Docket:
T-278-12
Citation: 2014 FC 30
Ottawa, Ontario, January 13, 2014
PRESENT: The Honourable Mr. Justice Barnes
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BETWEEN:
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BRISTOL-MYERS SQUIBB &
GILEAD SCIENCES, LLC AND
MERCK SHARP & DOHME CORP.
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Applicants
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and
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TEVA CANADA LIMITED AND
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THE MINISTER OF HEALTH
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Respondents
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PUBLIC REASONS FOR JUDGMENT AND JUDGMENT
[1]
This is an application by Bristol-Myers Squibb
& Gilead Sciences, LLC and Merck Sharp & Dohme Corp. seeking an order
under the Patented Medicines (Notice of Compliance) Regulations,
SOR/93-133 as amended (PMNOC regulations) prohibiting the Minister of Health
(Minister) from issuing a Notice of Compliance (NOC) to Teva Canada Limited
(Teva) for a generic version of the Applicants’ combination anti-retroviral
medicine marketed under the brand Atripla. The Applicants seek relief until
the expiry of Canadian Letters Patent 2,279,198 (198 Patent) which expires
on February 2, 2018.
[2]
Merck is the owner of the 198 Patent and
BMS and Gilead hold a joint venture license from Merck. Any reference
hereafter to Merck will, unless otherwise indicated, include all of the
Applicants.
[3]
Teva served a Notice of Allegation (NOA) on December
22, 2011 asserting, inter alia, that the 198 Patent was invalid on
numerous grounds including obviousness and anticipation. Teva also asserted
that its proposed product will not infringe any of the claims of the
198 Patent.
[4]
In the Notice of Application herein Merck relies
only on Claims 1, 2 and 3 of 198 Patent. Merck maintains that those
claims are valid and that the Teva product will infringe.
[5]
This is the second proceeding that the Court has
heard under the PMNOC regulations concerning the 198 Patent. In Bristol-Myers
Squibb Canada Co. v Mylan Pharmaceuticals ULC, 2012 FC 1142, [2012] FCJ No
1251, the validity of the 198 Patent was upheld. Nevertheless, Mylan
successfully defended the application on the ground that the Applicants had
failed to establish an infringement. It is unnecessary on this occasion to
repeat all of the background scientific points that were covered in those
earlier reasons. Those matters are not the subject of controversy in this
proceeding.
[6]
A voluminous evidentiary record was developed by
the parties in connection with the validity of the 198 Patent compound
claims. Through no fault of the parties the Court has been left with a
relatively brief period of time to comprehensively resolve all of the issues
they have argued. Because the infringement issue is determinative, it is unnecessary
and probably unwise to attempt to resolve the validity issues. I will say,
however, that Teva presented a stronger case for invalidity on the ground of
obviousness than was before me in the Mylan proceeding.
[7]
The infringement issue in this proceeding concerns
the likelihood that Teva’s tablets will contain some amount of the compound
claimed by the 198 Patent (ie. Form I efavirenz). It is common ground
that Teva’s starting medicinal compound (hereafter “Form Teva”) does not
contain Form I efavirenz. The question in dispute is whether Form Teva will convert
in some measure to Form I during Teva’s tablet manufacturing process.
[8]
In order to avoid the potential for conversion,
drug manufacturers usually prefer to use the most stable crystal form of a
medicinal compound – provided, of course, that it fulfils the manufacturers’
efficacy criteria. Faced with a patent on the most stable crystal form,
generic manufacturers will sometimes use a less stable or metastable crystal
form for the active medicinal compound and thereby attempt to avoid an
infringement.
[9]
Form I is the most stable crystal form of
efavirenz and it is the subject of Claims 1, 2 and 3 of the 198 Patent.
It is undisputed that, with the input of sufficient energy, all metastable
crystal forms of efavirenz, including Form Teva, will convert to Form I.
[10]
Teva’s NOA asserts that Form Teva will not
contain Form I and, therefore, will not infringe. The NOA acknowledgements
that less stable crystal forms will “often” convert to a more stable crystal
form, that Form I is the most stable crystal form of efavirenz and that “all
other forms convert to Form I on heating” do not detract from Teva’s fundamental
assertion that, under the prevailing manufacturing and storage conditions, its
product will not convert to Form I.
Issues
[11]
Has Merck met its burden of proving that Teva’s
product will, in all probability, contain Form I efavirenz?
Analysis
[12]
For the purposes of this decision, I adopt the
legal principles set out in the Reasons for Judgment issued in Bristol-Myers
Squibb Canada Co. v Mylan Pharmaceuticals ULC, above, and will not repeat
them here.
[13]
Merck led expert evidence from
Dr. Allan Myerson in support of its case for infringement.
Dr. Myerson, in turn, relied upon testing carried out by
Dr. Mark Taylor at the University of Toronto. Dr. Taylor made a
small quantity of Form Teva and, under the instructions of Dr. Myerson,
subjected the undiluted samples to a series of tests to determine if any
conversion to Form I could be observed. Dr. Myerson interpreted
Dr. Taylor’s data and concluded that Form I was present in some of the
test samples.
[14]
Teva responded to Merck’s opinion evidence with
that of Dr. Harry Brittain. Dr. Brittain, in turn, relied, in
part, on testing carried out by Dr. James Britten at McMaster University. Dr. Britten’s testing partially replicated Dr. Taylor’s
work but differed in two aspects: he used samples of Form Teva mixed with
Teva’s excipients and he did not apply heat. Dr. Brittain concluded that
Teva’s manufacturing process would not convert Form Teva to Form I.
[15]
All of the witnesses were well-qualified to
speak to the issues bearing on infringement. The determinative issue did not,
however, turn on a point of profound intellectual or scientific judgment but
rather on a difference of opinion between Dr. Myerson and
Dr. Brittain as to the comparative validity of Merck’s testing to Teva’s
manufacturing process.
Claims Construction
[16]
I agree with Teva that the 198 Patent is
primarily directed at a process for crystallizing efavirenz to make Form I.
Efavirenz is identified as a known reverse transcriptase inhibitor. The
problem said to be overcome by the Patent was the absence of a reliable method
to make Form I. This is described at page 11 in the following way:
This
crystallization process is advantageous over the prior method. The instant
method allows one to isolate a crystalline product with consistent physical
properties namely the ability to produce the desired crystal form of the
product or convert to Form I with mild drying conditions (heating to about 40
to 60°C). The alcohol-water crystallizations have also been shown to reject
some impurities carried forward from the chemical synthesis. The final product
slurry is less viscous and more homogenous with the instant process and is thus
easier to mix and handle.
Claims 1, 2 and 3
of the 198 Patent also claim the compound Form I efavirenz as defined by
its disclosed XRPD patterns. Even though the 198 Patent specification is
almost entirely devoted to process descriptions, there is nothing inherently
objectionable about including claims for a novel compound or compound form produced
by the patented process provided that those claims are not otherwise invalid.
The inventive promise for Form I efavirenz made by the claimed process is the
production of “the desired crystal form” of efavirenz which is said to have
“consistent physical properties”. It seems to me that the promise of the
198 Patent as read by the skilled reader is only that the Form I crystal is
useful. No promise is made that the form is better than any other solid form
of efavirenz. Nevertheless, the claims to Form I efavirenz are more than the
simple characterization of Form I by XRPD analysis. As I held in Bristol-Myers
Squibb Canada Co. v Mylan Pharmaceuticals ULC, above, Claims 1 and 2 would
be infringed if any detectable amount of Form I is found in Teva’s efavirenz
product. It does not matter that the amount may be so small that it provides
no medicinal advantage.
[17]
One other construction issue arises from the
evidence. Teva’s experts maintain that the person of skill would find an
admission in the 198 Patent that Form I efavirenz was publically known.
The passages they relied upon for this ostensible admission are the following:
The
synthesis of the reverse transcriptase inhibitor (RTI), (-)-6-chloro-4-cyc1opropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,l-benzoxazin-2-one,
also known as DMP-266 has been described in US Patent 5,519,021 issued on May
21, 1996 and the corresponding PCT International Patent Application WO 95/20389,
which published on August 3, 1995. Additionally, the asymmetric synthesis of an
enantiomeric benzoxazinone by a highly enantioselective acetylide addition and
cyclization sequence has been described by Thompson, et al., Tetrahedron
Letters 1995, 36, 937-940, as well as the PCT publication, WO 96/37457, which
published on November 28, 1996.
The
compound was previously crystallized from a heptane-tetrahydrofuran (THF)
solvent system. The crystallization procedure required the use of high temperatures
(about 90°C) to dissolve the final product. Crystals formed by nucleation
during the cooling process. The crystals which were produced were Form II. and
are converted to the desired Form I while drying under vacuum at 90°C. This
crystallization provided minimal purification and produced material with
inconsistent physical properties. The final product slurry was extremely
difficult to mix and handle due to its high viscosity and heterogeneous nature.
[See the Applicant’s
Record at p 16]
[18]
Despite the absence of any prior art references
expressly disclosing Form I efavirenz the above acknowledgement that Form I
“was previously crystallized” is said by the Teva witnesses to be an admission
by Merck of public disclosure.
[19]
I do not agree that the person of skill would
infer a public disclosure from the bare statement that Form I had been
previously crystallized. The fact that something has been done says nothing
about its notoriety. It is also inconceivable to me that any fair-minded
reader of the 198 Patent would interpret the specification in a way that
would immediately invalidate all of its compound claims.
Infringement
[20]
It is agreed by the parties that Form Teva is a
different crystal form of efavirenz than Form I. Accordingly there will
be no proven infringement of any of Claims 1, 2 or 3 of the 198 Patent
unless Merck can establish on a balance of probabilities that Form Teva
converts to detectible levels of Form I during or after the manufacturing
process. The mere possibility of infringement is insufficient: see Novopharm
Ltd v Pfizer Canada Inc, 2005 FCA 270 at para 24, [2005] FCJ No 1318.
[21]
The same issue was before me in the Bristol-Myers
Squibb Canada Co. v Mylan Pharmaceuticals ULC, above. In that case Merck relied
upon an ostensible admission in Mylan’s NOA that all known crystal forms of
efavirenz will convert to Form I under mild drying conditions. In reliance on
what it took to be an admission by Mylan, Merck called no evidence to
establish actual conversion. After finding that Mylan’s NOA did not admit that
its crystal efavirenz product would convert to Form I, I was left with no
evidence from Merck to establish its infringement allegation. In the result, I
held that Merck had not met its burden.
[22]
In holding against Merck on its argument
that an adverse inference ought to be drawn from Mylan’s failure to either
produce its tablets for testing or to conduct its own testing, I made the
following points:
128 A problem for
BMS is that Mylan refused its request for detailed information about its
manufacturing processes and provided no information about the final composition
of its efavirenz tablet. Mylan also refused to turn over a sample of the final
product to allow BMS to conduct its own testing. BMS says that Mylan held all
of the evidentiary cards and that an adverse inference ought to be drawn from
its failure to disclose that evidence.
129 There is no
doubt that Mylan could have put that issue squarely to rest by producing the
information requested by BMS or by producing reliable data from its own testing
of the product if any was done. Instead, Mylan asked Dr. Cima to opine about
this infringement issue on the strength of his general knowledge of the science
of crystallization and the typical manufacturing processes that would be
expected for the production of such a tablet. Mylan very deliberately failed to
inform Dr. Cima about the details of the process it uses to produce its
efavirenz tablet. I agree with BMS that it would have been a relatively simple
exercise for Dr. Cima to have tested Mylan's efavirenz tablet to determine if
Form I was present, but Mylan avoided that option as well.
130 The essential
problem with BMS's position is that it, too, could have done much more to
establish the likelihood of conversion. Mylan did not hold all of the
evidentiary cards on this critical issue of infringement.
131 Dr. Myerson
admitted that he had the ability and knowledge to make Form [omitted]: see
Cross-Examination of Dr. Myerson at p 172.). He also had the ability to subject
Form [omitted] to a set of conditions that would mimic a typical wet
granulation drying process. I have no doubt that had Dr. Myerson conducted an
experiment of this sort and established some level of conversion, BMS would
have met its burden of proof - provided that Mylan was unable to contradict it.
[23]
There is similarly no basis for drawing an
adverse inference in this case. Although Teva refused to turn over samples of
Form Teva or its final efavirenz tablets to Merck, Teva acknowledged that Form
Teva could be made using a process disclosed in another patent application. In
the result, Merck was able to make the compound for testing purposes. Teva
also undertook that it would not assert that the sample obtained and tested by Merck
was different in character or composition to Form Teva.
[24]
I am satisfied that Merck had the capacity to
scale up the process and to make a sufficient amount of Form Teva to permit a close,
if not exact, replication of Teva’s manufacturing process. Instead
Merck chose to make a small sample of Form Teva that only allowed it to conduct
small scale testing presumably intended to mimic Teva’s manufacturing process.
The primary dispute among the experts is, then, whether the Merck testing
methods are a reliable proxy for what actually happens during Teva’s
manufacturing process. Another issue is whether any conversion of Form Teva
to Form I actually occurred during that testing.
The Conversion Experiments
[25]
The Merck case for conversion is based on a series
of tests conducted by Dr. Taylor and interpreted by Dr. Myerson.
Because Merck did not have access to the Teva tablets it was required to create
the compound in accordance with a disclosed process. Merck had Dr. Taylor
synthesize a small quantity of Form Teva which was then subjected to three
discrete tests, specifically:
(a) heating
Form Teva at [omitted] for 1, 2, 3 and 4 weeks;
(b) grinding
Form Teva with mortar and pestle for approximately [omitted];
(c) grinding Form Teva with mortar and pestle for approximately
[omitted] followed by hearing at [omitted] for 1, 2, 3 and 4 weeks.
Each of the
processed samples was then subjected to an XRPD analysis to determine the
presence, if any, of Form I efavirenz.
[26]
In addition, Dr. Taylor was asked to synthesize
a quantity of Form I by exposing Form Teva to heat at [omitted] for 3.5 and 5.5
days. With this sample, an XRPD analysis of different mixed quantities of Form
Teva and Form I was carried out. From this Dr. Myerson was able to plot
the intensity ratio versus the ratio by mass of Form I to Form Teva in a given
mixture. This, in turn, allowed Dr. Myerson to estimate the percentage of
Form I relative to Form Teva in a mixture where the relative weights are not
known (see the Myerson Affidavit at para 120, Applicant’s Record at p 1336).
[27]
Of the three tests carried out by
Dr. Taylor only the Form Teva samples that were subjected to grinding
followed by heating at [omitted] for several days arguably revealed any Form I.
Dr. Myerson asserts at paragraph 127 of his affidavit that XRPD analysis
of the Form Teva sample exposed only to mortar and pestle grinding “indicates
to me the presence of a very small quantity of Form I efavirenz”. This is an
unjustified view. I do not accept that the modest and broad XRPD “peak” or
“bump” seen in Exhibit K to Dr. Myerson’s affidavit is sufficient, on its
own, to prove the presence of Form I. Dr. Myerson conceded that reliance
on a single XRPD peak would typically be unsound unless it was one of large
intensity that did not overlap with that of another compound. Dr. Myerson
also acknowledged that the peak observed at the approximate 6.08 position obtained
by Dr. Taylor fell within the margin of error for overlap between Forms I
and II efavirenz but he refused to fully retreat from the position adopted in
his affidavit (see Applicant’s Record at pp 5472-5474).
[28]
On this point I prefer the evidence of
Dr. Brittain who testified that it is the pattern of XRPD peaks that
constitutes a fingerprint for a particular crystal structure. According to
Dr. Brittain an accurate XRPD identification usually requires an
observation of the ten most intense peaks and should not be made on the
strength of a single peak (see the Brittain affidavit at paras 33-40,
Applicant’s Record at pp 3141-3144 and Brittain testimony, Applicant’s Record
at pp 5961-5962 and p 6028).
[29]
Although a small amount of Form I may have been
present in these samples, the evidence of its presence was inconclusive at
best. It seems to me that the conclusion offered at paragraph 127 of
Dr. Myerson’s affidavit and his attempted defence of that position under
cross-examination detracts from his overall credibility.
[30]
Dr. Taylor also exposed Form Teva to
heating at [omitted] for periods of time between 7 to 27 days. These samples,
however, had not been subjected to mortar and pestle grinding.
Dr. Myerson concedes at paragraph 140 of his affidavit that no measurable
Form I could be detected from these heated samples – a finding that he said was
consistent with Teva’s accelerating aging studies of Form Teva (see paragraph 141,
Applicant’s Record at p 1339). Nevertheless, Dr. Myerson makes the
statement that these results offer evidence of “significantly slower”
conversion than samples exposed to grinding (see paragraph 140,
Applicant’s Record at p 1339). Not surprisingly Dr. Brittain challenged
this statement in his affidavit:
43. Dr. Taylor
also subjected the efavirenz Form [Teva] samples to heating at [omitted] for
varying periods up to 28 days. The samples were not subjected to grinding. I
have reviewed XRPD patterns at Exhibits “32” to “43” of the Taylor
Affidavit, which represent heating at [omitted] for 7 to 27 days, and I do not
see evidence for any conversion to Form I. I note that Dr. Myerson comes to a
similar conclusion at paragraph 140 of his affidavit, although I disagree
with his characterization that conversion to Form I is “significantly slower”
absent grinding. Rather, there is simply no evidence of any conversion to Form
I. These results, coupled with the grinding-plus-heating experiments discussed
below, demonstrate that grinding of pure drug substance was required to induce
any conversion of Form [Teva] to Form I.
[Emphasis added]
[Applicant’s Record at p 3145]
[31]
I agree with the above criticism. Dr. Myerson’s
attempt to interpret a null finding as evidence supporting his theory of
conversion is disingenuous and it undermines his credibility. The inference
that an objective person would draw from Dr. Taylor’s heating experiments
is that lengthy exposure of Form Teva to the maximum temperature used by Teva [omitted]
causes no conversion to Form I efavirenz.
[32]
Dr. Taylor also exposed Form Teva to
heating at [omitted] for several days and observed a conversion to Form I.
This outcome is of no relevance to the conversion issue because Teva’s
manufacturing process does not employ temperatures that high nor does it
require prolonged heating. It is not a matter in dispute that Form Teva is
less stable than Form I and it will convert if enough heat is applied and the Merck
witnesses do not seemingly rely on this result to establish an infringement.
[33]
In response to Dr. Taylor’s tests, Dr. Britten
was asked by Teva to subject a sample of Form Teva and Teva’s excipients
to mortar and pestle grinding followed by an XRPD analysis. Presumably this
approach was designed to illustrate the importance of the excipients to the
potential for conversion. Dr. Britten used a highly sensitive XRPD scan
which could detect the presence of Form I at levels “better than 1 percent”
(see Applicant’s Record at p 6109). Perhaps not surprisingly, no Form I was
detected. Dr. Britten, however, did not attempt to otherwise replicate
Dr. Taylor’s work. Dr. Taylor exposed his ground samples to
prolonged heating with a view to incubating any Form I “seeds” that were
present. It was only through heating that detectible levels of Form I were ultimately
found in Dr. Taylor’s samples. Dr. Britten did not heat his samples
and it was only possible for him to assert that after grinding no amount of
Form I was detectable under XRPD analysis.
[34]
Given that the sensitivity of Dr. Britten’s
XRPD analysis was only in the vicinity of 1%, these results do not contradict
what Dr. Taylor and Dr. Myerson observed. According to
Dr. Myerson’s analysis, Dr. Taylor’s Form Teva ground samples
contained undetectable levels of Form I that only grew to detectable levels
after lengthy incubation. It is not possible to say that similar results would
not have been obtained had Dr. Britten heated his samples in the same
way. Because Dr. Britten failed to match Dr. Taylor’s approach, the
results Dr. Britten obtained do not clearly establish the significance of
the excipient load to the potential for some conversion of Form Teva to
Form I from grinding.
[35]
I am satisfied that some small amount of Form I
was present in Dr. Taylor’s samples after grinding because Form I was
clearly detected after those samples were heated for several days at [omitted].
This conclusion is not seriously challenged by the Teva witnesses (see the
Brittain affidavit at para 43, Applicant’s Record at p 3145). The significance
of grinding to the conversion of Form Teva is the most plausible explanation
for the absence of Form I when Form Teva was simply heated for several days at [omitted].
It was only through the grinding of Form Teva that sufficient energy was
introduced to start a conversion to Form I. Once the samples were seeded with
Form I the application of heat then enhanced the conversion and produced
observable data.
[36]
Dr. Myerson estimated the amount of Form I
that would be present in Teva’s tablets by applying a regression analysis to
the data that emerged from prolonged heating of Dr. Taylor’s ground
samples. According to Dr. Myerson the estimated amount of Form I present in
those samples and ostensibly in Teva’s tablets was in the range of 0.022% and
0.046%. These amounts are, of course, too small to be directly detected by
XRPD analysis and are predicted only by ex post facto extrapolation.
[37]
All of these experimental results illustrate the
importance of the manual grinding exercise to the conversion findings made by
Dr. Myerson. In the absence of grinding or prolonged exposure to
temperatures exceeding those used by Teva, Form Teva did not convert.
Conversion By Grinding Form Teva
[38]
The central issue in dispute between the parties
is whether the mortar and pestle grinding carried out in Dr. Taylor’s
laboratory is a reliable proxy for the [omitted] that Teva employs in its
manufacturing process. The specific issue is whether Teva’s process includes
the application of sufficient energy to incite a conversion of Form Teva to
Form I.
[39]
Although Dr. Brittain acknowledged under
cross-examination that [omitted] are all capable of causing a phase
transformation of a metastable crystal form, he did not concede “that all those
processes do the same thing for all compounds” (see the Brittain testimony at p
75, Applicant’s Record at p 5975). This is consistent with the evidence of all
of the witnesses that the introduction of energy by thermal, mechanical or
chemical means may initiate a transformation reaction. According to
Dr. Brittain, the issue remains whether the amount of introduced energy is
sufficient to overcome the “activation energy barrier”.
[40]
Teva’s manufacturing process is accurately
summarized in Merck’s Memorandum of Fact and Law at para 40:
[omitted]
[41]
It is common ground that Teva’s process also
involves [omitted].
[42]
Dr. Taylor was instructed to grind Form
Teva “on its own” and he did not include the Teva excipients in his samples (Applicant’s
Record at p 5840). Under cross-examination, he said he was not aware of the
size of the samples subjected to grinding by his assistant (see Applicant’s
Record at p 5845). The only quantitative evidence in the record describing the
amount of grinding pressure that was applied by Dr. Taylor’s assistant is
that it was not “light” (see Applicants’ Record at p 5844). Dr. Taylor
testified that he was not specifically instructed “how exactly to do the
grinding” and he could not recall if he was present (see Applicant’s Record at p
5839). It appears that Dr. Taylor was not asked to consider the problem
of energy equivalency before he proceeded to have his assistant grind the
samples without Teva’s excipients. As far as I can tell from the record no one
involved in setting up the manual grinding exercise considered the materiality
of sample size or composition to the outcome of the testing.
[43]
Dr. Brittain took issue with
Dr. Taylor’s failure to include any of the Teva excipients in the sample
exposed to grinding. According to Dr. Brittain the presence of excipients
in the mixture would be expected to reduce the input energy applied to Form
Teva by either [omitted] or grinding. In effect, the dilution of the samples
by adding excipients spreads the energy among all of the constituent parts.
This point is made at paragraph 23 of the Dr. Brittain’s affidavit:
23. Even
assuming for the moment that the degree of energy used by Dr. Taylor in his
grinding experiment would be comparable to that of [omitted], his decision to
exclude the excipients in the Teva Tablets from his experiments means that his
results cannot be taken as being representative of the Teva [omitted] Process,
or of the resulting form of efavirenz present in the Teva Tablets. In
particular, the Teva Tablets contain [omitted] with the Form [Teva] efavirenz.
Accordingly, [omitted] (and other excipients present) would bear the brunt of
any [omitted] forces that may be applied to the mixture of ingredients during
the manufacturing process. [omitted]. Their presence would greatly reduce the
effect of [omitted] conditions experienced by the API. Accordingly, one cannot
legitimately rely on the experiments of Dr. Taylor that were performed on
unformulated efavirenz Form [Teva] to deduce whether there would be any amount
of phase conversion during the Teva Granulating Process.
[Footnotes omitted]
[Applicant’s Record at p 3138]
[44]
Dr. Brittain also challenged
Dr. Myerson’s equation of hand grinding by mortar and pestle with [omitted]
used in Teva’s tabletting process. According to Dr. Brittain, it is
well-known that mechanical grinding applied to a compound can induce a phase
transformation. The differences in the two approaches are described by
Dr. Brittain at paragraphs 27 and 28 of his affidavit:
27. While [omitted]
pressure (or stress) on the mixture, it does not equal (or even come close to)
the pressure that results from grinding in a mortar and pestle. There are also
significant differences between the two in terms of the way they apply force.
These differences are clear when one considers that [omitted]. In contrast,
when Dr. Taylor used a mortar and pestle, he was in effect putting Form [Teva] efavirenz
between a rock and a hard place for [omitted]. The result is that Dr. Taylor’s
grinding experiments almost certainly exerted far more stress and pressure on
the API than would occur in [omitted]. This is particularly evident given that
Dr. Taylor did not include any of the excipients during his grinding work.
28. I also note
that Dr. Taylor provides no information regarding the degree of pressure that
was exerted during his grinding experiments. Exhibit “44” of the Taylor
Affidavit merely states that a sample was “ground for 11 minutes with a mortar
and pestle”. Was this a heavy grind, or a light grind? It is difficult to
replicate Dr. Taylor’s experiments without more information on how heavy
of a grind was used. There was no attempt by Dr. Taylor to determine what
amount of pressure had to be applied, or for how long, in order to mimic the
force that would be applied by a [omitted]. As noted above, [omitted] the Teva [omitted]
Process. Nevertheless, Dr. Taylor simply ground his samples for the same
amount of time as the material is mixed in the Teva [omitted] Process.
[Applicant’s Record
at p 3140]
It is noteworthy
that under cross-examination Dr. Brittain was not challenged on these
points.
[45]
Given the importance of the grinding step in
seeding the samples with Form I, the failure by Dr. Myerson and
Dr. Taylor to establish any apparent standards or to otherwise control for
the energy that was applied during Dr. Taylor’s conversion grinding experiments
is a surprising deficiency. Dr. Myerson’s experience-based opinion was
only that the two processes would exert “roughly equivalent” levels of energy.
In the absence of any empirical evidence of energy equivalency, considering the
minute quantities of Form I extrapolated by Dr. Myerson to be present after
grinding and in the face of Dr. Brittain’s evidence, I am not prepared to
infer that the uncontrolled use of mortar and pestle grinding of a small undiluted
sample for [omitted] is a reliable surrogate for the [omitted] used by Teva.
Indeed, the inference I draw from the essentially uncontradicted evidence of
Dr. Brittain is that the process followed by Dr. Taylor would apply
levels of energy to Form Teva far in excess of what would be expected from
Teva’s manufacturing process. Although minute and undetectable quantities of
Form I were likely present in Dr. Taylor’s mortar and pestle samples, I am
not satisfied that the same can be said for the Teva tablets. Of course, if I
am wrong about that Merck always has the option of commencing an infringement
action once those tablets reach the market.
[46]
In the result, Merck has failed to meet its
burden of proving that Teva tablets will contain Form I efavirenz and its
application is dismissed.
[47]
The issue of costs is reserved pending the
receipt of written submissions from the parties not to exceed 10 pages in
length. Teva will have 21 days to make its submissions and Merck will have 14
days to respond.
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