Docket: T-1161-13
Citation:
2015 FC 751
Ottawa, Ontario, June 15, 2015
PRESENT: The
Honourable Mr. Justice Barnes
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BETWEEN:
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TAKEDA CANADA
INC. AND
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TAKEDA GMBH
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Applicants
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And
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THE MINISTER OF
HEALTH AND
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MYLAN
PHARMACEUTICALS ULC
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Respondents
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PUBLIC JUDGMENT AND REASONS
(Confidential
Judgment and Reasons issued June 15, 2015)
[1]
In this proceeding Takeda Canada Inc. and Takeda
GMBH [hereafter Takeda] seek an Order under the Patented Medicines [Notice of Compliance]
Regulations prohibiting the Minister of Health [Minister] from
issuing a Notice of Compliance [NOC] to Mylan Pharmaceuticals ULC [hereafter
Mylan] for its proposed version of Takeda’s branded medicine, TECTA.
[2]
The patent in issue is Canadian Letters Patent
No. 2,341,031 [the 031 Patent]
claiming, among other things, the compound pantoprazole
magnesium dihydrate. The 031 Patent was filed on August 12, 1999 claiming
priority to August 18, 1998. Takeda is the owner of the patent.
[3]
Pantoprazole magnesium was known in the prior
art for use as a gastric acid inhibitor but, according to Takeda, the discovery
of its dihydrate form to treat gastric acid disorders was novel and non-obvious.
[4]
The inventive concept of the 031 Patent is
not in dispute. It is the compound pantoprazole magnesium dihydrate to treat
disorders of the stomach and intestine.
[5]
Claim 1 is the principal claim in issue. It
claims the compound pantoprazole magnesium dihydrate. Takeda also asserts
Claims 2, 8, 9, and 10 to 21 but the validity of Claim 1 underlies all of the
other asserted claims. Similarly, if Claim 1 is not infringed by the Mylan
product none of the other claims of the Patent will be infringed.
[6]
Mylan’s Notice of Allegation [NOA] and its Abbreviated
New Drug Submission [ANDS] assert that its proposed pantoprazole magnesium product
does not infringe the 031 Patent because it is a hemipentahydrate and not
a dihydrate. It is common ground that dihydrates and hemipentahydrates of
pantoprazole magnesium are distinct crystal forms containing different amounts
of crystal bound water. Accordingly, the issue of infringement turns on the
characterization of the hydration state of Mylan’s product.
[7]
Mylan’s NOA also raised a number of validity
challenges to the 031 Patent some of which it has subsequently abandoned.
For the purpose of this decision, it will be sufficient to address only the
issue of anticipation.
I.
Background Science
[8]
Almost all of the matters of relevant scientific
background are not in dispute.
[9]
Many chemical species have the ability to
crystallize into more than one crystal structure. This phenomenon is known as
polymorphism. Different polymorphs of the same material will display different
structures and this can lead to variations in solubility, dissolution rate and
bioavailability. Pseudopolymorphism refers to the ability of certain chemical
species to crystallize around a solvent such as water. When water is the
solvent, the crystal form is referred to as a hydrate. There can be any number
of hydration states for a given chemical species. When a hydrate contains two
molecules of water to one molecule of the chemical species, it is characterized
as a dihydrate. When the ratio is 5 to 2, the hydrate is said to be a
hemipentahydrate.
[10]
Pantoprazole magnesium is a magnesium salt of
pantoprazole. Every molecule of pantoprazole magnesium is made up of two molecules
of pantoprazole to one molecule of magnesium. The dihydrate form of
pantoprazole magnesium incorporates two molecules of water into the crystal
lattice for every molecule of pantoprazole magnesium. For the hemipentahydrate
form the ratio is 2.5 to 1.
[11]
Hydrates can typically be identified or
characterized by a variety of methods including X-Ray Powder Diffraction [XRPD],
Differential Scanning Calorimetry [DSC], Thermogravimetric analysis [TGA], Karl
Fischer titration [KF] and melting point.
[12]
XRPD involves the exposure of a test sample to
x-rays and the recording of the diffraction pattern. In almost every case
different polymorphs will give off unique x-ray diffraction patterns. Two
samples exhibiting the same pattern will almost always be the same compound.
[13]
DSC can also distinguish between different
polymorphs or pseudopolymorphs. DSC measures the difference in energy or heat
flow between a sample and a reference sample as the temperature is increased
over time. If two samples exhibit materially different melting points, their
structures will be different. This test will not always be helpful because heat
can cause different hydrates to convert to the same crystal form before the
common form melts. In such circumstances, the test cannot assist in the
identification of the original crystal form.
[14]
TGA and KF are methods of measuring the amount
of solvent in a pseudopolymorph. TGA measures the weight differential of the
sample as the solvent is driven off with heating. KF directly measures the
water content of the sample. Both tests are subject to a margin of error and
can be affected by the applied experimental conditions.
[15]
Mylan’s ANDS submitted to the Minister reports
that its product was characterized by KF, TGA, XRPD and DSC and found to be a
hemipentahydrate.
II.
Person of Skill in the Art
[16]
The parties agree the person of skill is a
chemist or chemical engineer with experience working with and characterizing
solid crystalline forms.
III.
Construction
[17]
It is necessary, of course, to construe the
claims of a patent in a purposive way before considering their validity or
whether they are infringed. This is done through the eyes of the notional
person of skill in the art to which the patent pertains. Claims are to be
considered in the context of the entire patent, being neither benevolent nor
harsh. Experts may assist as to the technical meaning of terms and as to the
state of the art at the material time, but ultimately construction is an issue
of law for the Court to determine. Experts do not construe the patent claims;
instead they assist the Court in doing so: see Whirlpool Inc v Camco Inc,
2000 SCC 67 at paras 43-45 and 57, [2000] 2 S.C.R. 1067.
[18]
The parties are in essential agreement about the
construction of the relevant claims. All of the asserted claims include
pantoprazole magnesium dihydrate. All of the experts in the case construed
Claim 1 to include all polymorphic forms of pantoprazole magnesium dihydrate:
see Dr. Myerson’s first affidavit at para 2(b)(v); Dr. Atwood’s affidavit
at para 59; Dr. Cima’s affidavit at para 81. In other words, the
claimed compound is defined by its hydration state and not by its crystal
structure per se. The effect of this construction is that Takeda is
asserting a monopoly over every possible dihydrate form of pantoprazole magnesium
to treat gastric acid disorders, whether or not they were known or could be
predicted at the time of the invention. This seemingly runs counter to the
evidence of all of the experts that one cannot predict in advance whether other
hydrous forms exist and finding such a form is inherently inventive. The
experts also agree that the utility of an unknown hydrous form cannot be
predicted in advance of its discovery.
[19]
I have some reservations about whether the
person of skill would interpret Claim 1 in this expansive way. Although on its
face, Claim 1 is not confined to any particular dihydrate form, the
031 Patent teaches methods for obtaining particular dihydrate forms. It
says nothing about whether other dihydrate forms are likely to exist, how they
could be made, or whether they would be likely to be useful. It is also of some
significance that the inventors made some effort to characterize the obtained
compounds by disclosing their water content values and melting points. These
stipulations seemingly belie the broad construction of Claim 1 proffered by the
experts, and support Mylan’s initial pre-hearing construction set out at page
20 of its NOA.
[20]
In my view, the person of skill would be more
likely to read Claim 1 to include only the dihydrate forms the inventors
discovered. Nevertheless, the determinative issues in this case are not
dependant on this point of construction and it is not necessary to finally
resolve this point.
IV.
Onus of Proof
[21]
The 031 Patent is presumed to be valid.
Mylan has the initial burden of adducing sufficient evidence to give its NOA
invalidity allegations an air of reality; on the determinative issue of
anticipation, it has met that burden. The ultimate burden of proof on this
issue thus rests with Takeda to prove, on a balance of probabilities, that
Mylan’s anticipation allegation is not justified. On the issue of infringement,
the burden rests on Takeda, on a balance of probabilities, to show that the
Mylan product infringes. Evidence establishing only a possibility of
infringement is insufficient to discharge this burden: see Pfizer Canada
Inc v Novophram Ltd, 2005 FCA 270 at paras 24 and 28, 2005 FCA 270.
V.
The Expert Witnesses
[22]
Takeda relies on the evidence of Dr. Allan
Myerson. Dr. Myerson is a Professor of the Practice in the Department of
Chemical Engineering at the Massachusetts Institute of Technology [MIT]. He is
a chemical engineer by training and has a 30-year history of working in the
field of industrial crystallization. Much of his current research focus and
professional writing concerns crystallization processes including novel
formulation development and pharmaceutical manufacturing.
[23]
Mylan relies on the evidence of
Dr. Michael Cima and Dr. Jerry Atwood. Ironically,
Dr. Cima works along-side Dr. Myerson at MIT. Dr. Cima has
written extensively in the field of materials processing with particular
emphasis on the discovery of novel crystal forms and formulations of
pharmaceuticals. Dr. Atwood is the Chair of the Department of Chemistry at
the University of Missouri-Columbia. He has considerable experience in the area
of crystal growth and crystal engineering. He, too, is widely published and has
served in an editorial capacity for several subject-related journals.
[24]
All of these experts are well-qualified to
express the opinions they gave in this proceeding. I can identify nothing about
their respective backgrounds or conduct that would undermine their opinion
evidence. In particular, I reject Takeda’s argument that Dr. Atwood was
somehow tainted by prior exposure to Mylan’s NOA before conducting his testing.
There is, quite simply, no evidence that his experimental techniques were
biased because of his background knowledge. Dr. Atwood explained his
methods and disclosed his findings all of which were then open to scrutiny.
[25]
There is nothing in the evidence that remotely
supports the argument that Dr. Atwood’s methodological choices were
inherently inappropriate or calculated to obtain a pre-determined outcome.
Indeed, Takeda elected not to conduct any testing of its own to directly
challenge Dr. Atwood’s data and Dr. Myerson failed to identify any
step taken by Dr. Atwood which would be expected to obtain a result
favourable to Mylan’s position.
VI.
Anticipation – What Does Example 10 of WO
114 Teach the Person of Skill?
[26]
Mylan relies for its anticipation case on
International Patent Application WO 97/41114 [WO 114] filed on April 22, 1997.
WO 114 describes a process for preparing magnesium salts of certain
benzimidazoles, including pantoprazole, known to be useful as gastric acid
inhibitors. The 031 Patent acknowledges WO 114 as relevant prior art
concerning the magnesium salt of pantoprazole but distinguishes the resulting
product as an anhydrous form. Mylan and its experts say that Example 10 of the
WO 114 necessarily produces pantoprazole magnesium dihydrate and it, therefore,
anticipates the subject matter of the 031 Patent claims in issue.
[27]
The point of disagreement between the parties is
whether, by following Example 10 of WO 114, the inevitable result is
pantoprazole magnesium dihydrate. The parties also disagree about whether WO
114, on its face, teaches the person of skill that the resulting product of
Example 10 will be an anhydrous form or a dihydrate form.
[28]
WO 114 does not explicitly disclose to the
person of skill whether the pantoprazole magnesium compound it produces is in
any particular anhydrous or hydrous form. Clearly, there is nothing in this
document tending to indicate that a dihydrate form is produced. At best, there
are arguments suggesting that either an anhydrous or an unspecified hydrous
form is produced.
[29]
I do not agree with Dr. Myerson that the
absence of a reference to water in the disclosed chemical formula is a
compelling consideration. This could just as easily be explained by the inventors’
indifference to the hydration state of the pantoprazole magnesium compound they
obtained.
[30]
I also do not accept that the person of skill
would characterize the hydration state of this compound by relying solely on
the stated values for theoretical and found magnesium content. Both Dr. Cima
and Dr. Atwood say the reported value for found magnesium in Example 10
was within the margin of error for both anhydrous and dihydrous forms of
pantoprazole magnesium. Dr. Myerson did not disagree that experimental
error should be taken into account. He did not agree, however, that it would
be considered by the person of skill to be as high as the value asserted by
Dr. Atwood (±0.4%).
[31]
Dr. Myerson took issue with Dr. Cima’s
statement that the actual magnesium content reported in Example 10 “falls well within the range, with margin of error, for both
a dihydrate and an anhydrous form of pantoprazole magnesium”. Based on
Dr. Cima’s failure to identify the standard margin of error to be applied
to the magnesium content value produced by Example 10, Dr. Myerson
described Dr. Cima’s conclusion as “unfounded”.
This criticism is substantially undermined by Dr. Myerson’s own failure to
state a value for the appropriate margin of error. In the absence of this
information, Dr. Myerson concluded with the following largely unhelpful
generalization:
121. The skilled chemist would not
ignore the information in Example 10 that an anhydrous form of pantoprazole
magnesium was prepared based on the potential experimental error in the found
magnesium content.
[32]
Considering the paucity of the evidence
presented, I do not believe the person of skill would, by reading the WO 114
and applying common general knowledge, draw any conclusions about the hydration
state of the pantoprazole magnesium compound produced by Example 10. Rather,
the person of skill would follow the described process and, if desired,
properly characterize the obtained compound by applying well-known and reliable
techniques.
[33]
I, therefore, agree with Takeda that, on its
face, WO 114 does not inform the person of skill that the compound produced by
Example 10 will be pantoprazole magnesium dihydrate or, indeed, any other
particular hydrous form. At the same time it does not teach the person of
skill that an anhydrous form will be obtained. The question remains, though,
whether by following the process described in Example 10, the person of skill
inevitably or necessarily obtains pantoprazole magnesium dihydrate.
[34]
The law of anticipation applying to this
question is well settled and was thoroughly summarized by Justice Roger Hughes
in Eli Lilly Canada Inc v Apotex Inc, 2008 FC 142 at paras 145-149,
[2008] FCJ No 171:
[145] Lord Hoffman in the Synthon
case, subsequent to Merrell Dow gave further consideration to the
question of anticipation. In that case SmithKline had a patent which claimed a
medicine called paroxetine methanesulfonate in a very particular crystalline
form. A previous patent application published by Synthon disclosed a method
for making paroxetine methanesulfonate but made no reference to any particular
crystalline form. The evidence showed that if one were to follow the Synthon
method, the particular SmithKline form would be made. Lord Hoffman therefore
had to discuss anticipation from the perspective of the disclosure and
enablement. He discussed Merrell Dow in this context at paragraphs 22
and 23 of Synthon:
22. If I may summarise the
effect of these two well-known statements, the matter relied upon as prior art
must disclose subject-matter which, if performed, would necessarily result in
an infringement of the patent. That may be because the prior art discloses the
same invention. In that case there will be no question that performance of the
earlier invention would infringe and usually it will be apparent to someone who
is aware of both the prior art and the patent that it will do so. But patent
infringement does not require that one should be aware that one is infringing:
"whether or not a person is working [an] ... invention is an objective
fact independent of what he knows or thinks about what he is doing":
Merrell Dow Pharmaceuticals Inc v H N Norton & Co Ltd [1996] RPC 76, 90. It
follows that, whether or not it would be apparent to anyone at the time, whenever
subject-matter described in the prior disclosure is capable of being performed
and is such that, if performed, it must result in the patent being infringed,
the disclosure condition is satisfied. The flag has been planted, even though
the author or maker of the prior art was not aware that he was doing so.
23. Thus, in Merrell Dow,
the ingestion of terfenadine by hay-fever sufferers, which was the subject of
prior disclosure, necessarily entailed the making of the patented acid
metabolite in their livers. It was therefore an anticipation of the acid
metabolite, even though no one was aware that it was being made or even that it
existed. But the infringement must be not merely a possible or even likely
consequence of performing the invention disclosed by the prior disclosure. It
must be necessarily entailed. If there is more than one possible consequence,
one cannot say that performing the disclosed invention will infringe. The flag
has not been planted on the patented invention, although a person performing the
invention disclosed by the prior art may carry it there by accident or (if he
is aware of the patented invention) by design. Indeed, it may be obvious to do
so. But the prior disclosure must be construed as it would have been understood
by the skilled person at the date of the disclosure and not in the light of the
subsequent patent. As the Technical Board of Appeal said in T/396/89 UNION CARBIDE/high tear strength polymers [1992] EPOR 312 at para 4.4:
"It
may be easy, given a knowledge of a later invention, to select from the general
teachings of a prior art document certain conditions, and apply them to an
example in that document, so as to produce an end result having all the
features of the later claim. However, success in so doing does not prove that
the result was inevitable. All that it demonstrates is that, given knowledge of
the later invention, the earlier teaching is capable of being adapted to give
the same result. Such an adaptation cannot be used to attack the novelty of a
later patent."
[146] The Synthon reasons
subsequently considered enablement beginning at paragraph 26 where Lord Hoffman
said:
Enablement means that the ordinary
skilled person would have been able to perform the invention which satisfies
the requirement of disclosure.
[147] At paragraph 28, Lord Hoffman
warned:
It is very important to keep in
mind that disclosure and enablement are distinct concepts, each of which has to
be satisfied and each of which has its own rules.
[148] He cited in paragraph 28 a decision
of Laddie J. in which that judge said:
The requirement to include an
enabling disclosure is concerned with teaching the public how the invention
works, not devising the invention in the first place.
[149] Then, Lord Hoffman considered the
question as to whether one must, as he put it, necessarily infringe, in light
of Merrell Dow in paragraph 33 of his Reasons:
There is also a danger of
confusion in a case like Merrell Dow Pharmaceuticals Inc v H N Norton & Co
Ltd [1996] RPC 76, in which the subject-matter disclosed in the prior art is
not the same as the claimed invention but will, if performed, necessarily
infringe. To satisfy the requirement of disclosure, it must be shown that there
will necessarily be infringement of the patented invention. But the invention
which must be enabled is the one disclosed by the prior art. It makes no sense
to inquire as to whether the prior disclosure enables the skilled person to
perform the patented invention, since ex hypothesi in such a case the skilled
person will not even realise that he is doing so. Thus in Merrell Dow the
question of enablement turned on whether the disclosure enabled the skilled man
to make terfenadine and feed it to hay-fever sufferers, not on whether it
enabled him to make the acid metabolite.
[35]
In AstraZenaca Canada Inc v Apotex Inc,
2010 FC 714, [2010] FCJ No 1014, Justice Hughes noted the variations in
language sometimes employed around the legal test for so-called inherent
anticipation. Nevertheless, it was unnecessary for him to sort out those differences
because, in the case before him, the prior art “would
at best only occasionally result in the [claimed] product” and was not
thus anticipatory [see para 125].
[36]
More recently in Synthon BV v Teva
Pharmaceutical Industries Limited, [2015] EWHC 1395 (Pat), [2015] All ER
(D) 200 (May) , Justice Birss dealt with the issue of novelty in the context of
choices left to the person of skill in carrying out prior art. His comments at
para 89 are helpful:
89. There is no issue about enablement
in this case, the question arising over the Lemmon prior art is about the first
limb of Synthon. The issue is whether the prior art would
fall within the claims. The test is a strict one, as the flag planting metaphor
employed by Sachs LJ was intended to indicate. The test is one of necessity and
inevitability. If a prior document leaves a choice open for the skilled person
and if the result only falls within the patent claim if the skilled person
adopts one way forward and not the other, then there is no lack of novelty. In
that circumstance evidence that a skilled person "would" do something
when faced with that choice is evidence relevant to obviousness, not novelty.
The claim may lack inventive step but it has not been anticipated. On the other
hand patentees will sometimes argue that a choice exists when in fact there is
no genuine choice and in fact the patented way forward really is inevitable. If
those are the facts then the claim lacks novelty but that is not because the
skilled person had to make a choice, it is because there really was no choice
at all. Fanciful supposed choices do not count.
[37]
In Abbott Laboratories v Sandoz Canada Inc,
2008 FC 1359 aff’d 2009 FCA 94, [2009] FCJ No 345 , Justice Hughes summarized
the law of anticipation into the following seven points:
1. For there to be anticipation
there must be both disclosure and enablement of the claimed invention.
2. The disclosure does not have to
be an “exact description” of the claimed invention. The disclosure must be
sufficient so that when read by a person skilled in the art willing to
understand what is being said, it can be understood without trial and error.
3. If there is sufficient
disclosure, what is disclosed must enable a person skilled in the art to carry
out what is disclosed. A certain amount of trial and error experimentation of
a kind normally expected may be carried out.
4. The disclosure when carried out
may be done without a person necessarily recognizing what is present or what is
happening.
5. If the claimed invention is
directed to a use different from that previously disclosed and enabled then
such claimed use is not anticipated. However if the claimed use is the same as
the previously disclosed and enabled use, then there is anticipation.
6. The Court is required to make its
determinations as to disclosure and enablement on the usual civil burden of
balance and probabilities, and not to any more exacting standard such as
quasi-criminal.
7. If a person carrying out the
prior disclosure would infringe the claim then the claim is anticipated.
[38]
In Apotex Inc v Sanofi-Synthelabo Canada Inc,
2008 SCC 61, [2008] 3 S.C.R. 265, the Court discussed the requirement for
enablement. In attempting to put the prior art into practice, the person of
skill is entitled to carry out routine trial and error experimentation
including the application of common general knowledge. The amount of work
required cannot constitute an undue burden but errors or omissions in the prior
art reference may be overcome if the person of skill could readily correct the
error or find what was omitted.
[39]
Applying the above principles to this
proceeding, the 031 Patent claims in issue will not be anticipated if, on
a balance of probabilities, Takeda can show that following Example 10 of WO 114
does not inevitably or necessarily produce pantoprazole magnesium dihydrate. If
the evidence discloses on a balance of probabilities only that a dihydrate will
sometimes be the result, Takeda will have met its burden.
[40]
The only direct evidence of what Example 10 of
WO 114 produces comes from Dr. Atwood. According to Dr. Atwood, he
followed the exemplified process and obtained a compound that he characterized
by XRPD, DSC and TGA as pantoprazole magnesium dihydrate. The XRPD pattern he
obtained matched one from US 623 for a dihydrate, and the melting point
and water content data he obtained corresponded closely to the characterization
data disclosed in the 031 Patent. In particular, the water content value
obtained by TGA was 4.43% as compared to the theoretical loss of bound water
expected for pantoprazole magnesium dihydrate of 4.37%.
[41]
Dr. Myerson did not attempt to replicate
Example 10 of WO 114 nor did he purport to challenge Dr. Atwood’s
characterization of the compound he made as pantoprazole magnesium dihydrate.
Instead Dr. Myerson took issue with Dr. Atwood’s methods and
experimental choices.
[42]
Dr. Myerson expressed the view that
Dr. Atwood could not have accurately replicated Example 10 because his
experimental yield was only half of what WO 114 had reported. According to
Dr. Myerson this indicated something was wrong with Dr. Atwood’s
experiment. The probable cause for the reduced yield was attributed to
Dr. Atwood’s supposed deviations from Example 10 for the addition of
water. Dr. Myerson described the problem as follows:
128. Dr. Atwood’s reduced yield can
likely be traced to his not following the procedure as described in Example 10
of the 114 patent. The example indicates that water should be added
dropwise and the solution should be held for 30 minutes after the end of the
water addition. In contrast, Dr. Atwood added the water over 30 minutes and
then immediately isolated the solution. This changed process appears to have
isolated the product while the solution was far from equilibrium thus resulting
in his reduced yield. Reducing this yield will potentially change the solid
form obtained.
129. Dr. Atwood’s procedure also
resulted in a very different saturation profile (crystallization driving
force). Higher supersaturation profiles are well known to have the potential of
producing different crystalline forms when compared to lower supersaturation
profiles. Supersaturation profile is well known to influence a solid form
obtained as is isolating a solid when the system is still far from equilibrium.
130. These deviations from the actual
procedures of Example 10 of the 114 application indicate that Dr. Atwood’s
procedure was not an accurate reproduction of this procedure.
[43]
Dr. Myerson also noted that it was
necessary for Dr. Atwood to fill in some testing gaps concerned with drying
time and temperature and the rate for adding water. According to
Dr. Myerson, changes to these experimental choices could result in a
compound with a different hydration state. Various passages in
Dr. Myerson’s affidavit describe this potential in different ways: eg: “can have a significant impact on the resulting product”,
“would likely affect the process and the resulting
product”, “the rate of addition of water can
affect the crystallization process and the hydration level of any resulting
crystalline product”, “reducing this yield will
potentially change the solid form obtained”.
[44]
Dr. Myerson concluded that
Dr. Atwood’s experimental choices and errors were sufficiently material to
the outcome that a person of skill following Example 10 but adopting a
different approach, would not expect to always obtain the same result.
[45]
Dr. Myerson concluded his anticipation
opinion in the following way:
139. In light of the above, it is my
opinion that the 114 Application does not disclose the pantoprazole
magnesium dihydrate claimed in the 031 Patent nor does it disclose a
process that necessarily makes such a hydrate.
140. I understand that, based on my
opinion that the 114 Application does not satisfy the disclosure prong of
anticipation, it is unnecessary for me to address the enablement prong.
[46]
Dr. Cima’s contribution to this issue
included corroboration of the characterization of the product Dr. Atwood
obtained as pantoprazole magnesium dihydrate. Dr. Cima also verified Dr. Atwood’s
experimental approach. Dr. Cima’s affidavit offers the following
concluding opinion:
154. Example 10 of the 114 Application
disclosed the subject-matter of claim 1 and enabled the POSITA to practice the
subject-matter of claim 1. The POSITA could follow what was taught in Example
10 and arrive at the subject-matter of claim 1, namely pantoprazole magnesium
dihydrate, as simply and as easily as Dr. Atwood did. Having reviewed
Dr. Atwood’s experiment, I conclude that he employed no more than the
common general knowledge of the skilled person in following the instructions of
the 114 Application.
155. In addition, the
114 Application disclosed that the pantoprazole magnesium dihydrate
produced in Example 10 was stable, useful as an inhibitor of gastric acid
secretion and suitable to make pharmaceutical formulations such as tables (see
page 1, lines 14-17 and page 2, lines 16-20 of the 114 Application). This
additional disclosure anticipates claims 2 and 8 to 21 of the 031 Patent
because it disclosed and enabled the subject-matter of claims 2 and 8 to 21 of
the 031 Patent.
156. Furthermore, Example 10 disclosed a
process in which pantoprazole was reacted with the magnesium salt, magnesium
sulfate, in an aqueous solvent (i.e., water). Therefore, Example 10 also
anticipates claim 36 of the 031 Patent because it disclosed and enabled
the subject-matter of claim 36. For all of these reasons, I conclude that the
114 Application anticipates the 031 Patent.
[Footnotes omitted]
[47]
I am satisfied on the evidence before me that
Dr. Atwood followed the process described in Example 10 of the WO 114 and
made reasonable and routine experimental choices where it was necessary to do
so. I am also satisfied that the compound he obtained was pantoprazole
magnesium dihydrate. This still leaves for determination how probable it is
that by making different choices a person of skill would, by following Example
10, obtain something other than a dihydrate.
[48]
Dr. Myerson’s stated concerns are all
theoretical. Nowhere in his evidence does he state that by applying different
drying methods or by taking different approaches to the addition of water,
something other than a dihydrate would be the likely result. At most, he says
that a different hydrous form might or could be obtained.
[49]
It was, of course, open to Dr. Myerson to
run his own experiment using his preferred methods, and to characterize the
hydration state of the resulting compound. Presumably he was directed by Takeda
not to take that step. Instead Dr. Myerson raised only theoretical
concerns about Dr. Atwood’s methods without saying how those choices would
be likely to produce something other than a dihydrate. In AstraZeneca Canada
Inc v Apotex Inc, 2015 FC 322, 252 ACWS (3d) 567, I expressed some
reservation about that type of strategic choice:
[361] The fact that a party may not agree
with a chosen experimental design is not an excuse for failing to replicate the
work to test the reliability of the reported data. The same applies to
criticisms about the testing techniques employed by an opposing expert witness.
An argument that other tests or controls could have been used loses much of its
strength where a party chooses not to employ those same suggested methods in
its own responding analysis to see if the results differ.
I would add, in the face of Takeda’s failure
to conduct a single test, its concern that Dr. Atwood only ran one is
somewhat of a dissimulation.
[50]
It is also of some significance that Dr.
Atwood was not cross-examined about Dr. Myerson’s stated concerns
and, thus, Takeda enjoyed the benefit of Dr. Myerson’s views in the
absence of effective reply.
[51]
Dr. Myerson’s concerns about
Dr. Atwood’s choices also stand in rather marked contrast to
Dr. Myerson’s testimony about the teaching of the 031 Patent. In that
context, Dr. Myerson had no difficulty in filling in methodological gaps
in the process described to arrive at pantoprazole magnesium dihydrate. In
particular, he acknowledged the absence of specific instructions about the rate
of addition of water containing magnesium salt. He also noted the absence of a
processing temperature for the resulting solution and he assumed it to be room
temperature (see p 4341). This is, of course, in contrast to
Dr. Myerson’s concern about Dr. Atwood’s approach where, for the
purpose of carrying out Example 10 of WO 114, he also ran the experiment at
room temperature.
[52]
In the absence of any test data to support
Dr. Myerson’s opinion and considering the reliable results obtained by
Dr. Atwood as verified by Dr. Cima, I find that Takeda has not met
its burden of showing that Mylan’s anticipation allegation is unjustified.
VII.
Does the Mylan Product Infringe?
[53]
Mylan asserted in its Notice of Application
[NOA] that its pantoprazole magnesium product does not infringe the
031 Patent because it produces a hemipentahydrate form of the compound and
the Patent covers only dihydrate forms. If, indeed, the Mylan compound is
pantoprazole magnesium hemipentahydrate, it is common ground that it does not
and will not infringe.
[54]
Takeda’s case for infringement rests on a number
of evidentiary points. It relies on Mylan’s product specification for water
content in a range that, at the lower end, would capture dihydrate forms. It
also argues for an inference that Mylan intends to make a dihydrate based on
Mylan’s unexplained alteration to its water content specification moving the
acceptable range more closely to a dihydrate standard.
[55]
Takeda also relies on Mylan’s product analyses
as disclosed to the Minister and says that, notwithstanding Mylan’s contrary
assurances, the data confirms the Mylan product is a dihydrate. Much of this
argument is based on Takeda’s interpretation of the test data measuring the
water content of Mylan’s product batches. According to this argument, these
data also indicate the Mylan product is a dihydrate.
[56]
Finally, Takeda contends that it was prevented
from conducting its own testing of Mylan’s product to conclusively characterize
its hydration state such that any uncertainty ought to be resolved in its
favour.
[57]
The determinative infringement issue, then, is
whether the Mylan product is pantoprazole magnesium hemipentahydrate as it
contends, or pantoprazole magnesium dihydrate as covered by the claims of the
031 Patent.
VIII.
The Mylan Specification
[58]
I put very little stock in the evidentiary
significance of the Mylan specification allowing for a water content in a range
of [redacted]% to [redacted]% w/w. This range captures the theoretical water
content for both the dihydrate and hemipentahydrate forms.
[59]
Although Dr. Myerson stated at paragraph 76
of his first affidavit that this specification “requires”
that the Mylan product contain pantoprazole magnesium dihydrate, elsewhere in
his affidavit and under cross-examination, he acknowledged the specification
did not go that far:
539 Q. Okay. But your evidence
is not that the specification -- Mylan’s specification prevents it from making
a hemipentahydrate?
A. What
they—I guess I’m not sure of what you mean, that it prevents them from.
540 Q. Well, you said that the
specification encompasses in your view both a dihydrate and a hemipentahydrate,
correct?
A. Well, the
water content specification.
541 Q. That’s correct.
A. There’s
all I’m talking about. Not how they make it; just the water content
specification.
542 Q. Well, we’re talking about
the whole specification of the product, including its XRPD, for example, right?
A. Okay. I’m
not talking about that either.
I made a very
precise statement that their product specification of the water content
encompasses both a dihydrate and a hemipentahydrate.
543 Q. Right. So, conversely,
Mylan’s specification allows it to make a hemipentahydrate as far as water
content is --
A. Meaning
that if they made a hemipentahydrate it would fall within their specified water
content range?
544 Q. Yes.
A. That’s
correct.
545 Q. Right. And Mylan has
represented to Health Canada that it will make a hemipentahydrate, correct?
A. That’s
what it says.
[60]
The fact that a product specification
incorporates a range of values that permits different compounds to be produced
says very little about what is actually produced.
[61]
In spite of relying on Mylan’s specification in
support of his opinion that its product is a dihydrate, Dr. Myerson
acknowledged the frailty of this type of evidence in the following passage at
paragraph 104 of his second affidavit:
For example, Mylan’s specification requires:
(b)
a water content by Karl-Fischer titration been [redacted]% w/w and [redacted]%
w/w, yet justifies this range only as “a moisture that could be present
in the material.” Mylan’s justification does not address at all why a range
which captures both a pantoprazole magnesium dihydrate and hemipentahydrate is
appropriate to characterize the product as a hemipentahydrate;
[Emphasis added]
[62]
I take Takeda’s point that Mylan did not
disclose the reason for altering its product specification for water content at
the low end of the acceptable range from [redacted]% to [redacted]%. However,
given the evidentiary limitations inherent in NOC proceedings, Mylan was not
required to offer an explanation for that change and I am not prepared to
speculate about its motivations. I, therefore, reject Dr. Myerson’s
unsupported and pejorative attribution at paragraph 83 of his first affidavit.
Indeed, it would take far stronger evidence than this to support an inference
that Mylan’s disclosure about its product to the Minister was deceitful.
IX.
Mylan’s Product Testing
[63]
The expert witnesses differed about the adequacy
of the analytical tools used by Mylan to assess the water content of its
product and to thereby accurately characterize its hydration state. The
significance of Mylan’s KF testing was a particular focus of their
disagreement.
[64]
Dr. Myerson expressed the opinion that the
measurements Mylan obtained were sufficiently accurate to establish the Mylan
product as a dihydrate. Drs. Cima and Atwood came to the conclusion that
the totality of the analytical evidence showed the Mylan product to be a
hemipentahydrate.
[65]
It is common ground that pantoprazole magnesium
dihydrate incorporates two molecules of water for every molecule of
pantoprazole magnesium. The water is bound into the crystal lattice of the
compound. This results in a theoretical bound water content of 4.37% w/w. The experts also
agree that the characterization of pantoprazole magnesium dihydrate cannot be
confined to products with a precise water content of 4.37%. Rather, a range of
water content values would be expected, taking account of experimental error
including testing variables.
[66]
Dr. Myerson relied heavily on Mylan’s KF
data measuring the water content of its product. According to Dr. Myerson
the Certificates of Analysis produced by Mylan to the Minister for each of its
four batches of pantoprazole magnesium product exhibited water content
consistent with a dihydrate and not a hemipentahydrate. Those data consisted
of the following water content values:
|
|
Batch No.
|
March 2012
|
April 2013
|
|
(a)
|
25500700
|
[redacted]% w/w
|
[redacted]% w/w
|
|
(b)
|
25500701
|
[redacted]% w/w
|
[redacted]% w/w
|
|
(c)
|
25500769
|
[redacted]% w/w
|
[redacted]% w/w
|
|
(d)
|
25500771
|
[redacted]% w/w
|
[redacted]% w/w
|
[67]
Dr. Myerson acknowledged these data all
fell above the theoretical water content of pantoprazole magnesium dihydrate
and below the theoretical water content of the hemipentahydrate form. Nevertheless,
the April 2013 reported water values were closer to the theoretical value for a
dihydrate than a hemipentahydrate, leading Dr. Myerson to conclude the
Mylan product batches were dihydrates. This view, he said, was reinforced
because it was more common for KF to overestimate the water content of a
hydrated crystal form due to the presence of adventitious water. Nevertheless,
he also acknowledged that KF can sometimes underestimate the water content of a
sample when it has been over-dried.
[68]
It is acknowledged by the experts that KF has
inherent limitations as a means of precisely determining the bound water
content of a crystal sample. A particular confounding variable with the use of
KF is its inability to distinguish between adventitious (ie. free) water and
bound water in a test sample. KF measures all of the water in a sample but
only the bound water content is relevant to the characterization of its
hydration state. To isolate bound water content it is necessary to drive off
the adventitious water and to measure what is left behind.
[69]
Dr. Myerson acknowledged, to an extent, the
imprecision associated with the measurement of bound water in a crystalline
sample with KF. At paragraph 62(b)(iv) of his first affidavit, he recognized
the existence of experimental error and the problem of removing residual
adventitious water from a test sample. Although samples are usually pre-dried
to drive off adventitious water, the process may either be incomplete or
excessive resulting in KF measurements that are either “slightly
higher” or “slightly below” the
theoretical value for water content. According to Dr. Myerson, actual KF
measurements ranging from 4.3% to 4.8% are consistent with the theoretical
water content of pantoprazole magnesium dihydrate of 4.37%. It is on this
point that Drs. Cima and Atwood parted company with Dr. Myerson.
[70]
Dr. Atwood did not accept that KF on its
own was sufficient to characterize the hydration state of pantoprazole
magnesium. He made the point at paragraph 67 of his affidavit in the following
way:
67. In my opinion, water content
measurements of 4.3-4.8% alone, made via KF titration, would not inform the
skilled person that a dihydrate of pantoprazole magnesium had been obtained.
Further characterization would be required.
[71]
Dr. Cima put the issue in a slightly
different way. Although he agreed a dihydrate has one molecule of active compound
for every two molecules of water, “each particular
hydrate has a range of water composition that can be tolerated without change
in crystal structure” [see paras 30 and 124 of his affidavit].
[72]
Despite his reliance on Mylan’s KF data,
Dr. Myerson did express some reservation about using a single method to
characterize the hydration state of a crystal form in the following exchanges:
125 Q. What techniques are commonly
use [sic] to characterize crystalline form?
A. Well,
clearly there’s a whole series, but normally you would start with powder x-ray
diffraction, differential scanning calorimetry, thermographic metric analysis.
126 Q. That’s TGA, right?
A. TGA, right.
Yeah, I’ll call those DSC and TGA as we go on since I’ve given the names, okay.
127 Q. Very well. And when you referred
to powder x-ray diffraction, that’s also sometimes called XRPD, right?
A. Right
128 Q. Okay.
A. We also
routinely do Raman spectroscopy. Sometimes FTIR; that’s Fourier Transform
Infrared Spectroscopy. Occasionally solid-state NMR. Light microscopy,
polarized light microscopy is something we typically do.
That would be the
-- the most common suite of things that we do in my lab
129 Q. Okay. And generally would
those be the most common techniques beyond your lab, as well to characterize crystalline
forms?
A. Yes.
…
406 Q. You -- you’ve taught a
number of seminars, correct? Seminars about polymorphism, for example, or
crystallization?
A. I’ve been
teaching crystallization short courses for the last 25 years.
407 Q. Excellent. And you don’t
teach to your students that a magnesium content test is a good test to
determine the hydration state of a crystal form; do you?
A, For determining
the hydration state, I would normally tell them to do DSC, TGA, Karl Fischer
analyses; and when necessary, I’ve talked to them about doing elemental
analysis actually as a means of determining content.
[73]
Mylan’s product testing also included a water
content analysis performed under TGA, which produced a value of [redacted]%.
Dr. Myerson discounted this finding on the basis that it overestimated the
weight loss due to dehydration by “approximately
1%”. In the result, the loss of bound water “should
be no more than [redacted]% in terms of the mass
of hydrated water lost from the crystal” [see para 96 of his first
affidavit]. Dr. Myerson supported this assessment by examining the DSC
tracing produced by Mylan. From that tracing he identified the point of the
onset of dehydration at “approximately 110ºC”.
Using this approach he estimated the correct starting weight percentage at 99%
weight value resulting in an adjusted TGA value of [redacted]%. Under
cross-examination he agreed the figure could be as high as [redacted]% [see
p 4354].
[74]
Although Dr. Cima agreed with Dr. Myerson that
an allowance for the presence of adventitious water was appropriate, he
disagreed that it would be as high as 1%. Based on a cited documentary
reference, Dr. Cima concluded that an adjustment for adventitious water of up
to 0.5% would be appropriate. This reduced the reported TGA value to no less
than [redacted]% – a value consistent with the theoretical water content of a
hemipentahydrate. Dr. Cima also identified a particular concern about Dr.
Myerson’s working assumption that the loss of bound water in the Mylan sample
all occurred at a temperature of 110ºC or higher. This point is addressed at
paragraph 121 of his affidavit:
121. I disagree with Dr. Myerson when he
states at paragraph 96 of his Affidavit that the amount of bound water lost
from Mylan’s product is [redacted]%. Dr. Myerson incorrectly assumes that only
water lost at 110°C or higher is bound water. When a hydrate is heated, bound
water is lost as soon as the equilibrium vapor pressure of water is disrupted
by raising the temperature. Simply put, water is removed from the crystal
structure as soon as the temperature is increased (see my discussion above).
Lower temperatures, such as 50°C, are sufficient to remove bound water. For
example, one can create an experiment where all of the bound water in a
crystalline compound is removed by heating the compound to a mere 50°C for a
long enough period of time. In fact, a TGA may be run at a constant temperature
of 50°C, but conducting such a TGA would take much longer. The gradual increase
in temperature to over 200°C allows a TGA test to be conducted much more
quickly. Therefore, I disagree with Dr. Myerson’s conclusion that only water
lost from the Mylan Product at temperatures greater than 110°C is bound water.
[Footnotes omitted]
[75]
What these water content data indicate is a
range of water content for the Mylan batch samples falling between the
theoretical water content of the dihydrate and the hemipentahydrate. In some
cases, the values are closer to the hemipentahydrate form while others are
closer to the dihydrate form. Even Dr. Myerson obtained a TGA value falling
slightly above the range he had set for characterization of the dihydrate
form. In short, these results are, on their own, equivocal and insufficient to
support a finding that the Mylan product is a dihydrate.
[76]
There are some additional difficulties
associated with Dr. Myerson’s reliance on these water content data.
[77]
Dr. Myerson did not specifically address Mylan’s
2012 KF values for the same batches which, in three of the four cases, were
closer to the theoretical water content of a hemipentahydrate and, in the
fourth case, was effectively equidistant. This evidence did not, however,
affect Dr. Myerson’s opinion. At paragraph 90 of his affidavit, he
stated:
90. I note that the modestly higher
water contents determined during the original analysis of Mylan’s four
pantoprazole magnesium batches are all still well below the theoretical water
content of pantoprazole magnesium hemipentahydrate. In my view, these earlier
water content measurements also support my conclusion that the four batches
were pantoprazole magnesium dihydrate.
In my view this type of analysis is largely
unhelpful. If the data on their face do not support the opinion being
advanced, it is not good enough to fall back on generalizations. The 2012 KF
values may have been “modestly higher” than the
2013 results but the fact remains they were, in three of four cases, closer to
the theoretical value of a hemipentahydrate than a dihydrate and, therefore, cannot
be dismissed as readily as Dr. Myerson suggests.
[78]
Dr. Myerson also failed to explain the
water content disparities between 2012 and 2013 where for each batch, the KF
values fell. In contrast, Dr. Cima explained why KF analysis can produce
inaccurate results:
129. In these circumstances, I rely on
Mylan’s TGA results in preference to Mylan’s KF results because TGA is
generally more reliable than KF. There are several reasons why a KF may produce
an erroneous water content reading, and relatively fewer reasons why a TGA
might do so. For example, a KF test will be inaccurate if the compound is not
completely dissolved during the test. In that case, not all of the water in the
sample would be available and this problem would cause a KF test to underestimate
a sample’s water content.
130. KF is also susceptible to other
errors. For example, the KF will produce erroneous water content readings if
there is contamination, or if the reagents were made incorrectly, are too old
or were loaded incorrectly. It is also known that many KF apparatuses are most
reliable when used with material containing only a small percentage of water or
when measuring a small amount of water, in absolute terms, from a sample. Based
on the foregoing and given the inconsistency between Mylan’s TGA and KF, I do
not put stock in Mylan’s KF results.
[Footnotes omitted]
Also see the affidavit of Dr. Atwood at
paragraphs 119, 129-130.
[79]
It seems to me that there is considerable
imprecision associated with the measurement of the bound water content of
pseudopolymorphs under both KF and TGA analysis. The results are partly
dependant on one’s ability to accurately detect when adventitious water in a
test sample has been completely removed and when dehydration of the crystal
bound water begins. I accept Dr. Cima’s evidence that there is no sharp
point of demarcation and the loss of adventitious and bound water can overlap
to some extent, thus making the required extrapolation more difficult.
[80]
In addition there are other experimental
variables which can affect the values obtained by KF and TGA analysis. Things
like the failure to fully dissolve the tested compound may result in the
under-reporting of water content by KF as noted above.
[81]
I am not satisfied on the record before me that
the KF and TGA data reported by Mylan support Dr. Myerson’s opinion that
the Mylan pantoprazole magnesium product is a dihydrate. The test results are
equivocal and, to some extent, inconsistent. They are also subject to a degree
of error and interpretive uncertainty. Even Dr. Myerson acknowledged
additional tests to KF and TGA would typically be required to fully
characterize the hydration state of a crystal form.
[82]
Dr. Myerson summarily dismissed the
relevance of Mylan’s melting point analysis, stating it is unhelpful to the
determination of a compound’s hydration state [see para 100 of his first
affidavit]. That point, in isolation, is undoubtedly correct but in this
situation it fails to deal with the melting point data set out in the 031 Patent.
[83]
At paragraph 107 of his affidavit Dr. Atwood
points out the Mylan product was shown to have a melting point of [redacted]ºC
as compared to the products in the 031 Patent which had reported melting
points between 194-198ºC. According to Dr. Atwood, this differential was
sufficient to show the compounds were different.
[84]
Under cross-examination, Dr. Myerson said
hydrates “don’t have melting points”. Instead
they only have “dehydration temperatures” or “decomposition points”. According to Dr. Myerson
the description of melting points in the 031 Patent and the Mylan
disclosure represented sloppy nomenclature. Nevertheless, he used the same
term in paragraph 100 of his first affidavit.
[85]
Dr. Myerson’s attempt to discount the
relevance of this data on highly technical grounds is not convincing.
[86]
The 031 Patent characterized the obtained
compounds with melting points in a range between 194ºC and 198ºC. These data
were obtained with DSC analysis and were apparently thought by the inventors to
be material to the characterization of their invented compounds. Mylan’s DSC
results disclosed a melting point of [redacted]ºC. I accept this difference
does not disclose the hydration state of the tested compounds but it does
indicate the Mylan compound is different from the compounds exemplified by the
031 Patent. Even Dr. Myerson seems to have acknowledged the
potential significance of this evidence in the following exchange under
cross-examination:
253 Q. The melting points that
are reported in the example of the 031 patent are within 1 to 2 degrees?
A. I believe
-- I don’t recall.
254 Q. Let’s take a look at it.
A. 90 – if we
look at page3 --
255 Q. That’s right.
A. -- in the
example, melting point, 194 to 196 was decomposition.
256 Q. Okay. That’s one.
A. So
they’re seeing the decomposition point.
257 Q. Look in Table 1, the
melting points reported, 196 to 197; that’s within 2 degrees?
A. Oh, yes,
so we have 196 to 197, 196 to 197, 197 to 198, and 195 to 196.
258 Q. Right. So these are all within
2 degrees; 2 degrees are reported for each one of these points?
A. That’s
correct.
259 Q. And those would be sharp points?
A. Yeah,
they’re sharp points. It’s not surprising because they’re decomposition points.
260 Q. If you have two samples
of the same substance and each sample has a different melting point, those two
samples must be different forms, correct?
A. Two
samples of the same substance, if you put in the caveat that they have the same
purity --
261 Q. Yes.
A. --and the
same level of crystallinity, meaning that they’re both highly crystalline --
262 Q. Yes.
A. -- if you
have different melting points, they should be different forms, that’s correct.
263 Q. They must be different
forms, right?
A. That’s
right.
264 Q. You agree that different polymorphs
have different melting points, correct?
A. Yes.
265 Q. You agree that melting
points are used to characterize crystal forms of compounds as well as to
indicate the chemical purity of these materials?
A. Correct.
266 Q. You agree that relatively
pure solids generally have melting points within a range of approximately 1
degree when measured?
A. Correct.
267 Q. You agree that different polymorphs
will have different melting points?
A. Yes.
268 Q. You agree that a melting
point range of 1 degree Celsius is considered a relatively sharp melting point
and would generally indicate a pure crystalline phase?
A. Yes.
269 Q. You testified in the efavirenz
case that a difference of 7 to 9 degrees in melting points was a substantial
difference; do you remember that?
A. Yes.
270 Q. And that was true?
A. Yes.
[87]
I accordingly reject Dr. Myerson’s
affidavit evidence that the melting point data were of no probative value in characterizing
the Mylan product.
[88]
A significant piece of evidence relied upon by
Mylan to characterize its product as a hemipentahydrate arises from a
comparative analysis of XRPD data. The XRPD pattern obtained by Mylan for its
product matches the XRPD pattern reported in US 623 for [redacted----------]
was characterized by the US 623 inventors as pantoprazole magnesium
hemipentahydrate. As well, the XRPD pattern reported in US 623 for two dihydrate
forms did not match the pattern for the Mylan product. Mylan uses [redacted------]
as the reference standard for characterizing its product [see Application
Record at p 2725].
[89]
Relying on the correctness of the XRPD data
reported in US 623, both Drs. Cima and Atwood concluded the Mylan
product was a hemipentahydrate. Dr. Myerson also acknowledged where a
crystalline form has been previously and unambiguously characterized by XRPD,
the resulting pattern can be used as the sole means of subsequently verifying
that form [see p 4327]. Dr. Myerson did not carry out a comparative
analysis of the XRPD data and, in the result, the evidence of Drs. Cima
and Atwood was left unchallenged.
[90]
Takeda’s only answer to this evidence is to
attempt to block its introduction as inadmissible hearsay. I have no doubt
this evidence is hearsay. Clearly Drs. Cima and Atwood based their
opinions on the correctness of the characterization of [redacted] as a
hemipentahydrate in US 623. If [redacted] was not a hemipentahydrate, as
the inventors reported, those opinions are unsupported.
[91]
Despite Mylan’s argument, I do not believe this
evidence falls clearly within one of the previously recognized exceptions to
the hearsay rule. In particular, there is no evidence before me to show that
the admission of this evidence was justified on the basis of its necessity.
That said, the opinions expressed by expert witnesses in patent litigation
frequently rest on their acceptance of the accuracy of hearsay references
concerning scientific issues or for the interpretation of prior art. In some cases,
this is justified on the ground that experts in a particular field are
permitted to rely on the accuracy of widely accepted and publicly reported
data.
[92]
Given the summary nature of NOC proceedings, I
am of the view that some latitude should be extended to the reliance by expert
witnesses upon hearsay contained within authenticated and facially reliable
scientific references. The contents of US 623 were disclosed in Mylan’s NOA
and its expert witnesses relied on the reported findings in support of their
own analysis. Where such a reference contains sufficient information to allow
the opposite party to replicate the work and assess the accuracy of the
reported data, that party suffers no material prejudice by the admission of
hearsay in support of an expert’s opinion. It was open to Takeda to run the
same tests reported in US 623 and to fully characterize the resulting
compounds. Despite the significance of this evidence, Takeda chose not to make
that effort.
[93]
This evidence, of course, strongly supports
Mylan’s representation to the Minister and to the Court that Mylan makes
pantoprazole magnesium hemipentahydrate.
[94]
Takeda also argues that it was unable to
replicate Mylan’s manufacturing process and it was not provided with a sample of
the Mylan product. This left it without the means of independently
characterizing the Mylan product – a disadvantage, it says, supports the
drawing of an adverse inference against Mylan.
[95]
Dr. Myerson reviewed the Mylan process
parameters and concluded “that it cannot be replicated
based solely on the information found in the Mylan Disclosure” [see
para 2 of his first affidavit]. A particular concern identified by
Dr. Myerson was the absence of information about [redacted-----------------------].
[96]
Whether or not Takeda had the ability to
faithfully replicate the Mylan process or to obtain Mylan’s exact seed material
is not a complete answer to its ability to conduct relevant testing.
[97]
Takeda was advised by counsel for Mylan in a
formal response to requests for production that Mylan’s product produces an
XRPD pattern comparable to the XRPD pattern disclosed for [redacted] in US 623.
Counsel’s letter provided Takeda with the following information:
In Tab 48, the Certificate of Analysis for
the Reference Standard indicates that the X-ray diffraction pattern “should be
comparable with pantoprazole magnesium hemipentahydrate”. We have been informed
by Mylan that the reference standard referred to in this document is the
crystalline [redacted] exemplified in Figure [redacted] of U.S. Patent Application
2008/0139623 Al. We attach a copy of US 2008/0139623 Al for your
convenience.
Takeda contends this is improper hearsay
[see para 60 of Takeda’s Memorandum of Fact and Law]. I do not understand
this argument. When counsel, in fulfillment of a party’s disclosure
obligation, makes a representation, it is binding on the client. It would not
have been open to Mylan to later disavow counsel’s representation in the face
of an attempt by Takeda to rely upon it.
[98]
Mylan represented to the Minister that its
product corresponds to a reference standard. Mylan told Takeda the reference
standard it uses for XRPD comparison is that disclosed in US 623 as [redacted].
[99]
It was thus open to Takeda to reproduce the US 623
process for making [redacted] and to fully characterize the obtained compound.
If that characterization identified the compound as a dihydrate, and if its
XRPD pattern corresponded to that for Mylan’s product, a strong case for
infringement would presumably be made out.
[100] On the question of Takeda’s ability to carry out relevant testing
seeking to corroborate Dr. Myerson’s opinion, I prefer the evidence at
paragraphs 140-144 of Dr. Atwood’s affidavit:
140. I disagree with the statement by
Dr. Myerson at paragraphs 113 to 118 of his affidavit that the Mylan
process could not be replicated without the seed material.
141. Page 20 of the document at Tab 153
of Exhibit C to the Burkhardt Affidavit states, “Pantoprazole Magnesium
Hemipentahydrate seed material is the approved batch of Pantoprazole Magnesium
Hemipentahydrate meeting the specifications”.
142. [redacted---------] US 623 provides
a method to make 100% chemically pure pantoprazole magnesium [redacted] which
is a hemipentahydrate and the comparator form for the Mylan-Pantoprazole-T
hemipentahydrate, as explained in Exhibit I to the Burkhardt Affidavit. [redacted]
does not require the use of a seed.
143. Had Dr. Myerson actually wanted to
perform the Mylan process, he could have made a seed according to the process
of [redacted-] of US 623 and then followed the process detailed at Tab 152 of
Exhibit C to the Burkhardt Affidavit.
144. The disclosure of the Mylan
process, together with the disclosure of the process in US 623 (which should
have alerted Dr. Myerson that pantoprazole magnesium hemipentahydrate
could be made with [redacted-------------------------------], shows that Dr.
Myerson’s could and should have been able to replicate Mylan’s process and
tested the product to determine it produced a hemipentahydrate.
Also see paragraph 138 of Dr. Cima’s
affidavit.
[101] I also do not accept Dr. Myerson’s evidence that the absence of
information in the Mylan disclosure about [redacted--------------] rendered him
incapable of replicating the Mylan process. Both Drs. Cima and Atwood
noted the capacity of these compounds to [redacted--------------------------------].
US 623 also disclosed experimental methods for making hydrous forms of
pantoprazole magnesium where the [redacted----------------------------------------------].
Although Dr. Cima acknowledged it is unusual to rely on [redacted---------------------------------------],
the Mylan batch sizes were, according to him, [redacted-------------------------------------------------------------------].
[102] Against this background it was not enough for Dr. Myerson to
predict failure without an attempt being made. If the process would not work,
he was capable of showing that to be the case.
[103] In the face of Takeda’s failure to take reasonable steps to
independently verify Dr. Myerson’ s opinions, I am not prepared to draw an
adverse inference against Mylan.
[104] In conclusion, Takeda has not met its burden of establishing that
the Mylan product infringes the 031 Patent and this application is
dismissed with costs payable to Mylan at the mid-point of Column IV.
X.
Post-Script
[105] As with many NOC proceedings, this one produced several evidentiary
gaps. Indeed, it is disconcerting that the parties to NOC proceedings often
fail to test in a meaningful way the reliability of the opinions expressed by
opposing expert witnesses. Instead the parties fall back on the largely
unchallenged opinions of their own experts. In the result, the Court does not
obtain the benefit of effective cross-examination on material issues of
scientific disagreement or it is left to wonder on the validity of
methodological criticism about otherwise unchallenged test data.
[106] This proceeding is a good example of that tendency. On some of the
central issues of scientific disagreement among the three experts, no
significant cross-examinations were conducted. This was particularly evident in
Dr. Myerson’s criticisms of Dr. Atwood’s testing methods.
Dr. Myerson identified certain theoretical weaknesses in Dr. Atwood’s
approach but Dr. Myerson was not directed to conduct his own testing using
his preferred method to determine if different data emerged. Furthermore,
Dr. Atwood was not cross-examined about Dr. Myerson’s criticisms,
presumably out of a concern that otherwise unavailable reply evidence could
thereby enter the record. It is perhaps noteworthy that in one of the Prothonotary’s
Orders in this proceeding, a motion to file Reply evidence was refused partly
in the expectation that the evidence would likely emerge under
cross-examination.
[107] By their very nature, NOC proceedings allow for the possibility of
evidentiary gaps. Reply evidence is often not permitted and product samples and
other relevant evidence not contained within an ANDS filing is usually not
discoverable. In this context, it does not assist the Court in getting to a
just and accurate result by failing to effectively join issue on the
conflicting opinion evidence which does enter the record.
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