Docket: T-2056-14
Citation: 2015 FC 1244
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BETWEEN:
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AMGEN CANADA
INC.
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Applicant
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and
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MYLAN
PHARMACEUTICALS ULC.,
THE MINISTER OF
HEALTH and
NPS
PHARMACEUTICALS, INC.
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Respondents
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REASONS
FOR JUDGMENT
PHELAN J.
I.
INTRODUCTION
[1]
This is an application, pursuant to s 6 of the Patented
Medicines (Notice of Compliance) Regulations, SOR/93-133, by Amgen Canada
Inc [Amgen] against Mylan Pharmaceuticals ULC [Mylan], the Minister of Health
[Minister] and NPS Pharmaceuticals, Inc [NPS], for an order prohibiting the
Minister from issuing a Notice of Compliance [NOC] to Mylan.
[2]
Mylan proposes to sell/distribute Cinacalcet
hydrochloride in tablet form for oral administration in 30, 60 and 90 mg
strength [Mylan-Cinacalcet] until after the expiry of Canadian Patent No. 2,202,879
[879 Patent or the 879], which expires October 23, 2015.
[3]
Amgen manufactures Cinacalcet hydrochloride in
tablet form for oral administration in 30, 60 and 90 mg strength under the
brand name Sensipar®.
[4]
The patent at issue is the 879 Patent, which
claims a vast number of compounds. The sole claim at issue is Claim 5, which specifically
claims the compound Cinacalcet and its pharmaceutically acceptable salts.
[5]
The parties have requested that the Court render
its judgment (if not its reasons) before the expiry of the 879 Patent (rather
than the expiry of the statutory hold date of October 3, 2016) so as to avoid
any issue of mootness in respect of s 8 damages. There is an issue whether the
Court has jurisdiction to make a prohibition order if the Patent in issue has
expired.
These
are the reasons for the Court’s judgment dismissing Amgen’s application
prohibiting the Minister from issuing an NOC to Mylan, which was issued on
October 19, 2015.
II.
BACKGROUND
A.
Facts
(1)
General
[6]
The parathyroid gland regulates calcium levels
in the body through the secretion of parathyroid hormone [PTH]. When
extracellular ionic calcium (Ca2+) levels are low, the glands
secrete PTH, which triggers processes to increase calcium levels. When the
calcium levels have returned to normal, the glands cease secretion of PTH. This
process of responses is understood to be an inverse relationship.
[7]
Parathyroid cells respond differently to calcium
than other cells. The mechanism by which this occurs – a calcium-sensing
receptor [CaSR] - forms the basis of the issues in this case. Previously, the
mechanism was thought to be a “calcium channel”
– a completely different process.
[8]
In 1992, after setting out to develop a drug
that targeted the calcium receptor, Drs. Nemeth and Van Wagenen at NPS
discovered that a large family of compounds, including Cinacalcet,
mimicked the effect of extracellular calcium at the parathyroid calcium
receptor. This led to the 828 Patent, discussed later. They believed that such
a drug could help regulate the secretion of PTH and treat diseases
characterized by abnormal levels of calcium ions or PTH, like
hyperparathyroidism [HPT].
[9]
The resulting drug, Sensipar, contains the
compound Cinacalcet. Sensipar is approved for the reduction of elevated calcium
levels (hypercalcemia) in patients with HPT for whom the removal of the
parathyroid gland is not appropriate, or for those suffering with parathyroid
carcinoma. It was also indicated for treatment of secondary HPT in patients
with chronic kidney disease [CKD]. Sensipar stems from the 879 Patent in issue.
[10]
Mylan filed its Abbreviated New Drug Submission
[ANDS] seeking an NOC for Mylan-Cinacalcet, containing Cinacalcet hydrochloride
in tablet form of 30, 60 and 90 mg. Mylan’s drug is indicated for the treatment
of secondary HPT in patients with CKD receiving dialysis; the reduction of
hypercalcemia in patients with parathyroid carcinoma; and the reduction of
clinically significant hypercalcemia in patients with primary HPT for whom
parathyroidectomy is not clinically appropriate or is contraindicated.
[11]
On August 19, 2014, Mylan served Amgen with a
Notice of Allegation [NOA] alleging that the 879 Patent was invalid and in any
event Mylan-Cinacalcet would not infringe the 879 Patent.
[12]
On October 3, 2014, Amgen filed its Notice of
Application in this Court asserting that none of Mylan’s allegations are
justified. In particular, the 879 Patent contains claims that are relevant,
valid and go to the medicinal ingredient, formulation, dosage form and/or use
of the medicinal ingredient and will be infringed by the making, constructing,
using and/or selling of Mylan-Cinacalcet.
(2)
The Drug
[13]
At the time of the development of Sensipar in
the early 1990s, there was a need for a drug that could help the body maintain
normal calcium levels.
The
operation of the parathyroid gland and the regulation of Ca2+ has
been described in paragraphs 6 and 7.
[14]
It is now known that parathyroid cells have a CaSR
on their surface, which detects extracellular Ca2+ and initiates
signalling events within the cell in part by triggering an increase in levels
of intracellular Ca2+.
[15]
The issue of novelty of the CaSR is significant
in this case. Amgen raised the issue of the novelty of the discovery of the existence
of the calcium receptor. In its response to Mylan’s NOA, Amgen described the
discovery of the CaSR as a “good news story”.
Mylan’s retort was that it was a story told in Patent 828, not in Patent 879.
[16]
On this issue, Amgen objected to Mylan’s use of
numerous publications that were not in its NOA and argues that this Court
should not consider the articles or the evidence of Mylan that relies on these
publications.
[17]
As Justice Hughes observed in Bayer Inc v
Cobalt Pharmaceuticals Co, 2013 FC 1061, at para 34, 441 FTR 72, the Court
of Appeal has firmly established that a generic has the obligation in its NOA
to raise all the facts and legal arguments upon which it relies in support of
its allegations. It cannot create new arguments, raise new allegations or new
facts or new prior art documents not set out in its NOA.
[18]
However, in the present case, Mylan was
responding to Amgen’s evidence as to the novelty of the existence of the CaSR
as part of its contention of non-obviousness.
That
evidence is properly before this Court in accordance with the decision in Pfizer
Canada Inc v Canada (Minister of Health), 2008 FC 13, 322 FTR 56, which
confirms that if the first party (the inventor) puts an issue in play, the
second party (the generic) is entitled to rebut the issue with other evidence.
(3)
The Relevant Patents
(a)
879 Patent
[19]
The patent in issue, the 879 Patent, is listed
by Amgen on the Patent Register. It is owned by NPS, and Drs. Van Wagenen,
Balandrin and Nemeth are three of the named inventors.
[20]
The 879 Patent is entitled “Calcium Receptor – Active Compounds” and was filed on
October 23, 1995, published May 2, 1996 and issued August 30, 2005. This patent
claims priority from PCT/US94/12117 (filed October 21, 1994) and US08/353,784
(filed December 8, 1994).
[21]
The 879 Patent describes the invention to
feature:
…compounds able to modulate one or more
activities of an inorganic ion receptor and methods for treating diseases or
disorders by modulating inorganic ion receptor activity. Preferred compounds
can mimic or block the effect of extracellular calcium on a cell surface
calcium receptor.
The
patent claims trillions of calcimimetic compounds defined by two separate
genera. The only claim in issue is Claim 5 (Cinacalcet) which reads:
The compound ( (R) -N- (3- (3-
(trifluoromethyl) – phenyl) propyl) -1- (1-naphthyl) ethylamine) or a pharmaceutically
acceptable salt or complex thereof.
[22]
The 879 Patent is claimed to be a selection
patent. Central to that issue and to whether Claim 5 of the 879 Patent is
anticipated, obvious or double patented, as alleged by Mylan, is Canadian
Patent No. 2,115,828 [828 Patent].
(b)
The 828 Patent
[23]
The 828 Patent is entitled “Calcium Receptor Active Molecules”. It was issued
September 20, 2011 and has expired on August 21, 2012. The same Drs. Nemeth and
Van Wagenen (as well as Dr. Balandrin) are named inventors and the patent is
owned by NPS.
[24]
The invention is summarized as follows:
Applicant is the first to demonstrate a Ca2+
receptor protein in parathyroid cells, and to pharmacologically differentiate
such Ca2+ receptors in other cells, such as c-cells and osteoclasts.
Applicant is also the first to describe methods by which molecules active at
these Ca2+ receptors can be identified and used as lead molecules in
the discovery, development, design modification and/or construction of useful
calcimimetics or calcilytics which are active at Ca2+ receptors.
Such calcimimetics or calcilytics are useful in the treatment of various
disease states characterized by abnormal levels of one or more components…
Further, the identification of different Ca2+ receptors in different
cell types, and the specific response of such receptors to different lead
molecules allows design and construction of specific molecules active in
treatment of specific diseases which can be affected by action at such specific
Ca2+ receptors.
[25]
The 828 Patent discloses an enormous genus of
compounds. There is no issue that this patent discloses in those compounds, the
very Cinacalcet at issue here in the 879 Patent.
[26]
Also germane to the issues in this matter is
that while the 828 Patent was issued on September 20, 2011, it was published
on May 2, 1996 and filed August 21, 1992. As such, Amgen has enjoyed patent
protection from that early date and the contents of the 828 Patent were in the
public domain from that point as well, despite the fact that it was issued
after the 879 Patent.
[27]
The WO 373 application [PCT application]
ultimately led to 828. Cinacalcet falls within Claims 99-101 of WO 373. This
has the same disclosure but different claims than 828.
[28]
WO 959, filed on February 23, 1993, and
published September 1, 1994, has largely the same teachings as WO 373 with
almost the identical disclosure. The chemical structures in WO 959 are
essentially identical to those disclosed in the 828 Patent.
While
this application has additional material related to the cloning of the bovine
parathyroid CaSR, importantly Cinacalcet is within Claims 99-101 of WO 959 as
it was in WO 373.
III.
SUMMARY OF KEY WITNESSES
[29]
There was no dispute as to the qualifications of
the experts to give their expert evidence nor real challenges to credibility. However,
there were significant issues as to weight to be given to certain witnesses.
A.
Applicant’s Witnesses
[30]
Dr. Nemeth was the Director of Biology at NPS
and one of the inventors of the 879 Patent. His evidence focused on the research
that led to the invention of Cinacalcet. He described the work involved and the
difficulty in gaining acceptance in the general scientific community of calcium
receptor theory. The existence of the calcium receptor was proposed as early as
1983. He described the work he did with Dr. Balandrin to develop a safe drug
but it was clear that it was Dr. Baladrin who steered research in a particular
direction because of his bias against the naphthyl group of compounds.
[31]
Dr. Van Wagenen was a research scientist at NPS
and also one of the inventors of the 828 and 879 Patents. He provided evidence
about the medicinal chemistry leading to the invention of Cinacalcet. Most
importantly, he addressed the unique philosophy of Dr. Balandrin who directed
the development of the drug and who guided Dr. Van Wagenen and the medicinal
chemistry group as a whole. Dr. Balandrin is alive yet not called as a witness
by Amgen.
[32]
Dr. Balandrin emphasized drug safety, not
potency. His approach to focus on compounds that were small, simple and had a
degree of success was, as admitted by Van Wagenen, not in line with the
pharmaceutical industry.
This
philosophy to limit testing of certain compounds had a direct bearing on the ease
with which Cinacalcet was developed. It has direct bearing on the issue of obviousness/obvious
to try.
[33]
While neither Nemeth nor Van Wagenen were called
as experts – they would hardly be objective in this case – they had
considerable experience in the relevant area. The remaining witnesses for each
party were experts in the traditional sense.
[34]
Dr. Bartlett is an Emeritus Professor of
Chemistry at the University of California, Berkeley. He provided evidence of
the person skilled in the art [POS]; the promised utility of Claim 5; double
patenting; obviousness and anticipation of Claim 5 (or more accurately, the
non-obviousness and non-anticipation); and the unexpected utility of Claim 5.
He
admitted that a POS making each of the compounds in Claim 1 of the 828 Patent
would make Cinacalcet. In respect of the 879 Patent, no examples are directed
specifically at Cinacalcet, no specific chemical synthesis is described and no
examples of the testing of Cinacalcet is given except for one line on Table 1a.
[35]
Dr. Shoback is a Professor of Medicine at the
University of California, San Francisco, and a trained clinical
endocrinologist. She was involved in a number of Sensipar clinical trials. Her
evidence related to the POS, the utility of the 879 Patent invention compared
to the 828 Patent, the unexpected utility of the 879 Patent and the clinical impact
of Sensipar.
Dr.
Shoback opined that the cloning of the receptor after publication of the 828 Patent
was the critical breakthrough. She was of the view that the utility of Cinacalcet
could not have been predicted from the data in the 828 Patent.
[36]
Dr. Shoback’s evidence, particularly under
cross-examination, did not hold up as well as other witnesses. She appears to
have been both defensive and dogmatic and her answers were often inconsistent
with objective documents. She tried to explain away an article she wrote with
Dr. Nemeth which showed that by 1988 it was apparent that there was a calcium
receptor. She also tried to suggest that the existence of a calcium receptor
and properties were uncertain because there was no absolute proof thereof – a
higher standard than usually applicable. Her evidence is also undermined by her
reading of the 828 Patent, not for what it discloses but whether it provided absolute
and conclusive proof. She was not focused on the right question about the
teachings of the 828 Patent.
B.
Mylan’s Witnesses
[37]
Dr. Lubell is a Professor of Chemistry at the
University of Montreal. His laboratory has been involved in the synthesis of
new compounds and drug candidates. He provided evidence with respect to POS,
background and definitions related to the scientific aspects of the 879; an
understanding of the invention claimed in the 879 Patent; whether the claims to
the 879 Patent are the same or an obvious variant to the 828 Patent; and
whether the claims (especially Claim 5) in the 879 Patent were disclosed and
anticipated by the 828 Patent or WO 959.
[38]
Dr. Lubell’s evidence was particularly helpful,
clear and objective. I accord it considerable weight.
It
was his opinion that the claim in the 828 Patent is directed to calcium
receptor active molecules which encompass or include Cinacalcet hydrochloride
and do not teach away from the structure of Cinacalcet. As such, Claim 5 in the
879 Patent is anticipated by the 828 Patent and WO 959 application and also
enabled thereby. Further, the 879 Patent does not disclose any unexpected
activity of Cinacalcet over and above what was known in the 828 Patent or WO
959 application. Dr. Lubell importantly pointed out that a POS would have made
Cinacalcet hydrochloride as part of a routine development based solely on the
teaching of the 828 Patent. It would have been obvious to achieve the invention
covered by Claim 5. The activity necessary to do so was not inventive but
simply mechanical. As indicated, using the preferred claims in the 828 Patent
and looking to the right and left of the molecule, there would be less than 200
compounds to test – Cinacalcet would be one of them.
[39]
Dr. Marsden is a Professor of Medicine at the
University of Toronto and a Nephrologist at the University of Toronto and St.
Michael’s Hospital. His evidence touched on the POS and how a POS would read
the 879 Patent, 828 Patent and WO 959, and evidence about the various assays
disclosed. His evidence was balanced and impartial; deserving of significant
weight.
He highlighted
that the assays referred to in the 828 Patent showed that the compounds in that
Patent, including Cinacalcet, modulated the effect of an inorganic ion on a
cell having an inorganic ion receptor, and that the inventors of the 879 Patent
acknowledged that the 828 Patent described compounds that modulate the effect
of the inorganic ion on a cell having an inorganic ion receptor. Although the
words “inorganic ion receptor” do not appear in
828, the functional target would be understood as such. Dr. Marsden also noted
that the disclosure of the 879 Patent is very similar to the 828 Patent or WO
979 but provides for one additional assay method.
[40]
Dr. Friedman is a Professor at the University of
Pittsburgh School of Medicine in the Department of Pharmacology and Clinical
Biology and the Department of Structural Biology. His evidence addressed
construing the 828 and 879 Patents; how a POS in the art in respect to both
patents would read the patents; whether Mylan’s drug fell within the scope of
the 828 Patent; differences in the inventions claimed in each patent; whether the
differences constituted an obvious step or required inventive ingenuity; and
finally, whether the 879 Patent identified any substantive or unexpected
advantage.
[41]
Dr. Friedman opined that the 828 Patent, WO 959
and the 879 Patent all enable a POS to make Cinacalcet and use it to modulate
calcium receptors and treat certain diseases. All three teach the same use. The
879 Patent in respect of Cinacalcet provided no surprising or substantial
advantage; its activity and effectiveness was comparable to other compounds in
the class and within the expected range.
Dr.
Friedman effectively rebutted Dr. Shoback’s comments and requirement for
absolute proof of the existence of the calcium receptor. Scientists routinely
draw inferences and a POS knew that the best evidence pointed to a calcium
receptor. A POS reading the 828 Patent would understand that the inventors
believed that a calcium receptor existed and that the compounds disclosed (of
which Cinacalcet is one) worked to modulate that receptor. His evidence
undermines Amgen’s contention that the 828 Patent teaches away from Cinacalcet.
[42]
Finally, Dr. Friedman opines that a POS would
conclude that the same invention is claimed by both patents, and that the uses
are the same. If there is any legal distinction between Claim 5 and the 828
Patent, it is an obvious variation. It would take no inventive skill or
ingenuity to select a compound from a class and claim it for the same purpose
as disclosed in the earlier patent.
[43]
In conclusion, while there is no reason to doubt
the skill, integrity or honesty of any of the witnesses, I conclude, for
reasons briefly discussed, that Mylan’s experts’ evidence is to be preferred
where it conflicts or qualifies the evidence of Amgen’s witnesses.
IV.
ISSUES
[44]
There are three principal issues in this
Application:
1.
When did the person of skill in the art accept
the calcium receptor theory?
2.
Is Claim 5 of the 879 Patent a selection invention/is
the 879 a selection patent?
3.
Is Claim 5 of the 879 Patent invalid because of
one or more of:
a)
obviousness – double patenting?
b)
anticipation by either the 828 Patent or WO 959?
c)
obviousness – general?
[45]
There is no issue that, as Mylan led evidence in
the NOA capable of establishing its allegations, the burden shifted to Amgen to
establish that the allegations as to the validity of the 879 Patent are not
justified.
[46]
Likewise, there is no issue that the person of
ordinary skill (the POS) is in fact a team with expertise in endocrinological
disorders as well as medicinal and synthetic chemistry. They would also have
experience with the assays described in the prior art.
V.
ANALYSIS
A.
Issue 1 – Acceptance of Calcium Receptor Theory
[47]
Amgen, possibly in order to avoid the selection
patent issue difficulties, argues that the calcium receptor [CaSR] theory was
settled and finalized only at the time of filing of the 879 Patent. Most
particularly, it was “accepted” after Dr.
Brown’s team of researchers cloned the bovine parathyroid calcium receptor in
1993, approximately six months after the August 21, 1992 filing date of both
the WO 373 application and the 828 Patent.
[48]
Amgen contends that the CaSR theory was
controversial, competing with the calcium channel theory and possibly other
receptor molecule theories. The CaSR theory was only accepted in 1993. Dr.
Shoback’s evidence is particularly relied upon to support this argument. That
evidence suffers from inconsistency and unreasonableness as discussed earlier.
[49]
However, the bulk of the credible evidence
supports the conclusion that before the filing of the 828 Patent, the CaSR
theory was accepted wisdom. As said earlier, Amgen argued that the CaSR
discovery was a “good news story” to which Mylan
properly responds “it is, but it was told in the 828
Patent”.
[50]
There are multiple evidentiary points that
establish that at the time of the filing of the 828 Patent, the inventors were
confident in the existence of the calcium receptor and that particular
molecules acted on those receptors. Those molecules were the compounds in the
828 Patent, including Cinacalcet. The inventors were so confident that the 828
Patent repeatedly refers to the CaSR.
[51]
That evidence, in summary, is:
•
the 828 Patent discusses research by Dr. Nemeth
and others which suggests there was a receptor on the surface of the
parathyroid cell. A 1990 article co-authored by Nemeth points to the
accumulating evidence of such a Ca2+ receptor which allows the
parathyroid cell to detect small changes in the concentration of extracellular
Ca2+;
•
the 828 Patent refers to measuring intracellular
calcium levels which provide an assay to assess the ability of molecules to act
“as agonists or antagonists at the Ca2+
receptor”;
•
Dr. Shoback’s research is noted in the 828
Patent. In 1988 Dr. Shoback wrote that her studies supported the hypothesis of
a Ca2+ receptor;
•
Dr. Nemeth wrote in 1993 that his own studies
indicated the presence of a Ca2+ receptor. The 828 Patent makes
consistent reference to a Ca2+ receptor. Amgen’s suggestion that
Table 6 in the 828 Patent could be attributed to a calcium channel is inconsistent
with the Patent itself;
•
the Summary of Invention in the 828 Patent says “Applicant has demonstrated that Ca2+ receptor
proteins enable certain specialized cells involved in bodily Ca2+
metabolism to detect and respond to changes in the concentration of
extracellular Ca2+”;
•
the 828 Patent correctly explains the mechanism
of action at the calcium receptor; and
•
the 828 Patent refers to lead molecules being
used to identify structural features that allow them to act on the Ca2+
receptor.
[52]
The experts in the field accepted the existence
of the CaSR at the time of the 828 Patent filing. Amgen suggests that it was
not accepted yet by the “scientific community”, which
it described so broadly that it includes people with a “passing
familiarity” of parathyroid research and those “very
peripherally involved”. Given the high level of knowledge of parathyroid
disorders that a POS would have, these people on the outer edges of the
relevant knowledge are not relevant to whether a POS would accept the CaSR’s
existence. They do not fall within the class of persons who would constitute a
POS for purposes of this case.
[53]
Amgen has produced no credible evidence on this
point and I conclude, based on the weight of the evidence, that a POS would
have known of the existence, importance and role of the CaSR as of the 828
Patent filing date.
B.
Issue 2 – Is the 879 a selection patent/Claim 5
a selection invention?
[54]
The starting point of any patent litigated,
selection patent or not, is the proper construction of the patent and relevant
claim.
(1)
Claim Construction/Claim 5
[55]
In considering Claim 5, regard must be had to
the Patent as a whole in claim construction (Whirlpool Corp v Camco Inc,
2000 SCC 67, [2000] 2 S.C.R. 1067). The 879 Patent sets out the context of the
invention in its Description, noting that the compounds covered modulate the
CaSR and the effectiveness of the compounds is measured against the EC50
standard. The means of measuring is well established in the prior art.
[56]
At page 13 of the Patent, there is a description
of the Preferred Embodiments. However, no promises are made as to their
activity or potency.
[57]
The process for measuring the activity of the
compounds, their ability to mimic calcium and descriptions of their potency
were known and described in the 828 Patent. Similarly, the examples reflected
what was contained in 828 or in WO 959.
[58]
The examples show that the activity of the
compounds is different at different concentrations.
Of
importance is that at page 98 of the 879 Patent, Compound 22J is acknowledged
to be Cinacalcet. There is no E50 value and it is not identified as the most
active compound. It does not stand out as a compound with special properties.
[59]
Claim 1 claims trillions of compounds and the
other Claims cover many compounds in addition to Cinacalcet. However, Claim 5
is the only claim in issue.
[60]
Claim 5 does not include a specific use, and no
use is otherwise specifically stipulated for Cinacalcet in the patent
disclosure.
The
879 Patent does not promise a particular level of activity for Cinacalcet, and
other compounds (for example, Compound 24M) are evidently more active such that
one is not drawn, at least by implication, to Cinacalcet as having outstanding,
unexpected features.
[61]
Dr. Lubell, on behalf of Mylan, makes two
telling points at paragraphs 41 and 42 of his affidavit.
41. In my opinion, a person skilled in
the art would conclude from the available EC50 values that the
claimed compounds, including cinacalcet (22J), fall within the promised range
of activity/potency of less than or equal to 1nM, to less than or equal to 5 NM
and could be used for modulating calcium receptor activity and for treating
diseases or disorders which can be affected by modulating one or more
activities of a calcium receptor.
42. Claim 5 reads as follows:
The compound (R)-N-(3-(3-(trifluoromethyl)-phenyl)propyl)-1-(1-naphthyl)ethylamine)
or a pharmaceutically acceptable salt or complex thereof.
[62]
Dr. Bartlett makes a similar point that 47 of
the 61 listed compounds elicited a larger increase in intracellular
calcium levels than did Cinacalcet. The data in Table 1a of the Patent shows
that Cinacalcet is not unique in having greater activity than the previous lead
component but also that Cinacalcet was not one of the most potent compounds
tested. He concludes:
There is no evidence (or even statement) in
the 879 Patent that Cinacalcet has a unique or substantial advantage over the
other compounds disclosed in the 828 Patent. On the contrary, Cinacalcet
appears to be less potent than many of the other previously disclosed
compounds.
[63]
Neither the Patent nor Claim 5 in particular
shines a light on Cinacalcet. The data point in Table 1a is not a promise of
performance.
(2)
Selection Patent Criteria
[64]
Amgen concedes that Cinacalcet was disclosed in
the prior art but claims that Claim 5 is a selection invention. Given its
admission of disclosure, the plea with respect to Claim 5 is an attempt to keep
the 879 Patent valid.
It
is my view that this is simply an attempt, by retroactive characterization, to
save Amgen’s pharmaceutical. Failure to establish a selection patent results in
the patent being invalid.
[65]
The basic criteria for a selection patent is set
out in Sanofi-Synthelabo Canada Inc v Apotex Inc, 2008 SCC 61, [2008] 3
SCR 265 [Sanofi]. Before setting out the non-exhaustive list of
conditions established (and adopted in this decision) in the leading case of In
re I.G. Farbenindustrie A.G.’s Patents (1930), 47 RPC 289 (Ch D), the U.K. court
noted that a selection patent does not, in its nature, differ from any other
patent (Sanofi, para 9).
[66]
The Supreme Court adopted Justice Maugham’s
requirement for a selection patent that the compound be novel and
possess a special property of an unexpected character.
[67]
Amgen has also argued that a valid selection
patent is a complete answer to an allegation of obviousness, anticipation or
double patenting. This argument is not a correct statement of principle. It is
inconsistent with paragraph 9 of Sanofi, noted above. Eli Lilly
Canada Inc v Novopharm Ltd, 2010 FCA 197, at para 33, [2012] 1 FCR 349, states
that a selection patent is “vulnerable to attack on any
of the grounds set out in the Act”. This principle was recently followed
by Justice Kane in Hoffman-La Roche Ltd v Apotex Inc, 2013 FC 718 at
para 140, 436 FTR 198.
[68]
A selection patent has at least three conditions
which must be satisfied:
1.
There must be a substantial advantage to be
secured or disadvantage to be avoided by the use of the selected members.
2.
The whole of the selected members (subject to “a few exceptions here and there”) possess the
advantage in question.
3.
The selection must be in respect of a quality of
a special character peculiar to the selected group. If further research
revealed a small number of unselected compounds possessing the same advantage,
that would not invalidate the selection patent. However, if research showed
that a larger number of unselected compounds possessed the same advantage, the
quality of the compound claimed in the selection patent would not be of a
special character.
(3)
Substantial and unexpected advantage
[69]
Amgen has been unclear in its submissions by
firstly asserting that the 879 Patent is a selection invention, and then that
it is Claim 5 which is the selection invention. It asserts that Cinacalcet has
unexpected utility over the previous genus (the class of compounds having been
disclosed in WO 373 and claimed in the 828 Patent) as well as the former lead
compound (NPS R-568).
[70]
Amgen has failed to establish a substantial and
unexpected advantage, either quantitative or qualitative, in respect of either
the 879 Patent as a whole or with respect to Claim 5 in particular.
On
the qualitative end, the actual mechanism by which the process works and the
target upon which Cinacalcet acts was the same in 879 as what the inventors had
expected in 828. Further, there is nothing in the potency of Cinacalcet that
was surprising – it was “similar” or “comparable” to that of R-568.
On
the quantitative side, 47 of the 61 compounds listed in Table 1a of 879 had a
larger increase in intracellular calcium levels than Cinacalcet did. Cinacalcet’s
potency fell within the range identified in the 828 Patent. A compound selected
from a broader genus that has the activity predicted for the genus can hardly
be said to offer an unexpected advantage.
[71]
In fact, NPS did not consider Cinacalcet to
offer a substantial advantage over the lead compound. Cinacalcet was first
synthesized in early 1995 and tested at least twice by June 1995. However,
until NPS 658, the lead compound, showed toxicity issues in March 1996, NPS did
not focus on Cinacalcet. Further, Cinacalcet was synthesized after the Claim
Date of January 30, 1995. Therefore, Cinacalcet was not “selected” at the Claim Date; NPS did not know Cinacalcet
had the special properties now claimed. If Cinacalcet truly offered such a
substantial advantage, NPS would likely have focused on it earlier.
[72]
There was no substantial and unexpected
advantage, and no advantage was even described in the Patent.
(4)
All selected members possess the advantage
[73]
Claim 5, as a selection invention, cannot meet
this test as there are no other members in that Claim except Cinacalcet. If, as
Amgen also argues, 879 is a selection patent, Cinacalcet would belong to a much
larger grouping of compounds that would comprise the selection patent. As Mylan
has established, many of the compounds are actually less potent than NPS R-568
and do not have a substantial or unexpected advantage over the prior genus.
(5)
The selection is in respect of a special
quality peculiar to the selected group
[74]
That Cinacalcet is known to act on the CaSR is
not a special quality as it would apply to all claimed compounds of the 828
Patent. If unexpected potency is the alleged special quality, there is
insufficient evidence that Cinacalcet and the other like compounds in 879 are
unique.
(6)
The specification must define the nature of
the characteristic in clear terms
[75]
In Alcon Canada Inc v Apotex Inc, 2014 FC
699 at para 146, 459 FTR 255, the Court held that one of the hallmarks of a
selection patent is a clear statement of the premise of the special advantages
of the selected compounds over the genus.
[76]
The central failing in respect of this part of
the selection patent analysis is that there is no singling out of Cinacalcet as
a selection invention. The 879 Patent does not describe any special advantages
of Cinacalcet nor of any of the other compounds of the alleged selection
patent. A single reference to Cinacalcet’s activity in a table that lists 61
other compounds is insufficient, absent something more, to meet this
requirement of special advantage. Nothing stands out from this single
reference.
(7)
Summary re Selection Patent/Invention
[77]
Given the foregoing, in summary the 879 Patent
is not a selection patent nor is Cinacalcet a selection invention because:
•
there is no language of selection used,
particularly there is no disclosure of the alleged selection of Cinacalcet;
•
the Patent is directed at a large class of
compounds without selection of a few compounds from a previously disclosed
class;
•
the 879 Patent does not promise any specific level
of activity of any compound;
•
the Patent never states that naphthyl compounds
were viewed as unsuitable – a view of Dr. Balandrin which steered NPS away from
Cinacalcet but which was erroneous;
•
nothing in the 879 Patent singles out Cinacalcet
- it is neither mentioned nor are its test results outstanding such as to
distinguish it from other compounds (unsurprising since Cinacalcet had not been
made by the Claim Date);
•
Amgen’s focus on Claim 5 is unwarranted as the 879
Patent neither focuses on Cinacalcet nor discloses a selection;
•
the 828 Patent clearly discloses Claim 5 is
claiming calcimimetic compounds;
•
the 828 Patent teaches all the relevant aspects
of the 879 Patent and Claim 5 in particular, including the EC50 values and how
to make all the compounds (including Cinacalcet);
•
the 828 Patent teaches that there is a calcium
receptor, and that the claimed compounds are active at that receptor and
further describes the testing protocol in support of those teachings;
•
Cinacalcet does not have a substantial and
unexpected advantage over the prior art genus; and
•
the 879 Patent claims compounds that are no
better than the compounds in the 828 Patent.
[78]
Therefore, the 879 Patent is not a selection
patent, and Claim 5 is not a selection invention. Amgen has failed to establish
that its patent is novel and to rebut Mylan’s allegation.
C.
Other Validity Challenges
[79]
Mylan had alleged, in addition to the selection
patent issue, that the 879 Patent was invalid for obviousness-type double
patenting, anticipation and obviousness.
(1)
Anticipation
[80]
The test for anticipation is well established.
It requires disclosure and enablement. I adopt Justice Hughes’ summary of the
legal requirements set out in AstraZeneca Canada Inc v Apotex Inc, 2010
FC 714, at para 122, 376 FTR 17:
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 [sic], 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.
[81]
In the present case, Amgen admits Cinacalcet is
disclosed in 828 and in WO 959. Dr. Bartlett conceded that a person working
Claim 1 of 828 would have made Cinacalcet. Dr. Lubell also concluded that a
skilled medicinal chemist would have understood Cinacalcet to be a member of
the class of formula compounds in both of 828 and WO 959.
[82]
Dr. Lubell’s evidence is particularly persuasive
as there is no evidence to effectively contradict it. Aside from disclosure by
828 and WO 959 (in addition to the supporting evidence of Dr. Friedman and the
cross-examination response of Dr. Bartlett), Dr. Lubell outlined how there is
no inventive step from 828 to get to Cinacalcet. Dr. Lubell, using claims 20-55
of the 828 and bearing in mind a preference for R-isomers, concluded that there
were at most 200 molecules to be tested. Cinacalcet was one of those molecules.
The testing itself was mechanical.
[83]
It is not necessary that the 828 Patent be prior
art to make out anticipation. Dr. Friedman confirms that WO 959 enables Cinacalcet.
[84]
However, on the issue of 828 as prior art, there
was an unusual circumstance surrounding 828. There was a long gap between
publication date (1993) and issue date (2011). As a result, 879 was issued
prior to 828. Amgen erroneously conflates the publication date with the issue
date to contend that 828 is not prior art.
[85]
However, s 28.2(1)(c) of the Patent Act,
RSC 1985 c P-4, makes the filing date relevant for purposes of a validity
analysis. The 828 Patent was filed before the 879 Patent – even the publication
date of 828 was before 879’s filing date.
[86]
The Federal Court of Appeal in Baker
Petrolite Corp v Canwell Enviro-Industries Ltd, 2002 FCA 158, at para 6, [2003]
1 FC 49, clarified that the crucial juncture is the disclosure to the public.
The Court adopted the analogy advanced by Adous J. in Lux Traffic Controls Ltd
v Pike Signals Ltd, [1993] RPC 107 (Eng Patents Ct) at p 133:
Further it is settled law that there is no
need to prove that anybody actually saw the disclosure provided the relevant
disclosure was in public. Thus an anticipating description in a book will
invalidate a patent if the book is on a shelf of a library open to the public,
whether or not anybody read the book and whether or not it was situated in a
dark and dusty corner of the library. If the book is available to the public,
then the public have the right to make and use the information in the book
without hindrance from a monopoly granted by the State.
[87]
While I find 828 to be prior art, more
importantly I find that Mylan has made out that the 879 Patent was anticipated
by the prior art – the 828 Patent and WO 959.
(2)
Obviousness
[88]
The Supreme Court has established a four-step
approach to the analysis of the issue:
(1) (a) Identify the notional “person
skilled in the art”;
(b) Identify the
relevant common general knowledge of that person;
(2) Identify
the inventive concept of the claim in question or if that cannot readily be
done, construe it;
(3) Identify
what, if any, differences exist between the matter cited as forming part of the
“state of the art” and the inventive concept of the claim or the claim as
construed;
(4) Viewed
without any knowledge of the alleged invention as claimed, do those differences
constitute steps which would have been obvious to the person skilled in the art
or do they require any degree of invention?
Sanofi, at para 67
[89]
The Court elaborated on the “Obvious to try” component of the fourth step,
appropriate where advances are often won by experimentation. As outlined at
paragraph 69 of that decision, the non-exhaustive factors to consider are:
[69] If an “obvious to try” test is
warranted, the following factors should be taken into consideration at the
fourth step of the obviousness inquiry. As with anticipation, this list is not
exhaustive. The factors will apply in accordance with the evidence in each
case.
1. Is
it more or less self-evident that what is being tried ought to work? Are there
a finite number of identified predictable solutions known to persons skilled in
the art?
2. What
is the extent, nature and amount of effort required to achieve the invention? Are
routine trials carried out or is the experimentation prolonged and arduous,
such that the trials would not be considered routine?
3. Is
there a motive provided in the prior art to find the solution the patent
addresses?
[90]
Applying the obviousness analysis to the facts,
the least contentious step is the POS, about whom there is general agreement.
[91]
With respect to the inventive concept, since Cinacalcet
is not an inventive selection, Claim 5 is Cinacalcet per se; it is not
Cinacalcet’s unexpected activity as a modulator of the CaSR. That activity had
been described in 828.
[92]
Regarding the difference between Claim 5 and the
prior art (particularly 828 and WO 959), there is no inventive difference as
opined by Dr. Friedman. Cinacalcet, its clinical structure and its function,
had been disclosed. Claim 5, at best, merely gave further specificity. As
Amgen’s witness Dr. Bartlett admitted, a POS could make Cinacalcet in view of
the prior art and common general knowledge.
[93]
As to obvious or obvious to try, in my view Cinacalcet
was obvious. At the very least, if there is a difference between the state of
the art and Claim 5, it was obvious to try to achieve the invention covered by
Claim 5. The 828 Patent and WO 959 disclosed compounds which included Cinacalcet,
and are active at the calcium receptor on parathyroid cells. The POS would have
found Cinacalcet by using known assays to screen compounds for activity at the
calcium receptor.
[94]
As Cinacalcet’s potency fell within the range
set out in 828, and acts on the CaSR as stated in 828, it was self-evident (or
should have been) that Cinacalcet would work on the CaSR with the expected
potency.
[95]
Dr. Lubell outlined how easy and mechanical the
process would be as mentioned in paragraph 38. There were only 200 molecules to
test, of which Cinacalcet was one. Simple verification as this test was
described is not an innovative step.
[96]
There are two subsidiary points to address.
Firstly, to the often rhetorical question “if it was so
obvious, why did you not do it”, the answer lies in part that the
compound was already covered by the 828 Patent. There would be no point and
indeed economic and legal risk in working an existing patent. This is not a
case of discovery for an originating patent, where the question has greater
validity. It is a case of working with an existing patent where the compound
enjoyed patent protection.
[97]
Secondly, the actual conduct of NPS (and
particularly Dr. Balandrin) was not helpful to Amgen. Dr. Balandrin had a bias
against the naphthyl group based on alleged safety concerns and steered NPS’s
research away from synthesis of compounds with the naphthyl group. As Dr.
Friedman opined, a skilled person would not have been so adverse to inclusion
of the naphthyl group with the compounds. At least two other drugs used the
naphthyl group.
[98]
Amgen cannot use Dr. Balandrin’s bias in product
development to justify delay in developing Cinacalcet as part of routine
development based on 828 and WO 959 or to claim now that it was not
obvious/obvious to try.
[99]
Lastly, on the issue of obviousness-type double
patenting, Mylan’s counsel said it was not a “toss off”
argument. However, in view of what has preceded this issue, it is not necessary
to address the issue separately from obviousness.
[100] The Court has held that, viewed from the perspective of a POS, Claim
5 is patentably indistinct from the 828 Patent.
[101] Amgen has not shown that the allegation that Claim 5 was obvious or
obvious to try was not justified.
VI.
CONCLUSION
[102]
For all these reasons, Amgen has not shown that Mylan’s
allegations are not justified. As such, the application to prohibit the
Minister of Health from issuing a Notice of Compliance is dismissed with costs.
"Michael L. Phelan"
Ottawa, Ontario
November 3, 2015
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