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.
[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.
[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.
[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.
[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.
[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
[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; a "mere scintilla" of utility will suffice.
However, where the specification sets out an explicit "promise",
utility will be measured against that promise: Consolboard; Pfizer Canada Inc. v. Canada (Minister of Health), [2009] 1 F.C.R. 253, 2008 FCA 108 (Ranbaxy). The question is
whether the invention does what the patent promises it will do.
[87]
The
requirement of utility begs the question “useful for what?”. Again, as Justice
Layden-Stevenson wrote in Eli Lilly Olanzapine FCA, above at para 80:
The promise of the patent must be
ascertained. Like claims construction, the promise of the patent is a question
of law. Generally, it is an exercise that requires the assistance of expert
evidence: Bristol-Meyers Squibb Co. v. Apotex Inc., 2007 FCA 378, FCJ No 1579 at para. 27. This is
because the promise should be properly defined, within the context of the
patent as a whole, through the eyes of the POSITA, in relation to the science
and information available at the time of filing.
[88]
In
construing the promise of the patent, the Court must look to the whole of the
disclosure as well as the specific language of the claims, “being neither
benevolent nor harsh, but rather seeking a construction which is reasonable and
fair to both the patentee and the public”: Consolboard Inc v
MacMillan Bloedel (Saskatchewan), [1981] 1 S.C.R. 504 at 156-157 (Consolboard).
Where a reasonable reading of the patent specification can be read to protect a
good invention, the Court should give effect to that construction.
[89]
The
promise of the patent is to be ascertained at the threshold of the utility
analysis. The promise is to be construed through the lens or perspective of the
skilled person, having regard to the science at the time of filing and the
patent as a whole.
[90]
Construction
of the promise of the patent is a question of law within the exclusive province
of the Court: GlaxoSmithKline rosiglitazone, above at para 86. Courts
should be careful in relying on expert evidence to construe the promise of the
patent. In Pfizer donepezil, above at para 224, Justice Roger Hughes
reinforces the need for a clear demarcation of roles:
These illustrations, which are by no
means exhaustive, demonstrate the perils in asking experts to stray from their
expertise and to enter into the realm of advocacy in construing a patent. It is
very tempting for lawyers to seek to put words into the mouths of experts and
then seek to urge upon the Court that these words be accepted as being
assistance from the expert in interpretation of a patent.
[91]
The
proper reading of the patent was the subject, of course, of considerable
argument by counsel and by experts.
[92]
AstraZeneca’s
position is that the patent only promises aromatase inhibition. AstraZeneca’s
expert, Dr. Dowsett, stated that he understands that the invention of the 420
Patent relates to compounds that inhibit the enzyme aromatase. In Dr. Dowsett’s
view, the 420 Patent offers the goal or object to inhibit aromatase with
fewer side effects than the other leading drugs, but does not specifically
promise this.
[93]
Mylan’s
position is that the patent contains a threefold promise: (1) the inhibition of
aromatase; (2) its therapeutic utility against estrogen dependent cancers; and (3)
fewer side effects than AG. I will examine each of the three promises alleged
by Mylan separately.
[94]
The
patent specification opens with the following description of the invention:
This invention relates to
(substituted-aralkyl)-heterocyclic compounds, and in particular relates to such
compounds which are useful as inhibitors of the enzyme aromatase.
[95]
This
paragraph of the specification is not controversial. The parties agreed that
this sentence promises that the invention will be useful as an aromatase
inhibitor. I note that this language speaks only of the invention’s
pharmacological action (inhibiting aromatase), and not of any possible
applications of the pharmacological action.
Does the Patent Promise Therapeutic Utility?
[96]
The
second paragraph describes some common general knowledge regarding the
treatment of breast cancer:
Aromatase is an enzyme which effects
aromatisation 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 aromatised 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
aromatisation of the steroid ring A, and the compounds of the invention are
useful for this purpose.
[97]
The
parties are agreed that the first two sentences in this paragraph are common
general knowledge regarding breast cancer. The parties take differing views on
the last sentence of this paragraph.
[98]
The
controversy focuses on the meaning of the words “for this purpose”. Mylan
contends that the purpose referred to at the end of the sentence is cancer
treatment. Oophorectomy and adrenalectomy were recognized treatments for breast
cancer. According to Mylan’s interpretation, the sentence effectively means “an
alternative way of [treating breast cancer] is by administering a chemical
compound which inhibits the aromatisation of the steroid ring A, and the
compounds of the invention are useful [for treating breast cancer]”.
[99]
In
contrast, AstraZeneca contends that the purpose referred to at the end of the sentence
is ‘inhibiting the aromatisation of the steroid ring A’. Oophorectomy and
adrenalectomy are surgical methods of removing the source of ring A aromatised
steroid hormones, and this paragraph is explaining that the invention can
remove the source of ring A aromatised steroid hormones through administering a
chemical compound.
[100] Both parties
rely on the expert evidence to support their interpretation of this paragraph.
[101] Mylan relies
on the evidence of Dr. Coombes. In cross-examination, Dr. Coombes stated in
very strong terms that he read the patent as promising therapeutic utility:
I would say this, these three paragraphs,
strongly imply and indicate that the whole point of this is for the treatment
of breast cancer. There can be no other interpretation, in my view, to the
rational human being that this is the intention of the entire work from start
to finish.
[102] Despite his
enthusiasm for the therapeutic promise, Dr. Coombes did concede that it was
also reasonable to conclude that the inventors were simply hopeful that the
compounds of the invention would be useful in the treatment of breast cancer. A
skilled person would understand that clinical trials would be required to
determine whether the compounds would be effective treatments for breast
cancer, and that the compounds might fail in the course of development. Having
made those concessions, Dr. Coombes went on to emphasize that a skilled person
would know that the research was driven by the desire to develop a treatment
for breast cancer.
[103] AstraZeneca,
for its part, relied on the evidence of Dr. Dowsett. With respect to a promise
of therapeutic utility, Dr. Dowsett stated:
Q: So at least in terms of how the
inventors were contemplating using these compounds, would you agree that it was
for the purposes of treating cancer?
A: Well, they do not explicitly state
that.
Q: Do they refer to anything else as the
use of the aromatase inhibitor in this patent?
A: They do not refer to anything else,
no.
Q: So reading this patent, you would
understand that what the inventors were referring to was the use of the
compound to treat cancer, would you not?
A: I would expect their focus to be on
breast cancer.
[104] Dr. Hartmann,
AstraZeneca’s obviousness expert, also stated that he understood that the
patent was directed towards the treatment of breast cancer.
[105] Neither party
relied on Dr. Redden’s evidence with respect to the promise of the patent.
[106] The experts provided
objective and relevant evidence consistent with their role in providing the
Court with the appropriate lens through which the patent was to be read.
[107] I accept the
experts’ views that a skilled person would read the 420 Patent with the
knowledge that aromatase inhibitors can be used in the treatment of breast
cancer. The experts agreed that an aromatase inhibitor with similar or more
serious side effects would not have been useful to the scientific community.
[108] In my view,
the experts’ understanding of the relevant scientific context is one factor to
consider when construing the promise of the patent, but it is not necessarily
determinative. The Court must also consider the plain language of the claims
and the disclosure.
[109] I find
AstraZeneca’s interpretation of the second paragraph of the 420 Patent to be
more persuasive. While this paragraph does refer to cancer treatment, the
language focuses on the pharmacological action of the invention. The purpose of
the invention is to inhibit the aromatisation of steroid ring A. While it may
be common general knowledge that aromatase inhibition can be used in the
treatment of breast cancer, I do not read an explicit promise of therapeutic
utility into this paragraph.
Situating
the Patent in the Scientific Context
[110] In support of
this conclusion, I note that the language of the 420 Patent does not approach
the degree of clarity or specificity of similar patents directed to the same
object – the treatment of estrogen dependent conditions. For example U.S.
Patent 283, filed as Exhibit 2 to the cross examination of Dr. Hartmann,
provides:
The compounds according to the invention
are particularly suitable for the treatment of hormone-dependent tumours,
particularly the hormone-dependent mammary carcinoma…
[111] In that case,
the compound was tested in vivo, on a tumour model, and this testing was
disclosed in the patent.
[112] Similarly,
and to the same effect, Exhibit 3 to the cross examination of Dr. Coombes - a
patent on which Dr. Coombes is named as the inventor - describes the utility of
an estrogen-antagonist compound this way:
This invention related to novel
therapeutic agents and in particular to steroids suitable for use in the
treatment of breast cancer.
and
The present invention therefore includes
a method for aiding the regression and palliation of breast cancer, of
benign breast disease, or of carcinoma of the corpus uteri, for preventing or
slowing the onset of breast cancer, or for treating an ovulatory infertility,
in a patient which comprises administering to that patient a therapeutically
effective amount of a compound of formula (I) as defined herein [emphasis
added].
[113] The language
of the 420 Patent also does not approach the degree of clarity or specificity
of other patents in which this Court has read a promise of therapeutic utility.
Situating
the Patent in the Jurisprudence
[114] To round out
the context within which the patent is situated, I note that in Pfizer
donepezil, above, Justice Hughes found that the patent promised that the
compound was effective in the treatment of Alzheimer’s. The patent
specification in that case included the following language:
The
invention relates to a cyclic amine compound, a therapeutical composition
and medical treatment of senile dementia.
…
The
compound of the present invention was found based on the acetylcholinesterase
inhibitory action and, therefore, is effective for treatment and prevention
of various diseases which are thought to be derived from the deficiency of
acetylcholine as a neurotransmitter in vivo.
Examples
of such diseases include various
kinds of dementia including Alzheimer senile dementia and further include
Huntington's chorea, Pick's disease, and ataxia.
Therefore,
the objects of the present invention are to provide a novel piperidine
derivative effective as a pharmaceutical, particularly for treatment and
prevention of central nervous system diseases, to provide a process for
preparing the same, and to provide a pharmaceutical comprising the same as an
effective ingredient [emphasis added, see para 232].
[115]
In Sanofi-Aventis
v Apotex,
2009 FC 676 (Sanofi
ramipril), Justice Judith
Snider found that the patent at issue promised that the compounds of the
invention had use as ACE inhibitors (a pharmacological action) and as
anti-hypertensives (therapeutic use). In this case, the patent specification
included this language:
The
present invention relates to carboxyalkyl dipeptides which
are useful as inhibitors of angiotensin-converting enzyme and as
antihypertensive agents. [Emphasis added]
The
compounds of this invention have useful pharmacological properties. They
are useful in the treatment of high blood pressure. The
compounds of the present invention can be combined with pharmaceutical carriers
and administered in a variety of well known pharmaceutical forms suitable for
oral or parental administration to provide compositions useful in the treatment
of cardiovascular disorders and particularly mammalian hypertension [emphasis added, see paras 121-122].
[116]
In Merck &
Co v Apotex Inc, 2010 FC 1265 (Merck lovastatin), Justice Snider found a promise of
therapeutic utility where the patent specification stated:
These
new compounds have excellent properties of inhibiting cholesterol biosynthesis
and are useful against hypercholesteremia and hyperlipemia.
…
The
compounds of this invention are highly useful as antihypercholesteremic agents
for the treatment of atherosclerosis, hyperlipemia and like diseases in humans
[see paras 69 and 75].
[117]
These are just a few examples of the type of language that has supported
a finding of therapeutic utility. In each case, there is clear language
promising that the pharmacological compound will be effective or useful in the
treatment of a disease. Such language cannot be found in the 420 Patent.
[118] Having reviewed the opinions of
the experts, similar patents, and the relevant case law, I conclude
that the second paragraph of the patent does not promise therapeutic utility.
At best, it recognizes that the compounds of the invention have the potential
to be developed as a treatment for breast cancer. In my view, the patent does
not promise that the compounds of the invention are effective as a treatment
for breast cancer.
Does the Patent Promise Fewer Side Effects than AG?
[119] The third
paragraph of the patent reads as follows:
A variety of compounds possessing
aromatase inhibitory activity is known, of which the most important clinically
is aminoglutethimide. Aminoglutethimide, 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 aminoglutethimide [emphasis added].
[120] I have
referred to the underlined portion of this paragraph as the ‘object clause’ of
the patent in these reasons.
[121] AstraZeneca
contends that this object clause is an expression of hope or wish on the part
of the inventors that anastrozole would have fewer side effects than AG, and
nothing more. AstraZeneca argued at length that the choice of the word “object”
was intentional. It is to be contrasted with the declaratory nature of the
promise with respect to the compound itself:
According to the invention, there is
provided… [emphasis added].
[122] Mylan, in
contrast, argues that this paragraph constitutes a clear promise to provide
compounds with fewer side effects than AG. Mylan emphasizes that the first,
third and fourth paragraphs of the patent all use the phrase “to provide” when
describing the novel class of compounds and their advantages over AG. Mylan
asserts that if the inventors intended to disclose mere aromatase inhibitors,
there would have been no need to refer to AG, or to compare anastrozole’s side
effects to AG’s.
[123] Dr. Coombes
expressed the opinion that the object clause constituted a promise of fewer
undesirable side effects than AG. Dr. Coombes emphasized that it would be
self-evident to a skilled person that AstraZeneca must have invented an
inhibitor with fewer side effects than AG, as there would be no use in yet
another inhibitor. There were, at the time, at least five aromatase inhibitors
already in use.
[124] Dr. Hartmann
agreed that a skilled person would read the object clause as saying that the
inventors had synthesized aromatase inhibitors which resulted in fewer
undesirable side effects. Though he did not expect to see clinical data to
support the claim that the compounds in the invention had fewer side effects
than AG, he did expect that the compounds “should have a good chance to be much
better than aminogluthemide regarding side effects”.
[125] Perhaps
unsurprisingly, Dr. Dowsett, AstraZeneca’s utility expert, expressed a
different view on the meaning of the object clause. He agreed that the entire
focus of aromatase inhibition research at this time was to find an inhibitor
with fewer undesirable side effects than AG. In fact, all of the experts were
agreed on this point. However, in cross-examination, Dr. Dowsett explained that
he did not read the object clause as a promise:
Q: You would agree with me that what the
inventors are setting out or stating in what we have just looked at is that
they have invented useful inhibitors of the enzyme aromatase with fewer
undesirable side-effects than AG?
A: I am not sure that that is what it is
saying. The long term objective is to achieve that. I am not sure that the
patent is actually stating that that is what they have achieved.
…
I am not an expert in interpreting patent
language, but to me the word ‘object’ is a goal. I do not know whether or not
that means one would actually require that to be demonstrated for this patent
to be valid. I read that as a goal. I do read that the compounds of the
invention are useful for the purpose of inhibiting aromatase.
…
Q: Right, so if you were an inventor and
you were setting out, ‘I have invented something’ in the context of what you
understood to be the research at the time, you would be saying ‘I have invented
a new aromatase inhibitor that has fewer undesirable side-effects than AG’.
A: That would be my object, yes.
Q: That would be what your invention
would be, would it not?
A: I think it is reasonable. I would
invent an aromatase inhibitor, I would then have the object of determining
whether it actually had more or less side-effects. Unfortunately, I would not
actually know that until I got it into the clinic.
[126] As noted
above, the views of the experts are one of several relevant factors to
consider. For the reasons that follow, I prefer the evidence of Dr. Dowsett,
which I find to be more consistent with the text of the 420 Patent, when read
as a whole. I agree with AstraZeneca that Dr. Coombes failed to link his
opinions to the text of the patent. His opinion was based in large part on the
relevant scientific context, the knowledge that there was a race to develop the
next blockbuster breast cancer drug, one that would have fewer side effects
than AG. There is no doubt that these were the research goals of the drug
development process. However, the inventors’ objectives or goals cannot elevate
the promise of the patent where the language of the patent does not support
that promise.
[127] As observed
by Justice Hughes, there is considerable jurisprudence on construing the
claims, but less jurisprudence on construing the promise of the patent: GlaxoSmithKline
rosiglitazone, above at para 83.
[128] The
jurisprudence regarding the construction of the claims has emphasized that the
meaning and scope of the patent monopoly must be grounded in the language of
the claims. In Free World Trust v Électro Santé Inc, [2000] 2 S.C.R. 1024
the Supreme Court held at paragraph 40 that “[t]he primacy of the claims
language was already rooted deeply in our jurisprudence and should, I think, be
affirmed again on this appeal”.
[129] The Supreme
Court’s ruling has a long antecedence in the jurisprudence. In Western
Electric Co v Baldwin International Radio of Canada, [1934] S.C.R. 570 at
572-573, the Supreme Court relied on Brooks v Steele and Currie (1896)
14 RPC 46, where Lord Justice Lindley stated that “after all, the nature of the
invention for which a patent is granted must be ascertained from the
specification, and has to be determined by the judge and not by a jury, nor by
any expert or other witness”. In Consolboard, above, the Court
held that “we must look to the whole of the disclosure and the claims to
ascertain the nature of the invention and methods of performance”.
[130]
Similarly,
the jurisprudence on construing the promise of the patent has consistently directed
judges to look for the promise of the patent in the patent specification. For
example, in Eli Lilly Olanzapine FCA, above at para 76, Justice
Layden-Stevenson held that “where the specification sets out an
explicit "promise", utility will be measured against that promise”.
[131] While I have
relied on the expert evidence, the jurisprudence, and the language of similar
patents, the promise must ultimately be grounded in the language of the patent
specification.
[132] A plain
reading of the word ‘object’ suggests that it is an aim to be fulfilled. The
Oxford English Dictionary (3rd ed, online version) includes the
following definition of ‘object’:
A goal, purpose, or aim; the
end to which effort is directed; the thing sought, aimed at, or striven for.
[133] Goals and
objectives are by definition forward looking. They refer to potential,
possibility or contingent events or consequences.
[134] Both Dr.
Dowsett and Dr. Coombes agreed that, as persons skilled in the art, they could
not determine whether there would be fewer side effects without some form of
clinical trial.
[135] A skilled
person would observe that the patent does not expressly claim an invention with
fewer side effects, and does not refer to any of the well-recognized tests for
the inhibition of cortisol synthesis. AstraZeneca argues that in the absence of
any clinical testing, a skilled person would not have understood the inventors
as promising fewer side effects. It would not be possible to do a
complete assessment of side effects without clinical testing.
[136] AstraZeneca
also referred to Harold G. Fox’s book The Canadian Law and Practice Relating
to Letters Patent for Inventions, 4th ed (Toronto: Carswell,
1969) at 152-153, arguing that merely pointing to certain advantages of the
compounds in object clauses does not amount to a promise:
But a distinction must be drawn here
between a case where a patentee claims a result and bases his claim for a
patent on the production of that result, and a case where a patentee merely
points to certain advantages that will accrue from the use of his invention. In
the former case failure to perform the promise of the specification is fatal to
the patent. The actual production of the result claimed is of the essence, and
if that result cannot be produced, then the patent is void on the theory that
it was based upon a false suggestion and the Crown has been deceived in its
grant.
…
In the second class of case, however, the
patentee does not base his claim to protection on the promise of a result but
merely points to advantages to be obtained. The failure to obtain those
advantages, while by no means an irrelevant circumstances, is not necessarily
fatal to the patentee. This principle was enunciated by Parker J. in Re
Alsop’s Patent: ‘Further, there may be cases in which the result which the
patentee claims to have produced can in fact be produced, but the patentee has
gone on to detail the useful purposes to which such result can be applied, and
that in fact the result produced cannot be applied to one or more of such
purposes. In such a case I do not think the patent is necessarily void,
provided there are purposes for which result is useful’.
[137] Mylan refers
to T.A. Blanco White, Patents for Inventions and the Protection of
Industrial Designs, 5th ed (London: Steven & Sons, 1983) at
4-403 on the fulfillment of objects:
So where the patentee promises (expressly
or impliedly) the attainment of a certain result, and this is not obtained, or
what is stated as the main object of the invention is not obtained, the patent
will be invalid; for “protection is secured by the promise of results; it does
not, and ought not to, survive the proved failure of the promise to produce the
results’.
[138] In my view,
this passage speaks generally to the promise of the patent, and not
specifically how to interpret object clauses. As I read it, this passage simply
reiterates the fundamental principle that the promise of the patent must be
demonstrated or soundly predicted. It does not assist in how to interpret the
statement that it is a ‘particular object’ of the patent to provide aromatase
inhibitory compounds with fewer undesirable side effects than AG.
[139] In sum, the
plain language of the patent, when read in the context of the patent as a
whole, does not support a promise of fewer undesirable side effects. I accept
AstraZeneca’s argument that not all statements of advantage in a patent rise to
the level of a promise. A goal is not necessarily a promise. The third
paragraph of the 420 Patent refers to a forward looking goal, a hoped-for
advantage of the invention.
[140] There is
nothing else in the patent which could support a promise of fewer side effects
or therapeutic utility. In fact, the only other references in the patent are to
the invention’s utility as an aromatase inhibitor.
[141] Page 11 of
the specification the 420 Patent states:
As indicated above, the compounds of this
invention of the formula I are useful as aromatase inhibitors.
Aromatase inhibition may be demonstrated by the following tests: - [emphasis
added]
[142] The following
two pages describe two tests which AstraZeneca says demonstrate the utility of
anastrozole as an aromatase inhibitor.
[143] Claims 13, 14
and 15 are in issue. As set out above, claim 13 describes anastrozole using
systemic nomenclature, claim 14 claims a pharmaceutical or veterinary
composition comprising an effective amount of anastrozole together with a
pharmaceutically or veterinarily acceptable diluents or carrier, and claim 15
claims the use of anastrozole as an inhibitor of the enzyme aromatase.
[144] A skilled
person reading the patent as whole and having regard to the nature of the
science required to establish claims of therapeutic utility and fewer side
effects of AG, would note the narrow scope of the claim and the limited testing
disclosed in the patent.
Conclusion on the Promise of the Patent
[145] I have
concluded that the patent promises only one thing: aromatase inhibition. This
interpretation is consistent with language of the patent, both when read in
terms of its individual claim and when read as a whole.
[146] The second
paragraph of the 420 Patent simply situates the invention in the context of the
general science of the day. When viewed through the perspective of the skilled
person, this paragraph would not be understood to be promising more than the
discovery of a new compound which inhibits aromatase.
[147] The third
paragraph of the 420 Patent also reflects the general science of the day,
noting that the goal of the invention is to provide a compound with fewer
undesirable side effects than AG. A skilled person would not read this
paragraph as promising that the goal had been achieved.
[148] For these
reasons, in my view claim 15 describes the promise of the patent in a manner
that is consistent with a fair-minded, informed reading of the specification:
The use of the compound [anastrozole] as
an inhibitor of the enzyme aromatase.
Was the Utility Demonstrated?
[149] There is no
dispute as to the actual utility of anastrozole. Mylan accepts that anastrozole
is a potent and selective aromatase inhibitor, which has fewer undesirable side
effects than AG, and is useful in the treatment of breast cancer. This is why
Mylan seeks to make a generic version of this compound. The issue is whether
AstraZeneca had demonstrated or soundly predicted the utility of the compound
by the Canadian filing date, June 15, 1988.
[150] AstraZeneca
argues that the promise of the 420 Patent - the inhibition of aromatase - is
demonstrated by the two tests in the patent (known as the AR1 and OI2/OI3
tests), and that the reliability of these tests is not seriously contested by
any of the experts.
[151] Mylan accepts
that the AR1 test demonstrate the inhibition of aromatase in vitro, but
argues that the OI2 and OI3 tests do not demonstrate the inhibition of
aromatase in vivo. Therefore, the promise of the 420 Patent has not been
demonstrated or soundly predicted.
[152] The first
test is the human placental aromatase in vitro test (the AR1 test). This
involved testing the potency of candidate compounds on human placental tissue,
which is high in aromatase activity. The results were not disclosed in the
patent, although they were attached to Dr. Dukes’s affidavit in this
proceeding. The results showed that anastrozole is an aromatase inhibitor 100
times more potent than AG.
[153] Mylan’s
expert, Dr. Coombes, acknowledged that the AR1 test is acceptable to
preliminarily assess relative aromatase inhibition activity. He also
acknowledged that the results were “strongly suggestive” that anastrozole is
more potent than AG. However, he stated that a skilled person could not draw
the conclusion that anastrozole was more potent than AG because the two drugs
were not directly compared in the same test.
[154] AstraZeneca’s
expert, Dr. Dowsett, explained that the researchers performed the AR1 test on
anastrozole, AG, and a control compound. The properties of the control compound
would have been well known. If the results for the control compound differed
from previously obtained results, then the researcher would be alerted to the
fact that there may be a problem with the experiment. The use of the control
compound permits meaningful comparison between the test results, even if AG and
anastrozole were not directly compared in the assay. Thus, it was possible to
conclude that anastrozole was more potent than AG, even if this result was not
proven to a scientific standard appropriate for scientific publication.
Furthermore, Dr. Dowsett is of the opinion that the difference in potency
between AG and anastrozole was so significant that there could be no
substantive doubt that anastrozole was more potent than AG.
[155] The second
test disclosed in the patent is the ovulation inhibition in rats in vivo
test, dosed at days 2 or 3 of oestrous cycle (OI2 and OI3). The AR1 test
strongly suggested that anastrozole was a potent aromatase inhibitor in
vitro. It cannot be assumed that a compound which is active in vitro
will also be active in vivo. Therefore, the OI2 and OI3 tests were
designed to confirm that candidate compounds inhibited aromatase in vivo.
The assumption of the test was that a potent aromatase inhibitor would also
inhibit ovulation in rats, by suppressing estrogen levels.
[156] Dr. Coombes
acknowledged that the test results disclosed in Dr. Dukes affidavit show that
anastrozole appears to be a more potent ovulation inhibitor than AG. However,
Dr. Coombes emphasizes that the test does not directly measure aromatase
inhibition. It measures ovulation inhibition. Ovulation inhibition may be the
result of many different mechanisms. Therefore, in Dr. Coombes’s view, the OI2
and OI3 tests may be relevant to assessing the promised utility, but cannot
demonstrate or predict it.
[157] Dr. Dowsett
agreed that the OI2 and OI3 tests do not directly measure aromatase inhibition,
and that there may be other possible explanations for ovulation suppression.
However, Dr. Dowsett stated that when viewed in light of the AR1 results, and
knowing that the compounds were non-steroidal in nature, the “only rational
explanation” for the OI2 and OI3 results was aromatase inhibition. Dr. Dowsett
also emphasizes that the results of the OI2 and OI3 tests are consistent with
the AR1 results. When combined with the AR1 results, the OI2 and OI3 tests
provide further evidence of the potency of anastrozole as an aromatase
inhibitor, and extend the AR1 findings by providing data from an in vivo
test.
[158] Dr. Coombes
and Dr. Dowsett largely agreed on what the results of the two tests disclosed
in the 420 Patent showed. Both experts agreed that the AR1 test showed that the
compounds of the invention was a potent aromatase inhibitor when tested in
vitro. Both experts also agreed that the results of the OI2 and OI3 test
were consistent with the AR1 results, but did not directly measure the
inhibition of aromatase.
[159] The point of
disagreement between Dr. Coombes and Dr. Dowsett was the level of certainty
required to demonstrate utility. For example, with respect to the AR1 test, Dr.
Coombes accepted that the results “strongly suggested” that anastrozole was a
potent inhibitor, but took the position that to conclusively establish that
anastrozole was more potent than AG, in the sense of removing all doubt, the
two drugs must be compared in a direct head-to-head experiment. This is the
standard that would be taught in a first year undergraduate class, and is also
the standard that would be required for publication in a scientific journal.
[160] Similarly,
both experts agreed that the OI2 and OI3 tests did not directly measure
aromatase inhibition. However, Dr. Dowsett was of the opinion that the results
were strongly suggestive of potent aromatase inhibition activity, while Dr.
Coombes’s opinion was that this test was not adequate to demonstrate aromatase
activity. Dr. Coombes stated that AR1 and OI2 tests:
… the results are consistent, suggestive,
but not proof that this is the exact target…
[161] In my view,
Dr. Dowsett’s opinion is more consistent with the standard required by the
jurisprudence. Dr. Coombes appeared to equate ‘demonstrate’ with “minimal or no
room for doubt”, or “prove, removing all doubt”, or the standard required for
publication in a peer reviewed scientific journal. This standard is higher than
what is required for patentability.
[162] As stated by
Justice Binnie in Apotex Inc v Wellcome Foundation Ltd, 2002 SCC 77
at para 77 (Apotex AZT):
The prerequisites of proof for a
manufacturer who wishes to market a new drug are directed to a different
purpose than patent law. The former deals with safety and effectiveness. The
latter looks at utility, but in the context of inventiveness.
[163] The standard
required to demonstrate utility is not equivalent to the regulatory standard
required by the Minister to establish the safety and effectiveness of drugs: GlaxoSmithKline
rosiglitazone, above at para 116.
[164] I note that
in Pfizer sildenafil FC at para 87, Justice Michael Kelen rejected the
argument that test results must be conclusive in order to demonstrate utility.
[165] The standard
for utility is low: Pfizer donepezil, above at para 209.
[166] There is no
doubt that further and better testing could have been done, but scientific
perfection is not required to demonstrate utility. I note that the AR1 test is
widely recognized as a reliable method of comparing relative aromatase
inhibitory activity, and that the test results were not contested by any of the
experts. The OI2 and OI3 test results were recognized by both experts as
consistent and suggestive of the promised utility. In Dr. Dowsett’s view, when
combined with the AR1 test, no explanation other than aromatase inhibition is
logical or likely.
[167] Having
considered all the evidence, I am satisfied that as a matter of fact, no
skilled person reviewing the test results would have doubts that anastrozole
had utility as an aromatase inhibitor. A skilled person would know that further
testing is necessary to determine whether the compounds of the invention would
be a safe and effective treatment for breast cancer.
[168] For the
purposes of demonstrating utility, it is sufficient that the test results are
‘strongly suggestive’ of utility, and that no other logical explanation for the
test results is likely. Therefore I find that the AR1 and OI2 and OI3 tests are
sufficient to demonstrate the promised utility of the 420 Patent. Accordingly,
the 420 Patent’s utility need not be established on the basis of sound
prediction.
[169] Mylan argues
that the test results specific to anastrozole should have been disclosed in the
420 Patent. The patent merely offers a generic result, stating that:
In the above tests, the compounds of
formula I are active at less than 10 µg/ml (in vitro), and the preferred
compounds of formula I are active at below 0.1 µg/ml (in vitro) and 1.0
µg/ml (in vivo), and no indication of any toxicity has been seen at
these doses.
[170] Dr. Coombes
criticized the sufficiency of the patent disclosure. He noted that there was no
data showing the number and identity of compounds tested, sample size,
replicates, duration of study, the presence of positive and negative controls,
reproducibility of the assays, the relative activity of the compounds tested,
or the statistical analysis to which the results were subjected (if any).
[171] In Dr.
Coombes’s opinion, it would be impossible for the skilled person to assess the
reliability and credibility of the summary of the test results. It would also
be impossible to determine the basis on which anastrozole was chosen from the
preferred compounds. There are no test results specifically relating to
anastrozole disclosed in the 420 Patent.
[172] Finally, Dr.
Coombes noted that the 420 Patent specification discloses no comparative data
showing the relative activity of the compounds of formula 1 as compared to
prior art compounds. The skilled person would not know whether anastrozole was
more or less potent than AG.
[173] There was no
dispute between the parties regarding what was actually disclosed in the patent
specification. I accept Dr. Coombes’s evidence with respect to the content of
what is disclosed in the patent. The issue is whether the disclosure in the 420
Patent is sufficient for the purposes of demonstrating utility.
[174] I am
satisfied that the disclosure in the 420 Patent is sufficient for the purposes
of demonstrated utility. The Federal Court of Appeal addressed the requirements
respecting disclosure in Novopharm Limited v Pfizer Canada Inc, 2010 FCA
242, leave to appeal to SCC granted (Pfizer sildenafil FCA). The Federal
Court of Appeal held that if the patent asserts that the invention has been
demonstrated to have the promised utility, there is no requirement to prove
utility in the disclosure, as long as the Court finds it to be proven when
challenged in Court. At paragraphs 88 and 90, the Federal Court of Appeal held:
In other words, the disclosure provides
direction, not proof: it tells practitioners how to practice the invention. It
does not prove to them its utility, though they can require proof through
invalidity proceedings.
…
So long as the disclosure makes reference
to a study demonstrating utility, there do not appear to be any other
requirements to fulfill section 2.
[175] In Pfizer
sildenafil, the Federal Court of Appeal upheld the decision of Justice
Kelen. At paragraph 82, Justice Kelen described the disclosure requirement this
way:
The
Court finds that there is no requirement in patent law that evidence of the
demonstrated utility of the patent must be included in the patent. It is
sufficient that the patent states that the invention has been demonstrated to
be useful, as the '446 Patent does by making reference to the clinical testing
of the compound (Study 350), and that the patent-holder is able to show
evidence of demonstrated utility if the validity of the patent is challenged.
[176] The Federal
Court of Appeal revisited the issue of disclosure requirements in the recent
decision Apotex Inc v Pfizer Canada Inc and Pharmacia Atkiebolag, 2011
FCA 236 (Pfizer latanoprost). In this case, at paragraph 30 the Court
held:
Section 2 of the Act requires that the
subject matter of a patent be new and useful. The granting of a patent is
dependent upon the disclosure of how the patent intends to fulfill its promise
(Pfizer Canada Inc. v. Canada (Minister of Health), 2008 FCA 108, [2009] 1 F.C.R. 253, at
paragraph 34, Wellcome AZT, at paragraph 66). The general principle is
that, as of the date of the filing, a patent must disclose either an actually
achieved result (i.e., prove that it does what it claims) or a basis for sound
prediction of the result (i.e., show that it is likely to do what it claims).
There is no requirement to prove demonstrated utility in the disclosure of the
patent; so long as the disclosure makes reference to a study demonstrating that
the patent does what it promises to do, this criteria is met (Pfizer Canada
Inc. v. Novopharm Ltd., 2010 FCA 242, at paragraph 90). In our case,
utility would be demonstrated if the patent disclosed studies showing that
latanoprost, when administered on a chronic basis, reduced intraocular pressure
without causing substantial side effects.
[177] In
consequence of the Federal Court of Appeal’s ruling, I agree with Justice
Robert Barnes, who had written in an earlier decision that it is now “beyond
debate in Canada that where a patentee asserts the utility of its invention has
been demonstrated, it need not assert its supporting evidence in the patent”: Novopharm
Ltd v Eli Lilly and Co, 2010 FC 915 at para 116. If there was any doubt,
as to the proposition, there is none subsequent to the decisions of the Federal
Court of Appeal in Novopharm sildenafil and Pfizer latanoprost.
[178] As I read
this jurisprudence, the disclosure requirement can be satisfied by simply
making reference to a test or study that demonstrates utility.
[179] The 420 Patent
asserts that the compounds of the invention have utility as aromatase
inhibitors. The patent discloses two tests for aromatase inhibition and generic
results, as well as a full description of the compounds and how to make them.
When challenged in Court, AstraZeneca provided details of the full cascade of
tests and the results, in the Dukes Affidavit.
[180] In both Novopharm
sildenafil FCA and Pfizer latanoprost, the Federal Court of Appeal
speaks of the need to refer to a study in the patent disclosure to demonstrate
utility. Both of these cases dealt with patents that promised therapeutic
utility, while I have found that the 420 Patent only promises pharmacological
action. The scope of the disclosure requirement is informed by or takes its
colour from the nature of the claim. While a full study might be necessary to
demonstrate therapeutic utility, I find that the two laboratory tests disclosed
in the 420 Patent are adequate to demonstrate pharmacological action as
aromatase inhibitors. The 420 Patent more than meets the requirements set out
in Novopharm sildenafil, above.
Are Therapeutic Utility and Fewer Side Effects
Demonstrated or Soundly Predicted?
[181] In the event
that I am incorrect about the limited nature of the promise of the patent, I
have considered whether AstraZeneca has demonstrated or soundly predicted the
two other promises alleged by Mylan: fewer side effects and therapeutic
utility.
[182] As noted
above, AstraZeneca put candidate compounds through a cascade of tests. In
addition to the AR1 and OI2 and OI3 tests discussed above, AstraZeneca
conducted a number of tests intended to determine whether anastrozole had fewer
undesirable side effects than other leading aromatase inhibitors.
[183] AstraZeneca
conducted the male side effects in rats in vivo (MSE) test to determine
whether the compounds had the same side effect as AG – inhibition of cortisol
synthesis. Both Dr. Coombes and Dr. Dowsett agreed that the test results
suggested that anastrozole did not result in suppression of cortisol synthesis,
and was therefore more selective than AG.
[184] AstraZeneca
also conducted four other tests to determine whether the candidate compounds
were likely to have the same side effects as the leading aromatase inhibitors.
Two of the tests were specifically directed at the side effects exhibited by
fadrozole, a leading aromatase inhibitor. In each case, the test results showed
that anastrozole was selective.
[185] Dr. Coombes
criticized the reliability of these tests. Dr. Dowsett agreed that one of the
tests may not be reliable, but expressed the opinion that the remaining four
tests were sufficiently reliable to draw meaningful conclusions from.
[186] In my view,
the MSE test alone would have been sufficient to demonstrate that anastrozole
was more selective than AG. However, the 420 Patent does not make any reference
whatsoever to the MSE test, nor does it assert that the compounds of the
invention do have fewer undesirable side effects.
[187] As I read Novopharm
Viagra, above, the patent disclosure must make some reference to a study
demonstrating utility. All of the experts agreed that the two tests referred to
in the patent could not assess potential side effects. Even under the most
minimal standard of disclosure, there is nothing in the patent that would
inform a skilled person that the compounds of the invention were more selective
than AG. The patent does not demonstrate the utility of fewer side effects, due
to lack of disclosure.
[188] The
disclosure requirements for sound prediction are more onerous than for
demonstrated utility. The patent must disclose the factual data on which the
prediction is based, and the sound line of reasoning: Justice Binnie in Apotex
AZT, above at para 70. For the purpose of sound prediction a patentee
cannot rely on a document that has not been included or referred to in the
patent: Eli Lilly Canada Inc v Apotex Inc, 2008 FC 142 at para 164 (Eli
Lilly raloxifene), affirmed by the Court of Appeal, 2009 FCA 97 at paras 14
and 15.
[189] If the 420 Patent
fails to disclose enough information to demonstrate utility, then it cannot
contain sufficient information to meet the standard required for sound
prediction. Without disclosure of any of the other tests AstraZeneca conducted,
the patent fails to disclose a sufficient factual basis and sound line of
reasoning for the compound’s predicted therapeutic utility.
[190] The same
analysis would apply if the promise of the patent includes therapeutic utility.
The full cascade of testing, together with the relevant scientific context and
knowledge about the treatment of breast cancer, might have supported a sound
prediction that anastrozole had therapeutic utility. However, the patent does
not set out a sound line of reasoning, nor does it include any references to
other tests that might support a finding of therapeutic utility. The patent
fails to establish therapeutic utility due to a lack of disclosure.
[191] In sum, if I
am wrong about the narrow scope of the promise of the patent, and the promise
includes either fewer side effects than AG or therapeutic utility as a
treatment for breast cancer, then the 420 Patent fails for lack of demonstrated
or soundly predicted utility, and the application should be dismissed.
OBVIOUSNESS
[192] Mylan
asserts, in the alternative, that if the Court finds that the invention in the
420 Patent is that of aromatase inhibitors, without any other promise of fewer
side effects than AG or therapeutic benefit as a breast cancer treatment, the
invention is obvious. Mylan notes that AstraZeneca did not adduce evidence from
the inventors of the 420 Patent. The Application Record does not disclose what
steps ICI took to arrive at anastrozole.
[193] The Supreme
Court set out a four part test for obviousness in Apotex Inc v
Sanofi-Synthelabo Canada Inc, 2008 SCC 61 at para 67 (Apotex Plavix):
a. Identify the
person skilled in the art and the relevant common general knowledge;
b. Identify the
inventive concept of the claim in question or, if that cannot readily be done,
construe it;
c. Identify
what, if any, differences exist between the matter cited as forming part of the
“state of the art” and the inventive concept; and
d. Viewed
without any knowledge of the alleged invention as claimed, do those differences
constitute steps that would have been obvious to the skilled person or do they
require a degree of invention?
[194] The first two
steps of this test are not in dispute. The parties are agreed on the
characteristics of the skilled person, as set out above. The inventive concept
is anastrozole as an aromatase inhibitor.
[195] At the fourth
step of the test, an ‘obvious to try’ test may be applicable where advances are
achieved through experimentation. Justice Rothstein, writing for the Court,
described the test at paragraphs 69 and 70 of Apotex Plavix:
If an ‘obvious to try’ test is warranted,
the following factors should be taken into consideration at the fourth step of
the obviousness inquiry. As with anticipation, this list is not exhaustive. The
factors will apply in accordance with the evidence in each case.
1. Is it more or less
self-evident that what is being tried ought to work? Are there a finite number
of identified predictable solutions known to persons skilled in the art?
2. What is the extent,
nature and amount of effort required to achieve the invention? Are routine
trials carried out or is the experimentation prolonged and arduous, such that
trials would not be considered routine?
3. Is there a motive in the
prior art to find the solution the patent addresses?
Another important factor may arise from
considering the actual course of conduct which culminated in the making of the
invention. It is true that obviousness is largely concerned with how a skilled
worker would have acted in the light of the prior art. But this is no reason to
exclude evidence of the history of the invention, particularly where the
knowledge of those involved in finding the invention is no lower than what
would be expected of the skilled person.
[196] If something
is ‘obvious to try’, then this means that it is more or less self-evident that
what is being tested will work. The obvious to try test is meant to be a high
standard, it is not the same as ‘worth a try’: Apotex Inc v Pfizer Canada
Inc, 2009 FCA 8 at paras 25-29.
Common General Knowledge: The Structural Diversity of
Inhibitors
[197] Before
addressing the obviousness evidence and arguments, it is helpful to review some
of the common general knowledge regarding aromatase inhibitors. Aromatase
inhibitors are part of a family of inhibitors known as cytochrome P450
inhibitors. For the purposes of obviousness, the important feature of
cytochrome P450 inhibitors is that they exhibit considerable diversity in their
chemical structure. They can be classified as either Type 1 or Type 2
inhibitors.
[198] Type 1
inhibitors can be divided into steroidal and non-steroidal inhibitors.
Steroidal inhibitors often bind irreversibly to aromatase, thereby inactivating
the enzyme. Steroidal inhibitors contain the 4-ring structure present in all
steroids. In the early 1970s, Harry and Angela Brodie tested numerous
steroidal-based compounds for activity against aromatase, and identified
formestane as a promising aromatase inhibitor. By the mid-1980s, formestane was
being tested in patients.
[199] Type 2
inhibitors can also be steroidal or non-steroidal, however in 1987 it
was not known that Type 2 inhibitors could be steroidal. Type 2 inhibitors
include a functional group capable of complexing the heme iron.
[200] Type 2
inhibitors can be divided into two types. In anastrozole and fadrozole, the
heme iron complexes with a heterocyclic nitrogen on the inhibitor. In AG, the
heme iron complexes with a different group, such as an amino group.
[201] By 1987, a
number of different research groups were investigating Type 2 inhibitors,
including Dr. Hartmann’s group, Ciba-Geigy and Eli Lilly. AG, AG analogs and
fadrozole are all Type 2 inhibitors.
[202] The structural
diversity of cytochrome P450 inhibitors can be illustrated as follows:
Steroidal
Type 1
Non-steroidal
Cytochrome P450
inhibitors
AG analogs (heme iron
complexes with a different group)
Type
2
Heterocyclic based compounds (heme iron complexes with a heterocyclic
nitrogen on the inhibitor)
Mylan’s Obviousness Argument
[203] Mylan did not
pursue its obviousness argument during the hearing, but was content to rely on
its written submissions.
[204] Mylan
contends that at the priority date for the 420 Patent, the skilled person would
have started his inquiry by considering the disclosure of Eli Lilly’s “EP 777”
patent application. EP 777 describes prior art compounds which are structurally
similar to aromatase, and which were known and expected to be aromatase
inhibitors. Two basic molecular structures, identified by Dr. Redden as
‘Structure 1’ and ‘Structure 2’ encompass most of the significant compounds in
EP 777.
[205] In Dr.
Redden’s view, a skilled person would have noted certain trends in these
compounds, and would have appreciated that Structure 1 compounds were more
active, easier to synthesize and presented greater options for identifying
novel compounds. Dr. Redden identifies two Structure 1 compounds that a skilled
person would have started with.
[206] Dr. Redden
states that a skilled person would have carried out two modifications to the
starting compounds:
- Adding electron
withdrawing substituents (such as Cl and F) to the central ring; and
- Adding bulk to the
substituents, and distance between the benzene ring, in order to
approximate the size and shape of EP 777 compounds.
[207] Using this
strategy, which Mylan says is unimaginative, the modifications would have
created a series of 24 compounds, including anastrozole. On this basis, if the
promise of the 420 Patent is simply to inhibit aromatase, then the 420 Patent
is invalid due to obviousness.
AstraZeneca’s Obviousness Argument
[208] AstraZeneca
argues that nothing in the art would have directed a skilled person to start
with the compounds identified by Dr. Redden. There were many possible starting
points, and nothing in the prior art directed a skilled person to one starting
point in preference to another.
[209] According to
AstraZeneca, the state of the art is not necessarily the compound that is most
similar to the invention. This is a hindsight analysis, since determining
similarity requires one to start from the invention and scour the art for a
similar compound.
[210] Dr. Redden
assumes that the skilled person would have started with the Structure 1
compounds disclosed in EP 777. However, Structure 1 was not preferred in EP
777. None of the most potent compounds disclosed in EP 777 are Structure 1.
Lilly in fact preferred Structure 2 compounds. Furthermore, Dr. Redden’s
starting compounds were never made or specifically disclosed by Lilly in EP
777, nor was there any statement in the application or elsewhere that they
should be used in preference to other known starting points.
[211] The structure
of anastrozole is unique in medicinal chemistry. Many other skilled groups
failed to arrive at the invention.
[212] AstraZeneca
argues that Dr. Redden’s analysis is based on hindsight and is deeply flawed.
Further, AstraZeneca asserts that Dr. Redden is not qualified to offer an
opinion on what a skilled person would have known at the relevant date. He was
unaware of the many possible starting points for developing aromatase
inhibitors. His analysis requires a skilled person to start with structures not
expressly disclosed in EP 777, to go against prior art teachings, and to pursue
areas of investigation not pursued by Lilly. There is no evidence that anyone
recognized Dr. Redden’s trends, or would have pursued the research he proposed.
[213] Even Mylan
conceded that Dr. Redden does not have the “renown and experience with
aromatase inhibitors” that Dr. Hartmann does. As a skilled person, Dr. Redden’s
evidence is admissible, and I have considered it. However, where his evidence
differs from Dr. Hartmann’s, I prefer Dr. Hartmann’s evidence, which I find to
be reliable and persuasive.
[214] I am
satisfied that there was no obvious starting point that would have led to the
development of anastrozole. There were a range of possible starting points for
a research program. For this reason alone, Mylan’s obviousness argument must
fail.
[215] Given the
structural diversity of cytochrome P450 inhibitors, choices for a starting
compound included:
·
Type
1 or Type 2
·
If
Type 1: steroidal or non-steroidal?
·
If
Type 2: AG analogs or heterocyclic based compounds?
·
If
heterocyclic compounds: heterocyclic head group contains at least 10 different
possibilities, and a variety of possibilities for the structure of the balance
of the inhibitor were available.
·
Assuming
that the skilled person decided to develop a heterocyclic-based inhibitor,
there would still be a number of possibilities to explore:
§
Choice
of the heterocyclic group that interacts with the heme. There are at least ten
different groups that could be chosen.
§
Design
of the balance of the inhibitor, including the number of rings and choice and
position of the ring substituents.
[216] According to
Dr. Hartmann, nothing in the prior art literature directed a skilled person to
one starting point in preference to another. There were not a finite number of
predictable solutions, when one considers the range of compounds under
investigation.
[217] Dr. Hartmann
provided several reasons why the ‘unimaginative strategy’ advanced by Mylan was
not obvious. I will mention three reasons that I find particularly persuasive.
[218] First, EP 777
does not list Structure 1 as a preferred compound. The majority of the
compounds disclosed in EP 777 are neither Structure 1 nor Structure 2. The most
structurally similar compound is less potent than 50 compounds tested in
vitro in EP 777. None of the ten most potent compounds tested in vitro
in EP 777 are Structure 1. No Structure 1 compounds were tested for anti-tumour
activity.
[219] Second, Lilly
in fact preferred Structure 2. The skilled person was more likely to have
started with Structure 2, instead of Structure 1.
[220] Dr. Redden’s
starting compounds were never made or specifically disclosed by Lilly. They are
not included among the examples in the 777 application, nor is there any
statement in the application or elsewhere that they should be used in
preference to other known starting points.
[221] Third, during
the relevant time, there was a race to develop the next generation breast
cancer drug. Many other skilled groups were actively searching for new and
better aromatase inhibitors, but failed to arrive at the invention.
[222] Academic
researchers working on aromatase inhibitors at the relevant time included:
§
Hartmann et
al
§
Foster et
al
§
Brodie et
al
§
Daly et
al.
[223] A number of
pharmaceutical companies were also working on developing novel aromatase
inhibitors:
§
Merrell
§
Farmitalia
§
AKZO
§
Schering
AG
§
Ciba-Geigy
§
Eli Lilly
[224] I note that
several of the different chemical structures described above were under
development by skilled groups at the relevant time. Daly et al, Hartmann
et al, and Foster et al were all working on analogs of AG. Farmitalia
and Eli Lilly were working on analogs of AG. Ciba-Geigy was working on analogs
of AG and compounds related to fadrozole. By 1987, Merrell, Farmitalia, AKZO
and Schering AG were also investigating type 1 steroidal inhibitors.
[225] Eli Lilly was
working on compounds disclosed in the EP 777 application. I note that Lilly did
not come up with anastrozole, despite working on the compounds for almost four
and a half years.
[226] Finally, over
the course of the years, ICI made and tested more than 1000 compounds before
arriving at anastrozole.
[227] Evidence that
highly skilled parties expended effort but did not arrive at the invention may
support a finding of non-obviousness: Apotex Plavix, above at
paras 70-71.
[228] As is evident
from Dr. Hartmann’s evidence, there is considerable structural diversity among
inhibitors. The fact that there was no obvious starting point for development
among this structural diversity is supported by the fact that at the relevant
time, there were many different research groups pursuing different structures
for development as aromatase inhibitors. Furthermore, anastrozole contains some
very unique structures. Dr. Hartmann states that the dimethylacetonitrile
substituents in anastrozole were “completely new in drug molecules” at the
relevant time. Even today, to Dr. Hartmann’s knowledge, anastrozole is the only
drug containing these unusual groups.
[229] Mylan has
failed to establish that the inventive promise of the 420 would have been
obvious to a skilled person.
CONCLUSIONS AND COSTS
[230]
In
sum, the promise of the patent is simply aromatase inhibition and AstraZeneca
has demonstrated that anastrozole has utility as an aromatase inhibitor.
AstraZeneca has met its burden in demonstrating that the allegations made by
Mylan in this application are not justified. The application will be allowed,
the Minister will be prohibited from issuing a Notice of Compliance to Mylan
until the expiry of the 420 patent.
[231] AstraZeneca
is entitled to recover costs from Mylan which I fix at the upper end of Column
IV. I allow for two senior counsel at the hearing. I will generally follow
the approach to costs adopted by Justice Hughes in Bristol-Myers Squibb
Canada Co. v Apotex Inc., 2009 FC 137, at paragraphs 190 to 192 and allow
costs for two counsel, if present, one senior and one junior, in conducting
cross-examination. Only one counsel, a senior, is allowed in defending a
cross-examination. No costs are allowed for other lawyers, in house or out
house, students, paralegal or clerical persons.
[232] Each party may,
within twenty (20) days from the release of these Reasons, make submissions as
to costs not exceeding five (5) pages in length if additional direction is
required.
[233] The Minister
did not participate in these proceedings. No costs will be awarded for or
against the Minister.
JUDGMENT
THIS COURT’S
JUDGMENT is that:
1.
An
order of prohibition is granted restraining the respondent Minister of Health
from issuing a Notice of Compliance to Mylan Pharmaceuticals ULC in respect of
anastrozole.
2.
Costs
are awarded to the applicant.
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