Docket: T-2510-14
Citation:
2016 FC 1361
Ottawa, Ontario, January 9, 2017
PRESENT: The
Honourable Mr. Justice O'Reilly
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BETWEEN:
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JANSSEN INC.
AND ALZA CORPORATION
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Applicants
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and
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ACTAVIS PHARMA
COMPANY
AND THE
MINISTER OF HEALTH
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Respondents
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PUBLIC JUDGMENT AND REASONS
(Identical to the Confidential Judgment
and Reason issued December 9, 2016)
I.
Overview
[1]
The applicants (Janssen) seek an order
prohibiting the Minister of Health from issuing a Notice of Compliance to the
respondent Actavis Pharma Company. The NOC would allow Actavis to market its
generic version of a drug marketed by Janssen under the brand name Concerta®.
Concerta is used in the treatment of Attention Deficit Hyperactivity Disorder
(ADHD). ADHD is one of the most prevalent mental disorders affecting children. Symptoms
include inattention, hyperactivity and impulsiveness. The active ingredient in
Concerta is methylphenidate (MP).
[2]
The patent for Concerta (Canadian Patent No
2,264,852 (the ‘852 patent)) does not relate to MP itself, a well-known
compound that has been used to treat ADHD for decades. Rather, it relates to
the use of compositions that release MP in a “sustained-ascending
dose over time”.
[3]
Actavis alleges that the ‘852 patent is invalid
and, in addition, that Actavis’s generic version of the drug will not infringe it.
Actavis says that the patent should not stand in the way of its receiving an
NOC.
[4]
In my view, Actavis has not met its burden of
showing that its allegations are justified. Therefore, I will grant the order
Janssen seeks, prohibiting the Minister from issuing an NOC to Actavis for its
generic MP product.
[5]
Both parties presented expert evidence to
support their positions. A summary of the experts’ qualifications is set out in
an Annex.
II.
The ‘852 Patent
[6]
Most of the history leading up to the ‘852
patent is uncontested. However, as will be seen below, the parties do dispute
the construction of the patent.
A.
Background
[7]
The first product containing MP for the
treatment of ADHD was Ritalin® IR, an immediate release tablet. Ritalin IR was
developed by Ciba-Geigy in the 1950s. Later, in the 1980s, Ciba-Geigy marketed a
sustained release version, Ritalin SR. Both products were problematic.
[8]
Ritalin IR was effective for 3-4 hours, so dosing
was recommended either twice a day (BID) or three times a day (TID).
Accordingly, most school children had to find a way to take it over their lunch
break. A number of issues arise from that scenario: Who will possess the
tablets and be responsible for administering them? (As MP is a controlled
substance, an adult has to be responsible). How will the tablets be controlled
to ensure that persons who have not been prescribed the drug do not have access
to it? How will the child’s privacy be protected?
[9]
In addition to these issues, MP’s side-effects –
insomnia, appetite suppression, and stomach aches – were believed to be
associated with the peaks and valleys in plasma concentrations of MP corresponding
with the two or three doses of Ritalin IR taken over the course of a day.
[10]
Ritalin SR was meant to overcome those issues.
The sustained release tablet was supposed to provide efficacy over an 8-hour
period, the length of an entire school day. However, it did not live up to
expectations. Ritalin SR turned out to be effective only for a few hours. Many
physicians stopped prescribing Ritalin SR and reverted back to Ritalin IR,
either BID or TID.
[11]
This was the state of the art in the early to mid-1990s,
when researchers at the applicant Alza Corporation started exploring ways to
provide a more effective treatment for ADHD. Available to them at that point was
a 1989 research paper showing the pharmacokinetics of Ritalin IR and SR,
including the maximum plasma concentration achieved, and the time taken to
reach that maximum (Patrick 1989). Patrick showed that the plasma
concentrations of MP for Ritalin SR rose until about two hours after
administration; the concentration plateaus for the next four, and then it drops
off.
[12]
Another paper available to Alza researchers was
a 1992 review by Dr Greenhill. He postulated a number of reasons why Ritalin SR
was ineffective, including poor compliance, faulty formulation, weight change, new
stress, and acute tolerance (tachyphylaxis).
[13]
Dr Suneel Gupta, then director of clinical
pharmacology at Alza, explained that researchers were puzzled about why Ritalin
SR achieved poor results. Ritalin SR’s effects appeared to be desirable –
achieving a relatively stable plasma concentration over a significant period of
time, and avoiding the peaks and troughs thought to be associated with Ritalin
IR’s side effects. Experts thought the problem might be the absence of the high
peaks achieved with the immediate release tablet, or with the wax matrix
formulation that was used.
[14]
Dr Gupta wished to test an alternate explanation
– acute tolerance. Acute tolerance refers to a situation where a patient
becomes tolerant to a drug, not over a long term, but, rather, within a single
dosing period. His colleagues were doubtful, believing that the real problem
was the formulation.
[15]
Rather than addressing the issue of tolerance in
customary ways by increasing the dose or decreasing the frequency of
administration, Dr Gupta wanted to try administering MP at a continuously
increasing rate. He says that his colleagues remained skeptical.
[16]
Dr Gupta’s team developed a study to test his
theory of acute tolerance, as well as his colleagues’ idea that a flat
concentration profile was most desirable. The team developed a “sipping study” which involves administering small
amounts of a drug to mimic the dynamics of various formulations. Four scenarios
were tested: the first replicated the twice-daily administration of MP, similar
to Ritalin IR BID; the second replicated the flat plasma concentration profile
of Ritalin SR; the third, Dr Gupta’s, created an ascending plasma profile of MP
over an 8-hour period; and the fourth was a placebo.
[17]
This double-blinded study also included
behavioural testing of the children to whom the drugs were administered
(so-called SKAMP and CLAM tests), to determine the drug’s dosing efficacy. The
placebo had no effect. The flat profile showed declining efficacy over the
course of the day. The ascending dose regime displayed improved results over
the day, comparable to the BID model, even when the plasma concentrations were
lower.
[18]
For Dr Gupta, this study confirmed his theory of
acute tolerance. A second study was devised to provide further data. The second
sipping study tested a modification of the ascending profile in which the
initial dose and the overall quantity of MP was higher. Again, four groups were
tested: the first replicated administration of Ritalin IR TID; the second was
Dr Gupta’s ascending profile; the third was a variation of the first, in which
the timing of the second dose was varied; the fourth, again, was a placebo.
[19]
The results of the second study showed that the
varied regime (group three) did not show an improvement over the Ritalin IR TID
pattern (group one). To Dr Gupta, this provided further evidence of acute
tolerance, and showed that the tolerance could not be addressed simply by
increasing the dose. The ascending dosage achieved equivalent behavioural
improvements to Ritalin IR TID, with no significant elevation of side effects.
These results were subsequently confirmed in a study of adults.
B.
Description of the ‘852 Patent
[20]
The ‘852 patent was filed on September 16, 1997.
It is entitled “Use of methylphenidate or a
pharmaceutically acceptable salt thereof”. The patent’s owner is Alza;
Dr Gupta is one of the named inventors.
[21]
The ‘852 patent states that the invention “pertains to both a novel dosage form and to a novel method
for administering a drug for producing a therapeutic effect”. The patent
specifies that the dosage form in question is one in which the drug is
administered “over a predetermined period” at a “sustained and continuously ascending rate”, and
includes a dosage form where an initial dose of the drug is administered and
then is followed by “a sustained and increasing dose”
“over an extended time”.
[22]
The patent sets out the background leading to
the claimed invention. It begins by referring to the class of drugs used for
treatment of ADHD, then makes clear that the invention is generic because it
relates to drugs administered according to “the dosage
forms and the method of the invention”. It gives the example of central
nervous system drugs, such as MP, which have been administered in an immediate
dose form and a sustained release form. With respect to the immediate dose
form, the patent points out some of the problems associated with multiple daily
doses. Regarding the sustained release MP drug, the patent states that patients
often develop acute tolerance to it, which diminishes the duration and
intensity of its effect.
[23]
Based on this background information, the patent
goes on to conclude that there is a “critical need”
for a drug that overcomes the problems in the prior art. In particular, the
patent notes the need for a dosage form and method for administering a drug at
a “sustained-increasing rate” to address the
problem of acute tolerance, particularly in the treatment of ADHD. The patent
specifically refers to the need to provide treatment throughout the school day.
[24]
Several pages of the ‘852 patent are devoted to
a description of the objects of the invention. I need only refer to the most
relevant parts. The patent stresses that one of the invention’s immediate
objects is to provide a means of overcoming the shortcomings in the prior art.
More particularly, the invention is meant to provide a dosage form that
increases the dose of the drug over time, especially to address the problem of
maintaining a therapeutic effect in patients who experience acute tolerance to
the drug. The patent addresses specifically the need to provide a dosage form
in which the drug, including a central nervous system drug, including MP, is
delivered at an increasing rate over a prolonged time period such as a school
day of 4 to 8.5 hours.
[25]
The next main section of the patent provides a “Detailed Disclosure of Specification”. This section
begins by describing acute tolerance with reference to scholarly papers on the
subject. It then sets out how a sustained ascending dosage form could be made.
It goes on to discuss central nervous system drugs, including MP, which can be
used to treat ADHD and points out the problem of acute tolerance. Again, it
describes the invention as addressing the problem with a sustained release
drug, including acute tolerance, referring specifically to the issue of acute
tolerance to MP, which can occur within hours of administration.
[26]
The patent then sets out a number of examples.
Example 1 describes the results of the first sipping study set out above.
Example 2 provides the results of the second sipping study. The remaining
examples teach methods for making various ascending-release formulations.
[27]
The patent contains 119 claims. Claims 1, 41,
and 78 are the independent claims in issue here:
1. Use of a
composition comprising 100 ng to 500 mg methylphenidate or a pharmaceutically
acceptable salt thereof, together with a pharmaceutically acceptable carrier,
the composition releasing methylphenidate or a pharmaceutically acceptable salt
thereof in a sustained-ascending dose over time, for regulation of tolerance to
methylphenidate or a pharmaceutically acceptable salt thereof.
41. Use of a
composition [. . . releasing methylphenidate . . .] in a sustained-ascending
dose over a period greater than 6 hours and up to 12 hours, for the treatment
of [ADHD].
78. Use of a
composition [. . . releasing methylphenidate . . .] in a sustained-ascending dose
over time, for treatment of [ADHD] and compensation of acquired tolerance to
methylphenidate or a pharmaceutically acceptable salt thereof.
C.
Construing the Claims of the ‘852 Patent
[28]
The parties agree that the claims should be
construed as of September 30, 1996. The parties also agree that the patent
should be construed from the perspective of a skilled person in the art, namely,
a composite hypothetical person who is a physician with at least two years’
experience treating ADHD and a good knowledge of pharmacology, and a drug
formulator with a graduate degree and two years’ experience in developing
extended-release products. The foregoing description of the skilled person was
accepted by Justice Russel Zinn in Janssen-Ortho Inc v Canada (Health),
2010 FC 42 at para 93 in respect of the same patent. I see no reason to depart
from that conclusion here. While Dr Chris Hollis, Actavis’s expert in clinical
psychology, suggested that the skilled person should also have experience
treating children and adolescents with ADHD, I do not see that his position
adds much to the description accepted by Justice Zinn.
[29]
Justice Zinn also construed the phrase “sustained-ascending dose over time” in the ‘852
patent to mean that the MP is released from the tablet at an increasing rate,
not that the plasma concentrations in the patient increased at an ascending
rate. As a result, he found that Novopharm’s product did not infringe the ‘852
patent. The parties agree that Justice Zinn’s interpretation should apply here.
[30]
Actavis maintains that the skilled person would
read the ‘852 patent as claiming a dosage form and a method of administering a
drug that involves providing an increasing rate of release throughout the
entire extended dosing period (eg, a full day), not just some portion of
it.
[31]
I do not agree with Actavis’s construction of
the patent.
[32]
In my view, the phrase “sustained-ascending
dose over time” does not mean “over an entire
dosing period”. Obviously, “over time”
connotes an extended period, not just any duration. For example, the Ritalin IR
tablet could be said to provide an ascending dose over time if one considered
only the first two hours after administration. The ‘852 patent specifically
distinguished the invention from an immediate release tablet. The word “sustained” also implies that the period under
consideration is relatively long compared to the profile of immediate release
products.
[33]
On the other hand, I do not believe the skilled
person would interpret the words “over time” and
“sustained” to mean an entire dosing period. One
of the main objects of the invention was to provide a medication that would be
effective over the course of a school day of 4 to 8.5 hours. A tablet would not
have to deliver a sustained-ascending release profile over the entire duration
of that period to be effective. The experts agree that efficacy is sustained
for a period of time beyond the point when MP is last released from the tablet.
Therefore, to be effective over an 8-hour period, for example, the
sustained-ascending dosage form would have to rise over the course of the first
6 hours or so, not the entire dosing period.
[34]
Dr John Markowitz, a clinical pharmacologist
testifying for Janssen, (see Annex for a Summary of experts’ qualifications), explained
that he did not regard the examples in the patent, which show a
sustained-ascending dosage form over the entire test period, as being identical
to what is claimed. A drug that had a sustained-ascending release profile over
a few hours would continue to be effective for a few hours after the drug
stopped releasing MP into the plasma. He read the patent as addressing a
sustained-ascending dosage form over a period of at least four hours.
[35]
While the four-hour sustained-ascending dose
might be at the low end for achieving efficacy for a school day, the patent,
according to Dr Markowitz, is directed to a treatment period of up to eight
hours, or longer.
[36]
Dr Hollis agreed that the effects of a drug containing
MP will generally continue for 1.5 to 2 hours after MP stops being released
into the plasma.
[37]
Actavis also submits that the patent should be
read as claiming dosage forms containing as little as 100 ng, and up to 500 mg,
of MP. It points out that those amounts are specifically mentioned in the
claims and that the claims must be interpreted accordingly.
[38]
I disagree. I do not believe a skilled person
would read claim 1, for example, to claim a dosage form containing a mere 100
ng of active ingredient that would be capable of regulating acute tolerance to
MP. Rather, I agree with Dr Markowitz that the likely explanation for including
100 ng in the claim was to address the minimum content of individual components
of a particular dosage form that might be formulated to deliver a
sustained-ascending release profile, the sum total of which might be as high as
500 mg. Dr Hollis conceded that Dr Markowitz’s interpretation was reasonable.
III.
Issue One – Is Actavis’s allegation of
invalidity justified?
[39]
Actavis’s principal argument is that the
invention identified in the ‘852 patent was obvious. The parties agree that the
test for obviousness is set out in Apotex Inc v Sanofi-Synthelabo Canada Inc,
2008 SCC 61.
[40]
Actavis alleges that the so-called invention set
out in the ‘852 patent was obvious and that the patent is therefore invalid.
[41]
I disagree. In my view, the invention of the
‘852 patent represented an inventive step over the state of the art at the
relevant time.
[42]
I have set out above the common general
knowledge that the skilled person would have possessed at the relevant time.
The skilled person would have aware of the performance and shortcomings of the
available drugs for treating ADHD. In particular, he or she would have regarded
administration of Ritalin IR BID or TID as the height of the art.
[43]
The inventive concept of the ‘852 patent is the
use of a formulation that delivers a sustained-ascending dose of active
ingredient over time in order to address acute tolerance. This represented an
advantage over the prior art, given the problems associated both with Ritalin
IR and Ritalin SR.
[44]
Actavis argues that the only difference between
the inventive step in the patent and the state of the art is that the inventors
confirmed the postulation in the prior art that the problem was acute tolerance
to MP. Researchers at Alza, according to Actavis, merely conducted routine
tests to arrive at that conclusion. Moreover, they arrived at a well-known
solution to the problem of drug tolerance: increasing the dose.
[45]
I disagree with Actavis’s submission on this
point. As the description of the background to the ‘852 patent, set out above,
makes clear, the inventors invested considerable effort in discovering the
underlying problem with Ritalin SR. Dr Gupta and his colleagues devised what Dr
Markowitz called an “elegant” and “imaginative” study to test a number of theories, one
of which was acute tolerance. The results surprised the Alza researchers.
[46]
The problem with acute tolerance to MP was
unknown in the prior art. True, Dr Greenhill mentioned it as one of the many
potential causes of reduced efficacy with Ritalin SR. However, no one prior to
the studies that led to the ‘852 patent had specifically identified it as the
source of Ritalin SR’s inefficacy. The inventors of the patent identified this
problem, and devised a novel and effective solution to it.
[47]
As described above, it was not obvious to try to
develop a sustained-ascending dosage form to address acute tolerance. Dr
Gupta’s colleagues doubted that acute tolerance was even a problem. Further,
using a sustained-ascending dosage form of MP had never before been tried as a
means of addressing acute tolerance.
[48]
Actavis’s experts have not persuaded me that the
invention contained in the ‘852 patent was obvious. Dr Rue assumed that acute
tolerance was a known problem and that an ascending release formulation was the
solution. He opined that if a skilled formulator had been asked to make a
sustained-ascending dosage form he or she could have done so using routine
techniques. Similarly, Dr Hollis assumed that acute tolerance was known to be a
potential problem based on the Greenhill paper. However, he would only go so
far as to assert that the skilled person would not have dismissed acute
tolerance as being one of the problems with Ritalin SR. He went on to state that
the skilled person would have tried to replicate the peaks (but not the
troughs) in the Ritalin IR TID profile as a means of addressing acute tolerance.
He concluded that the skilled person would have easily arrived at a
sustained-ascending formulation that would have achieved the desired result.
[49]
I see nothing in the prior art or common general
knowledge that would have allowed the skilled person to operate from the
assumption that acute tolerance to MP was a problem to be solved. Dr Hollis’s
opinion strikes me as impermissible hindsight. Accordingly, even if the
solution to that problem would have been obvious to the skilled person, as
alleged by Actavis, I cannot conclude that the invention contained in the ‘852
patent was itself obvious. This allegation is unjustified.
[50]
Actavis also alleges that the utility of the
invention described in the ‘852 patent was neither demonstrated nor soundly
predicted at the relevant time.
[51]
I disagree. The stated utility of the ‘852
patent is that the claimed invention will regulate acute tolerance by means of
a sustained-ascending dosage form for the treatment of ADHD. In my view, that
utility was clearly demonstrated by way of the two sipping studies, described
above. The data from those studies was provided in the patent and support the
inventors’ conclusions. I find that this allegation is also unjustified.
[52]
Actavis further submits that the patent lacks
utility because it covers a range of inoperable products, namely, tablets
containing as little as 100 ng of MP. I have set out above my construction of
the relevant claims. Accordingly, I find that the patent does not claim a
tablet containing 100 ng of MP; rather, it claims a dosage form in which as
little as 100 ng of MP may be contained in one of its components. Therefore, I
find that Actavis’s allegation is also unfounded.
[53]
Finally, Actavis suggests that the ‘852 is
invalid because its claims are overbroad. This allegation also relates to the
inclusion of 100 ng of MP within the patent’s claims. I agree that 100 ng is
not an effective dosage of MP. However, as above, I do not believe a skilled
reader would interpret the patent as claiming a sustained-ascending dosage of
100 ng of MP.
[54]
Actavis also alleged inutility at the upper end
of the claimed range. Specifically, Actavis asserts that a 500 mg dose of MP
would be fatal. However, I have no evidence before me to support that assertion,
other than a remark made by Dr Hollis in cross-examination. Accordingly, I find
that this allegation is unjustified.
[55]
Overall, therefore, I find that Actavis’s several
allegations of invalidity are unjustified.
IV.
Issue Two – Is Actavis’s allegation of
non-infringement justified?
[56]
Actavis maintains that its product does not
infringe the ‘852 patent because the MP contained in its tablets is not
released at a sustained-ascending rate over an extended period to compensate
for acute tolerance. It relies on the analysis carried out by Dr Peter Rue, an
expert formulator, who studied the release rate of MP in Actavis tablets in a
variety of media.
[57]
Dr Peter Rue found that, on average, the Actavis
tablets did not release MP at a sustained-ascending release rate over time. Further,
he opined that not enough of the active ingredient would be released at a
sustained-ascending rate to deal with acute tolerance. Dr Rue concluded from
this that the Actavis product would not infringe the ‘852 patent.
[58]
I disagree. The preponderance of evidence shows
that the Actavis product does release MP at a sustained-ascending rate over a
sufficiently long period to regulate acute tolerance. Therefore, the Actavis
tablets infringe the ‘852 patent.
[59]
Janssen identifies a number of problems with Dr
Rue’s evidence. I need not deal with all of them. I am satisfied that Dr Rue’s
opinion is questionable in two areas, causing me to doubt his conclusions.
First, Dr Rue construed the ‘852 patent to claim a sustained-ascending release
rate of MP over an entire dosing period. I have already considered and rejected
that interpretation. However, Dr Rue erroneously relied on that construction to
conclude that since the Actavis tablets did not provide a sustained-ascending
dose over an entire dosing period, they would not infringe the ‘852 patent.
[60]
Second, Dr Rue relied on mean data, not the
results from analyzing individual Actavis tablets. Accordingly, his analysis
tells us only whether a batch of tablets might infringe the patent. However, a
batch of tablets might not infringe the patent even when a substantial portion
of the individual tablets within it might do so. Dr Rue’s approach could permit
a large quantity of infringing material to enter the market.
[61]
Dr Leah Appel, also an expert formulator and who
provided opinion evidence for Janssen, thoroughly analyzed the dissolution data
for the Actavis tablets in various media. She measured the release of MP over
hourly periods and found that most of the tablets release MP at a
sustained-ascending rate for a minimum of 4 hours, and some for longer periods.
Her analysis was based on tablet-by-tablet data, not mean figures for batches.
[62]
Dr Appel’s analysis of the Actavis tablets
showed that they contain an initial dose of MP and thereafter release MP at a
sustained-ascending rate over a sufficient period of time, at least 4 hours, to
regulate acute tolerance. Dr Appel compared her data against all of the claims
of the ‘852 patent and found that many of them were infringed, most
particularly the independent claims set out above – claims 1, 41, and 78.
[63]
Further, Actavis’s product monograph confirms
that the tablets will release MP at an ascending rate for 6 to 10 hours.
According to Dr Markowitz, the release rate profile of Actavis’s tablets
largely corresponds to Janssen’s. Similarly, Dr Declan Quinn, a specialist in
child psychiatry who provided expert evidence for Janssen, confirmed that
physicians reading the Actavis product monograph would note that it is
virtually identical to the Concerta product monograph, and would prescribe the
Actavis product in the same way as they would Concerta. Accordingly, Dr Quinn
concludes that the monograph is essentially telling physicians that the Actavis
product provides a sustained-ascending dosage form for MP that can overcome
acute tolerance.
[64]
In my view, this evidence shows that Actavis’s
allegations of non-infringement are not justified.
V.
Conclusion and Disposition
[65]
Actavis has not established that its allegations
of invalidity and non-infringement are justified; the preponderance of evidence
is to the contrary. Accordingly, I will grant the order Janssen seeks
prohibiting the Minister of Health from issuing an NOC to Actavis for its
generic version of Concerta. Janssen is entitled to its costs.
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