Date:
20121011
Docket:
T-1652-10
Citation:
2012 FC 1189
Ottawa, Ontario,
October 11, 2012
PRESENT: The
Honourable Mr. Justice O'Keefe
BETWEEN:
|
ASTRAZENECA CANADA INC. and
ASTRAZENECA AB
|
|
|
Applicants
|
and
|
|
PHARMASCIENCE INC. and
THE MINISTER OF HEALTH
|
|
|
Respondents
|
|
|
|
REASONS FOR
JUDGMENT AND JUDGMENT
[1]
In
this application, the applicants, AstraZeneca Canada Inc. and AstraZeneca AB,
collectively referred to as AstraZeneca, address allegations of patent
invalidity made by the respondent, Pharmascience Inc.
(Pharmascience) in its notice of allegation dated August 27, 2010 (the NOA).
The NOA was filed pursuant to section 5 of the Patented Medicines
(Notice of Compliance) Regulations, SOR/93-133 (the NOC Regulations) for Canadian Patent No. 2,290,531 (the ‘531 Patent) and
Canadian Patent No. 2,346,988 (the ‘988 Patent). In an order dated
August 8, 2011, Prothonotary Mireille Tabib dismissed the application with
respect to the ‘988 Patent. The scope of this
application is therefore limited to the ‘531
Patent.
[2]
AstraZeneca requests a declaration that the NOA is neither a valid
notice of allegation nor a detailed statement as contemplated by the NOC
Regulations. In the alternative, AstraZeneca requests an order prohibiting the Minister of Health (the Minister)
from issuing a notice of compliance (NOC) to Pharmascience for its 20 and 40 mg
dosage esomeprazole magnesium capsules (the Pharmascience capsules) until the
expiry of the ‘531 Patent.
Background
[3]
Pharmascience
filed an Abbreviated New Drug Submission (ANDS) with the Minister seeking an
NOC for its Pharmascience capsules. These capsules are intended to treat duodenal ulcer disease associated
with Helicobacter pylori infection. In its ANDS, Pharmascience compared
the Pharmascience capsules to AstraZeneca’s 20 and 40 mg dosage capsules of NEXIUM to demonstrate
bioequivalence under subsection 5(1) of the NOC Regulations.
[4]
In
its NOA, Pharmascience alleged that the claims made in the ‘531 Patent were irrelevant
and/or invalid on the following grounds:
- Insufficient
disclosure/lack of support;
- Claims broader than
invention made or disclosed;
- Lack of novelty and
anticipation by prior use;
- Double-patenting;
- Lack of inventive
step/obviousness;
- Not an invention (under
section 2 of the Patent Act, RSC, 1985, c P-4);
- Lack of sound prediction
and lack of utility;
- Not a valid selection
patent; and
- Fraud on the patent officer
(under subsection 34(1) and section 53 of the Patent Act).
[5]
The
main polymer at issue is hydroxypropyl methylcellulose (HPMC). HPMC has
different properties depending on its molecular weight. The molecular weight of
HPMC is proportional to the viscosity of an aqueous solution of HPMC; thus, as
the molecular weight of HPMC increases, so does the viscosity of an aqueous
solution of HPMC. High molecular weight HPMC has a viscosity greater than 4,000
cps and dissolves slowly in water which makes it advantageous for controlled release
formulations that require slow release of drugs. Conversely, low molecular
weight HPMC has viscosity ranging from 5 to 15 cps and is often used in film
coatings due to its faster dissolution in water.
‘531 Patent
[6]
The
‘531 Patent,
entitled Pharmaceutical Formulation of Omeprazole, issued on December
12, 2006 from an international patent application filed in Canada on May 18, 1998. The ‘531 Patent
claimed priority from Swedish patent application No. 9702000-2 filed on May 28,
1997. The ‘531 Patent
was published on December 3, 1998 and expires on May 18, 2018.
[7]
The
inventors of the ‘531 Patent
are Magnus Erikson (Sweden) and Lars Josefsson (Sweden). The patent is owned by
AstraZeneca AB and is listed on the Minister’s Patent Register for
AstraZeneca’s NEXIUM brand of 20 and 40 mg esomeprazole magnesium trihydrate
tablets.
[8]
Specific
terms are defined as follows in the ‘531 Patent:
Omeprazole,
an alkaline salt thereof, the (-)-enantiomer of omeprazole and an alkaline salt
of the (-)-enantiomer of omeprazole
[…]
Cloud
point is the temperature at which this polymer phase separation occurs. Cloud
point is determined by measuring the light transmission through the polymer
solution.
[9]
The
‘531 Patent
is directed at the use of low viscosity HPMC of a specific quality (as
reflected by its CP) in an enteric-coated omeprazole immediate release
formulation. The enteric coating, an acid, is used to withstand the omeprazole,
an acid labile compound, from the acidic conditions of the stomach. The HPMC
layer serves as a binder and/or separating layer between the
omeprazole-containing core and the enteric coating. The inventors stated that
they surprisingly found that different batches of a single low viscosity HPMC
product, as gauged by the cloud point (CP), may have different abilities to
influence the rate of release of omeprazole from an enteric-coated formulation.
The “Claimed CP”
[10]
The
patent’s claimed CP for low viscosity HPMC is as follows:
- CP of not less than
45.6˚C at 96% light transmission measured with a Mettler FP90/FP81C
instrument, where the CP is determined by dissolving the HPMC in a
concentration of 1.2% (w/w) in a mixed solution of phosphate buffer 0.235 M and
simulated gastric fluid pH 1.2 in the proportions 4:5 at a pH of 6.75 to 6.85;
and
- CP of not less than
44.5˚C at 95% light transmission measured with a spectrophotometer, where
the CP is determined by dissolving the low viscosity HPMC in a concentration of
1% (w/w) in a mixed solution of phosphate buffer 0.235 M and simulated gastric
fluid pH 1.2 in the proportions 4:5 at a pH of 6.75 to 6.85.
[11]
The
patent states that this claimed CP ensures sufficient drug release from the
formulation. Thus, by following the ‘531 Patent, the amount of product discarded from
insufficient release is reduced, which results in a significant advantage.
Claims
[12]
The
‘531 Patent has 20 claims.
[13]
The
first claim is for an enteric coated oral pharmaceutical formulation comprising
the following three layers:
1. Core material
consisting of an active ingredient (omeprazole, as defined above, in admixture
with one or more pharmaceutically accepted excipients and an optional binding
agent) and optionally an alkaline reacting compound;
2. Separating layer
on the core material; and
3. Enteric coating
layer on the separating layer.
[14]
The
optional binding agent and/or constituent of the separating layer are comprised
of low viscosity HPMC with at least the claimed CP.
[15]
Claims
2 to 8 add the following specifications:
Claim 2: subset of Claim 1
where the constituent of the separating layer is low viscosity HPMC.
Claim 3: subset of Claim 2
where the enteric coating layer is methacrylic acid copolymer.
Claim 4: subset of Claim 1
where the binding agent is low viscosity HPMC.
Claim 5: subset of Claims 1
to 4 where the low viscosity HPMC has a viscosity of less than 7.2 cps in 2%
aqueous solution.
Claim 6: subset of Claims 1
to 5 where the active ingredient is omeprazole.
Claim 7: subset of claims 1
to 5 where the active ingredient is magnesium salt of omeprazole.
Claim 8: subset of Claims 1
to 5 where the active ingredient is magnesium salt of the (-)-enantiomer of
omeprazole.
[16]
Claims
9 and 10 specify an enteric coated oral pharmaceutical formulation manufactured
with an optional binding agent and a separating layer of low viscosity HPMC at
the claimed CP of 45.6˚C and 44.5˚C, as described above,
respectively. Similarly, Claims 11 and 12 specify an enteric coated oral
pharmaceutical formulation that does not contain a separating layer but is
manufactured with at least a binding agent of low viscosity HPMC at the claimed
CP of 45.6˚C and 44.5˚C, as described above, respectively. Claim 13
pertains to any of the Claims 9 to 12, wherein the low viscosity HPMC has a
viscosity of less than 7.2 cps in 2% aqueous solution.
[17]
Claims
14 to 17 describe the process for the manufacture of an enteric coated oral
pharmaceutical formulation in accordance with Claims 9 to 12, respectively.
[18]
Claims
18 and 19 describe the use of a pharmaceutical formulation as defined in any
one of the Claims 1 to 8 for the manufacture of a medicament in the treatment
of gastrointestinal diseases and in the treatment of gastrointestinal diseases,
respectively.
[19]
Finally,
Claim 20 describes a commercial package comprising a pharmaceutical formulation
as defined in any one of Claims 1 to 8, with instructions for the use thereof
in the treatment of gastrointestinal diseases.
Experiments
[20]
Three
experiments (examples) were presented in the ‘531 Patent. Two different batches
of low viscosity HPMC were tested in these experiments: Type A and Type B.
[21]
Examples
1 and 2 tested the rate of release of omeprazole from omeprazole pellets
layered with two different batches of low viscosity HPMC used as a constituent
of the separating layer. The omeprazole pellets were prepared according to the
description in EP 247 983. The test methodology was described as follows:
The
pellets were pre-exposed to simulated gastric fluid USP (without enzyme) at
37˚C for 2 hours. Thereafter the drug release in buffer solution pH 6.8 at
30 minutes was determined by liquid chromatography. The buffer solution pH 6.8
was a mixture of 100.0 parts of simulated gastric fluid USP (without enzyme)
and 80.0 parts of 0.235 M disodium hydrogen phosphate solution, pH should be
between 6.75 and 6.85. The simulated gastric fluid USP (without enzyme) was
prepared by dissolving 2.0 g NaCl and 7.0 ml conc. HCl and add water to 1000
ml. The 0.235 M disodium hydrogen phosphate solution was prepared by dissolving
41.8 g Na2HPO4.2H20) and add water to 1000 ml.
[22]
The
composition of the core material, separating layer and enteric coating layer of
the tested omeprazole pellets was set out at pages 10 and 11 of the ‘531
Patent. The separating layer included Type A or Type B HPMC at 6 cps.
[23]
The
CP determinations were performed with two different apparatus: a commercial
equipment from Mettler (example 1) and a spectrophotometer equipped with a
heating coil and stirring function (example 2). The results were presented in a
table on page 11 of the ‘531 Patent (the page 11 table), as follows:
Pellets containing HPMC
|
Cloud Point
(˚C)
|
Release
of omeprazole from enteric coated pellets [%]
|
Ex. 1 (n=2)
|
Ex. 2 (n=1)
|
Type A
|
44.4
|
42.5
|
69 (60-84)
|
Type B
|
47.5
|
47.2
|
93 (93-94)
|
[24]
The
results of examples 1 and 2 were depicted on figures 1 and 2, respectively.
Compared to the marketing approval for the Losec® capsule formulation of at
least 75% release of omeprazole within 30 minutes in a buffer solution (the
marketing standard), the results on the tests on the Type A and Type B
separating layers showed, respectively, unacceptable (i.e., 69% below 75%) and
acceptable (i.e., 93% above 75%) release of omeprazole for a pharmaceutical
product.
[25]
The
patent also stated that:
Results
from a number of experiments with different batches of HPMC indicate
that HPMC with a cloud point of at least 45.6˚C is desirable in fulfilling
the regulatory requirements on rate of release of omeprazole, when the cloud
point determination is performed in a commercial Mettler instrument. [emphasis
added]
[26]
Example
3 tested the two types of low viscosity HPMC when used as a binding agent in
the preparation of core material for pellets. The pellets were not coated with
a separating layer or an enteric coating layer. The core material was prepared
by spray leaching omeprazole magnesium salt and HPMC on sugar spheres in a
fluidized bed. The composition of the core material was indicated on page 13 of
the ‘531 Patent. The prepared pellets were then tested to determine the rate of
release of omeprazole in a buffer solution of pH 6.8 with identical composition
as used in example 1 at 37˚C with a paddle speed of 100 rpm. The release
of omeprazole was determined with a spectrophotometer.
[27]
The
results of example 3 were presented on figure 3. The graphs shows that the
release of omeprazole was delayed for Type A compared with Type B.
Evidence
[28]
The
witnesses whose evidence is on the record are as follows:
For Pharmascience – Dr.
Colombo, Dr. Miller, Dr. Desbrières, Mr. Alderman.
For AstraZeneca – Dr.
Bodmeier.
Pharmascience’s Experts
[29]
Dr.
Paolo Colombo is a professor in the Department of Pharmacy at the University of
Parma, Italy. Dr. Colombo has worked in academia since receiving his Pharm. D.
in 1968. Dr. Colombo has published extensively and has been involved in
research related to cellulose polymers such as HPMC since 1983. Dr. Colombo was
asked to provide background information on delayed release pharmaceutical
dosage forms and the use of HPMC in delayed release formulations.
[30]
Dr.
Colombo provided a background on delayed release formulations, noting that the
dosage form of a pharmaceutical product is chosen based on the intended site of
administration and the time period over which a therapeutic agent is to be
administered. A delayed release dosage form delivers the therapeutic agent in
the gastrointestinal tract. Dr. Colombo explained that delayed release formulations
typically contain an acid resistant outer layer, termed an enteric coating, to
protect the drug. This layer dissolves in the neutral-to-basic conditions of
the intestine such that the drug is immediately released when the dosage form
enters the intestine. Some polymers conventionally used as enteric coatings
contain acidic groups that can cause degradation of sensitive drugs and Dr.
Colombo noted that he had encountered such problems with omeprazole tablets.
[31]
Turning
to HPMC, Dr. Colombo noted that this polymer has been widely employed as a thin
film coating on conventional tablets since the 1980s. Low viscosity HPMC dissolve
under both acidic and basic conditions and are suitable for preparing films
that dissolve rapidly at the target site. Dr. Colombo referred to an article by
Rowe that indicated that the disintegration time of tablets coated in HPMC is
directly related to the polymer molecular weight. At paragraphs 20 and 22 to 24
of his affidavit, Dr. Colombo discussed high molecular weight/high viscosity
HPMC, which is commonly used to form controlled release matrixes that allow
slow release of a drug.
[32]
Based
on his familiarity with formulations containing omeprazole and esomeprazole,
Dr. Colombo reviewed Canadian Patent No. 1,292,693 and WO 95/01783 at
paragraphs 26 to 38 of his affidavit.
[33]
Canadian
Patent No. 1,292,693 involved a separating layer, such as low viscosity HPMC,
to protect omeprazole formulation discolouring arising from the interaction of
the enteric coating and the active ingredient. The rate of drug release would
be dictated by the type and thickness of the enteric coating and the amount and
type of excipients used in the core, not the type of HPMC film used which Dr.
Colombo stated only functions as a physical barrier between the omeprazole and
the material of the enteric coating. Dr. Colombo noted that a person skilled in
the art (PSA) would know that low viscosity HPMC would be required to fulfill
this role of requiring quick dissolution in water.
[34]
WO
95/01783 pertained to the same formulation as Patent No. 1,292,693, but focused
on a novel physical form of omeprazole magnesium salt. Dr. Colombo noted that
the reported rate of dissolution would be considered an immediate release (93%
dissolution within 30 minutes) and this rate was not reduced by the thickness
of the enteric coating.
[35]
Turning
to the ‘531 Patent, Dr. Colombo noted that the formulation described therein
was the same as that described in the two patents discussed above. At
paragraphs 39 to 44, Dr. Colombo summarized the information contained in the
‘531 Patent. Dr. Colombo noted that the different release profiles for two core
pellets (one made of Type A and the other of Type B) depicted in figure 3
appeared to be by chance as the pellets were both manufactured by spray
layering and both dissolved over 90% in 30 minutes. This was consistent with
the fact that the amount of HPMC in the core would not affect the release rate.
With regards to the experiment set out on pages 10 and 11 that suggested
different release rates for Type A and Type B, Dr. Colombo noted that this
difference could not be attributed to the low viscosity HPMC, which would dissolve
immediately, unless there was a problem with the amount of polymer deposited on
the pellet that was not directly controlled. Dr. Colombo stated that the
difference would not be caused by a difference in CP.
[36]
In
addressing whether there was enough information in the ‘531 Patent for the PSA
to understand the nature of the invention and how it works, Dr. Colombo noted
the naming of HPMC used in the patent as “Type A” and “Type B”. As commercially
available HPMC is well characterized in terms of viscosity and levels of
methoxyl and hydroxypropyl substitution, Dr. Colombo found this naming approach
questionable. To reproduce the formulation and understand whether there was
actually a difference between the two types of HPMC, Dr. Colombo stated that a
PSA would require more detailed information on the types of HPMC tested.
[37]
Dr.
Colombo also stated that the data did not support a finding that there was an
actual difference between the two types of HPMC used. Rather than showing
replicated results (typically 12 tests), there was only one acceptable value
provided in the page 11 table for the Type A sample. Dr. Colombo concluded that
without a strict characterization of the film applied, it was not possible to
assign an effect on drug dissolution to the small difference measured in CP of
the two batches of HPMC having nominally the same viscosity.
[38]
With
regards to whether the invention would achieve what the patent promised, Dr.
Colombo noted that the thickness of the film deposited remained unspecified.
[39]
Dr.
Colombo noted that the low viscosity (7.2 cps or lower) HPMC separating layer
described in the ‘531 Patent was neither intended to exert control over the
rate of drug release, nor capable of exerting such control. To exert any
control over the rate of drug release, high viscosity (greater than 4,000 cps)
HPMC that leads to strong polymer gel formation would need to be employed. Dr.
Colombo stated that it is well known to formulators that low viscosity HPMC is
most suitable for preparing thin films that dissolve rapidly and completely.
[40]
At
paragraph 56 of his affidavit, Dr. Colombo explained that another critical
parameter to determining whether any control over the rate of drug release
could be achieved was the thickness of the coating layer surrounding the core
unit. In light of existing test results and the general knowledge of a PSA, Dr.
Colombo stated that the low viscosity HPMC described in the ‘531 Patent was too
thin to exert any control over the rate of drug release. After reviewing the
formulations described in pages 10 and 11 of the patent, Dr. Colombo found at
paragraph 59 of his affidavit that the amount of low viscosity HPMC polymer
described in the ‘531 Patent could not function to control the rate of drug
release from the omeprazole containing core units described therein.
[41]
At
paragraphs 60 to 67, Dr. Colombo highlighted information missing in the patent,
including:
- the dosage form tested;
- the strength of the final
dosage form;
- the conditions under
which the dissolution studies were carried out;
- which apparatus was used
for conducting dissolution testing;
- number of samples tested;
and
- the thickness or
uniformity of the separating layer produced with the two types of HPMC.
[42]
Dr.
Colombo commented that the most glaring oversight of the numbers reported on
page 11 was the assertion that they represented a release of omeprazole from a
formulation because rather than representing a release, these numbers
represented dissolution of omeprazole in the buffer solution at a particular time.
[43]
At
paragraphs 69 to 73, Dr. Colombo also criticized the dissolution testing
reported in Figure 3 of the ‘531 Patent, stating that when used as a binding
agent, HPMC cannot exert control over the rate of drug release.
[44]
Finally,
Dr. Colombo considered whether a PSA would consider that the ‘531 Patent
disclosed an invention. Dr. Colombo highlighted that the prior art disclosed
the identical formulation to that found in the ‘531 Patent, including the use
of low viscosity HPMC for the film separating layer. Dr. Colombo noted that:
80. […]
The addition of an irrelevant parameter, namely Cloud Point, does not create a
difference between the formulations of the ‘531 Patent and those of the prior
art.
81.
Low viscosity HPMC (having a viscosity lower than 7.2 cps) applied as a thin
separating layer or as binder cannot control the rate of release of omeprazole.
The bioavailability of omeprazole will be determined by the rate of dissolution
of omeprazole within the gastrointestinal tract. This is independent of the
cloud point of low viscosity HPMC.
[45]
For
these reasons, Dr. Colombo concluded that the ‘531 Patent cannot be considered
an invention.
[46]
Dr.
Robert Miller is the president of MPD Consulting, a consulting company to the
pharmaceutical industry in the areas of dosage form formulation and
manufacturing process design. Dr. Miller received his Ph.D. in Pharmaceutics in
1977. He was employed in the pharmaceutical industry from 1978 to 1994. From
1994 to 2002, Dr. Miller was employed as an assistant professor and also
provided technical pharmaceutical services to private industry.
[47]
At
paragraphs 15 to 22 of his affidavit, Dr. Miller provided a background summary
on the use of HPMC in pharmaceutical formulations. Dr. Miller noted that no
specifications for CP were provided in the 1995 edition of the United States
Pharmacopeia (USP) for low viscosity HPMC. CP was not something that a
pharmaceutical formulator would consider when designing a formulation in 1997
or today; rather, the primary governing factors are molecular weight and
viscosity. Dr. Miller noted that a low molecular weight HPMC would provided an
immediate release. As well, when used as a binder in a formulation, HPMC would
not impact the release rate of the formulation.
[48]
At
paragraphs 23 to 63 of his affidavit, Dr. Miller considered the following prior
art patents on omeprazole: Canadian Patent No. 2,025,668; Canadian Patent No.
1,292,693; Canadian Patent No. 1,302,891; WO 94/27988; WO 95/01783; WO
96/01623; Canadian Patent No. 2,184,842; and Canadian Patent No. 2,184,037.
[49]
From
this review, Dr. Miller listed various factors that the PSA would learn from
formulations of benzimidazoles such as omeprazole and esomeprazole at paragraph
64 of his affidavit. These findings included the following:
HPMC
is recommended as a separating layer to be used in between the active and the
enteric coating; and the recommended thickness of the separating layer is 2-4
μm (which would be a thin film coating)
[…]
the
separating coating must be water soluble or in water rapidly disintegrating –
which would mean a low viscosity/low molecular weight HPMC as this type of HPMC
will dissolve in water; …
[50]
A
PSA would take these factors into account and use a grade of HPMC as a binder
or separating layer that would not impact the release rate of the formulation.
The delayed release of the active ingredient would be determined by the enteric
coating, which would withstand the stomach acid but dissolve immediately in the
alkaline intestine.
[51]
Dr.
Miller then considered the ‘531 Patent at paragraph 66 of his affidavit. Dr.
Miller noted that the testing reported in the patent and the clinical use of
the capsules was at 37˚C. This was below the claimed CP of both types of
HPMC referred to in the patent. Dr. Miller also noted that the following
information was missing on the tests reported in the patent: the specific grade
of HPMC, the number of hydroxypropyl groups, the number of methoxy groups and
which specific HPMC was tested. Dr. Miller found that prior art provided
teachings on the appropriate thickness and weight of the HPMC layer to ensure
an acceptable release rate.
[52]
With
regards to whether there was sufficient information for a PSA to understand the
invention and how it works, Dr. Miller noted that the patent did not disclose sufficient
information on what Type A and Type B HPMC was; thus, key information was
missing to allow the PSA to obtain the correct quality of HPMC. In addition,
Dr. Miller stated that the testing in the ‘531 Patent did not show that the CP
of HPMC affects drug release. Based on his own experience, Dr. Miller was
skeptical that CP in and of itself has any effect on release. Dr. Miller noted
that no information was provided on the coating amounts on the spheres or the
size of the spheres; differences in the amount of coating could account for the
numbers provided in the page 11 table. Dr. Miller found that a PSA could not
put the invention into practice without difficulty in light of the lack of
information on what type of HPMC to purchase.
[53]
With
regards to the patent’s suggestion that different batches of HPMC may differ in
their abilities to influence the rate of release of omeprazole in simulated
intestinal fluid, Dr. Miller noted that, in his experience, there were no
obvious differences in 1997 in different batches of a particular grade of HPMC.
The overall characteristics of a certain grade of HPMC are and were the same
from batch to batch. At paragraph 93 of his affidavit, Dr. Miller also noted
that the differences in release rates reported in the testing of HPMC as a
separating layer could not be attributed to CP because that temperature was not
reached in the course of the testing (which was done at 37˚C). In
conclusion, Dr. Miller found that “[t]here is no invention in adding parameters
to the specifications for HPMC – i.e. cloud point, particularly when the
parameters are irrelevant to the use of the formulation in the body”.
[54]
Dr.
Jacques Desbrières is a professor at the University of Pau, France. Dr.
Desbrières obtained a degree in chemical engineering in 1980. He worked as a
research engineer and project leader at a pharmaceutical company between 1981
and 1988. In 1990, he entered academia where he remains today. Dr. Desbrières
has published extensively and teaches in the areas of physical chemistry and
polymer science.
[55]
At
paragraphs 15 to 24 of his affidavit, Dr. Desbrières provided a summary on HPMC
polymers and their physical properties, including thermal gelation and CP. Dr.
Desbrières highlighted the findings of a study published by Sarkar in 1979. In this
study, the thermal gelation temperatures and CPs of numerous HPMC polymers
produced by Dow Chemical Corporation (Dow) under the trade-mark METHOCEL were
determined experimentally. A significant finding in this study was that the
thermal gelation temperatures and CPs are predominantly determined by the
percentage of methoxyl groups present on the polymer. However, where methoxyl
groups and hydroxypropyl groups were similar, the CP was found to be within a
narrow range for HPMC polymers having vastly different molecular weights.
[56]
At
paragraphs 25 to 31 of his affidavit, Dr. Desbrières discussed his experiments
on low viscosity HPMC to determine CPs. He conducted these tests on samples of
METHOCEL E5, E6 and E15 from Dow and on Pharmacoat 603 and 606 from Shin-Etsu
Chemical Corporation (Shin-Etsu). In Table 1 of his affidavit, Dr. Desbrières
presented the results of his experiments as follows:
Sample
|
IPT*
buffer C=1%
|
CP*
buffer CP=1%
|
%**
Methoxyl
|
%**
Hydroxypropyl
|
Viscosity
(cP)**
|
Mn*
(g/mol)
|
Mw*
(g/mol)
|
Pharmacoat
603
|
47.8
|
49.2
|
28.9
|
9.1
|
3.09
|
12100
|
15600
|
Pharmacoat
606
|
45.8
|
47
|
28.7
|
9.0
|
5.96
|
19100
|
24600
|
Dow E5
|
47.7
|
49.3
|
28.5
|
8.9
|
4.4
|
15900
|
19000
|
Dow E6
|
46.6
|
48
|
29.5
|
8.0
|
5.6
|
18600
|
22700
|
Dow E15
|
45.2
|
46.2
|
28.7
|
9.1
|
15
|
30300
|
38200
|
* = Determined Experimentally
** = Provided by Manufacturer
[57]
The
first column, entitled IPT, provides the results that correspond with the CP as
defined in the ‘531 Patent (i.e., the temperature where light transmission is
reduced to 95% when measured using a spectrophotometer with an ultraviolet detector).
The second column, entitled CP, provides the results that correspond with the
temperature at which light transmission was reduced to 50% (i.e., the true CP;
namely the definition that Dr. Desbrières stated is prevalent in the literature
and understood by a PSA). Dr. Desbrières noted that for polymers having
viscosities below 7.2 cps, both these data returned narrow temperature ranges.
In tests on buffer solutions containing phosphate salts, results of which were
presented in Table 2 of his affidavit (not reproduced here), the IPTs and CPs
were depressed and remained within narrow temperature ranges for polymers of
low viscosity.
[58]
Dr.
Desbrières considered the ‘531 Patent at paragraphs 33 to 37 of his affidavit.
He noted that CP values obtained using a Mettler FP90/FP81C instrument would be
slightly higher than values obtained using a spectrophotometer, which explained
why the curves in Figures 1 and 2 were slightly different. In addition, Dr.
Desbrières noted that these figures showed that the two types of HPMC used in
the patent would be fully dissolved at body temperature.
[59]
In
considering whether a PSA would understand the nature of the invention and how
it works, Dr. Desbrières stated that “claiming a low viscosity HPMC with a specific
cloud point appears to be an indirect way of claiming a low viscosity HPMC with
a certain degree of methoxyl groups and hydroxypropyl groups” (at paragraph
38). Thus, to put the invention into practice without difficulty, Dr.
Desbrières noted that the patent should have specified the degree of
substitution for the methoxyl groups and the molar substitution for
hydroxypropyl groups; information provided by manufactures on their certificates
of analysis.
[60]
Finally,
Dr. Desbrières noted that he did not see a scientific reason for choosing HPMC
at the claimed CP because, when used as an excipient in a pharmaceutical
formulation, HPMC would not be exposed to temperatures above body temperature
(37˚C). Thus, the CP would not affect the polymer’s solubility under
physiological conditions.
[61]
Mr.
Daniel Alderman obtained a chemical engineering degree in 1975. From graduation
through to 2000, Mr. Alderman held increasingly senior positions at Dow in the
areas of emulsion polymers and cellulose ethers. Between 2000 and 2002, Mr.
Alderman worked in the Dow automobile division. Between 2002 and his retirement
in 2008, Mr. Alderman was the corporate research and new business development intellectual
asset manager at Dow.
[62]
At
paragraphs 11 to 20 of his affidavit, Mr. Alderman provided a background on the
HPMC products sold by Dow. Dow’s HPMC products for pharmaceutical application
as film formers were the low viscosity METHOCEL E5 Premium and E6 Premium.
These were designed to dissolve quickly in water or gastric fluids. They were
not designed to nor did they affect the performance or release of the active
ingredients in the tablet. Mr. Alderman noted that when used as a film former,
it is important that the low viscosity HPMC be applied in a continuous film,
without holes or cracks. Mr. Alderman stated that, to the best of his
recollection, Dow did not receive any complaints from their customers
(including AstraZeneca) on batch-to-batch performance variation of their low
viscosity HPMC products. Mr. Alderman also remarked that the HPMC products
produced by Dow under the trade-mark METHOCEL in 1997 and 1998 are the same
HPMC polymers produced today.
[63]
At
paragraphs 14 to 17 of his affidavit, Mr. Alderman explained the chemical
structure of Dow’s METHOCEL HPMC polymers. Mr. Alderman also explained that Dow
has developed innovative processes to prepare HPMC polymers with controlled
physical properties. The HPMC monograph in the USP was created according to
Dow’s specifications. The USP specifications relating to methoxyl content and
hydroxypropyl content have not changed in the last 25 years. In addition,
methods for testing HPMC polymers were developed by Dow and the American
Standards Association for Testing and Materials.
[64]
Mr.
Alderman considered the ‘531 Patent at paragraphs 21 to 25 of his affidavit. He
noted that although it is highly unlikely that significant differences exist
between different lots of HPMC, a reason for such differences could relate to
differences in the continuity of the separating layers formed by the Type A and
Type B HPMC described in the patent. Mr. Alderman observed that the formulation
described on page 11 for the separating layer did not contain a plasticizer.
Plasticizers are important for creating defect-free continuous films. This is
particularly true for very thin films, where cracks or imperfections would have
a greater deleterious effect and for films made of low viscosity polymers that
tend to be more brittle and prone to cracking.
[65]
At
paragraphs 29 to 30 of his affidavit, Mr. Alderman explained the HPMC
manufacturing process. Mr. Alderman noted that it is known that the apparent
viscosity of an aqueous solution of a HPMC polymer is proportional to its
molecular weight. Similarly, it is known that the dissolution of HPMC varies
directly with the molecular weight. Mr. Alderman explained that the viscosity
of HPMC polymers produced by Dow is controlled through the manufacturing
process.
[66]
At
paragraphs 34 to 38, Mr. Alderman described the results of studies on the
thermal gelation and CP temperatures of HPMC polymers. He explained that HPMC
polymers possess a unique property of decreased solubility in water above a
critical temperature; thus, where a solution of HPMC is dissolved in water and
heated above that critical temperature, the decreasing solubility of HPMC is
manifested as an increase in viscosity and an onset of cloudiness or turbidity
of the solution. The temperature at which the amount of light transmitted
through the solution is reduced to 50% is termed the CP temperature and is
dependent on the percentage of methoxyl groups present in the polymer. The
molecular weight and viscosity of a polymer has a very small effect on the CP.
The process of increasing cloudiness or turbidity is reversible by cooling the
solution. At paragraph 35 of his affidavit, Mr. Alderman explained that this
phenomenon has been attributed to an association of methoxyl groups along the
same polymer chain and the association of methoxyl groups on different polymer
chains.
[67]
At
paragraph 43 of his affidavit, Mr. Alderman noted the following regarding the
CP of a solution of HPMC:
The
cloud point of a solution of a given HPMC is a property of the polymer that
arises from its physical properties, in particular, the percentage of methoxyl
groups present on the polymer chain. If the physical properties of a given HPMC
polymer are known, such as percentage methoxyl groups, the cloud point of an
aqueous solution of the polymer can be predicted within a very narrow
temperature range. Methocel E5 and E6 have had the same percentage of methoxyl
groups (and viscosity/molecular weight) since at least 1997 to today.
[68]
At
paragraphs 47 to 49 of his affidavit, Mr. Alderman considered the claims
contained in the ‘531 Patent and whether the alleged invention would have been
obvious to a PSA. As low viscosity HPMC having a specific CP was essentially a
claim to an inherent property of a known material, Mr. Alderman concluded that
the ‘531 Patent would be obvious to a PSA.
[69]
Finally,
Mr. Alderman considered whether there was sufficient information in the ‘531
Patent for a PSA to understand the nature of the invention and how it works.
However, as the patent did not disclose information that would have been found
in HPMC specifications in 1998, namely, the percentage of methoxyl groups or the
molecular weight, Mr. Alderman concluded that a PSA would not be able to choose
the correct HPMC with the specified cloud point. Thus, the results in the
patent would not be reproducible by a PSA and could not be relied on for
practical applications.
AstraZeneca’s Expert
[70]
Dr.
Roland Bodmeier is a professor at the Institute für Pharmazie Freie Universität Berlin, Germany. Dr. Bodmeier obtained his Ph.D. in pharmaceutics in 1986 and
a post-doctorate degree in 1993. Since 1994, he has been employed in his current
position. Dr. Bodmeier has published extensively and consulted to the
pharmaceutical industry in the areas of drug dosage forms and controlled drug
delivery systems.
[71]
At
paragraphs 11 and 12, Dr. Bodmeier provided a background on the terminology of HPMC
and CP. Dr. Bodmeier noted that there is no generally accepted level of light
transmission that defines a CP; a percentage between 50 and 97.5 is typically
chosen.
[72]
Turning
to the ‘531 Patent, Dr. Bodmeier noted that in December 1998, the inventors’ finding
that different batches of low viscosity HPMC differ in their ability to
influence the rate of release of omeprazole from an enteric coated formulation;
a difference that can be gauged by reference to the CP and would have been
surprising to a PSA for two reasons.
[73]
First,
the use of low viscosity HPMC in a pharmaceutical formulation was not generally
known to be capable of influencing release rate. The opposite would have been
believed because low viscosity HPMC dissolves quickly in water. Thus, if a PSA
saw that their omeprazole enteric formulations were being released at different
rates, the PSA would have considered other process or formulation parameters
rather than investigating variability of different batches of subtypes of a
specific product family of HPMC. As such, Mr. Alderman’s statement that he did
not recall receiving any complaints on batch-to-batch variation from customers
was not surprising. Dr. Bodmeier also highlighted that a PSA would have
understood that the reference to different batches in the patent is a reference
to different batches of one subtype of HPMC, not different batches of different
subtypes. Second, CP was not a factor considered in selecting a low viscosity
HPMC for use as a binder and/or separating layer.
[74]
Dr.
Bodmeier further noted that CP of low viscosity HPMC is primarily affected by
the level of methoxyl and hydroxypropyl substitution of a given HPMC polymer.
As categories of HPMC are defined in the USP by reference to specific ranges of
percent methoxyl and hydroxypropyl substitution, there are an infinite number
of possible combinations, each of which will affect CP. Dr. Bodmeier noted that
CP is also affected by other variables, such as the nature of substitution
along a given cellulose backbone and molecular weight/viscosity of the polymer.
Further, as HPMC polymers consist of dozens to hundreds of repeating glucose
units, the assigned percent methoxyl and hydroxypropyl substitution is simply
an average of the substitution of all glucose units in the polymer. Thus, even
when batches have identical viscosity and methoxyl and hydroxypropyl content,
the pattern of substitution and distribution can vary which will affect CP.
[75]
As
it is highly improbable that different lots will have identical substitution
patterns because the number of substitution sites on the polymer chain far
exceeds the number of possible substituents, the CP of an HPMC batch can only
be obtained from direct measurement. Dr. Bodmeier further highlighted that the
allowable ranges for viscosity and percentage substitution of methoxyl and
hydroxypropyl, as indicated in Dow’s certificate of analysis for METHOCEL E5,
highlights the infinite number of variations of HPMC for one subtype. This can
be further complicated by the distribution of substituted groups along the
polymer chain and on individual glucose units. By characterizing HPMC by
reference to its CP, Dr. Bodmeier explained that the inventors of the ‘531
Patent provided an elegant and objective proxy to assess the sum effect of the
infinite combination of these variables. Concurrently, the inventors determined
that when the CP exceeded a certain value when measured with a specific
instrument, there was greater release of omeprazole within 30 minutes.
[76]
At
paragraphs 35 to 50 of his affidavit, Dr. Bodmeier provided a summary of the
claims contained in the ‘531 Patent. In the remainder of his affidavit, Dr.
Bodmeier responded to the affidavits of Pharmascience’s experts.
[77]
At
paragraphs 51 to 55 of his affidavit, Dr. Bodmeier responded to Dr. Desbrières’
affidavit. Dr. Bodmeier disagreed with Dr. Desbrières’ characterization of CP
as the temperature at which light transmission is reduced to 50%. Rather, Dr.
Bodmeier stated that there was and is no common understanding as to what light
reduction level defines a CP. Dr. Bodmeier stated that the testing reported in
Dr. Desbrières’ affidavit was premised on an incorrect understanding of the invention
of the ‘531 Patent. Rather than comparing batches of a single low viscosity
HPMC subtype, Dr. Desbrières’ testing compared different subtypes of HPMC
products. Dr. Desbrières’ testing results are thus not informative.
[78]
Dr.
Bodmeier also stated that even though HPMC is expected to be fully dissolved at
37˚C, this does not mean that all HPMC batches dissolve at the same rate.
Dr. Bodmeier states that Dr. Desbrières ignored the date in the table at page
11 of the ‘531 Patent that explicitly shows that when tested in simulated
gastric conditions at 37˚C, two batches of HPMC resulted in different
average omeprazole release rates; one within the marketing standard and one
that was not. Thus, different batches of one subtype of HPMC interact
differently with water, which results in the release of omeprazole at different
rates.
[79]
At
paragraphs 56 to 68 of his affidavit, Dr. Bodmeier responded to Mr. Alderman’s
affidavit. At the outset, Dr. Bodmeier noted that Dr. Desbrières, Dr. Miller,
Dr. Colombo and Mr. Alderman provided several of the same statements. Where
that was the case, his comments on one affidavit applied equally to the others.
[80]
Dr.
Bodmeier noted Mr. Alderman’s suggestion that low viscosity HPMC would not
affect the release of the active ingredient in the tablet. However, Dr.
Bodmeier noted that Mr. Alderman concurrently contradicted that statement by
noting that HPMC dissolution varies with molecular weight and that there is a
clear correlation between increasing viscosity and increasing time of
disintegration. Based on the data on viscosity and tablet disintegration time
presented in the Rowe study and the range for viscosity stated in the
certificate of analysis for METHOCEL E5 (4.0 to 6.0 mPas), Dr. Bodmeier showed
that batch-to-batch variation in viscosity for METHOCEL E5 correlated with an
approximately 30 second difference in disintegration times between batches.
Thus, Dr. Bodmeier stated that Mr. Alderman’s statement that HPMC would not
affect release rate of the active ingredient was incorrect.
[81]
In
response to Mr. Alderman’s suggestion that a possible reason for the difference
in release rates between different batches of HPMC (as reported in the page 11
table) could be imperfections in the film from lack of plasticizer use, Dr.
Bodmeier noted that this appeared to merely be an unfounded guess. In addition,
neither batches included a plasticizer.
[82]
Dr.
Bodmeier also noted that Mr. Alderman incorrectly stated that methoxyl groups,
rather than hydroxypropyl groups, are responsible for turbidity. The Sarkar
article clearly showed that both groups are responsible for the turbidity
caused by phase transition. In addition, Dr. Bodmeier disagreed with Mr.
Alderman’s statement that if the physical properties of a given HPMC polymer
were known, the CP of an aqueous solution of the polymer could be predicted
within a very narrow range. Rather, CP is influenced by the nature of the
substitution and distribution of both methoxyl and hydroxypropyl along the
polymer chain and on the individual glucose units and by the molecular
weight/viscosity of the polymer.
[83]
Turning
to the sufficiency of disclosure, Dr. Bodmeier disagreed with Mr. Alderman’s
statement that a PSA would not be able to choose the correct HPMC with the
specified CP without having the percentage of methoxyl groups provided. Dr.
Bodmeier noted that methoxyl groups are not the only determinant of CP. In
addition, this statement ignored the invention of the ‘531 Patent, which
improved on prior art omeprazole formulations by providing a means (HPMC at the
claimed CP) to avoid having to know physical properties of a given batch of
HPMC in selecting an HPMC batch that would result in the required levels of
omeprazole release within 30 minutes. Thus, the ‘531 Patent clearly teaches a
PSA how to select a specific quality of HPMC for omeprazole enteric
formulation.
[84]
At
paragraphs 69 to 76 of his affidavit, Dr. Bodmeier responded to Dr. Miller’s
affidavit. Dr. Bodmeier noted that none of the patents cited by Dr. Miller as
prior art discussed concerns with batch-to-batch variation in HPMC, nor did
they direct the PSA towards selecting an HPMC above the claimed CP. The invention
of the ‘531 Patent was not obvious in light of any or all the prior art cited.
Dr. Bodmeier noted that Dr. Miller’s critique on the absence of information on
the specific grade of HPMC being tested and the coating amounts of HPMC on the
spheres or size of the spheres missed the point of the invention. Based on the
‘531 Patent, the PSA would understand that any suitable grade or coating amount
of low viscosity HPMC could be used to prepare an enteric omeprazole
formulation as long as it meets the claimed CP.
[85]
Dr.
Miller’s observation that the release for Type A HPMC was acceptable for at
least one of the coated pellet batches because the range of release reached 84%
also missed the point. What the patent teaches is a means of selecting a
specific quality HPMC to avoid variation. In addition, Dr. Bodmeier disagreed
with Dr. Miller’s statement that the dissolution results for the two cores in
Type A and Type B listed in Figure 3 do not vary greatly. Rather, there is a
difference of approximately six minutes between the two profiles, which is
equivalent to approximately 20% of the total release time of approximately 30
minutes; a significant difference for immediate release, uncoated pellet cores.
[86]
In
addition, contrary to Dr. Miller’s statement that the ‘531 Patent does not
indicate what type of HPMC a PSA should purchase, Dr. Bodmeier stated that the
patent clearly provides that the PSA should purchase a low viscosity HPMC at
the claimed CP. Where the HPMC is selected at the claimed CP, the patent teaches
that all batches will sufficiently release 75% of the active ingredient in 30
minutes (in accordance with the marketing standard), thereby reducing product
discard due to failed formulations.
[87]
Finally,
at paragraphs 77 to 88 of his affidavit, Dr. Bodmeier responded to Dr.
Colombo’s affidavit. Dr. Bodmeier noted Dr. Colombo’s statement that the amount
of HPMC in the core would be less than 3% thereby not affecting the release
rate. However, Dr. Bodmeier stated that this calculation was incorrect. Rather,
there is approximately 15% HPMC which is a significant amount in the drug and
would be expected to affect the drug release rate. In addition, although low
viscosity HPMC is commonly understood to dissolve quickly, there are
differences in the dissolution rates of HPMC and low viscosity HPMC used as a coating
does affect the rate of immediate release of the active ingredient.
[88]
Dr.
Bodmeier also noted that Dr. Colombo’s statement that dissolution tests require
12 replicate dissolutions was incorrect. Rather, as per scientific literature,
a maximum of three to six replicates are generally used. Dr. Bodmeier
highlighted that the patent indicates that the findings are based on a “number
of experiments”. Dr. Bodmeier critiqued several of Dr. Colombo’s claims on the
basis that they pertained to controlled release formulations and not to
immediate release formulations, the subject matter of the ‘531 Patent.
[89]
Dr.
Bodmeier further noted Dr. Colombo’s statement that the ‘531 Patent did not
specifically state what final dosage form and strength was tested which would
cause the PSA to not know which USP standards to compare the tests to and what
apparatus was used for conducting the dissolution testing. However, Dr.
Bodmeier stated that the PSA, on reading the patent as a whole, would clearly
understand that the tests should be compared to 75% release in 30 minutes (the
marketing standard) and that the apparatus used was the Dissolution Apparatus 2
(paddle). Dr. Bodmeier also stated that Dr. Colombo’s critique of the word “release”
as opposed to “dissolve” was incorrect and stemmed from confusion between
controlled release and immediate release. Dr. Bodmeier finally stated that Dr.
Colombo’s calculation of the similarity factors between the two release
profiles for the core pellets shown in Figure 3 of the ‘531 Patent was error
prone and unfounded.
Issues
[90]
AstraZeneca
submits the following point at issue:
Are Pharmascience’s
allegations of invalidity of the ‘531 Patent justified?
[91]
Pharmascience
submits the following points at issue:
1. Is the patent
invalid for inutility?
2. Does the patent
meet the requirements of sufficiency?
3. Is the claimed
invention obvious?
[92]
I
would rephrase the issues as follows:
1. Is the ‘531
Patent not an invention as defined in section 2 of the Patent Act
because it merely ascertains the properties of a known substance?
2. Does the ‘531
Patent meet the validity requirements for utility?
3. Does the ‘531
Patent meet the validity requirements of sufficient disclosure?
4. Does the ‘531
Patent meet the validity requirements for obviousness?
AstraZeneca’s Written Submissions
Evidence
[93]
AstraZeneca
submits that Pharmascience is strictly limited to making submissions on those
invalidity allegations for which it filed evidence, namely: obviousness,
insufficiency and lack of demonstrated utility. Thus, Pharmascience cannot rely
on its other allegations of invalidity that it did not address in its evidence,
namely: lack of novelty, claims broader, double patenting, lack of sound
prediction, not a valid selection patent and fraud on the Patent Office.
[94]
AstraZeneca
also notes that the order of evidence was reversed by Prothonotary Tabib’s order
dated February 15, 2011. A reversal of evidence is intended to define more
narrowly the allegations of invalidity that will be argued by the generic
company, thereby limiting the issues at play.
Patent Construction
[95]
AstraZeneca
submits that when the ‘531 Patent was published in December 1998, the
inventors’ discovery that different batches of low viscosity HPMC, as reflected
by their CP, may have different abilities to influence the rate of release of
omeprazole from an enteric coated formulation would have been very surprising
to a PSA. This was because the use of low viscosity HPMC in a pharmaceutical
formulation was not generally known to be capable of influencing release rate.
Moreover, a PSA would actually have believed the opposite to be true because
low viscosity HPMC is a polymer that dissolves quickly in water. AstraZeneca also
notes that the reference to different batches in the patent would be clearly
understood by a PSA to mean different batches of the same subtype of low
viscosity HPMC.
[96]
AstraZeneca
notes that experts for both sides agreed that in December 1998, a PSA would not
have referred to or categorized HPMC by reference to its CP. However, on
reading the patent, it would have become apparent to a PSA that by selecting
low viscosity HPMC in accordance with its CP, the inventors had provided a
proxy by which to assess the sum effect of the infinite combinations of
different variables that were understood to affect the CP and the release rate
of omeprazole.
[97]
AstraZeneca
highlights the statement in the patent that an upper limit for the CP is not
critical and must therefore not be specified. From this, a PSA would understand
that when selecting a low viscosity HPMC, the upper limit is not important as
long as the requirements defined in phamacopoeial monographs and the claimed CP
are fulfilled. As a higher CP reflects higher water solubility, it would not be
expected to decrease the rate of release of omeprazole. Thus, it is the specification
for the lower limit, not the upper limit, that is critical to achieving the
desired rate of release.
[98]
In
addition, the inventors stated in the patent that the reduction of product
discard was a real economic advantage resulting from selecting a low viscosity
HPMC in accordance with the claimed CP. On following the patent, a PSA would
also learn how to reduce unpredictable variations in release rates between
different batches of formulations, further reducing product discard.
[99]
Finally,
AstraZeneca notes that none of Pharmascience’s experts provided a discussion on
the understanding of the PSA of the batch-to-batch variation described in the ‘531 Patent. This
is fundamental to an understanding of the patent invention. Although the
experts stated their general disbelief that differences in low viscosity HPMC
as gauged by reference to the CP can affect the release of a drug, they did not
provide evidence disproving the correlation or any credible basis for their
disbeliefs.
Invention under Section 2 of the Patent
Act
[100] AstraZeneca
submits that Pharmascience’s allegation that the ‘531
Patent is not an invention is fundamentally
flawed as it is premised on an incorrect construction of the patent. When
properly construed, the patent does not merely contribute a verification of the
CP but also teaches that by selecting low viscosity HPMC above the claimed CP,
a pharmaceutical formulator can reduce the amount of product discard that does
not meet omeprazole release specifications. This was a surprising and
unexpected teaching offering a substantial advantage.
[101] Furthermore,
Pharmascience’s evidence that the ‘531 Patent claims an inherent property of a known
compound is flawed as it is premised on testing that purportedly indicates that
low viscosity HPMC in 1998 and today would have a CP above the claimed CP. This
testing failed to consider the batch-to-batch variation in CPs. Concurrently,
it provided a clear admission that the CP of some batches of the same low
viscosity HPMC product can in fact be below the claimed CP.
Utility
[102] AstraZeneca
submits that the patent’s inventors demonstrated that by selecting low
viscosity HPMC at the claimed CP for use in the omeprazole enteric formulation,
at least 75% of the omeprazole would be released in a buffer solution in the
first 30 minutes (as per the marketing standard). In reading this in the
context of the whole patent, a PSA would clearly understand that different
batches of a subtype of HPMC can differ in CPs. This difference can result in
one batch with a certain CP releasing omeprazole within the prescribed 30
minutes while another batch with a different CP does not.
[103] AstraZeneca
notes that the Federal Court of Appeal has explicitly rejected the notion that
utility must be demonstrated in the patent disclosure. Nevertheless,
AstraZeneca highlights the patent’s reference to results from a number of
experiments. These experiments demonstrated that selecting a batch of HPMC with
at least the claimed CP is desirable for achieving the marketing standard.
[104] AstraZeneca
submits that the Pharmascience experts’ disbelief, which relies on Dr.
Desbrières’ testing, is pure conjecture and is not based on evidence. In
support, AstraZeneca notes that Dr. Desbrières’ testing does not address the
invention of the ‘531 Patent
and whether there is batch-to-batch variation of CPs in a given subtype of low
viscosity HPMC. Moreover, these experts’ disbelief is directly contradicted by
actual data in the ‘531 Patent and in a table produced by Pharmascience at
page 60 of its allegation.
[105] AstraZeneca
notes that Pharmascience did not share this information with its witnesses,
including Dr. Desbrières, before he conducted the testing described in his
affidavit. After considering this information, AstraZeneca submits that Dr.
Desbrières admitted in cross-examination that test results showed some batches
of low viscosity HPMC with a CP below 44.5˚C. This contradicted his
affidavit evidence that all HPMC would have a CP above the claimed CP.
Similarly, AstraZeneca notes Mr. Alderman’s affidavit evidence that, based on
Dr. Desbrières’ testing, the CP of METHOCEL E5 in 1996 and today would have
exceeded 45˚C. However, on cross-examination, Mr. Alderman admitted that
he had not seen the data from Dr. Desbrières’ testing when he provided his opinion,
nor did he write that particular sentence in his affidavit.
[106] AstraZeneca also
notes that Pharmascience’s experts agree that within a subtype of low viscosity
HPMC, there are allowable ranges of methoxyl and hydroxypropyl content and that
both of these have an effect on CP. In addition, when a particular HPMC subtype
is manufactured, it is highly improbable that one lot will have an identical
distribution of substitutes as another because the number of sites on the
polymer chain where the substitution occurs far exceeds the number of possible
substituents. Dr. Desbrières admitted that in a heterogenous industrial
process, the distribution of substituents of the HPMC will vary from batch to
batch. Dr. Desbrières’ evidence also shows that the distribution of
substituents can affect gelation temperature, which can lead to differences of
at least 20˚C for CP.
[107] AstraZeneca
further notes that the experts agree that within a given subtype of low
viscosity HPMC, there are allowable ranges of molecular weight and viscosity.
Albeit to a lesser extent, CP is also affected by the molecular weight or
viscosity of the polymer. These unpredictable differences will affect the CP
and AstraZeneca notes that it is unchallenged that the CP of a low viscosity
HPMC batch can only be obtained from direct measurement.
[108] AstraZeneca
highlights that Pharmascience directed Dr. Desbrières to conduct testing on
certain HPMC samples in support of its invalidity allegations. Dr. Desbrières
admitted that he did not compare the CP of different batches of a given subtype
of HPMC, rather, he compared the CP of different subtypes. As Dr. Desbrières’
testing did not address the batch-to-batch variation addressed by the patent
and is premised on a fundamentally incorrect understanding of the patent,
AstraZeneca submits that his test results are not informative.
[109] AstraZeneca also
submits that Dr. Desbrières’s testing should be disregarded as he was unaware
of the chain of custody of some of the HPMC samples he tested, particularly
with what happened to the samples between the time they were shipped from Dow
to his counsel and ultimately to him. AstraZeneca also notes the following in
support of its submission that Dr. Desbrières’ evidence should be treated with
circumspection. Dr. Desbrières:
1. is not an expert
in the formulation of enteric coatings and has never conducted a gastric acid
release test;
2. gave an opinion
that the differences in release rates disclosed in the gastric acid release
tests in the ‘531 Patent
could be erroneous even though he did not know the margin of error of these
tests and has never conducted such a test;
3. suggested that
the claimed CP was not a true CP because it was not designated as the
temperature at which light transmission is reduced to 50%. However, he later
admitted that CP does not have a fixed definition and gave no explanation as to
why he defined CP at 95% in a 1997 publication;
4. gave affidavit
evidence that low viscosity HPMC would have a minimum CP of 44.5˚C. However,
he later admitted that he had no data as to whether the CP of multiple batches
of one subtype of HPMC would fall below this temperature and admitted that the
data provided by Pharmascience in its NOA shows several batches of the same
subtype of HPMC with CPs below this temperature; and
5. approached the ‘531 Patent
improperly as he applied all his knowledge gained up until drafting his
affidavit rather than focusing on the understanding of a PSA reading the patent
at the publication date.
[110] AstraZeneca also
notes that although Pharmascience’s experts provided affidavit evidence that CP
does not affect release rate, Dr. Desbrières admitted that gelation properties
(related to CP) have an effect on release and the heterogeneity of substitution
provides a poor predictability of release. On Mr. Alderman’s suggestion that a
possible reason for the difference in release rates could be imperfections in
the film caused by a lack of use of plasticizer, AstraZeneca notes that this
appears to be a guess without basis. In addition, Mr. Alderman’s experience
with pharmaceutical formulations pertains to controlled release formulations
rather than immediate release formulations and Mr. Alderman has also not been
actively engaged in the field of controlled release since about 1988.
[111] AstraZeneca
submits that Dr. Miller’s statement that the release for Type A HPMC was
acceptable for at least one of the coated pellet batches misses the point. The
fact that one example has a release rate within the required limits is
irrelevant. The patent teaches that the variation in release rates can be
avoided by selecting an HPMC exceeding the claimed CP.
[112] In response to
Dr. Colombo’s statement that differences in the release rates for different
types of HPMC cannot be attributed to differences in CPs because the HPMC would
dissolve immediately, AstraZeneca notes that low viscosity HPMC are commonly
understood to dissolve quickly. However, it is not true that there are no
differences in the dissolution rates of HPMC or that low viscosity HPMC, when
used as a coating, does not affect the rate of release of the active
ingredient. Rather, prior to the release of the ‘531
Patent, a PSA would have generally believed
that there were no relevant differences in the release characteristics of low
viscosity HPMC designed for immediate release.
[113] The ‘531 Patent
surprisingly and clearly shows that differences in low viscosity HPMC, as
gauged by reference to the CP, do result in difference in release rate of
omeprazole. Thus, selecting batches of low viscosity HPMC that exceed the
claimed CP ensures that omeprazole release is consistently within the marketing
standard. AstraZeneca submits that Dr. Colombo’s statement on the quick
dissolution of low viscosity HPMC and that is not used in preparing controlled
release formulations confuses the matter because neither of these situations
are taught in the ‘531 Patent. The ‘531 Patent pertains to avoidance of variations in
immediate release formulations.
[114] With regards to
Example 3, where low viscosity HPMC was used as a binder rather than a
separating layer, AstraZeneca notes that in stating that the dissolution rates
for the two cores did not vary greatly, Dr. Miller ignored that this test
pertained to the release from uncoated pellet cores, for which there is a
significant difference in immediate release. In addition, in his calculation of
the similarity factor between the two release profiles, Dr. Colombo did not
have the necessary information from the patent, nor did he indicate what
assumptions he made in his calculation. Nevertheless, the figure that Dr.
Colombo’s calculation was based on (Figure 3) was developed from an experiment
related to the use of low viscosity HPMC as a binder. The low viscosity HPMC
was not exposed to gastric acid in that experiment as would have been the case
for enteric formulation with the separating layer containing the low viscosity
HPMC.
[115] AstraZeneca
highlights that Pharmascience’s own evidence shows that the least important
cause of differences in CP, namely viscosity, also has an effect on the
release. This data indicates that batch-to-batch variation in viscosity for METHOCEL
E5 correlates with an approximately 30 second difference in disintegration
times between batches at either end of the allowable range.
[116] Finally,
AstraZeneca notes that although HPMC is expected to be fully dissolved at
37˚C, this does not mean that HPMC batches dissolved at the same rate. In
fact, as admitted by Dr. Miller, different batches of HPMC dissolve at
different rates and these rates are important to the release from a dosage
form. AstraZeneca submits that Pharmascience’s argument on body temperature
also considers HPMC solubility in isolation. This is not the subject of the ‘531 Patent which
is directed to the effect of HPMC on the release of the active ingredient. In
fact, the data in the patent shows that when tested in simulated gastric
conditions at 37˚C, two batches of HPMC resulted in different average
omeprazole release rates, only one of which met the marketing standard. This shows
that different batches of one subtype of HPMC in formulations that are
otherwise identical interact differently with water, resulting in the release
of omeprazole at different rates.
Sufficiency
[117] AstraZeneca
notes that an attack on the basis of insufficiency is a technical attack and
will only succeed where the PSA, equipped with common general knowledge, could
not put the invention into practice. Here, AstraZeneca submits that all the
allegedly missing information would be clearly known to a PSA on reading the
patent as a whole. Thus, the allegations of insufficiency are not justified.
[118] AstraZeneca
notes that Pharmascience’s evidence acknowledges that use of low viscosity HPMC
in a separating layer and as a binding agent was well known at the date of
publication. The ‘531 Patent
adds to this prior art by teaching that the CP of HPMC should be above a
certain limit (the claimed CP) to ensure desirable release characteristics. As
there is no question that CP as defined in the patent is understood and can be
determined, there is no insufficiency of disclosure.
[119] With regards to
the statement by Pharmascience’s experts that the ‘531
Patent does not indicate what type of HPMC a
formulator should choose or purchase, AstraZeneca notes that the patent, on its
face, could not be clearer. AstraZeneca submits that a PSA would understand
that any suitable grade of low viscosity HPMC can be used to prepare an enteric
omeprazole formulation, as long as it exceeds the claimed CP. The patent also
clearly explains how to determine the CP. Thus, a PSA could put the invention
into practice by testing that it exceeds the claimed CP.
[120] AstraZeneca
further submits that contrary to the evidence from Dr. Colombo, a dissolution
test need not be run in replicates of 12. Rather, in scientific literature,
three to six replicates is the standard. Thus, it is not credible for Dr.
Colombo to suggest a lack of understanding of the patent data based on the
number of replicates run.
[121] In response to
Dr. Colombo’s statement that the apparatus used for conducting dissolution
testing was not disclosed in the patent, AstraZeneca states that a PSA, upon
seeing the reference to the requirement of 75% release in 30 minutes (the
marketing standard) and the reference to the use of a paddle in the patent,
would clearly know that the inventors used the Dissolution Apparatus 2
(paddles). The patent also clearly states that enteric pellets were used in the
testing. AstraZeneca notes that Dr. Colombo resiled from this position on
cross-examination.
[122] With regards to
Dr. Miller’s statement that there is no information in the patent on the
coating amounts of HPMC on the spheres or the size of the spheres, AstraZeneca
submits that a PSA would understand that any suitable amount of coating of low
viscosity HPMC can be used to prepare an enteric omeprazole formulation as long
as it exceeds the claimed CP.
[123] AstraZeneca
further submits that the allegation by Pharmascience’s witnesses that a PSA
would not be able to choose the correct HPMC without knowing the percentage of
methoxyl groups highlights their misunderstanding or mischaracterization of the
‘531 Patent.
This patent improves on prior art omeprazole formulations by ensuring adequate
release without having to know or determine specific physical properties of a
given batch of low viscosity HPMC. Moreover, as admitted by Pharmascience’s
experts, certain characteristics cannot be readily determined. Thus, the patent
provides an elegant means for incorporating all the various physical properties
of low viscosity HPMC that affect release by reference to CP as a proxy.
[124] Finally,
AstraZeneca notes that Dr. Colombo alone took issue with the fact that the ‘531 Patent does
not specifically state which final dosage form and strength was tested in the
release studies. Dr. Colombo alleged that as a result, a PSA would not know to
which USP-stipulated standards to compare the release tests of the patent.
However, AstraZeneca submits that a PSA, having read the patent and seen the
numerous references to USP and Losec®, would have understood that the release
tests should be compared to 75% release in 30 minutes (the marketing standard).
AstraZeneca highlights that Dr. Colombo also resiled from this evidence on
cross-examination.
Obviousness
[125] AstraZeneca
notes Pharmascience’s reference to other patents as indicative of prior art.
However, AstraZeneca highlights that none of these patents discuss the concerns
with batch-to-batch variations in HPMC. In addition, the other patents do not
direct a PSA towards selecting and using HPMC above a particular CP to reduce
product discard during manufacturing.
[126] AstraZeneca
submits that the invention of the ‘531 Patent would not be obvious from all or any of the
prior art cited. In fact, prior to 1998, a PSA would not have considered the
low viscosity HPMC on seeing that omeprazole enteric formulations were being
released at different rates. Rather, a PSA might have considered other
formulation or process parameters to solve his or her problems.
[127] All experts also
agreed that CP was not a factor considered in selecting low viscosity HPMC for
use as a binder and/or separating layer. In fact, this information was not
included in low viscosity HPMC sold commercially in December 1998 nor was it
considered by PSAs in their selection or design of a formulation. The nexus
between the CP of low viscosity HPMC and release rate was an important and
counter-intuitive innovation born out of the differential release data in the ‘531 Patent.
[128] In conclusion,
AstraZeneca submits that Pharmascience’s invalidity allegations are not
justified. AstraZeneca therefore requests that this Court prohibit the Minister
from issuing a NOC for the Pharmascience capsules until the expiry of the ‘531 Patent.
Pharmascience’s Written Submissions
[129] Pharmascience
submits that the ‘531 Patent does not disclose
an invention or a useful contribution to the science of formulations. Rather, a
clear reading of the ‘531 Patent indicates that there is no invention at all.
Evidence
[130] Pharmascience
notes that it is settled law that the ultimate burden of proof rests on
AstraZeneca to disprove Pharmascience’s allegations of invalidity on a balance
of probabilities. Conversely, Pharmascience merely has an evidentiary burden to
present sufficient evidence to give its allegations of invalidity an air of
reality.
[131] Pharmascience
highlights that it provided evidence from four separate experts, all of whom
were straightforward in giving their evidence. Conversely, AstraZeneca only
filed evidence from one expert (Dr. Bodmeier) and none from the patent
inventors. In giving his evidence, Dr. Bodmeier acted as an advocate for
AstraZeneca. Pharmascience therefore submits that, to the extent that there is
any conflict between the evidence from the two parties, the evidence from their
witnesses must be preferred.
[132] Pharmascience
notes that the viscosity of HPMC is controlled through the manufacturing
process. Pharmascience submits that the article by Rowe shows that the
disintegration time of tablets coated with HPMC is directly related to the
molecular weight. The sole batch-to-batch variation that AstraZeneca’s expert
identified from this article was a 30 second variation for METHOCEL E5.
[133] Further, a paper
by Sangalli shows that a coating of METHOCEL E5 is not thick enough to induce
control over the rate of drug release. Notably, the coating of METHOCEL E5 in
that testing was 30 times greater than the thickness of the separating layer
used in the ‘531 Patent.
[134] Thus,
Pharmascience submits that the literature supports a finding that low viscosity
HPMC, when used as a binder or as a separating layer in a pharmaceutical
formulation, does not delay the release of the drug. Pharmascience notes that
AstraZeneca has not provided any scientific literature that indicates that low
viscosity HPMC will impact drug release. In addition, Dr. Bodmeier either did
not report any effect of HPMC on the release of the drug or in fact reported
that low viscosity HPMC increased the release rate of drugs in the papers he
authored.
Prior Art Patents
[135] Pharmascience
submits that prior art patents on formulations of omeprazole have consistently
disclosed the following three layer formulation:
1. Core with
omeprazole and an alkaline compound or an alkaline salt of omeprazole;
2. Coating layer
that is soluble in water or rapidly disintegrating in water and that consists
of non-acidic inert substances such as HPMC; and
3. Enteric coating.
[136] Pharmascience
submits that a PSA would understand that the HPMC used as a binder in the core
and in the coating layer would be a low viscosity HPMC. In addition, most prior
art patents disclose that rapid dissolution of the formulation in the intestine
is needed and the formulation that provides such dissolution is this three
layer formulation. This is the formulation described in the ‘531 Patent.
[137] Pharmascience
summarizes the basic teaching of prior art patents as follows:
- Omeprazole is susceptible
to degradation in acid reacting and neutral media;
- A fully bioavailable
dosage form of omeprazole must release the active drug rapidly in the proximal
part of the gastrointestinal canal;
- Omeprazole must be
protected from the acidic juice of the stomach by enteric coating;
- Enteric coatings are made
of acidic compounds and if applied directly to omeprazole, the omeprazole will
become badly discoloured; and
- The three layer
formulation is used to protect omeprazole with the separating layer protecting
omeprazole from the enteric coating.
[138] Pharmascience
submits that the teaching of prior art patents is to use the three layer
formulation when formulating benzimidazoles such as omeprazole and esomeprazole
and that HPMC is used in the separating layer as part of a rapidly dissolving
formulation. A skilled formulator would know that low viscosity HPMC used as a
separating layer or as a binder would not impact on the release rate of the
formulation. Further, no problems with the dissolution of HPMC were indicated
in the prior art patents and no problems with batch-to-batch variation were
reported by AstraZeneca to its supplier, Dow. Pharmascience submits that the CP
of HPMC would not be considered when designing a formulation either in 1997 or
today. Rather, the primary governing factors are molecular weight and
viscosity.
Cloud Point (CP)
[139] Pharmascience
submits that the two main manufacturers of HPMC (Dow and Shin-Etsu) manufacture
HPMC using the same technology and their products meet the same pharmacopeial
specifications. The HPMC polymers that were commercially available in 1997 are
the same HPMC polymers that are available today. These are: METHOCEL E3, E5 and
E15 and Pharmacoat 603, 606 and 615.
[140] Pharmascience
submits that the CP of a solution of HPMC is an inherent property of the
polymer that arises from its physical properties. In particular, the percentage
of methozyl groups present on the polymer chain. This percentage is determined
through the manufacturing process. As METHOCEL E5 and E6 have had the same
percentage of methozyl groups, they would have CPs within a narrow range.
Further, the specifications of METHOCEL E6 and Pharmacoat 606 are identical and
they can therefore be considered two batches of the same subtype. Pharmascience
notes that the CPs for Pharmacoat 606, METHOCEL E6 and METHOCEL E5 range from
45.8˚C to 47.7˚C, all of which exceed the claimed CP.
[141] In response to
AstraZeneca’s attack on the chain of title for the samples sent to Dr.
Desbrières, Pharmascience notes that the samples came either from counsel or
directly from the manufacturer, both of which are reliable sources.
[142] Further,
although AstraZeneca submits that the differences in the substitution of
methoxyl and hydroxypropyl groups along the backbone of HPMC has significant
effects on the CP, these submissions were unsupported by scientific evidence.
In addition, although AstraZeneca seeks to rely on the gelation properties of
HPMC and their correlation to the release of the drug, these were not covered
by the ‘531 Patent.
Patent Construction
[143] Pharmascience
highlights that the ‘531 Patent admits that extensive information about the
ingredients at issue therein was already known. The main qualification that
this patent adds pertains to the CP of HPMC.
[144] Contrary to
AstraZeneca’s assertion that the formulation is an immediate release
formulation, Pharmascience submits that it is a delayed release formulation
since the drug is not released until the formulation travels through the
stomach and into the intestine.
[145] Pharmascience
submits that the patent does not present any tests or supporting evidence as to
why the claimed CPs were selected. As such, they are arbitrary choices. Further,
Pharmascience notes that the ‘531 Patent does not disclose that the CP of HPMC
has any effect on drug release. Rather, it discloses the opposite as the tests
included therein pertained to only one batch of low viscosity HPMC at the
claimed CP. These tests can therefore not show batch-to-batch variation. In
addition, Pharmascience notes that the three tests in the ‘531 Patent purport
to compare two unidentified types of HPMC, one above and one below the claimed
CP. As AstraZeneca admits that these two types are equivalent, Pharmascience
notes that they could be one batch of METHOCEL E6 and one batch of Pharmacoat
606.
[146] Pharmascience
further notes that Figures 1 and 2 in the ‘531 Patent indicate full dissolution
of both types of HPMC at body temperature. Thus, the patent does not teach
anything on a cause and effect relationship between the CP of the HPMC and the
release of the drug at body temperatures. In addition, contrary to
AstraZeneca’s submissions, Dr. Miller did not agree that different batches of HPMC
dissolve at different rates. Rather, Dr. Miller stated that low viscosity HPMC
would provide an immediate release while high viscosity HPMC would not dissolve
as fast.
[147] With regards to
the test results depicted in Figure 3 of the ‘531 Patent, Pharmascience notes
that HPMC was used as a binder in that experiment and there was no confounding
factor such as an enteric coating. The results of this testing indicated that
both types of HPMC meet the dissolution specification for omeprazole and that,
when used as a binder, HPMC cannot exert control over the rate of drug release.
[148] Pharmascience
further notes that AstraZeneca attempts to dismiss its own patent tests on the
basis that the HPMC is not exposed to gastric acid in the experiment, as would
be the case for enteric formulation. However, Pharmascience submits that this
argument overlooks the fact that the enteric coating is expected to withstand
the gastric juices and dissolve at the higher pH of the intestine. Only then
will the HPMC layer dissolve. This is the clear teaching provided by
AstraZeneca’s patents on the three layer formulation.
[149] Pharmascience
also notes that significant data is missing from the enteric coated pellet test
reported in the ‘531 Patent; including: number of pellets made and tested;
whether the pellets were tested separately or as part of a capsule or tablet
formulation; dosage form tested (pellets, capsules or tablets); strength of the
final dosage form; thickness of the enteric coating; quantity of omeprazole in
the pellets when they were placed in the buffer solution; whether the same
conditions were employed for the pellets containing Type A and Type B HPMC; number
of dissolution studies performed for the pellets containing the different types
of HPMC; and information on any statistical analysis conducted.
[150] Pharmascience
notes that, contrary to AstraZeneca’s allegation, some of the Type A batch did
release within the 30 minute time frame. Further, as there was only one batch
of HPMC Type A, the differences in the dissolution were not due to the nature
and properties of the HPMC. In addition, given that the pellets made with Type
A HPMC worked, there was nothing to indicate that the HPMC affected the
dissolution. Finally, Pharmascience notes that the pharmacopeial specifications
for omeprazole allow for the dissolution of 70% in 30 minutes for 40 mg
capsules. At that dose, all the Type A and Type B pellets met the
specifications.
[151] Pharmascience
highlights that the ‘531 Patent does not show that the HPMC is the rate
controlling step in the dissolution of the drug. Rather, the difference
reported in the ‘531 Patent is more likely attributed to something in the
enteric coating than in the sub-coat. Further, if one wants to determine if
HPMC is affecting the release of a coated pellet, the pellet should be tested
both with and without HPMC. This test was not conducted in the ‘531 Patent.
With no direct cause and effect between the HPMC and the dissolution of the
drug shown in the ‘531 Patent, Pharmascience submits that it is clear that another
explanation accounts for the dissolution. Possible alternate explanations
include:
1. Release may be
affected by the thickness of the polymer and by the types and amounts of
plasticizers in the polymer enteric coating;
2. Aggregates can
form during the coating process that might create a thicker layer on some
spheres rather than others;
3. Excipients in the
core can have an effect on the release of omeprazole;
4. Thickness or
uniformity of the separating layer produced with the two types of HPMC may be
different and a very thin separating layer would reduce the integrity of the
layer making it susceptive to cracks, holes and deformation;
5. Spraying the HPMC
too quickly could cause the pellets to stick together, thereby impacting the
integrity of the film; and
6. There could have
been a loss of omeprazole (which was not measured) at the first stage of the
test in the acidic conditions.
[152] Pharmascience
notes that before December 1988, a PSA would have investigated the other
parameters that can cause delay in release, such as spray rate, product
temperature and air flow. Pharmascience also notes that there is not a single
specification for HPMC after the ‘531 Patent publishing date that contains a CP
measurement. Meanwhile, pharmaceutical formulators before and after that date
continue to consider factors such as viscosity and molecular weight.
Invention under Section 2 of the Patent
Act
[153] Pharmascience
submits that in May 1998, it was already well known that low viscosity HPMC
dissolved in aqueous solutions under both basic (intestinal) and acidic
(stomach) conditions. This renders it suitable for preparing films that
dissolve rapidly at the target site. In addition, when used as a thin coating
on the outside of tablets or as a separating layer, it provides immediate
release and does not exert any control over the rate of dissolution or drug
release.
[154] Pharmascience
thus submits that no invention was provided in the ‘531 Patent. Prior art
patents disclosed the three layer formulation made with low viscosity HPMC both
as a binder and as a separating layer. HPMC becomes cloudy and viscosity
increases at 41˚C. However, this is not relevant to the formulation
because it must dissolve at 37˚C (body temperature).
[155] Even if this
Court finds that CP is relevant, Pharmascience notes that it is a factor
determined primarily by the percentage of methoxyl groups in the HPMC.
Pharmascience highlights that the uncontradicted testing evidence shows that
low viscosity HPMC with the methoxyl content used for over thirty years will
have CPs within the claimed CP.
Utility
[156] Pharmascience
submits that the ‘531 Patent does not meet the requirement of utility. It is
insufficient to state that the tests were run. Once challenged, the patentee
must file evidence of those tests. Here, AstraZeneca has not filed evidence of
utility and Pharmascience submits that utility is not demonstrated in the ‘531
Patent. Pharmascience also submits that where a patent had made a promise of
commercial utility, the patentee must be held to that standard. Here,
AstraZeneca has failed to meet that standard. Thus, the patent offers nothing
beyond the prior art three layer formulation.
[157] Pharmascience
notes that a sole data point cannot demonstrate consistency throughout a range.
Thus, a single batch cannot evidence batch-to-batch variation. Where the
claimed invention does not have the promised utility, such as better
dissolution and elimination of batch-to-batch variation, then an attack of
invalidity is justified.
[158] Where a PSA can
come to no meaningful conclusion based on the information in the patent, the Court
will find inutility. Here, two of the three tests clearly show that there is no
difference in the dissolution of the two types of HPMC. In the third test, some
of the units tested worked fine so there is no demonstration that the CP of the
HPMC was the cause of any dissolution problems. Thus, the patent does not show
the utility of HPMC of a certain CP. In addition, Pharmascience submits that
the basis of the patent is not shown in the patent or in the evidence. Thus,
the ‘531 Patent is invalid for lack of utility.
Sufficiency
[159] Pharmascience
submits that the ‘531 Patent fails to provide the public with any meaningful
new information on the making of a three layer tablet that they did not already
know. The patent also lacks sufficiency because the underlying data demonstrates
that the result is much less than promised.
Obviousness
[160] Finally,
Pharmascience submits that there is nothing inventive in finding a solution to
a problem that never existed. Here, AstraZeneca never complained to its HPMC
supplier about batch-to-batch variation. As CP is an irrelevant parameter,
Pharmascience submits that there are no differences between the three layer
formulation in the prior art and that claimed in the ‘531 Patent.
[161] Even if this
Court were to accept that the claimed CP has some meaning, it is an inherent
property of low viscosity HPMC that was used in the prior art patents. It was
thus a known and measurable parameter. There is also no suggestion that
measuring CP is inventive. Finally, Pharmascience notes that a claim based on HPMC
with a certain CP is indirectly a claim based on the percentage of methozyl
groups in the HPMC, something that was already well known.
[162] For these
collective reasons, Pharmascience requests that this application be dismissed.
Analysis and Decision
Preliminary Determinations
[163] The respondents
submitted that Dr. Bodmeier acted as an advocate and accordingly, if there was
a conflict between the evidence of the respondents’ experts and that of Dr.
Bodmeier, the evidence of the respondents’ experts should be preferred. I have
reviewed the evidence of Dr. Bodmeier and I do not agree that he was acting as
an advocate. He was elaborating on his answers.
[164] I would also
note that I accept Dr. Bodmeier’s evidence that the ‘531 Patent refers to
different batches of the same HPMC product. He stated at paragraph 19 of his
affidavit (hearing compendium of AstraZeneca Canada Inc., part 1, tab 5, volume
6, page 2224 of the application record):
It
should be noted that when the 531 patent makes reference to “different batches”
it would be understood as a reference to different batches of the same HPMC
product, for example, a specific subtype of HPMC. It was known that the
quality of excipients, including HPMC, may differ depending on the subtype and
it would be contrary to accepted practice to use different HPMC subtypes in
commercial manufacture of pharmaceutical formulations since consistency is
critical. A skilled person would understand that a specific HPMC subtype will
have been selected for use in the final manufacturing formulation and that
batch to batch variations therefore refer to different batches of that subtype.
For example, Dow Chemical makes several product families of HPMC, including
METHOCEL A, E, F, J and K. Within METHOCEL E, there are several subtypes such
as E5, E6, and E15. Therefore when the patent refers to different batches, it
is a reference to different batches of one subtype of HPMC listed above, for
example, different batches of METHOCEL E5. Commercial vendors will identify
different batches of an HPMC subtype by batch number.
[165] The evidence
shows that Dr. Desbrières’ tests deal with five different subtypes of
low-viscosity HPMC rather than tests of different batches of the same subtype.
[166] At the outset,
the regulatory process at issue here is worth noting. The Federal Court of
Appeal described this process succinctly in Pfizer Canada Inc v Mylan
Pharmaceuticals ULC, 2012 FCA 103, [2012] FCJ No 386 as follows:
4
In order to sell a new drug in Canada, an innovator must obtain regulatory
approval from the Minister of Health under Division 8 of Part C of the Food
and Drug Regulations, C.R.C. c. 870. This approval is by way of a notice
of compliance, which may be issued only following a submission containing sufficient
information and material enabling the Minister to assess the safety and
effectiveness of the drug, including detailed reports of the tests made to
establish its safety for the purpose and under the conditions of use
recommended, and substantial evidence of its clinical effectiveness.
5
If a generic manufacturer then wishes to market a generic version of
that drug, it must file a submission (designated as an abbreviated
new drug submission) with the Minister of Health in which it makes
specified comparisons between its generic drug and the innovator drug for
the purpose of satisfactorily meeting the conditions set out in Division 8 of
Part C of the Food and Drug Regulations in order to obtain a notice of
compliance for the generic drug.
6
The NOC Regulations, adopted pursuant to section 55.2 of the Patent
Act, R.S.C. 1985, c. P-4, allow an innovator who files a new drug
submission to also submit to the Minister of Health a patent list
relating to the submission. A patent on this list may then be added to a
register of patents maintained by that Minister.
7
A generic drug manufacturer who seeks a notice of compliance in respect of a
drug and which compares that drug with another drug marketed in Canada under a
notice of compliance must, with respect to each patent listed on the register
for that other drug, either accept that it will not obtain the Minister's
approval until the patent expires, or allege (through what is known as a
"Notice of Allegation") that the patent is not valid or would not be
infringed, and include a detailed statement of the legal and factual
basis for the allegation: section 5 of the NOC Regulations.
8
An innovator that is served with such a Notice of Allegation may apply to
the Federal Court for an order prohibiting the Minister of Health from issuing
a notice of compliance to the generic manufacturer until after the
expiration of its patent. The court must make such an order if it finds that
the allegations relating to that patent and contained in the Notice of
Allegation are not justified: section 6 of the NOC Regulations.
9
The Supreme Court of Canada and our Court have determined that such an
application is a highly fact specific summary proceeding, the sole object
of which is to prohibit the issuance of a notice of compliance under the Food
and Drug Regulations. Consequently, issues of patent infringement or
validity cannot be finally determined in such a proceeding: Eli Lilly
& Co. v. Novopharm Ltd., [1998] 2 S.C.R. 129 at paras. 95-96; Merck
Frost Canada Inc. v. Canada (Minister of Health and Welfare) (1994), 55
C.P.R. (3d) 302 (F.C.A.) at pp. 319-20; David Bull Laboratories (Canada) Inc. v. Pharmacia Inc., [1995] 1 F.C. 588 (C.A.) at p. 600.
10
If the innovator is successful in the proceeding, the Minister of Health is
prohibited from issuing to the generic a notice of compliance for its generic
drug until the relevant patent has expired. If the generic is
successful, the Minister may issue a notice of compliance for its generic
version of the drug. Whatever the outcome of the proceeding under the NOC
Regulations, patent validity and patent infringement proceedings under the
Patent Act may be initiated or continued by the parties before any competent
court. [emphasis added]
[167] The notice of allegation
frames the proceeding under the NOC Regulations. Thus, any allegation not
included therein cannot be addressed in the proceeding (see Pfizer Canada (2012) above, at paragraph 29).
[168] Guiding
principles on notice of allegations were summarized by Mr. Justice Roger Hughes
in GlaxoSmithKline Inc v Pharmascience Inc, 2011 FC 239, [2011] FCJ No
287, as follows:
40
Without comment as to whether they are right or wrong as a matter of “fairness”,
certain principles have emerged as a result of judicial interpretation as to an
NOA, including:
i. The
NOA cannot be amended once legal proceedings have commenced except that certain
allegations made can be omitted or no longer relied upon (e.g. Hoffmann-La
Roche Ltd v. Canada (Minister of National Health and Welfare) (1996), 70
C.P.R. (3d) 1, (FCA); Bayer A/G v. Novopharm Ltd. (2006), 48 C.P.R.
(4th) 46 (FC) at paras 72 to 84).
ii. The
Notice of Allegation must be sufficient so as to make the "first
person" fully aware of the grounds raised as to invalidity or
non-infringement (Mayne Pharma (Canada) Inc. v. Aventis Pharma Inc. (2005),
38 C.P.R. (4th) 1 (FCA) at paras. 19-21).
iii. A
second person cannot, in proceedings taken in Court, present argument
and evidence relating to an issue that is outside the scope of its NOA
(e.g. Ratiopharm Inc. v. Canada (Minister of Health) (2007), 58 C.P.R.
(4th) 97 (FCA) at para. 25.
iv. The
second party may not shift ground or raise a new ground during the legal
proceedings that
has not been raised in its NOA (Pfizer Canada Inc. v. Canada (Minister of Health) (2006), 54 C.P.R. (4th) 279 (FC) at paras 70 - 71).
41 In
the Court proceedings, a first person is required to demonstrate, in
accordance with subsection 6(2) of the NOC Regulations, that "none of
those allegations is justified". Thus, the object of the proceedings
is to look at the allegations, consider the evidence, apply the law, and
determine whether an allegation made in the NOA is justified. Such a
determination, for instance, whether an allegation as to invalidity is
justified or not, does not preclude that issue from being litigated in an
ordinary action respecting the patent, in other words, there is no res
judicata (Aventis Pharma Inc. v. Apotex Inc. (2006), 46 C.P.R. (4th)
401 (FCA) at para. 7). [emphasis added]
[169] In this case,
AstraZeneca requests a declaration that the NOA is
neither a valid notice of allegation nor a detailed statement as contemplated
by the NOC Regulations. The sufficiency
of a notice of allegation is a question of mixed fact and law (see Pfizer Canada (2012) above, at paragraph 30).
[170] In Pfizer
Canada Inc v Apotex Inc, 2007 FC 26, 59 CPR (4th) 183 (aff'd 2007 FCA 195,
leave to appeal refused [2007] SCCA No 371), Mr. Justice James O’Reilly described
the burden of proof in an NOC proceeding (at paragraph 12):
To
summarize, Pfizer bears the legal burden of proving on a balance of
probabilities that Apotex's allegations of invalidity are unjustified. Apotex
merely has an evidentiary burden to put its case "into play" by
presenting sufficient evidence to give its allegations of invalidity an air of
reality. If it meets that burden, then it has rebutted the presumption of
validity. I must then determine whether Pfizer has established that Apotex's
allegations of invalidity are unjustified. If Apotex does not meet its
evidential burden, then Pfizer can simply rely on the presumption of validity
to obtain its prohibition order.
[171] On
review of the NOA at issue here, I find that Pharmascience has provided a
sufficiently detailed statement of the legal and factual basis for its
allegations, as required under subparagraph 5(3)(b)(ii) of the NOC Regulations.
As mentioned above, Pharmascience provided extensive submissions on the
following grounds of invalidity in its NOA:
1. Insufficient
disclosure/lack of support;
2. Claims broader
than invention made or disclosed;
3. Lack of novelty
and anticipation by prior use;
4. Double-patenting;
5. Lack of inventive
step/obviousness; not an invention (under section 2 of the Patent Act);
6. Lack of sound
prediction and lack of utility;
7. Not a valid
selection patent; and
8. Fraud on the patent
officer (under subsection 34(1) and section 53 of the Patent Act).
[172] In this
proceeding, Pharmascience limited its submissions to the grounds of: not an
invention (#6), lack of utility (#7), insufficient disclosure (#1) and lack of
inventive step/obviousness (#5). As all these grounds were adequately raised by
Pharmascience in the NOA, I find that Pharmascience has met its evidentiary
burden of putting its case into play. Thus, pursuant to subsection 6(2) of the NOC
Regulations, the burden of proof now rests on AstraZeneca to establish that
Pharmascience’s allegations on these issues are not justified. In rendering its
decision, this Court must “look at the allegations, consider the evidence,
apply the law, and determine whether an allegation made in the NOA is
justified” (see GlaxoSmithKline above, at paragraph 41).
[173] Issue 1
Is the ‘531 Patent not an
invention as defined in section 2 of the Patent Act because it merely
ascertains the properties of a known substance?
Pharmascience submits that
no invention was provided in the ‘531 Patent because it only pertains to the CP
of low viscosity HPMC, which is an inherent physiochemical property that is
primarily determined by the percentage of methoxyl groups in the HPMC. In support,
Pharmascience submitted test results of experiments conducted by Dr.
Desbrières. The low viscosity HPMC products that Dr. Desbrières tested each had
different contents of methoxyl and hydroxypropyl. Dr. Desbrières’ test results
for CP, determined in accordance with the methodology presented in the ‘531
Patent, exceeded the claimed CP for each type of low viscosity (less than 7.2
cps) HPMC tested, thereby suggesting that the low viscosity HPMC products
commonly sold on the market are already manufactured to the claimed CP.
[174] Pharmascience
also notes that prior art patents have disclosed the three layer formulation
made with low viscosity HPMC both as a binder and as a separating layer. In
addition, Pharmascience states that the claimed CP is irrelevant to the
formulation because, in application, it must dissolve at the lower temperature
of 37˚C (i.e., body temperature). Pharmascience also submits that when
used as a thin coating on the outside of tablets or as a separating layer, low
viscosity HPMC provides immediate release and does not exert any control over
the rate of dissolution or release of the active ingredient.
[175] Conversely,
AstraZeneca submits that Pharmascience’s allegation is fundamentally flawed as
it is premised on an incorrect construction of the ‘531 Patent. A correct
construction provides the surprising teaching that the amount of product
discard can be reduced by only selecting those batches of a low viscosity HPMC
product that exceed the claimed CP. AstraZeneca claims that this advantage stems
from the patent’s finding that the rate of release of omeprazole from an
enteric coated formulation is affected by a variation in CP between different
batches of the same low viscosity HPMC product. AstraZeneca submits that this
teaching was clearly provided in the page 11 table of the patent, which showed
one batch exceeding the marketing standard while another batch of the same low
viscosity HPMC did not. As a result of a number of experiments, the patent
inventors identified the claimed CP that would ensure consistent release of 75%
of omeprazole within 30 minutes (i.e., at the marketing standard). Thus,
AstraZeneca submits that the patent teaches that the selection of a batch of
low viscosity HPMC in accordance with the claimed CP ensures the marketing
standard is consistently met, which reduces the product discard associated with
a failure to meet prescribed drug release requirements.
[176] On review of the
evidence and the ‘531 Patent, I agree with AstraZeneca that the patent provides
more information than merely identifying inherent physiochemical properties of
a known substance. Rather, as submitted by AstraZeneca, the patent delves into
batch-to-batch variations of a single low viscosity HPMC product and a property
that can be tested to ensure consistent release of omeprazole in accordance
with the marketing standard.
[177] The first two
experiments described in the patent show that the use of different batches of
one type of low viscosity HPMC product can result in different release rates of
omeprazole from enteric coated pellets. Notably, the third experiment does show
the release of omeprazole meeting the marketing standard for both batches.
However, that experiment was not conducted on enteric coated pellets and the
pertinent finding from that test is instead that the different batches exhibit
different release rates of omeprazole.
[178] Finally,
although Dr. Desbrières’ test results suggest that low viscosity HPMC products
already exceed the claimed CP, I note that he did not provide any results on
tests conducted on different batches of the same type of low viscosity HPMC. I
therefore do not find that his results are sufficient to render the findings
presented in the ‘531 Patent merely inherent physiochemical properties of a
known substance.
[179] Issue 2
Does the ‘531 Patent meet
the validity requirements for utility?
The requirement that an
invention have “utility” has statutory grounding in section 2 of the Patent
Act, which defines an invention as something that is “new and useful”. At
the outset, it is notable that utility does not depend on marketability. As
stated by Madam Justice Judith Snider in Sanofi-Aventis Canada Inc v Apotex
Inc, 2009 FC 676, [2009] FCJ No 986 at paragraph 145:
…
assessing whether an invention has utility, the issue is not whether the
invention is sufficiently useful as to be able to support commercialization,
unless commercial utility is specifically promised; …
[180] Utility must be
demonstrated or soundly predicted based on the information and science
available at the time of the prediction, as of the relevant date (see Sanofi-Aventis
above, at paragraph 143). The relevant date is the date of filing of the
Canadian patent application (see Sanofi-Aventis above, at paragraph 145).
[181] Demonstrating or
soundly predicting that an invention will produce at least one useful result,
or “a "mere scintilla" of utility” is sufficient where no particular
result has been promised (see Sanofi-Aventis above, at paragraph 145).
However, where a particular result has been promised in the patent specification,
the claims must demonstrate or soundly predict that result or promise (see Sanofi-Aventis
above, at paragraph 145).
[182] In construing
the specification of a patent, “the promise should be properly defined, within
the context of the patent as a whole, through the eyes of the [PSA], in
relation to the science and information available at the time of filing” (see Eli
Lilly Canada Inc v Novopharm Limited, 2010 FCA 197, [2010] FCJ No 951,
leave to appeal refused in [2010] SCCA No 377 at paragraph 80). Thus, while
determining the promise (or lack thereof) of a patent is a question of law, the
assistance of experts is useful in this assessment.
[183] In GlaxoSmithKline
above, Mr. Justice Roger Hughes explained the general manner in which a
patent specification should be read:
84
The Supreme Court of Canada has set out the approach to construction of the
specification of a patent in Consolboard Inc. v. MacMillan Bloedel
(Saskatchewan) Limited, [1981] 1 S.C.R. 504 at pages 520 - 521:
We
must look to the whole of the disclosure and the claims to ascertain the nature
of the invention and methods of its performance, (Noranda Mines Limited v.
Minerals Separation North American Corporation [1950] S.C.R. 36]), being
neither benevolent nor harsh, but rather seeking a construction which is
reasonable and fair to both patentee and public. There is no occasion for
being too astute or technical in the matter of objections to either title or
specification for, as Duff C.J.C. said, giving the judgment of the Court in Western
Electric Company, Incorporated, and Northern Electric Company v. Baldwin
International Radio of Canada [1934] S.C.R. 570], at p. 574, "where
the language of the specification, upon a reasonable view of it, can be so read
as to afford the inventor protection for that which he has actually in good
faith invented, the court, as a rule, will endeavour to give effect to that
construction". Sir George Jessel spoke to like effect at a much earlier
date in Hinks & Son v. Safety Lighting Company [(1876), 4 Ch. D. 607].
He said the patent should be approached "with a judicial anxiety to support
a really useful invention".
[…]
89
The late Dr. Harold Fox in his book "The Canadian Law and Practice
Relating to Letters Patent for Invention", 4th ed., 1969, Carswell, Toronto
(Fox on Patents) provided a useful insight into this issue at pages 208 - 209
(omitting footnotes):
IMPARTIAL
CONSTRUCTION
Originally
patents were regarded with disfavour as being in the nature of monopolies and
there existed a great tendency to be unnecessarily strict in construing patents
against the patentee. The tendency then swung to the other extreme and courts
were often found construing a patent most benevolently in favour of the
patentee who had introduced a new manufacture. It should not be necessary to
observe that a construction that is, even in the slightest degree, either too
strict or too benevolent, ceases to be an impartial construction and is,
therefore, improper. A patent specification is subject to the same impartial
canons of construction as ordinarily apply to written documents generally. As
Chitty J. observed in Lister v. Norton. "It certainly ought not to be
construed malevolently; I will not say it ought to be construed benevolently; I
do say it ought to be construed fairly. It must be read by a mind willing to
understand, not by a mind desirous of misunderstanding."
...
The
court should, therefore, in construing a specification, be the fair and
impartial arbitrator between the patentee and the public. The construction must
be reasonable, fair and logical, in accordance with the manner of construction
of all written documents according to the true intent. Nothing should be
presumed in favour of the patentee or an alleged infringer, although it is
proper for the court to endeavour to support a patent if it can be done
honestly and fairly and without improper construction, for it is a reasonable
presumption that a patentee would not claim anything that would render his
patent void. [emphasis added]
[184] As noted above,
if the utility of an invention has not been demonstrated as of the relevant
date, an inventor can still rely on the doctrine of sound prediction to justify
his or her patent claims. The purpose of this doctrine was explained by Mr. Justice
Ian Binnie in Apotex Inc v Wellcome Foundation Ltd, 2002 SCC 77, [2002] 4
SCR 153 (at paragraph 66):
The
doctrine of "sound prediction" balances the public interest in early
disclosure of new and useful inventions, even before their utility has been
verified by tests (which in the case of pharmaceutical products may take years)
and the public interest in avoiding cluttering the public domain with useless
patents, and granting monopoly rights in exchange for misinformation.
[185] The test for
determining whether a utility has been soundly predicted was also set out in Apotex
above:
70 The
doctrine of sound prediction has three components. Firstly, as here, there must
be a factual basis for the prediction. In Monsanto and Burton Parsons,
the factual basis was supplied by the tested compounds, but other factual
underpinnings, depending on the nature of the invention, may suffice. Secondly,
the inventor must have at the date of the patent application an articulable and
"sound" line of reasoning from which the desired result can be
inferred from the factual basis. In Monsanto and Burton Parsons,
the line of reasoning was grounded in the known "architecture of chemical
compounds" (Monsanto, at p. 1119), but other lines of reasoning,
again depending on the subject matter, may be legitimate. Thirdly, there must
be proper disclosure. Normally, it is sufficient if the specification provides
a full, clear and exact description of the nature of the invention and the
manner in which it can be practised: H. G. Fox, The Canadian Law and Practice
Relating to Letters Patent for Inventions (4th ed. 1969), at p. 167. It is
generally not necessary for an inventor to provide a theory of why the
invention works. Practical readers merely want to know that it does work and
how to work it. In this sort of case, however, the sound prediction is to some
extent the quid pro quo the applicant offers in exchange for the patent
monopoly. Precise disclosure requirements in this regard do not arise for
decision in this case because both the underlying facts (the test data) and the
line of reasoning (the chain terminator effect) were in fact disclosed, and
disclosure in this respect did not become an issue between the parties. I
therefore say no more about it.
71 It
bears repetition that the soundness (or otherwise) of the prediction is a
question of fact. Evidence must be led about what was known or not known at the
priority date, as was done here. Each case will turn on the particularities of
the discipline to which it relates. In this case, the findings of fact
necessary for the application of "sound prediction" were made and the
appellants have not, in my view, demonstrated any overriding or palpable error.
[186] More recently, Madam
Justice Snider succinctly set out this three-step test as follows (see Sanofi-Aventis
above, at paragraph 146):
1. There
must be a factual basis for the prediction;
2. The
inventor must have an articulable and "sound" line of reasoning from
which the desired result can be inferred from the factual basis; and
3. There
must be proper disclosure.
[187] Madam Justice
Snider added that to be sound, a prediction does not need to amount to a
certainty, as it does not exclude the risk that some compounds within the area
claimed may, at some later time, prove to be devoid of utility (see Sanofi-Aventis
above, at paragraph 147).
[188] In determining
the type of evidence that would satisfy the three-step test for a sound
prediction, the Federal Court of Appeal noted in Eli Lilly above:
84
AZT does not define the threshold required for sound prediction. However,
Binnie J. states that more than mere speculation is required (para. 69). He
also provides the following indicia:
*
the requirement is that the claims be fairly based on the patent disclosure
(para. 59);
*
it must be prima facie reasonable that the patentee should have a claim
(para. 60);
*
it cannot mean a certainty (para. 62);
*
the desired result must be able to be inferred from the factual basis (para.
70).
85
In my view, these indicia signify that a sound prediction requires a prima
facie reasonable inference of utility. Notably, in AZT, the factual
basis for the sound prediction of a new use compound rested upon the results of
an in vitro test of AZT against the HIV in a human cell line along with
Glaxo's data on AZT, including animal tests (para. 72). The line of reasoning
was found to be Glaxo's knowledge of the mechanism for reproduction of a
retrovirus.
[189] In this case,
Pharmascience submits that the ‘531 Patent did not indicate that any tests were
performed to demonstrate that the low viscosity HPMC actually possessed the
claimed utility and no substantive data was provided to demonstrate the
promised utility. Once utility is challenged, Pharmascience submits that it is
insufficient to state that tests were run; evidence must be filed of those
tests. In addition, as AstraZeneca promised commercial utility, the patent must
be held to that standard, a burden that Pharmascience submits AstraZeneca has
failed to meet. Thus, Pharmascience submits that the ‘531 Patent offers nothing
over the prior art three layer formulation.
[190] AstraZeneca
submits that the Federal Court of Appeal has explicitly rejected the notion
that utility must be demonstrated in the patent disclosure. It relies in
support on Pfizer Canada Inc v Novopharm Ltd, 2010 FCA 242, [2010] FCJ
No 1200 (leave to appeal granted in [2010] SCCA No 443, currently on reserve),
which states:
87
Although there is no jurisprudence dictating whether or not utility need
be demonstrated in the patent disclosure, I am of the view that the answer is
that it need not be demonstrated in the patent disclosure. First, there
is nothing in the Act which leads one to conclude that such a demonstration is
necessary. Second, there is no a priori reason to think that the patent
disclosure should contain proof of all the elements required to obtain the
patent. Hughes &Woodley, supra, describe the goal of the disclosure
as follows at
s.
25:
The
description of the invention ... is to give the public adequate details as will
enable a workman skilled in the art to which the invention relates to construct
or use that invention when the period of the monopoly has expired. In essence
what is called for in the specification (including both disclosure and claims)
is a description of the invention and the method of producing and constructing
it, coupled with a claim or claims which state those novel features in which
the applicant wants the exclusive right; the specification must define the
precise and exact extent of the exclusive property and privilege claimed.
88
In other words, the disclosure provides direction, not proof: it tells
practitioners how to practice the invention. It does not prove to them its
utility, though they can require proof through invalidity proceedings.
89
Indeed, the Supreme Court's most recent decision on utility, Wellcome
(SCC), supra, makes no mention of any requirement to prove utility in
the disclosure. At paragraph 56 of his Reasons, Binnie J. wrote as follows:
[56]
Where the new use is the gravamen of the invention, the utility required
for patentability (s. 2) must, as of the priority date, either be demonstrated
or be a sound prediction based on the information and expertise available. If a
patent sought to be supported on the basis of sound prediction is subsequently challenged,
the challenge will succeed if, per Pigeon J. in Monsanto Co. v.
Commissioner of Patents, [1979] 2 S.C.R. 1108, at p. 1117, the prediction
at the date of the application was not sound, or, irrespective of the soundness
of the prediction, "[t]here is evidence of lack of utility in respect of
some of the area covered."
90
The appellant's argument that Pfizer was required to include evidence of
demonstrated utility in the patent disclosure is without merit. The
requirements for demonstrated utility can be provided in evidence during
invalidity proceedings as opposed to in the patent itself. So long as the
disclosure makes reference to a study demonstrating utility, there do not
appear to be any other requirements to fulfil section 2. [emphasis
added]
[191] AstraZeneca
submits that it demonstrated utility in the statement at page 12 of the ‘531
Patent that: “[r]esults from a number of experiments with different batches of
HPMC indicate that HPMC with a cloud point of at least 45.6˚C is desirable
in fulfilling the regulatory requirements on rate of release of omeprazole”.
AstraZeneca submits that this is sufficient to meet its burden for proving
utility. Although this evidence is relatively non-descriptive, I do not find
that the law requires that AstraZeneca meet a higher burden.
[192] AstraZeneca also
submits that Pharmascience’s expert’s disbelief that the CP of low viscosity
varies such that it falls below the claimed CP is directly contradicted by data
included in the NOA. Specifically, AstraZeneca highlights the table at the
bottom of page 60 of the NOA. This table shows different CPs for different
batches of the same subtype of HPMC. Three of these samples have CPs below the
claimed CP. AstraZeneca questioned Dr. Desbrières about these results on
cross-examination. However, Dr. Desbrières highlighted that those samples that
had CPs below the claimed CP were described in a column on the table as
“non-approved”. Although Dr. Desbrières was unable to provide greater detail on
the meaning of such non-approval, I find that the classification of those batch
samples as “non-approved” undermines AstraZeneca’s reliance on them as evidence
of batches of low viscosity HPMC having CPs below the claimed CP.
[193] Nevertheless, I
do not find that Dr. Desbrières’ own test results lend support to
Pharmascience’s position. All Dr. Desbrières’ tests were conducted on different
subtypes of low viscosity HPMC. Although these all had CPs above the claimed
CP, Dr. Desbrières did not test different batches of the same low viscosity
HPMC product. I therefore do not find that his test results sufficiently
undermine the results from the “number of experiments” relied on in the ‘531
Patent. The risk of variability between different batches of the same subtype
is accentuated by the number of factors that can affect the CP that were
highlighted by Dr. Bodmeier in his affidavit.
[194] Finally, I note
Pharmascience’s submission that AstraZeneca was required to establish
commercial utility. On review of the ‘531 Patent, I find that the relevant
“promise” of such utility is as follows (at page 4):
From
an economic aspect it is advantageous to specify and check the HPMC quality and
keep the discard of produced pharmaceutical product low.
[195] As mentioned
above, there is no requirement to show marketability to establish utility.
However, where a promise is made, it must be upheld. I do not find that this
statement clearly promises commercial utility. Rather, it promises that by
following the patent, the discard of produced pharmaceutical product will be
kept low. The patent does teach that predetermining the CP of a particular
batch of low viscosity HPMC and limiting selection for use in enteric coated
oral pharmaceutical formulations to those batches with CPs that exceed the
claimed CP, will ensure that the release rate of omeprazole will meet the
marketing standard. Without this teaching, some batches of low viscosity HPMC
may be used in the manufacture of enteric coated oral pharmaceutical
formulations; formulations that must later be discarded for failure to adequately
release omeprazole. Thus, I find that the patent adequately upholds this
promise.
[196] In summary, I
find that Pharmascience has failed to demonstrate “that the invention will not
work, either in the sense that it will not operate at all or, more broadly,
that it will not do what the specification promises that it will do” (see Consolboard
Inc v MacMillan Bloedel (Saskatchewan) Ltd, [1981] 1 S.C.R. 504; and Eli
Lilly above, at paragraph 75).
[197] Issue 3
Does the ‘531 Patent meet
the validity requirements of sufficient disclosure?
The specification in a
patent must disclose sufficient information to enable a PSA to make and use the
claimed invention. Sufficiency is a question of fact, determined as of the date
of publication. The sufficiency requirement is mandated under subsection 27(3)
of the Patent Act.
[198] The test for
sufficient disclosure was set out in Pioneer Hi-Bred Ltd v Canada (Commissioner of Patents), [1989] 1 S.C.R. 1623 at paragraph 27:
[…]
The applicant must disclose everything that is essential for the invention
to function properly. To be complete, it must meet two conditions: it
must describe the invention and define the way it is produced or built (Thorson
P. in Minerals Separation North American Corp. v. Noranda Mines Ltd.,
[1947] Ex. C.R. 306, at p. 316). The applicant must define the nature of the
invention and describe how it is put into operation. A failure to meet the
first condition would invalidate the application for ambiguity, while a failure
to meet the second invalidates it for insufficiency. The description must be
such as to enable a person skilled in the art or the field of the invention to
produce it using only the instructions contained in the disclosure (Pigeon
J. in Burton Parsons Chemicals Inc. v. Hewlett-Packard (Canada) Ltd., [1976]
1 S.C.R. 555, at p. 563; Monsanto Co. v. Commissioner of Patents, [1979]
2 S.C.R. 1108, at p. 1113) and once the monopoly period is over, to use the
invention as successfully as the inventor could at the time of his application
(Minerals Separation, supra, at p. 316). [emphasis added]
[199] More recently,
in Eli Lilly above, the Federal Court of Appeal explained the
requirement of sufficient disclosure (at paragraph 113):
In
addition to meeting the tests for patentability, an invention must also be
sufficiently disclosed. The specification represents the bargain between the
Crown on behalf of the public and the inventor (Consolboard).
Accordingly, the patent must contain enough information to allow a [PSA] to
make the invention. The claims must be precisely laid out, without being
overbroad. If the disclosure requirements are not met, the patent will
be invalid even if it is new, useful and not obvious. These requirements
for a patent specification are set out in subsections 27(3) and 27(4) of the
Act. [emphasis added]
[200] In this case,
Pharmascience submits that the ‘531 Patent inadequately describes the invention
and does not provide the public with any meaningful or new information on the
making of a three layer tablet. The patent also fails to indicate the specific
type of low viscosity HPMC used in the experiments. Thus, the patent provides
insufficient disclosure of the alleged invention.
[201] Conversely,
AstraZeneca submits that the allegations of insufficiency are unjustified
because all the allegedly missing information would be clearly known to a PSA
on a thorough reading of the patent. AstraZeneca notes that the use of low
viscosity HPMC in a separating layer and as a binding agent was well known at
the date of publication. In addition, there was no question that CP as defined
in the patent could be understood and determined as per the instructions
provided therein.
[202] In response to
Pharmascience’s allegation that the patent did not indicate what type of HPMC
to use, AstraZeneca submits that a PSA would easily understand that any
suitable grade of low viscosity HPMC can be used to prepare an enteric
omeprazole formulation, as long as it exceeds the claimed CP. The patent
clearly referred to HPMC having a viscosity of 6 cps. Similarly, AstraZeneca
submits that on seeing the reference to the marketing standard and the
reference to the use of a paddle, a PSA would understand that the inventors used
the Dissolution Apparatus 2.
[203] Further,
AstraZeneca submits that a PSA would also understand from the patent that any
suitable amount of coating of low viscosity HPMC can be used to prepare an
enteric omeprazole formulation as long as it exceeds the claimed CP.
[204] On reading the
‘531 Patent, I would agree with AstraZeneca’s characterization of the
sufficiency of the disclosure provided therein. I note that AstraZeneca’s last
point on the amount of coating is somewhat troublesome in light of the evidence
from Pharmascience’s experts on the importance of an adequate layer. However, I
also note that those experts did not offer any concrete evidence to show that
the thickness of the coating caused the variability presented in the patent and
therefore do not find it determinative.
[205] I would also
note that the ‘531 Patent does not explicitly state the temperature of the
buffer solution in which the omeprazole release was measured. However, at page
10, the ‘531 Patent does state that: testing was conducted in accordance with
marketing approval for the Losec® capsule formulation; “[t]he pellets were
pre-exposed to simulated gastric fluid USP (without enzyme) at 37˚C for 2
hours”; and the buffer solution comprised “simulated gastric fluid USP (without
enzyme)”. This suggests that the testing was done at 37˚C (i.e., body
temperature). I note that the later reference to temperature ranges from
35˚C to 50˚C (at page 12 of the patent) pertained to the CP
determination of the two different batches (Type A and Type B) of the same low
viscosity HPMC. Thus, those temperatures clearly do not pertain to the
measurements of the release of omeprazole in the buffer solution.
[206] In summary, I
find that the ‘531 Patent sufficiently defines the nature of the invention and
describes how it is put into operation. Based on the description provided, I
find that a PSA could learn the teaching provided therein and select an
appropriate batch of low viscosity HPMC for use in an enteric coated oral
pharmaceutical formulation as contemplated in the ‘531 Patent.
[207] Issue 4
Does the ‘531 Patent meet
the validity requirements for obviousness?
To be valid, a patent must
not be obvious, it must have an inventive step. This requirement is mandated
under section 28.3 of the Patent Act.
[208] In Apotex Inc
v Sanofi-Synthelabo Canada Inc, 2008 SCC 61, [2008] 3 S.C.R. 265, the Supreme
Court of Canada adopted a four-step approach to the inquiry into obviousness.
Writing for the Court, Mr. Justice Marshall Rothstein explained:
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 (p. 872),
[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.
i.
When Is the "Obvious to Try" Test Appropriate?
68
In areas of endeavour where advances are often won by experimentation, an
"obvious to try" test might be appropriate. In such areas, there may
be numerous interrelated variables with which to experiment. For example, some
inventions in the pharmaceutical industry might warrant an "obvious to
try" test since there may be many chemically similar structures that can
elicit different biological responses and offer the potential for significant
therapeutic advances.
ii.
"Obvious to Try" Considerations
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.
[209] In this case,
Pharmascience submits that there is nothing inventive in finding a solution to
a problem that never existed. As CP is an irrelevant parameter, there is
nothing inventive presented in the patent that was not already known in the
prior art. Notably, CP is indirectly based on the percentage of methozyl groups
in the HPMC, a fact that was already well known.
[210] Conversely,
AstraZeneca notes that none of the prior art considered batch-to-batch
variation in one subtype of low viscosity HPMC, nor did any of it direct PSAs
to select batches that had CPs exceeding the claimed CP to reduce product
discard. In fact, prior to 1998, a PSA would not have considered the low
viscosity HPMC on seeing that omeprazole enteric formulations were being
released at different rates. It was thus not surprising that Mr. Alderman did
not recall receiving any complaints on batch-to-batch variability and the
effect thereof on the release of omeprazole.
[211] To evaluate this
claim, it is necessary to consider the four-step approach adopted in Sanofi-Synthelabo
above.
[212] The first step
entails identifying the PSA and that person’s common general knowledge. In
their submissions, the parties offer similar descriptions of the PSA as
follows. AstraZeneca, “Pharmaceutical formulator with knowledge of HPMC used in
pharmaceutical formulations.” And Pharmascience, “pharmaceutical formulator, a
polymer chemist or chemical engineer with a PhD or with a Bachelors or Masters
Degree and relevant experience in polymer chemistry.” This person would be “familiar
with low viscosity HPMC used as a thin coating or as a binder that would
readily dissolve in water” and “would be familiar with omeprazole formulations
using a separating layer between the core material and the enteric coating.”
[213] Drawing from
these definitions, I find that the appropriate PSA here is a pharmaceutical
formulator, polymer chemist or chemical engineer with experience in polymer
chemistry and knowledge of low viscosity HPMC and omeprazole formulations.
[214] The second step
entails identifying or construing the inventive concept of the claim. Here, the
inventive concept is that there is batch-to-batch variation in low viscosity
HPMC products used as a binding agent and/or a constituent of a separating
layer in an enteric coated oral pharmaceutical formulation. This variation may
affect the release rate of omeprazole from the formulation, resulting in
failures to achieve marketing standards. However, these standards can
consistently be achieved when the formulation is only manufactured of batches
of low viscosity HPMC with CPs exceeding the claimed CP.
[215] The third step
entails identifying what, if any, differences exist between the prior art and
the inventive concept identified in the second step. Pharmascience’s experts
provided an extensive review of the prior art. The knowledge contained therein
can be summarized as follows:
- omeprazole is susceptible
to degradation in acid reacting and neutral media;
- a fully bioavailable
dosage form of omeprazole must release the active drug rapidly in the proximal
part of the gastrointestinal canal;
- omeprazole must be
protected from the acidic juice of the stomach by enteric coating;
- enteric coatings are made
of acidic compounds and if applied directly to omeprazole, the omeprazole will
become badly discoloured; and
- the three layer
formulation is used to protect omeprazole with the separating layer protecting
omeprazole from the enteric coating.
[216] There are clear
differences in the inventive concept of the ‘531 Patent, as described in the
second step above and in this prior art. As indicated, the prior art does not
delve into batch-to-batch variations of a low viscosity HPMC product. Nor does
it provide information on CPs, or on the claimed CPs described in the ‘531
Patent.
[217] Finally, the
fourth step evaluates whether these differences would have been obvious to the
PSA or whether they required a degree of invention. Based on the evidence on
the record, I find that these differences required a degree of invention and
would not have been obvious to the PSA. The fact that CP of low viscosity HPMC
could be determined may have been obvious to a PSA, but I do not find that the
relevance of this property to the rate of release of omeprazole, or the actual
claimed CP above which variations in the release of omeprazole between batches
of the same product would be minimized, would be obvious to the PSA. I therefore
find that the ‘531 Patent was not obvious on the claim date.
[218] As I have found
that AstraZeneca has discharged its burden of proving that the allegations
raised by Pharmascience in its NOA and relied upon at the hearing are not
justified, an order prohibiting the Minister from issuing a notice of compliance
to Pharmascience for its 20 mg and 40 mg esomeprazole
magnesium capsules will issue.
[219] JUDGMENT
THIS
COURT’S JUDGMENT is that:
1. The Minister of Health
is prohibited from issuing a notice of compliance to Pharmascience for its 20
and 40 mg esomeprazole magnesium capsules until after the expiration of
Canadian Patent No. 2,290,531.
2. AstraZeneca shall have
its costs of the application.
“John A. O’Keefe”
ANNEX
Relevant
Statutory Provisions
Patent Act,
RSC, 1985, c P-4
2. In
this Act, except as otherwise provided,
. . .
“invention”
means any new and useful art, process, machine, manufacture or composition of
matter, or any new and useful improvement in any art, process, machine,
manufacture or composition of matter;
27. The
specification of an invention must
(a) correctly
and fully describe the invention and its operation or use as contemplated by
the inventor;
27.
(3) The specification of an invention must
(a) correctly
and fully describe the invention and its operation or use as contemplated by
the inventor;
(b) set
out clearly the various steps in a process, or the method of constructing,
making, compounding or using a machine, manufacture or composition of matter,
in such full, clear, concise and exact terms as to enable any person skilled
in the art or science to which it pertains, or with which it is most closely
connected, to make, construct, compound or use it;
(c) in
the case of a machine, explain the principle of the machine and the best mode
in which the inventor has contemplated the application of that principle; and
(d) in
the case of a process, explain the necessary sequence, if any, of the various
steps, so as to distinguish the invention from other inventions.
28.3 The
subject-matter defined by a claim in an application for a patent in Canada must be subject-matter that would not have been obvious on the claim date to a
person skilled in the art or science to which it pertains, having regard to
(a) information
disclosed more than one year before the filing date by the applicant, or by a
person who obtained knowledge, directly or indirectly, from the applicant in
such a manner that the information became available to the public in Canada
or elsewhere; and
(b) information
disclosed before the claim date by a person not mentioned in paragraph (a) in
such a manner that the information became available to the public in Canada or elsewhere.
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2. Sauf
disposition contraire, les définitions qui suivent s’appliquent à la présente
loi.
. . .
«
invention » Toute réalisation, tout procédé, toute machine, fabrication ou
composition de matières, ainsi que tout perfectionnement de l’un d’eux,
présentant le caractère de la nouveauté et de l’utilité.
27. Le
mémoire descriptif doit :
a) décrire
d’une façon exacte et complète l’invention et son application ou
exploitation, telles que les a conçues son inventeur;
27.
(3) Le mémoire descriptif doit :
a) décrire
d’une façon exacte et complète l’invention et son application ou exploitation,
telles que les a conçues son inventeur;
b) exposer
clairement les diverses phases d’un procédé, ou le mode de construction, de
confection, de composition ou d’utilisation d’une machine, d’un objet
manufacturé ou d’un composé de matières, dans des termes complets, clairs,
concis et exacts qui permettent à toute personne versée dans l’art ou la
science dont relève l’invention, ou dans l’art ou la science qui s’en
rapproche le plus, de confectionner, construire, composer ou utiliser
l’invention;
c) s’il
s’agit d’une machine, en expliquer clairement le principe et la meilleure
manière dont son inventeur en a conçu l’application;
d) s’il
s’agit d’un procédé, expliquer la suite nécessaire, le cas échéant, des
diverses phases du procédé, de façon à distinguer l’invention en cause
d’autres inventions.
28.3 L’objet
que définit la revendication d’une demande de brevet ne doit pas, à la date
de la revendication, être évident pour une personne versée dans l’art ou la
science dont relève l’objet, eu égard à toute communication :
a) qui
a été faite, plus d’un an avant la date de dépôt de la demande, par le
demandeur ou un tiers ayant obtenu de lui l’information à cet égard de façon
directe ou autrement, de manière telle qu’elle est devenue accessible au
public au Canada ou ailleurs;
b) qui
a été faite par toute autre personne avant la date de la revendication de
manière telle qu’elle est devenue accessible au public au Canada ou ailleurs.
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Patented
Medicines (Notice of Compliance) Regulations, SOR/93-133
5. (1) If
a second person files a submission for a notice of compliance in respect of a
drug and the submission directly or indirectly compares the drug with, or
makes reference to, another drug marketed in Canada under a notice of
compliance issued to a first person and in respect of which a patent list has
been submitted, the second person shall, in the submission, with respect to
each patent on the register in respect of the other drug,
(a) state
that the second person accepts that the notice of compliance will not issue
until the patent expires; or
(b) allege
that
(i) the
statement made by the first person under paragraph 4(4)(d) is false,
(ii) the
patent has expired,
(iii) the
patent is not valid, or
(iv) no
claim for the medicinal ingredient, no claim for the formulation, no claim
for the dosage form and no claim for the use of the medicinal ingredient
would be infringed by the second person making, constructing, using or
selling the drug for which the submission is filed.
. . .
(3) A
second person who makes an allegation under paragraph (1)(b) or (2)(b) shall
(a) serve
on the first person a notice of allegation relating to the submission or
supplement filed under subsection (1) or (2) on or after its date of filing;
(b) include
in the notice of allegation
(i) a
description of the medicinal ingredient, dosage form, strength, route of
administration and use of the drug in respect of which the submission or
supplement has been filed, and
(ii) a
detailed statement of the legal and factual basis for the allegation;
(c) include
in the material served a certification by the Minister of the date of filing
of the submission or supplement; and
(d) serve
proof of service of the documents and information referred to in paragraphs
(a) to (c) on the Minister. . . .
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5. (1) Dans
le cas où la seconde personne dépose une présentation pour un avis de
conformité à l’égard d’une drogue, laquelle présentation, directement ou
indirectement, compare celle-ci à une autre drogue commercialisée sur le
marché canadien aux termes d’un avis de conformité délivré à la première
personne et à l’égard de laquelle une liste de brevets a été présentée — ou y
fait renvoi —, cette seconde personne doit, à l’égard de chaque brevet ajouté
au registre pour cette autre drogue, inclure dans sa présentation :
a) soit
une déclaration portant qu’elle accepte que l’avis de conformité ne sera pas
délivré avant l’expiration du brevet;
b) soit
une allégation portant que, selon le cas :
(i) la
déclaration présentée par la première personne aux termes de l’alinéa 4(4)d)
est fausse,
(ii) le
brevet est expiré,
(iii) le
brevet n’est pas valide,
(iv) elle
ne contreferait aucune revendication de l’ingrédient médicinal, revendication
de la formulation, revendication de la forme posologique ni revendication de
l’utilisation de l’ingrédient médicinal en fabriquant, construisant,
utilisant ou vendant la drogue pour laquelle la présentation est déposée.
.
. .
(3) La
seconde personne qui inclut l’allégation visée à l’alinéa (1)b) ou (2)b) doit
prendre les mesures suivantes :
a) signifier
à la première personne un avis de l’allégation à l’égard de la présentation
ou du supplément déposé en vertu des paragraphes (1) ou (2), à la date de son
dépôt ou à toute date postérieure;
b) insérer
dans l’avis de l’allégation :
(i) une
description de l’ingrédient médicinal, de la forme posologique, de la
concentration, de la voie d’administration et de l’utilisation de la drogue
visée par la présentation ou le supplément,
(ii) un
énoncé détaillé du fondement juridique et factuel de l’allégation;
c) joindre
à la signification une attestation par le ministre de la date du dépôt de la
présentation ou du supplément;
d) signifier
au ministre la preuve de toute signification des documents et renseignements
visés aux alinéas a) à c).
.
. .
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