Dr. Redden “does not have Dr. Hartmann’s academic renown and experience with aromatase inhibitors”, but argues that he can still provide the perspective of a skilled chemist to the problem of synthesizing aromatase inhibitors in the mid-1980s.
[59] There is no doubt that Dr. Redden is currently a skilled person. He has an advanced degree in a relevant field and approximately ten years of experience in drug development, including anti-estrogen compounds. However, his affidavit discloses that he was not a skilled person at the time the 420 Patent was filed.
[60] The 420 Patent was filed on June 15, 1988. Dr. Redden worked on his Ph.D. from 1985-1989. He did not complete a Master’s degree prior to his Ph.D., and therefore had not obtained a higher level degree at the time the 420 Patent was filed. It does not appear that Dr. Redden had any experience with medicinal chemistry or pharmaceutical applications at this point. His affidavit indicates that he began working with chemicals that had potential for use in therapeutic indications in 1993.
[61] AstraZeneca did not bring a motion to have Dr. Redden’s evidence struck. In oral argument, AstraZeneca stated that their position was that Dr. Redden’s evidence was inadmissible, and in the alternative should not be given weight.
[62] In my view, AstraZeneca’s attack on Dr. Redden’s credentials as an expert goes to weight and not admissibility. I note that in Eli Lilly Canada Inc v Apotex, 2007 FC 455 (Eli Lilly olanzapine) at paras 201-205, Justice Johanne Gauthier admitted evidence from an expert who did not have the characteristics of an ordinary person skilled in the art as defined by the Court, either prior to the claims date or at the time of the hearing. Justice Gauthier dealt with his lack of expertise by assigning the evidence very little weight. In this case, Dr. Redden currently has the characteristics of a skilled person, but he did not have these characteristics at the time the patent was filed.
[63] Dr. Redden can give an opinion on the issues raised in this case from the perspective of a skilled person.
NOC PROCEEDINGS
[64] The NOC Regulations were introduced in 1993 to replace the previous compulsory licensing scheme for drug patents in Canada. The NOC Regulations identify a “first person”, usually a brand or an innovator, who owns a patent and who has received permission to sell a drug relating to the patent in Canada. A “second person”, usually a ‘generic’ drug company, seeks to use the NOC Regulations to obtain approval to sell a generic version of the drug. The second person can state that they will wait for the patent to expire, or that the patent will not be infringed, or that the patent is invalid.
[65] The second person must notify the first person that they intend to seek approval to sell the drug. This notification takes the form of a “Notice of Allegation” (NOA). The NOA is required by subsection 5(3)(a) of the NOC Regulations. Subsection 5(3)(b)(ii) states that the NOA must include “a detailed statement of the legal and factual basis for the allegations”. The NOA must be sufficiently detailed to make the “first person” fully aware of the grounds raised as to invalidity or non-infringement of the patent. In Court, a “second person” cannot present argument and evidence relating to an issue outside the scope of the NOA.
[66] Under subsection 6(2) of the NOC Regulations, the first person is required to demonstrate that none of the allegations is justified. As stated by Justice Roger Hughes, “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”: GlaxoSmithKline Inc v Pharmascience, 2011 FC 239 at para 41 (GlaxoSmithKline rosiglitazone).
BURDEN OF PROOF
[67] Section 43(2) of the Patent Act states that “in the absence of any evidence to the contrary” a patent is presumed to be valid. In a NOC proceeding, the first person bears the legal burden throughout the proceeding. The first person’s legal burden is to show that it is entitled to the order of prohibition: Abbott Laboratories v Canada (Minister of Health), 2007 FCA 153 at para 9; GlaxoSmithKline rosiglitazone, above, at paras 43-44.
[68] The first person may rely on the presumption of validity, which as noted above operates “in the absence of any evidence to the contrary”. Using this presumption, the first person could meet their burden merely by proving the existence of the patent. However, the presumption is weakly worded, and if the second person leads any evidence that could support a finding of invalidity, the presumption is displaced, and the burden rests with the first person to prove the validity on a balance of probabilities. The second person bears an evidential burden to put its allegations into play. The burden is merely to provide some evidence to give its allegations an “air of reality”: Pfizer v Novopharm, 2009 FC 638 at paras 32-36 (Pfizer sildenafil FC).
[69] To summarize the NOC proceedings with respect to the burden of proof:
a. Mylan has the evidentiary burden to present a sufficient factual and legal basis to give its allegations of invalidity “an air of reality”; and
b. AstraZeneca has the legal burden of proving on a balance of probabilities that Mylan’s allegations of invalidity are unjustified.
ASTRAZENECA’S MOTION TO STRIKE
[70] At the outset of the hearing, AstraZeneca moved to strike portions of Mylan’s memorandum of fact and law. AstraZeneca alleged that Mylan’s memorandum of fact and law contained an argument that exceeded the scope of the Notice of Allegation (NOA) and that this argument was revealed for the first time in the memorandum of fact and law.
[71] I declined to hear the motion at the outset of the hearing. A memorandum of argument is not a pleading which can be struck, and interlocutory motions in applications are exceptional and are not to be encouraged: Bayer AG v Apotex Inc, [1998] FCJ 1946, per Justice Rothstein at para 3.
[72] The rationale which underlies this rule is rooted in sound considerations of legal policy. The court should have the complete record before it. The court is not, at the outset of the hearing, well situated to make a decision as the scope of what is in issue before the court. The recognized exceptions to this, such as where a party relies on documents not in the record, or there is significant prejudice to a party, are not in issue here. I therefore dismissed the motion, and directed that issues as to the scope and adequacy of the Notice of Allegations and the appropriateness of certain aspects of Mylan's argument be made in the application.
[73] In issue is the scope of the allegations in the Notice of Allegation. AstraZeneca contends that the Notice of Allegation did not give notice or warning of the argument advanced in its memorandum of fact and law that the testing of anastrozole on animals bearing cancer tumours (animal tumour models) would have been necessary in order to demonstrate or soundly predict utility as of the filing date of the 420 Patent.
[74] As noted above, subsection 5(3)(b)(ii) of the NOC Regulations states that a NOA shall include "... a detailed statement of the legal and factual basis for the allegation." The Federal Court of Appeal discussed the sufficiency of a NOA in Novopharm v Pfizer Canada Inc, 2005 FCA 270 at para 4:
In its more recent jurisprudence, this Court has repeatedly stated that the test of the adequacy of a NOA is whether the detailed statement was sufficient to make the patentee (Pfizer) fully aware of the grounds on which the generic (Novopharm) claimed that the relevant patent would not be infringed if a NOC was issued by the Minister (see AB Hassle v. Canada (Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.) at paragraph 17, per Stone J.A. (AB Hassle 1); SmithKline Beecham Inc. v. Apotex Inc. (2001), 10 C.P.R. (4th) 338 (F.C.A.) at paragraph 26, per Noël J.A.; and also Pfizer Canada Inc. v. Apotex Inc. (2004), 38 C.P.R. (4th) 400 (F.C.A.) at paragraph 24, per Evans J.A.).
[75] In Pfizer Canada Inc v Canada (Minister of Health), 2007 FC 642 Justice Michael Phelan noted that the purpose of the NOA is to “frame the factual and legal issues with sufficient particularity that a potential applicant in this court can know whether and how to rebut the allegations” (para 14). In Smithkline Beecham Pharma Inc v Apotex (2001), 10 CPR (4th) 338 (FCA) at para 27, the NOA was found to be sufficient because it did not force the applicant to guess at the real grounds for the respondent’s allegations.
[76] While Mylan’s NOA could have been more direct and explicit, I find that it provided a sufficient legal and factual basis for its allegation of lack of utility as informed by the case law. The NOA raises the lack of demonstrated or soundly predicted therapeutic utility of anastrozole. The NOA stated at page 9 that "[t]here is no testing at all disclosed in the 420 Patent to support the therapeutic utility of anastrozole... thus no information is disclosed that demonstrates that anastrozole has any or all the utility promised by the 420 Patent... ”As well, the Notice of Allegation specifically contrasts the 420 Patent with another contemporary aromatase inhibitor patent which relied on induced animal tumour testing to establish utility. In its memorandum of fact and law, AstraZeneca expressly addressed the role animal tumour testing done in respect of anastrozole:
ICI did not test anastrozole in an animal cancer model (where a tumour is induced in the animal and then treated) until 1995 (and only at the insistence of the Japanese regulatory authority). Moreover, this testing was conducted after anastrozole had been administered to human breast cancer patients [emphasis in the original].
[77] As well, the issue of tumour testing was discussed in the expert affidavits of both the applicant and respondent and was the subject of extensive cross examinations.
[78] At no point in the course of a three day hearing did the issue of the adequacy of the record, prejudice to, or the capacity of, AstraZeneca to make its case arise. The parties engaged fully on all aspects of the testing, including the impact of animal tumour testing in support of the utility argument. Argument was not stopped because of evidence on the point, nor did AstraZeneca point to evidence which it would have called but for the fact that it was taken by surprise.
[79] The core purpose of the NOA is twofold. It is put the party in a position to make an informed decision whether to seek an order of prohibition (AB Hassle v Apotex Inc, 2006 FCA 51 at para 4). The second purpose is to frame and control the scope of the evidence and argument on the prohibition application itself. In this case, the twin requirements of providing notice were met. AstraZeneca had notice, or ought reasonably to have been put on notice that the question of animal tumor testing was in issue. In any event, the parties fully joined on the issue and AstraZeneca was not, in any way, prejudiced.
PERSON OF ORDINARY SKILL IN THE ART
[80] The parties agree that the person skilled in the art (POSITA, or the skilled person) has an advanced degree (a medical degree or a Ph.D.) in a relevant field (medicinal or organic chemistry, biochemistry) and 2 to 3 years experience in the pharmaceutical research and drug development. Alternatively, a skilled person might have a less advanced degree, but more years experience in the pharmaceutical field.
[81] The skilled person could therefore include a synthetic chemist with an interest in aromatase inhibitors, or a physician with an interest in using aromatase inhibitors to treat breast cancer.
CONSTRUCTION OF THE CLAIMS
[82] The Court must construe the patent and claims at issue before turning to utility and obviousness: Whirlpool Corp v Camco Inc, 2000 SCC 67 at para 43. Here, only claims 13-15 are at issue. For ease of reference, I will repeat them here:
13. The compound 2,2’ –[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di (2-methylpropiononitrile).
14. A pharmaceutical or veterinary composition which comprises an effective amount of the compound 2,2’-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile) together with a pharmaceutically or veterinarily acceptable diluents or carrier.
15. The use of the compound 2,2’-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile) as an inhibitor of the enzyme aromatase.
[83] The experts agree that the skilled person’s understanding of claims 13-15 of the 420 Patent would be the same on the date of issue (October 24, 1995), the date of filing (June 15, 1988) or today. The experts also agree on how a skilled person would have understood the claims of the 420 Patent:
i. Claim 13 describes anastrozole using systemic nomenclature.
ii. Claim 14 claims a pharmaceutical or veterinary composition comprising an effective amount of anastrozole together with a pharmaceutically or veterinarily acceptable diluents or carrier.
iii. Claim 15 claims the use of anastrozole as an inhibitor of the enzyme aromatase.
[84] Anastrozole is a novel compound. A novel compound is a proper subject matter for a claim, as long as it meets the other requirements of patentability: Pfizer v Mylan, 2011 FC 547 at paras 192-193 (Pfizer donepezil). The compound’s utility must be disclosed in the specification, but it does not have to be included as part of the claim.
[85] Here, anastrozole’s utility as an aromatase inhibitor is claimed in claim 15. Because anastrozole is a novel compound, utility can also be derived from the specification.
UTILITY
Requirement for Utility
[86] Section 2 of the Patent Act (RSC, 1985, c P-4) (the Act) requires the proposed invention to be both “new and useful”. A number of principles associated with the concept of utility were neatly summarized by the Court of Appeal in Eli Lilly Canada Inc. v Novopharm Limited, 2010 FCA 197 at paras 74-76 (Eli Lilly Olanzapine FCA):
The general principle is that, as of the relevant date (the date of filing), there must have been either demonstration of utility of the invention or a sound prediction of the utility. Evidence beyond that set out in the specification can, and normally will, be necessary.
To establish lack of utility, the alleged infringer must demonstrate "that the invention will not work, either in the sense that it will not operate at all or, more broadly, that it will not do what the specification promises that it will do" :Consolboard Inc. v. MacMillan Bloedel (Sask.) Ltd., [1981] 1 S.C.R. 504 (Consolboard).
Where the specification does not promise a specific result, no particular level of utility is required;