Date: 20101029
Docket: T-1565-08
Citation: 2010 FC 1065
Ottawa, Ontario, October 29, 2010
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
ELI
LILLY CANADA INC.
Applicant
and
APOTEX INC.
THE MINISTER OF HEALTH
Respondents
and
ELI LILLY AND COMPANY
Respondent/Patentee
REASONS FOR JUDGMENT AND JUDGMENT
[1]
This
application was brought Eli Lilly Canada Inc. (Lilly) against Apotex Inc.
(Apotex) and the Minister of Health (Minister) under the Patented Medicines
(Notice of Compliance (NOC)) Regulations SOR/93-133 as amended. Lilly seeks an
order prohibiting the Minister from issuing a NOC to Apotex until the expiry of
Canadian Letters Patent No. 2,209,735 (the ’735 Patent). The Respondent Eli
Lilly and Company is the patentee of the ’735 Patent and was made a party to
this proceeding under ss. 6(4) of the NOC Regulations.
[2]
The
’735 Patent claims the use of atomoxetine (formerly named tomoxetine) for
treating attention-deficit hyperactivity disorder (ADHD) in adults, adolescents
and children. The ’735 Patent was filed in Canada on January 4, 1996 claiming priority from
the United
States
patent application No. 08/371,341 (the ’590 Patent) which was filed on January
11, 1995. The ’735 Patent expires on January 4, 2016.
[3]
Atomoxetine
was approved for use in Canada on December 24, 2004
and it has since been marketed by Lilly under the trade-name Strattera.
[4]
Lilly’s
application was brought in response to a Notice of Allegation (NOA) delivered
by Apotex by letter dated September 2, 2008. Apotex alleged that the ’735
Patent was invalid on the grounds of, inter alia, anticipation,
obviousness and inutility. Lilly asserts that none of the Apotex allegations
are justified and it is, therefore, entitled to an order of Prohibition.
Attention Deficit
Hyperactivity Disorder
[5]
ADHD
is a common neurobehavioral disorder that occurs in children, adolescents and
adults. It is characterized by age inappropriate hyperactivity, inattention
and impulsivity and it often causes functional impairments in school, at work
and in social settings. According to the Diagnostic and Statistical Manual of
Mental Disorders there are three subtypes of ADHD:
(a) primarily
inattentive;
(b) primarily
hyperactive/impulsive; and
(c) a combination
of the other two types.
[6]
The
cause or causes of ADHD are unknown and it has no cure. Nevertheless, the
symptoms of ADHD can, in many cases, be successfully ameliorated.
[7]
Since
the 1950s ADHD has most often been treated with stimulant therapy, which
remains the first line treatment choice. It was found, though, that the
stimulants did not work for every patient. For some patients with
co-morbidities or with substance abuse issues, the stimulants were not
appropriate. For other ADHD sufferers, the stimulants simply did not work.
This led to a search for alternative therapies and by at least the 1970s,
non-stimulant medications began to be used off-label as second-line treatment
choices. Since that time, the most commonly utilized non-stimulant medications
have been the tricyclic antidepressants or TCAs (e.g. imipramine, desipramine
and nortriptyline), alpha-2 adrenergic agonists (e.g. clonidine and guanfacine)
and bupropion. These drugs, however, came with their own set of limitations,
including less than desirable side-effect profiles. Accordingly, the search
for alternative drug therapies continued and it was out of that effort that
atomoxetine emerged.
I.
The
Development of Atomoxetine
[8]
There
is no disagreement between the parties about the development history of atomoxetine.
That evidence was provided by Lilly’s U.S. Director of Product Research and
Development, Dr. Martin Hynes III.
[9]
Dr. Hynes
deposed that in or around 1980, Lilly first synthesized atomoxetine and soon
thereafter discovered that it was a selective norepinephrine reuptake inhibitor
(NRI). This mechanism of action blocked the reuptake of the neurotransmitter,
norepinephrine, in the synaptic cleft of the brain thereby enhancing the
availability of norepinephrine.
[10]
Lilly’s
initial interest in atomoxetine concerned its potential to treat depression.
According to Dr. Hynes, Lilly conducted several substantial clinical
trials with atomoxetine for that indication between 1983 and the early 1990s. While
only one of those studies showed that atomoxetine was useful to treat
depression, they did demonstrate that the compound was safe and well-tolerated
in humans. These poor results led Lilly to abandon development of atomoxetine
as an anti-depressant. One other trial of atomoxetine in 1994 to treat urinary
incontinence was also unsuccessful.
[11]
At
around this same time a Lilly employee, Dr. John Heiligenstein, took
an interest in atomoxetine as a potential ADHD medicine. He was able to
convince Lilly management to pursue his idea and, by late 1994, Lilly and a
team from the Massachusetts General Hospital (MGH) reached an agreement to
conduct a clinical trial. According to Dr. Hynes the MGH then conducted a
seven-week placebo controlled, double blind, cross-over pilot study involving
21 adult patients with ADHD.
[12]
By
May 1995 the MGH Study was completed and, on May 18, 1995, the MGH Study report
was delivered by Dr. Thomas Spencer to Lilly. That paper was subsequently
edited and published in the American Journal of Psychiatry in 1998 under the
title “Effectiveness and Tolerability of Tomoxetine in Adults with Attention
Deficit Hyperactivity Disorder”. This is the study that Lilly relies upon to
establish the utility of atomoxetine to treat ADHD.
[13]
Following
on the MGH Study, Lilly filed the ’735 Patent and pursued Canadian and United
States regulatory approval for atomoxetine. An outline of the subsequent
clinical trials of the compound conducted on behalf of Lilly is set out in the
Product Monograph for Strattera attached as an exhibit to Dr. Hynes’s
affidavit.
The Patent In Issue
[14]
There
is no dispute about the inventive promise of the ’735 Patent. The 16 patent
claims involve the use of atomoxetine for treating ADHD in three of its
manifestations among all age groups (children, adolescents and adults). The
patent does not claim the compound atomoxetine but only its use to treat ADHD.
The patent does not assert nor would it have been expected by a person of skill
that atomoxetine would work for every person.
[15]
The
patent specification sets out a non-controversial history of ADHD and the
then-current treatments of choice for the disorder. The oldest and largely
successful medications are said to be a class of stimulants which includes
methylphenidate. Other effective drugs, it states, are antidepressant
tricyclics (TCAs) including imipramine, desipramine, nortriptyline,
amitriptyline and clomipramine. Nevertheless, the side-effects and usage
limitations of the available treatments created a “need for a safe and
convenient treatment for ADHD” which, in turn, led to “the present invention”
(’735 Patent at p. 2, lines 3-4, 7).
[16]
The
patent acknowledges that atomoxetine “is a well-known drug” with a recognized
mechanism of activity as a norepinephrine reuptake inhibitor (’735 Patent at p.
2, line 15). The specification also states the following:
Tomoxetine is quite active in that
function, and moreover is substantially free of other central nervous system
activities at the concentrations or doses at which it effectively inhibits
norepinephrine reuptake. Thus, it is quite free of side effects and is
properly considered to be a selective drug.
Tomoxetine is a notably safe drug, and
its use in ADHD, in both adults and children, is a superior treatment for that
disorder because of its improved safety. Further, tomoxetine is effective at
relatively low doses, as discussed below, and may safely and effectively be
administered once per day. Thus, difficulties created by the multiple dosing
of patients, particularly children and disorganized adults, are completely
avoided (’735 Patent at p. 2, lines 21-35).
[17]
The
specification also contains preferred dosage ranges for children and adults but
ultimately defers this question to the judgment of the treating physician. The specification
concludes with the statement that “there is no significant difference in the
symptoms or the details of the manner of treatment among patients of different
ages” (’735 Patent at p. 7, lines 21-23).
[18]
As
with the ’590 Priority Patent, the ’735 Patent offers no information about the
nature or sources of the evidence relied upon by the inventors to support the
promise of atomoxetine’s utility to treat ADHD by demonstration or by sound
prediction.
The Evidence
[19]
Lilly’s
evidence consisted of affidavits from Dr. James McGough and Dr. Russell Barkley,
each of whom provided opinion evidence concerning the scientific issues as they
related to the contested legal issues of anticipation, obviousness and
utility. Evidence about the development of atomoxetine up to and including its
approval for use in the United States and Canada was provided by Dr. Hynes.
[20]
Apotex’s
opinion evidence came from Dr. Ronald Brown,
Dr. Cecil Reynolds and Dr. Ronald Kuczenski.
[21]
From
my review of the qualifications of the expert witnesses, I am satisfied that they
were all well qualified to speak to the matters upon which they gave evidence.
Given the inherent procedural limitations in this process, especially the way
in which expert evidence is presented (see Eli Lilly Canada Inc. v. Apotex
Inc., 2009 FC 320 at para. 19) the Court is not in a position to effectively
pass judgment on the overall credibility of any of the witnesses.
[22]
It
was a point of particular controversy on this application that Lilly attempted
to introduce the MGH Study report as an exhibit to the affidavit of
Dr. Hynes and not through one of its named authors. This led to a
pre-application motion to exclude the MGH Study along with those portions of
Lilly’s expert opinion evidence which were based upon the Study. Apotex
argued, not without some justification, that Lilly was attempting to put this
evidence of utility forward without exposing its authors to cross-examination.
I will say more about this issue when I deal with the issue of utility later in
these reasons.
[23]
The
primary area of disagreement among the expert witnesses concerned the
likelihood that a person of skill in the art would conclude that atomoxetine,
as a selective NRI, ought to treat ADHD. The Apotex witnesses opined that the
efficacy of atomoxetine would have been self-evident because its profile
closely matched those of several other successful ADHD drugs, particularly the
TCA desipramine. The Lilly expert witnesses were of the view that in 1995 no
one knew why the successful ADHD drugs worked and, given the complexity of
their pharmacological profiles and neuronal impacts, no one could have
predicted that atomoxetine would also be successful. In short, although some
successful ADHD drugs affected norepinephrine reuptake, they also had other
neurotransmitter effects, and it was not known what aspects of a particular
drug’s pharmacology contributed to the treatment of ADHD.
II. Issues
[24]
What
is the standard of proof required?
[25]
Was
Lilly’s claim that atomoxetine could be used to treat ADHD obvious to a person
of skill in the art?
[26]
Was
the ’735 Patent anticipated by the ’009 Patent?
[27]
As
of the Canadian filing date of the ’735 Patent did Lilly have evidence that
demonstrated the utility of atomoxetine to treat ADHD in humans?
[28]
What
is the significance of the outcome of Novopharm Limited v. Eli Lilly and
Company, 2010 FC 915 to the outcome of this proceeding?
[29]
Costs?
III. Analysis
Burden of Proof
[30]
On
the issue of the burden of proof in NOC proceedings, I adopt the analysis
provided by Justice Roger Hughes in Eli Lilly Canada Inc. v. Apotex Inc.,
2009 FC 320, 75 C.P.R. (4th) 165 where he stated at paras. 37 - 40:
[37] The
issue as to who bears the burden of proof in NOC proceedings, as to validity of
a patent or infringement of a patent is an issue that I had thought had been
put to rest. Nonetheless the parties in such proceedings continue to argue the
point. It seems that my recent decision in Brystol-Myers Squibb Canada Co.
v. Apotex Inc., 2009 FC 137 has given fresh ammunition to those continually
wishing to stir the pot in this regard. Let me state emphatically that I did
not intend in Brystol-Myers to say or apply any burden different than I
had stated in previous decisions.
[38] To
be perfectly clear, when it comes to the burden as to invalidity I canvassed
the law, in particular recent Federal Court of Appeal decisions, in Pfizer
Canada Inc. v. Canada (Minister of Health), (2008), 69 C.P.R. (4th) 191,
2008 FC 11 and concluded at paragraph 32:
32 I
do not view the reasoning of the two panels of the Federal Court of Appeal to
be in substantial disagreement. Justice Mosley of this Court reconciled these
decisions in his Reasons in Pfizer Canada Inc. v. Apotex Inc., [2007]
F.C.J. No. 1271, 2007 FC 971 at paragraphs 44 to 51. What is required, when
issues of validity of a patent are raised:
1. The
second person, in its Notice of Allegation may raise one or more grounds for
alleging invalidity;
2. The
first person may in its Notice of Application filed with the Court join issue
on any one or more of those grounds;
3. The
second person may lead evidence in the Court proceeding to support the grounds
upon which issue has been joined;
4. The
first person may, at its peril, rely simply upon the presumption of validity
afforded by the Patent Act or, more prudently, adduce its own evidence as to
the grounds of invalidity put in issue.
5. The
Court will weigh the evidence; if the first person relies only on the
presumption, the Court will nonetheless weigh the strength of the evidence led
by the second person. If that evidence is weak or irrelevant the presumption
will prevail. If both parties lead evidence, the Court will weigh all the
evidence and determine the matter on the usual civil balance.
6. If
the evidence weighed in step 5 is evenly balanced (a rare event), the Applicant
(first person) will have failed to prove that the allegation of invalidity is
not justified and will not be entitled to the Order of prohibition that it
seeks.
[39] I
stated the matter more succinctly in Pfizer Canada Inc. v. Canada (Minister of Health), 2008 FC 500 at paragraph 12:
12 Here
the only issue is validity. Pharmascience has raised three arguments in
that respect. Each of Pfizer and Pharmascience have led evidence
and made submissions as to those matters. At the end of the day, I must decide
the matter on the balance of probabilities on the evidence that I have and the
law as it presently stands. If, on the evidence, I find that the matter is
evenly balanced, I must conclude that Pfizer has not demonstrated that Pharmascience's
allegation is not justified.
[40] The
above cases state correctly in my view, the law as to the burden in NOC
proceedings as to invalidity.
[31]
The
law is clear that with respect to any allegation of invalidity contained in a
NOA, the patentee is entitled to rely upon the presumption of validity set out
in ss. 43(2) of the Patent Act. This presumption obligates the respondent, at
a minimum, to lead evidence that, if accepted, is capable of rebutting the
presumption: see Abbot Laboratories et al. v. Canada, 2007 FCA 153, 59
C.P.R. (4th) 30 at para. 10. This initial evidential burden has
sometimes been described as putting the allegation “into play”: see Sanofi-Aventis
Canada Inc. v. Ratiopharm Inc., 2010 FC 230, 82 C.P.R. (4th) 414 at
para. 26.
[32]
With
respect to Apotex’s allegation of inutility in this proceeding, a serious issue
does arise as to whether it has met the initial evidentiary burden.
Obviousness – Legal
Principles
[33]
In Sanofi-Synthelabo
Canada Inc. v. Apotex Inc., 2008 SCC 61, 69 C.P.R. (4th) 251 the Supreme
Court of Canada considered the issue of obviousness in the context of a
challenge to the validity of a pharmaceutical selection patent. The decision
is particularly instructive in a case where the line of inquiry pursued by an
inventor would be thought by others to be at least promising or with a
semblance of a chance of success. Although the Court accepted that
"obvious to try" was one of several factors that should be
considered, it also said that this consideration needed to be applied cautiously
and with particular regard to the need to encourage pharmaceutical research and
development. The obvious-to-try test was said to be satisfied only where it
was self evident that what is being tried ought to work.
[34]
At
paragraph 67 the Court adopted the following four step framework for an
obviousness inquiry:
(a) identify
the notional person skilled in the art and the relevant common general
knowledge of that person;
(b) identify
the inventive concept of the claim or claims in issue and, if necessary,
construe them;
(c) identify
the differences, if any, between the “state of the art” and the inventive
concept of the patent; and
(d) viewed
without any knowledge of the alleged invention as claimed, do those differences
constitute steps which would have been obvious to the person skilled in the art
or do they require any degree of invention.
[35]
It
is only at the fourth step of the above analysis that "obvious to
try" will arise. I would add to this that what may be obvious to examine
may not be obviously useful if more than simple verification is required in
proof. The obvious to try analysis will, in each case, turn on several further
considerations including the number of available options or solutions to the
problem, the nature and extent of effort required to achieve the invention
(routine trials versus prolonged or arduous experimentation), the extent to
which others had tried and failed to find a solution, and the degree of
motivation to find a solution. Ultimately, if the evidence only establishes the
possibility that a promising compound or approach might work, obviousness is
not made out: see Apotex Inc. v. Pfizer Canada Inc., 2009 FCA 8, 72
C.P.R. (4th) 141 at para. 45.
Obviousness – The
Evidence
[36]
The
parties were in essential agreement in their characterization of a person of
skill in the art.
They also agreed about the inventive concept of the ’735 Patent. Their
disagreement centered on whether the prior art established that the
identification of atomoxetine to treat ADHD was obvious or uninventive.
[37]
Apotex’s
obviousness argument was premised on establishing that the TCAs (particularly
desipramine or DMI) which worked to treat ADHD did so “because of their
inhibition of norepinephrine reuptake” (see transcript p. 776). According to
Apotex, because atomoxetine was known to be a highly selective NRI a person
skilled in the art would expect that it, too, would treat ADHD.
[38]
There
is no question that the successful TCAs were, in relative terms, NRIs. Indeed
desipramine was as good at blocking the reuptake of norepinephrine as
atomoxetine. However, the essential problem with the Apotex evidence is that
it does not establish that, in 1995, a person of skill would have understood
that the blockade of norepinephrine reuptake was the mechanism of action
responsible for treating ADHD.
[39]
I
accept that there was a theory linking norepinephrine to ADHD and some
suggestion in the prior art that ADHD could be treated by increasing
norepinephrine levels in the synaptic cleft. Nevertheless, Apotex’s evidence
is only sufficient to establish the existence of one unproven hypothesis
sitting among of number of others.
[40]
Dr. Reynolds’
affidavit contains a comprehensive review of the prior art confirming the
utility of the TCAs and particularly imipramine, desipramine, and nortriptyline
for treating ADHD. He points to the relative similarity of these compounds as
norepinephrine reuptake inhibitors and compares them to atomoxetine, which was
long known to be a highly selective NRI. What is markedly absent, though, from
the prior art he relies upon is evidence establishing a causal link between the
noradrenergic profiles of these compounds and their clinical efficacy.
Notwithstanding the absence of such evidence, Dr. Reynolds was able to
opine that it was the selectivity of these compounds for the blockade of the
reuptake of norepinephrine that was the mechanism of action responsible for
their efficacy in treating ADHD.
[41]
I
reject Dr. Reynolds’ evidence on this issue largely because of his
apparent willingness to stretch the prior art to fit his opinion. A good
example of this can be found at para. 84 of his affidavit where, in discussing
desipramine, he interprets the equivocal words “perhaps by increased NE
availability at nerve terminals” as meaning that desipramine worked “because”
of its altering effect on norepinephrine levels in plasma. The rest of the
prior art relied upon by Dr. Reynolds either says nothing at all about
this cause and effect issue or expresses it only as an unproven hypothesis. Indeed,
Dr. Reynolds drew support from a study by Dr. Joseph Biederman which found desipramine to
have relatively high selectivity against the reuptake of norepinephrine.
Although the authors of that study described their data as being suggestive of
a link between desipramine’s noradrenergic properties and the treatment of ADHD
they categorically stated in conclusion that “[t]he pharmacological mechanism
of action of DMI in ADHD remains unknown”. This latter acknowledgement is
surprisingly not to be seen in Dr. Reynolds’ affidavit but it was accepted
by Dr. Kuczenski under cross-examination [see transcript at p. 2802] and
eventually accepted by Dr. Reynolds [see transcript at p. 2666].
[42]
Dr. Reynolds
was confronted on cross-examination with certain prior art reference that did
not support his opinion about what was understood about the responsible
mechanism of action of desipramine and the TCAs generally. His responses were
not particularly definitive or persuasive:
446 Q. All right. So, with
Dr. Biederman, what we can get out of this is that even in respect to
norepinephrine, DMI has multiple effects and the one that is leading to its
mechanism of action in ADHD remains unknown.
A. It remains unknown, but he suggests
clearly that it’s related to the drug’s actions on the central neurotransmitter
system that’s shared by those stimulants. And throughout this, we’ve seen that
it enhances the use of norepinephrine. So, I think that’s what he’s telling
us, that he’s suggesting that, sir.
447 Q. But ultimately, he’s saying we
don’t know for certain.
A. Ultimately, I think that I would agree
that he would say we don’t know for certain. My suggestion would be that you
would ask Biederman that, but I think he would agree with that.
[…]
480 Q. So, it’s clear for the record
what I’m asking you whether you agree on is: Their mechanism of action in ADHD
is unknown and it is probable that this mechanism is far less specific than
that of the stimulant – than that of stimulant medications.
A. And
the question is?
481 Q. Do you agree with that?
A. I
agree that that’s what it says. I don’t know that I agree with the statement,
no.
482 Q. So, this is one of those areas probably
in science that you’re talking about that the two respective researchers can
look at the data and come to different conclusions?
A. I
think so, yes.
[43]
Dr. Kuczenski
was more cautious in his assessment of the prior art but, in the result, his
opinion about the expected efficacy of atomoxetine to treat ADHD was stated
only as a hypothesis (see his affidavit at para. 60). He also began his
assessment of this evidence with an acknowledgement of the complexity of the
interactions within the brain created by the administration of psychotropic
drugs:
23. All
psychotropic drugs produce their behavioural effects by interacting with one or
more of these specialized sites affect the inter-neuronal communication
associated with each neurotransmitter. In addition to each of these various
sites within each neurotransmitter system – synthesis, storage, break-down,
receptor activation, and termination – drugs can also act on more than one of
the dozens of different neurotransmitters at the same time. Communication
through one neurotransmitter can be inhibited by the drug, while communication
through another neurotransmitter can be facilitated by the same drug. It is
multiplicity of sites and neurotransmitters at which drugs can interact that
accounts for the extremely wide range of unique and complex behavioural effects
associated with different drugs.
[44]
Although
Dr. Kuczenski was able to point to the relative similarity of many of the
successfully ADHD drugs (TCAs and stimulants) for the inhibition of the
reuptake of norepinephrine, he also noted the areas where they differed and, in
particular, their varied effects on other neuronal receptor systems. Under
cross-examination, he also conceded that in 1995 there were “very, very many
hypotheses [for successfully treating ADHD]. I mean, there were too much of
one transmitter, not enough of another transmitter, sugar hypothesis, there
were any number of hypotheses” [see transcript at p. 2779]. This is a
significant concession because in the absence of an understanding of the
mechanism of action responsible for achieving treatment it is a profoundly difficult
task to predict whether a promising drug candidate ought to work.
[45]
The
evidence from Dr. Brown is no stronger than that of Dr. Kuczenski.
He, too, noted the relative similarity of noradrenergic profiles of the ADHD
drugs but he was also not able or willing to categorically attribute their
efficacy to that aspect of their mechanism of action. This is apparent from
the very guarded summary to be found at para. 39 of his affidavit:
39. In
summary, the use of antidepressant medications, specifically the tricyclic
antidepressants including desipramine, had long been used as a second line
treatment to stimulant medication for the management of symptoms associated
with ADHD. In particular, desipramine and the other antidepressant agents had
been found to have a specific affinity to norepinephrine. Thus, the logic
provided in the ’735 Patent that atomoxetine, an antidepressant medication that
had been employed with adults for many years, would be potentially
efficacious for the management of ADHD, does not in my opinion represent a
distinct therapeutic approach. It was already known by January 1995 that the
medication of action of atomoxetine was the selective inhibition of
norepinephrine reuptake at the level of the synapse, and it was also already
known at that time that other norepinephrine reuptake inhibitors were
efficacious in treating ADHD.
[Emphasis
added]
[46]
On
cross-examination, Dr. Brown was effectively challenged on these issues as
can be seen from the following testimony:
383 Q. Let’s start with Exhibit 2.
Let’s go here. Strike the first part of the question. When we looked at the
stimulant methods of action, all right, we said that the stimulant -- I think
you agreed that the stimulants exert affects on multiple neurotransmitters.
A. Yeah, but specifically dopamine.
384 Q. So it has -- so specifically
dopamine. So it affects numerous neurotransmitters, but primarily dopamine, is
that correct?
A. Yes.
385 Q. If we look at this Exhibit 2,
Page 594, do you see under the heading “Antidepressants”?
A. Yes.
386 Q. About two inches down, three
inches down, it says:
“Their
mechanism of action in ADHD is unknown, and it is probable that this mechanism
is far less specific than that of stimulant medications?”
You
wrote that in 2002?
A. Yes.
387 Q. And the reason you wrote it, you
believed it to be true?
A. Yes. In 2000 -- when did this come out? 2002? Yes,
that was the pervasive thought.
388 Q. So what you are saying, in 1987
the prevailing thought was that desipramine exerted its influence on doparnine?
A. In ‘87?
389 Q. Yes. That’s what -- the paper I
just took you to, the Zametkin.
A. Yes. That exerted an effect on -- that was the
belief at the time.
390 Q. In 1987?
A. In
‘87.
391 Q. And your belief in 2002 was that
it was far less specific than the stimulants.
A. Probably. This was written in 2000, 2001.
392 Q. So in 2000, 2001, you thought it
was a good mechanism -- the purported mechanism of action of the -- of the
TCA’s, that it had a mechanism far less specific than that of stimulant
medications?
A. Generally.
393 Q. Generally, yes?
A. That was sort of the mode of thought, yeah. You
know, that was a probability. That was my thinking at the time.
394 Q. Nonetheless, when you look back
at 1987 or 1995 or 2002, the mechanism of the TCA’s is unknown. You would
agree with that?
A. No. You know, there was the notion that it affected
norepinephrine and dopamine, the synapse.
395 Q. So in your statement, this is
your 2002 paper, when you say:
“Their
mechanism of action in ADHD is unknown?”
You wrote that, right?
A. Either I or the coauthor.
396 Q. You are suggesting that maybe
this is something your coauthored wrote, you reviewed?
A. I
reviewed it.
397 Q. Right.
A. Right. It’s not referenced. It’s just, you know, some
thinking at the time.
398 Q. That thinking was based upon your
then understanding of the ADHD literature, correct?
A. Right.
399 Q. And at the time you had an
awareness of the Zametkin paper we took you to, right?
A. Yes.
400 Q. As well as other papers, right?
A. Right.
401 Q. And the conclusion that is
expressed is that the mechanism of TCA’s in ADHD is unknown.
A. That there was no -- there wasn’t anything
specifically conclusive. That there was no, you know -- there was nothing
definitive. I guess that’s what I meant.
402 Q. Now, let’s mark the Zametkin
paper.
But, Doctor, in terms -- when this paper
-- so this is your paper, Exhibit 2.
First of all, you submitted it for
publication, you or your coauthor, right?
A. Yes. We were asked to write this
particular paper.
403 Q. So you knew that it was going to
be read by your peers?
A. Yes.
404 Q. And, in, fact before it was
published it was reviewed by peers, correct?
A. Yes.
405 Q. It went through the editing
process?
A. Yes.
406 Q. And the statement that you wrote,
wasn’t that -- you know, there is nothing definitive can be said about the
mechanism of actions of TCA’s, that’s not what you wrote, is it?
MR.
BRODKIN:
The words speak for themselves.
BY MR.
SMITH:
407 Q. And those words are:
“The
mechanism of action in ADHD is unknown,”
and
that’s in reference to TCA’s, right?
MR. BRODKIN: The words speak for themselves.
And by that I mean, the words that are on
the page are on the page. He’s told you and given you testimony as to what he
understood and believes those words to mean.
MR.
SMITH: Just give us five minutes.
MR.
BRODKIN: Okay.
--
Off-the-record discussion
BY MR. SMITH:
408 Q. So, Doctor, just a last question
in terms of the Exhibit 2 that we were looking at, Page 94, and that
quote.
“The
mechanism of action in ADHD is unknown.”
Is there a difference between what you
meant and what you wrote?
OBJ
MR. BRODKIN: Don’t
answer the question.
He’s
already answered those questions.
[47]
It
is of some interest that Dr. Brown was directed by counsel not to answer a
highly relevant question in a situation where he was having obvious
difficulty. The inference that I draw from this is that had he been permitted
to answer, Dr. Brown would have conceded that the mechanism of action of
the TCAs in treating ADHD was not understood in 1995.
[48]
In
the absence of evidence to establish that the successful ADHD drugs worked
because of a common noradrenergic effect, I do not accept that a person of
skill in 1995 could have confidently predicted that atomoxetine would also work
for that indication. The evidence for this proposition given by the Apotex
witnesses rises only to the level of a possibility of efficacy which is not
enough to establish obviousness: see Apotex Inc. v. Pfizer Canada Inc.,
2009 FCA 8, 72 C.P.R. (4th) 141 at para. 45.
[49]
In
comparison, I find the evidence from the Lilly witnesses to be compelling and
well-supported by the prior art.
[50]
Dr.
McGough notes that in 1995 the mechanism of action responsible for the
efficacy of stimulant therapy in treatment ADHD was not well understood. These
drugs, he says, were also not good comparators to atomoxetine because, in
varying degrees, they affected multiple neurotransmitter systems. The TCAs
were also broader acting compounds than atomoxetine.
[51]
Dr. McGough’s
evidence is supported by Dr. Barkley’s assessment of what was known about
the drugs that were useful to treat ADHD and about what was known about
atomoxetine. I accept without reservation Dr. Barkley’s outline of the
prior art as set out below:
58. As
was noted in the ’735 Patent, both dopamine and norepinephrine were affected by
the use of stimulants but it was far from certain what the reason was for their
effectiveness in alleviating the symptoms of ADHD. This uncertainty is
reflected in the conclusion of Dr. Calis in his 1990 article (Apotex’
Document #10), where at page 633 it is stated:
Preclinical
studies have shown that both dextro amphetamine and methylphenidate block the
reuptake of dopamine and norepinephrine at the presynaptic neuron. Despite the
similarities in their mechanism of action, some differences in the behavioural
and biocheminal effects of these two stimulants have been noted in animals and
humans. … Although their exact roles have yet to be fully elucidated, both
dopamine and norepinephrine appear to contribute to the pathophysiology of
ADHD.
59. To
the extent there was agreement in the field, dopamine was hypothesized by many
to be the predominant neurotransmitter involved in both the underlying etiology
of ADHD and in the efficacy of stimulants in the treatment of ADHD. For
example, the Cook et al. 1995 publication attached hereto at Exhibit “F”,
considered the dopamine transporter as the primary candidate gene for ADHD and
the Castellanos 1997 Review, attached hereto as Exhibit “G” highlights
the predominance of the dopamine pathway in ADHD.
[…]
66. Contrary
to what is being suggested by Apotex’ experts, while there was certainly
literature on the usefulness of TCAs for the management of ADHD in the
1980s-90s, the manner by which this efficacy was achieved was unknown. The
tricyclic antidepressants were known at the time to also have antihistaminic,
anticholinergic, serotonergic and dopaminergic effects apart from those on
norepinephrine and no one had parsed the relative contributions of each of
these effects on the beneficial effects the drugs may have had on ADHD
symptoms. Even Dr. Brown concedes this point in para. 44 where he
states that the TCAs were “…posited to involve a number of neurotransmitters”.
67. In
paragraphs 76 and 77 of his affidavit, Dr. Reynolds suggests that a number
of references “disclose that desipramine is a norepinephrine reuptake inhibitor
(“NRI”), and the fact that it is a NRI explains why desipramine is effective in
the treatment of ADHD”. The first reference he cites is a 1983 article by
Dr. Garfinkel. While Dr. Garfinkel (Apotex’ Document 20) does state
that “desipramine (DMI) and norclomipramine block the reuptake of
norepinephrine”, he goes on to state:
Since
it is not known that blocking monoamine reuptake is the TCA [tricyclic
antidepressant] pharmacodynamic property which determines the therapeutic
response, inferences about neurotransmitters must be limited.
68. As
discussed in greater detail below, desipramine is not exclusivity a
norepinephrine reuptake inhibitor. Even in the quote from Donnelly et al.
(Apotex’ Document 14) referenced by Dr. Reynolds in paragraphs 82 and 84,
the authors acknowledge that the role of NE as the mechanism of action for TCAs
and as a possible causal contributor to ADHD itself were “hypotheses” and not
well-established facts. This is also evident in the quote from this paper by
Dr. Reynolds in paragraph 84 where the word “perhaps” appears in
the quote “The mechanisms of action, perhaps by increased NE availability at
nerve terminals…”.
69. The
simple truth is that the mechanism of actions of TCAs, including desipramine,
in treating ADHD were not established as of 1995 or even today. While some of
the many different activities of desipramine (DMI) were discussed in the
context of side-effects, there is nothing to suggest that these other
activities were not also contributing to its efficacy in treating ADHD. For
instance, in his discussion of his study’s results of a large trial of DMI for
patients with ADHD Dr. Biederman, a leading child psychopharmacologist, in
Apotex’ reference 1:
“The
pharmacological mechanism of action of DMI and ADDH remains unknown.” (p. 783)
[52]
From
my own review of the prior art, I also accept Dr. McGough’s
characterization of what a person of skill looking at atomoxetine would have
understood from drugs like desipramine:
107. In
paragraph 42 of Dr. Brown’s affidavit he states “[t]he tricyclic
antidepressants had been demonstrated prior to January 1995 to exert their
effects at the level of the synapse by blocking the reuptake of
norepinephrine.” As discussed above, the tricyclic antidepressants were
considered in the field of psychiatry to be “dirty drugs”, which had wide
ranging effects on multiple neurotransmitter systems. For example, in addition
to its ability to inhibit norepinephrine reuptake, desipramine was known to
have activities at alpha-1, alpha-2 and beta adrenergic receptors; cholinergic;
D2 dopaminergic; H-1 and H-2 histaminergic; muscarinic; and serotonergic
receptors. Thus, a person skilled in the art could not attribute the efficacy
of any TCA, including desipramine, to any one aspect of its pharmacology,
including the ability to inhibit norepinephrine reuptake. Moreover, before
1995, it was not possible tell how these drugs were distributed and bound in
the human brain, even in light of in vitro potency studies.
[53]
I
also accept Mr. McGough’s criticisms of the opinions of Drs. Brown,
Kuczenski and Reynolds set out at paras. 103 to 117 of his affidavit and I
agree with him that those opinions are based on an inappropriately selective
review of the prior art including a number of passages taken out of context.
[54]
My
own review of the prior art evidence indicates that the profiles of the drugs
that worked to treat ADHD were simply too diverse, and their mechanism of
presumed action within the highly complex neurological systems involved were
too uncertain to draw any firm conclusion about the efficacy of atomoxetine.
Examples of this include the following prior art references:
Andrew Shenker, “The Mechanism of Action of Drugs Used to
Treat Attention-Deficit Hyperactivity Disorder: Focus on Catecholamine Receptor
Pharmacology” (1992) 39 Adv. Pediatrics 337.
[55]
This
comprehensive survey of the prior art indicates that even compounds that are
highly selective for a particular neurotransmitter system can be expected to
have multiple and poorly understood effects on other systems. Shenker also
observes that highly selective compounds may not be the best candidates for
ADHD drug development.
Angela LaRosa
and Ronald T. Brown, “Recent Developments in the Pharmacotherapy of
Attention-Deficit/Hyperactivity Disorder (ADHD)” (2002) 33(6) Professional
Psychology, Research and Practise 591.
[56]
It
states:
The
stimulant medications are believed to exert their action through the
enhancement of dopamine and norepinephrine neurotransmission, although the
precise mechanism of action is unknown [p. 592].
[…]
Their
[TCA] mechanism of action in ADHD is unknown, and it is probable that this
mechanism is far less specific than that of stimulant medications [p. 594].
Joseph Biederman et al., “A Double-Blind Placebo Controlled
Study of Desipramine in the Treatment of ADD: I” (1989) 28(5) J. Am. Acad.
Child Adolesc. Psychiatry 777.
[57]
It
states:
The
pharmacological mechanism of action of DMI in ADDH remains unknown [p. 783].
Barry Garfinkel et al., “Tricyclic Antidepressant and
Methylphenidate Treatment of Attention Deficit Disorder in Children” (1983)
22(4) J. Am. Acad. Child Adolesc. Psychiatry 343.
[58]
It
states:
Since
it is not known that blocking monoamine reuptake is the TCA pharmacodynamic
property which determines the therapeutic response, inferences about
neurotransmitters must be limited [p. 343].
L.L Greehill, “Pharmacologic Treatment of Attention Deficit
Hyperactivity Disorder”(1992) 15(1)
Psychiatr Clin North Am.1
[59]
It
states:
Treatment
studies of ADHD children showed just the opposite, leading to the rejection of
the dopamine hypothesis of ADHD, as well as other single
neurotransmitter-deficit etiologic models [p. 5].
Timothy Wilens et al., “Pharmacotherapy of Adult ADHD” in A
Comprehensive Guide to Attention Deficit Disorder in Adults (Brunner/Mazel: New
York, 1995) at 168.
[60]
It
states:
While
not entirely sufficient, alteration in dopamenergic and noradrenergic functions
appears necessary for clinical efficacy of the anti-ADHD medications including
the stimulants [pp. 171 to 172].
S.R Pliska et al. “Catecholamines in Attention-Deficit
Hyperactivity Disorder: Current Perspectives” (1996) 35(3) ) J. Am. Acad.
Child Adolesc. Psychiatry 264.
[61]
It
states:
[…]
no comprehensive model has been explicated which successfully describes the
underlying pathophysiology of ADHD and the mechanisms by which medications
ameliorate its symptoms [p. 264].
[62]
In
conclusion, the evidence provided by Lilly’s witnesses with respect to the
issue of obviousness is compelling and Apotex’s invalidity allegation is
rejected.
Anticipation
[63]
I
have no difficulty with Apotex’s argument that the legal principles applicable
to an allegation of anticipation were modified by the Supreme Court of Canada
in Sanofi, above ,and I would adopt the following helpful summary of the
law provided by Justice Hughes in Abbott Laboratories et al. v. Canada,
2008 FC 1359, 71 C.P.R. (4th) 237 at para. 75:
[75] To
summarise the legal requirements for anticipation as they apply to the
circumstances of this case:
1. For
there to be anticipation there must be both disclosure and enablement of the
claimed invention.
2. The
disclosure does not have to be an “exact description” of the claimed
invention. The disclosure must be sufficient so that when read by a person
skilled in the art willing to understand what is being said, it can be
understood without trial and error.
3. If
there is sufficient disclosure, what is disclosed must enable a person skilled
in the art to carry out what is disclosed. A certain amount of trial and error
experimentation of a kind normally expected may be carried out.
4. The
disclosure when carried out may be done without a person necessarily
recognizing what is present or what is happening.
5. If
the claimed invention is directed to a use different from that previously
disclosed and enabled then such claimed use is not anticipated. However if the
claimed use is the same as the previously disclosed and enabled use, then there
is anticipation.
6. The
Court is required to make its determinations as to disclosure and enablement on
the usual civil burden of balance and probabilities, and not to any more
exacting standard such as quasi-criminal.
7. If
a person carrying out the prior disclosure would infringe the claim then the
claim is anticipated.
[64]
Apotex
contends that the inventive promise of the ’735 Patent that atomoxetine is
useful to treat ADHD was anticipated by United States Patent No. 4,194,009
(’009 Patent). This is an issue of mixed fact and law: see Calgon Carbon
Corporation v. Corporation of North Bay, 2008 FCA 81, 64 C.P.R. (4th) 337
at paras. 5 - 6.
[65]
The
’009 Patent covers a multitude of compounds, some of which it describes as
NRIs. Atomoxetine is not specifically disclosed but it is, as conceded by
Lilly’s witnesses, one of the compounds claimed. The specification compares
the mechanism of action of some of these compounds to TCAs and notes their
potential to treat depression. Other possible uses are said to be as
treatments for sleep disorders, sexual performance, appetite, muscular function
and pituitary function. There is no mention at all of ADHD.
[66]
The
only claim made by the ’009 Patent is that the administration of all of its
compounds will cause a potentially useful “psychotropic effect”.
[67]
Dr. Reynolds
linked the ’009 Patent to the inventive promise of the ’735 Patent at
paras. 140-143 of his affidavit:
140. A
“psychotropic action” would have been understood by a person skilled in the art
in January 1995 to mean that the administration of the compound to a patient
would affect the patient’s behaviour (either overt, covert, or both) in some
way. The ’009 Patent provides some examples of such behaviour, the main one
being depression – the compounds are said clearly to have “potential as
anti-depressant compounds” (column 14, line 1). Other examples include the
treatment of schizophrenia, and disorders of sleep, sexual performance,
appetite, muscular function, and pituitary function (column 14).
141. In
my opinion, the treatment of ADD [now an archaic term] and ADHD would have been
understood by a person skilled in the art to be included within the general
term “psychotropic action”. ADHD was known by January 1995 to be a behavioural
disorder (see for example Reference 30 at pages 317 and 350), and it was known
that ADHD was one of the most if not the most frequent psychiatric diagnosis
given to children in North America (Reference 40 at page 444).
142. It
is my opinion that a person skilled in the art would have understood that the
’009 Patent disclosed the use of a group of compounds, which includes
atomoxetine, that provide a psychotropic effect or action, including being
useful in the treatment of ADHD. The person skilled in the art would have
understood from the ’009 Patent that the psychotropic effect was due to the
fact that many of the compounds selectively block norepinephrine uptake with a
reduction in undesirable effects associated with many other medicines.
143. I
am in agreement, therefore, with the statement in the Apotex NOA at page 8 that
a person skilled in the art would have known that ADHD is a psychotropic
illness, and that the use of atomoxetine to treat ADHD is equivalent to the use
of atomoxetine to provide a psychotropic effect.
[Emphasis
added]
[68]
As I
read these statements, Dr. Reynolds is saying that because a skilled
person would know that ADHD is a common psychotropic disorder amenable to
treatment with psychotropic agents, such a person would also know that the ’009
Patent compounds would treat ADHD. In addition, Dr. Reynolds appears to
be saying that the NRI profile of some of the ’009 Patent compounds would also
lead a person of skill to the same conclusion. Mr. Brodkin framed this
latter point as follows:
The next point in respect of the patent
is that it explains to a reader the mechanism upon which the psychotropic
agents impact the norepinephrine reuptake mechanism.
It's not any old psychotropic effect,
it's psychotropic effects that act upon a particular pathway, the particular
pathway, norepinephrine reuptake, which, of course, is implicated in ADHD
treatments.
[69]
To
the extent that the Apotex anticipation argument is based on its position that
it was known in 1995 that the efficacy of ADHD drugs was caused by their
inhibition of the reuptake of norepinephrine, the argument fails for the same
reason that the inventive promise of the ’735 Patent was not obvious.
[70]
I do
accept Mr. Brodkin’s point that ADHD is a psychotropic condition. This
was conceded by Dr. Barkley in his cross-examination and it is the only
reasonable interpretation of those words. But what remains for determination
is whether the fact that ADHD falls within that “umbrella” term in the ’009
Patent is enough to establish anticipation. I am not satisfied that it does.
[71]
Apotex
relied heavily on the decision of Justice Anne Mactavish in Lundbeck v.
Ratiopharm Inc., 2009 FC 1102, 79 C.P.R. (4th) 243. That case involved a
patent for the drug memantine for the treatment of Alzheimer’s disease. The
anticipatory references indicated that memantine was useful to treat “organic
brain syndrome”, “organic psychosyndrome” and “dementia”. All of those terms
were understood to include Alzheimer’s disease. Indeed, Alzheimer’s disease
was described as the most common form of dementia. One of the other conditions
named in the patent was cerebral ischemia which was a condition that similarly
fell within the scope of “organic brain syndrome”.
[72]
Not
surprisingly, Justice Mactavish found that the anticipatory references
disclosed and enabled the treatment of the Alzheimer’s disease and cerebral
ischemia and therefore offered nothing new or inventive.
[73]
I am
not satisfied, however, that the Lundbeck decision can be fairly applied
to the facts of this case.
[74]
As
Justice Hughes pointed out in Abbott Laboratories, above, the prior
anticipatory disclosure does not have to be an exact description of the claimed
invention, but the claimed uses must be essentially the same. It is also a
requirement that the person carrying out the prior disclosure would infringe
the patent claim. In Lundbeck, above, the anticipatory references
referred to the exact compound subsequently claimed in the patent for uses that
closely overlapped. The situation before me involves a prior patent that
includes thousands of compounds and where neither atomoxetine nor ADHD is
specifically disclosed.
[75]
The
person of skill looking at the ’009 Patent is trying to understand what it
means and in so doing would be influenced by the prior art. I do not accept
that such a person would equate the use of achieving a psychotropic effect in
the ’009 Patent with the successful treatment of ADHD, particularly in the face
of the other suggested uses for those compounds and considering what was known
about the available ADHD treatment options at that time. In such a context a
person following the teaching of the ’009 Patent would have no obvious reason
to consider any of the compounds claimed as being useful ADHD drugs, let alone
necessarily infringe by attempting to put them into use for that purpose.
[76]
As I
understand Mr. Brodkin’s argument, the ’009 Patent would be anticipatory
with respect to any subsequent claim to the use of any one of its compounds for
any psychotropic indication. It is only in that context that one could
conclude that by carrying out the teaching of the ’009 Patent an infringement
of the ’735 Patent would necessarily occur. This is an interesting argument
which is not without some appeal. I am, however, not persuaded that the
teaching of the ’009 Patent anticipates the inventive promise of the ’735
Patent. I say that because the person of skill would appreciate that not every
psychotropic drug will treat ADHD, nor will every NRI. Even if one accepts
that in assessing the ’009 Patent as anticipatory one should consider
each compound as a separate invention, one would still have to make a decision
to use atomoxetine to treat ADHD in the absence of any suggestion that it would
work.
[77]
Although
I am not free of all doubt on this issue, I am satisfied that Lilly has met the
requisite burden of proof with respect to the anticipation issue and that
allegation fails.
Utility –
Legal Principles
[78]
Section
2 of the Patent Act, R.S., 1985, c. P-4, stipulates that an
invention be "useful". It is this provision that incorporates the
concept of utility into Canadian patent law.
[79]
In
Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1
S.C.R. 504, 56 C.P.R. (2d) 145, the concept of inventive utility was described
as follows at pages 524 to 526:
There is but a single test,
and that test is whether the specification adequately describes the invention for
a person skilled in the art, though, in the case of patents of a highly
technical and scientific nature, that person may be someone possessing a high
degree of expert scientific knowledge and skill in the particular branch of
science to which the patent relates. It might be added that there was no
evidence by the respondent as to any respect in which the specifications of the
two patents in issue would have been considered deficient by a workman of
ordinary skill in the art.
In my respectful opinion the
Federal Court of Appeal erred also in holding that s. 36(1) requires distinct
indication of the real utility of the invention in question. There is a helpful
discussion in Halsbury's Laws of England, (3rd ed.), vol. 29, at p. 59, on the
meaning of "not useful" in patent law. It means "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". There is no suggestion here that the invention will not give the
result promised. The discussion in Halsbury's Laws of England, ibid.,
continues:
... the practical usefulness of the
invention does not matter, nor does its commercial utility, unless the
specification promises commercial utility, nor does it matter whether the
invention is of any real benefit to the public, or particularly suitable for
the purposes suggested. [Footnotes omitted.]
and concludes:
... it is sufficient utility to support a
patent that the invention gives either a new article, or a better article, or a
cheaper article, or affords the public a useful choice. [Footnotes omitted.]
Canadian law is to the same effect. In Rodi
& Wienenberger A.G. v. Metalliflex Limited (1959), 32 C.P.R. 102, 19
Fox Pat. C. 49, [1960] Que. Q.B. 391n; affirmed in this Court 35 C.P.R. 49,
[1961] S.C.R. 117, 21 Fox Pat. C. 95, the Quebec Court of Appeal adopted at
p. 107 C.P.R., p. 53 Fox Pat. C., the following quotation from the case of
Unifloc Reagents, Ltd. v. Newstead Colliery, Ltd.(1943), 60 R.P.C. 165
at p. 184:
If when used in accordance with the
directions contained in the specification the promised results are obtained,
the invention is useful in the sense in which that term is used in patent law.
The question to be asked is whether, if you do what the specification tells you
to do, you can make or do the thing which the specification says that you can
make or do.
[80]
Utility
is not established on the basis of a mere hypothesis, an unproven idea or sheer
speculation, even if later established, but it can rest upon a foundation of
sound prediction. In Apotex Inc. v. Wellcome Foundation Ltd., 2002 SCC
77, 21 C.P.R. (4th) 499 (hereinafter referred to as AZT),,
the concept of sound prediction was described in the following passage at
paras. 70 and 71:
70 The doctrine of sound
prediction has three components. Firstly, as here, there must be a factual
basis for the prediction. In Monsanto and Burton Parsons, the
factual basis was supplied by the tested compounds, but other factual
underpinnings, depending on the nature of the invention, may suffice.
Secondly, the inventor must have at the date of the patent application an
articulable and “sound” line of reasoning from which the desired result can be
inferred from the factual basis. In Monsanto and Burton Parsons,
the line of reasoning was grounded in the known “architecture of chemical
compounds” (Monsanto, at p. 1119), but other lines of reasoning, again
depending on the subject matter, may be legitimate. Thirdly, there must be
proper disclosure. Normally, it is sufficient if the specification provides a
full, clear and exact description of the nature of the invention and the manner
in which it can be practised: H. G. Fox, The Canadian Law and Practice
Relating to Letters Patent for Inventions (4th ed. 1969), at p. 167. It is
generally not necessary for an inventor to provide a theory of why the
invention works. Practical readers merely want to know that it does work and
how to work it. In this sort of case, however, the sound prediction is to some
extent the quid pro quo the applicant offers in exchange for the patent
monopoly. Precise disclosure requirements in this regard do not arise for
decision in this case because both the underlying facts (the test data) and the
line of reasoning (the chain terminator effect) were in fact disclosed, and
disclosure in this respect did not become an issue between the parties. I
therefore say no more about it.
71 It bears repetition that the
soundness (or otherwise) of the prediction is a question of fact. Evidence
must be led about what was known or not known at the priority date, as was done
here. Each case will turn on the particularities of the discipline to which it
relates. In this case, the findings of fact necessary for the application of
“sound prediction” were made and the appellants have not, in my view,
demonstrated any overriding or palpable error.
Utility – The
Evidence
[81]
The
approaches taken by the parties to the issue of utility were unusual. Apotex
comprehensively addressed the issue in its NOA in the following passage:
First, there is no factual basis set out
in the ‘735 Patent upon which a sound prediction could be made that atomoxetine
was safe and effective for the treatment of ADHD in children, adolescents and
adults. The disclosure of the ‘735 Patent fails to provide any information,
data or test results purporting to show that the administration of atomoxetine
to children, adolescents and adults suffering from ADHD is safe and is
effective in the sense that treatment of ADHD will result.
The only purported factual basis
disclosed in the ‘735 Patent on which any prediction could be made is
information about what was already known about atomoxetine and ADHD from the
prior art. If what was previously known about atomoxetine is a sufficient
factual basis upon which a sound prediction can be made, then the claimed
invention would have been obvious to a person skilled in the art.
Eli Lilly has confirmed that the first
clinical trials or experiments assessing the safety and efficacy of atomoxetine
for treating ADHD were not conducted until after the filing of the priority
‘341 Application.
Apotex asserts that any results and data obtained from those clinical trials or
experiments could not have formed a sufficient factual basis or sound line of
reasoning upon which a sound prediction could be made of the safety and
efficacy of atomoxetine for treating ADHD. Alternatively, if those clinical
trials or experiments were sufficient to confirm the safety and efficacy of
atomoxetine for treating ADHD, which Apotex denies, then Eli Lilly failed to
disclose the results and data from those clinical trials and experiments in the
‘735 Patent.
Second, the purported inventors did not
have an articulable and “sound” line of reasoning from which the promised
utility that atomoxetine was safe and effective for treating ADHD could be
inferred from the factual basis. The only purported sound line of reasoning
disclosed in the 1735 Patent on which any prediction could be made is what was
already known about atomoxetine from the prior art. If what was previously
known about atomoxetine provides a sound line of reasoning from which a sound
prediction can be made, then the claimed invention would have been obvious to a
person skilled in the art.
Third, there is no proper disclosure in
the ‘735 Patent of a factual basis and a sound line of reasoning from which the
purported inventors could soundly predict that atomoxetine would be sale [sic]
and effective for treating ADHD, including for treating “predominantly inattentive
type of attention deficit/hyperactivity disorder” or “predominantly
hyperactive-impulsive type of attention deficit/hyperactivity disorder”. The
purported inventors did not have a factual basis nor sufficient information to
be able to soundly predict that atomoxetine was safe and effective for the
treatment of ADHD in the patient groups recited in the claims, namely adults,
adolescents, and children.
[Emphasis added]
[82]
Lilly
answered the NOA with a Notice of Application which stated:
41. The claims of the ‘735 Patent
claim the use of atomoxetine for treatment of ADHD. Atomoxetine is useful for
the treatment of ADHD in adults, adolescents and children, and as such, Lilly
Canada denies that the invention claimed in the ‘735 Patent lacks utility as alleged
by Apotex in its Notice of Allegation. The relevant date for assessment is as
of the Canadian filing date namely January 4, 1996. As of January 4, 1996, Lilly
had established by virtue of studies that atomoxetine was useful for the
treatment of ADHD and, in any event, had a factual basis for the alleged
predictions by virtue of studies that had been conducted; there was an
articulable and sound line of reasoning from which the desired result could be
inferred from the factual basis and there was proper disclosure of the nature
of the invention and manner in which it could be practised in the ‘735 Patent.
[Emphasis added]
[83]
Because
the order of presentation of the evidence in this proceeding was reversed,
Apotex led with its affidavits. That evidence was limited to the observation
that the ’735 Patent gave no indication of testing of atomoxetine to
substantiate the inventive promise of utility. Dr. Brown’s affidavit
noted the absence of data in the patent and suggested that the utility of
atomoxetine must therefore have rested upon what was already known in the prior
art:
40. Finally, the ‘735 Patent does
not include any data whatsoever, including any data from clinical trials, which
are the gold standard for evaluating any type of pharmacotherapy. There are no
data provided in the ‘735 Patent to show or even suggest the efficacy of
atomoxetine for the management of ADHD and to show that atomoxetine is a
“notably safe drug”. Consequently, the argument that atomoxetine is an
effective pharmacotherapy for the management of ADHD appears to be circular and
draws from the use of other antidepressant agents for treating ADHD, including
desipramine, where the primary action of the medication is associated with the
reuptake of norepinephrine, at the level of the synapse, and from what was
already known about atomoxetine.
[84]
This
evidence is not consistent with the Apotex NOA which conceded some knowledge of
the existence of clinical trials run after the U.S. priority
application. Despite that knowledge, Apotex framed its case around the issue
of sound prediction and failed to put up any evidence contesting Lilly’s
assertions of demonstrated utility.
[85]
Lilly
responded to Apotex’s allegations by producing the MGH Study report and a later
published version of the Study as exhibits to the affidavit of Dr. Hynes.
Both Dr. Barkley and Dr. McGough then examined the MGH Study report,
including its reported design and findings, and concluded that it was
sufficient to demonstrate the utility of atomoxetine as of the Canadian filing
date of the ’735 Patent (see Barkley affidavit at paras. 35 to 45 and McGough
affidavit at paras. 90 to 102).
[86]
Apotex
again elected not to challenge this evidence on matters of substance. Instead,
it moved to strike the evidence in its entirety as inadmissible hearsay and the
parties devoted a full day of argument to that issue immediately in advance of
the hearing of the application.
[87]
It
is not entirely clear on the evidence before me how much Apotex knew or could
have discovered about the MGH Study before it was produced by Lilly in proof of
the utility of atomoxetine. What is clear is that the MGH Study was not
disclosed in the ’735 Patent and, because of the reversal of the order of
presentation of evidence, Apotex did not have a meaningful opportunity to
address the issue when it filed its initial evidence. Nevertheless, in a
situation where the evidence of utility is not self-evident on the face of the
patent or otherwise fully disclosed in the public domain and where the second
party can show that it is not attempting to split its case, it would have a
strong entitlement to a right of reply.
[88]
In
this case when Apotex was informed from Lilly’s affidavits that the MGH Study
was the foundation of its assertion of utility, Apotex chose not to seek to
file reply evidence or to cross-examine Lilly’s witnesses in a challenge to the
Study’s reliability or sufficiency. Instead, Apotex made a very deliberate
strategic decision to attempt to exclude the MGH Study on the basis that it constituted
inadmissible hearsay.
[89]
I
understand Apotex’s concern that Lilly ought not to be permitted to establish a
utility case by tendering the MGH Study through a witness who had little if any
involvement with its completion. In the absence of evidence that the MGH Study
could not have been tendered by one of its authors this does appear to have
been a strategic ploy by Lilly to prevent Apotex from directly challenging the
MGH Study through cross-examination.
[90]
In
short, both parties in some measure attempted to skirt the substantive utility
issues in favour of arguments about whether the other party had met its burden
of proof.
[91]
The
only evidence that Apotex has put forward in response to the MGH Study is that
it and its data are nowhere referenced in the ’735 Patent. Apotex says that
that is enough to put the issue into play. I do not agree.
[92]
Where
a patentee maintains that it can demonstrate the utility of its invention, its
disclosure obligation is limited to the provision of a full description of the
invention and the means to work it: see Consolboard v. MacMillam
Bloedel, [1981] 1 S.C.R. 504 at 526, 56 C.P.R. (2d) 145, Pfizer Canada
Inc. v. Canada (Minister of Health), 2008 FCA 108 at paras. 57 to 62, 67
C.P.R. (4th) 23 and Apotex Inc. v. Wellcome Foundation Ltd., 2002 SCC 77
at para. 70, 21 C.P.R. (4th) 499.
[93]
It
is only where the patentee relies upon a sound prediction of utility that it is
required to disclose in the patent both the factual data on which the
prediction is based and the line of reasoning followed to support it.
According to Justice Ian Binnie in AZT, above, this requirement
to disclose the basis of the prediction in the patent specification is “to some
extent the quid pro quo” the patentee offers an exchange for the patent
monopoly: see para. 70.
[94]
Lilly
asserted in its Notice of Application that it had “established by virtue of
studies that atomoxetine was useful for the treatment of ADHD”. Because Lilly
was relying upon an assertion of demonstrated utility, it says that it carried
no obligation to disclose the MGH Study or its findings in the ’735 Patent. I
agree. In the result, Apotex’s evidence pointing only to the absence of such
evidence in the ’735 Patent would not, if accepted, be capable of rebutting the
statutory presumption of validity.
[95]
I
am accordingly bound on this record to reject Apotex’s allegation of inutility
because it has failed to satisfy its initial evidentiary burden. Because Lilly
effectively had no case to answer, it is unnecessary for me to determine
whether the evidence bearing on the MGH Study, at least in the manner tendered,
was inadmissible hearsay. Even if that evidence was not admissible, I am still
left with the initial problem of whether the Apotex evidence was sufficient to
put the allegation of inutility into play and, as noted above, I find that it
was not. For this issue, the statutory presumption of validity prevails.
[96]
This
is, of course, a surprising result in the face of my earlier finding in Novopharm
Limited v. Eli Lilly and Company, 2010 FC 915, that the MGH Study was not
sufficient to demonstrate utility. But in that case the issue was addressed by
the parties on the strength of considerable evidence that went to the merits of
the MGH Study. Here, Apotex took a different approach and elected not to meet
Lilly’s assertion of demonstrated utility head-on. In the result, its
allegation of inutility fails.
Disposition
[97]
Having
declared the ’735 Patent to be invalid in Novopharm Limited v. Eli Lilly and
Company, above, I invited the parties to make further submissions
concerning the appropriate disposition of this application. Counsel for the
Minister advised that a NOC would issue to Apotex because of the intervening in
rem declaration of invalidity and I have since been told that this has been
done.
[98]
The
parties are in agreement that this application is now moot but they disagree
about its proper disposition having particular regard to the implications for a
claim by Apotex to damages under s. 8 of the NOC Regulations. Section 8
creates a potential liability for losses sustained by the second person
(Apotex) by being wrongly denied entry to marketplace. Such a claim can be
triggered by the first person’s withdrawal or discontinuance of its application
for prohibition or by a dismissal by the court hearing the application.
[99]
Lilly
is concerned that if it were to prevail on the merits of its application, it
might still be exposed to s. 8 damages if its application is dismissed for
mootness. It therefore proposes that the Court either declare the Apotex
allegations to be unjustified; terminate but not dismiss the application; or
issue an order of prohibition.
[100] Apotex
maintains that the only disposition available to the Court is the dismissal of
Lilly’s application. It argues that the Court should not render a decision
which might, on its face, limit is ability to pursue s. 8 damages. That, it
says, is an issue for separate determination before a court properly seized of
it.
[101] Much of what
the parties rely upon concerns the appropriateness of a claim to s. 8 damages
in this unusual situation. In Eli Lilly v. Apotex, 2010 FC 952, Justice
Johanne Gauthier expressed reservations about whether a s. 8 claim could be
advanced where, after an order of prohibition had been issued, the underlying
patent was declared invalid in another proceeding. Justice Gauthier may well
be correct in doubting that s. 8 damages would be available where the patent in
issue has been determined to be invalid in another proceeding between different
parties. That issue is not, however, before me.
[102] All that is
being decided by me in this instance is that none of Apotex’s allegations were
justified on the record that was before this Court, and that because of the
intervening determination that the ’735 Patent was invalid, Lilly’s application
must be dismissed on the basis of mootness. But for that determination,
Lilly’s application would have been allowed and an order for prohibition would
have issued. It remains open to Lilly to defend any claim by Apotex for s. 8
damages on the basis outlined by Justice Gauthier and on the strength of an
argument that the expression in s. 8 “dismissed by the court hearing the
application” means a dismissal on the merits of the application and not simply
for mootness.
[103] I am not
convinced that any of the forms of relief proposed by Lilly would be
appropriate or even permitted. Indeed, there is much to be said for Apotex’s
concern that its potential claim to damages not be prematurely curtailed by the
use of creative language in the final judgment of the Court before that issue
can be argued fully on the merits.
[104] In the
result, Lilly’s application is dismissed on the ground of mootness.
Costs
[105]
I
will consider written submissions from the parties concerning costs. Lilly
will have 30 days for make its submission. Apotex will have 15 days thereafter
to respond. Lilly may reply within 5 following days. The primary submissions
are not to exceed 10 pages in length and Lilly’s reply is not to exceed 3
pages.
JUDGMENT
THIS COURT ADJUDGES that this application for an order prohibiting the Minister from
issuing a NOC is dismissed with the issue of costs to be reserved.
“ R. L. Barnes ”
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