Dockets: T-1409-04
T-1890-11
Citation:
2015 FC 322
Ottawa, Ontario, March 16, 2015
PRESENT: The
Honourable Mr. Justice Barnes
Docket: T-1409-04
|
BETWEEN:
|
ASTRAZENECA CANADA INC. AND AKTIEBOLAGET HÄSSLE
|
Plaintiffs
|
and
|
APOTEX INC.
|
Defendant
|
Docket:
T-1890-11
|
AND
BETWEEN:
|
ASTRAZENECA AB AND AKTIEBOLAGET HÄSSLE
|
Plaintiffs
|
and
|
JUDGMENT AND REASONS
I. The Patent 2
II. The Expert Evidence. 8
A. Dr. Martyn Davies. 8
B. Dr. Roland
Bodmeier 23
C. Dr. Frank Bright 31
D. Dr. Peter
Griffiths. 40
E. Dr. Arthur Kibbe. 46
F. Dr. William Amos. 55
III. Claims Construction. 60
A. Principles of Claims
Construction. 60
B. The Construction
Issues. 64
C. Does Claim 1 Cover
Subcoatings That Form in Situ?. 65
D. What is the Meaning of
the Term Inert?. 76
E. What are the Essential
Structural Features of the Claimed Subcoat?. 78
IV. Validity. 84
A. Anticipation. 84
B. Obviousness. 88
V. Overbreadth, Inutility
and Ambiguity. 115
VI. Infringement 125
A. Criticisms of
Dr. Davies’ Testing Methods. 125
B. What Are the
Constituent Elements and Structural Makeup of the Apotex Subcoating and to What
Extent is it Compromised by Holes, Gaps or Other Anomalies?. 133
C. Thickness. 150
VII. Standing. 160
VIII. Foreign Issue Estoppel 163
IX. Remedies. 166
A. Deception. 166
B. Conclusions Re
Infringement 169
C. Limitations. 172
D. Is AstraZeneca
Entitled to an Elect an Accounting of Profits?. 174
X. Conclusion
Re Relief. 175
[1]
In these proceedings AstraZeneca Canada Inc., Aktiebolaget
Hässle and AstraZeneca AB assert that Apotex Inc. [Apotex] has infringed
Canadian Letters Patent 1,292,693 [the 693 Patent] – in which they all claim an
interest. Except where otherwise expressly or contextually indicated, any
reference to AstraZeneca in these reasons will apply collectively to the
Plaintiffs.
[2]
The proceedings have been bifurcated so that
this decision concerns only the issue of liability.
[3]
The 693 Patent sets out 19 claims pertaining to
a formulation for omeprazole but only Claims 1, 5, 6, 13 and 19 are in issue.
Apotex challenges the validity of the 693 Patent on several grounds. It also
argues that its omeprazole formulation does not infringe any of the asserted
claims. Much of its infringement defence is built around the construction of
the language of Claim 1 with a view to establishing essential differences with
its omeprazole formulation.
[4]
The 693 Patent describes the field of the
invention as the discovery of a new stable pharmaceutical preparation
containing omeprazole for oral use and a method for its manufacture. This
formulation has been successfully marketed by AstraZeneca under the trade name
LOSEC.
[5]
In the Background of the Invention, the
inventors describe what was generally known about omeprazole. Omeprazole had
been shown to be a powerful inhibitor of gastric acid secretion and was useful
to treat gastric and duodenal ulcers. The 693 Patent cites Pilbrant and
Cederberg Scand. J. Gastroenterology 1985; 20 (suppl. 108) p 113-120
[hereafter referred to as the Pilbrant reference] for the knowledge that
omeprazole is susceptible to degradation in acid reacting and neutral media and
can be stabilized in solution in the presence of higher pH values. Pilbrant is
also cited for the proposition that a conventional enteric coat doseage form of
omeprazole had been shown to provide sufficient stability for clinical
studies. This approach was, however, later found to provide inadequate
stability in long term storage. Following the Pilbrant citation, the inventors
state “the stability profile [of omeprazole] is similar
in solid phase”.
[6]
The stability problem associated with
conventional enterically coated omeprazole formulations is described in the 693
Patent as follows:
In order to obtain a pharmaceutical dosage
form of omeprazole which prevents omeprazole from contact with acidic gastric
juice, the cores must be enteric coated. Ordinary enteric coatings, however,
are made of acidic compounds. If covered with such a conventional enteric
coating, omeprazole rapidly decomposes by direct or indirect contact with it, with
the result that the preparations become badly discolored and lose in omeprazole
content with the passage of time.
In order to enhance the storage stability
the cores which contain omeprazole must also contain alkaline reacting
constituents. When such an alkaline core is enteric coated with an amount of a
conventional enteric coating polymer such as, for example, cellulose acetate
phthalate, that permits the dissolution of the coating and the active drug contained
in the cores in the proximal part of the small intestine, it also will allow
some diffusion of water of gastric juice through the enteric coating into the
cores, during the time the dosage form resides in the stomach before it is
emptied into the small intestine. The diffused water of gastric juice will
dissolve parts of the core in the close proximity of the enteric coating layer
and there form an alkaline solution inside the coated dosage form. The
alkaline solution will interfere with the enteric coating and eventually
dissolve it.
[7]
At page 4 of the 693 Patent, the object of the
invention is said to be the development of an omeprazole formulation which
provides acceptable gastric acid resistance that dissolves rapidly in neutral
to alkaline media (ie. the intestine), and that has good stability during long
term storage. This object is said to be fulfilled with a new doseage form made
up of three structural elements:
a.
Cores of neutral or alkaline salts of omeprazole
optionally mixed with alkaline compounds;
b.
A separating sublayer coating or coatings
soluble or rapidly disintegrating in water consisting of non-acidic, otherwise inert
pharmaceutically acceptable substances; and
c.
An outer layer consisting of an enteric coating.
The final doseage form is then treated in a
suitable way to reduce the water content to a very low level in order to obtain
good stability during long term storage.
[8]
In the Detailed Description of the Invention,
the omeprazole cores are further described. Gelatine capsules are said to be “used as cores for further processing”. The
separating layer and its purpose are described in detail in the following way:
The omeprazole containing alkaline reacting cores
must be separated from the enteric coating polymer(s) containing free carboxyl
groups, which otherwise causes degradation/discolouration of omeprazole during
the coating process or during storage. The subcoating layer, in the following
defined as the separating layer, also serves as a pH-buffering zone in which
hydrogen ions diffusing from the outside in towards the alkaline core can react
with hydroxyl ions diffusing from the alkaline core towards the surface of
coated articles. The pH-buffering properties of the separating layer can be
further strengthened by introducing in the layer substances chosen from a group
of compounds usually used in antacid formulations such as, for instance, [examples
omitted] or similar compounds; or other pharmaceutically acceptable
pH-buffering compounds such as, for instance the sodium, potassium, calcium,
magnesium and aluminium salts of phosphoric, citric or other suitable, weak, inorganic
or organic acids.
The separating layer consists of one or more
water soluble inert layer, optionally containing pH-buffering compounds.
The separating layer(s) can be applied to
the cores - pellets or tablets - by conventional coating procedures in a
suitable coating pan or in a fluidized bed apparatus using water and/or
conventional organic solvents for the coating solution. The material for the
separating layer is chosen among the pharmaceutically acceptable, water
soluble, inert compounds or polymers used for film-coating applications such as,
for instance sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol,
hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose,
hydroxypropyl methylcellulose, polyvinyl acetal diethyl-aminoacetate or the
like. The thickness of the separating layer is not less than 2 μm, for
small spherical pellets preferably not less than 4 μm, for tablets
preferably not less than 10 μm.
In the case of tablets another method to
apply the coating can be performed by the drycoating technique. First a tablet
containing omeprazole is compressed as described above. Around this tablet a
layer is compressed using a suitable tableting machine. The outer, separating layer,
consists of pharmaceutically acceptable, in water soluble or in water rapidly
disintegrating tablet excipients. The separating layer has a thickness of not
less than 1 mm. Ordinary plasticizers colorants, pigments, titanium dioxide,
talc and other additives may also be included into the separating layer.
In case of gelatin capsules the gelatin
capsule itself serves as separating layer.
[9]
Much of the expert evidence presented in this
case was concerned with the language of Claim 1. At the heart of the
infringement dispute is whether Claim 1, properly construed, has been infringed
by the manufacture and sale of Apotex’s omeprazole formulation, Apo-Omeprazole.
A key aspect of the dispute is whether Apo-Omeprazole contains a subcoating
layer meeting the criteria described in Claim 1. Apotex’s challenges to the
validity of the 693 Patent were similarly directed at Claim 1. Among other
issues, Apotex and its experts maintain that the formulation described in Claim
1, however construed, was anticipated, obvious and overbroad.
[10]
Claim 1 of the 693 Patent describes the
formulation in the following terms:
1. An oral pharmaceutical preparation
comprising: (a) a core region comprising an effective amount of a material
selected from the group consisting of omeprazole plus an alkaline reacting
compound, an alkaline omeprazole salt plus an alkaline reacting compound and an
alkaline omeprazole salt alone; (b) an inert subcoating which is soluble or
rapidly disintegrating in water disposed on said core region, said subcoating
comprising one or more layers of material selected from among tablet excipients
and polymeric film forming compounds; and (c) an outer layer disposed on said
subcoating comprising an enteric coating.
[11]
Claims 5, 6 and 13 are all directly or
indirectly dependant on Claim 1. Claim 19 covers the use of the formulation
according to any of the Claims 1 to 16 for the treatment of gastrointestinal
diseases.
[12]
The 693 Patent has a priority date of April 30,
1986, a Canadian filing date of April 29, 1987 and a date of issuance of
December 3, 1991. It is common ground that the relevant date for construing
the patent claims is December 3, 1991 and the relevant date for assessing
obviousness is April 30, 1986.
[13]
In order to more fully understand the
construction, validity and infringement issues arising in these proceedings, it
is helpful to first consider the scientific evidence presented by the expert witnesses
and, in particular, the few points where they agreed and the many where they
disagreed.
[14]
AstraZeneca’s case was advanced by Dr. Martyn
Davies and Dr. Roland Bodmeier. Apotex led evidence from Dr. Peter
Griffiths, Dr. William Amos, Dr. Frank Bright and Dr. Arthur Kibbe.
[15]
I accept that all of these witnesses were
appropriately qualified. My assessments of their credibility and the weight I
have attributed to their evidence are set out later in these reasons.
[16]
Dr. Davies has a record of extensive work,
research and professional recognition in the areas of pharmaceutical testing
analysis and characterization of drug formulations. He has widely employed
advanced analytical techniques in his work. He has been qualified to testify
as an expert witness on 12 occasions and, in particular, his evidence was
accepted in the United States patent infringement proceedings involving the
equivalent to the 693 Patent. He was qualified as an expert in pharmaceutical
formulation, particularly the formulation of coated oral doseage forms,
including enteric coatings.
[17]
Dr. Davies was retained by AstraZeneca to
ascertain the composition of the Apotex omeprazole pellets. His precise
mandate is set out at paragraph 23 of his initial report. He had previously
been retained by AstraZeneca in the United States in connection with patent
infringement litigation between AstraZeneca and a number of competitors,
including Apotex.
[18]
Dr. Davies subjected the Apotex pellets to
a number of tests including various forms of microscopy, infrared spectroscopy,
visual inspection, video micro-imaging, pH measurement, and water content
analysis. Some of his testing was conducted in 2004 in support of his opinions
in the United States’ litigation concerning the equivalent patent. That
testing was replicated, in part, in 2011 in connection with this proceeding.
[19]
Dr. Davies designed and oversaw the 2004
and 2011 experiments that were carried out in his laboratory. He gave evidence
that he observed the vast majority of the experiments and the recording of
data. He was responsible for reviewing the data and formulating the opinions
he provided in the United States and in Canada.
[20]
Dr. Davies was provided with samples of the
Apotex uncoated omeprazole cores, capsules containing fully formulated
enterically coated omeprazole pellets and the Apotex excipients.
[21]
Dr. Davies removed the enteric coating from
some of the Apotex pellets by dissolving the MACP coating in
acetone/isopropanol [IPA] solvent. IPA is known to dissolve MACP. The solvent
wash procedure was conducted for 2 minutes in 2004 and for 4 minutes in 2011.
This was followed by a solvent rinse and drying on paper. A number of washed
pellets were then randomly sectioned near their equators and fixed to metal
discs using adhesive UV curable resin for microscopic examination.
[22]
In 2004, Dr. Davies combined MACP and PVP
in solution and observed that a precipitate readily formed. That precipitate
was washed three times in water and kept for further analysis. This procedure
was not repeated in 2011.
[23]
The imaging techniques that Dr. Davies used
involved Confocal Laser Scanning Microscopy [CLSM] and wide-field-UV
fluorescence microscopy (2004 only) at 10X and 50X magnification.
[24]
Dr. Davies also exposed his samples to
Attenuated Total Reflectance Fournier Transfer Infrared Spectroscopy [ATIR] as
a means of detecting their molecular “fingerprints”.
[25]
In 2004 and in 2011 Dr. Davies exposed
washed pellets to a water bath and video-imaged the reaction that took place.
[26]
Finally, in 2004 Dr. Davies carried out pH
and water content measurements on the Apotex samples.
[27]
In 2004 Dr. Davies examined over 20
bisected enteric coated Apotex pellets and over 20 washed pellets with UV
fluorescence and CLSM fluorescence and reflectance microscopy. Many individual
and “representative” CLSM optical slices were
examined for each pellet. The same process was followed in 2011 with CLSM
imaging. According to Dr. Davies, all of the images he obtained showed
the presence of a distinct and continuous brightly fluorescing ring or corona
at the interface of the pellet cores and the enteric coating. No gaps in the
fluorescent ring could be seen. The ring was detected both within the
enterically coated pellets and at the surface of the washed pellets. When
Dr. Davies examined some 20 bisected Apotex pellet cores using CLSM and UV
fluorescence microscopy, he found the cores to be weakly fluorescent but there
was no bright fluorescent ring at the surface of the samples [see Schedule 27
to Exhibit 6]. According to Dr. Davies, the fact the fluorescent ring
remained intact after the enteric coating was washed off in solvent indicates
the chemical solubility of each structure was different.
[28]
When Dr. Davies measured the thickness of
the fluorescent layer in 2004 from individual CLSM images, he obtained a range
of between 2 and 6 microns. His thickness measurements from 2011 fell between
1 micron and 6.8 microns. On a recorded sample size of 50, the average thickness
measurement came to 3 microns.
[29]
In 2004 and in 2011, Dr. Davies performed
ATIR analysis on the surface of the Apotex enteric coated pellets, on the
fluorescing layer of the washed pellets and on the uncoated cores. He then
compared the spectra obtained to the known spectra for the components used by
Apotex (omeprazole, povidone [PVP], mannitol, MACP and the known omeprazole
degradation products) and to the MACP-PVP complex he had prepared.
[30]
When Dr. Davies scanned the Apotex cores,
he observed spectral peaks he attributed to omeprazole, mannitol and PVP. In
particular, he found PVP to be present on the surface of the cores. The
spectra he took from the enteric coating of the Apotex pellets matched the
spectrum for a sample of MACP supplied by Apotex.
[31]
Dr. Davies then examined the fluorescing
layer. In 2004 he assessed ten washed pellets and recorded spectra from five.
The ATIR spectra he obtained disclosed differences from the spectra for MACP.
In particular, the spectra for the fluorescing layer disclosed an additional
absorption peak that he attributed to a complex that had formed in a reaction between
the MACP enteric coating and PVP in the pellet cores. Dr. Davies noted
that those two polymers are known to complex with each other due to hydrogen
bonding. He described the complex as a methacrylic acid copolymer-PVP complex
chemically distinct from the enteric coating. To confirm this finding,
Dr. Davies compared a spectrum taken from the fluorescing layer to a
spectrum taken from the MACP-PVP complex precipitate he prepared. The two
spectra were comparable.
[32]
In addition to finding the complex in the Apotex
sublayer, Dr. Davies found evidence of the presence of MACP magnesium
salt. This compound, he said, formed from a reaction with magnesium hydroxide
during the enteric coating process. Mannitol peaks that appeared in the washed
pellet spectra were said by Dr. Davies to arise from the detection of
mannitol immediately below the sublayer. No evidence of omeprazole or its
degradation products was observed.
[33]
The ATIR data led Dr. Davies to conclude
that both the complex and MACP magnesium salt in the fluorescing sublayer
formed from a reaction between MACP and PVP and magnesium hydroxide during the
Apotex enteric coating process.
[34]
Dr. Davies’ visual inspection of the Apotex
pellets revealed no discolouration as an indication of degradation.
[35]
After submerging 20 washed pellets in a water
bath, Dr. Davies observed a film-like layer peeling away from the cores.
The loss of the sublayer was complete at about 7 minutes and the pellets fully
disintegrated within 10 minutes. Time-lapse videos of this reaction were
recorded.
[36]
Dr. Davies’ 2004 pH measurements disclosed
values of between 8.81 and 9.39. Similar results were obtained in 2011. When
Dr. Davies compared the pH values for MACP and PVP to the values for the
complex, he observed that the complex was 2 pH units higher. This indicated to
Dr. Davies that the complex was chemically distinct from either of its
constituent compounds. His measurement of water content in the Apotex pellets
resulted in a range from between 1.52% to 1.97%.
[37]
From the above test results, Dr. Davies
drew the following conclusions:
a.
The cores of the Apotex pellets contain
omeprazole.
b.
The presence of a subcoating outside of the
Apotex pellet cores had been demonstrated by CLSM fluorescence and reflectance
microscopy. The fluorescing ring that he observed conformed to the contours of
the cores.
c.
The subcoating layer has different chemical
properties from the enteric coating. This was demonstrated by its continued
presence after the enteric coating was removed with acetone/IPA solvent, by the
different ATIR spectra that were obtained from both regions and by differences
in their acidity levels.
d.
Neither the MACP-PVP complex nor the MACP salt
present in the sublayer appeared to degrade omeprazole. The pellets showed no
evidence of discolouration and the ATIR data did not disclose omeprazole
degradation products in the sublayer.
e.
Although Dr. Davies did not rule out the
presence of acidic functional groups from the enteric coating in the sublayer,
he concluded that most would have been taken up in the MACP-PVP reaction. To
the extent that unreacted acidic functional groups did remain in the sublayer,
they were likely to be segregated away from the cores and not available to
degrade the omeprazole at the surface of the cores.
f.
In water, the subcoating does not dissolve but
it rapidly disintegrates. This was evident from the water disintegration
tests.
g.
The ATIR data showed that the sublayer does not
contain omeprazole or an alkaline salt of omeprazole.
h.
The complex and MACP salt are polymeric film
forming compounds. The film-like character of the complex is evident in the
disintegration videos.
i.
The enteric coating layer of the Apotex pellets
is composed of MACP and is distinct from the sublayer containing the complex.
j.
The Apotex cores exhibit pH values of between
8.81 and 9.39.
[38]
In reply to the responding expert reports from
Dr. Griffiths and Dr. Bright, Dr. Davies offered additional
justification for his testing conclusions. Dr. Davies disagreed that he
had attempted to use fluorescence data to identify the complex in the sublayer
region. He acknowledged that fluorescence is not a suitable technique to
identify a chemical composition but could be used to study the structure of
pharmaceutical compositions. Fluorescence was only one technique he used to
assess the presence and structure of the sublayer. Dr. Davies stated that
he had not conflated the observed fluorescent ring with the complex nor had he
concluded the complex was the only constituent compound in the sublayer.
[39]
Dr. Davies confirmed that his ATIR
interrogations consistently disclosed the presence of the complex in the
sublayer and his multiple UV and CLSM examinations all exhibited a continuous
bright fluorescent layer.
[40]
Dr. Davies asserted again that the
detection of mannitol bands in some of the ATIR spectra resulted from the
detection of mannitol sitting below the sublayer in the omeprazole cores.
According to Dr. Davies the suggestion that the presence of mannitol bands
indicated gaps in the sublayer was based on a flawed assumption about the depth
of penetration of his ATIR signal. He also observed that Dr. Griffiths’
analysis of sublayer thickness was very indirect and that no attempt was made
to replicate his direct measurements using a standard technique.
[41]
Dr. Davies did not agree that omeprazole
degradants were more likely to be the sources of the observed fluorescence.
There was no reliable empirical evidence produced to show degradants in the
sublayer and, even if they were present below levels of ATIR detection, they
would be insignificant.
[42]
In responding to ATIR spectra obtained by
Dr. Hawker, Dr. Davies noted an anomalous and significant signal from
the starting control (the blank). According to Dr. Davies this rendered
all of the Hawker data unreliable. Dr. Davies also criticized the method
employed at Temple University to obtain CLSM images. He said the pellets were
crudely cracked and not, as he had done, carefully sliced and, unlike his Z series
of CLSM images, only one image was taken for each pellet examined.
[43]
Dr. Davies’ response to Dr. Griffiths’
comment that he had not directly ascertained the chemical composition of the
fluorescent layer is set out at paragraph 35 of his reply report and further
discussed at pages 433-434 of his testimony:
Q. So to
begin with, Dr. Davies, I would like to ask you about part of your reply report
which starts at page 12, under the heading "Experiments Conducted to
Directly Analyze Composition of Fluorescent Subcoating Layer".
In paragraph 35 of
your reply report you note that Dr. Griffiths states that you carried out
no experiments to elucidate directly the composition of the intense fluorescing
layer observed in Apotex's enteric coated pellets. You say that that is
untrue. Could you please explain your basis for saying so?
A. My basis
is that I employed ATR FTIR analysis on that subcoating layer on the surface of
the solvent washed pellets to elucidate the composition of that layer to
demonstrate that it contained the MACP PVP complex and the MACP salt.
I also undertook
the UV CLSM fluorescence and reflectance data on the bisected pellets which
were enteric coated pellets, the washed pellets, the uncoated cores, to
identify the presence of that layer and confirmed that it remained after
washing. So it had different properties to that of the enteric coating.
I then went on to
make the complex to show that the complex had the same chemical signals, diagnostic
signals for the complex in the ATR FTIR analysis.
I then compared
that spectra to the spectra I saw for the washed pellets. And, again, I showed
that what I saw in the complex that I had made in the test tube was the same
signal that I saw for the complex that I saw on Apotex's washed pellet.
So I took a number
of steps to show that, in fact, that I had done a number of experiments to show
that I was directly analyzing the composition of that layer.
[44]
Dr. Davies addressed Dr. Griffiths’
identification of carboxylic acid groups (MACP that had not reacted with PVP)
in the sublayer by pointing out that any unreacted MACP was unlikely to be in
contact with the cores and that Dr. Griffiths had not tested his
hypothesis. If these acid groups were available to react with omeprazole at
the surface of the cores measurable degradation products ought to have been
present. Apotex’s own sensitive HPLC tests of its finished products showed
only insignificant or undetectable levels of degradation products.
[45]
The Apotex criticisms about the
representativeness of Dr. Davies’ testing were addressed. It was
acknowledged that the area of ATIR interrogation carried out by Dr. Davies
was 44 microns in diameter from a total pellet diameter of about 1000 microns.
Dr. Davies examined at least 15 washed pellets and recorded 10 spectra for
each. All of the spectra disclosed the presence of the complex. This was said
to be consistent with Dr. Davies’ UV and CLSM fluorescence microscopy
where over 25 bisected coated pellets and 25 bisected washed pellets were
imaged. In every case a bright fluorescent ring was observed. Dr. Davies
noted that Dr. Bright had not attempted to conduct his own testing to
challenge the representativeness of Dr. Davies’ data.
[46]
In a further response to the suggestion that he
had assumed the fluorescent band to be the complex, Dr. Davies answered in
the following way:
56. However, merely because
fluorescence is not a suitable technique for identifying the MACP-PVP complex
does not mean that it cannot be used in combination with other tests to show
where the complex is located. As set out in my 2011 Report, I used wide-field
UV and CLSM fluorescence in combination with reflectance microscopy to show
that a continuous brightly fluorescent layer is present in Apotex’ s pellets on
the outside of the pellet core where the enteric coating is first applied. I
then used ATR-FTIR spectroscopy to show that the fluorescent subcoating layer
contains an MACP-PVP complex, which is not present in either the core or
enteric coating. In combination, these tests show that the MACP-PVP complex and
the subcoating layer are located together.
[47]
To Dr. Griffiths’ postulation that
omeprazole degradants were more likely than the complex to be the source of the
fluorescent ring, Dr. Davies pointed out that the complex was actually
detected in the sublayer and omeprazole degradants were not. In the absence of
data to show the presence of omeprazole degradants in the sublayer and in the
face of an acknowledgement that fluorescence alone cannot identify a particular
molecule, Dr. Griffiths’ opinion was described as speculation.
[48]
The representativeness of Dr. Davies’
sublayer thickness measurements was defended in the following way in his reply
report:
72. First, the thickness data for the
fluorescent subcoating layer was obtained using a standard analytical
technique. Second, the thickness data was consistent across multiple pellets in
both 2004 and 2011. In particular, all the pellets examined in 2011 had a
fluorescent subcoating layer with an average thickness of at least 2 microns,
which was consistent with the range of thickness measured in 2004. Third, this
thickness data is consistent with both CLSM reflectance microscopy and ATR-FTIR
spectra of bisected washed pellets.
[49]
Dr. Davies confirmed his thickness
measurements were not conducted from maximum intensity images but, rather, from
individual CLSM Z-slice images. This point was advanced to displace the
suggestion that Dr. Davies’ thickness measurements had been taken from
maximum intensity images.
[50]
Dr. Davies dealt with Dr. Griffiths’
opinion concerning the presence of mannitol bands in some of the ATIR washed
pellet spectra. Much of the debate focussed on the assessment of the depth of
the penetration of the beam generated by Dr. Davies’ ATIR spectrometer.
According to Dr. Davies, Dr. Griffiths had significantly understated
the depth of signal penetration and thus underestimated the thickness of the
subcoating layer. A key point of disagreement between Dr. Davies and Dr. Griffiths
concerned the angle of the spectrometer beam inherent to Dr. Davies’
instrument. Dr. Griffiths assumed a median angle of incidence of 45º and
Dr. Davies said it fell in a range of between 27º and 45º. I will say more
about this later in these reasons.
[51]
In response to Dr. Griffiths’ doubt that
the film-like layer falling away from the Apotex washed pellets when immersed
in water was the complex and, instead, could be residual MACP, Dr. Davies
said the MACP readily dissolved in a solvent wash and was unlikely to have
remained except in minute amounts. Since the ATIR spectra of the washed
pellets consistently showed the complex to be present, it was the only
film-like compound that could plausibly remain.
[52]
The Apotex criticisms of Dr. Davies’ testing
methods were addressed in Dr. Davies’ reply report. Dr. Bright’s
concern about possible contamination by Dr. Davies’ use of drying paper
and adhesive resin was countered in the following ways:
a.
The fluorescent ring was present in both the
washed and unwashed pellet and therefore could not have resulted from paper
residue.
b.
Paper contamination would have been localized.
The fluorescent ring formed a corona around the pellet cores.
c.
The pellets were never embedded in resin but
instead were affixed at the base well away from the area under inspection.
[53]
To Dr. Bright’s concerns that
Dr. Davies bisected the Apotex pellets only near their equators and
otherwise failed to obtain representative data, Dr. Davies said that he
wanted to avoid a plane that intersected the sublayer at an angle and that,
unlike Dr. Rez Fassihi, he took numerous CLSM images through each pellet
sample. Having regard to the uniformity of Apotex’s manufacturing methods, the
location of pellet analysis would not be expected to allow for significant
coating anomalies.
[54]
Dr. Davies challenged Dr. Bright’s
opinion that the CLSM images showed discontinuities in sublayer fluorescence.
He noted that the bisected pellets had irregular surfaces such that portions of
the image will typically be out of focus. According to Dr. Davies, in
order to properly analyze the entire surface of a non-planar pellet, a series
of CLSM sections is required to discern which portions of each image are in
focus. With a non-transparent sample, the intensity of fluorescence diminishes
as the focal plane moves into the interior. This attenuation effect means that
the fluorescent image obtained from the in-focus surface of a partially opaque
sample imparts the most reliable information. Multiple Z-scan images of each sample
are thus required to accurately determine the continuity of any observed
fluorescence. According to Dr. Davies, Dr. Bright failed to
appreciate these points and took his discontinuity observations from single and
unrepresentative CLSM Z-scan images from well above and below the pellet
surface. For those CLSM images where the focal plane intersected the pellet
surface, no discontinuities in sublayer fluorescence could be observed.
[55]
Dr. Davies expressed the same concern about
Dr. Bright’s use of 3D images reconstructed from individual CLSM images.
His reply report at paragraphs 167-169 addressed the problem as follows:
167. Based on my CLSM three dimensional
(“3D”) images for Apotex’s enteric coated pellets, capsule Lot FD9104B and the
3D montages Dr. Bright created using my 2011 CLSM data, Dr. Bright
concludes that discontinuities in the subcoating layer are “many and obvious”.
I disagree for the following reasons.
168. It is improper to assess continuity
of the subcoating layer by visual inspection of the 3D images reconstructed
from the CLSM sections of the bisected pellet. The image formed using CLSM
reflects the intensity of the fluoresced light detected in the focal plane.
However, as previously explained, the intensity depends on the depth and
orientation of the focal plane in relation to the bisected pellet surface. CLSM
images with focal planes taken above or below the bisected pellet surface will
not accurately reflect the level of fluorescence at the surface. Even when a
focal plane intersects a bisected pellet surface, some portions of the surface
may be out of focus if the focal plane is not exactly parallel with the pellet
surface. A 3D stack of such CLSM images suffers from the same limitations. Dr.
Bright did not account for this effect when analyzing the 3D CLSM images. As a
result, he misinterpreted the dark areas in the images as discontinuities.
169. Moreover, had there been actual
discontinuities in the subcoating layer, they would have presented themselves
as gaps in portions of the 2D CLSM images where the bisected pellet surface is
in focus. However, no such gaps were evident. [Footnotes omitted]
[56]
To Dr. Bright’s opinion that the overall
intensity of fluorescence emanating from the sublayer was not appreciably
different from the surrounding areas, Dr. Davies observed that when
intensity was assessed from in-focus areas at the sample surface it was
appreciably brighter than its surroundings. In those areas a distinct bright
fluorescing layer could be seen resting on the weakly fluorescing cores. In
contrast, fluorescence arising from background noise would be random and would
not be represented in the images as a bright continuous corona.
[57]
Dr. Davies took umbrage at
Dr. Bright’s allegation that many of his CLSM images had been artificially
altered to highlight specific regions. He pointed out that the images were
automatically generated by his CLSM instrument and not altered by any operator
manipulation.
[58]
In commenting on the Temple University CLSM 10X
fluorescence images, Dr. Davies pointed out that the pellets were crudely
bisected and therefore difficult to clearly image. Because each sample was
only imaged once, the images were insufficient to support any meaningful
conclusions. Multiple images are required to determine which areas are in
focus.
[59]
In response to Dr. Amos’ opinion that
Dr. Davies’ CLSM images were saturated, Dr. Davies stated that he
took the steps necessary to avoid this problem.
[60]
Dr. Bodmeier was qualified as an expert in
pharmaceutical formulation, particularly the formulation of coated oral doseage
forms, including enteric coatings. He has extensive experience as an academic
and in working with different coating technologies including the application of
coatings in drug formations (often to obtain specific release profiles). He is
a prolific scientific author and researcher. He also frequently acts as a
consultant to the pharmaceutical industry.
[61]
Dr. Bodmeier was initially retained by AstraZeneca
to construe the relevant claims of the 693 Patent as read by the notional
person of skill and to assess whether, in view of Dr. Davies’ test
results, the Apotex omeprazole capsules infringe Claims 1, 5 and 6 of the 693
Patent. In a subsequent responding report [Exhibit 67] Dr. Bodmeier addressed
Apotex’s invalidity evidence bearing on anticipation, obviousness, overbreadth,
utility, sufficiency, claims broader and ambiguity. In a final report [Exhibit
68], he addressed a few specific evidentiary points raised by the Apotex experts
mainly concerning the degradation of omeprazole.
[62]
Dr. Bodmeier described the object of the 693
Patent as the provision of a storage stable and gastric acid resistant
omeprazole formulation. Because omeprazole was known to be unstable in acidic
aqueous environments, it required a protective enteric coating to pass through
the stomach for release in the intestine. However, in that formulation, long
term storage stability was compromised as evidenced by discolouration.
[63]
Dr. Bodmeier noted that when the inventors addressed
the storage instability problem by adding either an alkaline reacting compound
[ARC] to the omeprazole cores or by using an alkaline omeprazole salt, a new
problem arose in the form of a decrease in gastric acid resistance. This was
caused by the premature degradation of the enteric coat. What was found to be
happening was that some gastric juice would diffuse through the enteric coat
into the cores, forming an alkaline solution. The alkaline solution caused the
enteric coat to dissolve from the inside leading to premature failure after
administration.
[64]
According to Dr. Bodmeier, the inventors’
solution to the formulation problem lay in the inventive combination of an
alkaline core separated from the enteric coat with a water soluble or rapidly disintegrating
subcoating layer. With the use of a subcoating layer the alkalinity of the
cores could be reduced without compromising the long term storage stability of
the formulation.
[65]
Dr. Bodmeier was asked to construe Claims
1, 5 and 6. In particular, he was asked to determine whether Claim 1 included
within its ambit a subcoating that formed in situ as the product of a chemical reaction between the enteric coat and
an alkaline omeprazole core. He was also asked to interpret the term “inert” as it related to the subcoating.
[66]
Dr. Bodmeier interpreted Claims 1, 5 and 6
as formulations per se
without any limitation to the process of manufacture. He construed the words “disposed on” as describing only the location of the
subcoating. His conclusion is set out in the following passage from his
initial report:
48. In response, as noted above,
claims 1, 5 and 6 of the ‘693 patent are not limited to a particular
method of formation of the composition, provided that the subcoating achieves
the goals of the patent, namely a storage stable and gastric resistant dosage
form. In particular, the advantages of the invention arise from the finished
dosage form structure and not from any particular process by which the
structure is made. Contrary to what Apotex suggests, the patent is not directed
to avoiding all possible reaction products. In certain circumstances, a
reaction product may provide the necessary subcoating layer which will assist
in achieving gastric resistance and storage stability. For example, the application
of an enteric coating material to a core can, depending upon process conditions
and ingredients, lead to a subcoating layer which is formed in situ.
This subcoating can comprise material distinct from the core and the enteric
coating. There is nothing in the disclosure teaching that such a reaction
product must be avoided. The skilled person would not read such a limitation
into the claims.
[67]
Dr. Bodmeier’s interpretation of the term “inert” was relative. The person of skill would not
expect the subcoating to be perfectly inert or entirely non-acidic, but only to
the extent necessary to avoid functional interference. As to whether the
subcoating was required to be entirely continuous, Dr. Bodmeier again
expressed a relative view. If the subcoating was sufficiently robust to
achieve good gastric acid resistance and long term storage stability, the
avoidance of all structural anomalies would not be thought by the person of
skill to be a requirement.
[68]
Concerning the degree of acceptable water content,
Dr. Bodmeier said that the person of skill knew that moisture had to be
minimized or otherwise managed. According to this view Claims 1, 5 and 6 were
not limited by any specific level of water content.
[69]
Based on his construction of the relevant claims
language and, in the face of the consistency of Apotex’s batch records and its
manufacturing practices, Dr. Bodmeier concluded that all of Apotex’s
omeprazole batches would have infringed Claims 1, 5 and 6 of the
693 Patent. Having regard to Apotex’s quality control practices,
Dr. Bodmeier was of the view that all of its shipped omeprazole product
would have met minimum storage stability and gastric acid resistance criteria
and would necessarily have incorporated a functioning and inert subcoating.
[70]
In his responding report, Dr. Bodmeier went
on to address Dr. Kibbe’s validity opinions. Dr. Bodmeier was of the
view that Dr. Kibbe’s assessment of the prior art was simplistic and was
based on hindsight. This general criticism is set out below:
279. Drs. Hopfenberg and Kibbe’s
analysis demonstrates a certain amount of prevision. They are able to find
their way through the formulation maze because they know the route in advance.
Interestingly, they make no mention of alternative pathways or problems that would
have inevitably been encountered during the formulation exercise. In my view,
even if a skilled person ultimately came to the invention (which I do not think
they would have been able to do), the path would have been much, more torturous
than that described by Drs. Hopfenberg and Kibbe and would have inevitably
involved extensive experimentation, including dead ends. Moreover, the research
would be exploratory and not simply confirmatory. A skilled person would not
have conceived of all the elements of the 693 patent prior to the start of
experimentation. [Also see para 108]
[71]
Given the research limitations that prevailed in
the 1980s, Dr. Bodmeier also doubted that several of the prior art
references relied upon by Apotex would have been available to the person of
skill, particularly with reference to some foreign trade publications.
[72]
Dr. Bodmeier considered the 1985 Pilbrant
reference to be the principal piece of prior art because it dealt specifically
with omeprazole. Pilbrant taught that omeprazole was unstable in aqueous
solution and required a protective enteric coat. Omeprazole was also sensitive
to moisture and required a desiccant in its packaging. Dr. Bodmeier
disagreed with Dr. Kibbe that Pilbrant warned the person of skill about
acid sensitivity of omeprazole in solid state formulations. In 1986 the person
of skill could not predict the stability of an active pharmaceutical ingredient
[API] in a solid state doseage form from its behaviour in solution. Similarly,
Pilbrant did not teach that an ARC would be necessary to achieve good storage
stability for enterically coated omeprazole. Although Pilbrant administered
omeprazole in solution along with sodium bicarbonate, that combination was
required to neutralize gastric acid and not to achieve long term storage
stability.
[73]
Dr. Bodmeier considered the significance of
EP 495 to Dr. Kibbe’s anticipation opinion. He acknowledged that this
reference disclosed that the alkaline salts of omeprazole were more stable than
its neutral form and that such a formulation could be protected by an enteric
coat. Nevertheless, because different salts have different solubility
properties, it would not have been obvious to the person of skill to apply this
information to the stability problem encountered by the 693 Patent
inventors. According to Dr. Bodmeier, EP 495 and the other prior art
references relied upon by Dr. Kibbe would not have led the person of skill
away from Pilbrant which taught that neutral omeprazole could be successfully
formulated with an enteric coat and that there was no apparent need to
introduce a stabilizing ARC.
[74]
As for the need for a subcoating,
Dr. Bodmeier accepted that this was a generally known formulation strategy
for separating pharmaceutical components. However, contrary to Dr. Kibbe’s
view, this step would not have been the first and only solution available to
the person of skill. Faced with evidence only of discolouration, the person of
skill would not know the source of the problem. A subcoating would only be of
value if the discolouration was caused by a reaction between the enteric coat
and the omeprazole core. It was also known that some acid sensitive or
alkaline drugs are sufficiently protected by conventional enteric coats.
[75]
Dr. Bodmeier expressed the view that the
first method the person of skill would attempt to overcome a known
incompatibility was to find alternative ingredients and not to add a processing
step. Dr. Bodmeier’s testimony described the problem facing the person of
skill in the following way:
So, first, you
maybe see something, discolouration, but you don't know the problem, you don't
know what discolours. You don't know what is responsible for gastric
resistance. I think this is all with hindsight, you know, these references
are, in my opinion, are collected because one knows the solution to the problem
and then you look for a subcoating, maybe for the alkaline reacting compounds.
But a formulator in
those days, that's not his starting point. He starts, let's say, with a
discolouration or he starts, even Pilbrant which says it's stable, he starts at
point zero. And, in my opinion, these references are of no help to him to
identify the problem, what's the cause of the problem or what's the cause of
the observation and then to find a solution.
I think this is
really very important to think back as a formulator where we stand, and I think
it's obviously difficult with hindsight, you know, once you have a solution to
look and to make it look obvious, but I think omeprazole, if I can just give my
opinion, is such a complex molecule that when somebody starts to formulate
this, I think these references would not be found by a skilled person.
[76]
According to Dr. Bodmeier, faced with
evidence of discolouration, the person of skill would not assume an
incompatibility between omeprazole and the enteric coat. Other possibilities
were present that required examination. Adding an ARC was also not an
inevitable choice because the addition of excipients can create other
undesirable reactions, as turned out to be the case with omeprazole. Another
stabilizing option identified by Dr. Bodmeier was the use of
anti-oxidants.
[77]
Once the gastric acid resistance problem arose
it, too, required a solution, Dr. Bodmeier’s report describes the options
then facing the person of skill:
239. Even if the skilled person became
aware of the reduced gastric resistance problem, he or she would need to
conduct experiments to solve the problem.
240. The skilled person would likely
first search in the enteric film coating itself for the reasons for the
insufficient gastric resistance, systematically investigating formulation and
process parameters. Insufficient gastric resistance can be caused by
insufficient thickness of the coating or uneven coating. The skilled person
might also consider the following:
•
amount and/or choice of plasticizer;
•
process parameters, including temperature, spray pressure, spray
rate, air throughput, drying;
•
remaining solvent;
•
porosity of the coating;
•
choice of solvent.
241. Contrary to Dr. Kibbe’s view at
para, 224 of his report, a logical response to insufficient gastric resistance
would have been to increase the thickness of the coating and thus try to
improve gastric resistance. Another logical response would have been to
consider the removal of the alkaline reacting compound.
[78]
Dr. Bodmeier was of the view that
omeprazole was a very difficult drug to formulate and he summarized his
obviousness evidence in the following way:
265. In my opinion, a tremendous amount
of effort would be required to achieve the invention as described in claims 1,
5 and 6 of the 693 patent. Omeprazole is an exceptionally difficult compound to
formulate, as it is highly acid sensitive, sensitive to heat, moisture, and
solvents, and is only effective when released in the intestinal tract. As noted
above, the task of identifying each of the problems encountered by the
inventors of the 693 patent would be challenging. Further, arriving at the
synergistic solution of the addition of an alkaline reacting compound to the
core and an inert subcoating layer of polymeric water-soluble film-forming compounds
between core and enteric coat to solve the degradation and gastric resistance
problems would not be considered routine. As noted, there would have been a
multitude of possible paths that the skilled person would likely have taken,
while the solutions described in the 693 patent would have remained
non-obvious.
[79]
Dr. Bodmeier addressed Dr. Kibbe’s
argument that Claims 1, 5 and 6 are broader than the invention disclosed
because they claim formulations that are not limited by the essential parameters
of water content and subcoating thickness. Dr. Bodmeier considered these
features to be non-essential to the inventive concept because the person of
skill inherently knows to control for water and for subcoat thickness and would
expect and tolerate some variability.
[80]
Dr. Bodmeier agreed with Dr. Kibbe
that the 693 Patent promises good long term storage stability and gastric acid
resistance. That objective was shown to be achieved with a doseage form having
the essential structural elements of Claim 1. Nevertheless, Dr. Bodmeier
acknowledged that not every omeprazole doseage form having the essential
structural features of Claim 1 would achieve the promise of the 693 Patent.
The formulator would still need to test the formulation to ensure that it
provided the expected advantages of long term stability and good gastric acid
resistance: [pp 1596-1601]. Dr. Bodmeier described the nature of this
required testing as routine.
[81]
Dr. Bright was accepted as an expert in
analytical chemistry, spectrochemical analysis, chemical instrumentation,
fluorescence and luminescence spectroscopy and microscopy-based imaging. He
has unquestionable experience and expertise in these general areas. He
acknowledged, however, that he has no prior experience in using his expertise
to analyze pharmacological products [p 4060] and he carried out no testing of
his own [p 4072].
[82]
Dr. Bright was retained to comment on
Dr. Davies’ methods and his findings. In particular, he was asked to
assess the evidence to determine if the observed “intense
fluorescing layer” in the Apotex omeprazole pellets is an inert,
continuous layer of MACP-PVP complex, with a minimum thickness of 2 microns,
which is soluble or rapidly disintegrating in water and which acts as a
separating layer between the pellet cores and the enteric coating.
Dr. Bright was also asked to assess the significance of the emission
spectra obtained by Dr. Hawker and the CLSM images produced Dr. Fassihi
on behalf of Apotex.
[83]
Dr. Bright was directed to assume that the
term “continuous” meant without gaps, breaks or
holes and that “inert” meant non-reactive with
the components of the pellet cores and the enteric coating or, alternatively,
chemically unreactive with omeprazole such that the sublayer does not contain
omeprazole degradation products. He was also told to assume that the complex
was shown by Dr. Davies to be present “at a single
point of interrogation on each pellet”.
[84]
Dr. Bright’s principal conclusion was that
Dr. Davies had failed to prove that the source of the CLSM fluorescence in
the sublayer region was the MACP-PVP complex. According to Dr. Bright the
observed fluorescence was more likely coming from other compounds in the
sublayer and, in any event, the presence of fluorescence is insufficient to
prove the “location, distribution or thickness”
of the complex or any other substance that may be present. Even if one were to
assume that the fluorescent ring in the sublayer coincided with the complex, no
conclusions about the continuity, thickness or the separating value of the
complex could be drawn. Since Dr. Davies had not ruled out the presence
of other compounds within the fluorescent ring, the layer had not been
demonstrated to be inert.
[85]
Dr. Bright had several concerns about
Dr. Davies’ testing methods. In particular, he stated that the detection
of fluorescence on the surface of the washed pellets “could
have been due in whole or in part to, or at least affected by, contamination”
from impurities transferred from drying paper to the pellet surfaces.
Dr. Bright thought that this should have ruled out experimentally.
Dr. Bright had similar concerns about contamination from the use of an “incorrect mounting medium” (ie. adhesive resin) or by
Dr. Davies fully embedding the pellets in resin.
[86]
Dr. Bright was critical of Dr. Davies’
failure to bisect the pellets along their major axis or near their ends.
Dr. Davies had consistently bisected close to the pellet equators (the
minor axis). Dr. Bright’s concern was that a sublayer anomaly that
commonly existed outside of the equatorial region would be missed.
[87]
Dr. Bright was troubled by what he took to
be discontinuities in the fluorescent ring. Some of Dr. Davies’ Z-scan
images did not show a fluorescent ring and Dr. Bright believed this to be
evidence of fluorescent discontinuity. At paragraph 70 of his report he
explained the problem as he saw it:
70. Inspection of Dr. Davies
experimental CLSM data presented in Exhibit “O” shows the following: (i) a
discontinuous ring in the x- and y-planes that is also
discontinuous in the z-plane (e.g., compare z=0 and z=35
and z=49 images in Exhibit “O” noting how the ring appears broken in z=0
and totally absent in z=49); (ii) an enteric coating layer that is also
clearly fluorescent (cf., z=39 and z=42 in Exhibit “O”); and
(iii) a core region that is also clearly fluorescent (cf., z=39 and z=42
in Exhibit “O”). These results are inconsistent with Dr. Davies’ description of
the “intense fluorescing ring” as a continuous structure between a
non-fluorescing core (see para. 139 of Dr. Davies’ report) and a
non-fluorescing enteric-coating region (see para. 148 of Dr. Davies’ report).
Similar observations apply to images from Dr. Davies’ 2011 testing, set out in
Exhibit “P”. [Footnotes omitted]
[88]
Further analysis of the pellet fluorescence led
Dr. Bright to conclude that the sublayer fluorescence “is not appreciably different from the intensity of the
surrounding area” and that the “purported bright
fluorescing ring is often not reliably detectable (ie. greater than 99%
confidence) above the strong background emission” from surrounding
areas. According to Dr. Bright, notwithstanding the visual presence of a
bright ring in the sublayer, Dr. Davies had not established that a bright
ring exists. In Dr. Bright’s report this deficiency was described as a
discontinuity. In his testimony he conceded that this may be evidence
of sublayer discontinuity.
[89]
Dr. Bright maintained that many obvious
discontinuities were apparent in Dr. Davies’ CLSM images. The
discontinuities identified by Dr. Bright in his chosen CLSM images were
almost all detected below the surface of the sample [see Figures 16 and 17 of
his report].
[90]
Dr. Bright criticized Dr. Davies’
apparent failure to follow appropriate image integrity policies based on
perceived unspecified alterations to his images. According to Dr. Bright “many” of Dr. Davies’ images had been “somehow colourized or somehow artificially highlighted
specific regions within the image”.
[91]
Dr. Bright considered the presence of
undetected omeprazole degradants within the fluorescent sublayer that were
possibly causing or contributing to the fluorescence. Dr. Davies could
not rule this out because the limits of detection of his ATIR instrument were
markedly inferior to his CLSM instrument. In reviewing the Hawker spectra,
Dr. Bright concluded that several known omeprazole degradation products
were substantially more fluorescent than MACP, PVP or the prepared complex.
Dr. Bright did note that Dr. Hawker’s control (the blank) was “anomalously high” but “this
happens from time to time, especially in analysis of solid samples”.
According to Dr. Bright’s report this problem did not “cast doubt on the remaining data”. Nevertheless, in
his testimony he appeared to question the validity of the MACP/PVP complex
readings obtained by Dr. Hawker because they all fell below the false
signal generated by the blank [p 3978].
[92]
Notwithstanding Dr. Bright’s
acknowledgement that fluorescence cannot distinguish between different
molecules that fluoresce under the same conditions and there “is simply no way to know based on the testing conducted by
Dr. Davies”, Dr. Bright concluded that the “fluorescence in Dr. Davies’ ‘bright ring’ is more
likely to be attributed to [omeprazole] degradants than to his MACP-PVP and
MACP-Mg complex”.
[93]
Dr. Bright summarized his views about the
scientific significance of Dr. Davies’ fluorescence data in the following
way:
116. Therefore, assuming that some
amount of Dr. Davies’ complex is present on the surface of the bisected, washed
pellets, there is no way to ascertain, based on Dr. Davies’
fluorescence work, how much complex is present, where it is located, its
minimum or average thickness, its extent of spatial and/or chemical continuity
around the core including the presence of small or large breaks, gaps or holes,
or whether MACP, PVP, omeprazole or its degradants (i.e., other species
capable of fluorescing in Dr. Davies’ system) may be present. In other words,
Dr. Davies cannot distinguish between the following scenarios, all of which are
consistent with the data;
(a)
A layer composed of complex that contains a quantity of a fluorescent
species below his ATR-IR detection limits (e.g., omeprazole degradants)
and continuous as a shell or corona around the core that has an average
thickness of 2 μm (i.e., his own interpretation);
(b)
Discrete patches of complex that are 500 nm thick within a minimum 2
μm-thick region that contains omeprazole degradants and other species; or
(c)
Any number of other possible geometries and/or species distributions,
117. For the same reasons, there are no
data in Dr. Davies report to support a conclusion that the “intense fluorescing
layer” detected within the bisected, enteric-coated pellets must also
contain a continuous layer of the complex.
[94]
Dr. Bright also considered Dr. Davies’
and Dr. Hawker’s CLSM data. He regarded Dr. Hawker’s sample
preparation to be preferable because it avoided exposing the pellets to resin.
Dr. Bright plotted radial intensity profiles across three vectors for two
of the Hawker CLSM 10X resolution images. In each case for two of the three
measured profiles the fluorescent intensity of the sublayer was said to be no
higher than that of the core region. Dr. Bright attributed this to a
discontinuity in the sublayer. Dr. Bright concluded that the Hawker
images “show significant discontinuity” at the
core-enteric coating interface “that is inconsistent
with a continuous layer”. Dr. Bright summed up the Hawker data in
the following way:
136. In short, the NEW CLSM image data
demonstrate behaviour that is clearly inconsistent with the features of
Dr. Davies’ proposed subcoat. One or more fluorescing species (e.g.,
omeprazole degradation products) are amongst the more likely causes of the
observed fluorescence in all the CLSM images. The MACP-PVP complex is an
unlikely contributor to the fluorescence.
[95]
Dr. Bright questioned the value of
Dr. Davies’ visual inspection of the Apotex pellets. Not all of known
omeprazole degradants were likely to appear in the form of discolouration.
Accordingly, neither ATIR nor a visual inspection could rule out their presence
and Dr. Davies, therefore, failed to establish that his proposed sublayer “is inert by reason of not degrading omeprazole”.
[96]
Based on the assumption that, in 2004,
Dr. Davies had measured sublayer thickness at a single location on a
single pellet, Dr. Bright stated that the data were insufficient to allow
for any representative determination of thickness. Also, because
Dr. Davies had failed to establish what was fluorescing in the sublayer,
it was an inappropriate proxy for measuring the thickness of the complex.
Dr. Davies’ thickness measurements from 2011 were not sufficiently
documented for Dr. Bright to assess their representativeness.
Dr. Bright also noted that some of the 2011 thickness measurements were
less than 2 microns.
[97]
Dr. Bright’s assessment of Dr. Davies’
disintegration video was limited to the observation that since it had not been
established that a continuous layer of the complex existed in the sublayer
region, he could not agree that the video images showed the rapid
disintegration of the complex. Dr. Bright offered no other explanation
for what it was that was peeling away from the pellet core.
[98]
In response to Dr. Davies’ reply report,
Dr. Bright continued to assert that paper contamination may have “contributed” to the fluorescence that was observed in
his washed pellet samples. In response to Dr. Davies’ point that the
observed fluorescence was the same for the washed and unwashed pellets,
Dr. Bright raised the “possibility” that
the sources of the fluorescence for each could be different. Dr. Bright
did not indicate how this would occur but he, nevertheless, challenged
Dr. Davies’ assumption that the fluorescent species were the same.
[99]
Dr. Bright also continued to express a
concern that Dr. Davies’ use of adhesive resin may have had an effect on
the observed fluorescence and he pointed to traces of fluorescence in some of
Dr. Davies’ images at locations well away from the sample under
investigation.
[100] Dr. Bright asserted in his Sur-reply report that
Dr. Davies made a critical error by assuming that the Apotex pellets were
completely opaque. The pellets could not be completely opaque because
Dr. Davies’ raw CLSM data were detected from well below the surface of the
samples. Dr. Bright went on to give several examples from the data to
show that Dr. Davies was wrong about the opacity of the samples and to
illustrate “major breaks and defects” in the
fluorescence from below the pellet surface [Figure 3]. This, in turn, led
Dr. Bright to consider the possibility that Dr. Davies had used
maximum intensity projections that had an obscuring effect and prevented a
proper assessment of fluorescent continuity and thickness. After reviewing the
raw CLSM data, it became clear to Dr. Bright that Dr. Davies had used
maximum intensity projections for some of his CLSM images. Dr. Bright
then went on to explain in detail how maximum intensity imaging can create a
false visual impression of homogeneity. He described Dr. Davies’ approach
as “highly inappropriate” and a “manipulation of data”. Nevertheless, he was able to
use these images at 10X magnification to illustrate the presence of
discontinuities in the fluorescence sublayer [Figure 9] along with the gaps he
observed in Dr. Davies’ individual Z-scan images.
[101] In response to Dr. Davies’ point that he had not identified
sublayer discontinuities at the surface of the Z-scan images, Dr. Bright
referred to one such image where the intensity of the fluorescence did not vary
to a material degree as the scan progressed over the pellet surface.
Dr. Bright continued to assert that Dr. Davies had failed to
establish a correlation between the observed fluorescent ring and the presence
of the complex. Thus, Dr. Davies’ CLSM images showed only that some
unknown amount of an unidentified chemical species was fluorescing. According
to Dr. Bright, this disclosed nothing relevant about the continuity of the
complex. Dr. Bright agreed with Dr. Davies that any omeprazole
degradants in the sublayer would be in very small amounts but would still be capable
of producing significant fluorescence. He clarified that he was not suggesting
that the sublayer fluorescence was attributable to omeprazole degradants and
nothing else. He was merely saying that Dr. Davies could not reliably use
that fluorescence to establish the location of the complex.
[102] In examining the Temple University CLSM images, Dr. Bright
acknowledged that the fractured surfaces of the pellets created a less planar
surface than Dr. Davies’ microtomed pellets. In testimony he agreed that
the failure by Temple University to obtain multiple Z-scan images of each sample
weakened the available data [p 3949-3950, p 4155]. Dr. Bright did not
accept, however, that a surface irregularity could result in an inability to
detect a gap below the pellet surface. The gaps in fluorescence identified by
Dr. Bright below the pellet surface were more likely caused by a gap in
the subcoating layer.
[103] Dr. Bright addressed Dr. Davies’ point that because the
pellet cores do not fluoresce as brightly as the sublayer, the core
constituents (eg. omeprazole, omeprazole degradants and PVP) could not be
responsible for the sublayer fluorescent ring. Although Dr. Bright
seemingly accepted that in some of the CLSM images the sublayer fluorescence
was brighter than its surroundings, it was not always the case to a relevant
degree of confidence. It was, therefore, difficult for Dr. Bright to
conclude that increased intensity at the enteric coating core interface was due
to the complex or to magnesium salt rather than some other unknown chemical
species.
[104] In responding to Dr. Davies’ point that he had failed to offer
an explanation for the likely migration of core constituents into the sublayer,
Dr. Bright postulated that the sublayer fluorescence may result from a
chemical change to the core during enteric coating or afterwards. In response
to a question by the Court, he was unable to suggest other possibilities beyond
paper or resin contamination [p 3989].
[105] Dr. Bright addressed Dr. Davies’ clarification of his
thickness measurements. Dr. Bright seemingly accepted that
Dr. Davies had used a standard method but he continued to question whether
the data obtained were representative. He complained that Dr. Davies had
failed to provide enough information to allow for a meaningful assessment of
his work and he again criticized what he believed was Dr. Davies’ use in
2004 of a maximum intensity projection to measure sublayer thickness.
Dr. Bright appeared to accept, however, that Dr. Davies’ thickness
measurements in 2011 came from individual Z-scan images and not from maximum
intensity projections. Dr. Bright explained his failure to take his own
thickness measurements on the basis that he had insufficient 50X images to
obtain representative data and because Dr. Davies had failed to clearly
explain what he had done to take his measurements.
[106]
Dr. Griffiths was qualified as an expert in
analytical chemistry, photon spectroscopy, infrared spectroscopy and
instrumentation, particularly, including Fourier transform infrared
spectroscopy, Ramon spectroscopy and chromatography.
[107] Dr. Griffiths is very experienced in the field of spectroscopy
and, in particular, in the use and interpretation of infrared and fluorescence
microscopy. He had little experience in applying those techniques to
pharmaceutical products.
[108] Dr. Griffiths was asked to assess Dr. Davies’ data to
determine if they supported his conclusion that the Apotex pellets contain a
continuous and inert separating sublayer made up of the complex and the
magnesium salt of MACP, having a minimum thickness of 2 microns (or,
alternatively, with an average thickness of 2 microns) and that is soluble or
rapidly disintegrating in water. Dr. Griffiths was also asked to comment
on Dr. Davies’ analytical techniques including the levels of detection for
omeprazole degradants that were available from his testing equipment.
[109] Like Dr. Bright, Dr. Griffiths concluded that
Dr. Davies’ data were insufficient to support his opinions concerning the
continuity, thickness and distribution of any complex that may be present at
the enteric coating-core interface of the Apotex pellets. Dr. Griffiths’
analysis of the data indicated to him that “if there is
a layer of complex on the surface of the washed pellets”, it was either
not continuous or it was less than 2 microns thick and would not act as a
separating layer. He also stated that the presence of fluorescence could not,
as Dr. Davies seemingly suggested, be spacially equated with the complex.
Unidentified chemical species, possibly including omeprazole degradants, could
be the source of the observed fluorescence. These uncertainties led Dr. Griffiths
to challenge Dr. Bodmeier’s opinion that all of the Apotex omeprazole
pellets would contain Dr. Davies’ asserted subcoat layer.
[110] As with all of the other expert witnesses, Dr. Griffiths
acknowledged that fluorescence microscopy cannot be used to identify a
particular compound in a mixed sample. In contrast, subject to the limits of
detection, infrared spectroscopy can be used to identify specific compounds in
a sample of unknown composition.
[111] Dr. Griffiths asserted that Dr. Davies did not directly
elucidate the composition of the fluorescent layer depicted in his CLSM
images. Instead, Dr. Davies is said to have inferred from his limited ATIR
testing that the CLSM sublayer fluorescence is a continuous layer of the
complex and MACP salt.
[112] Dr. Griffiths pointed to the variation in Dr. Davies’ ATIR
spectra for the complex in both 2004 and 2011. This lack of uniformity
suggested that the “proposed” layer of complex
was either not uniform in thickness or that poor experimental conditions
existed. Dr. Griffiths also noted the presence of clear signs of
carboxylic acid in the washed pellet samples which indicated the presence of
MACP that had not reacted with PVP. This free MACP was said to be “presumably in contact with the core region”, meaning
the “proposed subcoat is not inert because acidic
groups would be in contact with the core and, omeprazole found in the core,
reacts with acidic groups”.
[113] Dr. Griffiths also identified a “large
amount of mannitol detected on the surface of the washed pellets” in
several of Dr. Davies’ ATIR spectra. This suggested to him that the
sublayer was either not continuous or was, in some locations, very thin.
[114] In Dr. Griffiths’ initial report, he characterized
Dr. Davies’ identification of MACP-magnesium salt in the sublayer as
having “no basis whatsoever”. According to
Dr. Griffiths, the ATIR “shoulder” that
Dr. Davies relied upon could not be magnesium salt because the same
feature was present in the spectrum obtained for the pure complex. The
firmness of this view was abandoned in Dr. Griffith’s testimony where he
acknowledged that the presence of magnesium salt was a possibility [pp 3373-3376].
[115] In Dr. Griffiths’ reports, he expressed reservations about the
actual presence of the complex at the enteric coating-core interface of the
Apotex pellets. Despite Dr. Davies’ ATIR data showing the presence of the
complex, Dr. Griffiths said that the complex “may
be present in some amount” [see paras 25 and 140], “if there is a layer of complex on the surface of the washed
pellets” [see paras 25 and 140] or “assuming
that MACP-PVP / MACP-Mg is present” [see para 25]. Nowhere in his
reports does Dr. Griffiths clearly acknowledge that the ATIR data proved
the presence of the complex in the Apotex sublayer. As with Dr. Bright,
Dr. Griffiths thought that Dr. Davies’ correlation of the CLSM
fluorescence data with the ATIR data, ostensibly to show continuity of the
complex, was speculative.
[116] Dr. Griffiths stated that the presence of omeprazole degradants
in the pellet sublayer could not be ruled out by the ATIR data. Degradation
products in the amounts reported by Apotex for its pellets would be below the
ATIR limits of detection but still be capable of fluorescing. The presence of
undetectable amounts of omeprazole degradants would establish that the sublayer
is not inert according to the definition of that term that Dr. Griffiths
was asked to assume.
[117] Dr. Griffiths challenged Dr. Davies’ sublayer thickness
measurements in several ways. He questioned the sufficiency of Dr. Davies’
measurements and the paucity of reported testing details. He also pointed out
that, in a few of the 2011 measurements, the reported thicknesses were less
than 2 microns.
[118] Several of Dr. Davies’ ATIR spectra for the washed pellets
disclosed the presence of mannitol. Dr. Griffiths proposed four possible
explanations for this result:
a.
the ATIR beam was detecting mannitol from below
the sublayer of 2 to 6 microns thick;
b.
mannitol was detected below a sublayer less than
1 micron thick;
c.
mannitol was present in the sublayer; or
d.
there are gaps in the sublayer that allowed the
ATIR beam to probe directly into the pellet core.
[119] Dr. Griffiths challenged Dr. Davies’ opinion that his ATIR
beam was capable of detecting mannitol below a 2 micron or greater sublayer thickness.
Dr. Griffiths concluded that Dr. Davies was relying on improper
calculations. His own calculations for the ATIR depth of penetration indicated
that “there is no way for the IR beam to see through a
thickness of 2 microns” given the presence of mannitol bands at 3400 cm-1
in the 2011 spectra. At that point in the spectra the depth of penetration was
said to be only 0.25 microns.
[120] Dr. Griffiths’ preferred explanation for the presence of
mannitol bands in some of Dr. Davies’ ATIR spectra was that gaps were
likely present in the sublayer such that the ATIR beam was able to probe the
pellet cores without sublayer interference. This explanation was said to be
consistent with the relative intensity of the mannitol and complex bands in the
2011 spectra. According to Dr. Griffiths, a gap in the sublayer was the
best explanation for the relatively high intensity of some of the observed
mannitol bands.
[121] Dr. Griffiths considered Dr. Davies’ video of the Apotex
washed pellets undergoing water immersion. Based on his view that
Dr. Davies had failed to establish a continuous layer of the complex was
present on the surface of the pellet cores, Dr. Griffiths was unprepared
to attribute any significance to the video beyond suggesting that what Dr. Davies
said was flaking off “could well be MACP”.
[122] Dr. Griffiths’ Reply report addressed matters addressed in
Dr. Davies’ and Dr. Bodmeier’s Reply reports.
[123] Based on the larger area of ATIR interrogation reported by
Dr. Davies, Dr. Griffiths concluded the sublayer gaps he had
previously identified were either more numerous or larger than he had initially
assumed. He also dismissed Dr. Davies’ contention that the mannitol bands
in the washed pellet ATIR spectra were detected beneath a 2-micron-thick
sublayer. These bands, he said, could only be explained by the presence of
gaps in the sublayer.
[124] Dr. Griffiths then set out in detail his calculation for the
depth of penetration for Dr. Davies’ ATIR instrument. He concluded, once
again, that mannitol bands in the area of 3300 to 3400 reciprocal centimetres
should not be seen if the core was covered by a layer that was more than 1
micron thick. This would be true for either his or Dr. Davies’ assumed
depth of penetration. This confirmed to Dr. Griffiths that mannitol was being
directly detected through gaps in the sublayer. In one spectrum, he estimated
the gaps represented about 40% of the area under interrogation. For two other
spectra, the gaps were said to be between 25% and 40% of the size of the ATIR
beam.
[125] Dr. Griffiths drew additional support for his belief from the
variation in intensity of the mannitol bands and from their relative strength.
In the presence of a continuous and uniform sublayer of more than 2 microns,
Dr. Griffiths would have expected to see more consistency and less
intensity in the mannitol bands. Much of this technical evidence was canvassed
in cross-examination about which more will be said later in these reasons.
[126] Dr. Kibbe holds a PhD in pharmaceutics. He is a Professor at
the Wilkes University School of Pharmacy. Among other accomplishments,
Dr. Kibbe acts in an advisory capacity to the Food and Drug
Administration. He was qualified as expert in pharmaceutics, pharmaceutical
doseage form design, development, and manufacture; including the evaluation of
the physical and chemical stability of formulations and the regulation of
pharmaceutical formulations, and pharmacokinetics.
[127] Dr. Kibbe’s definition of the person of skill was essentially
that of a pharmaceutical formulator or the equivalent professional with
experience in treating patients with gastric acid-related diseases. That
person would have at least two years of practical experience as a formulator in
addition to a Bachelor’s degree in pharmacy or a closely related discipline.
[128] Dr. Kibbe was retained by Apotex primarily to address validity
and construction issues. His first report described in detail the state of the
art concerning the use of enteric coatings to protect acid-sensitive compounds,
with particular reference to omeprazole. He noted that polymeric or “film” coatings were frequently used as early as the
1940’s to protect active pharmaceutical ingredients from prematurely degrading
in the stomach. Before 1986, such coatings were developed with various
solubility profiles in order to target a specific site of release along the
intestinal tract.
[129] The protective feature of polymeric coatings was said to lie in
their molecular structure – specifically the presence of acidic carboxyl groups
which makes them insoluble under acidic conditions but soluble in the higher pH
of the intestine. In more neutral conditions, the acidic groups ionize and
convert to a water soluble salt. Typically enteric coatings were and continue
to be tested by simulating the conditions of human ingestion. The product will
be exposed for 2 hours or more in acidic solution followed by a
measurement of how much of the API was released. If too much was released
(often set at 10%), the product would have failed the gastric acid resistance
test. If the product passes the gastric acid resistance test, it is exposed to
a buffer solution to determine whether the API is sufficiently released in
conditions that mimic intestinal pH. Assuming the product passes this test, it
is then exposed to accelerated storage conditions to ensure its long-term
stability. This can include a visual inspection for discolouration which may
indicate degradation.
[130] According to Dr. Kibbe, in the development of any
pharmaceutical formulation routine testing is always carried out to select
compatible ingredients and to avoid undesirable reactions. Where
incompatibilities are observed, alternate ingredients can be selected or the
offending ingredients can be separated in a variety of ways including the use
of subcoatings.
[131] Dr. Kibbe reviewed the 693 Patent against the background of
what would have been known by the person of skill on its date of issue,
December 3, 1991. He drew from the Patent disclosure that it was directed at
the discovery of an enteric coated doseage of omeprazole that is resistant to
degradation in the stomach and dissolves rapidly in the intestine. The skilled
person would also expect the formulation to be stable in storage conditions
(less than 10% omeprazole degradation) over a period of years.
[132] According to Dr. Kibbe, the person of skill knew before
December 1991 that omeprazole was acid sensitive and susceptible to rapid
degradation in acid media. He cited the Pilbrant reference from 1985 as the
source of this knowledge. With this knowledge the person of skill would know
that omeprazole required an enteric coating.
[133] Dr. Kibbe noted the teaching of the 693 Patent that direct or
indirect contact between the enteric coating and omeprazole in the core causes
omeprazole to decompose as manifested by discolouration and the loss of
omeprazole content over time. Discolouration was said to be a marker for
assessing the stability of the formulation examples tested by the inventors.
[134] According to Dr. Kibbe the person of skill already knew that omeprazole
could be stabilized for long-term storage by using an alkaline salt form of
omeprazole. This knowledge came from EP 495 referenced as prior art in the 693
Patent.
[135] Dr. Kibbe addressed the inventors’ use of an ARC as an
alternative means of improving the storage stability of omeprazole. This
approach was said by the inventors to cause the unwanted degradation of the
enteric coat from the diffusion of gastric juice through the enteric coat, resulting
in an undesirable reaction with the ARC. This reaction created an alkaline
environment that dissolved the enteric coat from the inside of the
formulation. According to Dr. Kibbe there was nothing surprising about
this problem. The person of skill would understand the observed difficulty and
would also be aware that a successful omeprazole formulation would require the
avoidance of absorbed moisture from any source. The means of minimizing water
content were routinely employed by pharmaceutical formulators including the use
of special packaging. The skilled person was also said to know from the 693
Patent that a separation between the enteric coat and the omeprazole containing
cores was necessary. In the absence of sufficient ARC, omeprazole would
degrade in storage and, in the presence of sufficient ARC, the enteric coat was
at risk of dissolution after ingestion. According to Dr. Kibbe the Patent
examples teach that it is not possible to achieve good gastric acid resistance
and good long-term stability in an omeprazole formulation where the enteric
coating is applied directly to the alkaline cores. The problem is overcome by
the use of a separating subcoating that is vital to the success of the
preparation.
[136] Dr. Kibbe contended that the person of skill would understand
that the subcoating must be a continuous layer to prevent the enteric coating
from contacting the core “at any stage during the
manufacturing process or thereafter”. It would also be understood that the
subcoat “is not to be a water insoluble material”
and it must be “inert” in the sense “it should not react with either the core or enteric coating
constituents”. To be inert, the subcoating “should
not contain optional alkaline reacting compounds” or be made of any
anionic material unless covered by a second subcoating devoid of such
materials. According to Dr. Kibbe a further essential feature of the
subcoating is a minimum thickness of 2 microns.
[137] Dr. Kibbe noted that an essential teaching of the Patent was to
maintain a low water content in the final doseage form and preferably not more
than 1.5% by weight. He referred to the Patent examples showing considerable
omeprazole degradation in the presence of water concentrations of 2% and 5%
with successful storage stability achieved at a water level of 1%. He took
this to be a teaching that any formulation with a concentration of 2% or more
of water would lack stability.
[138] Dr. Kibbe went on to consider the 693 Patent claims. The
person of skill would know that an “effective amount”
of omeprazole or its alkaline salt form was an amount that achieved the desired
therapeutic effect. The words “disposed on”
meant applied to or placed on the core. “Inert”
meant the subcoat “does not adversely affect omeprazole
or the other ingredients in the core or in the outer enteric coating”.
[139] Dr. Kibbe was asked to compare the subject matter of the 693
Patent claims to EP 495. EP 495 describes alkaline salts of
omeprazole said to have improved storage stability over neutral omeprazole. It
also describes various formulations including enterically coated doseage forms
and gelatine capsules. According to Dr. Kibbe, the EP 495 claim to
enterically coated gelatine capsules containing an omeprazole salt describes a subject
matter covered by Claim 1 of the 693 Patent. EP 495 also provides the
person of skill with sufficient information to prepare the claimed composition
with no more than routine testing.
[140] Dr. Kibbe was asked to comment on how the person of skill would
interpret the promise of utility of the 693 Patent and whether the claimed
formulations have the promised utility. He stated that the Patent promises
omeprazole formulations with good gastric acid resistance, rapid dissolution in
neutral to alkaline media and good long-term storage stability against
degradation and discolouration. As to whether the 693 Patent delivers on those
promises, Dr. Kibbe said it did not. He asserted that Claim 2 of the
Patent contemplates formulations which include the presence of an alkaline
reacting compound in the subcoating. These formulations would, however, only
have good long-term storage if a second subcoating was employed. Since the
Patent did not appropriately limit the use of an ARC in the subcoating layer,
Claims 1, 5, 6, 11 to 13, 18 and 19 necessarily include preparations lacking
the promised characteristic of good long-term storage stability.
[141] A similar argument was advanced by Dr. Kibbe with respect to
water content. Despite the advice in the Patent disclosure that it is critical
to keep the water content low, the scope of Claim 1 was not limited in any
way with respect to water content. Claim 13, however, covers a
formulation which limits water content to 1.5% or less. Dr. Kibbe
asserted Claim 13 is rendered redundant if Claim 1 is interpreted as
being similarly limited. This led Dr. Kibbe to the view that Claim 1
would be interpreted by the person of skill to be unlimited with respect to
water content. Since omeprazole preparations having a water content of more
than 2% were shown to be unstable, Claims 1, 5, 6, 11, 12, 18 and 19
necessarily lack the promised utility of good long-term storage stability.
Claim 13 also fails, according to Dr. Kibbe, in the absence of any
evidence of a useful omeprazole formulation with a water content as high as
1.5%. On the basis of the testing reported in the Patent, the inventors had no
basis to soundly predict the utility of an omeprazole formulation with a water
content any greater than 1%.
[142] Although none of the Patent claims specify a minimum subcoat
thickness, the disclosure states that a thickness value not less than 2 microns
is required for a pellet formulation. According to Dr. Kibbe the person
of skill would nevertheless interpret the claims to include subcoatings
less than 2 microns thick and, therefore, Claims 1, 5, 6, 11 to 13, 18 and
19 encompass more than what is disclosed for utility.
[143] Dr. Kibbe expressed the opinion that the 693 Patent
claims would have been obvious to the person of skill as of April 30,
1986. His obviousness analysis includes the following assertions:
a.
All of the information in the Background section
[paras 33-62] of the 693 Patent would have been known to the person of
skill;
b.
Omeprazole and its salts were known to be useful
to treat gastric acid-related diseases;
c.
Omeprazole was known to be sensitive to acid and
to degradation from high temperatures and high humidity;
d.
Water content was a known concern and was
something the skilled formulator routinely seeks to control;
e.
The person of skill would know storage stability
for an omeprazole formulation could be improved with the creation of an
alkaline environment around the omeprazole molecules and by reducing water
content;
f.
Omeprazole salts were known to be more stable
than neutral omeprazole;
g.
The use of alkaline compounds with benzimidazole
formulations was known in the prior art. The person of skill knew that
omeprazole was very closely related to other benzimidazole formulations where
alkaline reacting compounds had been used. Although this prior art did not
expressly identify the purpose of using an ARC, the person of skill knew that
it was used to improve the stability of the API;
h.
The use of enteric coatings in conjunction with
plasticizers was widely known and routinely done;
i.
The use of subcoatings to avoid adverse
pharmaceutical reactions was known; and
j.
The potential for an adverse reaction between
enteric coating polymers and alkaline materials was well-known along with the
avoidance of their incompatibility with non-reactive undercoats.
Based on the foregoing understandings,
Dr. Kibbe concluded that there was no inventive difference between the
state of the art on April 30, 1986 and the inventive concept of Claim 1 of
the 693 Patent or its dependant claims.
[144] Dr. Kibbe concluded his report by stating that the 693 Patent
teaches away from the direct application of an enteric coating to the
omeprazole containing cores. He was aware of nothing in the prior art
describing an in situ
subcoating layer and thus the person of skill would have no cause to consider
that possibility or the information required to make it. Furthermore, there is
nothing in the Patent to show that such a subcoating would actually work or be
predicted to work. On the issue of prediction Dr. Kibbe stated:
265. It is impossible in my view to
predict all of the potential reactions that might occur between potential
excipients within the alkaline core or between any one or more of those
excipients and an enteric coating polymer. It is thus impossible to predict
whether any inert, water soluble reaction product formed by the interaction of
excipients or film-forming polymers which might arise at the interface of the
core and the outer coating - whether ionic or covalently bound material, or a
complex of one or more substances bound by weak or strong forces - would confer
on the resulting formulation good gastric acid resistance and good long-term
storage stability to degradation/discoloration.
All of this Dr. Kibbe contrasted with
the teaching of the subsequently issued 037 Patent. The 037 Patent
specifically describes an omeprazole formulation with an in situ subcoating and the means to make
it. According to Dr. Kibbe this supports his view that such formulations
were not part of the 693 Patent invention.
[145] Dr. Kibbe’s Reply Report addresses Dr. Bodmeier’s evidence
that the person of skill would not equate a gelatine capsule with the
subcoating described in Claim 1. Dr. Kibbe took a contrary view.
The person of skill would not identify a distinction between a separating layer
describing a gelatine capsule and a subcoating layer. Both served the same purpose
of effecting a separation.
[146] Dr. Kibbe’s Further Expert Report discusses the potential
presence of omeprazole degradants in the Apotex omeprazole product and the
limitations inherent in their detection by visual inspection. Some degradation
of omeprazole would be expected from the process of manufacture. In response
to Dr. Bodmeier’s opinions on subcoating continuity and inertness,
Dr. Kibbe stated that the person of skill would contemplate some variation
in thickness but not breaks in continuity and would not accept the presence of
any material that could lower pH, such as acidic functional groups.
[147] Dr. Amos is an Emeritus Research Staff Member at the Medical
Research Council, Laboratory of Molecular Biology at Cambridge University. He
has a PhD in the field of cell biology but the major focus of his research for
more than 30 years has been in the area of optical microscopy. He, along with
others, was instrumental in the development of the confocal laser scanning
microscope. He has lectured and published extensively on the theory and
practice of confocal microscopy. However, before this case, he had never used
the equipment to analyse the structure of a pharmaceutical doseage form.
[148] Dr. Amos was accepted as an expert in optical microscopy with
particular expertise in the theory and practise of CLSM.
[149] Dr. Amos was asked by Apotex to consider Dr. Davies’
various reports and his imaging results. For comparison purposes, he was also
asked to review CLSM imaging conducted at Temple University. He did no testing
of his own.
[150] A particular focus of Dr. Amos’ assessment had to do with
Dr. Davies’ methods and his analysis of the imaging results concerning the
presence and structure of a subcoating layer in the Apotex omeprazole pellets.
[151] Dr. Amos criticized Dr. Davies for a supposed error concerning
the opacity of the imaged specimens. Dr. Amos said that Dr. Davies
was wrong in saying the specimens were totally optically opaque. Much of his
report was then dedicated to proving why Dr. Davies was wrong on this
point [see paras 40 to 52].
[152] While Dr. Amos recognized the presence of a band of
fluorescence in the region between the pellet cores and the enteric coating, he
stated Dr. Davies’ 10x images were not suitable for assessing the continuity
of that band.
[153] After examining Dr. Davies’ 50x images, Dr. Amos concluded
the depicted subcoating “clearly shows
microheterogeneity and possible holes or a flaky structure”.
Dr. Amos criticized Dr. Davies for not using a frame averaging
technique to improve the quality of his images.
[154] While recognizing that the Temple University images were not
obtained as a Z-scan series, Dr. Amos observed that, where those images
were in focus, gaps similar to those seen in Dr. Davies’ images could be
seen.
[155] Dr. Amos also considered the quality of Dr. Davies’ images
for purposes of measuring the thickness of the observed fluorescent band. At
paragraph 76 of his report, he said that he could see nothing in
Dr. Davies’ reports to suggest that measures were taken to avoid image
saturation. Dr. Amos tested one of Dr. Davies’ images and found it
to be strongly suggestive of saturation. Dr. Amos also noted “it seems likely that many of the ‘images’ used by
Dr. Davies to assess continuity and for thickness measurements may in fact
be projections of all of the confocal images from many levels”. Such a
use of projections was said to be “highly inappropriate”,
“unjustified”, and “misleading”.
In testimony, Dr. Amos said these particular data were “manipulated”. Dr. Amos also described
Dr. Davies supposed use of projected images to measure the thickness of
the fluorescent band as invalid.
[156] Under cross-examination, Dr. Amos acknowledged that he made no
inquiries about Dr. Davies’ methods.
[157] With respect to the analysis of the continuity of the observed
fluorescent band, Dr. Amos acknowledged the following points:
a.
The presence of large gaps can be produced by a
gross loss of focus [p 3038];
b.
The large gaps in the zone of fluorescence in
the Temple University CLSM images are due to a loss of focus [p 3046,
pp 3063-3064];
c.
The CLSM signal will diminish at depth
[p 3047];
d.
The value of the Temple University images was
diminished by the failure to make a full Z series [p 3048, p 3059];
e.
Some of the images Dr. Bright had used to assess
continuity of the fluorescent band were not suitable for that purpose
[p 3051];
f.
The opacity of the sample will give an
appearance of low fluorescence due to signal absorption at depth [p 3071]
– an effect that may not be uniform [p 3075];
g.
CLSM 50x images are better for assessing small
scale continuity and thickness [pp 3078-3079];
h.
All other things being equal, 50x images are
better than 10x images for assessing continuity and thickness [p 3082];
i.
Dr. Amos had not included any 50x in-focus
images taken at the surface of a sample in his report [p 3197];
[158] Dr. Amos was questioned about a montage of images he had put
together during Dr. Davies’ cross-examination. On a number of those
images, he had placed question marks beside perceived anomalies. When asked
about these images and his apparent equivocation, he gave the following
answers:
Q. The image
beside AP5417 1, you agree that the confocal section of this image was not at
the surface of the bisected pellet?
A. I agree.
Q. The image
was taken below the surface of the bisected pellet?
A. It, it,
it may well have been below the surface because I don't see the telltale
reflection artifact that one sees at the surface.
Q. And you
don't know how far down this image was taken?
A. I don't.
Q. Will you agree
that where you have arrows with "hole" followed by a question mark,
that there is pale fluorescence in those regions?
A. Certainly.
Q. And when
you use the question mark, would you agree that it is possible that the
features that you identify as holes are not, in fact, holes?
A. Yes.
Q. And can I
take it that that's the same for the other two montages?
A. Yes.
Although as I said before, I think that the montage of Stub 12 is different
from the others in that it is clearly very close to the surface.
Q. I will
take you to that.
MR. HACKETT: This
isn't an objection, but my friend said they are the same. I just don't know if
it's perfectly clear now, especially in light of what Mr. Biernacki said about
"we will come to the last one", what he means by "same".
Maybe we should have just a bit of clarity on that.
MR. JUSTICE
BARNES: It is up to Mr. Biernacki. I suppose if he doesn't want to go there,
you can go to it in re examination.
MR. HACKETT: Fair
enough, good.
BY MR. BIERNACKI:
Q. By
"same", I was referring to your use of the labels and the meaning of
the question mark. Is that what you understood me as asking, Dr. Amos?
A. Yes. And
so my answer is, yes, the label and the question mark has the same significance
in all of the images in these montages.
Q. Thank
you.
And perhaps we can
short circuit this. With the exception of Stub 12, which I will come to
specifically, do you agree that none of the remaining three images in the other
two montages are from the surface of a bisected pellet?
A. Yes.
Q. And would
you agree that you do not indicate how far below the bisected pellet those
images were taken?
A. I do
not. In other words, I do not indicate.
[159] In describing the effect of signal attenuation, Dr. Amos
provided the following useful analogy:
A. Absorbant
material quite widespread causing attenuation, and it is something that you see
in hollow shells and spirals and objects of all kinds, also in totally
homogeneous materials.
Now, I think if you
- - let me see. Let's suppose you have the misfortune to be involved in an
avalanche and snow piles up on top of you. As the snow covers you, you will,
at first, be able to see light. Then as the layer gets thicker and thicker,
you will see less and less. We would not say that you are in a shadow there.
We would say that there is absorption, in general, above you, and so you are
receiving less light.
I think it is a
difference in the lateral extent of the effect that is crucial here.
Q. You
accept that absorbant material can reduce signal below it in CLSM; correct?
A. Absolutely.
[160] The outcome of this case turns on several issues of claims
construction. These are matters of law for the Court to determine, to a
greater or lesser extent, with the aid of expert witnesses: see Pfizer
Canada Inc v Canada (MOH), 2007 FCA 209 at para 39, [2007] FCJ no 767
(QL). The first step in a patent suit is always to construe the claims without
regard to issues of validity or infringement.
[161] The parties agree that the construction of patent claims must be
carried out purposively and in accordance with the principles discussed in Whirlpool
Corp v Camco Inc, 2000 SCC 67 at paras 55-56, [2000] 2 S.C.R. 1067 [Whirpool],
and Free World Trust v Électro Santé Inc, 2000 SCC 66, [2000] 2 S.C.R. 1024
[Free World].
[162] I have previously discussed the principles that apply to the
construction of claims language in Bristol-Myers Squibb Canada Co v Mylan
Pharmaceuticals ULC, 2012 FC 1142 at paras 67-72, 222 ACWS (3d) 230
and I apply those principles here:
[67] Claims language is a critical
component of the public notice requirement and subsection 27(4) the Patent
Act, RSC 1985, c P-4, emphasizes its importance:
27.(4) The specification must end
with a claim or claims defining distinctly and in explicit terms the
subject-matter of the invention for which an exclusive privilege or property
is claimed.
|
27.(4) Le mémoire descriptif se termine par
une ou plusieurs revendications définissant distinctement et en des termes
explicites l’objet de l’invention dont le demandeur revendique la propriété
ou le privilège exclusif.
|
[68] The
Supreme Court of Canada emphasized the purpose and importance of requiring
clear language in the drafting of patent claims in Free World, above, at
paragraphs 14, 15 and 42:
14 Patent claims are
frequently analogized to "fences" and "boundaries", giving
the "fields" of the monopoly a comfortable pretence of bright line
demarcation. Thus, in Minerals Separation North American Corp. v. Noranda
Mines, Ltd., [1947] Ex. C.R. 306, Thorson P. put the matter as follows, at p. 352:
By his
claims the inventor puts fences around the fields of his monopoly and warns the
public against trespassing on his property. His fences must be clearly placed
in order to give the necessary warning and he must not fence in any property
that is not his own. The terms of a claim must be free from avoidable ambiguity
or obscurity and must not be flexible; they must be clear and precise so that
the public will be able to know not only where it must not trespass but also
where it may safely go.
15 In reality, the
"fences" often consist of complex layers of definitions of different
elements (or "components" or "features" or
"integers") of differing complexity, substitutability and ingenuity.
A matrix of descriptive words and phrases defines the monopoly, warns the
public and ensnares the infringer. In some instances, the precise elements of
the "fence" may be crucial or "essential" to the working of
the invention as claimed; in others the inventor may contemplate, and the
reader skilled in the art appreciate, that variants could easily be used or
substituted without making any material difference to the working of the
invention. The interpretative task of the court in claims construction is to
separate the one from the other, to distinguish the essential from the
inessential, and to give to the "field" framed by the former the
legal protection to which the holder of a valid patent is entitled.
…
42 The patent system is designed
to advance research and development and to encourage broader economic activity.
Achievement of these objectives is undermined however if competitors fear to
tread in the vicinity of the patent because its scope lacks a reasonable
measure of precision and certainty. A patent of uncertain scope becomes "a
public nuisance" (R.C.A. Photophone, Ld. v. Gaumont-British Picture Corp.
(1936), 53 R.P.C. 167 (Eng. C.A.), at p. 195). Potential competitors are
deterred from working in areas that are not in fact covered by the patent even
though costly and protracted litigation (which in the case of patent disputes
can be very costly and protracted indeed) might confirm that what the
competitors propose to do is entirely lawful. Potential investment is lost or
otherwise directed. Competition is "chilled". The patent owner is
getting more of a monopoly than the public bargained for. There is a high
economic cost attached to uncertainty and it is the proper policy of patent law
to keep it to a minimum.
[69] Notwithstanding the above
cautions, the law is clear that a purposive approach requires the Court to
examine claim language in the sense that the patentee is presumed to have used
it and not through the lens of strict literalism. Even a term that appears to
be plain and unambiguous may, when read in the context, reasonably support a
different meaning. Whirlpool, above, also counsels that the search for
meaning is not carried out through the eyes of a grammarian, but rather in
light of the common knowledge of the person of ordinary skill in the field to
which the patent relates. Thus, it is permissible to look to the patent
disclosure to ascertain the technical meaning of terms used in the claims.
[70] I have no difficulty with the
point that purposive construction is capable of expanding or limiting a literal
text: see Whirlpool, above, at para 49. It seems to me, though, that
there is some judicial concern about importing essential features of an
invention from the disclosure to the claims, particularly where the disclosure
is somewhat unclear about the scope of the invention. In other words, even if
one resorts to the disclosure to interpret the claims “the precise and exact
extent of the exclusive property and privilege claimed” must always be
identifiable: see Consolboard Inc v MacMillan Bloedel (Saskatchewan) Ltd,
[1981] 1 S.C.R. 504 at para 26, 122 DLR (3d) 203.
[71] In BVD Co v Canadian Celanese
Ltd, [1937] S.C.R. 441, [1937] 3 DLR 449 [BVD], the Court declined to read
into a patent claim an “essential” feature of an invention and struck the
patent down because the claims, as written, exceeded the scope of the
invention. This decision predates the decisions in Whirlpool and Free
World, above, and their elaboration of the principles of purposive
construction. Nevertheless, BVD has not been overruled and it continues
to underscore the importance of ensuring that a patent clearly delineates the
subject matter of an invention and the importance of the claims language in
achieving that end: see also Apotex Inc v Sanofi-Synthelabo Canada Inc,
2008 SCC 61 at para 77, [2008] 3 S.C.R. 265; Amfac Foods Inc v Irving Pulp
& Paper, Ltd, [1986] FCJ no 659 (QL), 72 NR 290 (CA).
[72] What I take from the authorities
is that resort to the disclosure is permissible, but only for the purpose of
comprehending the meaning of words or expressions found in the claims.
Essential information that is contained in the disclosure that is not relevant
to the search for meaning of claims language cannot be imported by implication
to qualify the claims: see Janssen-Ortho Inc v Canada (MOH), 2010 FC 42
at para 119, 361 FTR 268 [Janssen-Ortho]. It is also not appropriate to
ascribe meaning to words in the claims by reference to “stray phrases” found in
the disclosure: see Electric & Musical Industries, Ltd v Lissen Ltd,
[1938] 4 All ER 221 at p 227, 56 RPC 23 (HL (Eng)).
I would add to the above that the claims and
the specification serve different purposes. The former describe the limits of
the asserted monopoly and the latter describes the invention.
[163] There is no dispute that the Apotex product contains omeprazole and
an ARC in the pellet cores. There is also no disagreement that Apo-Omeprazole
is enterically coated. The parties disagree, however, about the meaning of several
terms that are found in Claim 1 with reference to the disclosed
subcoating. In particular, they disagree about the meaning of “inert”, “subcoating”
and “disposed on”. Apotex’s principal argument
is that, on a purposive reading of Claim 1, a subcoating that forms in situ from a chemical reaction is not
covered. According to Apotex, Claim 1 covers only a subcoating that is
physically applied to the pellet core and which is wholly free of holes, gaps
or structural anomalies. A sublayer that forms from a chemical reaction is not
a “subcoating” nor is it “disposed on” the core.
[164] Apotex also asserts that the person of skill would interpret “inert” as it applies to the subcoating to be a
compound that is wholly unreactive with any of the other constituents of the omeprazole
pellet whether or not there are functional implications.
[165] AstraZeneca maintains that Claim 1 is a product claim. It
covers a class of omeprazole formulations defined by three basic structural
elements:
a.
An omeprazole core region that can include an
alkaline reacting compound;
b.
An inert subcoating; and
c.
An outer enteric coating.
AstraZeneca says that if these basic
elements are present and if they constitute a viable formulation, it does not
matter how the structure is formed. In particular, a subcoating that forms in situ from a reaction between the core
and the enteric coating is a matter of process that does not circumscribe or
limit the claim to the product.
[166] AstraZeneca also asserts the requisite subcoating need not be perfect.
It can contain minor gaps, holes or defects provided its functional integrity
is not compromised.
[167] AstraZeneca makes a similar argument about the meaning of “inert”. The person of skill would interpret this
word to mean a compound that will not cause a deleterious reaction with either
the enteric coating or with the omeprazole core. According to this view, the
word is not used in Claim 1 in its purest scientific sense but in a
relative way, teaching the person of skill to avoid materials that will lead to
undesirable reactions.
[168] Apotex raises a number of interesting grammatical points in support
of its argument that Claim 1 does not include a subcoat which forms in situ. Most of these arguments are drawn
from the language of the disclosure and not directly from the language of the
claims. This, it says, is consistent with current jurisprudence emphasizing
the importance of using the disclosure as a guide to the purposive
interpretation of claims language.
[169] Apotex advances the following points in support of its favoured
construction:
a.
In the pharmaceutical arts, a coating is a
covering that is physically applied to a formulation (from the verb “to coat”); coatings formed in
situ were not known in the art
at the time.
b.
The words “disposed on”
and “selected from” connote a deliberate choice
of materials to be applied to the product and not to in
situ reaction products.
c.
The Patent disclosure teaches away from the
direct application of an enteric coat to the pellet core to avoid the very
reaction problem that the patent formulation is said to solve.
d.
The Patent discloses only processes of direct
application of a subcoating layer and nowhere discloses or enables an in situ reaction product.
e.
The properties and performance of an in situ reaction product would be difficult
for a formulator to evaluate or control.
f.
The decisions in Rhoxalpharma Inc v Novartis,
2005 FCA 11, 3 FCR 261, and Miken Composites, LLC v Wilson Sporting Goods Co,
515 F 3d 1337 (Fed Cir 2008), recognize that what may, at first blush, appear
to be process limitations can be, in fact, structural limitations.
g.
On reading the 693 Patent, the skilled
formulator would never contemplate that it covered a subcoating formed in situ and neither did the inventors.
[170] None of the experts who were asked to interpret the disputed claims language
provided much in the way of specialized insight. For example, Dr. Kibbe
and Dr. Bodmeier agreed the phrase “disposed on”
was not a term of art in the world of a formulator. The remainder of the
arguments advanced by the parties concerning the scope of the word “subcoating” are largely matters of grammar and
context where expert opinion adds little, in any, interpretive value. Although
the experts gave their respective opinions, they were essentially conclusions.
[171] A significant impediment to Apotex’s construction argument is the
decision by the Federal Court of Appeal in Apotex Inc v AB Hassle, 2003
FCA 409, 126 ACWS (3d) 690. That decision arose from a proceeding brought by AstraZeneca
under the Patented Medicines (Notice of Compliance) Regulations concerning the
693 Patent. AstraZeneca had prevailed on the application on the strength of an
argument that Apotex’s Notice of Allegation was legally deficient. Accordingly,
the application Judge found it unnecessary to construe the language of Claim 1.
[172] When the matter came before the Federal Court of Appeal, Apotex
argued that the application Judge erred by failing to construe the disputed claims language
– the same language contested here. It also argued that the application Judge
erred by finding its Notice of Allegation to be legally deficient.
[173] The same interpretation arguments advanced by Apotex to the Federal
Court of Appeal were advanced to me. Each of those arguments was rejected. The
decision by Justice Marshall Rothstein bears repeating in substantial
measure:
[14] There is no issue about paragraphs
(a) and (c) of claim 1. It is paragraph (b) that is in controversy. Apotex says
that paragraph (b) does not cover inert material formed between the core and
enteric outer layer in situ
from reaction between certain components of the core and the enteric outer
layer. Rather, Apotex submits that paragraph (b) only covers a subcoating which
is applied to the core and which is then covered by the enteric outer layer.
[15] In support of this interpretation
of paragraph (b), Apotex relies upon certain paragraphs of the patent
disclosure. Apotex says that the patent disclosure excerpts upon which it
relies indicate that the scope of the invention described in patent claim 1
only covers a product in respect of which the intermediate subcoating is
applied to the core before the outer enteric coating is applied to the
subcoating. Apotex says that the description of the product requires the core
and the enteric coating to never come into contact with each other. Rather, it
says the core and enteric coating must be separated during the coating process,
as well as during storage. The excerpts relied upon by Apotex are:
Outline of the invention
Cores containing omeprazole mixed with
alkaline compounds or an alkaline salt of omeprazole optionally mixed with an
alkaline compound or coated with two or more layers, whereby the first
layer/layers is/are soluble in water o [sic] rapidly disintegrating in water
and consist(s) of non-acidic, otherwise inert pharmaceutically acceptable
substances. This/these first layer/layers separates/separate the alkaline
core material from the outer layer, which is an enteric coating (page 4).
Separating layer
The omeprazole containing alkaline
reacting cores must be separated from the enteric coating polymer(s) containing free carboxyl groups, which otherwise cause
degradation/discolouration of omeprazole during the coating process or
during storage (page 6).
Enteric coating layer
The enteric coating layer is applied onto
the sub-coated cores by conventional coating
techniques such as, for instance, pan coating or fluidized bed coating using
solutions of polymers in water and/or suitable organic solvents or by using
latex suspensions of said polymers (page 7).
The cores are coated with an inert
reacting water soluble or in water rapidly disintegrating coating, optionally containing a pH-buffering substance, which separates
the alkaline cores from the enteric coating.... the subcoated dosage form is
finally coated with an enteric coating rendering the dosage form insoluble
in acid media, but rapidly disintegrating/dissolving in neutral to alkaline
media such as, for instance the liquids present in the proximal part of the
small intestine, the site where dissolution is wanted.
...
Process
A process for the manufacturer [sic] of the
oral dosage form represents a further aspect of the invention. After the
forming of the cores the cores are first coated with the separating layer and
then with the enteric coating layer. The coating is carried out as
described above (pages 8 and 9). [Emphasis in original]
Apotex further argues that of all the
examples shown in the patent, none disclose a subcoating formed in situ from the reaction of components in
the core and enteric coating.
[16] I have some difficulty with
Apotex's reliance on the patent disclosure. In this case, patent claim 1, as a
product claim, appears to be clear and in such a case, it is not appropriate to
look to the disclosure to construe the claim and, in particular, to vary the
scope or ambit of the claim (Dableh v. Ontario Hydro, [1996] 3 F.C. 751
at paragraph 30 (C.A.)). I will, therefore, first construe claim 1 itself.
However, since Apotex largely rested its case on the patent disclosure, I will
then deal with Apotex's argument based on the disclosure.
[17] Claim 1 describes an "oral
pharmaceutical preparation" or, in every day language, a tablet. The
tablet is described as having a core region, an inert subcoating and an outer
layer or enteric coating. Claim 1 does not purport to place any limitations on
the inert subcoating. It does not say that the inert subcoating must be created
in any particular manner.
[18] Claim 1 does provide that the inert
subcoating is to be "disposed on said core region". Apotex says this
must mean that the core is coated with the subcoating or that the subcoating is
placed on or applied to the core. Apotex says this is not just a process
limitation but a limitation on the product which would exclude a tablet whose
inert separating layer was formed in situ by the reaction of certain materials in the core and enteric
coating.
[19] The evidence of Dr. Rees, expert
for Astra, was that the term "disposed on said core region" should be
construed to describe the need to have a subcoating located between the core
and the enteric coating in the finished preparation. The evidence of Apotex's
experts, Dr. Niebergall and Dr. Schnaare, was that, since the purpose of the inert
subcoating was to avoid any reaction between the enteric coating and the
medicinal core, the product of a reaction between the enteric coating and the
core could never be a subcoating within the meaning of the patent. Dr.
Niebergall further stated that a reaction between the enteric coating and the
core could never produce a continuous subcoating at least 10 μm thick,
which he believed the patent required.
[20] In respect of the required
thickness of the subcoating, it appears that Dr. Neibergall misread the disclosure.
The disclosure indicates that the thickness of the separating layer cannot be
less than 2 μm, although a greater thickness is preferable. His evidence
does not say that a 2 μm thickness could not be formed in situ.
[21] I would give greater weight to Dr.
Rees's evidence. Because claim 1 is clearly a product claim and not a process
claim, I construe the term "disposed on said core region" as
describing the structure of the finished pharmaceutical preparation. The term,
in the context of a product claim, describes the location of the subcoating and
not the process by which it was formed.
[22] If, as I construe it, claim 1
describes a finished product, nothing in the disclosure detracts from the
interpretation that the inert subcoating need not be formed by any particular
process or formation. In the finished product, a subcoating applied to the core
or a subcoating formed in situ would separate the core from the enteric coating. That the
disclosure provides that the core and enteric coating must be separated
"during the coating process" might help to construe an ambiguous
process claim. But I do not see those words as having any application to a
claim that clearly describes a finished product. Similarly, the other
references in the disclosure relied upon by Apotex describe one process for
making the pharmaceutical preparation - sequentially applying the subcoating to
the core and then the enteric coating to the subcoating. But nothing in claim 1
purports to place a process limitation on the finished pharmaceutical
preparation.
[23] Apotex argues that such a
construction is inconsistent with the disclosure because the very problem the
invention was designed to solve is that direct contact between the omeprazole
core and the enteric coating results in discolouration and the eventual
degradation of the core. However, the patent goes on to teach that this storage
stability problem can be solved by adding sufficient alkaline reacting
constituents to the core. A subcoating is only needed to prevent the premature
dissolution in the stomach of the enteric coating of tablets with an alkaline
core. That problem only occurs when the tablet is ingested and thus claim 1
does not preclude the core and the enteric coating from coming into contact
during the manufacturing process so long as a subcoating exists in the final
product.
[24] I conclude that patent claim 1
describes a pharmaceutical preparation which, in its finished product form,
contains a subcoating or separating layer between the core and enteric coating,
however the subcoating or separating layer is formed.
[174] This decision was subsequently applied by Justice Carolyn
Layden-Stevenson in NOC proceedings in AB Hassle v Genpharm, 2003 FC
1443, [2003] FCJ no 1910, and, later, in AB Hassle v Apotex, 2005 FC 234,
2005] 4 FCR 229.
[175] I accept Apotex’s point that a decision by the Federal Court of
Appeal in a NOC proceeding is provisional only, and it does not bind me. On
the other hand, in a case like this where the construction issues are not to be
resolved on the strength of much, if any, specialized knowledge, the unanimous views
of the Federal Court of Appeal carry some persuasive weight.
[176] Apotex argues that more recent Supreme Court of Canada jurisprudence
recognizes the increased importance of the disclosure in the purposive
construction of claims language. At the time of Justice Rothstein’s
decision, resort to the disclosure was, as he noted in paragraph 16, more
limited. The difficulty with this point is that, notwithstanding Justice
Rothstein’s observation that resort to the disclosure was not justified, he
went on to address Apotex’s disclosure-based arguments and rejected them all.
[177] Additional support for this construction holding can be found in the
decision of the United States District Court in Astra Aktiebolag v Andrx
Pharmaceuticals Inc, 222 F Supp 2d 423 at pp 46-47 and upheld in the Court
of Appeal for the Federal Circuit, 84 Fed Appx 76. In second wave litigation
involving Apotex, the construction decisions were maintained: see In re
Omeprazole Patent Litigation 490 F Supp 2d 381 upheld at 536 F 3d 1361.
[178] If I had any material reservation about the correctness of this
prior jurisprudence, I would not hesitate to differ. In my view, however, the
Apotex position is not persuasive.
[179] Although AstraZeneca undoubtedly did not contemplate the in situ method of creating a subcoat when
it applied for patent protection, that is not a point which detracts from its claim
to a novel product. The fact that, in places, the 693 Patent disclosure refers
to the “coating process” or like terms in the
discussion of the omeprazole formulation does not thereby incorporate a process
limitation into Claim 1. Indeed, this speaks to the danger of relying too
heavily on the disclosure as an interpretive guide to claims language.
Having regard to the requirement of enablement, one could well expect some
blending of product and process language in the disclosure narrative. Such
general references may not be helpful as interpretive guides to claims language.
It is in the claims where the use of precise and consistent language is
important and expected. If Claim 1 of the Patent is limited to subcoats
physically applied to the cores, the question arises as to why the words “disposed on” were used. Those words can refer to
spacial arrangements or to the relative position of things and are not limited
to the means of their placement. The objective reader would understand the
purposive use of a general term to define the product would be insufficient to
import a process limitation. Indeed, the person of skill would be hard-pressed
to understand what purpose is served by limiting the scope of a product claim to
any particular process of manufacture.
[180] Dr. Kibbe testified that the term “disposed
on” was not a term of scientific art.
Under cross-examination, he acknowledged the word “applied”
would have been a more obvious way of expressing a process limitation of this
sort [p 4776]. I would add, even though the Apotex sublayer presumably forms
from a chemical reaction, it does so in the course of applying the
enteric coat to the core. In this sense it is a product that immediately results,
perhaps unexpectedly, from a process.
[181] The only references in the 693 Patent to “disposed on” are in Claim 1 and in the matching
language found at page 5 of the disclosure. In all other passages in the
disclosure different language is used. For instance at page 5 the process for
making the formulation speaks to “coating a core region”.
At page 6 there are references to “the coating process”
and to “[t]he separating layers(s) can be applied to
the cores”. At page 7 “another method to apply the coating” is
described. If Claim 1 was limited to subcoatings formed by direct
application, one would expect to find an appropriate distinguishing verb and
not the more generic term “disposed on”.
Furthermore, assuming that the verb “to coat”
originates from the noun “coat” there is no
interpretive rule of which I am aware that would equate their meanings in
common use.
[182] The fact that neither the notional person of skill nor the actual
inventors would have had an in situ subcoat in mind or, indeed, any other means by which a subcoat could
be formed does not help to define the scope of Claim 1. There may well be
a number of methods available to produce the essential elements of a novel
formulation that have not been identified or contemplated by the inventors.
All that is required is the disclosure of one viable method of manufacture.
[183] In the case of the 693 Patent the inventors disclosed processes
for making the claimed formulation. They did not disclose the process for
making an in situ
subcoating. I am not favourably disposed to the suggestion that a product claim ought
to be interpreted to exclude a process that the Patent never mentions and, at
the same time, to limit the claim to the processes that are disclosed.
The patentee is entitled to protect the product regardless of the means of its creation.
[184] Dr. Kibbe was asked by Apotex to comment on the ability of the
skilled person to understand how to avoid infringing Claim 1. The
underlying premise of the question was that a patentee is required to
communicate to the world what is being fenced-in and, conversely, what may be
practised safely. Not surprisingly Dr. Kibbe obliged by concluding that
the 693 Patent claims fail to teach the person of skill how to avoid a
subcoating which forms in situ as a reaction product. Dr. Kibbe’s proposition is effectively
a variation on Apotex’s construction argument that the 693 Patent does not
include subcoats which form in situ.
[185] I reject the notion that AstraZeneca had an obligation to teach its
competitors how to avoid an infringement. A patentee has no obligation to
inform the world of all the processes which may give rise to an infringing
product. AstraZeneca described its formulation and explained how to make it.
It was up to others to avoid an infringement.
[186] According to Apotex, the 693 Patent taught away from the very method
that Apotex employed. If Apotex was relying on that teaching, it ought to have
been surprised to see that its product actually worked. If, as Dr. Kibbe
testified, the person of skill would expect a possible reaction between the
Apotex cores and a conventional enteric coating, Apotex could have looked to
see what, if anything, had formed between those layers – just as
Dr. Davies did.
[187] I accept Apotex’s point that a skilled reader of the 693 Patent
would understand that there was found to be a problem associated with a
formulation where a conventional enteric coat rested on an omeprazole core. I
do not agree, however, that such a reader would thereby exclude the possibility
that a separating subcoat formed in situ could never be a viable solution to the recognized gastric acid
resistance and storage stability problems associated with omeprazole
formulations. The Patent speaks generally to “a demand
for the development of new enteric preparations of omeprazole with better
stability” [p 3, line 5] and to effecting a separation of the core from
the enteric coating [p 4, lines 34-36]. How the separating layer is obtained
is not a subject addressed by Claim 1. In my view, the general admonition
in the Patent disclosure to separate the enteric coating and the cores would
not be seen as an impediment to a subcoat formed by a transitory in situ reaction during pellet manufacture.
Once the subcoat is formed it represents the barrier that is said to be part of
the invention and the problem of ongoing incompatibility is avoided. On this
point, I accept Dr. Bodmeier’s evidence at paragraph 48 of his initial
report that the advantage of the invention lies in its finished doseage form
structure and not by how one gets there.
[188] The authorities relied upon by Apotex on this issue have no
application. Rhoxalpharm Inc v Novartis, above, concerned an in situ reaction which occurred after the
completed formulation was ingested by the patient. This is a far different
situation than this one where the in situ reaction is said to occur during the manufacture of the product.
[189] Miken Composites, LLC v Wilson Sporting Goods Co, above, concerned the claim term “insert”.
The patent claim described the structural improvement to a baseball bat as
an “insert”. The alleged infringing product
achieved the same advantage by composite layering. In upholding the trial
decision the Court held that the layering approach did not involve the use of
an insert. The Court was influenced by the consistent use of the term in the
disclosure and in the claims and found it meant “something
inserted or intended for insertion”. This unambiguous language did not “impermissibly import a process limitation into [the] product
claim”. In this case the words “disposed on”
do not carry a clear and particular meaning. If Claim 1 had used a
limited verb such as “applied”, “coated” or “sprayed”,
Apotex’s argument would likely have prevailed.
[190] Claim 1 stipulates that the subcoating must be “inert”. The question, of course, is what the skilled
formulator would make of that word in attempting to follow the teaching of the
Patent.
[191]
According to Dr. Kibbe: “Inert is inert. Inert by definition, means it doesn’t react
with the components. Even if the reaction is limited in nature, it is still a
reaction, and that means it is no longer inert. And that is – the simplest way
of looking at it is, we are trying to put something there that will do nothing
to affect either side [the enteric coat or the core] except to keep them
separate from each other” [p 4779].
[192]
Although it is
apparent that Dr. Kibbe understood “inert” to be limited to the potential for
the subcoating to react with other formulation constituents, he was adamant
that there was no permissible reaction margin whatever the functional
consequences might be [pp 4784-4787].
[193]
Dr. Bodmeier
adopted a more flexible view. He stated that “inert” meant only that the
subcoating will not interfere with the function of the enteric coating or the
stability of omeprazole in the core [p 1773]. Dr. Bodmeier further stated
that the skilled formulator knows that “some minor level of reaction is
expected in any formulation”. According to this view “inert” is a
relative and not an absolute term. Dr. Bodmeier found support for this
view in the disclosure where potentially acidic subcoating materials are
identified as acceptable. The person of skill would also know that the
presence of an ARC in the core would neutralize acidic reactions particularly
within the subcoating layer which, according to the Patent, acts as a pH
buffering zone. According to Dr. Bodmeier, the Patent reference to “non-acidic,
otherwise inert” would be read by the person of skill to permit some level of
acidity provided that the efficacy of the formulation was not compromised.
[194]
The evidence
shows that all compounds will react and degrade in their particular
environments in their own time. That is precisely why pharmaceutical products
have a stipulated storage life. In the context of a pharmaceutical compound
the term “inert” cannot be purposively construed in an absolute sense. No
person of skill would consider an inert subcoat to be completely unreactive
within its environment. The word “inert” in Claim 1 would be read to be
limited to reactions that adversely affect the functionality of the
formulation. The Patent teaches the person of skill to avoid a subcoat
material that will compromise the enteric coat or the omeprazole core. A
purposive construction does not preclude any and all reactive potential between
the subcoat and the other formulation constituents however trivial or
functionally inconsequential it may be. Indeed, the person of skill knows
without being told to avoid ingredients that could cause unwanted reactions.
In reading the Patent the skilled formulator is thinking about what will work
and would not dismiss a promising coating material simply because it is not
perfectly or absolutely inert in a strict scientific sense.
[195]
I therefore
reject Dr. Kibbe’s view of this word and instead adopt Dr. Bodmeier’s
more nuanced interpretation.
[196]
Apart from stating that the desired
subcoating should be a polymeric film former and achieve a minimum thickness of
two microns, the Patent offers no other guidance about its structural
characteristics or integrity.
[197]
Apotex asserts
that the claimed subcoating must be continuous and free of pinholes or gaps
that would permit any direct contact between the enteric coating and the
omeprazole cores. AstraZeneca says that minor breaks or defects in the
subcoating would be expected and that substantial continuity of the subcoating
is all that is required, provided that the formulation works.
[198]
Dr. Kibbe
did acknowledge that the continuity of the subcoating was related to its
protective function [p 4474]. According to Dr. Kibbe, in the presence of
through holes or gaps, the subcoating would simply not work. This evidence was
somewhat tempered in Dr. Kibbe’s testimony under cross-examination. There
he conceded that “everything we do in formulation has a certain amount of variability”
[p 4633] and some discontinuities “are not necessarily functional
discontinuities” [p 4670]. He also observed that most polymorphic films are
hydrophilic and attract water [p 4704].; as they absorb water they thicken into
a gel [p 4705]. This process slows the passage of more water and allows for an
“acid based neutralization to occur long before it gets to the bottom of the
enteric coat” [p 4713]. This would also probably close any small gaps or holes
that were present in the dry state [p 4744].
[199]
It seems to me
that the person of skill would view the presence of small gaps or holes in a
polymorphic subcoating with these considerations in mind. If they did not
compromise the formulation, they would not present a practical concern.
[200] I do not agree with Apotex that the person of skill would expect the
subcoating to be structurally perfect. Even the best processes of manufacture
will give rise to some anomalies and imperfections. The person of skill is
looking for a formulation that sufficiently separates the enteric coating and
the cores so as to achieve acceptable storage stability and gastric acid
resistance. Defects that do not compromise the efficacy of the product would
be tolerated. If perfection was the standard to be achieved, a party could
easily avoid an infringement by creating a poor but still effective copy.
[201] The person of skill knows that the sublayer must have sufficient
physical integrity to constitute an effective barrier between the enteric
coating and the pellet cores. The disclosure informs the person of skill that
a minimum subcoat thickness of 2 microns is required to fully obtain the
promised advantage. The fact that Claim 1 does not include this
information does not mean that the person of skill is oblivious to the
disclosure advice. The same is true of the stated need to minimize water
content and of the implicit need to employ a subcoat that provides
substantially continuous coverage of the cores. A skilled formulator would
understand that a subcoating that manifestly fails to meet these requirements
simply would not work.
[202] All of this is not to say that minor lapses or deviations from these
disclosure teachings would be sufficient to take a formulation outside of the
scope of Claim 1. The person of skill understands that processes of
manufacture allow for some variation in the finished product. As to the
requirement for a minimum subcoat thickness, the person of skill would
interpret Claim 1 with some allowance for variability and not as an
absolute threshold that would render the product useless for its intended
purpose. Claim 1 encompasses a subcoating that is substantially
continuous in coverage with a thickness that is sufficient to achieve its
intended purpose.
[203] For what it is worth, I do not accept Dr. Bodmeier’s evidence
that the thickness advice provided by the disclosure means an “average” thickness of 2 microns. Dr. Bodmeier
expresses the opinion that the person of skill would essentially read out of
the Patent the words “not less than” in
reference to the expected thickness of the subcoating and substitute for it an “average” thickness of 2 microns [p 1457].
[204] I do not understand Dr. Bodmeier’s interpretation. If the
intention was to state an average thickness, one would expect to see that
language. “[N]ot less than” is an absolute and
invariable expression. Furthermore, in terms of achieving efficacy, an average
thickness is meaningless to the formulator. The fact that the person of skill
would expect to see some variation in the uniformity or continuity of the
subcoating does not exclude the advice that a minimum thickness is desired.
Indeed, in the context of an applied subcoating where the process can be well-controlled,
the idea of a minimum effective thickness is hardly surprising.
[205] I do agree with Dr. Bodmeier that the numerical convention of
rounding does apply to a value that is expressed without a decimal point. That
evidence was not challenged by the Apotex witnesses. In the result, I accept
that the person of skill would interpret the reference to 2 microns to include
the value of 1.5 microns but, in any event, I do not agree that the Patent
claims incorporate a thickness limitation beyond the expectation that the
sublayer needs to be sufficiently robust that it constitutes an effective
barrier.
[206] Apotex also contends that Claim 1 would be construed as though
it includes no limitation for water content. It draws this interpretation from
the explicit limitation in Claim 13 to a formulation with a water content
of less than 1.5%. According to Apotex, the person of skill would take from Claim 13
that Claim 1 was unlimited as to water content. If it were otherwise, Claim 13
is rendered redundant.
[207] I do not agree with this suggested approach to the construction of Claim 1
and its dependant claims. The claims are to be read in conformity with
what the person of skill knows or is otherwise taught by the Patent. The
person of skill knows that water content can be a problem for maintaining the
stability of omeprazole (and many other compounds) and would employ techniques
to deal with it. The person of skill is also aware that, while some variations
in water content can be tolerated or managed, there is a point of saturation
where the formulation will fail: see Bodmeier Infringement Report at para 83.
According to Dr. Bodmeier, the level of acceptable water content will vary
according to the constituents of the formulation, and in the context of the
teaching of the 693 Patent, the person of skill would not assume an “absolute number” [p 1747]. The subject claims should
not be read as though the person of skill would ignore the clear teaching of
Patent favouring, instead, a highly technical rule of interpretation.
[208] On this issue, I accept Dr. Bodmeier’s evidence at pp
1550-1551:
A. Yes. So
the water content and the minimum thickness, they are important, and I think I
mentioned this already yesterday. Like the 693 Patent that allow water content
is important and also talks about a certain minimum thickness, but it's my
opinion that this is not part of the inventive concept which is this oral
pharmaceutical formulation.
And I think if we
first talk about the water content, I think that a skilled person knows that
water content has to be low, I think that's mentioned in the patent at several
occasions. There are also numbers given, but a skilled person would not see
these numbers as a limit of the claim, he would know that a low water content
is important, but that will depend on the formulations. There are some
formulations, they can take a little bit more water and others less. That
depends on the excipients, also depend on the packaging, on a variety of
factors.
And the same with
regard to minimum thickness. I think the patent clearly states that there is a
minimum thickness, we had the argument yesterday -- or I had the argument with
the experts of Apotex that I see there is an average minimum thickness, that
there is a clear statement in the patent that the minimum thickness, what I see
as an average minimum thickness, is not less than 2 micrometre.
Q. And so --
A. But I
don't see these two parameters as an essential concept of the invention.
In my view, Claim 1 and its dependant claims
do not incorporate a water content limitation.
[209] Apotex asserts that the terms “subcoating”
and “separating layer” mean the same thing. It
draws this interpretation from a passage at page 6 of the description stating
that “[t]he subcoating layer, in the following defined
as the separating layer, also serves as a PH buffering zone…” This
position is helpful to Apotex because the Patent also discusses the use of
gelatine capsules as a means of separating the enteric coating from the pellet
cores.
[210] AstraZeneca maintains that a gelatine capsule can perform a
separating function but it does not, by definition, constitute a subcoating as
that term is used in Claim 1.
[211] The Patent language on this issue is certainly not free from
difficulty. I agree with Dr. Bodmeier that in normal parlance a gelatine
capsule is a type of container and not a sublayer disposed on a pellet core and
that, while a subcoating is included within the more general term “separating layer”, the reverse was not intended.
[212] At page 7, gelatine capsules are said to “serve
as [a] separating layer”. This latter phrase suggests to me that, by “serving as” a separating layer, gelatine capsules are
not to be construed as separating layers per se. At page 5b gelatine capsules “are used as
cores for further processing”. This language suggests that the
inventors did not consider gelatine capsules to be subcoatings as that term is
used in Claim 1. In a number of the succeeding claims, the subcoating is
described but not with reference to a gelatine capsule. Accordingly, I do not
accept that the reference to a subcoating in Claim 1 includes the use of
gelatine capsules. In my view, the Patent contemplates the use of gelatine
capsules as part of the core region providing a separating function but not
acting as an inert subcoating within the meaning of Claim 1.
[213]
In Free Word Trust v Electro Santé Inc,
2000 SCC 66, [2000] 2 S.C.R. 1024 at para 26, the Court applied Hugessen’s J.A.’s
classic statement of the disclosure element for anticipation by prior
publication from Beloit Canada Ltd. v Valmet OY:
The test for anticipation is difficult to
meet:
One must, in effect, be able to look
at a prior, single publication and find in it all the information which, for
practical purposes, is needed to produce the claimed invention without the
exercise of any inventive skill. The prior publication must contain so clear a
direction that a skilled person reading and following it would in every case
and without possibility of error be led to the claimed invention.
(Beloit Canada Ltd. v. Valmet OY
(1986), 8 CPR (3d) 289 (FCA), per Hugessen JA, at p. 297)
[214] The above statement continues to be the legal standard on this issue
(see Bell Helicopter v Eurocopter, 2013 FCA 219 at paras 109-110, [2013]
FCJ no 1043).
[215] A useful summary of the requirements for proving anticipation can be
found in Abbott Laboratories v Canada, 2008 FC 1359, [2009] 4 FCR 401
aff’d 2009 FCA 94, [2009] FCJ no 345 where Justice Roger Hughes said:
[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.
[216] The burden of proof on this issue rests with Apotex on a balance of
probabilities.
[217] Apotex asserts that Claim 1 of the 693 Patent is anticipated by Hässle’s
European Patent Application 124,495 [EP 495] published on November 7, 1984. The
anticipatory passage in EP 495 is said to be the following:
Soft gelatine capsules may be prepared with
capsules containing a mixture of the active compound or compounds of the
invention, vegetable oil, fat, or other suitable vehicle for soft gelatine
capsules. Soft gelatine capsules are preferably enteric coated as described
above. Hard gelatine capsules may contain enteric-coated granules of the active
compound. Hard gelatine capsules may also contain the active compound in
combination with a solid powdered carrier e.g. lactose, saccharose, sorbitol,
mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or
gelatine; the hard gelatine capsules are preferably enteric coated as described
above. [Footnote omitted]
[218] Dr. Kibbe maintained that the above example includes all of the
structural features of Claim 1. His evidence at p 4788 was as follows:
Q. Okay.
And whether it's Example 12 or the general discussion of the 495, or any
discussion about an enteric coated gelatin capsule in the 495, none of those
discussions would disclose to the skilled reader whether such a formulation
would, in fact, have the three functional properties that we have been talking
about? That's pretty clear; isn't it?
A. I am
sorry, the 495 says that the alkaline salt of omeprazole is more stable. And
the alkaline salt of omeprazole is one of the components of the core that is
described in the 693 as a way of improving the stability. Okay. So that is in
the game, as it were.
And then the
composition
Q. Let's
look at the 495, your D 8.
MR. RADOMSKI:
Sorry, sorry, Dr. Kibbe was in mid sentence.
BY MR. GAIKIS:
Q. Go
ahead.
A. That's
okay.
And the composition
that is described in the patent as an example composition, and it contains the
magnesium salt of omeprazole and an enteric coat, and it doesn't include a
separating layer, but the if I could check my own little notes to myself
okay, so, therefore, the 495 has both a compound which is considered to be a
more stable form of omeprazole according to the 693 Patent, and it has an
enteric coat.
And according to
the 493 (sic), enteric coatings may be applied to granules, tablets or gelatin
capsules, hard or soft, okay, which means that the 495 is telling you, you
could take the alkaline salt of omeprazole, put it in a capsule and enterically
coat it.
And if that's the
case, then we could look at the 693 which says that that would be one of the
uses or one of the ways of making the product in that patent, and that's in the
detailed description of the patent where it says specifically on page 7, line
11:
"In case of
gelatin capsules, the gelatin capsule itself serves as a separating layer, and
then it has a core and an enteric coat."[as read]
So it seems like
the 495 has each of the three elements of the 693.
Q. Structural
elements?
A. Yes.
[219] The simple and complete answer to this evidence is that, as
discussed above, the term “subcoating” found in
Claim 1 does not include a gelatine capsule and, therefore, EP 495 does not
anticipate that essential feature of the 693 Patent. On this point I much
prefer the evidence of Dr. Bodmeier to that of Dr. Kibbe.
[220] It is true that EP 495 discloses, among other approaches, an
enterically coated alkaline salt formulation of omeprazole and the means of
making of it. It does not, however, disclose the use of a subcoating to
overcome the stability/gastric acid resistance problem addressed by the 693
Patent. Indeed, Example 12 discloses an enteric coated tablet containing an
alkaline omeprazole salt and it fails to identify a problem.
[221] There is no evidence that the application of an enteric coating to
an omeprazole core containing an ARC will inevitably lead to the formation of
an in situ subcoating
layer. There may well be effective combinations of such compounds where an
infringing subcoating layer does not form. In the absence of evidence that, by
practising the teaching of EP 495, a subcoating layer will be the inevitable
result, I do not accept Apotex’s argument that the 693 Patent teaches only
an inherent characteristic of what was already disclosed in the EP 495.
EP 495 does not anticipate.
[222] The principles that apply to obviousness are well-known. The party
asserting the defence - in this case, Apotex - has the burden of proof on a
balance of probabilities.
[223] In Novartis Pharmaceuticals Canada Inc v Cobalt Pharmaceuticals
Co, 2013 FC 985, 440 FTR 1 (Eng.), Justice Hughes described the concept in
the following way:
[60] One of the most difficult issues
faced by a Court in patent litigation is that of obviousness. The Court must
address the alleged invention through the eyes of a person skilled in the art
and ask whether it is deserving of patent protection; that is, whether it is
either inventive or obvious.
[61] The rationale has been put well by
Professor Carl Moy of William Mitchell College of Law, author of Moy’s
Walker on Patents, Thomson/West, in addressing a Master of Law Class at
Osgood Hall Law School. He said that a patent is a bargain between the public
and the patentee which provides a monopoly to a person (patentee) in respect of
certain scientific subject matter, provided that it is purchased from the
public by disclosing something that is new, useful and inventive. If it is not
new, then the monopoly has been purchased for nothing and cannot be valid. If
it is something that that the public would get anyway from a person of ordinary
skill practicing their craft, then nothing has been paid for the monopoly and
the monopoly cannot be valid.
[62] The concepts of inventiveness or
obviousness are elusive, which has caused the Courts to endeavour to articulate
tests and criteria to be examined and assessed against the evidence. The
current state of such tests in Canada is that set out by the Supreme Court of
Canada in Apotex Inc v Sanofi-Synthelabo Canada Inc, 2008 SCC 61,
[2008] 3 S.C.R. 265 (“Plavix”), per Rothstein J, for the Court, at paragraphs 67
and 69 to 70:
67 It will be useful in an
obviousness inquiry to follow the four-step approach first outlined by Oliver
L.J. in Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd.,
[1985] R.P.C. 59 (C.A.). This approach should bring better structure to the
obviousness inquiry and more objectivity and clarity to the analysis. The
Windsurfing approach was recently updated by Jacob L.J. in Pozzoli SPA v. BDMO
SA, [2007] F.S.R. 37, [2007] EWCA Civ 588, at para. 23:
In the
result I would restate the Windsurfing questions thus:
(1) (a)
Identify the notional "person skilled in the art";
(b)
Identify the relevant common general knowledge of that person;
(2)
Identify the inventive concept of the claim in question or if that cannot
readily be done, construe it;
(3)
Identify what, if any, differences exist between the matter cited as forming
part of the "state of the art" and the inventive concept of the claim
or the claim as construed;
(4)
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? [Emphasis
added.]
It will be at the fourth step of
the Windsurfing/Pozzoli approach to obviousness that the issue of "obvious
to try" will arise.
…
69 If an "obvious to
try" test is warranted, the following factors should be taken into
consideration at the fourth step of the obviousness inquiry. As with
anticipation, this list is not exhaustive. The factors will apply in accordance
with the evidence in each case.
(1) Is
it more or less self-evident that what is being tried ought to work? Are there
a finite number of identified predictable solutions known to persons skilled in
the art?
(2) What
is the extent, nature and amount of effort required to achieve the invention?
Are routine trials carried out or is the experimentation prolonged and arduous,
such that the trials would not be considered routine?
(3) Is
there a motive provided in the prior art to find the solution the patent
addresses?
70 Another important factor
may arise from considering the actual course of conduct which culminated in the
making of the invention. It is true that obviousness is largely concerned with
how a skilled worker would have acted in the light of the prior art. But this
is no reason to exclude evidence of the history of the invention, particularly
where the knowledge of those involved in finding the invention is no lower than
what would be expected of the skilled person.
[224] It is clear from the authorities that the mere possibility of
finding an invention is not enough to establish obviousness. The invention
must be self-evident from the prior art and the common general knowledge of the
person of skill. The fact that known methods were used by an inventor to
obtain the desired result is not a determinative consideration. What always
remains is the question of how likely was it that the discovery would emerge
from the application of those methods. This involves an assessment of whether
the distance between the common general knowledge and the inventive concept
could be bridged by routine experimentation. This, in turn, can be informed by
the inventors’ course of conduct in getting to the discovery – the so-called
invention story: see Sanofi Aventis v Apotex Inc, 2013 FCA 186 at
paras 73-74, 81, 137.
[225] The parties agree that the person of skill is someone with a
university degree in natural sciences and practical experience in the
development of pharmaceutical doseage forms – in other words, a skilled
pharmaceutical formulator.
[226] It is in its post-trial Brief Apotex succinctly and fairly set out
its position on obviousness in the following paragraphs:
18.
At bar, the parties agree that the inventive concept of the claims is a
formulation of omeprazole containing an alkaline core, an inert subcoating and
an enteric coating which provides good long-term storage stability and gastric
acid resistance.
19.
It follows that the central issue to be decided in the obviousness
inquiry is whether inventiveness was required to obtain such a formulation.
20.
Apotex submits that no inventive ingenuity was required: the solution
provided by the 693 Patent is little more than a straightforward solution to an
easily recognizable formulation problem.
•
No more than routine work would be required to achieve the claimed
invention.
21.
A significant amount of evidence was devoted to the issue of obviousness
at trial. Nevertheless, the issue turns on two, straightforward, matters.
•
What was known about omeprazole and its formulations as of April 30,
1986 — the priority date of the 693 Patent?;
•
Would a person skilled in the art have arrived at the solution taught
by the 693 Patent without the exercise of inventive ingenuity? [Footnotes
omitted]
[227] The above arguments rest primarily on the evidence of
Dr. Kibbe.
[228] Dr. Kibbe recognized the tension that existed between the
competing properties of acceptable gastric acid resistance and long-term storage
stability. His evidence on this point can be found on pages 4351-4353 of the
trial transcript where he discussed the problem described by the inventors in
the 693 Patent:
A. I am
going to do two things simultaneously.
Q. Okay, I
am going to let you do what you need to do.
A. Okay. We
are talking about the two comparative examples, okay. And basically what they
have done is they have made tablets without an intermediate layer, and they
have looked at what goes on with those tablets, and they have noticed that when
the levels of alkaline material is sufficient to prevent colour change, which
would be what is Roman numeral 3, then the coating, the enteric coating, begins
to fail and it allows a large amount of material to escape during the two hour
test in the acid media. If they add sufficient amount of - - or insufficient
amount of alkaline material, the core changes colour to brown, but the enteric
coat is relatively stable.
And the amount of
material, I think, is in a, if I remember correctly, is in a wonderful table,
and it goes from - - there we are.
Q. What
page?
A. If you go
to page 22 of the patent itself, these three examples are laid out. Okay.
And the key here is
that the only difference between these three examples is that 1 and 2, have two
grams of alkaline material and 8 grams of alkaline material respectively, and
Number 3 has 24.
Q. You are
talking about the disodium hydrogen phosphate?
A. Yes, I
am. I apologize. Disodium hydrogen phosphate is an alkalizing material.
And so what they
show here is that 24 grams is sufficient to prevent discolouration, but it
causes a deleterious effect to the enteric coat, causing the enteric coat to
release 42 per cent of the drug during the two hour stress test.
However, if you
give lower amounts of alkaline material, 2 grams and 8 grams, then the
core is not stable but the coat is stable. And so the issue is in front of
them, how do I do both things? And the answer is, in all of their examples and
in their patent, is the intermediate subcoat or separating layer.
Q. Okay.
And I think that's what you say in your paragraph 81?
A. In fact,
I even quote them from page 4.
Q. Right.
So then in
paragraph, if we can skip to paragraph, I guess, 86, you talk about Examples, I
guess, 2 to 10?
A. Right.
Q. And
Comparative Examples 1 to 5, Roman numeral 1 to 5, and you draw from that
as to what the skilled person would understand, and I am going to ask you to
explain what you say at the end of paragraph 86.
A. Okay.
It's really quite clear from all the examples that whenever they wanted to make
a stable product, they applied an intermediate coat of an inert polymeric
material to separate the core with an alkaline material from the coat, which is
the enteric coat. And whenever they omitted that, then they made the
comparative examples, okay. And that means they are making examples to compare
to what they are suggesting is the examples within the patent.
And in every one of
those cases, they failed one way or the other, they either discoloured or they
released prematurely.
[229] Dr. Kibbe’s opinion is that the incompatibility problem faced
by AstraZeneca was to be expected and its solution was routine and
non-inventive. His initial report described the problem facing the person of
skill in the following way:
217. In my opinion, there is no
inventive difference between the state of the art at April 30, 1986 and the
inventive concept of claim 1 of the ‘693 Patent, as described above.
Further, since there is nothing inventive in the additional elements of claims
5, 6, 11 to 13, 18 and 19 of the ‘693 Patent, it follows that there is no
inventive difference between the state of the art and the inventive concept of
those claims.
218. Given the known sensitivity of
omeprazole to acid, as for example set out in Pilbrant (Exhibit “D-13”) and the
‘495 Application (Exhibit “D-8”), the skilled person would have appreciated
that omeprazole could not be administered as such, because it would not survive
the low pH environment of the stomach. For an oral solid dosage form — a dosage
form which would be strongly preferred — the use of an enteric coating was
required.
219. From the ‘495 Application, it was
known that alkaline salts are more storage stable. The skilled person would
have realized that the same stabilizing effect in the presence of moisture
could be achieved by admixing omeprazole and an alkaline reacting compound, e.g.,
a base. The skilled person would have known that stability of the API is one of
the most important parameters in pharmaceutical formulation development and
would have been motivated to prepare oral solid dosage forms containing an
alkaline salt of omeprazole or omeprazole and an alkaline material.
220. From standard texts, the skilled
person would have known that enteric coatings are intended to dissolve in an
alkaline environment, and that these coatings have exposed acidic functional
groups which ionize above a certain pH. The skilled person would have
anticipated a potential incompatibility between such polymers and an acid sensitive
API like omeprazole in the presence of water (there would be no concern if the
oral dosage form could be kept perfectly dry, a condition which cannot
practically be achieved). The potential for such a problem would have been
confirmed by the technical bulletins (Exhibits “D-25”, “D-26”, “D-27”),
Dechesne (Exhibit “D-21”) and the ‘764 Application (Exhibit “D-22”).
221. The skilled person would thus have
tested for incompatibilities between omeprazole or a salt thereof and candidate
excipients, including enteric coating materials, as part of routine
preformulation work. The incompatibility between omeprazole or a salt thereof
and enteric coating compounds would have been identified.
222. While a number of different
approaches to solving API-excipient incompatibilities were known at April 30,
1986, for the reasons that follow, the skilled person would not have pursued
solutions other than the use of a barrier coat or layer between the alkaline
API-containing core and the acidic enteric coat.
[230] In my view neither the problem faced by AstraZeneca nor its solution
were as simple as Dr. Kibbe suggests. His approach to the prior art was
also highly selective and, in the result, his obviousness opinions were
effectively rendered in hindsight with the 693 Patent solution in mind.
[231] I have particular concerns about the approach Dr. Kibbe took to
his assessment of the prior art. He did no independent prior art search and,
instead, relied upon a set of documents produced by Apotex [p 4505]. An
expert who carries out an obviousness analysis largely or solely on the
strength of prior art references selected by retaining counsel runs a real risk
of offering a hindsight opinion. A thorough prior art review necessarily
includes a search for all of the available relevant literature whether it
supports inventiveness or not. It requires consideration of relevant art in
the larger context of other possible pathways to the patent solution or to
ideas that point away from that solution.
[232] Dr. Kibbe’s selective review is confirmed in the following
exchange in cross-examination:
Q. So let me
put it to you this way: You looked at the 693 Patent; you made an assessment of
what is the invention that’s claimed --
A. Right.
Q. -- and
then you went to the references that Apotex gave to you, and you looked for
those elements of the invention claimed?
A. Well,
obviously, I did a background piece, and then I laid out what the claims meant
and what have you, and then I said, “Would this have been obvious a person of
ordinary skill in the art”? And I believed that it would, and then we looked
to see if there was corroborating evidence in the literature. [Emphasis
added]
[233] Dr. Kibbe also read too much into the prior art. In
particular, he initially read the Pilbrant reference to teach the person of
skill that the acid lability of omeprazole would be similar in aqueous and
solid-state formulations. Under cross-examination, he conceded that Pilbrant
provided no solid state stability data [p 4547] and that the instability
of an API in solution does not necessarily apply to solid state formulations
[p 4513]. The limited value of Pilbrant to the person of skill looking
for a solid state formulation for omeprazole was effectively acknowledged by
Dr. Kibbe in the following exchange:
Q. But insofar
as Pilbrant applied an enteric coating to omeprazole, then the enteric coating
would not be considered the acidic substances or amongst the acidic substances
referred to on page 113, right-hand column, of the language that you were
referring to; is that correct?
A. I think
that’s a little bit of a stretch. He was talking about mostly acidic, the
studies he did, the acidic materials that he exposed it to. I don’t think he
spoke directly to the acidic nature of enteric coats.
Q. No, no, but I didn’t say that.
Wouldn’t it be fair
that a person reading this, realizing that Pilbrant applied an enteric coating
to a core containing omeprazole, no reference to an ARC, and he said the
stability for his purposes was fine, wouldn’t that person conclude that there
shouldn’t be a problem applying an enteric coating to a core containing
omeprazole? Isn’t that fair?
A. I think
that a formulator with Pilbrant in their hand, that might be their first
experiment, but then if they found a problem, they would go back and try to
correct it. And the correction would clearly be to make the core more alkaline.
And if that, then, create a second problem, they would go back and correct it,
and the correction for that would be to put intermediate layer.
And so if we start
with Pilbrant and ignore everything else we know, then we would go through a
set of experiments and arrive at the same place I think the 693 arrived at.
Q. Last
question on Pilbrant, at least for now. You agree that Pilbrant does not teach
a problem applying an enteric coating to a core containing omeprazole?
A. It does
not teach that the enteric coat they used created a problem. [Emphasis added]
This particular passage generally
corroborates Dr. Bodmeier’s evidence that once the stability problem is
identified a cascade of choices and experimentation is required to find a
solution.
[234] In other testimony Dr. Kibbe accepted that there were numerous
acid sensitive API formulations on the market that successfully employed the
direct application of enteric coatings [p 4518]. This, too, would
suggest to the person of skill that a conventional enteric coated formulation
would be the place to begin in attempting to formulate omeprazole.
[235] The uncertainty faced by the person of skill is further reflected in
Dr. Kibbe’s evidence at p 4527:
Q. In fact,
it is the role of enteric coatings to protect acid sensitive drugs from the
stomach; isn't that the case?
A. Yes. Or
protect the stomach from irritating drugs.
My point is that,
even if you could, in the past, coat an acid sensitive material with an enteric
coat without a subcoat, then it's the degree of acid sensitivity that might
lead you to question whether that would be successful and if I would have
to do something else to stabilize that compound, because it was extremely
sensitive to acid.
Q. So you
say it might lead you to do something else?
A. It
might. Everything you do is a function of how to get a commercially viable
formulation prepared that would be stable and deliver the drug appropriately, and
you test as you go. [Emphasis added]
[236] What the above evidence acknowledges is that the person of skill
would not have anticipated the formulation problem that AstraZeneca ultimately
faced and overcame. Indeed, the person of skill would have thought that an
enteric coating of a simple omeprazole core might be sufficient for a
successful formulation. What Dr. Kibbe is left with is the assertion that
the subsequently encountered problems of poor gastric acid resistance and
storage stability could be overcome by the person of skill through the routine
and singular steps of adding an ARC, introducing an intermediate layer and
testing for efficacy.
[237] Dr. Kibbe’s selective approach is further borne out by what he
failed to address in his obviousness opinions but ultimately acknowledged in
cross-examination.
[238] Dr. Kibbe acknowledged that the presence of discolouration in
an omeprazole formulation would be interpreted by the person of skill only as “something happened, and it could be an excipient changing
colour” [p 4535]. In other words, no assumption about the
degradation of omeprazole would be justified without a further assay of the
formulation. The person of skill “would want to figure
out what was discolouring and how to prevent it” [p 4535]. At page
4530, he also said:
Q. And do
you agree that a formulator, in April 1986, seeking to formulate omeprazole
would have been aware of numerous possible causes of discolouration if they, in
fact, saw discolouration as part of such a formulation exercise?
A. Okay.
Formulations can discolour either due to changes in the active ingredient or
the excipients. And so you would be cognizant that colour meant change, but
you wouldn't know exactly what had changed.
This is relevant to the obviousness issue
because the inventors’ recognition that a problem exists can be considered to
be relevant to inventiveness just as well as its solution: see Bayer AG v
Novopharm Ltd, 2006 FC 379 at para 44, 289 FTR 263.
[239] Similarly, as Dr. Kibbe acknowledged, in the presence of a
gastric acid resistance problem, the person of skill would look at “a limited number of things” [p 4536] including
the choices for an enteric coating and plasticizer [pp 4536-4537], the
prevailing process conditions [p 4537] and possible alterations to the
core [p 4539]. Dr. Kibbe conceded he had failed to identify all of
these issues in his reports [p 4539].
[240] Although adding an ARC to the core was a potential answer to the
storage stability problem faced by AstraZeneca, I accept Dr. Bodmeier’s
evidence that the usual instinct of a formulator is to minimize the use of
excipients. According to this view, adding excipients creates more room for
unexpected and undesired reactions within the formulation [see p 1527].
This, in fact, is precisely what happened when an ARC was added to AstraZeneca’s
omeprazole formulation. That combination presented an unexpected gastric acid
resistance problem when the ARC in combination with gastric juice diffusing
through the enteric coating created sufficient alkalinity to degrade the enteric
coating from the inside. Dr. Bodmeier then fairly described the choices
facing the person of skill in the following testimony:
A. Yes. So,
again, let's say the scientist observes this gastric resistance problem and
then he has to think about how to solve it, he doesn't have the solution of the
693 Patent in front of him just waiting for it to be used. There is a
multitude of solutions which he can think about, and they are described in 240.
So the skilled
person would likely first search in the enteric film coating itself for the
reasons for the insufficient gastric resistance, because you have insufficient
gastric resistance, you can say, okay, must be something wrong with my enteric
polymer, so systematically investigating formulation and processing parameters.
So insufficient
gastric resistance can be caused by insufficient thickness of the coating or
uneven coating. So one could just, for example, make a -- try to solve it with
a thicker coating.
Then you could, for
example, try other enteric polymers, you know. We have worked with different
enteric polymers and sometimes you use this one, sometimes you use the other
ones. So there is a choice in polymer.
You could choose,
for example, plasticizers, different amounts, different choices, they add a
little bit of flexibility to the polymer, may change the properties of the
polymer.
Then process
parameters, including temperature spray, pressure spray rate, air thru put
drying. So sometimes when you have, for example, poor processing conditions, it
could happen that you get a very porous film and then the acid goes through and
you fail your gastric resistance test.
So the structure of
the film is important, we have seen that many times, that the processing
conditions, even if you coat with the same polymer, can result in films with
completely different properties.
And then the
remaining solvent is also a point, residual solvent in the coating can affect
the performance and that is why you also have certain minimum levels required
for the residual solvent. Primarily not actually because of toxicity reasons,
because the solvents which are often used, like ethanol, they are not that
toxic, but because the solvent can affect the performance of the coating
negatively.
Porosity of the
coating, I mentioned already. That depends how you spray. You can make a
porous film, so you have some holes in it, the medium can go through. Or you
can make a more denser film, that's also a question of processing conditions.
For example, if you spray faster, you have wetter, it's overall wetter, you get
a denser film compared to when you spray drier, you get a more porous film.
And also the choice of solvent.
So it's not just
like I say, 'okay, let's put the subcoating there, I have the solution'. This
is with hindsight, I can only mention this and repeat myself, a formulator,
when he sees a problem, first he needs to know the cause and they already went
through it, he may not know that it's an interaction between the omeprazole and
the enteric polymer, or between the alkaline reacting agent and the enteric
polymer. So he has a multitude of possibilities to find a solution.
[241] I also accept Dr. Bodmeier’s testimony at pages 1523-1530 where
he described the cascade of issues and potential solutions that the person of
skill would face in attempting to overcome the gastric acid resistance/storage
stability incompatibility problem (i.e. enhancing alkalinity in the core to
improve stability degraded the viability of the enteric coat and led to
unacceptable gastric acid resistance). There, too, the usual first option for
the person of skill would be to attempt to eliminate the conflict by
substitution and not by adding things. This evidence seems to me to be a far
more objective assessment of the prior art than the simplified and categorical
views expressed by Dr. Kibbe.
[242] Dr. Bodmeier was taken in cross-examination to numerous prior
art references that discuss the use of subcoats and alkaline compounds to
resolve a variety of pharmaceutical formulation problems. While acknowledging
that adding subcoatings and ARCs were known techniques to resolve, among other
problems, incompatibility and stability issues, he effectively distinguished
these references as being largely unhelpful to the person of skill looking for
an effective formulation specific to omeprazole.
[243] I accept Dr. Bodmeier’s evidence that the person of skill
starts the process of formulating omeprazole with reference to Pilbrant and
believes that a conventional enteric coating may suffice. There is no
beginning expectation that storage stability will be a problem because not all
acid sensitive molecules will degrade in the presence of an acidic enteric
coat. When discolouration became evident, the person of skill must first
determine its cause. When the person of skill identifies the cause of the
stability problem, he would not turn immediately to the addition of an ARC. I
agree with Dr. Bodmeier that the skilled formulator would not immediately
add another excipient but would be more inclined to look for a compatible
substitute for the offending enteric coating material. Adding more excipients
can create another set of issues just as it did when AstraZeneca added an ARC
to its omeprazole cores to improve the storage stability of its formulation.
The ARC then became the source of gastric acid resistance problem that required
its own solution. Adding an appropriate subcoat was one potential solution to
the gastric acid resistance problem but it was not the only option available to
the person of skill.
The general idea of separating reactive materials in pharmaceutical
formulations was known to skilled formulators but there was no expectation that
any particular subcoat material in combination with any particular amount of an
ARC would achieve the desired balance of storage stability and good gastric
acid resistance. I also accept Dr. Bodmeier’s evidence that the selection
of a water soluble subcoat was a non- obvious choice as protective barrier for
the reasons he gave.
[244] Omeprazole turned out to be a particularly difficult API to
formulate. Not all of its idiosyncrasies were known in the prior art and AstraZeneca
did not know from the outset the difficulties it was facing or the means by
which they could be overcome. The person of skill is certainly aware of enteric
coats, ARCs and subcoats in various formulation applications but would not be
drawn immediately and without difficulty to combine those elements into the
particularized arrangement described in the 693 Patent as a means to solve the
several formulation issues presented by omeprazole. If the solution was as
simple as applying a conventional enteric coating, nothing inventive would have
taken place. But the solution obtained here was multifaceted. It required AstraZeneca
to finely balance the incompatibility between alkalinity necessary for
acceptable storage stability and the preservation of the enteric coating
necessary for good gastric acid resistance. In my view the process required to
obtain the solution was neither routine nor obvious.
[245] Dr. Bodmeier’s evidence also conforms
very closely with the history of the invention.
[246] Dr. Kurt Lovgren testified on behalf of AstraZeneca. He was
one of the six inventors named in the 693 Patent. The others were Mitsuru
Yasumura, Satoshi Morigaki, Minoru Oda and Naohiro Ohishi, all of Japan and
Dr. Ake Pilbrant from AstraZeneca in Sweden.
[247] Dr. Lovgren holds a PhD in pharmaceutical sciences. He began
employment with Hässle in 1974 as an organic chemist in the chemistry
department. At that point, he was involved in making new compounds. He
described Hässle at that time as “a minor
pharmaceutical company” focussing on cardiovascular and gastrointestinal
research.
[248] Dr. Lovgren and Dr. Pilbrant were leaders of the research
teams that were principally involved in the search for an effective omeprazole
formulation at AstraZeneca. The role of the Japanese inventors was limited to
the work described in Example 1 of the 693 Patent.
[249] Dr. Lovgren identified the assignment of the inventors’
interest in the 693 Patent to Hässle executed by all of the inventors in the
early part of 1987 [see Exhibit 85, Tab 2] and confirmed the financial consideration
that he received in return.
[250] When Dr. Lovgren joined Hässle, it was already looking at
synthesizing benzimidazoles as promising compounds in the treatment of peptic
ulcers. One of its early candidates was timoprazole. Ultimately timoprazole
was dropped because of toxicity concerns. In 1976 picoprazole was identified
and studied. This was followed in 1979 by the synthesization of omeprazole.
Because omeprazole was found to be more potent than picoprazole, it became
Hässle’s lead compound. At that point Dr. Lovgren was working in Hässle’s
pharmacy department as a research scientist focussing on the development of
solid doseage forms. In that capacity, he was directly involved in the
research and development of solid doseage forms for picoprazole and
omeprazole. That work included the making of cores and coatings suitable for
further research including bioavailability and clinical studies.
[251] In 1982, Dr. Lovgren became an Assistant Manager in Hässle’s
pharmacy department with responsibilities for hands-on experimentation and the
supervision of others engaged in formulation research.
[252] Dr. Lovgren testified that over the course of his work with
omeprazole formulations, he conducted or supervised hundreds of experiments.
The goal of this work was to develop a doseage form which could be conveniently
administered to human patients in all phases of Hässle’s clinical trials.
[253] Dr. Lovgren described omeprazole as a particularly difficult
molecule to formulate. It has very low solubility and is very acid and
moisture sensitive. For Phase I clinical trials, it was necessary to
administer omeprazole in a suspension. For Phase II clinical trials, the goal
was to develop a solid doseage form. The formulation used in Phase II trials
included an ARC in the cores and an enteric coating. It did not incorporate a
subcoating layer. Dr. Lovgren testified that the formulation used in Phase
II trials proved to be inconsistent in terms of gastric acid resistance.
[254] Hässle’s first attempts to overcome the gastric acid resistance
problem were directed at the enteric coating. It was thickened and different
polymers, plasticizers and hydrophobic materials were tried. Dr. Lovgren
described these efforts in the following way:
We also decided to
mix different enteric coating polymers to see if that -- they -- the mixture
behaved better. We used -- in an enteric coating, normally you can have, or
normally you have a plasticizer, and we did different attempts with that
plasticizer, different types and concentrations. ,
We used hydrophobic
material. The idea there is that hydrophobic material is normally water
repellant, so, by including hydrophobic material, we thought that that could
resist permeation of water or gastric juice in the stomach and, therefore,
maybe leading to better results. So we included hydrophobic material into the
enteric coating.
We made a layer of
hydrophobic material on top of the enteric coat, and we used laminate, thinking
that we should have more than one layer. As I said earlier, one could be a
hydrophobic layer, but it could also be two different layers of enteric
coating.
And we also did
experiments around the core, surface of the core, tried to have smoother
surface. We tried to have thinking about what sort of ingredients you should
use in the core.
[p 2138]
[255] The initial adjustments to the enteric coating described by
Dr. Lovgren were mainly directed at making it less permeable. Adjustments
to the core involved substitutions and quantitative variations to the ARC. It
was only after these attempts failed that a water soluble subcoating layer was
introduced. This approach led to the formulation used in Phase III clinical trials
and described in Claim 1 of the 693 Patent.
[256] Dr. Lovgren was taken through Hässle’s research records
detailing the work that went into the development of a stable and gastric acid
resistant omeprazole formulation between 1980 and 1986. Those records are
primarily contained in Exhibit 85 and they corroborate Dr. Lovgren’s
evidence about the amount of effort that went into the development of the
patented formulation. A representative example confirming the work undertaken
can be found at Exhibit 85, Tab 13 where testing was carried out with varying
amounts of enteric coating and with additives. Dr. Lovgren described the
work as follows:
What is going on
there?
A. Yes, it's
attempt now to also coat granules, and the note saying that the best film from
2 should be added to the omeprazole granules with varying buffer. So it's,
stepwise, that we are evaluating a different amounts of enteric-coating
polymers on the same granules under 2, and then we are spraying one selected
coating onto the granules that I should prepare for different amounts of
alkaline material.
[p 2200]
…
Q. Okay,
page 3 at the top, there is a reference to "Christina" and some
tests. And I see there is a reference to L 100; would that be the Eudragit
that you mentioned earlier?
A. That is
an enteric-coating polymer, Eudragit, with a brand number 100, yes.
Q. Okay, so
it looks like she is mixing it with different, like 10 per cent ethyl
cellulose, et cetera, she is mixing the enteric coating with other ingredients?
A. Correct.
Q. And what
is ethyl cellulose?
A. Ethyl
cellulose is an insoluble polymer. So the idea here was to see could we obtain
a tighter enteric coat by adding 10 per cent of an insoluble material like
ethyl cellulose.
As well as we used
different plasticizers, you'll see next line, Citroflex, DB phthalate, two
different plasticizers, and we even made a mixture of ethyl cellulose and
racemic oil as hydrophobic material into the film to see how that impacted the
film properties.
[p 2201]
[257] A problem with enhancing the impermiability of the enteric coating
is noted at Exhibit 85, Tab 14. In discussing this reference,
Dr. Lovgren noted that a drawback with a tighter enteric coating is that
it may inhibit dissolution at the desired point of release.
[258] Dr. Lovgren summed up the situation as of the end of November
1980 in the following way:
Q. Okay. So
this memo we just looked at was the end of November 1980. Can I ask you, by
the end of 1980, where did things stand in terms of the development work on an
oral solid dosage form of omeprazole?
A. I think
as is reflected in these minutes, in these results we have seen for these
experiments, that we were far away from being close to a proper functioning
dosage form that behaved, had properties that was acceptable for any sort of further
clinical testing of efficacy and effect and even stability concerns. So we had
a lot of work to do still from this point, from this time point, end of 1980.
[p 2230]
[259] In early 1981, Hässle began to look at subcoats. Exhibit 85, Tab 22
is a work protocol comparing a subcoated formulation with an un-subcoated
formulation. Dr. Lovgren testified that this was the first record of a
subcoating experiment [p 2246].
[260] A summary of Hässle’s work as of May 27, 1981 can be found in
Exhibit 85, Tab 30. According to Dr. Lovgren, this confirmed Hässle was
then still looking at a variety of formulation approaches including a laminated
enteric coating.
[261] A meeting Minute from June 25, 2981 [Exhibit 85, Tab 32] notes the
project was then 6 months behind schedule due to the previous lack of substance
and difficulties with doseage forms.
[262] Minutes of a meeting on September 14, 1981 indicate that a Phase II
formulation had been selected subject to bioavailability studies.
Dr. Lovgren also noted that long term storage stability was still an
unresolved issue with respect to finding a commercially viable formulation [p 2282].
[263] According to Dr. Lovgren, the Phase II formulation lacked the
necessary stability for Phase III studies and for commercial use [p 2295].
When he was asked what was then understood about the source of the gastric acid
resistance problem, he gave the following evidence:
Q. Did you
have an understanding at that time as to what caused inadequate gastric acid
resistance in the Phase II formulations, at least by Hassle's standard, at that
point in time?
A. I think
we had an understanding after all these investigations, so for up to this, say,
end of 1981, where we are right now in the development, that we had permeation
of gastric juice, and being acidic water, and we had some ideas that that
penetration could eventually coming through the enteric coating and starting to
dissolve alkaline material being present in the core, and maybe, during that
way, started to dissolve the enteric coating from the inside, and maybe then
have some impact on the total quality. If it was started to be eating up from
the inside, then even more could, during the test, penetrate. And so that was
discussed, and we had some idea about that.
Q. Were you
ever able to confirm that idea in terms of that mechanism that you described?
A. I think I
will say yes to that.
[p 2296]
[264] The Minutes of a meting held on December 10, 1981 described the
status of Hässle’s search for a formulation in the follow way:
4. The development of granules
continues according to the following guidelines:
- Buffer
quantity adjusted for maximum stability and minimum degradation during passage
through the stomach.
- Formulation
of spherical granules will be studied with regard to excipients and technical
properties. The influence of granule size on technical properties, such as the
coating process will be studied.
- The
possibility to obtain a more diffusion tight (i.e. less permeable) film is to
be further examined.
- The
possibility of using a subcoat will be studied.
5. Process parameters, among others
regarding milling is to be studied.
6. Questions of stability to be
further studied. The importance of buffering for stability in solid phase to
be clarified.
When Dr. Lovgren was asked about the
status of Hässle’s testing at this point with particular reference to the use
of a subcoating, he gave the following answer:
Q. Okay.
Just back, I guess, to point 4 and the reference to the possibility of using a
subcoat there with reference to the granules. So did you ultimately try a
subcoating there?
A. Yes, we
did. I think we addressed all of these points that are mentioned in paragraph
4, and I think we should consider this to be efforts to obtain better gastric
acid resistance when we are talking about more diffusion tight films, and we
are talking about use of a subcoat.
Q. What kind
of a subcoating did you try after this point in time?
A. Yes. We
tried a water soluble subcoat.
Q. Did you
have, before trying the water soluble subcoat, did you have any expectation as
to whether it would work or not?
A. No. I
think the expectation was not that optimistic that a water soluble substance or
a water soluble coat should do anything dramatic in relation to gastric acid
resistance.
Q. Why did
you that view?
A. We, I
think if we had a problem which we thought we had and which we understood we
had, that it was diffusion of acidic water through the enteric coating, then
how could water a soluble substance lead to any dramatic differences when we
already had experience to making that enteric coating, for instance, thicker in
itself? And that wasn't the solution to the problem. Then we were not
optimistic that a water soluble substance should have any effect in leading to
a better acid resistance, for instance.
Q. Why not
try a water insoluble subcoat?
A. Yes. I
agree that that should have been much more logical. However, we had already
done experiments in these lines by using hydrophobic or water insoluble
material in relation to the enteric coating experiments.
Q. And is
that -- do you have any examples of that in terms of what we have looked at so
far?
A. Yes. We
have already seen how we are discussing using hydrophobic material, being the
water repellent. We have seen examples of including stearyl alcohol. We have
seen examples of including ethyl cellulose, being a water insoluble polymer, so
we had experience of that. The experience there we had was that, yes, we saw
positive effects; we saw increased gastric acid resistance. However, we entered
into a new problem, and that was the dissolution rate.
Q. And what
was the problem with dissolution rate?
A. The
problem was that, by making the enteric coating tighter, less permeable by
water repellant or hydrophobic or water insoluble material, that led to
consequences that, when we then exposed these cores, coated cores, to buffer
solutions in which we wanted a fast dissolution rate of omeprazole, we got very
low figures.
[pp 2299-2301]
[265] Comparative testing of subcoated and non-subcoated formulations is
reported in February and March 1982. Those tests showed that subcoating
improved the gastric acid resistance of the formulation. Some of the test
results are exemplified in the 693 Patent and are found at Tabs 44, 46 and
49 of Exhibit 85.
[266] A meeting Minute dated September 17, 1982 indicates that the search
for a Phase III formulation had been narrowed to two choices, one of which was
preferred. A small pilot study was proposed before a choice would be made. By
the end of 1982, the essential structural elements of the patented formulation
appear to have been identified subject to some additional testing carried out
over a period of years [see Dr. Lovgren evidence at pp 2339-2340 and
Tabs 55, 59 and 60 of Exhibit 85].
[267] Dr. Lovgren concluded his evidence in chief by confirming that
Example 2 of the 693 Patent is the formulation that is marketed by AstraZeneca.
[268] In cross-examination Dr. Lovgren was extensively questioned
about the importance of minimizing water content in the patented formulation.
Dr. Lovgren acknowledged that this was an important process parameter but
an absolute maximum value for water was not required for a viable formulation.
[269] A report authored by Dr. Lovgren and dated January 14, 1986
outlined the work done to develop an omeprazole formulation for all phases of Hässle’s
clinical studies. That report discussed the modifications to the Phase II
formulation leading to the formulation used in Phase III studies in the
following passage:
During the
enteric-coating process the phase II formulation is discoloured due to the
direct contact between the alkaline reacting pellet core and the free carboxyl
groups of hydroxyl-propyl methylcellulose phthalate. The discolouration is
avoided in the formulation used in phase III clinical studies.
4.3 Omeprazole
enteric-coated pellets used in phase III clinical studies
In order to
achieve better technical properties a modified pellet core formulation was
developed and used in phase III studies. A better product stability was also
obtained by using mannitol as filler agent. The introduction of a separating
layer of hydroxypropyl methylcellulose between the core and the enteric-coating
improves the discolouration and stability during storage. [Exhibit 94]
[270] Although Dr. Lovgren acknowledged that he had not found any
earlier explicit record reflecting a discolouration/gastric acid resistance
concern, he did reference earlier Phase II test data where the gastric acid
resistance data was inconsistent and, in some instances, fell below Hässle’s
required standard [p 2709, p 2710, pp 2712-2714]. He also
relied on the Minutes of research meetings where the problem and approaches to
overcoming it were discussed.
[271] Dr. Lovgren was not effectively impeached under
cross-examination. I accept his evidence describing the efforts that went into
the development of the formulation described in Claim 1 of the 693 Patent.
What this evidence discloses is that, while the incorporation of an ARC was an
early feature of Hässle’s work with omeprazole, the idea of using a subcoating
came much later in the development process and not before a number of other
options were explored and rejected. The subcoat idea first appears in the
research record in February 1981 but it did not become a focal point for study
until late that year. I accept as accurate Dr. Lovgren’s evidence that
the intervening references to a subcoat had to do with attempts to smooth out
the surface of the cores and not as a means of effecting a separation between
the enteric coat and the pellet cores.
[272] I am satisfied the work that went into the development of the
patented formulation was complex and time-consuming. It was decidedly not
routine bench-work. The research team at Hässle struggled to overcome the
formulation problems it encountered and explored a number of options before it
found an omeprazole formulation that was viable for Phase III clinical studies
and, ultimately, for commercial exploitation.
[273] Based on the foregoing, I find that the discovery claimed by the
693 Patent was inventive and, therefore, non-obvious.
[274] Apotex argues that there are a number of ways a stable and gastric
acid resistant omeprazole formulation can be made that do not involve a
subcoating. Because AstraZeneca concedes the person of skill would not know
without further testing whether a formulation with the structural features of
Claim 1 would actually work, Apotex says that Claim 1 is overbroad and
ambiguous. This argument is put in the following way:
8.
Apotex submits that AstraZeneca’s suggestion that the claims embrace
any formulation with the generalized structure provided they ate gastric
resistant and storage stable is a classic example of overbroad claiming.
•
In effect, AstraZeneca defines any subcoating which generates
a storage stable and gastric resistant product to be a subcoating within the
meaning of the claims.
➢ A subcoating
made up of highly reactive products is nevertheless deemed inert, because the
resulting formulation is storage stable and gastric resistance.
➢ A subcoating
made up of acidic products is nevertheless deemed non-acidic, because the
resulting formulation is storage stable and gastric resistance.
➢ A subcoating
that is 0 μm thick in certain places (i.e. has gaps) is deemed to have a
minimum thickness of 2 μm, for the same reason.
•
The approach, as explained by Dr. Kibbe, is scientifically
unintelligible:
Whether a product has a subcoating cannot
be determined by considering the stability of the formulation - there are many
other ways apart from subcoatings that these types of formulations can be made
stable. In my view, whether a product has a subcoating is determined by the
presence of a subcoating as described in the claims... (e.g., inert, soluble or
rapidly disintegrating in water). I see no basis to change that definition to
encompass a different set of attributes - i.e. the stability and acid
resistance of the final product.
•
The approach, as explained by Justice Snider, is also legally flawed.
➢ In Schering-Plough
Canada v. Pharmascience, the Court considered a claim to an “anhydrous
pharmaceutical composition”. The applicant, Schering-Plough, contended that any
compound that was stable was properly defined as anhydrous. In rejecting the
viability of this construction, the Court held:
This, in my view, is a blatant example of
overbroad claiming. The requirement of stability is analogous to growing hair
on bald men. . . one cannot stretch Claim 16 to cover everything that is
stable.
•
There is no basis for this Court to take a different approach in the
case at bar. [Footnotes omitted]
Essentially the same argument is advanced in
support of the plea of ambiguity. Apotex complains no one could, with any
measure of accuracy, determine the boundaries of Claim 1.
[275] I have no doubt there are ways to make a useful omeprazole
formulation that would not involve a subcoat and, in the United States
litigation, this proved to be the case for some defendants. Indeed,
Dr. Sherman looked for ways to work around the 693 Patent and thought he
had succeeded.
[276] One fundamental problem with Apotex’s overbreadth argument is that
the 693 Patent does not claim formulations with “highly
reactive products” or with no limitations concerning the physical
characteristics of the required subcoating. The person of skill brings to the
workbench considerable background knowledge and experience. The requirement
that the subcoating be “inert” directs the
person of skill away from highly reactive constituents. The person of skill
also knows water and heat are undesirable and seeks to minimize or control
them. The person of skill knows a subcoating replete with fissures, gaps or
other continuity deficiencies is unlikely to work and, therefore, avoids them.
[277] A patent claim is not overbroad because it leaves it to the person of
skill to avoid known unsuitable choices: Burton Parsons v Hewlitt Packard
Ltd, [1976] 1 S.C.R. 555 at pp 565-566, 1 NR 553. It is also not invalid
because it is not a model of concision and lucidity. It is to be read by the
notional person of skill who brings practical knowledge and experience to the
exercise: see Letourneau v Clearbrook Iron Works Ltd, (2005), 44 CPR (4th)
345 at para 37, [2005] ACF no 1589.
[278] In my view, the 693 Patent imparts useful and sufficient information
to the person of skill to craft an omeprazole formulation that would be
expected to solve the incompatibility problem the inventors encountered. That
some routine stability and gastric acid resistance testing would still be
required to know whether a formulation with the structural features of Claim 1
actually worked as expected does not mean the claim is overbroad or unclear.
[279] Furthermore, the 693 Patent does not contain a promise that every
omeprazole formulation with the structural features of Claim 1 will fulfill the
dual objective of good storage stability and gastric acid resistance. Instead,
it teaches the person of skill that by following its instructions and by
applying common general knowledge a useful formulation will be the expected -
not the inevitable – result. With routine testing and some adjustments, if
necessary, the person of skill is able to obtain a useful formulation.
[280] Even Dr. Kibbe seems to have conceded this point at least for
the purpose of comparing the teaching of EP 495 to that of the 693 Patent:
A. In order
for a formulation to fall within Claim 1, it has to have the elements within
Claim 1.
Q. Just the
structural elements, not the functional elements?
A. Well,
Claim 1 doesn't describe any functional elements. That all comes from the
background and the intent of the benefit of the invention. But we can
assume that a product made using the information from the 495 would be as
successful as a product made using the three elements in Claim 1, but we would,
of course, test it.
Q. Okay.
Obviously Claim 1 says what it says, but I had assumed, reading your report,
that you had come to the opinion that the disclosure portion of the 693 would
tell the skilled reader that the whole purpose of this exercise was to come up
with a gastric resistant and storage stable product that would dissolve in the
small intestine, that that was, that that was the invention here, and that
those elements, then, are understood to be part of the dosage form that is
claimed to be the invention.
A. The
elements of the Claim 1 are clearly present in the description of the 495. The
intent of Claim 1 is to have a viable product. But there is no guarantee that
just having those essential elements will make every product you make a viable
product. And so the product described in the 495 would be expected to work but
would have to be tested. And the examples in the 693 which had the three
elements that the patent eventually patented were expected to work, but they
were tested. And in some cases, the products without one element or
another didn't work as well. [Emphasis added]
[281] The difficulty facing a patentee in a case like this is to draft the
claims in a way that will afford a reasonable level of protection. If the
claims are drafted too narrowly, they are easily avoided and if they are
drafted too broadly, they are vulnerable to validity attack. If AstraZeneca
had claimed a very specific structural formulation, a competitor could easily
design a work-around. At the same time, AstraZeneca had to provide sufficient
information for others to work the invention at the close of the patent
monopoly. The formulation claimed in the 693 Patent achieves the appropriate
balance in the sense that it affords protection for a useful discovery without
sacrificing the enablement requirement. The fact that the person of skill
needs to apply some basic knowledge or routine testing to work the invention is
not fatal to the claims as drafted because the essential framework of the
invention is provided. I made the same point in Delp v Fresh Headies
Internet Sales Ltd, 2011 FC 1228 at paras 13 to 19:
[13] The Defendants’ contention that
the patent contains a promise of utility at all temperature points within the
stated range of 0°C to 15°C is, therefore, incorrect. The promise of the
patent is that it will work for different plants at different temperatures and
that the person skilled in the art will be quite capable of optimally working
the invention through some routine trial and error.
[14] The fact that some adjustments may
be required by a person skilled in the art to work an invention does not render
a patent void for inutility. I am reinforced in this view by the Supreme Court
of Canada decision in Burton Parsons Chemicals Inc v Hewlett-Packard
(Canada) Ltd, [1976] 1 S.C.R. 555, 54 DLR (3d) 711 and by the House of Lords
decision in Henriksen v Tallon Limited, (1965) RPC 434 HL (Eng).
[15] Burton Parsons concerned a
patent for the invention of a conductive cream useful in facilitating
electrocardiograms. The argument advanced there for inutility was similar to
the one advanced in this case: that the patent claims were broader than the
effective scope of the invention. The Court did acknowledge the basic point
that where the scope of a claim includes some method which is useless,
the claim cannot be saved by showing that no skilled person would ever try that
method. Nevertheless, the Court found that a patent does not fail simply
because it leaves some room to the person skilled in the art to employ suitable
methods or materials.
[16] I do not read Burton Parsons,
above, as narrowly as counsel for the Defendants urged. It did not turn solely
on the language of the impugned claim which included a reference to the product
being compatible with normal skin. The Court went further than that as can be
seen from the following passages:
This is the
distinguishing feature from the other cases in which the properties of
xanthates in froth flotation and those of some substituted diamines as
antihistamines were the object of the invention. The inutility of cellulose
xanthate in Minerals separation as well as that of some isomers of
tripelennamine in Rhône-Poulenc was not known to the prior art. This is totally
unlike the undesirable properties of some highly ionizable salts which
Hewlett-Packard listed as objectionable. Their noxious character was well known
and no man skilled in the art would have thought of using them in making a
cream for use with skin contact electrodes any more than any such worker would
have needed to be told that in making such a cream, he had to use such
proportions of liquid and of emulsified material as to obtain a suitable
consistency.
Such
applications of the art of a skilled person is to be put on the same footing as
the addition of a pharmaceutically acceptable carrier to a drug when this is
required for its proper administration. In Commissioner of Patents v. Farbwerke
Hoechst A.G. [[1964] S.C.R. 49], this Court held that this last step in the
production of a drug in dosage form was not patentable because there is no invention
involved in it. In my view, the avoidance of unsuitable salts due to their
known noxious properties is similarly nothing but the application of the proper
knowledge to be expected from a man skilled in the art. In Sandoz Patents Ltd.
v. Gilcross Ltd. [(1973), 8 C.P.R. (2d) 210], we had no hesitation in upholding
claims for "therapeutically tolerable salts" of thioridazine to be
obtained by reacting "with a therapeutically acceptable acid". I
cannot think that the omission of the qualification "therapeutically
acceptable" would have voided the patent and I will note that in the
Rhône-Poulenc case this question was left open.
[17] To similar effect is the House of
Lords decision in Henriksen, above. There the Court emphasized the
point that a patent need only describe the invention in a way that will permit
the skilled reader to work it. Beyond that, the patentee “is entitled within
fairly wide limits to leave it to the addressee to choose appropriate material
from a class which he specifies if he makes it plain that the choice is left to
the addressee.” [see p 441]. This point is made again in the following
passages from the decision:
I can now return to what I have
called the crucial question. Claim 1 applies to jumbo as well as to capillary
tubes. One must approach its construction with the knowledge of the skilled man
that a liquid can form a satisfactory plug in a capillary tube but that no
liquid can do so in a jumbo tube. There a paste-like mass is required. If the
patentee has asserted or represented that even for a jumbo tube a liquid can be
used (if the right one is chosen) then, the claim is invalid and it is not
saved by the fact that the skilled man knows that that is untrue. But if he has
merely asserted that the addressee must choose a suitable liquid or viscous or
paste-like mass as the case may be according to the kind of tube he wants to
make then the objections of inutility and false representation disappear.
Applying the ordinary methods of construction I have no doubt that the latter
is the true meaning.
It is a general principle of
construction that, where there is a choice between two meanings, one should if
possible reject that meaning which leads to an absurd result. One must construe
this claim with the knowledge that the skilled addressee would know that it
would be absurd to claim that any kind of liquid plug could be effective in a
jumbo tube. That factor, added to those to which I have already referred, tips
the scale conclusively in favour of the latter meaning. I have therefore no
doubt that claim 1 is valid.
[per Lord Reid at p 443]
…
The claim must be fairly and
reasonably construed and words must be given a natural and not a strained
meaning. As a matter of construction it may well be that the words in claim 1
give rise when they are read to a moment of hesitation. In the words “a liquid
or a viscous or paste-like mass” does the word “or” denote that each one of
several kinds of plugs may in each and every one of several kinds of pens be
used, or does it denote that a process of rational selection is involved? When
construing the specification it is reasonable to pay regard to the fact that
the claim is addressed to persons skilled in the art. How, then, would the
skilled pen-maker understand claim 1? He would, I consider, understand it as
giving him an answer to the problem of preventing that deterioration of ink
which contact with the air will cause. He and he alone would know what variety
of ball tip fountain pen he proposed to produce: he and he alone would know
what size and type of reservoir he intended to use: he and he alone would know
what kind of ink he proposed to use (which might be in a fluid or pasty
condition). If he were following the direction contained in claim 1 and wished
to have a plug for the purpose of keeping the air from the ink he would choose
that form of plug (within the range of a liquid or viscous or paste-like mass)
which would be appropriate for his pen. He would know that (within the range of
a liquid or viscous or paste-like mass) he must choose so that (a) his plug
will not mix with his ink and (b) so that his plug must move with the surface
of the ink column and (c) so that his plug will prevent air from contacting the
surface of the ink. He would not consider that any and every kind of viscous or
paste-like mass would do for any and every kind of pen or for any and every
kind of ink. He would not consider that a liquid plug would do for any and
every pen and for any and every size of reservoir. He would not consider that
the inventor was so claiming. He would understand that in following claim 1 he
would be directed to choose such form of plug (within the range of a liquid or
viscous or paste-like mass) as would be appropriate for the pen he was
producing having the kind and size of tubular ink reservoir that he was
adopting and with the kind of ink that he was using. A pen maker skilled in the
art could by trial and error and without the exercise of any inventive faculty
readily discover for himself the particular type of plug that suited his
particular type of pen (compare No-Fume Ltd. v. Pitchford (1935) 52
R.P.C. 231).
[per Lord Morris at pp 446-447]
[18] In this case, the 815 Patent
claims an invention over a new method for extracting resin from different plant
species by using an ice-water bath. I have no doubt that the skilled person
would be capable of working the invention by the described method without
adding any inventive ingenuity to the exercise and, indeed, the patent
expressly contemplates the application of some practical skill depending on the
nature of the plant material being utilized.
[19] Counsel for the Defendants
submitted that the 815 Patent could have been saved by omitting any temperature
range from the claims and by substituting a reference to “water at a suitable
temperature”. However, that is what the drafter did by the device of leaving
it to the skilled person to find a suitable operational temperature. Such a
person would not assume from the patent language that the claimed method would
work optimally, or necessarily at all, with any beginning temperature in the
stipulated range. [Emphasis in original]
[282] If, as I have found, the promise of the patent is a formulation
meeting the essential structural elements of Claim 1 that would be expected to
provide good gastric acid resistance and long-term storage stability, the utility
of the invention has been demonstrated. This point was effectively acknowledged
by Dr. Kibbe in the following exchange:
A. Right.
If they made something that was identical to one of the examples, then they
would be very confident that when they tested it, it would work in their
hands. Then if they wanted to use different excipients, let's just say they
wanted to use mannitol instead of lactose, that probably would work. It fits
the general requirement of the active ingredient plus an ARC or an enteric coat
and an intermediate coat. But they certainly would test it.
Q. Right,
so in a sense, the patent, it shows the reader the way; that, you know, these
are the elements, this is my concern, I got to have an ARC, the reader knows
about solubilities, et cetera, and so the reader can assimilate that
information and apply it to make other formulations that the reader would have
a reasonable expectation would work?
A. Right.
Q. But
they'd have to test to make sure?
A. Well,
we always test.
Q. Okay.
A. I mean,
you -- well, you just can't go on faith.
Q. And then,
I guess there is some more of the same in paragraph 89, looking at this about
six lines down, you are talking about Examples 2 to 8, and six lines down, you
say:
"I note that
there is no indication in the patent disclosure as to whether any of Examples 2
to 8 were tested for all three characteristics."[as read]
And then you set
those out in parenthesis, and then you say:
"But given the
similarities between the preparations, the skilled person would understand that
each preparation would have the properties that the patent promises for
them."[as read]
So that's the same
notion, that there is a teaching, and the skilled person would understand that
it should work, but they would always have to test.
A. Right.
And the point would be, like, for instance, Example 5, it has 93 per cent acid
resistance but there is no appearance. Well, I would have to check, you know,
you go back and look; right? And that's the same with this missing data, you
would go back and test that study that wasn't done.
Q. Right,
but you are saying that based on the information in the patent, the skilled
reader would have an understanding that even though test results for all three
things were not included for every example, as you put it, given the
similarities between the preparations, the skilled person would understand that
each preparation would have the properties promised.
A. They
would -- the skilled person --
Q. They
would expect?
A. -- they
would expect it. [Emphasis added]
[283] I am accordingly satisfied that the promised utility of the 693
Patent has been demonstrated.
[284]
What remains for determination is whether
Apo-Omeprazole infringes Claim 1 of the 693 Patent and its dependant
claims and, in particular, whether that product incorporates an inert
subcoating that is soluble or rapidly disintegrating in water disposed on the
core comprising one or more layers of polymeric film forming compounds.
[285] The Apotex experts went to considerable length to attack
Dr. Davies’ methods and his scientific integrity with the intent of
casting doubt on his findings. Virtually all of their methodological criticisms
fell well short of the mark.
[286] Dr. Amos was specifically retained by Apotex to review
Dr. Davies’ CLSM methods and to comment on the reliability of
Dr. Davies’ opinions concerning those images. Dr. Amos was also
asked to consider the CLSM images obtained at Temple University. Dr. Amos
carried out no independent imaging of the Apotex omeprazole pellets.
[287] Dr. Amos is an exacting scientist with very high methodological
standards. He is particularly knowledgeable about the use of CLSM technology
having been intimately involved in its development between 1983 and 1986 and he
is a recognized expert in the field. Nevertheless, he has had virtually no
experience using CLSM technology to analyze pharmaceutical doseage forms. This
substantially weakened his evidence insofar as he was attempting to interpret
the relevant images.
[288] Although I accept that Dr. Amos is extremely bright and
intimately aware of the intricacies of CLSM theory and practices, he was a less
reliable witness when he was making assumptions – particularly with reference
to Dr. Davies’ opinions and motivations. The overall impression left by
Dr. Amos was that his concerns about Dr. Davies’ methods unduly
coloured his assessment of the data that Dr. Davies obtained. In my view
those data had considerably more scientific value than Dr. Amos was
prepared to credit to them.
[289] Many of Dr. Amos’ criticisms of Dr. Davies’ opinions
relate to deviations from his own preferred methods. He expressed concern
about the quality of Dr. Davies’ images and was of the view that better
evidence could have been obtained had better practices been followed. In some
cases Dr. Amos made unwarranted assumptions about what Dr. Davies had
actually done and he assumed the worst.
[290] For example, Dr. Amos was sharply critical of Dr. Davies
for failing to explicitly state in his initial report that some of the CLSM
images he had used were maximum intensity images that could visually
misrepresent the underlying data. Similar concerns were expressed by
Dr. Bright.
[291] The problem with the use of maximum intensity images is one of
potential bias. These images are effectively composites because they draw
three dimensional data from below the surface of the sample and project all of
the data onto a two-dimensional image. To the uninformed viewer this can
magnify or intensify the resulting fluorescence and may suggest it is all
emanating from the surface of the sample. Dr. Amos testified that by not
appropriately advising the reader, Dr. Davies was attempting to pass off
his projections as raw data:
Q. The
absence of any depth information, wouldn't that have been an indication to a
skilled microscopist, such as yourself, that it was some sort of projection?
A. No.
Because other images were individual Z scans, and the mere omission of
information from a title in a report was not clear enough an indication that
this was manipulated data rather than raw data. And the difference between the
maximum brightness projection and raw data is so significant in a scientific
report that it should be explicitly stated in the legend to the figure. It's
not something that should be left for somebody to infer from the absence of
figures. It's really I am trying to keep this to the facts, but let's just
say that somebody looking at the report of Dr. Davies could be deceived by
this, because there is not a clear enough indication that what is being shown
is manipulated data using a dangerous and inappropriate method of projection
and that that is not raw data. That is the uncharitable view would be that
he was passing it off as raw data.
Q. You
weren't deceived?
A. Well, I
was, I was at first a little confused, but I worked it out in the end. I
certainly was not able to work out that it was a maximum brightness projection
until I saw Dr. Davies doing the same manipulation and showing that it
generated this remarkably, apparently continuous fluorescent layer.
MR. HACKETT: This
is not an objection. I just think Dr. Amos misspoke when he said he saw Dr.
Davies doing it.
THE WITNESS: Sorry,
Dr. Bright. [pp 3090-3091]
[292] The above evidence was, in fact, an excessively pejorative view of
Dr. Davies’ approach and it was not untoward for Dr. Davies to
characterize the criticism as “scurrilous”. Dr. Davies
gave extensive evidence in the proceeding in the United States involving Apotex
and clearly acknowledged his use of maximum intensity imaging. Those
acknowledgements were well-known to Apotex and they were also contained in the
evidentiary record that Dr. Davies included with his reports in this
proceeding. With a careful examination of Dr. Davies’ data,
Dr. Bright was able to discern that some of the images were maximum
intensity projections. The problem identified by Dr. Amos, such as it was,
was more the making of Apotex than of Dr. Davies. The information was
known to Apotex and therefore available to its experts. It was, accordingly,
unwarranted for Dr. Amos and Dr. Bright to suggest Dr. Davies
was attempting to pass off maximum intensity images as something else.
[293] Dr. Amos, Dr. Griffiths and Dr. Bright all went out
of their way to identify issues with Dr. Davies’ testing methods or to
challenge his results whether or not there was evidence to support their
purported concerns.
[294] No reasonable reading of Dr. Davies’ report would attribute to
him a belief that the Apotex omeprazole pellets and, in particular, the
sublayer, were totally opaque. Nevertheless, Dr. Amos and Dr. Bright
made that assumption and then went to considerable effort to prove
Dr. Davies was mistaken. Dr. Amos’ attribution of a mistake to
Dr. Davies is even more surprising in the face of his concession under
cross-examination that “opaque” is not a precise
scientific term [p 3092] and that it can be used in a relative sense [p 3093, p
3096]. He also accepted that a substance shown to emit fluorescence at depth
(as Dr. Davies had shown) cannot be considered totally opaque [p 3101].
Notwithstanding that evidence, Dr. Amos also testified that “opaque is opaque” and we do not normally speak of
degrees of opacity [p 3092]. This is an example of both Dr. Amos and
Dr. Bright going well out of their way to unjustifiably find fault with
Dr. Davies and it detracts from their credibility.
[295] Other examples of unwarranted criticism by the Apotex expert
witnesses include the suggestion by Dr. Bright that Dr. Davies’
washed pellets may have been contaminated by drying paper or by the resin he
had used to fix the samples for imaging. Those assertions were clearly
intended to discredit Dr. Davies and to characterize him as a sloppy scientist.
In the end, there was no reliable evidence produced to back up these points
and, indeed, the evidence that did emerge was to the contrary. Dr. Bright
was unable to satisfactorily explain why the fluorescent ring that was present
in the images of the unwashed pellets that had not been exposed to drying paper
looked the same as the imputed contaminated washed pellets. No fair-minded
observer would speculate that Dr. Davies had buried every one of his
pellet samples in resin before they were imaged, particularly after
Dr. Davies had explained what he had done. And yet, even in his trial
testimony, Dr. Bright refused to completely abandon these concerns.
[296] The Apotex witnesses were also critical of Dr. Davies’ efforts
to remove the enteric coating from the Apotex pellets by washing the pellets in
acetone. In my view those criticisms were unjustified.
[297] There is no basis for questioning the acetone washing technique
employed by Dr. Davies. He used a solvent known to solubilize the enteric
coating in a simple washing experiment. As he expected, the wash readily
removed the enteric coating and he was able to examine what was left behind.
The CLSM images he obtained showed the presence of a distinct layer both before
and after the wash. In other words, the sublayer remained intact. In
comparison, the fluorescent ring was not detected when the naked Apotex cores
were similarly analyzed. The reflectance images taken from the washed pellets
depict the same layer with a distinct composition from the inner core
material. The same layer is seen in Dr. Davies’ water disintegration
videos. Dr. Davies and Dr. Bodmeier established that the sublayer has
distinct chemical properties. If the sublayer had a similar solubility profile
to the enteric coat, one would expect it to be completely removed by the
relatively large volume of acetone used, particularly after 4 minutes. These
results cannot be explained away by hypothetical criticisms and possibilities.
[298] An implicit criticism of Dr. Davies’ results is that he may
have been selective in the choice or use of test data. I reject any suggestion
that Dr. Davies manipulated his data. In particular, there is absolutely
no evidence that Dr. Davies or his research team selected their data to
fit a hypothesis or ignored or discarded contradictory or ambiguous results.
The experiments Dr. Davies designed and carried out or supervised were
readily reproducible. Apotex was well aware of those methods having been a
party to the United States litigation where Dr. Davies testified at
length. With only a few variations, the tests he carried out in this case were
identical to those performed in the United States. The Apotex expert witnesses
were, therefore, well informed and quite capable of replicating
Dr. Davies’ work or of modifying that work to attempt to improve upon it.
In large measure, they failed to do so and, instead, focused their criticisms on
methodological matters. It is easy to take pot-shots from the sidelines; it is
riskier to challenge experimental data head-on. The limitations inherent to
Apotex’s approach were noted by Justice Hughes in AbbVie Corporation et al v
Janssen Inc, 2014 FC 55 at para 62, [2014] FCJ no 59, 116 CPR (4th) 399,
237 ACWS (3d) 473, where he said:
[62] Only AbbVie conducted tests on the
Janssen STELARA product. Notwithstanding that STELARA is Janssen’s product, and
that Janssen undoubtedly has the means to perform the necessary tests on its
product, it did not provide in evidence the results of any such tests. Janssen
chose only to offer criticisms of the tests performed at the request of AbbVie.
Accordingly, I must weigh the AbbVie tests only against criticisms, and not
against other tests. If Janssen clearly believed that its product did not fall
within certain parameters, I would have expected it to provide evidence as to
testing that demonstrated that fact.
[299] Apotex also objects to Dr. Davies’ evidence, in part, because
his testing was carried out ex parte. The Court now has a testing protocol dealing with this issue but
at the time of Dr. Davies’ work there was no strict requirement that
expert testing be opened up to opposing parties. The legal considerations that
apply to this situation were described by Justice Hughes in AbbVie
Corporation et al v Janssen Inc, above, at para 64:
[64] Unlike the practice in the United
Kingdom as described in the “White Book”, Civil Procedure, Volume 2, 2013,
Sweet & Maxwell, London at page 730, there is, as of yet, no Federal Courts
of Canada Rule specifically directed to testing conducted for the purposes of
trial. In Omark Industries (1960) Ltd v Gouger Saw Chain Co, (1965) 1
Ex C R 457 at page 516, Justice Noel discussed a “salutary” rule to the effect
that an opposite party should be given notice of and an opportunity to attend
at such experiments. He did, however, also say that an ex
parte test may be admissible, subject to weight,
particularly where, in his case the opposite party could readily have conducted
the same test. Most recently Justice O’Reilly of this Court in Apotex Inc.
v. Pfizer Canada Inc., 2013 FC 493 at paragraph 40, held that where a party
had ample notice as to the testing and ample knowledge as to what would be
done, a party cannot be held to say that the testing results are inadmissible
because the party did not attend.
[300] Dr. Davies’ work was appropriately recorded and the results
were subject to review and criticism. Indeed, the Apotex experts did not
appear to be disadvantaged in criticizing Dr. Davies’ work. Although
Dr. Davies did not record every test he performed, he did produce
reviewable, representative data. He also testified that no results were
obtained that were inconsistent with the data he produced. In this context,
there is no basis for Apotex to complain that the work was performed without
prior notice.
[301] I had a good opportunity to assess Dr. Davies. He is a
cautious and careful person not prone to excess or exaggeration. He has
developed a solid academic and professional reputation that would be
jeopardized by taking an unprofessional approach to research. In a situation
like this where Dr. Davies’ work could be easily reproduced, I reject any
suggestion the results he obtained were anything other than he has reported.
[302]
I take Apotex’s point that
Dr. Davies’ memory of the 2004 testing methods was shown to be somewhat
inconsistent and there is no doubt, had all of the methods used been recorded
contemporaneously, those gaps in memory would have been overcome. But in the
end, the points of uncertainty do not materially impact the results he had
obtained. There is no basis for the Court to refuse to consider
Dr. Davies’ test results or to treat them with suspicion. What remains to
be determined is how those results should be interpreted.
[303]
There is no question on the evidence that a
distinct structural layer is present at the interface of the Apotex pellet
cores and the enteric coating. It is also not a matter of serious controversy
that MACP-PVP complex is present within that sublayer. The complex is
indisputably the end product of an in situ chemical reaction that occurs when the enteric coat is applied by
Apotex to the pellet cores. Although Dr. Griffiths was unjustifiably coy
in his reports about the presence of the complex [paras 25, 126, 131, 140,
158, 162, 165, 194 and para 7 of his Reply report] he did admit in his
testimony that the complex was present in the sublayer [pp 3533-3534; also
see Dr. Bright’s testimony at p 4079]. Even Dr. Sherman seems to
have anticipated a reaction between the enteric coating and the pellet cores although
he disputed the possibility of an in situ subcoating [see p 183 of Volume 23B].
[304] One example of Dr. Griffiths’ initial lack of objectivity on
this issue can be seen at paragraph 165 of his report. Instead of
acknowledging that some of the spectra from the surface of the washed pellets
were, in fact, identical to those seen in the spectra of Dr. Davies’ pure
complex, all Dr. Griffiths would say was that “some
of the major bands in these two spectra may be identical [emphasis
added]”. Dr. Griffiths was not otherwise hesitant to ascribe
unreserved meaning to spectral peaks when it supported a point he was making.
[305] Dr. Griffiths’ initial unwillingness to concede the obvious
reflects a lack of objectivity and detracts from his credibility. It bears
repeating that expert witnesses are not advocates. The role of an expert
witness is to fairly acknowledge points of agreement and to take issue only
where an honest scientific disagreement arises. Dr. Griffiths should have
conceded from the outset the factual matters that were not in dispute.
[306] What fairly remains in dispute in this case is whether the complex is
a polymeric film forming compound (or is comprised of such compounds) and
whether the complex constitutes a substantially continuous and inert subcoating
that is an effective barrier between the pellet cores and the enteric coating.
According to the Apotex witnesses, AstraZeneca failed to establish the complex
is sufficiently present to constitute an effective separating layer. They also
maintain, whatever the precise composition of the sublayer may be, it is
replete with holes and gaps. Given the likely presence of omeprazole degradants
and unreacted acidic functional groups in the sublayer, it also cannot be
considered to be inert.
[307] Apotex argues that AstraZeneca failed to prove the “alleged” subcoating that forms in its pellets from a
reaction between MACP and PVP is a polymeric film forming compound. Apotex
challenges the weight of the evidence offered by Dr. Davies and
Dr. Bodmeier on this point but it put forward no evidence of its own.
[308] Dr. Davies’ initial report characterized the MACP-PVP complex
in the following way:
147. The MACP-PVP complex and MACP salt
are polymeric film forming compounds. Further, the film forming characteristic
of the subcoat is demonstrated by the fact that the complex forms and adheres
to the core in the Apotex product as shown by CLSM. The polymeric film is also
visible as a sheeting or coating in the disintegration images and videos.
This evidence was corroborated by
Dr. Bodmeier at para 136 of his initial report.
[309] Dr. Davies testified that MACP and PVP are each well known polymeric
film formers and he provided references to that effect [p 795-797]. He
also testified that he observed the MACP-PVP complex coming away from the
Apotex pellets in his water disintegration tests in the form of a film
[p 799]. This testimony is fully consistent with the associated videos
tendered in evidence.
[310] In the absence of a direct challenge to this evidence, I am
satisfied AstraZeneca has met its burden of proof on this point.
[311] The evidence concerning the structural continuity of the Apotex subcoating
layer was troubling. Dr. Davies stridently resisted the suggestion the
subcoating layer presented any holes or gaps. Dr. Amos and
Dr. Bright were equally dogmatic in their views that the Apotex sublayer
was replete with major discontinuities in the form of gaps and holes and
presumably the sublayer served no useful purpose by being there.
[312] In my view the truth lies between these extremes but much closer to
the views expressed by Dr. Davies than by Drs. Amos, Griffiths and
Bright whose evidence was successfully challenged on many points under
cross-examination. I am satisfied the Apotex sublayer does contain minor
defects of no functional significance – perhaps, in part, because of
Dr. Kibbe’s explanation that, in the presence of water, the complex could
absorb water and close down any imperfections present in the dry state.
[313] On this issue there was some common ground developed between
Dr. Amos and Dr. Davies. For instance, Dr. Amos agreed with
Dr. Davies that the presence of large undefined areas or gaps in
Dr. Davies’ and the Temple University CLSM images was likely caused by a
loss of focus [see p 3038, p 3046, p 3048 and para 68 of the Amos
report] or from a loss of signal at depth [p 3047]. Dr. Amos agreed
that these areas of the images were not appropriate to assess the continuity of
the sublayer [p 3050] or its thickness [p 3051]. Dr. Amos attributed the
loss of focus to the sample surface not being planar [p 2955].
[314] Dr. Amos also partially accepted Dr. Davies’
interpretation of five CLSM images that Dr. Bright had used to attempt to
show discontinuity in the fluorescing sublayer. Dr. Amos agreed that one
of those images (z=49) was not suitable to assess the continuity or thickness
of the sublayer [pp 3051-3052]. He also said that the absence of sublayer
fluorescence in a CLSM image taken at depth (z=0) could be caused by a weak or
absent signal or it could be from a large gap in the sublayer [p 3053].
Nevertheless, in the end, he adopted the view that most of the gaps evident in
the sublayer fluorescent ring were caused by breaks or holes in the sublayer
and not by a loss of signal.
[315] Dr. Amos did acknowledge the general absence of fluorescence in
those areas of the images taken below the pellet surface could be explained by
signal attenuation in the partially opaque sample [pp 3071-3072]. This
would not, however, explain the apparent discontinuities he said he could see
in those areas where the signal was very strong [p 3056]. According to
Dr. Amos those were actual holes [p 3056]. To Dr. Amos this
explanation was a “unifying theory” that best reconciled all of the available CLSM data.
[316] Dr. Amos’ testimony about the presence of gaps and holes was
substantially less equivocal than the language used in his reports. In his
report, he described the sublayer anomalies as “apparent
gaps”, “possible holes”, “seems to have holes or lacunae” and “perhaps consist of isolated flakes”. He also
labelled the images he chose with similar expressions of uncertainty and
question marks. Dr. Amos justified his initial use of equivocal language
as a cautious scientific approach taken to each piece of evidence. He
characterized his ultimate written conclusion about the existence of holes in
the sublayer as being firm. This is not completely borne out by his report
where, after a lengthy critique of Dr. Davies’ methods and the quality of
his images, he offered his conclusion without much conviction [see paras 61
and 69 of the Amos report].
[317] In contrast, under cross-examination about his description of a “possible hole” in Figure 8, his opinion had
reached the point of “overwhelming probability”,
it was “really a hole” [p 3187] and beyond a
reasonable doubt [p 3188].
[318] Although Dr. Amos testified that he observed holes in the CLSM
images depicting the surfaces of samples, it is noteworthy that the one image
he relied upon in his report to depict a “possible
hole” [ie Figure 8] was taken at depth. The other images he produced at
trial [Exhibit 110] were also taken at depth and Dr. Amos conceded
that he could not be certain that the loss of fluorescence in places
represented actual holes [pp3204-3205]. The failure to directly challenge
Dr. Davies’ opinion that the most reliable evidence of fluorescent
continuity came from the surface of the samples is striking. One would have
expected Dr. Amos to produce multiple surface CLSM images at 50X
magnification showing holes instead of the less reliable images taken at depth
where signal attenuation was a confounding variable.
[319] At one point Dr. Amos appeared to revert to his initial
qualified view of Figure 8 (“the things could be holes
and that frame averaging should have been done”) only to conclude
Dr. Davies’ response to his guarded approach contained “a certain degree
of mockery” [p 3199]. This answer suggests Dr. Amos’ views about
sublayer continuity hardened somewhat in the face of what he took to be
unjustified and unscientific criticism by Dr. Davies.
[320] What is also difficult to comprehend about Dr. Amos’ views
about sublayer continuity is how he could express so much confidence about what
he claimed to see in Dr. Davies’ images in the face of his strong
criticisms about the quality of those images. If Dr. Davies’ images were
insufficient to support his opinions, they were equally insufficient to support
Dr. Amos’ contrary view. My impression of Dr. Amos’ evidence is that
what was written under the supervision of legal counsel was a more accurate
representation of his views than his sometimes firmer trial testimony.
[321] When Dr. Amos was taken to Dr. Davies’ 50X magnification
CLSM images from stub 6 [Exhibit 11], he agreed the sublayer fluorescence at
the sample surface was in focus and depicted no obvious holes. This evidence
was qualified by his belief the image (along with many others) was saturated
and unreliable [pp 3227-3233]. Dr. Amos accepted that CLSM data from
the pellet surface could be important but he apparently felt Dr. Davies
had destroyed their value by saturating his images.
[322] What these images show is, at the sample surface, there is a substantially
continuous fluorescent band. As the Z-scan images depart from the surface, the
continuity of the band begins to break up. Dr. Davies attributed this to
the attenuation effect. To some extent even the Apotex witnesses eventually
acknowledged that signal attenuation in a substantially opaque and
heterogeneous sample could interfere with the quality of the received signal. For
example, Dr. Bright was asked about the concept of signal attenuation. He
answered in direct examination that, although the CLSM signal will lose
strength as it probes deeper into a partially opaque sample, the loss would be
expected to be uniform. Accordingly, if a feature of a sample was continuous,
defects ought not to appear in the image at depth. The signal would simply
deplete in a uniform way [p 3888]. This expected pattern was not what
Dr. Bright observed in Dr. Davies’ CLSM images where, at depth,
numerous defects, holes and breaks appeared throughout the sublayer
fluorescence [p 3894].
[323] This evidence was not fully consistent with Dr. Bright’s
evidence under cross-examination. In a lengthy exchange [pp 4097-4104]
Dr. Bright agreed the Apotex pellets are not homogenous in terms of their
opacity and, even within the various pellet structures, the CLSM signal was unlikely
to be homogenously absorbed [p 4099]. Dr. Bright simply could not say
with certainty whether sublayer absorbance would be homogeneous or heterogeneous
[p 4101] or that the loss of signal at depth would be uniform in all
places [p 4104].
[324] Dr. Bright also held to his view that it was wrong for
Dr. Davies to draw a correlation between the presence of a fluorescent
ring at the enteric coating-core interface and the infrared data showing the
presence of the complex in that area. His testimony at pp 4160-4161
explained the problem as he saw it:
A. So the
fluorescence doesn't -- does not tell one anything about the MACP-PVP per se
because it doesn't detect it. It's telling me that there is some fluorescence
there. And that's the disconnect, is there is no connection between the
fluorescence and the infrared in terms of connecting what is fluorescent to the
infrared characteristics. One has to make an assumption to do that.
[325] What is interesting about the way Dr. Bright approached this
issue is how selective he was in the choice of relevant data. He acknowledged
that his primary focus was on “the fluorescence aspect
and the microscopy aspect of things” [p 4072]. He paid scant attention
to the reflectance images that, by his own somewhat guarded acknowledgement,
depicted a different “average topology” to the
core. Dr. Bright’s reluctance to attribute significance to the distinct
topology depicted in the sublayer reflectance images and their substantial
physical conformity to the fluorescent sublayer band detracts from his overall
opinion. His testimony on these points [p 4165] was unconvincing as was his
very non-committal evidence dealing with Dr. Davies’ water disintegration
videos. An objective assessment would have required Dr. Bright to
consider all of the data obtained by Dr. Davies and from the Apotex
testing and not to essentially ignore evidence that did not fit with his
views.
[326] I agree with Dr. Davies: the best available evidence of
fluorescent continuity comes from data obtained at or very near the sample
surface where the image is in focus. The fact that continuity anomalies
commonly appear at depth and hardly ever at the surface of the bisected pellets
indicates the anomalies are related to a loss of signal or the loss of focus and
they do not represent actual gaps or holes.
[327] I reject Dr. Amos’ singular view that many of Dr. Davies’
CLSM images were “grossly” saturated.
Dr. Amos claimed he was able to visually detect saturation. His concern
about saturation appeared to grow as his evidence unfolded. By the time he was
cross-examined, he offered the opinion that the “majority”
of Dr. Davies’ Z-scan images were saturated and, when projected, gave a
false impression of continuity.
[328] None of the other witnesses professed to have the ability to
visually detect saturation nor did they express any concern about this issue.
Dr. Bright assessed some of Dr. Davies’ images and found no evidence
of saturation [p 4219, pp 4222-4223]. He was apparently not comfortable with
the idea that saturation could be visually observed and testified “I would measure it”.
[329] Dr. Amos empirically assessed one of Dr. Davies’ images
for saturation using image analysis software. The data he obtained are set out
at Figure 12 of his report in the form of a curve that flattens at a gray level
value just about 150. Those data are equivocal and Dr. Amos’ attempt to
explain their significance was not compelling [p 2993].
[330] Dr. Davies testified that he used the appropriate method to
avoid the problem of saturation. I do not accept that Dr. Davies was
unmindful of the need to avoid saturation and failed to employ the available
and routine safeguards. Dr. Amos’ evidence on this point was not
believable and it detracts significantly from his overall credibility.
[331] Dr. Bright’s evidence about the presence of numerous gaps and
holes in the fluorescent ring depicted in Dr. Davies’ CLSM images was
similarly not convincing. His initial report contains a significant error
based on a false assumption. In his initial report he stated that as
individual Z-scan images were recorded through the Apotex pellets the
expectation would be that the fluorescent ring would be largely the same
[para 69 of Dr. Bright’s report]. He contrasted this with
Dr. Davies Z-scan images where he noted discontinuities in the fluorescent
sublayer. In making this observation, he included images taken from deep in
the sample and also from above the pellet surface. On cross-examination, he
conceded that his reliance on these images was wrong and that he also did not
appreciate the pellets were being imaged on a slant. He went on to acknowledge
that, as the CLSM probes more deeply into a partially opaque sample, the signal
is attenuated and provides less reliable information because of the
interference of background noise:
MR. JUSTICE
BARNES: I think you said a minute ago that, and correct me here if I am wrong,
that the further down you go, the less reliable the image for assessing
continuity? The deeper you go, you are losing some signal, and does it make
those scans less reliable as evidence of continuity?
THE WITNESS: So I
apologize for interrupting.
I think as one gets
as the total signal drops in an experiment, at a given Z position, you become
completely noise dominated, and, therefore, you can't discriminate. It becomes
difficult to tell if there is anything there. So I think that's the answer you
are looking for.
[332] This evidence is generally consistent with Dr. Davies’ view
that the best evidence of sublayer continuity is obtained at or very near the
pellet surface.
[333] Dr. Griffiths’ testimony concerning the existence and extent of
gaps in the Apotex sublayer was also not convincing. The opinion he gave in
his report manifestly overstated the significance of the mannitol signal
obtained from some of the ATIR spectra. His initial opinion given in
direct-examination was that up to 50% of the recorded signal was contributed by
mannitol in the pellet cores thus showing gaps in the MACP-PVP complex of about
50% of the area of interrogation [p 3400]. Under cross-examination he
acknowledged the spectra in question exhibited enormous variability [p 3558]
and were not internally consistent. He attempted to explain the variability in
band intensities by a possible contact problem between the internal reflection
element of the instrument and the sample [p 3465, pp 3471-3473].
Notwithstanding the unexpected intensity in the spectra for the complex, he
maintained his position that the intensity of the mannitol bands was evidence
of large gaps in the complex [p 3467].
[334] When Dr. Griffiths was asked about the range of error that
applied, he said that “[t]here is quite a lot of
estimation around here” and he reduced his estimate of gaps in the
complex to a range of between 25% to 50%. He said that 25% would represent the
bottom end of the range and 50% “was probably at the
top end” [p 3474].
[335] Under further cross-examination Dr. Griffiths conceded that, in
order to accurately quantify the extent of gaps in the complex, “you probably would have to control a lot of these variables
more carefully” [p 3556].
[336] In a particularly effective cross-examination by Mr. Biernacki,
Dr. Griffiths acknowledged a significant error in one of his assumptions
about the relative absorbances of mannitol and the complex. Dr. Griffiths
had assumed equivalent absorbancies. When this error was pointed out to him,
he further reduced his estimate of the extent of gaps in the complex to about
10%. His testimony at pp 3563-3566 was as follows:
Q. Okay.
And so based on what we looked at with reference spectrum for mannitol versus
the reference spectrum for the complex, it appears that the mannitol spectrum
produces intensity five times as high at the 1030 to 1090 band as the complex
does at 1700?
A. Okay.
Q. Correct?
So in order to make
a comparison regarding the relative contribution or concentration of these
ingredients in this spectrum, you should be multiplying the mannitol peak by 5;
is that fair? Either that or dividing the complex by 5?
A. Remember
that I didn't look at -- in my report, I didn't give concentrations, I gave
absorbances. And so when I was looking at the effect, for example, of layer
thickness, 6 in the table in my report, I was looking at absorbances, not at
concentrations.
Q. We will
get to your chart and analysis that you did there, but when you were looking at
washed-pellet Spectrum 2, you were doing an internal analysis between relative
peak heights assuming that those compounds absorbed equally at their particular
wavenumbers. And I think we have shown, albeit very roughly, that that's not
correct. And what I would like to do is to see how the adjusted relative
absorbances would affect that analysis.
So am I correct that if the mannitol
generates a signal at the lower band, so the 1030 to 1090, it is five times as
high as the 1700 band?
A. The
signal is not five times as high.
Q. The
intensity.
A. Okay, but
the intensity isn't five times as high either.
Q. Oh, no,
it's not in this spectrum, but if you wanted to take a look at those relative
peak heights and make an assessment about the relative contribution, you would
have to divide the complex by 5, at least the intensity, to be comparing --
A. Divide or
multiply?
Q. Well, you
are either going to have to multiply the mannitol by 5 or divide the complex by
5.
A. If you
multiply the mannitol by 5, you are talking about enormous mannitol bands. So
I think I see where you are going, I think you got it exactly wrong, around the
wrong way, but, nonetheless, I think --
Q. My friend
is pointing out to me, you are correct, I think everyone is correct other than
me on this point, we should be dividing the mannitol peaks by 5?
A. Yes.
Q. So, then,
when you made a comparison between the mannitol peaks with the complex peaks,
you would not have a 50 to 50 ratio but a ratio of closer to 20 per cent or
even less?
A. Okay.
That's if you, that's -- it doesn't negate the table that I made which was
based on absorbencies and not concentrations.
It may affect the
gap size and may even bring it down to 10 per cent, but 10 per cent is still a
whole lot more than zero. It's still not -- this spectrum here shows the
existence of gaps in the layer. Otherwise, you would not see those mannitol
bands as you don't in the, certainly the one spectrum where you see only
complex. And the complex is there to about the same height. So it doesn't, it
doesn't affect the potential, the probable -- excuse me, that is the word I
meant to say, the probable existence of gaps which, when you bring your
argument in, rightly or wrongly, and I think there is some, there are some
changes that have to be made based on lambda and I think there are some changes
that have to be made based on the fact that you are using the most -- you are
not using a representative number for the mannitol bands in the uncoated core,
but, nonetheless, I mean, it is still showing, this does not negate the
existence of gaps in the sample.
Q. Well,
wait a second. I am not using the most extreme signal of mannitol from the
core. We avoided that by going to the reference spectrum for mannitol and
comparing that to the reference spectrum for the MACP complex; correct?
A. Okay,
yeah.
Q. So
whatever other issues there may be, that is not one of them. And so if there
is --
A. There is
still a contact issue.
Q. There is
not a contact issue with respect to the reference spectra for mannitol and
complex --
A. Not a
contact of the bottom of the sample with the internal reflection element but
the probe -- I will withdraw that.
Q. If you
divide the mannitol peaks by 5, taking the analysis that you had done earlier,
would that leave you to estimate the relative proportions of the signal between
mannitol and the complex to be around -- actually, let me rephrase that.
If you did that
analysis, would that lead you to conclude that the signal from mannitol was
around 20 per cent or less?
A. If you
made that assumption, yes.
Q. Yes. And
so that would be the kind of spectrum that you might see if 20 per cent of the
signal was coming from mannitol?
A. Yes.
The clear impression left by this evidence
is that Dr. Griffiths’ indirect method of assessing the continuity of the
complex through the interpretation of Dr. Davies’ ATIR spectra was subject
to so many uncontrolled variables and subjectivity that it was unreliable. As
used by Dr. Griffiths, the technique is, at best, only a very approximate
means of assessing the relative concentration of two or more substances and it
was not useful as a measure of sublayer continuity in this case. There is no
other plausible explanation for the profound change in Dr. Griffiths’
evidence that began with continuity breaks of up to 50% and ended with gaps approaching
10%. I agree with Dr. Davies that his ATIR data are not useful to assess
the continuity of the complex and they cannot be used as a reliable proxy for
that purpose.
[337] Apotex adopted an unusual approach to its own CLSM and FTIR
analysis. Instead of asking its expert witnesses to conduct or supervise that
work, it was independently assigned to Dr. Reza Fassihi at Temple
University and to Dr. Craig Hawker at the University of California. Both
were given considerable latitude in the conduct of their work and, in some
instances, they adopted practices inconsistent with those the Apotex experts
would have preferred. The Apotex experts were then asked to analyse the Fassihi
and Hawker data.
[338] In the end the Apotex testing did not undermine Dr. Davies’
results. The Temple University CLSM images depict a fluorescent ring at the
interface of the pellet cores and the enteric coating. This is particular
evident in Tabs 41 through 48 of Exhibit 158. Where the images are in focus,
the fluorescent corona is quite distinct. Dr. Bright acknowledged as much
under cross-examination [p 4128 and pp 4156-4159]. Dr. Bright
also expressed reservations about the comparative value of the Temple images in
the following exchange:
Q. Will you
agree that Dr. Davies' 50x images had better lateral pixel resolution than any
of the new CLSM images?
A. As I
recall the Temple University CLSM, the best resolution was 20x, two times
digital on ten. So I would agree with what you said.
Q. The
Temple CLSM images were all single optical plane images?
A. Yes.
Q. You were
not provided with a Z series for any pellets from Temple - - from Temple
University?
A. I was
not.
Q. And so
the single plane images that you obtained from Temple don't tell you where
within the pellet that plane is from?
A. That's
true. Obviously when the analyst took the images they were focused and so on.
I mean, obviously the image didn't come out of the blue straight out of the
gate, so I suspect there was some optimization to get a position. But I don't
know, the answer to your question.
Q. Parts of
the image may have been below the surface of the pellet?
A. That's
possible.
Q. Similarly,
parts of the image - - let me be more precise. In parts of the image, the
optical plane could have been above the surface of the pellet?
A. In
certain regions?
Q. Yes.
A. Perhaps,
yes.
Q. And
without a Z series, it's impossible to make that assessment?
A. What is
"that" that you are saying to me?
Q. Whether
part of the optical plane is above or below the surface and to what degree?
A. I believe
that's true.
[pp 4154-4155]
Also see Dr. Bright’s evidence at
p 3950 and p 3998.
[339] Under cross-examination, Dr. Amos agreed the large gaps in the
zone of fluorescence in the Temple University CLSM images were due to the
sample being out of focus [p 3046]. Like Dr. Bright, he agreed the
value of the Temple University images was reduced by the failure to obtain a
full Z series and by other imaging deficiencies [p 3048 and pp
3181-3181]. Dr. Amos also acknowledged that Dr. Davies’ 50x images
provided better resolution than those obtained by Dr. Fassihi
[p 3082].
[340] Dr. Bright was sufficiently troubled by the anomalous signal in
Dr. Hawker’s blank that he expressed reservations about the validity of
some of the data [p 3978]. In a case as important as this one, it is
surprising that a problem of this sort would be left unresolved. I do not
accept Dr. Hawker’s attempt to explain away this problem as
insignificant. The taking of a blank is an important experimental control and
the anomalous reading should have been addressed. I, therefore, agree with
Dr. Davies that the Hawker data were insufficient to counter
Dr. Davies’ contrary findings.
[341] It was apparent to me that Dr. Bright and Dr. Amos were
not particular impressed by the quality of the Temple CLSM images and, had they
been asked to carry out that work, they would have adopted different methods.
This placed the Apotex witnesses at a disadvantage relative to Dr. Davies
who ran his own tests and interpreted his own data. In some instances, the
Apotex experts were left to guess about how Dr. Fassihi and
Dr. Hawker obtained their data.
[342] This segregation of experimentation from data analysis was
consistent with Apotex’s overall approach. None of the Apotex experts was
asked to consider all of the evidence with a view of expressing an over-arching
opinion. Each was asked to consider pockets of data relevant to their area of
expertise. This, in turn, unfairly discounted the value of the whole of the
evidence. I am satisfied Dr. Davies’ approach was the more reliable one
and his opinion about the structure of the Apotex product is in all
probability, correct.
[343]
At paragraph 170 of Dr. Griffiths’ initial
report, he estimated the thickness of the “layer of
complex” in 4 of 5 of Dr. Davies’ 2004 spectra at “about 0.5 microns”. This was based on his estimate
of a depth of signal penetration of 1 micron. Dr. Griffiths testified that
a depth of penetration of 2.0 was more appropriate leading him to a revised
sublayer thickness in a range of 0.5 microns to 1.7 microns. For one 2004
spectrum he acknowledged a thickness of up to 1.7 microns [pp 3584-3585].
When Dr. Griffiths was then asked to adjust his thickness values using an
angle of incidence of 36º instead of the angle he had used of 45º, he provided
a hypothetical thickness range from 1 micron to 2.92 microns for four of the
2004 spectra and higher than that for another [p 3588]. Using a depth of
penetration of 2.0 and an angle of incidence of 36º, Dr. Griffiths agreed
that a sublayer thickness of at least 2 microns was plausible. Nevertheless,
he refused to accept that the angle of incidence employed by Dr. Davies’
instrument was less than 45º [p 3590, p 3592].
[344] The first observation to be made about Dr. Griffiths’ method
for calculating the thickness of the Apotex sublayer concerns its inherent
imprecision. The ranges of values it produced were extraordinary and fell markedly
short of what would be necessary to rebut Dr. Davies’ direct thickness
measurements.
[345] A second observation to be made about Dr. Griffiths’ thickness
analysis concerns the vagaries of the assumptions he employed. The thickness
values he obtained were based on generalizations about the depth of penetration
of Dr. Davies’ ATIR tests including the angle of incidence employed. As
Dr. Griffiths acknowledged, the median angle of incidence can affect the
depth of penetration by a factor of two or more [p 3619].
[346] Dr. Griffiths was prepared to adjust his depth of penetration
assumption up to a point but, despite Dr. Davies’ evidence about the angle
of incidence employed by his instrument, Dr. Griffiths refused to depart
from an assumed angle of incidence of 45º. This, he conceded, was an
after-the-fact justification [p 3610].
[347] The implication Dr. Griffiths was, in effect, advancing was
that Dr. Davies was lying about the angle of incidence.
[348] It is surprising to me that after subjecting Dr. Davies’
analysis to years of scrutiny in the United States and Canadian litigation
there would remain any lingering doubt as to either his methods or his testing
equipment. In the absence of any plausible evidence to establish
Dr. Davies’ ATIR tests were performed with a median angle of incidence of
45º, I accept his evidence to the contrary. It was open to Apotex to conduct
its own equivalent testing and it chose not to do so. It should not be the
beneficiary of any uncertainty that could easily have been dispelled.
[349] The third observation to be made about Dr. Griffiths’ approach
concerns his avoidance of any direct thickness measurements. I understand the
concern that the fluorescent band seen on top of the Apotex cores in
Dr. Davies’ CLSM images is, at least arguably, not coincident with the MACP-PVP
complex. However, measuring the thickness of the band is not an
acknowledgement of its chemical make-up. Furthermore, the reflectance images
taken from the washed pellets are strong evidence of a well-defined structure distinct
from the underlying pellet core. The chemistry of this structure was also
shown to be different from that of the enteric coating. Direct measurement of
the reflectance images was a simple exercise and yet it was avoided by the
Apotex witnesses with reliance, instead, placed on Dr. Griffiths’ less
accurate indirect thickness assessment.
[350] Dr. Griffiths’ approach to measuring sublayer thickness by
reference to the relative intensity of the mannitol peaks seen in some of
Dr. Davies’ spectra was also subject to some professional judgment. As
with his continuity analysis, Dr. Griffiths acknowledged that the various
spectra showed variation in the intensity of mannitol peaks [p 3656]. He then
selected a representative value by simply looking at the spectra [p 3661]. He
did no measurements to confirm the ratio he employed across the available
spectra nor did he calculate the median angle [p 3659, p 3661]. He also failed
to account for the contribution of the background signal to the complex when he
measured peak heights [p 3662-3663]. His response to this omission was not a
compelling endorsement of the validity of his thickness assessment:
A. Right.
Q. And one
way of doing so could have been to take a spectrum for a washed pellet, which
has what appears to be a thick layer and no signal for mannitol, and use that
as a background; couldn't you have done that?
A. Umm...
Yes -- I'm sorry to equivocate on this one, but the answer is yes and no,
because the spectra where you are predominantly measuring the spectrum of the
complex have varying amounts of carboxylic acid on there. And the carboxylic
acid is going -- the amount of carboxylic acid in the spectrum, as shown by the
1700 wavenumber band, is going to affect the lower frequency region of the spectrum.
I know that as a spectroscopist. So there are going to be other bands which
are associated with carboxylic acid's relatively broad bands in the spectrum,
which contributes to that baseline.
So either way, you
are making approximations. Even if you did the procedure that you just
outlined, which is not unreasonable, you would still get probably an incorrect
value, so taking the baseline at zero, I felt, was as good a way of doing it as
any.
Q. There is
a difference between not being perfect and being better. And I suggest to you
that had you taken into account the background, to the best of your abilities,
that that would have provided a more accurate measure of the mannitol peaks in
the washed pellets, which would have provided a more accurate analysis?
A. I will
agree with you, yes.
[351] On this issue I also accept Dr. Davies’ evidence that assessing
the thickness of the Apotex sublayer with ATIR data was unreliable.
[352] Dr. Bright criticized Dr. Davies’ thickness measurements
principally on the basis that Dr. Davies inappropriately used maximum
intensity images and because he did not adequately explain or document his
work. Dr. Davies answered this criticism by providing additional detail. He
confirmed that his thickness measurements were performed on representative
individual Z-scan fluorescence and reflectance CLSM images at evenly spaced
intervals along the subcoating layer – not from maximum intensity images. In
response to Dr. Bright’s criticism that Dr. Davies had not identified
precisely where the thickness measurements were taken from, Dr. Davies
pointed out that Dr. Bright had all of the data required to perform
independent measurements. Dr. Bright answered in the following way at
paragraph 159 of his Sur-Reply Report:
159. In paragraph 229, Dr. Davies
comments that I could have analysed the thickness of the asserted subcoating
layer of the washed pellet myself to calculate an average thickness. I
disagree. The thickness measurements were obtained by Dr. Davies using images
at 50x magnification from a very small portion of bisected, washed pellets. By
failing to provide an adequate selection of 50x images (the number would be
huge), it would be impossible for me to obtain measurements representative of
the pellet. Using Dr. Davies’ images, I could only take measurements in
that tiny region. Furthermore, I cannot use the raw CLSM images to determine
thickness in the manner that Dr. Davies did in 2011, because he has not
explained in sufficiently clear terms what he did to take those measurements.
[353] I do not accept this evidence as a sufficient response to
Dr. Davies’ point. It is easy to raise theoretical methodological issues
in the work of others. The weight of this type of criticism is significantly
diminished where the critic has the ability to carry out an independent
assessment of the available data and decides or is directed not to do so.
Dr. Bright did not need to know precisely where or how Dr. Davies
took his thickness measurements. He could easily have taken his own
measurements with any of the available images using his own method to determine
if the range of thicknesses of the sublayer matched Dr. Davies’ results [p
3999]. In the absence of any reliable evidence to challenge Dr. Davies’
thickness measurements or to show that those measurements were not
representative, I accept those data unreservedly. I also accept that
Dr. Davies’ measurements are sufficient to support a finding that they are
representative of all of Apotex’s omeprazole pellet production.
[354] I do not accept Dr. Griffiths’ indirect method of assessing the
continuity or thickness of the Apotex sublayer. This approach is subject to
too many uncontrolled variables. The totality of the evidence presented by
Dr. Davies is much more persuasive. I accept that any one of Dr. Davies’
tests would, on its own, be insufficient to establish a continuous MACP-PVP
subcoating of at least 2 microns thickness. However, when all of
Dr. Davies’ tests are considered together, his conclusion is the most
probable.
[355] I do accept the point that Dr. Davies’ fluorescence images are,
on their own, insufficient to establish the presence or the topology of the Apotex
subcoating. Dr. Davies did not contend otherwise. However, in the
presence of the other testing carried out by Dr. Davies, I have concluded
that the fluorescent corona that can be seen at the core/enteric coating
interface of the washed and enterically coated pellets is substantially the
product of the MACP-PVP complex that is present at that location.
[356] The Apotex expert witnesses were given selective mandates. This
allowed them to avoid the integration of all of the available data into their
respective opinions. Two particularly strong examples of this involved the
approach they took to the reflectance images and to the water disintegration
videos. Very little attention was paid to this evidence and how it could be
reconciled with the other evidence. To the extent that it was addressed by the
Apotex witnesses, it was treated very thinly or with speculation. Their
treatment of the water disintegration videos was particularly troubling.
[357] In my view, compelling evidence of the presence of a substantially
continuous subcoat layer in the Apotex pellets comes from Dr. Davies’
videos of the Apotex washed pellets submerged in a water bath. The videos
depict a fairly rapid disintegration of a film-like layer. It does not float
off in isolated or discontinuous pieces but as cloak. The layer floats away
from the core in sheets. Dr. Griffiths ultimately conceded the complex is
present on the surface of the washed pellets and he agreed the observed film
coating is the complex, possibly with some “free”
MACP. This point came out in cross-examination and was not apparent from any
of Dr. Griffiths’ reports. At paragraph 187 of his first report,
Dr. Griffiths said only that “the material that
Dr. Davies observes ‘flaking off’ the solvent washed pellets…could well be
MACP”. Left unchallenged, this statement and the following paragraph
strongly suggest the film was not the complex at all. The weakness of
Dr. Griffiths’ evidence is exemplified by the convoluted explanation he
offered under cross-examination between pages 3668 and 3672 of the trial
transcript. My interpretation of the evidence is that Dr. Griffiths could
not scientifically reconcile the disintegration videos with his other
opinions. In writing his reports, he, therefore, chose to ignore what he saw.
[358] The reflectance images also demanded meaningful consideration.
Those images depict a substantially continuous and visually distinct structural
band on the surface of the pellet cores. The CLSM fluorescence images of the
sublayer band are also substantially coincidental with the matching reflectance
images. There are a few variations in places but, for the most part, the
contours of each band mirror one another [see for example the images at Tab 28
of Volume 6 of Dr. Davies’ Statement]. It cannot be coincidental that the
CLSM fluorescent coronas substantially overlap the sublayer structure depicted
in the reflectance images. Nevertheless, the Apotex witnesses failed to
address this evidence in a meaningful way. That failure undermines their
theoretical concerns about the inherent limitations associated with CLSM as a
method for identifying sample structures and chemistry.
[359] Dr. Davies built his opinion on all of the evidence considered
collectively. He was willing to accept that any one of his tests was
insufficient to support his final opinion but, when viewed together, he found
the evidence to be compelling. His opinion was based on the following points
of evidence:
a.
The presence of the complex – a chemically
distinct compound – was detected each time the Apotex pellet sublayer was
probed by ATIR.
b.
MACP and PVP are both present in the Apotex
pellets and were proven, as expected, to react with each other to form the
complex.
c.
A fluorescent ring is present in all of the CLSM
images taken of the coated and washed pellets at the interface of the enteric
coating and the cores.
d.
The Apotex sublayer is chemically different from
the enteric coating in that it did not dissolve with the enteric coating when
washed in a solvent.
e.
The reflectance images of the washed pellets
show a structurally distinct sublayer sitting above the pellet cores. The
boundaries of the sublayer from those images closely conform to the fluorescent
ring boundaries when the images are compared.
f.
Subject to the prevailing limits of detection,
no compounds were proven to be present in the sublayer except for the complex,
magnesium salt and some unresolved acidic functional groups. Each of those
compounds could reasonably be expected to be present in the sublayer.
g.
The disintegration videos depict a substantially
continuous film-like layer rapidly coming away from the washed pellet cores in
a water bath. The Apotex experts offered no meaningful challenge to
Dr. Davies’ evidence that this film-like coating was the MACP-PVP
complex.
[360] On balance, I much prefer the evidence of Dr. Davies to that
offered by the Apotex experts. Dr. Davies’ approach to testing may not
have matched the approach of others but in several instances the data he
obtained were not directly challenged. I reject any suggestion that
Dr. Davies’ data were compromised by his methods.
[361] The fact that a party may not agree with a chosen experimental
design is not an excuse for failing to replicate the work to test the
reliability of the reported data. The same applies to criticisms about the
testing techniques employed by an opposing expert witness. An argument that
other tests or controls could have been used loses much of its strength where a
party chooses not to employ those same suggested methods in its own responding
analysis to see if the results differ.
[362] The complaint by Apotex that not every test performed by
Dr. Davies was recorded is a theoretical concern. Dr. Davies testified
that his recorded tests were representative of the tests not recorded. If
Apotex believed the recorded data was not representative, it was fully capable
of doing its own testing and recording the data to determine if different
results emerged.
[363] Dr. Davies proved the complex was present at every point he
subjected to ATIR interrogation and he proved it is a chemically distinct
compound. When matched, the contours of the sublayer seen in Dr. Davies’
CLSM fluorescence images are substantially coincidental with the physical
contours seen in his reflectance images [see Tab 28, Volume 6 of the Davies’
report]. These reflectance images of the washed pellets depict a continuous
structure resting above and distinct from the cores. Given the design, length
and vigour of Dr. Davies’ washing technique, I reject any suggestion that
this observed layer could be a remainder of the enteric coating. When
everything is considered in combination with Dr. Davies’ water disintegration
videos, the inescapable conclusion is that the film-like material peeling away
from the pellet cores must be substantially comprised of MACP-PVP complex.
[364] For the reasons given above, I am satisfied that the Apotex
omeprazole product contains a substantially continuous polymeric film subcoating
that forms in situ from a
reaction between the enteric coating MACP and the core excipient PVP during
pellet manufacture. Notwithstanding the presence of some acidic functional
groups and magnesium salt in the subcoating, it is primarily made up of the
complex and it remains functionally inert. If it were otherwise one could
reasonably expect to find meaningful levels of omeprazole degradants under ATIR
analysis. None were found. It is also this structure that is depicted in
Dr. Davies’ water disintegration videos.
[365] I am also satisfied that the Apotex subcoating is sufficiently
robust that it provides an effective protective barrier as described in the
693 Patent. It has the thickness characteristics described by Dr. Davies
and in almost every instance exceeds a thickness of 2 microns.
[366]
Apotex developed a formation that worked and
could have looked to see if the subcoating was present before it took it to
market – just as Dr. Davies was able to show. It could also have
presented expert evidence that it had obtained a useful omeprazole formulation
by different means than those claimed by the 693 Patent. It chose,
instead, to challenge the quality and cogency of the evidence presented by
AstraZeneca and there it came up short. The inference I draw from the evidence
before me is that the Apotex omeprazole product works because its formulation
matches the formulation described in Claim 1.
[367]
Apotex argues that neither AstraZeneca Canada
Inc. nor AstraZeneca AB have standing to prosecute their respective claims to
damages for infringement in these proceedings. No challenge to Hässle’s
standing has been advanced and it is clear that Hässle has standing as the
patentee. As with many challenges to standing, this one has no merit.
[368] Section 55(1) of the Patent Act affords standing in patent
infringement actions to the patentee and to “all
persons claiming under him for all damages sustained”. The question
here is whether AstraZeneca AB and AstraZeneca Canada Inc. are parties with
sufficient interests in the 693 Patent to claim under Hässle.
[369] The test for standing is not particularly onerous. The issue was
thoroughly briefed by Justice Judith Snider in Laboratoires Servier, et al v
Apotex Inc, 2008 FC 825, 332 FTR 193 (Eng). There, after reviewing much of
the relevant jurisprudence, Justice Snider summarized the principles in the
following way:
[77] In sum, the Canadian jurisprudence
has provided a broad interpretation of “persons claiming under” the patentee.
The ability of a party to claim under a patentee does not necessarily require
the existence of an express licence. Where no express licence exists, each case
will be determined on its facts to determine whether an implied licence or
other right exists that gives rise to a claim “under the patentee”.
[370] In
Signalisation de Montreal Inc v Services de Béton Universels Ltée
(1992), 46 CPR (3d) 199 at pp 210-211 (FCA), [1993] 1 FC 341, the Court held
that a claim under a patentee arise from a right of use of the invention that can
be traced directly back to the patentee. The technical means of giving effect
to the right of use could be by licence (express or implied), by assignment or
by the terms of sale of an article.
[371] The
evidence supporting the Plaintiffs’ claims to standing was provided by AstraZeneca’s
former Chief Legal Officer, Göran Lerenius. In that capacity, he was familiar
with the corporate arrangements that existed among the Plaintiffs in these
proceedings. The substance of that evidence was not effectively challenged.
[372] Mr. Lerenius
testified that Hässle was acquired by AB Astra in the 1960s. After a corporate
merger, AB Astra became AstraZeneca AB and Hässle remained its wholly owned
subsidiary. In about 1991, Hässle was reorganized and relinquished its
research business. It then became a patent owning company. In that capacity
it continued to own the 693 Patent.
[373] Mr. Lerenius
identified a Company Commissioner Agreement between Hässle and AB Astra signed
in 1985. That agreement provided for AB Astra to effectively control all of
the business of Hässle. Mr. Lerenius said that there were no other
agreements between those parties concerning Hässle’s patent interests. The
Company Commissioner Agreement continued to govern the business relationship
between Hässle and AstraZeneca AB (as the successor to AB Astra) without
interruption. According to Mr. Lerenius, this was the simplest means of
giving ongoing effect to AstraZeneca AB’s control over Hässle and it fully
accorded with Swedish law.
[374] Mr. Lerenius
also testified that AstraZeneca AB and AstraZeneca Canada Inc. are affiliate
companies in the sense that both are wholly owned subsidiaries of AstraZeneca
PLC. He identified a Distribution Agreement entered into between AstraZeneca
AB and AstraZeneca Canada Inc. that provided for AstraZeneca AB to supply
products to AstraZeneca Canada Inc. intended for resale on a non-exclusive
basis. Those products were agreed to be held after delivery at AstraZeneca
Canada Inc.’s risk. The agreement makes the following provision for
intellectual property rights:
24.1 All intellectual property rights relating to the
Products shall remain the property of ASTRAZENECA at all times. The Distributor
shall not acquire any intellectual property rights relating to the Products and
shall only have permission to use rights in so far as is necessary to exercise
the rights granted to the Distributor under this Agreement.
24.2 The Distributor will inform ASTRAZENECA of any intellectual
or suspected infringement of any of ASTRAZENECA’s intellectual property rights
in the Market which comes to the notice of the Distributor. ASTRAZENECA will
take all reasonable steps, at its own expense, to prosecute infringers. The Distributor
will give ASTRAZENECA all reasonable assistance in such prosecution.
[375] I
am satisfied by the evidence of Mr. Lerenius that, by virtue of AstraZeneca
AB’s control of the business of Hässle under the Company Commissioner
Agreement, AstraZeneca AB effectively controls the 693 Patent and the
rights flowing from it. This is a sufficient interest in the Patent to
establish AstraZeneca AB’s standing as a Plaintiff in these proceedings.
[376] According
to other unchallenged evidence, AstraZeneca AB has supplied LOSEC to AstraZeneca
Canada Inc. for resale in Canada under the terms of their Distribution
Agreement. AstraZeneca AB maintained title to that product up to the point of
Canadian delivery. That agreement also grants permission to AstraZeneca Canada
Inc. to use AstraZeneca AB’s intellectual property rights to the extent
necessary to give effect to AstraZeneca Canada Inc.’s contractual rights. Both
parties are before the Court and it is implicit that AstraZeneca Canada Inc.’s
prosecution of a claim to damages is conducted with the permission of AstraZeneca
AB. AstraZeneca Canada Inc.’s rights to exploit the 693 Patent are
limited but they are nevertheless contractually supported. I am, therefore,
satisfied that the evidence provides a sufficient foundation to support AstraZeneca
Canada Inc.’s standing as a Plaintiff in T-1409-04.
[377] AstraZeneca argues the Court ought to apply the principles of issue
estoppel and abuse of process by relitigation to a number of findings of “fact” made by the United States District Court for
the Southern District of New York in earlier litigation between the parties:
see In re Omeprazole Patent Litigation, 490 F Supp 2d 381 aff’d by the
United States Court of Appeals Federal Circuit, In re Omeprazole Patent
Litigation 536 F 3d 1361.
[378] The issues that Astra seeks to foreclose from an independent review
are pleaded at paragraph 45 of its Fourth Amended Statement of Claim:
(a)
Apotex’s Omeprazole capsules all use identical pellets;
(b)
Apotex’s Omeprazole capsule pellet cores contain omeprazole, povidone
(“PVP”), magnesium hydroxide, and mannitol;
(c)
Apotex applies an enteric coating to its Omeprazole capsule pellet
cores;
(d)
Apotex’s Omeprazole capsule pellets are dried until the moisture content
is not more than 1.5% by weight;
(e)
Apotex’s Omeprazole capsule pellets contain an enteric coating layer
that includes copolymerized methacrylic acid (“MACP”) and triethyl citrate;
(l)
Apotex’s Omeprazole capsules are oral pharmaceutical preparations;
(g)
Apotex’s Omeprazole capsule pellets contain a therapeutically effective
amount of omeprazole;
(h)
Apotex’s Omeprazole capsule pellets have cores with a microenvironmental
pH between 7 and 12;
(i)
Apotex’s Omeprazole capsule pellets have a core region containing
omeprazole, a sublayer around the core region, and an enteric coating;
(j)
The sublayer in Apotex’s Omeprazole capsule pellets ‘is 2 to 6 microns
thick;
(k)
Apotex’s Omeprazole capsule pellets have a continuous, inert sublayer
that hugs the surface of the core and separates the core from the enteric
coating; and
(l)
Apotex’s Omeprazole capsule pellets contain an in situ formed sublayer
that is inert, continuous, and rapidly disintegrating in water.
[379] The application of estoppel, at least to the factual findings made
by a foreign court, has some theoretical appeal. Permitting the same parties
to relitigate identical evidentiary points and to ignore the findings of a
competent foreign court may be seen to be a wasteful exercise, particularly in
an age where judicial resources are increasingly stretched and where the costs
of litigation are steadily rising. Nevertheless, the practical problems of
applying estoppel in a way that will actually protect judicial resources cannot
be ignored. Those problems were quite apparent in this case.
[380] Given the discretionary nature of the application of foreign issue
estoppel, AstraZeneca could not prudently assume the doctrine would be
applied. It, therefore, independently led evidence on all of the above
evidentiary points required to make its case. The practical effect of this was
that no time was saved. In fact, by pleading estoppel, the trial was
substantially lengthened. In response to AstraZeneca’s plea of estoppel,
Apotex led fact evidence from two attorneys involved in the United States
omeprazole proceedings, Martin Endres and Robert Silver. It also led
opinion evidence from two legal experts, Judge Benson Legg (retired) and
Mr. John Whealan. That evidence described the approach that the United
States District Court took to the management of its multi-party infringement
actions including the separation of the proceeding into waves. The purpose of
this evidence was to attempt to explain the differences between United States
and Canadian procedures and substantive patent law and to show that the two
systems are sufficiently distinct that the application of estoppel would work
an injustice on Apotex.
[381] Considering the somewhat unusual process that was followed in the
United States second wave proceedings involving Apotex, the practical
disadvantages of applying issue estoppel to only a handful of findings made in
that proceeding, and the fact that it is not necessary to rely upon the
doctrine to fill a gap in the evidentiary record, I decline to apply the
principle here.
[382] AstraZeneca argues that Apotex was deceptive in the context of the
settlement obtained in earlier NOC proceedings involving the 693 Patent
[T-1446-93] and claims, in the result, punitive damages or solicitor/client
costs or both. This assertion is based on a misrepresentation that Apotex made
in the NOC proceeding concerning its then proposed omeprazole formulation. There
Apotex relied on an affidavit sworn by Dr. Paul Niebergall stating that
the Apotex omeprazole formulation would contain dibasic sodium phosphate as an
ARC. This is a compound exemplified by the 693 Patent. However,
unbeknownst to AstraZeneca, when Apotex submitted its application for a New
Drug Submission to the Minister, it substituted magnesium hydroxide as the
proposed ARC, apparently motivated by the need to avoid another AstraZeneca
patent [the 377 Patent] which claimed dibasic sodium phosphate. When
Dr. Sherman was examined under oath in the earlier NOC proceeding, he was
questioned about the Apotex formulation and the correctness of Dr. Niebergall’s
affidavit. There he gave the following evidence:
Q. Now,
Apotex then has pending a New Drug Submission which specifies this particular
composition, the one that is set out in the Niebergall affidavit; is that
correct?
A. Yes,
it is.
Q. In that
submission this is the only composition that is specified?
A. That’s
correct. In fact, it’s superior to your client’s product, which may be
irrelevant, but it’s substantially superior.
…
Q. So you
only have and you have only ever had only one New Drug Submission in respect of
omeprazole; is that correct?
A. Yes.
Q. And
the information that is Exhibit 2 to Niebergall’s affidavit, that information
discloses or those pages, rather, disclose the details of that composition.
A. Yes.
Q. I think
you are saying that although in theory Apotex could make changes to that
composition as part of the approval process there is no intention on the part
of Apotex to do so in this case.
A. That is
correct. It has been optimized. That is an excellent formulation. It meets
every regulatory requirement and it is superior to your client’s product in
that it is more stable.
Q. Indeed
are you prepared to undertake on the record that Apotex will not make any
change to this formulation in respect of its seeking an NOC for omeprazole?
A. No. I can
only go so far as to tell you there is no intention to do so, nor can I
envision any reason that I would want to do so, but I can’t see any reason to
bind myself should it ever be necessary to make a change. If the Health
Protection Branch comes back and says we want some minor change for some reason
we would have to have the right to do that, but I can tell you this
categorically, that we will not change it in any way that will bring it within
the scope of your client’s patent. Your client’s patent - - is this a
confidential record? [Emphasis added] [See Exhibit 133, Tab 8 at pp 12-14]
[383] Dr. Sherman has acknowledged in this proceeding that Dr. Niebergall’s
affidavit was wrong insofar as it identified dibasic sodium phosphate and that
his own evidence on the point in the NOC proceeding was also not accurate.
These mistakes, he now says, were innocent and immaterial. According to
Dr. Sherman, the Apotex product required an ARC and that, for the purpose
of avoiding the 693 Patent, it did not matter what that substance was.
The NOC settlement was instead based on Apotex’s assertion that its product
would not incorporate a subcoating layer.
[384] AstraZeneca argues that it does not matter whether the Apotex
misrepresentation in the NOC proceeding was innocent or deliberate. It relies
on jurisprudence that indicates that “grave
consequences” may flow from the failure of a second person to accurately
represent the particulars of its proposed product in a NOC proceeding: see Hoffman-LaRoche
Ltd v Nu-Pharm Inc (1996) 70 CPR (3d) 206 at 213, [1996] FCJ no 1333.
[385] In AstraZeneca Canada Inc v Apotex Inc, 2004 FC 1278 at paras
27-33 aff’d 2005 FCA 58, Justice Michael Kelen considered the significance of
the Apotex misrepresentation in the context of an application by AstraZeneca to
set aside the NOC issued to Apotex. Justice Kelen declined to set aside the
Minister’s NOC but not before he recognized that the issue of misrepresentation
could be relevant in any later infringement proceeding:
[27] Apotex represented to the Minister
that its revised formulation is not materially different than the formulation
already the subject of an Order of this Court in a prohibition proceeding under
the Regulations between the same parties, with respect to the same patents, and
with respect to the same drug.
[28] In Syntex (U.S.A.) L.L.C. et
al. v. Minister of Health et al. (2001), 15 C.P.R. (4th) 312 I held that if
a generic drug company makes inaccurate, misleading, or untrue submissions to
the Minister for the purpose of the Regulations, the proper recourse for the
patentee is a common law action for infringement of the patent, not judicial
review under the Federal Courts Act. At paragraph 17 I stated:
If the generic drug company's new
drug submission contains inaccurate or misleading information, the Federal
Court of Appeal has repeatedly held that a patentee will be in a position to
test the accuracy of a generic drug manufacturer's statements with respect to
the drug after the product reaches the market, and if the statements or omissions
by the generic drug company are shown to be inaccurate, the consequences for
the generic drug company "could well be very grave indeed". The
patentee has a common law action for an infringement of patent, an injunction
and punitive damages.
[386] If the evidence before me had established that Apotex’s undisclosed
substitution of one ARC for another was a material factor in the settlement of
the earlier NOC proceeding, a good case for punitive damages would have been
made out. That evidence is lacking here. I am also not satisfied that Apotex
deliberately misrepresented its omeprazole formulation to deceive AstraZeneca.
There does not appear to have been any particular advantage gained by Apotex
misrepresenting its intended ARC to AstraZeneca. However, when the error was
identified, Apotex failed in its duty to inform AstraZeneca. Both Dr. Niebergall
and Dr. Sherman were careless about the accuracy of their sworn evidence
and remiss in not correcting the record at the first available opportunity.
The need for scrupulous accuracy and fair dealing under the NOC system is
manifest. Parties must understand that carelessness and a lack of absolute
candour cannot be condoned. These are matters which may bear on the issue of
costs. The parties request that costs be held in reserve. I will, therefore,
hear from them at a later point about the significance, if any, of this
evidence to the award of costs.
[387] Beyond questioning the evidence of Dr. Davies and
Dr. Bodmeier on the accuracy and representativeness of the testing data,
Apotex did not assert that its Apo-Omeprazole product lacks uniformity. Given
regulatory requirements, this is not surprising. The evidence also discloses
that all of the Apotex batches were made in accordance with the same
specification using consistent process parameters and with the same
concentrations. Apotex’s quality control testing of representative batch
samples as reported to Health Canada produced consistent and acceptable
results. Dr. Davies’ representative testing of the Apotex samples he was
given consistently established infringement. Dr. Bodmeier testified that
Dr. Davies’ testing was sufficient to support an inference that every
batch of Apo-Omeprazole would be expected to have the same characteristics as
those reported by Dr. Davies. This evidence is sufficient to establish
that Apo-Omeprazole consistently matches the characteristics found in Claim 1
of the 693 Patent.
[388] Fact evidence was given on behalf of Apotex by its vice-president of
business operations, Gordon Fahner. Mr. Fahner has been employed by
Apotex in various management positions since 1989, and is thus familiar with
its manufacturing and distribution practises.
[389] Mr. Fahner testified that Apotex has made all of its Apo-Omeprazole
in Ontario. In the period from 2004 to 2008, its customers included pharmacy
wholesalers, large retain chains, banner stores, regional retail chains,
independent pharmacies, and hospitals across Canada. Most customer orders have
been processed from the Apotex order desk in Toronto and distributed from any
of its Toronto, Calgary or Montreal distribution centres. Calgary typically
supplied Saskatchewan and west and, until mid-2005 when it closed, Montreal
supplied Quebec and New Brunswick. Toronto serviced the remainder of the
country which, according to Mr. Fahner, amounted to about 90% of shipped
orders. Fifty-five to 60% of omeprazole sales were shipped to Ontario
customers, in some cases for onward distribution.
[390] Under cross-examination, Mr. Fahner agreed that Apotex sold
Apo-Omeprazole to customers across Canada. The product was then resold
throughout Canada to patients. Apotex had sales representatives contacting
customers throughout Canada and it promoted its Apo-Omeprazole product on its
nationally accessible website and by other promotional means. Apotex also
exported its Apo-Omeprazole capsules to its affiliates in the United States, and
the Czech Republic, and into several other countries.
[391] I am satisfied on the evidence before me (including
Dr. Sherman’s evidence and AstraZeneca’s read-ins) that, since 2004,
Apotex directly and consistently infringed Claims 1, 5, 6 and 19 of the 693
Patent by promoting and selling its Apo-Omeprazole capsules across Canada, and
by its international sales. I am also satisfied on the evidence before me
that, with some exceptions, the Apo-Omeprazole capsules infringed Claim 13.
Apotex also induced infringement by its customers and by end-users throughout
Canada. I agree with AstraZeneca that Apotex actively promoted Apo-Omeprazole
to customers and directly compared that product to LOSEC for the same medical
indications. This is inducing activity as described by Justice Hughes in Abbvie
Corporation v Janssen Inc, above, at para 106:
[106] The law in Canada is clear. A
person, such as Janssen, who sells a product for an infringing use by another,
which product has no other significant commercial use, has induced that
infringement, and is itself an infringer (see eg. Dableh v Ontario Hydro
(1996), 68 CPR (3d) 129, at pages 148-149 (FCA)).
[392] Apotex has pleaded a partial defence to these proceedings based on
what, it says, is a two year limitation period.
[393] Apotex contends that, with respect to its sales of Apo-Omeprazole in
Ontario, AstraZeneca cannot pursue damages for more than two years before the
commencement of these proceedings. This does not appear to present an
impediment to the initial proceeding [T-1409-04] which was commenced in 2004.
In the case of T-1890-11, Apotex says that, if the Ontario limitation period
applies, the claim is statute barred after November 22, 2009. If the
limitation period is six years, the claim to damages would be statute barred
for any infringing activity that took place before November 22, 2005.
[394] The determination of the applicable limitation period turns on the
interpretation of section 39 of the Federal Courts Act, RSC, 1985,
c F-7, which provides:
39. (1) Except as
expressly provided by any other Act, the laws relating to prescription and
the limitation of actions in force in a province between subject and subject
apply to any proceedings in the Federal Court of Appeal or the Federal Court
in respect of any cause of action arising in that province.
|
39. (1) Sauf
disposition contraire d’une autre loi, les règles de droit en matière de
prescription qui, dans une province, régissent les rapports entre
particuliers s’appliquent à toute instance devant la Cour d’appel fédérale ou
la Cour fédérale dont le fait générateur est survenu dans cette province.
|
(2) A proceeding
in the Federal Court of Appeal or the Federal Court in respect of a cause of
action arising otherwise than in a province shall be taken within six years
after the cause of action arose.
|
(2) Le délai de
prescription est de six ans à compter du fait générateur lorsque celui-ci
n’est pas survenu dans une province.
|
[395] Apotex argues that its sales into the Ontario market constitute a
cause of action “in that province”, such that a
two-year limitation applies. Logic would, of course, dictate that sales into
each provincial market would thereby be subject to the applicable provincial
limitation period in each case.
[396] AstraZeneca contends that its cause of action in this Court cannot
be parsed into pieces. Apotex’s commercial activity was national and
international in scope. While that activity could have been the subject of
separate litigation in each province or, presumably, in each place of export, AstraZeneca
framed its cause of action in recognition of the national and international
character of Apotex’s business. AstraZeneca says that it is, accordingly,
entitled to the benefit of a six-year limitation period.
[397] It seem to me that one of the distinct purposes of section 39 of the
Federal Courts Act is to facilitate a judicial forum providing for the
one-time resolution of disputes that concern activity crossing provincial
boundaries and international borders. If it were otherwise, the burden
associated with the segregation and characterization of relevant evidence could
be enormous. Problems with establishing when and where title to products
passed or where effective delivery occurred would inevitably arise as the
responsible party attempted to bring itself within the sphere of the most
favourable provincial limitation period. In the case of patent infringement
proceedings the problem would be exacerbated because an infringing sale into
one province could also constitute an infringement in another if the same
product was resold or reshipped or where there was downstream inducement in
other jurisdictions.
[398] The purpose of section 39(2) of the Federal Courts Act, was
obviously to avoid these types of evidentiary difficulties and to provide a
unitary limitation period in cases like this. Support for this view can be
found in Hislop v Canada, 2008 Carswel Ont 1117, 165 ACWS (3d) 163 (Ont
SCJ), which dealt with the same statutory language found in the Crown
Liability and Proceedings Act, RSC, 1985, c C-50, at section 32.
[399] It follows that the limitation period that applies in this case is
six years regardless of the place where the infringing activity took place.
[400] Whether a successful plaintiff in an infringement action can elect
to take an accounting of profits is at the complete discretion of the trial
court and is based on equitable considerations. There is no presumption
favouring a plaintiff in the granting of this remedy: see Merck & Co v
Apotex Inc, 2006 FCA 323 at para 127, [2006] FCJ no 1490.
[401] The list of considerations that can apply is non-exhaustive but
delay and market abandonment by the patentee were the basis of refusing an
election in Merck, above.
[402] Apotex has not asserted any specific factors in its post-trial
submissions and simply argues that it is up to AstraZeneca to prove its entitlement
to this form of relief.
[403] There is not much evidence before me to explain the time this case
took to come to trial but the causes for delay after the expiry of the patent
in 2008 are of no apparent significance. The initial action was commenced not
long after a NOC was issued to Apotex and, of course, the parties were actively
involved in similar litigation in the United States. AstraZeneca also points
to Apotex’s continued infringement after its construction arguments were
rejected by the Federal Court of Appeal in 2003 and after it was found to have
infringed the equivalent patent in the United States in 2007. AstraZeneca also
maintains that it did not abandon the market and made efforts to mitigate
through a licensing arrangement with an authorized generic.
[404] I am satisfied that this is an appropriate situation to permit AstraZeneca
to elect an accounting of profits. There is no evidence to suggest any of the
Plaintiffs have engaged in inequitable conduct or that they have unduly delayed
the advancement of this litigation. Apotex, on the other hand, did not alter
course when its position did not find favour in earlier judicial proceedings.
This is a factor that is relevant to the assessment of its good faith: see Beloit
Canada Ltd v Valmet-Dominion Inc, [1997] 3 FC 497 (FCA) at para 119, 71
ACWS (3d) 138.
[405] For the foregoing reasons, I have concluded that Claims 1, 5, 6, 13
and 19 of the 693 Patent are valid. A declaration to that effect is,
therefore, granted.
[406] I also find that Apotex, by its manufacture, promotion, and sale of
Apo-Omeprazole in Canada and elsewhere, has infringed the rights of the
Plaintiffs as granted in the asserted claims.
[407] I will hear the parties concerning costs on a date to be arranged.