Docket: T-772-13
Citation:
2015 FC 570
Montebello, Quebec, May 1, 2015
PRESENT: The
Honourable Mr. Justice O'Reilly
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BETWEEN:
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TAKEDA CANADA INC.
AND TAKEDA GMBH
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Applicants
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and
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THE MINISTER OF HEALTH
AND APOTEX INC.
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Respondents
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JUDGMENT AND REASONS
I.
Overview
[1]
The applicants, Takeda Canada Inc and Takeda
GmbH (together, Takeda), seek an order prohibiting Apotex Inc from going to
market with a generic version of Takeda’s product called OMNARIS®. OMNARIS is a
nasal spray used in the treatment of conditions such as allergic rhinitis.
[2]
The active ingredient in OMNARIS is ciclesonide
(CS). Takeda’s first patent on CS expired in 2011 (Canada Patent No 2,050,812).
[3]
Takeda has listed three other patents for its
product on the register. Canadian Patent No 2,388,322 (the ‘322 patent) relates
to a pharmaceutical composition for CS. Canadian Patent No 2,388,325 (the ‘325
patent) relates to an aqueous pharmaceutical composition for CS. Canadian
Patent No 2,538,419 (the ‘419 patent) relates to the use of CS in the treatment
of respiratory diseases in children.
[4]
By way of a notice of allegation (NOA), Apotex
alleges that the three Takeda patents are invalid on various grounds, including
anticipation, obviousness, double-patenting, lack of utility, sufficiency and
overbreadth. Since Apotex has tendered sufficient evidence to put these issues
into play, Takeda bears the burden of establishing that Apotex’s allegations
are unjustified.
[5]
I find that Takeda has failed to meet its burden
on obviousness in respect of all three patents. Therefore, I must dismiss its
application. It is unnecessary to consider Apotex’s other allegations.
II.
General Description of the Patents in Issue
A.
The ‘322 Patent
[6]
The ‘322 patent, published on April 26, 2001, is
entitled “Ciclesonide Contained Pharmaceutical
Composition for Application to Mucosa”. The abstract explains that the
invention provides a pharmaceutical composition with low osmotic pressure that
contains CS, a water insoluble and/or water-low soluble substance, and an
aqueous medium, for application to the mucosa. It goes on to say that the
composition is superior to others due to its CS retentivity and permeability to
the submucosa, or to the blood at the mucosa.
[7]
A more detailed description of the invention outlines
the prior art as teaching that the application of medications directly to the
mucosa, such as through the use of nasal sprays, can be useful. Further, the
prior art discloses that the absorption of drugs can be enhanced in a number of
ways, including by varying osmotic pressure.
[8]
The patent describes CS as a “newly generated lipophilic corticoid”. However, CS
compositions tend to cause liquid dripping, which does not allow the drug to be
transported or permeated to the mucosa tissue. Use of an absorption enhancer could
help, but it might cause irritation of the nasal mucosa. Accordingly, the
patent states, it is “strongly desired” to find
a suitable CS composition that would allow transport of an adequate amount of
active ingredient through the mucosa to the submucosa, or to the blood.
[9]
The invention, then, is stated to be an aqueous
pharmaceutical composition with markedly efficient and high CS permeability.
This was achieved by using a composition with low osmotic pressure; the
corresponding increase in CS absorption is “drastic”.
Data in the patent, based on a rabbit study, shows that CS retentivity was
better at an osmotic pressure of 5 mOsm than at 330 mOsm. The corresponding
increase in permeability would mean that good results could be achieved at
comparatively low doses, thereby reducing side-effects.
[10]
The patent claims compositions of CS with
varying osmotic pressures, ranging from 10 mOsm or less, to 290 mOsm or less.
Some of the compositions include an osmotic pressure-controlling agent; others
include water-insoluble and/or water-low soluble substances, and/or a
surfactant such as Polysorbate 80.
B.
The ‘325 Patent
[11]
The ‘325 patent, also published on April 26,
2001, is entitled “Ciclesonide-Containing Aqueous
Pharmaceutical Composition”. The abstract explains that the invention
provides an aqueous composition of CS and hydroxypropylmethylcellulose (HPMC).
This composition, the patent says, avoids variations in CS concentrations as well
as decreases in CS recovery during production.
[12]
A more detailed description of the invention
explains that CS is resistant to wetting and tends to aggregate in an aqueous
solution. The prior art discloses use of a wetting agent, including the
surfactant Polysorbate 80, or vigorous stirring to address this problem. The prior
art also shows the use of a cellulose-based polymer like HPMC was in the
context of redispersion, that is, to address concentration variations caused by
settling during storage, not dispersion of the drug during production. The
latter involves the migration of CS towards bubbles created by stirring, and
the adsorption of CS to the walls of instruments used in production.
[13]
Therefore, the invention of the ‘325 patent is
stated to be the use of HPMC to effect a more uniform concentration of CS
throughout the manufactured solution, and in order to lose less CS to
adsorption during production.
[14]
The patent includes comparative data showing the
concentrations of CS achieved with different amounts of HPMC, as well as the
recovery rates for the various compositions. These were compared with
compositions not containing HPMC. In most cases (3 out of 5), the compositions
containing HPMC achieved uniform concentrations of CS. All of them yielded
recovery rates of CS at about 100%. The compositions not containing HPMC showed
variations in CS concentration, as well as lower recovery rates (43% and 78%).
[15]
The inventors deduced from these data that use
of HPMC avoided variations in CS concentration and decreases in CS recovery
during production.
[16]
The patent claims compositions of CS and HPMC in
various concentrations, as well as those compositions in combination with water
soluble, water insoluble, and water-low soluble substances, such as crystalline
cellulose carmellose sodium (a mixture of carboxymethylcellulose sodium and
crystalline cellulose).
C.
The ‘419 Patent
[17]
The ‘419 patent, published on March 24, 2005, is
entitled “Use of Ciclesonide for the Treatment of
Respiratory Diseases”. The abstract explains that the invention relates
to a new method of treating respiratory diseases, particularly asthma in
children.
[18]
A more detailed description of the invention
explains that children with respiratory diseases can be treated effectively
with CS, and that common side-effects associated with use of other
corticosteroids, including growth-suppression, can be reduced or avoided. The
patent addresses a variety of delivery mechanisms for CS.
[19]
The patent describes a clinical study of
children with asthma in which 24 patients, aged 6 to 12, received varying doses
of CS. The clinicians concluded that there was no evidence of side-effects
commonly associated with similar compounds.
[20]
The patent claims numerous CS compositions for a
variety of uses, mostly for children.
III.
Has Takeda shown that Apotex’s allegations of obviousness
are unjustified?
[21]
The test for obviousness is well-settled (Apotex
v Sanofi-Synthelabo Canada, 2008 SCC 61, [2008] 3 S.C.R. 265 at para 67). It
involves a comparison between the state of the art and common general knowledge
of the skilled person, on the one hand, and the inventive concept of the
patent’s claims, on the other. If there is no difference between the two
comparators, the claims are obvious. If there is a difference, the claims are obvious
if the skilled person would not need to take any inventive steps to bridge the
gap. In pharmaceutical cases, it will often be useful also to consider whether
the steps taken by the inventors were “obvious to try”.
Relevant factors to take into account would include: whether there was a motive
to find the solution that the patent teaches; whether it was more or less
self-evident that the steps taken would work; and whether routine trials were
carried out, as opposed to prolonged and arduous experimentation.
A.
The ‘322 Patent
(1)
The Skilled Person
[22]
According to the experts, the ‘322 patent is
addressed to a person with a Bachelor’s or Master’s degree in pharmacy or
chemistry, with experience in the pharmaceutical industry, particularly in
formulating drugs (Dr Russell Mumper; Dr Roland Bodmeier. See Annex A for
description of experts’ qualifications). I agree with these opinions and would
add, as Dr Bodmeier did, that the skilled person would also have experience in
formulating drugs to be applied to the mucosa.
(2)
The Inventive Concept
[23]
The inventive concept of the claims of the ‘322
patent is not seriously in dispute. It is clear from the patent’s description
of the invention: an aqueous pharmaceutical composition for application to the
mucosa, which contains CS, and a water-insoluble and/or water-low soluble
substance, and which has an osmotic pressure of less than 290 mOsm. The
inventive concept includes superior CS retentivity and permeability compared to
conventional compositions.
(3)
The State of the Art and Common General
Knowledge
[24]
The relevant date for considering the state of
the art and the skilled person’s general knowledge is the claim date of the
‘322 patent – October 20, 1999.
[25]
Dr Bodmeier stated that the skilled person would
have had difficulty applying knowledge of other pharmaceutical compositions to
the task of creating a CS formulation with high retentivity and permeability. In
his view, the prior art, as described in the patent, taught only that a
composition containing a hormone-releasing agent and having an osmotic pressure
of 290 mOsm or lower would be effective. Similarly, the prior art would inform the
skilled person that a secretin solution with an osmotic pressure of 290-1450
mOsm was quickly absorbed through the mucosa. Further, the prior art taught
that absorption enhancers could improve absorption through the mucosa.
[26]
I note that Dr Bodmeier relied only on three of
the prior art references contained in Apotex’s NOA and cited by Dr Mumper. Dr
Bodmeier did not address all of the relevant prior art, and never referred to
the standard text sources mentioned in the NOA and cited by Dr Mumper. I find,
therefore, that on the subject of the state of the art and the common general
knowledge, Dr Mumper’s opinion is more helpful.
[27]
Dr Mumper did not confine his opinion to the
prior art cited in the patent. Rather, after confirming that a skilled person
tasked with formulating an effective CS composition would have readily found
it, he reviewed the prior art cited in Apotex’s NOA. Before knowing what the
invention was, Dr Mumper concluded that the skilled person, based solely on the
prior art and his or her common general knowledge, would have prepared an
aqueous CS composition containing a viscosity increasing agent, such as a cellulose-based
polymer, and having a low osmotic pressure, just as claimed in the ‘322 patent.
[28]
Dr Mumper stated that a skilled formulator would
begin by conducting a literature search on CS formulations in various
databases, standard texts, scientific journals, and patents. The skilled person
would obviously look for information specifically about CS, but also for related
subjects, such as, “corticosteroid”, “nasal”, “delivery”, “allergic
rhinitis”, and compounds similar to CS.
[29]
In my view, Dr Mumper’s methodology provided a
helpful tableau that depicted the state of the art and the common general
knowledge available to the skilled person at the relevant time. His opinion was
given before knowing what was claimed in the patent in dispute. This approach
has gained favour in other cases: Astrazeneca Canada Inc v Apotex Inc,
2014 FC 638 at para 321; Teva Canada Innovation v Apotex Inc, 2014 FC
1070 at para 94.
[30]
According to Dr Mumper, the information obtained
from a reasonably diligent search would have revealed the following:
- CS is an
anti-inflammatory glucocorticoid that is poorly water-soluble;
- CS has been used
in formulations for treating allergic rhinitis;
- Glucocorticoids
tend to cause side-effects when administered systemically, as compared to
application at local sites, so the preferred method of delivering CS would
be by way of topical administration to the mucosa;
- Intranasal
delivery would be appropriate;
- An aqueous
suspension would be most desirable;
- A means of
enhancing retentivity would be sought in order to maximize the amount of
time the drug remained in the nasal cavity;
- Formulations
that either have low osmotic pressure or high osmotic pressure have high
absorption rates;
- Retentivity can
also be enhanced by increasing the viscosity of the formulation, and cellulose-based
polymers act as suspending and/or viscosity increasing agents;
- Various tonicity
adjusting agents were known, including dextrose and sodium chloride; and
- Aqueous
suspensions of CS (and similar compounds) were already known, including
ones that employed tonicity adjusting agents (e.g., sodium
chloride) and viscosity enhancers.
[31]
The parties dispute whether a paper referred to
as the “Dua study” would form part of the state
of the art or the skilled person’s common general knowledge (Dua et al.,
“The influence of tonicity and viscosity on the
intranasal absorption of salmon calcitonin in rabbits” (1997) 147:2 International
Journal of Pharmaceutics 233-242). Dr Bodmeier notes that the Dua study
examines viscosity and tonicity, but it does not mention CS. The study
concluded that both low tonicity and high tonicity compounds achieved greater
bioavailability of the active ingredient, than an isotonic compound.
[32]
While the Dua study does not mention CS
specifically, I agree with Dr Mumper that it discloses the benefits of both low
and high tonicity compounds. Other prior art, including a patent cited in the
‘322 patent, pointed to the benefits of using a compound with low osmotic
pressure. In my view, the skilled person, based on the state of the art and
common general knowledge, would have been led toward a formulation with low
tonicity.
(4)
Conclusion on Obviousness
[33]
In my view, in light of this evidence, Takeda
has failed to discharge its burden of establishing that Apotex’s allegation of
obviousness is unjustified.
[34]
For Takeda, Dr Bodmeier concluded that the prior
art would not have helped a skilled person arrive at the invention contained in
the ‘322 patent. However, as discussed above, Dr Bodmeier did not canvass the
entire state of the art and the common general knowledge of the skilled person
at the relevant time.
[35]
Dr Mumper concluded that, based on the state of
the art and the common general knowledge at the time, the “skilled formulator would therefore prepare an aqueous
suspension of micronized [CS] with increased viscosity, by including viscosity
increasing agents such as cellulose-based polymers, … and with a low osmotic
pressure.” Again, he arrived at that opinion before being provided the
‘322 patent. Unsurprisingly, Dr Mumper went on to conclude that the only
difference between the inventive concept of the ‘322 patent, as compared to the
prior art and common general knowledge, is that there was no explicit
disclosure of a CS formulation with low osmotic pressure in the prior art.
[36]
Dr Mumper was reinforced in his conclusion by
the absence of evidence of any prolonged study or experiments on the part of
the inventors. The patent simply mentions a routine test comparing two
formulations that differed in osmotic pressure. It could have been completed in
a matter of hours. The formulation with low osmotic pressure performed better,
as would be expected, than a formulation that was only slightly hypertonic.
Therefore, the difference between the inventive concept of the ‘322 patent and
the state of the art and common general knowledge did not, according to Dr
Mumper, involve any inventive steps.
[37]
The preponderance of the evidence shows that a
skilled person would have arrived at the formulation set out in the ‘322 patent
simply by reviewing readily-available relevant publications and applying his or
her general knowledge. The inventive concept of the ‘322 patent and the relevant
art, taken as a whole, are coextensive. There was no gap to bridge; no
inventive step was taken.
B.
The ‘325 Patent
(1)
The Skilled Person
[38]
The experts agree that the ‘325 patent is
directed to a person with a degree in pharmacy or chemistry, with experience in
pharmaceutical formulations, especially pharmaceutical suspensions (Dr
Bodmeier; Dr Pardeep Gupta).
(2)
The Inventive Concept
[39]
The inventive concept of the claims of the ‘325
patent is clear from the patent itself, and is not in dispute. It involves a
pharmaceutical composition containing CS and HPMC in an aqueous medium. The
composition avoids variations in CS concentration and decreases in CS recovery
during production.
(3)
The State of the Art and Common General
Knowledge
[40]
The relevant date for considering the state of
the art and the skilled person’s common general knowledge is the claim date of
the ‘325 patent – October 20, 1999.
[41]
Dr Bodmeier explained that the skilled person
would have had difficulty using knowledge about other unrelated compounds to
produce a CS composition that would avoid variations in CS concentration and
decreases in CS recovery during production. While CS was known as an active
pharmaceutical compound, little was known about how to avoid variations in CS
concentration or decreases in recovery during production. However, HPMC was a
known excipient, and the surfactant Polysorbate 80 was known to help increase
dispersivity. Use of Polysorbate 80 is mentioned in the prior art references
set out in the ‘325 patent. Another prior art reference related to redispersion
of a composition after storage (not dispersion during production) and,
therefore, according to Dr Bodmeier, it would not help the skilled formulator
in addressing the problems solved in the ‘325 patent.
[42]
Again, on this point, I am persuaded by the
contrary opinion of Dr Gupta. His approach was similar to Dr Mumper’s. He
agreed that the skilled formulator asked to prepare a CS formulation in 1999 would
begin by conducting a literature search. In doing so, he or she would have
located all the prior art mentioned in Apotex’s NOA. In addition, the skilled
formulator would have had access to general knowledge relating to CS,
excipients, preservatives, stabilizers, tonicity-adjusting agents, wetting
agents, viscosity modifiers, and dispersing agents.
[43]
In my view, Dr Gupta’s approach provided a
helpful overview of the state of the art and the common general knowledge
available to the skilled person. His opinion was given before knowing what was
claimed in the patent in dispute.
[44]
Dr Gupta concluded that the skilled formulator
would know that:
- CS is an
anti-inflammatory steroid administered in a variety of ways, including
nasal inhalation, for the treatment of conditions of the nose or lungs;
- CS is poorly
soluble in an aqueous solution, so it would most likely be used in an
aqueous suspension, as the prior art already disclosed;
- Viscosity agents
are often used to improve uniformity in the concentration of an active
ingredient contained in a formulation;
- One of the most
common viscosity agents used in drug formulations, including formulations
of glucocorticosteroids, is HPMC;
- Other
formulations of corticosteroids use suspending agents, such as Avicel, a
combination of microcrystalline cellulose and sodium
carboxymethylcellulose;
- Formulations
that involve suspended particles may also use a dispersing agent which
helps reduce particle agglomeration and adsorption of particles to the
surface of containers; and
- HPMC was known
to act as a dispersing agent.
[45]
Dr Bodmeier refuted the relevance of some the prior
art references contained in Apotex’s NOA and cited by Dr Gupta, particularly a
number of prior patents or patent applications. However, Dr Bodmeier did not
address all of them and never referred to the standard text sources mentioned
in the NOA and cited by Dr Gupta. I find, therefore, that on the subject of the
state of the art and common general knowledge, Dr Gupta’s opinion is more
helpful.
(4)
Conclusion on Obviousness
[46]
Based on the prior art and common general
knowledge, Dr Gupta concluded that a skilled formulator would have prepared a
composition of CS in a stable, aqueous suspension and, to optimize the
manufacturing process, would have selected appropriate excipients, particularly
HPMC, which acts both as a suspending and a dispersing agent. In other words,
the skilled formulator, using only the prior art and his or her general
knowledge, would have arrived at the putative invention set out in the ‘325
patent.
[47]
Therefore, the preponderance of the evidence
relating to the state of the art and common general knowledge shows that a
skilled person would have arrived at the formulation set out in the ‘325 patent
simply by reviewing the relevant literature and applying his or her general
knowledge. There is no difference between the relevant art and the inventive
concept of the ‘325 patent.
C.
The ‘419 Patent
(1)
The Skilled Person
[48]
According to Dr David Skoner, the ‘419 patent is
addressed to a physician, someone experienced in treating allergies and
respiratory illnesses using corticosteroids, with a particular focus on
children. This skilled person would have at least five years’ experience in the
area. However, Dr Skoner conceded that some aspects of the ‘419 patent are
addressed to issues of formulation and medicinal chemistry, particularly as
they relate to CS.
[49]
In contrast, Dr Gary Rachelefsky believed that
the skilled person should be viewed as a notional team, including a physician
experienced in developing and treating respiratory diseases in adults and
children, and a pharmacologist involved in studying the properties of drugs,
including corticosteroids like CS.
[50]
Dr Leslie Hendeles, a clinical pharmacist,
stated that the ‘419 patent is directed to persons involved in the development
of treatments for pediatric allergic diseases. This would include physicians,
formulators, and clinical pharmacists working in the area.
[51]
I agree that the ‘419 patent is addressed both
to physicians experienced in treating respiratory diseases, particularly in
children, and to persons knowledgeable about CS and related compounds, whether
formulators, chemists or clinical pharmacists.
(2)
The Inventive Concept
[52]
Even though the patent claims a broad range of
CS compositions, means of administration, and dosages, Dr Skoner interpreted
the inventive concept of the claims of the ‘419 patent as being simply the
daily use of an aqueous CS formulation in an intranasal spray for the safe
treatment of rhinitis in children. Dr Rachelefsky’s opinion is similar, but he
would add that the inventive concept includes the reduction or avoidance of
side-effects long associated with corticosteroids, particularly growth
suppression in children with long-term exposure to the drug. Dr Hendeles, in
effect, agreed with Dr Rachelefsky.
[53]
I, too, agree with Dr Rachelefsky– the inventive
concept of the ‘419 patent, according to the description set out in it,
involves the use of CS in the treatment of children with chronic respiratory
diseases with reduction or avoidance of common side-effects associated with use
of other corticosteroids, including growth-suppression.
(3)
The State of the Art and Common General
Knowledge
[54]
The relevant date for the obviousness analysis
of the ‘419 patent is September 15, 2003.
[55]
Dr Skoner stated that the skilled person would
be familiar with the use of steroidal and non-steroidal treatments for respiratory
diseases. CS would be included among the former. The skilled person would also
be aware of the variety of delivery mechanisms available, including nasal
sprays. He or she would also be familiar with techniques for monitoring and
adjusting dosages, including titration, and the array of potential systemic side-effects
from use of corticosteroids, including adrenal suppression and growth
suppression. The skilled person would also be familiar with the available tests
for detecting growth suppression, including stadiometry and knemometry, but
would only be capable of conducting less than adequate stadiometry tests.
Knemometry can only be conducted by a few leading researchers across the world,
and not the skilled person. Further, the skilled person would not have been
able to interpret the results of growth suppression tests.
[56]
Dr Skoner explained that the skilled person
would have been familiar with CS and its properties as a pro-drug that acts
locally, rather than systemically. The skilled person would also have been
aware of the safety concerns around the use of corticosteroids in children,
particularly the risk of growth suppression. However, literature also described
the safe use of some corticosteroids, including budesonide, at comparatively
low doses. However, as a class, corticosteroids were regarded as having the
potential to cause growth suppression. Accordingly, the US FDA required a
warning in respect of all corticosteroids.
[57]
Dr Skoner himself conducted studies in the late
1990s in which he found that corticosteroids caused growth suppression in
certain doses over time, even where adrenal suppression was absent. Other
studies yielded similar results.
[58]
Dr Rachelefsky provided a contrary opinion. In
his view, in 2003, the skilled person would have known that certain leading
corticosteroids could be safely administered to children at doses of up to 200
μg or higher. Further, the skilled person would have been familiar with CS
and its high therapeutic index, and would have developed a CS formulation that
could be safely administered to children.
[59]
Both Dr Rachelefsky and Dr Hendeles were of the
view that the skilled person tasked with developing or prescribing
corticosteroids for the treatment of respiratory diseases, including in
children, would begin by conducting a literature search for information about
CS, corticosteroids, systemic side-effects, intranasal administration, and so
on. They both confirmed that the art cited in Apotex’s NOA would have been
located on a reasonably diligent search.
[60]
In my view, this approach provides a helpful
overview of the state of the art and the common general knowledge available to
the skilled person. Both of these experts provided their opinions on this issue
before knowing what was claimed in the patent in dispute.
[61]
Based on those documents and the common general
knowledge at the time, Dr Rachelefsky concluded that the skilled person would
have known that:
- Poorly
controlled asthma can affect growth;
- Allergic
rhinitis causes inflammation of the nasal mucosa;
- Corticosteroids
have anti-inflammatory properties and have long been recognized as being
suitable for the treatment of asthma and allergic rhinitis;
- Corticosteroids,
when administered orally, were known to cause systemic side-effects, so
researchers explored means of administering them locally by way of nasal
inhalers;
- By 2003, inhaled
corticosteroids were considered the most effective treatment available for
asthma and allergic rhinitis. Several were on the market;
- Concern about
growth suppression caused by corticosteroids led the US FDA to require
drug companies to give warnings to users;
- Physicians used
stadiometry to measure growth rates in patients. In 2003, no one, other
than Dr Skoner, was using knemometry;
- Growth
suppression was considered to be linked to adrenal suppression, so drugs
with little adrenal effect were considered unlikely to cause growth suppression;
- CS was known to
be a pro-drug, whose method of action reduced its potential to cause side-effects;
- A long-term
study of an inhaled corticosteroid (budesonide) in 1993 showed no effect
on growth suppression in pediatric patients. A similar study in 1995 came
to the same conclusion;
- By 2003, it was
widely accepted that inhaled corticosteroids at doses of 400 μg or
less were safe for children. Any effects on growth were considered to be
minimal and transient;
- CS was
recognized as early as 1992 as having high anti-inflammatory effects with
low systemic effects;
- By 2002, CS was
in Phase III clinical trials, and CS nasal inhalers were in development;
and
- CS was regarded
as being superior to budesonide at lower doses, with fewer risks of side-effects.
[62]
Based on those same documents and the common
general knowledge at the time, Dr Hendeles concluded that the skilled person
would have known that:
- The typical
treatment for asthma was by way of inhaled corticosteroids;
- The typical
treatment for allergic rhinitis was oral anti-histamines, although severe
cases were treated with intranasal steroids;
- Inhaled
corticosteroids reduced or avoided the systemic side-effects associated
with oral treatments and were the most effective treatment available for
allergic rhinitis. Several products were on the market at that time;
- Growth
suppression and adrenal suppression were rare for children receiving effective,
but low, doses of inhaled corticosteroids;
- With one
exception, nasal steroids had no systemic side-effects, including growth
suppression, on children;
- Some
corticosteroids, when administered on a long-term basis to pre-pubertal
children, caused growth suppression and adrenal suppression. Low doses of
inhaled corticosteroids did not have that effect. Still, the FDA requires
a warning label on corticosteroids;
- CS was known to
have a high therapeutic index and would be expected to cause fewer
systemic side-effects;
- Prolonged
administration of another corticosteroid, budesonide, was found to be
beneficial and safe for children – it had no long-term effect on growth;
- Inhaled
corticosteroids in doses of 800 μg over 1 to 5 years did not affect
bone growth in children;
- Low doses of
budesonide (less than 400 μg) had a marked anti-asthmatic effect
without systemic side-effects;
- The consensus
view was that inhaled corticosteroids at relatively low, but effective, doses
did not cause systemic side-effects;
- CS was known to have
a superior pharmacological profile to other corticosteroids;
- Inhaled
corticosteroids were the first-choice anti-inflammatory treatment for
asthma. Doses at 100 to 200 μg were highly effective and safe for
children;
- Clinical trials
of CS showed anti-asthmatic activity with no clinically relevant
side-effects at doses from 100 to 1600 μg; and
- Phase II and III
clinical trials of CS showed good efficacy without systemic side-effects. It
appeared that doses below 400 μg would be safe for children;
[63]
Dr Hendeles also considered the ‘322 and ‘325
patents and the disclosures contained in them as part of the state of the art
and common general knowledge for purposes of the ‘419 patent.
(4)
Conclusion on Obviousness
[64]
Based on the prior art and the common general
knowledge, Dr Rachelefsky concluded that the invention described in the ‘419
patent simply conformed to what the skilled person would have expected – that
inhaled intranasal CS compositions would be effective and would not affect
children’s growth in the prescribed dosages of 20 to 200 μg. Certainly,
according to Dr Rachelefsky, the CS compositions in the ‘419 patent would have
been obvious to try. A routine clinical trial, such as that described in the
patent itself, is all that would have been required to confirm what the skilled
person would already have expected. Appropriate doses of CS for children could
readily be determined by the skilled physician, based on studies in
corticosteroids in adults.
[65]
Dr Rachelefsky specifically addressed Dr
Skoner’s contrary opinion. In Dr Rachelefsky’s view, Dr Skoner overlooked the
evidence showing how favourable CS was viewed in the relevant time period. Dr
Rachelefsky actually co-authored a study in 2000 with Dr Skoner, which Dr
Skoner cited as providing evidence of growth suppression by a corticosteroid
(beclomethasone dipropionate). Dr Rachelefsky points out that that study
involved a fairly high dosage (336 μg) compared to the dosages claimed in
the ‘419 patent. In addition, a skilled person would have known that CS had a
superior pharmacological profile than the studied drug. Dr Rachelefsky
expressed the same opinion in respect of a 2000 study of budesonide.
[66]
Dr Hendeles also concluded that there was no
difference between the inventive concept of the claims of the ‘419 patent and
the state of the art. Further, no inventive ingenuity would have been required
to arrive at the ‘419 patent’s inventive concept.
[67]
Therefore, the preponderance of the evidence
relating to the state of the art and common general knowledge shows that a
skilled person would have known that administering CS in the dosage range set
out in the ‘419 patent would not cause systemic side-effects. Therefore, there
is no difference between the relevant art and the inventive concept of the ‘419
patent.
IV.
Conclusion and Disposition
[68]
All three patents in issue reflect the state of
the art and the common general knowledge of the respective skilled persons at
the relevant time. Even if there had been gaps between the prior art and the
patents’ inventive concepts, no inventive steps would have been required to
bridge them. Accordingly, Takeda has not persuaded me that Apotex’s allegations
of obviousness are unjustified. I must, therefore, dismiss Takeda’s
application, with costs.
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