Docket: T-1395-07
AND
BETWEEN:
LUNDBECK CANADA INC.
Applicant
and
THE MINISTER OF HEALTH AND
COBALT PHARMACEUTICALS INC.
Respondents
and
H. LUNDBECK A/S
Respondent/Patentee
PUBLIC VERSION OF REASONS FOR
ORDERS
(Identical to Confidential Reasons for
Orders issued 12 February 2009)
HARRINGTON J.
[1]
These
three applications deal with two words not in every day use; enantiomers and
racemates. The patent in issue relates to (+) citalopram which is an enantiomer
of citalopram. Citalopram, the subject of a patent which expired years ago, is
a racemic compound containing unresolved (+) citalopram and (-) citalopram in
equal amounts. It has been found useful as an antidepressant. Lundbeck claims
that (+) citalopram, which has come to be known as escitalopram, is also useful
as an antidepressant.
[2]
The
applications seek an order prohibiting the Minister from authorizing Genpharm,
Apotex and Cobalt (hereinafter the respondents) from manufacturing and selling
their generic versions of escitalopram until the patent expires in 2014, the
whole pursuant to the Patented Medicine (Notice of Compliance) Regulations.
[3]
Escitalopram
is covered by Canadian patent 1,339,452 which was applied for in June 1989
based on a United
Kingdom
priority date of June 1988. It was granted in 1997 and expires in 2014. The Patent
Act as it was immediately prior to 1 October
1989,
applies. The patent is held by H. Lundbeck A/S of Denmark.
Escitalopram is sold in Canada by its Canadian
subsidiary, Lundbeck Canada Inc., in virtue of a Notice of Compliance obtained
from Health Canada. Lundbeck
Canada Inc. also succeeded in having the patent listed in the Register maintained
by the Minister pursuant to the said PM (NOC) Regulations. Subsequent
references to “Lundbeck” are either to the Danish or Canadian corporation as
dictated by context.
[4]
Unless
the hurdles incorporated in the PM (NOC) Regulations are overcome, the
Minister is disentitled from permitting the respondents from marketing their
generic versions of escitalopram until the patent expires. These regulations
have been intensely litigated and need not be analyzed in detail here.
Reference is made to the decisions of the Supreme Court in Merck Frosst
Canada Inc. v. Canada (Minister of National Health and Welfare), [1998] 2
S.C.R. 193, 80 C.P.R. (3d) 368; Bristol-Myers Squibb Co. v. Canada (Attorney
General), 2005 SCC 26, 39 C.P.R. (4th) 449 at paragraphs 5-24 (Biolyse) and
Apotex Inc. v. Sanofi-Synthelabo Canada Inc., 2008 SCC 61, 69 C.P.R.
(4th) 251 at paragraphs 7 and 12-17, as well as to the decision of Mr. Justice
Hughes in Ferring Inc. v. Canada (Minister of Health), 2007 FC 300, 55
C.P.R. (4th) 271.
[5]
Not
content to await the expiry of the patent, each of the three respondents served
Lundbeck with a “Notice of Allegation”, the upshot of each are submissions that
patent ‘452 is invalid. Lundbeck responded by instituting these three
applications for prohibition orders. The applications in effect serve as a
statutory injunction for up to two years. As applicant, the overall burden of
proof falls upon Lundbeck to persuade the Court that the factual and legal
bases of the allegations are not justified. However since only invalidity is in
issue, cognisance must be taken of the legally rebuttable presumption that the
patent is valid. That presumption is a weak one, but it does behove the
respondents to, at the very least, lead enough evidence to put validity in
play. (Abbott Laboratories v. Canada (Minister of Health), 2007 FCA 153,
59 C.P.R. (4th) 30 and Pfizer Canada Inc. v. Apotex Inc., 2007 FC 971,
61 C.P.R. (4th) 305, per Mr. Justice Mosley at paragraphs 44-51)
ISSUES
[6]
Ultimately,
the only issue is whether or not the Minister should be prohibited from issuing
a Notice of Compliance to one, some, or all of the respondents. The penultimate
step in the process is to determine whether or not Lundbeck has persuaded the
Court, on the balance of probabilities, that the allegations of invalidity are
not justified. In some instances, but not the ones at hand, a determination
that the allegations are not justified does not lead to a prohibition order.
For instance, a party may be barred from obtaining such an order on the basis
of abuse of process (Sanofi-Aventis Canada Inc. v. Novopharm Ltd., 2007
FCA 163, 59 C.P.R. (4th) 416 and Sanofi-Aventis Inc. v. Laboratoire Riva
Inc., 2007 FC 532, 58 C.P.R. (4th) 109).
[7]
All
three respondents allege that the patent in issue is a selection patent chosen
from a previous U.S. patent and is invalid because it falls short of
the requisite criteria. Selection patents were dealt with very recently by the
Supreme Court in Sanofi-Synthelabo, above. I shall refer to that
decision as Plavix after the compound in issue so as to distinguish it
from other cases cited herein in which either Sanofi or Apotex appears in the
style of cause. Lundbeck asserts that escitalopram is not a selection patent; it
is a per se patent for escitalopram itself. However, should it be found
that it is a selection patent then it meets all the requirements thereof. I
regard this issue as fundamental. If escitalopram is an invalid selection
patent, it is not necessary to deal with the other allegations of invalidity.
[8]
Although
couched in somewhat different language, the three respondents further allege
that, in any event, Lundbeck invented nothing deserving of a patent. One or
more allege that escitalopram is not novel, was anticipated, was obvious, and
lacks utility. Finally, more technical grounds of invalidity are asserted such
as insufficiency of the specification and disclosure, overclaiming, or making
irrelevant claims, lack of sound prediction, ambiguity and a lack of candour as
well as wilful omissions contrary to section 53 of the Act.
DECISION
[9]
Although
they have not succeeded on every point, each of the respondents has, in my
opinion, lead enough evidence to put validity into play. However, I have
reached the conclusion that Lundbeck has established that the allegations are
not justified in each of the three applications and so prohibition orders shall
issue.
NATURE OF THE PROCEEDINGS
[10]
It
has been well-established that applications pursuant to the PM (NOC)
Regulations are intended to be summary in nature and are not ultimately
binding upon the parties as to validity or infringement. The parties are
entitled to litigate those issues in a proper action, as well as other patent
claims not covered by the Regulations such as product by process claims.
Lundbeck only has to meet the allegations set out in the separate Notices of
Allegation. Consequently, the result could differ from application to
application. Non-infringement was not raised at all and so is not before me.
These proceedings determine neither validity nor infringement.
[11]
The
advantages of an action over an application are well known. They include: a
full discovery of documents based on affidavits in which all must be disclosed,
not just the documents relied upon; viva voce examination for discovery;
experts are qualified as such by the Court before testifying; a trial where
witnesses are heard; and the judge is able to ask clarifying questions. In
applications the evidence is heard outside court by way of affidavits and cross-examinations
thereon. Transcripts, by their very nature, are sterile. By way of example, in Janssen-Ortho
Inc. v. Novopharm Ltd., 2004 FC 1631, (2005), 35 C.P.R. (4th) 353 Mr.
Justice Mosley held in the context of a PM (NOC) application that the
patent was invalid for obviousness. Janssen-Ortho then took action for patent
infringement and, following a full trial, succeeded before Mr. Justice Hughes (Janssen-Ortho
Inc. v. Novopharm Ltd., 2006 FC 1234, 57 C.P.R. (4th) 6, aff’d 2007 FCA
217, 59 C.P.R. (4th) 116, leave to appeal to S.C.C. refused, [2007] S.C.C.A.
No. 442.(QL)).
[12]
I
consider it important to emphasize the limited value of this decision because patents
directed to escitalopram has been under attack in several jurisdictions.
[13]
At
trial in the U.K., it was
found that claims 1 and 3 were invalid for insufficiency because they claimed
the enantiomer made by any method but the specification only disclosed two ways
of making it. (Generics (U.K.) Ltd. & Ors. v. H.
Lundbeck A/S, [2007] EWHC 1040 (Pat), 2007 R.P.C. 32. However the Patents
Court decision was reversed by the Court of Appeal in H. Lundbeck A/S v.
Generics (U.K.) Ltd. & Ors., [2008] EWCA Civ 311, [2008] R.P.C.
19. I was informed during the course of argument that the case is proceeding to
the House of Lords on the insufficiency point.
[14]
In
the United States, the American version of the patent was upheld both at trial
and in appeal. I was informed that the appeal decision is final. (Forest
Labs., Inc. v. Ivax Pharms., Inc. 438 F. Supp. 2d 479 (D. Del., 2006) aff’d
501 F.3d 1263 (Fed. Cir. 2007).
[15]
The
Australian patent was held to be valid at trial in Alphapharm Pty Ltd., v.
H. Lundbeck A/S, [2008] FCA 559. That decision is said to be under
appeal.
[16]
However
in Germany the Federal
Patent Court
ruled the patent was invalid on the grounds that the subject matter of the
alleged invention was not novel and was not based on an inventive step. The
nature of the proceedings was somewhat different from a common law trial.
Witnesses were not heard and the judge was assisted by three others who had
expertise in the field. That decision is also said to be under appeal.
[17]
Of
course, none of these decisions, either in findings of fact or in conclusions
of law, is binding upon me. That is not to say that the rationale of those
decisions may not be persuasive.
[18]
In
addition I was told that proceedings are pending in several other jurisdictions.
[19]
These
are three distinct applications which, although heard consecutively, were never
joined. Lundbeck’s evidence is tailored somewhat to meet the different Notices
of Allegation, but the affidavits of its factual and expert witnesses are
essentially the same. However, these witnesses were cross-examined on three
separate occasions. With the exception of Dr. Newton, called by both Genpharm
and Cobalt, the respondents’ witnesses are different, although much of what
they have had to say is the same.
[20]
In
each proceeding, Lundbeck obtained a protective order which had the effect of
keeping much of the information in each of the applications confidential. They
were kept absolutely separate and distinct until shortly before the hearings
when, following a case management conference, it was agreed that counsel for
the respondents could attend all three hearings without facing an in camera
application. Memoranda of fact and law in all three applications were also
exchanged.
[21]
The
application records, excluding copies of case law, total more than 29,000
pages. Argument on the validity of three claims of one patent lasted thirteen
days. Given that the degree of commonality greatly surpasses the
distinctiveness of each application, I have decided to render one set of
reasons, identifying where necessary the points in issue which were not raised
by all three respondents.
AN ORGANIC CHEMISTRY
PRIMER
[22]
As
stated at the outset, citalopram is what is known as a racemate and
escitalopram is one of the two enantiomers inherent therein. The parties assure
me that every undergraduate student of organic chemistry, much less the skilled
addressee of a patent, knows, and at all relevant times knew, that carbon-centered
molecules have a three-dimensional structure. If that carbon atom is bonded to
four different atoms or groups of atoms (as is the case here), the molecule is
described as having an asymmetric centre. These compounds are identical save
that they exist in two space-occupying forms called “enantiomers”. They are
non-superimposable mirror images of one another. Such asymmetric molecules are
called chiral, coming from the Greek word for hand, as a left hand and right
hand are mirror images of each other and are not superimposable. When many
drugs are created or synthesized, the result is an equal mixture of the two
enantiomers. This mixture is called a racemic mixture or a racemate.
[23]
Although
the racemate and its enantiomers do not differ in their chemical or physical
properties (and thus may be difficult to separate or resolve), they can, as
noted by Professor Jenner, a witness called by Apotex, dock within the human
body in different ways with biomolecules, such as proteins, which also have
three-dimensional structure.. “…The best analogy to draw is a key and lock
interaction… As a consequence they can have differing pharmacological
properties...”
[24]
Enantiomers
are a subset of stereoisomers, which in turn are a subset of isomers. Isomers
are molecules with the same chemical formula, but in which the atoms are
arranged differently. Stereoisomers are isomers with the same atomic
connectivity, but whose atomic arrangement in space is different. Enantiomers
are stereoisomers that, as aforesaid, are mirror images of each other and not
superimposable. They are molecules which have only one chiral centre and are to
be distinguished from diasteromers which are stereoisomers that are not mirror
images and may have more than one chiral centre. This distinction is important
when it comes to separating or resolving a racemate.
[25]
Enantiomers
are the subject of two unrelated nomenclatures. An enantiomer is capable of
directing the plane of polarization of polarized light in one direction or
another. If the plane is turned clockwise, to the right, the enantiomer is
called (+), d or dextro-rotary. If the plane is turned counter-clockwise it is
called (-), l or levo-rotary.
[26]
The
second naming method is the Cahn-Ingold-Prelog convention which specifies
absolute configuration. The substituents around the chiral centre are “sized”
according to their atomic numbers. If the sequence from the largest to the
smallest flows in a clockwise direction, the molecule is assigned the R or rectus
designation. Otherwise it is assigned the S or sinister designation.
[27]
There
is no relationship between the plus and minus designations and the S and R
designations. Escitalopram was first described as (+) or dextro, and only later
as sinister.
[28]
Although
this information is drawn from the affidavits of Professor Stephen Davies,
called by Lundbeck, and Dr. Frank Newton, called by both Genpharm and Cobalt, I
have found no disagreement among the various experts as to the basic chemistry
involved or that the racemate and each of its two enantiomers may work
differently within the body.
PATENT CONSTRUCTION
[29]
At
the heart of any dispute regarding a patent is its meaning. The principles have
been well-established and were clearly set forth by the Supreme Court in Free
World Trust v. Électro Santé Inc., 2000 SCC 66, 9 C.P.R. (4th) 168 and Whirlpool
Corp. v. Camco Inc., 2000 SCC 67, 9 C.P.R. (4th) 129. As applicable to
these applications:
a.
It is a statutory requirement that the patent
contain a specification and end with a claim or claims “defining distinctly and
in explicit terms the subject-matter of the invention for which an exclusive
privilege or property is claimed”. The specification must be sufficiently full,
clear, concise and exact “as to enable any person skilled in the art or science
to which it pertains, or to which it is most closely connected, to make,
construct, compound or use it”. (Patent Act, pre-1 October 1989, s. 34).
b.
The patent is notionally addressed to a person
skilled in the art or science of the subject-matter and is to be read as such a
person would have read it when it first became public.
c.
The
claims are to be read in an informed and purposive way to permit fairness and
predictability and to define the limits of the monopoly.
d.
The
claim portion of the patent specification takes precedence over the disclosure
portion in the sense that the disclosure is read to understand what was meant
by a word in the claims “…but not to enlarge or contract the scope of the claim
as written and thus understood” (Whirlpool at para. 52).
e.
To overclaim is to lose everything. If the
inventor underclaims, the court will not broaden the monopoly in the interests
of the “spirit” thereof
f.
A patent is not an ordinary document. It meets
the definition of a “regulation” in the Interpretation Act, and must be
read to assure the attainment of its objects. “[C]laims construction is a
matter of law for the judge, and he was quite entitled to adopt a construction
of the claims that differed from that put forward by the parties.” (Whirlpool
at para. 61.)
(See also Biovail Pharmaceuticals Inc.
v. Canada (Minister of
National Health and Welfare), 2005 FC 9, 37 C.P.R. (4th) 487, at para. 15).
[30]
Pursuant
to section 27 of the Patent Act, as it was prior to 1 October 1989, an
inventor or legal representative thereof was entitled to obtain a patent for:
…an
invention that was
(a) not known or used by any
other person before he invented it,
(b) not described in any patent
or in any publication printed in Canada or in any other country more than two
years before presentation of the petition hereunder mentioned, and
(c) not in public use or on sale
in Canada for more than two years prior to his application in Canada,.
|
…une invention qui
a) n'était pas connue ou utilisée par une
autre personne avant que lui‑même l'ait faite,
b) n'était pas décrite dans
quelque brevet ou dans quelque publication imprimée au Canada ou dans tout
autre pays plus de deux ans avant la présentation de la pétition ci‑après
mentionnée, et
c) n'était pas en usage
public ou en vente au Canada plus de deux ans avant le dépôt de sa demande au
Canada
|
[31]
An
invention was defined at section 2 as meaning:
[…]
any new and useful art, process, machine, manufacture or composition of
matter, or any new and useful improvement in any art, process, machine,
manufacture or composition of matter
|
[…] Toute réalisation, tout procédé, toute machine, fabrication
ou composition de matières, ainsi que tout perfectionnement de l'un d'eux,
présentant le caractère de la nouveauté et de l'utilité.
|
SKILLED ADDRESSEE
[32]
The
qualities of the person to whom a patent addressed were dealt with in Whirlpool,
above. Mr. Justice Binnie, at paragraph 70, quoted Mr. Justice Dickson in Consolboard
Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 at 523,
56 C.P.R. (2d) 145 quoting H.G. Fox, Canadian Law and Practice Relating to
Letter Patent for Invention, 4th ed. (Toronto: Carswell, 1969)
at page 204:
The persons to whom the specification is addressed are
“ordinary workmen”, ordinarily skilled in the art to which the invention
relates and possessing the ordinary amount of knowledge incidental to that
particular trade. The true interpretation of the patent is to be arrived
at by a consideration of what a competent workman reading the specification at
its date would have understood it to have disclosed and claimed.
[33]
Mr.
Justice Binnie added at paragraph 71 that ““Ordinariness” will, of course, vary
with the subject matter of the patent. Rocket science patents may only be
comprehensible to rocket scientists.”
[34]
Considerable
detail was set out in the various affidavits as to the identity of this person,
or group of persons, particularly as regards the common general knowledge
prevalent at the time and the depth of the research required of such person
into the prior art. This concern flows from the fact that at paragraph 70 of Whirlpool
Mr. Justice Binnie also quoted from Beloit
Technologies Inc. v. Valmet Paper Machinery Inc., [1997] EWCA Civ
993, [1997] R.P.C. 489 where Aldous L.J. said at page 494:
The notional skilled addressee is the ordinary man who may
not have the advantages that some employees of large companies may have.
The information in a patent specification is addressed to such a man and must
contain sufficient details for him to understand and apply the invention.
It will only lack an inventive step if it is obvious to such a man.
[Emphasis added.]
[35]
I
very much doubt that, at the time, such an addressee had the analytical tools
to find, and the inclination to read and digest, every single published document
pertaining to racemates and enantiomers, as does today’s pharmaceutical company
which, with the aid of more sophisticated computers and search engines, is
driven to list an encyclopedia of prior art in its Notice of Allegation when it
cannot market its product because it is on “patent hold”. Dr. Newton, for one,
was armed with more prior art in these applications than he was in the U.K. trial.
However, nothing turns thereon as I am persuaded that the resolution of
citalopram by any method was not obvious even to an addressee who was perfect
in every way.
[36]
Suffice
it to say that the patent is addressed to a team centred around a medicinal
chemist who has access to and makes use of others with different skill sets
such as analytical chemists and psychiatrists. It is not necessary to make a
definitive finding as to the balance between the team’s formal education and
laboratory experience, be it in a university or at a pharmaceutical company. Theoretical
knowledge of, and practical experience in, the methods of resolving racemates
is essential.
SELECTION PATENTS
[37]
The
term “selection patent” is to be found nowhere in the current or previous Patent
Acts. It is a product of English jurisprudence. In E.I. Du Pont de Nemours
& Co. (Witsiepe’s) Application, [1982] F.S.R. 303 (H.L.), Lord
Wilberforce stated at page 309: “…[t]he difficulty arises when disclosure is
made of a group or class of substances for which some advantage is claimed, and
later it is found that one or more of this group or class possesses special
advantages not belonging to the rest of the group or class and not previously
identified. …”
[38]
Following
the decision of the Supreme Court in Plavix, above, there can be no
doubt that in principle such patents are valid in Canada. Mr. Justice
Rothstein drew upon English jurisprudence, more particularly the decision of
Mr. Justice Maugham in the leading case of In re I.G. Farbenindustrie A.G.’s
Patents (1930), 47 R.P.C. 289 (Ch.D), and stated at paragraph 9:
.… At p. 321, he explained
that in the field of chemical patents (which would of course include
pharmaceutical compounds), there are often two “sharply divided classes”. The
first class of patents, which he called originating patents, are based on an
originating invention, namely, the discovery of a new reaction or a new
compound. The second class comprises patents based on a selection of compounds
from those described in general terms and claimed in the originating patent.
Maugham J. cautioned that the selected compounds cannot have been made before,
or the selection patent “would fail for want of novelty”. But if the selected
compound is “novel” and “possess[es] a special property of an unexpected
character”, the required “inventive” step would be satisfied (p. 321). At p.
322, Maugham J. stated that a selection patent “does not in its nature differ
from any other patent”.
Plavix was an enantiomer
specifically claimed in the original or genus patent.
[39]
The
genus patent in Plavix only described the overall class of more than
250,000 compounds, racemates and enantiomers alike, in general terms. In order
to discover Plavix’s special qualities, a racemate had to be resolved. This was
the inventive step as found by Mr. Justice Shore in first instance
(2005 FC 390, 39 C.P.R. (4th) 202), a finding which held sway throughout (2006
FCA 421, 59 C.P.R. (4th) 46).
[40]
Although
it may seem a little peculiar, and contrary to section 34(1)(b) of the
Act, that if one claims a group of compounds, it may only be necessary to give
a few examples as to how a few within the group may be made, it must be kept in
mind that the genus patent may literally claim millions of different compounds.
In May & Baker Limited and Others v. Boots Pure Drug Company Limited,
[1950] UKHL 1, [1950] R.P.C. 23, not less than 97 million compounds had been
claimed.
PATENT ‘452
[41]
Patent
‘452 entitled “Enantiomers of Citalopram and Derivatives Thereof” states in the
abstract of the disclosure that the invention relates to the two novel
enantiomers of citalopram and to their use as antidepressant compounds. It is
said to include pharmaceutically acceptable salts. After stating that previous
attempts to resolve citalopram (which it noted had been previously disclosed in
U.S. patent number 4,136,193, which was filed in January 1977) by crystallizing
diastereomeric salts of citalopram had failed, it was discovered that a
precursor of citalopram, a diol disclosed in U.S. patent number 4,650,884
filed in August 1985 entitled “Novel Intermediate and Method for Its Preparation”
(which was also a racemic mixture) could be resolved into its enantiomers and
in a stereoselective way converted to the corresponding citalopram enantiomers.
Patent ‘452 described two reaction schemes by which the (+) enantiomer of
citalopram could be obtained. Of the 11 claims only 1, 3 and 5, to the extent
it is dependent on 3, are in issue. They claim:
- 1 -
A compound selected from substantially
pure (+)-1-(3-Dimethylaminopropyl)-1-(4’-fluorophenyl)-1,
3-dihydroisoben-zofuran-5-carbonitrile and non-toxic acid addition salts
thereof.
[…]
- 3 -
A pharmaceutical composition in unit
dosage form useful as an antidepressant comprising a
pharmaceutically-acceptable diluent or adjuvant and, as an active ingredient,
an effective amount of a compound as defined in Claim 1.
[…]
- 5 -
A pharmaceutical composition in unit
dosage form, useful as an antidepressant according to claim 3 or 4, wherein the
active ingredient is present in an amount from 0.1 to 100 milligram per unit
dose.
[42]
U.S. patents ‘193
and ‘884, or at least ‘193, are said to be the patents from which Canadian
patent ‘452 was selected. Patent ‘193 discloses a formula which might generate
a few hundred different compounds. Citalopram was specifically claimed. Neither
U.S. patent makes
mention of stereochemistry in general, or the enantiomers of citalopram in
particular, much less claims them.
Is escitalopram special?
[43]
The
most favourable reading that can be given to the ‘452 patent, a reading some of
the respondents dispute, is that escitalopram is about 1.6 times more potent
than citalopram. Since it was well within the realm of possibility that more,
and indeed sometimes all, of the desired biological activity of a racemate might
rest within one enantiomer rather than in the other, the discovery that
escitalopram may be more beneficial than citalopram is not surprising. Indeed,
if all of the desired activity resided in escitalopram, it would only be twice
as potent as citalopram, which is not sufficiently unexpected to serve as the basis
of a selection patent (GlaxoSmithKline v. Pharmascience Inc., 2008 FC
593). Surprises arise outside this range. There is no indication that
escitalopram has other desirable or surprising traits such as less toxicity or
an unexpected and substantial increase in solubility, stability, handling
properties, processability or in its side effects profile. Consequently, if
escitalopram is a selection patent, it is invalid.
[44]
However,
I am satisfied that escitalopram is not a selection patent. In Plavix,
the Supreme Court clarified the circumstances in which a patent, selection or
otherwise, may be invalided on the grounds of anticipation. In first instance,
Mr. Justice Shore cited Free World, above, which approved the test for
anticipation set out by Mr. Justice Hugessen in Beloit Canada Ltd. et al v.
Valmet Oy (1986), 8 C.P.R. (3d) 289 (F.C.A.) at p. 297:
…. One must, in effect, be able to look at a prior, single
publication and find in it all the information which for practical purposes, is
needed to produce the claimed invention without the exercise of any inventive
skill. The prior publication must contain so clear a direction that a
skilled person reading and following it would in every case and without
possibility of error be lead to the claimed invention. … [Emphasis added by
Mr. Justice Shore.]
However, and drawing from the decision of
Lord Hoffmann in Synthon B.V. v. SmithKline Beecham plc, [2005] UKHL 59,
[2006] 1 All E.R. 685, [2006] R.P.C. 10, Mr. Justice Rothstein held that
there are two components to anticipation: prior disclosure and enablement. “…[P]rior
disclosure means that the prior patent must disclose subject matter, which, if
performed, would necessarily result in infringement of that patent…” (para. 25).
[45]
No
trial and error experimentation is permitted at the disclosure stage, but such
experimentation is permitted at the enablement stage (para. 27). The decision
of Mr. Justice Hugessen has now been held to only be applicable to the
disclosure stage.
[46]
The
evidence is clear that if the subject matter of either prior U.S. patent were
worked, the result would be a racemate, not an enantiomer. Consequently it
cannot be said that patent ‘452 formed part of either U.S. patent, and
so the selection patent argument falls for lack of prior disclosure. (See Abbott
Laboratories v. Canada (Minister of Health), 2008 FC
1359 at paragraph 75.)
[47]
It
was urged upon me that as a result of the Plavix decision, the
disclosure and claim of a racemate in a prior patent is automatically a
disclosure and claim of the enantiomers. That cannot be so. It is not enough to
say that everyone knew there were two enantiomers within citalopram. That is no
better than saying that any undergraduate student in organic chemistry could
have read the formula and realized that citalopram contains a carbon atom
bonded with four separate constituents. Nowhere do I see support in Plavix
for the proposition that the claim of a racemate is ipso facto a claim
for its two enantiomers. Considering that if one overclaims one gets nothing,
and considering that one could not possibly know the exact qualities of the enantiomers,
i.e. which, if either, would be useful in treating depression, I cannot
construe the patent as invited by the respondents. In fact, at paragraph 19 Mr.
Justice Rothstein said:
….Apotex implies that the
current understanding of the law sets the bar for proving anticipation too high
and that the acceptance of a system of genus and selection patents necessarily,
or at least on the facts of this case, involves anticipation and therefore invalidity.
I would reject the broader objection. …
[48]
As
shall be discussed later in these reasons, the utility of escitalopram could
not be determined until citalopram was resolved in sufficient quantities to
allow for suitable testing. Before the results were in, all that could be said
was that escitalopram might be more beneficial than citalopram, or less
beneficial, or toxic, or otherwise useless. It is common ground among the
experts that some enantiomers are toxic or useless. If to claim a racemate
useful in the treatment of depression is to claim the same usefulness for each
of the two enantiomers then in such circumstances the inventor would have
overclaimed and lost everything. U.S. Patent ‘193 is not one which contains
layer upon layer of distinct claims such that, if the claim with respect to one
enantiomer fell, the claim with respect to the other might survive. Although
the R-enantiomer has some activity, no evidence was led that it is useful in
the treatment of depression.
[49]
We
now turn to whether Lundbeck has established, on the balance of probabilities,
that the other allegations are not justified, or that the respondents did not
lead sufficient evidence to even put some of them in play.
ANTICIPATION
[50]
The
single document contemplated by section 27 of the Act and published not less
than two years prior to the ‘452 application which might describe the subject
matter claimed in a subsequent invention need not itself be a patent. Apart
from the U.S. patents, the
respondents rely on each of the two papers published by Dr. D.F. Smith in 1985
and 1986, which discuss depression and drugs that inhibit serotonin uptake. He
also prepared a model and wrote “…Although effects of the individual
enantiomers of citalopram have never been studied, the model predicts that the
(R)-enantiomer…is far more potent than the (S)-enantiomer as 5-HT
uptake inhibitor… Thus, the present model can be tested in determining whether these
predictions are correct.” The prediction was incorrect as post the ‘452 patent
it was determined that the (S) enantiomer was by far the more potent.
[51]
This
led, for example, Dr. McClelland, a chemist called by Apotex, to say “In these
two papers Dr. Smith has clearly disclosed the two enantiomers of citalopram”.
This cannot be correct. It was known to the addressee of the patent, and indeed
to undergraduate organic chemistry students, that within citalopram were two
enantiomers. Although it might not be a surprise that one might be more potent
than the other, I agree with Professor Stephen Davies, called by Lundbeck, that
one would not know the qualities of the two enantiomers without separating and
testing them.
[52]
As
pointed out by Justice Lindgren of the Federal Court of Australia in Alphapharm,
above, the Smith articles teach away from the invention covered by the ‘452
patent. The Smith articles do not disclose escitalopram as useful in the
treatment of depression and are in no way enabling. Nor does the 1983 article
by Waldmeier cited by Cobalt.
OBVIOUSNESS
[53]
The
Supreme Court’s decision in Plavix has also clarified the application of
Beloit, above, to invalidity
on the grounds of obviousness. Mr. Justice Hugessen had said at page 294:
The test
for obviousness is not to ask what competent inventors did or would have done
to solve the problem. Inventors are by definition inventive. The classical
touchstone for obviousness is the technician skilled in the art but having no
scintilla of inventiveness or imagination; a paragon of deduction and
dexterity, wholly devoid of intuition; a triumph of the left hemisphere over
the right. The question to be asked is whether this mythical creature (the man
in the Clapham omnibus of patent law) would, in the light of the state of the
art and of common general knowledge as at the claimed date of invention, have
come directly and without difficulty to the solution taught by the patent. It
is a very difficult test to satisfy.
[54]
The
skilled addressee is now allowed some imagination and intuition. After
reviewing developments in the United States and the United
Kingdom,
Mr. Justice Rothstein held at paragraph 68 that there are circumstances which permit
an element of “obvious to try”. He agreed with the current state of the law in
the United Kingdom as summarized by Lord Hoffmann in the Court of Appeal on
this same escitalopram invention (Generics (U.K.), above). Lord Hoffmann
had in turn endorsed, at paragraph 24, the state of the law expressed at trial by
Mr. Justice Kitchin:
…. The question of
obviousness must be considered on the facts of each case. The court must
consider the weight to be attached to any particular factor in the light of all
the relevant circumstances. These may include such matters as the motive to
find a solution to the problem the patent addresses, the number and extent of
the possible avenues of research, the effort involved in pursuing them and the
expectation of success.
[55]
Mr.
Justice Rothstein went on to apply the four-step approach outlined in the
United Kingdom in Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd., [1985] R.P.C. 59 (C.A.) and in Pozzoli
Spa v. BDMO SA, [2007] EWCA Civ 588. They are, as set out in Pozzoli
by Jacob L.J.:
…In the
result I would restate the Windsurfing questions thus:
(1)
(a) Identify the notional “person skilled in the art”;
(b) Identify
the relevant common general knowledge of that person;
(2)
Identify the inventive concept of the claim in question or if that cannot
readily be done, construe it;
(3)
Identify what, if any, differences exist between the matter cited as forming
part of the “state of the art” and the inventive concept of the claim or the
claim as construed;
(4)
Viewed without any knowledge of the alleged invention as claimed, do those
differences constitute steps which would have been obvious to the person
skilled in the art or do they require any degree of invention?
[56]
Mr.
Justice Rothstein noted that it is at this fourth step that the “obvious to
try” issue will arise. At paragraphs 69 and 70 he set out four non-mandatory,
non-exhaustive, factors to consider:
a)
Is it more or less self-evident that what is being tried
ought to work?
b)
What is the extent, nature and amount of effort required?
c)
Is there a motive provided in the prior art to find the
solution?
d)
The actual course of conduct which culminated in the making
of the invention.
[57]
This
is not to say that other factors as listed by the Court of Appeal in Janssen-Ortho
Inc. v. Novopharm Ltd., 2007 FCA 217, 59 C.P.R. (4th) 116, may not be relevant
as well. Apart from motivation, at paragraph 25 the Court of Appeal referred to
“[t]he climate in the relevant field at the time the alleged invention was
made” and as secondary factors, commercial success and meritorious awards.
[58]
Turning
to Pozzoli, I have already identified the notional “person skilled in
the art” as a team centered on a medicinal chemist, which team would also
include analytical chemists.
[59]
The
construction of the claims does not present difficulty. Claim 1 is for
substantially pure escitalopram and non-toxic acid additional salts thereof.
Claim 3 is a chemical composition in unit dosage form useful as an
antidepressant, and claim 5, insofar as it is dependant on claim 3, is for a
unit dosage form wherein the active ingredient ranges from 0.1 to 100
milligrams per unit dose. The inventors do not claim that escitalopram is
better than citalopram, notwithstanding some puffery to that effect in the
disclosure.
[60]
The
difference between the prior art and the inventive concept of the invention is
that, while the prior art disclosed the racemate citalopram useful as an
antidepressant, it did not disclose or enable its enantiomers or even predict whether
either of them would be useful as an antidepressant. The prior art did not
allow the skilled addressee to “have come directly and without difficulty to
the solution thought by the patent”, i.e. the resolution of the racemate in
sufficient quantity to permit the testing disclosed in the patent. In my view,
resolution was the inventive step. Once a sufficient quantity had been
obtained, the testing to allow a prediction that escitalopram was useful as an
antidepressant was mundane. It was the same test used for citalopram itself.
[61]
The
remaining question is whether viewed without knowledge of the escitalopram
invention, would the differences between it and the prior art coupled with
common general knowledge constitute steps obvious to the skilled addressee, or
do they require a degree of invention.
[62]
Obviousness
is assessed at the date of invention. Lundbeck asserts that escitalopram was
invented 21
April 1988.
The fallback position is the U.K. patent application filed 14 June 1988. Among the
respondents, Apotex originally took the position that the U.K. priority date
was inappropriate because of differences in the text of the U.K. and Canadian
patent applications. However, during oral argument it said it would accept
Lundbeck’s position. In any event there is a consensus that there is no
difference in the state of the art and common general knowledge between the two
dates.
EXPERT WITNESSES
[63]
The
parties called as expert witnesses a number of chemists who offered their
opinions as to how the patent would be read by its addressees, the common
general knowledge, the state of prior art at the time, the motivation, if any,
to resolve racemates in general and citalopram in particular and most
importantly, the methods available to resolve citalopram and whether those methods
would have been considered routine.
[64]
Lundbeck
called Professor Stephen Davies and Professor Brian J. Clark. Professor Davies
is the Chairman of Chemistry at the University of Oxford, has
consulted with pharmaceutical companies over the years, is the founder of a
private corporation specializing in asymmetrical problems, founded in 1989, and
is still editor-in-chief of Tetrahedron Asymmetry, a journal which
reports advances in knowledge of all aspects of stereochemistry. He professes
to have an overall knowledge of racemates, the methods to resolve them and the
motivating factors at the time.
[65]
Professor
Clark is the Associate Dean for Research and Innovation in the School of Life
Sciences
and an academic in the School of Pharmacy at the University of Bradford,
U.K. Professor Clark is particularly knowledgeable about one of the ways of
resolving racemates, chiral HPLC (high pressure liquid chromatography).
[66]
Both
Genpharm and Cobalt called Dr. Roger Newton, who worked as a medicinal chemist for
Glaxo in the U.K. from 1971 to 1996, has been the CEO of a small company which
designs and synthesizes specialist research based organic chemicals for the
pharmaceutical industry, has consulted for other pharmaceutical companies and
was the resident medicinal chemist in the Chemistry Department at the
University of Cambridge from 1996 to 2005. Like Professor Davies, he has a
sound overall knowledge of the subject and various methods to resolve racemates.
[67]
Genpharm
called Professor Michael Chong, of the University of Waterloo and Director
of its Guelph/Waterloo Centre for Graduate Work in Chemistry. He also offers an
opinion as to methods available at the time to resolve racemates and the ease
thereof.
[68]
Genpharm
also called Dr. Roland Collicott who has spent almost his entire professional
career in the U.K. in
pharmaceutical research and development with specialization in chiral and
polymorphic analysis and chiral separation. He has personally used chiral HPLC
columns since 1982.
[69]
Dr.
John Keana was called by Apotex. Except for a leave of absence in the late 1990s
when he worked in private industry on drug discovery efforts, he is an academic
and was an associate professor or professor at the University of Oregon
from 1965 to 2003. He is now professor emeritus there and serves as a
consultant for a number of pharmaceutical companies. He deals with methods to
achieve resolution of citalopram and is of the view that such methods were
routine at the time.
[70]
Professor
Timothy Ward, called by Apotex, first worked with Professor Daniel Armstrong
who developed one of the chiral HPLC columns used to resolve racemates. After
working in industry for a number of years he now teaches at Millsaps College where he
became the Chair of the Chemistry Department and Dean of Science. His
speciality is chiral chromatography.
[71]
Dr.
Robert McClelland was also called by Apotex. He served as a professor of
chemistry at the University of Toronto for many years and is
now professor emeritus. He is knowledgeable in organic and bioorganic
chemistry and in the field of medicinal chemistry. He has also offered an
opinion on the above-mentioned topics.
[72]
In
addition to Dr. Newton, Cobalt called Dr. Peter Kissinger who has been a
professor of analytical chemistry at Purdue for many years. His research is
focused on liquid chromatography techniques. He founded a company in 1974 which
manufactures instrumentation and develops software and has done contract
research for pharmaceutical and biotechnology companies. He covers many of the
areas dealt with by Dr. Collicott.
[73]
All
these experts are qualified to assist the Court. I am of the impression that
some, if not all, of them are overqualified. They certainly are not “ordinary
workmen” (Consolboard, above).
[74]
Lundbeck
was particularly aggressive in attacking the objectivity of some of the experts
called by the respondents. Counsel should realize that it is difficult to
assess these allegations since the experts are not even “talking heads”. They
are merely words on pieces of paper. Such an attack invites retaliation as
happened here, none of which was at all useful to the Court. It is difficult,
if not impossible, to assess such allegations based on transcripts of
cross-examination. The criticism of Dr. McClelland is particularly noteworthy.
It was centred on the fact that he has been called by Apotex more than 20 times
in a career spanning over 30 years. The implication is that if he is not a man
for all seasons, he is certainly a man for all patents. However, I was not
aware that there was a limit to a number of times a witness could appear. It
may well be that Apotex has come to rely upon his opinion. It may well be that
there have been times when NOAs were not issued because his advice was that the
patent was valid, or that Apotex’s method would infringe, based on his
understanding of the common general knowledge and prior art. A reading of his
cross-examination in its entirety, not just in bits and pieces, shows his
objectivity in this case. No adverse inference should be drawn from the fact
that I have come to prefer the evidence of Professor Davies.
[75]
Dr.
Kissinger found himself in an embarrassing situation not wholly of his own
making. A good deal of his affidavit was drawn by counsel who, unbeknownst to
him, liberally borrowed from an affidavit given by Dr. Collicott in the U.K. case. This
is not to say that Dr. Kissinger did not personally believe in what was said in
his affidavit. No doubt, the next time both Dr. Kissinger and counsel will keep
in mind that expert evidence presented to the Court should be, and should be
seen to be, the independent product of the expert uninfluenced as to form and
content by the exigencies of litigation. The expert witness should provide
independent assistance to the Court by way of objective unbiased opinion (Merck
& Co. v. Apotex Inc., 2004 FC 567, (2004) 32 C.P.R. (4th) 203, citing National
Justice Compania Riviera S.A. v. Prudential Assurance Co. (“the Ikarian
Reefer”), [1993] 2 Lloyd’s Rep. 68, reversed on another point, [1995] 1 Lloyd’d
Rep. 455).
[76]
Although
I doubt the skilled addressee would have been quite as knowledgeable as
suggested by the experts called by the respondents and would have carried out
the research into prior art done by respondents almost 20 years later (or been
capable of so doing), I also doubt that the addressee would have been quite as
ordinary as suggested by Professors Davies and Clark. However, in the result
nothing turns on this difference of opinion.
Motivation
[77]
Motivation is one of the factors taken into
consideration in assessing whether an alleged invention was obvious. This is one
of several issues where the parties, all of them, bolted down more rabbit holes
than Alice did in
Wonderland. The respondents allege that there was motivation within the
pharmaceutical industry at large to resolve citalopram, an allegation Lundbeck
denies. Lundbeck suggests that resolution was a pet project of its Dr. Klaus Bøgesø, a co-inventor of citalopram and
eventually a co-inventor of escitalopram. One would have thought, if anything,
that Lundbeck would have boasted that the entire industry was trying to resolve
citalopram and since it was the first to succeed the prize of the patent should
go to it; and that the respondents would have argued that, had there been any
interest in resolving citalopram, it would have been done routinely by any one
of several methods.
[78]
This results-oriented approach arises
from some case law. At paragraphs 57 and 58 of Plavix, Mr. Justice Rothstein
refers to the decision of the U.S. Supreme Court in KSR Intern. Co. v. Teleflex Inc., 127 S.Ct. 1727 (2007).
At page 1742 Justice Kennedy said:
… When there is a design need
or market pressure to solve a problem and there are a finite number of
identified, predictable solutions, a person of ordinary skill has good reason
to pursue the known options within his or her technical grasp. If this leads to
the anticipated success, it is likely the product not of innovation but of
ordinary skill and common sense…
However
Mr. Justice Rothstein also quoted that part of Justice Kennedy’s reasons in
which he opined that previous U.S. case law “set forth a broad inquiry and
invited courts, where appropriate, to look at any secondary
considerations that would be instructive.” [My emphasis.]
[79]
Motivation does not prove instructive in
this case. The experts rely upon papers from the U.S. Food and Drug
Administration, the first in 1987, and the other in 1992, as well as Japanese
and European commentaries which indicated an interest by regulatory bodies in
knowing the qualities of enantiomers within racemates. The evidence with
respect to the 1987 FDA paper is appallingly thin. Experts retained by the
respondents only appear to refer to it because it was in the list of prior art
cited by the respondents. Indeed, the copy filed in court appears to have come
out of a course given in 1994, which lends itself to the possibility that prior
thereto it was only an unpublished internal document. In any event, no
regulatory body made it “de rigueur” that marketing approvals were contingent
upon disclosing details of the enantiomers, notwithstanding the oft-cited drug
thalidomide which was said to be marketed as a racemate, one enantiomer of
which it was useful in dealing with morning sickness while the other led to
terrible birth defects. However even on this point the evidence is really
anecdotal. Professor Davies considers the problem may have been that the good
enantiomer spontaneously converted back to the racemate.
[80]
There is evidence that some drugs in citalopram
category were marketed as racemates and others as enantiomers.
[81]
Apotex went so far as to allege, without
any foundation whatsoever, that the U.S. and Japanese authorities had required
Lundbeck to provide evidence with respect to the enantiomers of citalopram, an
allegation successfully refuted by Lundbeck’s Director, Corporation Patents and
Trade-marks, John Meidahl Petersen.
[82]
On the other hand, Lundbeck is
downplaying its interest in resolving citalopram. Not only had Dr. Bøgesø involved other scientists from
Lundbeck, one in turn who engaged an outside laboratory, but internal papers
publicly disclosed at the Australian trial, which considered that escitalopram
would extend the monopoly granted by the citalopram patent, led Cobalt, in
particular, to submit that Lundbeck was less than forthright. However, as said
earlier an application does not require a full disclosure of documents. No one
sought an order for further production as allowed by Rule 313.
[83]
There is also evidence from
Dr. Newton in the Genpharm and Cobalt applications that pharmaceutical
companies were not particularly interested in resolving racemates which were
covered by a patent issued to a competitor. There was no bonhomie about this.
Not only would the patentee likely have a head start on resolving the racemate,
but at best one would end up in cross-licensing agreements. If a competitor produced
escitalopram, it probably could not use it because it infringed the citalopram
patent. On the other hand, Lundbeck could not use escitalopram. Research and
development may well have been directed to other molecules as suggested by
Professor Davies. Suffice it to say that I do not consider the evidence
respecting motivation helpful in considering whether the invention of
escitalopram was obvious.
Resolution of Citalopram
[84]
Although Professor Davies suggests that
there were 13 ways to resolve racemates at the time, some better known than
others, the focus of all the chemists has been more restrictive. What could be
resolved and by what method? In addition to the resolution of citalopram
itself, the process could begin with a precursor, such as a diol, covalent bond
formation or modification of the molecule. Then one of two methods would be
applied: the long-standing “classical” method of fractional crystallization or chiral
HPLC.
[85]
As explained by Dr. McClelland, the
classic method takes advantage of the difference between enantiomers and
diastereomers and goes back to Pasteur. Since the two enantiomers have
identical physical properties, separation based on standard techniques will not
work. Consequently, the racemate is reacted with a second substance that is
also capable of existing as a pair of enantiomers. However, only one of the
enantiomers of the second substance is employed. This is the resolving agent.
The product of this reaction is a 50/50 mixture of stereoisomers. Since they
have different physical properties, they can then be separated based on such differences
as solubility, boiling points or retention times on a chromatography column. Once
these diastereomers are separated the resolving agent is removed or cleaved.
The oldest method of separating the enantiomers of a racemic amine, such as
citalopram, is to form diastereomeric salts which are then separated by
fractional crystallization. Because of a difference in solubility, one salt
crystallizes out leaving the other in solution.
[86]
The ‘452 patent states that previous attempts to
crystallize diastereomeric salts of citalopram enantiomers had failed. Certainly,
efforts by Lundbeck had failed and there is no evidence that anyone else had even
tried to resolve citalopram by any method. Success was achieved not by using
citalopram, but rather by using one of its precursors or intermediates, the
diol, which was disclosed in U.S. patent ‘854. Diols are molecules
containing two distinct hydroxyl (OH) groups. The citalopram diol is also a
racemate. The diol was resolved into its enantiomers. Each enantiomer was then
subjected to a reaction known as cyclization to form an enantiomer of citalopram.
[87]
Two
routes or reaction schemes were provided, both of which involved the resolution
of the citalopram diol, or an ester thereof, followed by conversion of the
resolved molecule to the (+) enantiomer of citalopram using specific reagents
and conditions. Scheme 1 involved reacting the diol with either the (+) or (-)
form of an agent called Mosher’s acid chloride to form diastereomeric esters on
the primary alcohol which could be separated by non-chiral HPLC followed by low
temperature ring closure using a strong base. Scheme 2 provided two methods.
Having made diastereomeric salts of the racemic diol, the ring closure involves
the further step of making a labile ester with the primary alcohol, followed by
low temperature selective ring closure using a weak base.
[88]
The
other resolution method cited by the experts was chiral HPLC. As explained by
Dr. Kissinger, chromatography refers to a collection of techniques used to
separate compounds based on different rates of migration. The mixture to be
separated is first dissolved into a liquid mobile phase and then passed over an
absorbent stationary phase that has been packed into a column. Around 1970
smaller diameter stationary phase particles were developed. They required
higher pressure in order to percolate the mobile phase through the stationary
phase bed. HPLC thus requires the use of high pressure pumping systems,
injection valves, columns that can withstand high pressure and detectors to
monitor the effluent from the column. However, these non-chiral phases cannot
distinguish between enantiomers. The chiral stationary phase contains small
molecules or a polymer-capable chiral recognition. The enantiomers are
separated through stereoselective retention as one enantiomer may interact more
strongly with the chiral stationary phase and is thus retained for a longer
period.
[89]
However,
both with fractional crystallization/diastereomeric salts and chiral HPLCs, the
devil is in the detail.
WHAT LUNDBECK DID
[90]
Lundbeck’s
evidence is found in the affidavits of Dr. Klaus Bøgesø and Mr. Klaus Gundertofte and the cross-examinations thereon.
Lundbeck was criticized for not providing affidavit evidence from the other co-inventor
of escitalopram, Dr. Perregaard, who is now in retirement, and from the fact
that certain failed experiments referred to in the affidavits were not fully
documented. However, the evidence was sufficient, in my view, to overcome the
allegations of invalidity. There is no reason to doubt what had transpired.
This is not a test in record keeping.
[91]
The
story began in 1971. Lundbeck had a number of projects in hand with a view to
producing pharmaceuticals effective in treating depression. One project
involved compounds which might have selective serotonin reuptake inhibition
activity. Some 60 compounds were synthesized. One of these, first made in 1972,
was what became known as citalopram.
[92]
In
1980, Dr. Bøgesø began his attempt to resolve
citalopram directly by using chiral acids and then to crystallize one of the diastereomeric
salts out of solution (as broadly described by Dr. McClelland). His attempts
using various resolving agents were not successful. Another unsuccessful
technique used to induce crystallization was to modify the molar ratio of the
acid being used as a resolving agent.
[93]
In addition, solutions and
oils of the reactions were left standing either at ambient temperature or in a
refrigerator or freezer for long periods, anti-solvents were used, solvents were
evaporated and so on, as detailed in his affidavit.
[94]
Come late 1983, he attended a
course run by one of the leading lights in the resolution of racemates,
Professor Collet. The course brought to his attention a new resolving agent,
bis naphthyl phosphoric acid, which, unlike the general rule for resolving
agents, did not contain a chiral carbon. As BNPPA was not commercially
available, he personally synthesized it but was again unsuccessful in his
resolution efforts. He studied the literature, including a book edited by one
Newman which gave hundreds of examples of successful resolutions, as drawn from
scientific papers.
[95]
Attention was then shifted to
citalopram derivatives and to conversion of those derivatives into the single
enantiomers of citalopram once they had been resolved. One idea was to alter
the shape and functionality of the molecule. Within Lundbeck there were
discussions of resolving the diol. They were concerned that the result would be
a racemate.
[96]
By
the fall of 1986, Dr. Bøgesø had a strategy of shortening the
distance between the salt forming group and the chiral carbon. Utilization of
this bromo/carboxylic acid derivative was ultimately unsuccessful, as were
other strategies.
[97]
Finally come the end of 1987,
Drs. Bøgesø and Perregaard took another look at
the diol route. Dr. Perregaard experimented and succeeded in making an ester of
the diol by using Mosher’s acid chloride. This was an unusual choice as Mosher’s
acid chloride was not known and used as a chiral agent, but rather as an
analytical reagent for NMR analysis. When the formula for citalopram and its
enantiomers is set out as a diagram one can see that one of the bonds attached to
the carbon centre is in pentagon form. However, in the diol one of the five
sides is open. The reaction mixture had to be kept cold and there would be
difficulty in isolating the ester long enough to get it to a non-chiral HPLC
column for resolution. If the ring closure occurred before separation, the result
would be citalopram, not an enantiomer. The team succeeded in obtaining a small
yield of the diol-ester which was resolved by non-chiral HPLC. Further purifications
were carried out by a “peak shaving” technique which resulted in enantiomerically
pure diol-ester isomers. Dr. Perregaard then carried out the ring closure
mechanism on the diol-ester with a strong base. This is scheme 1 described in
the patent.
[98]
This ring closure reaction also provided
another way to make citalopram. Further work to resolve the diastereomeric
salts of the diol was carried out. Crystals and the salt of the (-) enantiomer of the diol were formed. Thereafter,
using the same ring closure mechanism they were converted via an ester to the
(+) enantiomer of citalopram. This is reaction scheme 2.
[99]
Apart from fractional
crystallization of citalopram or a derivative, Lundbeck also attempted to
resolve citalopram using chiral HPLC. There were many types of columns available
in this rapidly advancing field. Klaus Gundertofte, another chemist, who had
experience with HPLC, tried unsuccessfully to resolve citalopram using a number
of chiral HPLC columns. Mr. Gundertofte joined Lundbeck in 1982. At that time
he had a master’s degree in chemistry and biology. His thesis had included the
use of high performance liquid chromatography. He developed considerable
experience in the HPLC lab, separating many hundreds of mixtures. Apart from the
choice of the column, there are other parameters such as the choice of
solvents, temperature, flow rate, pressure, PH, and the stationary phase. His
experience was such that, following a presentation at the Technical University
of Denmark, he prepared a paper published in Dansk Kemi (Danish Chemistry) which discusses the theoretical and practical
considerations involved in using HPLC.
[100]
He endeavoured to resolve
citalopram with a number of different analytical columns. An analytical column
will allow one to analyze which compounds and impurities are present in a given
reaction mixture but, unlike a preparative HPLC, cannot be used to obtain much
of the desired compound.
[101]
By 1988 there were more than 30
chiral columns on the market, but it has been generally accepted that they fell
into five basic types. Mr. Gundertofte used four. In addition, in or around
1987, he retained the Royal Danish School of Pharmacy which had a microcrystalline cellulose
triacetate chiral HPLC column. Lundbeck did not have access to such a column at
that time as it was not commercially available. The University reported back
that they were unable to achieve separation of citalopram.
[102]
To take the example set out
by Mr. Justice Rothstein in paragraph 71 of Plavix, the inventors and their team did not reach “…the invention quickly,
easily, directly and relatively inexpensively, in light of the prior art and
common general knowledge, that may be evidence supporting a finding of
obviousness…” Genpharm suggests that Lundbeck was a victim of its earlier
success with citalopram, that Dr. Bøgesø had built-in biases because of that
experience and so did not have an open mind, since it was obvious that
attention should have been focused on the diol. On the other hand, Apotex
suggests that the Lundbeck scientists were not sufficiently competent. I am
satisfied that the evidence of Dr.
Bøgesø, and Mr. Gundertofte, as well as the
experts called by Lundbeck refute these suggestions.
[103]
Even if it were obvious to
try to resolve citalopram, or a diol thereof, it was certainly not self-evident
that what was being tried ought to work. In commenting on this approach as
enunciated in Plavix Mr. Justice Marc Noël recently noted that: “…According to
this test, an invention is not made obvious because the prior art would have
alerted the person skilled in the art to the possibility that something might
be worth trying. The invention must be more or less self-evident. …” (Apotex Inv. v. Pfizer Canada Inc. et al, 2009 FCA 8 at paragraph 29). In fractional crystallization,
the logical starting point was citalopram itself. If that failed, one might
then try to resolve other molecules such as the diol. The experts retained by
the respondents did not sufficiently divorce themselves from the knowledge they
had of the alleged invention as claimed. Why select the diol disclosed in the
‘884 patent rather than the five precursors disclosed in the ‘183 patent?
Without going into the chemistry, which was intensely debated, the closure of the
diol ring and its timing was a crucial process which led to discussions of SN1
and SN2 reactions. Furthermore, there was an almost infinite combination of
reagents and conditions to draw from.
[104]
Although spoken of anticipation by
publication, the following passage taken from Mr. Justice Binnie’s speech in Free World
Trust,
above, at paragraph 25 is à propos: “…It
takes little ingenuity to assemble a dossier of prior art with the benefit of
20-20 hindsight…”
[105]
Since this is a per se patent claiming escitalopram
howsoever made, had it been obvious to resolve citalopram, directly or
indirectly, with the aid of a chiral HPLC column, the patent would be invalid. As
aforesaid, there were more than 30 commercial models available, falling into
five broad groups. Again, the parameters were almost endless: the choice of
column, mobile phase, stationary phase, pressure, temperature and so on.
Lundbeck carried out or commissioned efforts using five different columns. The
criticism that they would have been successful had they not stopped these
efforts in 1987 and instead continued through into 1988, is simply not
warranted.
[106]
All the chemists called by the
respondents are naturally and properly imbued with a sense of professional
pride. Had they been asked prior to June 1988 to resolve citalopram they
believe they could have done so without difficulty, or at least properly
instructed lab technicians how to do so. The fact of the matter is that not one
of them had ever attempted to resolve citalopram, and it is now a fairly
straightforward task.
[107]
These experts have not successfully shed their
20 years of after-acquired knowledge and returned to the days of their relative
youth. Although the poem describes a judge, judges and chemists have sufficient
common bonds to bring into play what Whittier said in Maud Muller:
…
God pity
them both! and pity us all,
Who vainly
the dreams of youth recall;
For of all
sad words of tongue or pen,
The saddest
are these: “It might have been!”
[108] It might have
been that the experts could have resolved citalopram. I think not, unless they
were inventive.
[109] The experts
called by the respondents would have one believe that systematic routine work
based either on fractional crystallization or chiral HPLC would have been
successful. The fact of the matter is that some racemates were easy to resolve
at the time while others were extremely difficult, if not impossible. Certainly
Dr. Newton acknowledged this. Overall, I prefer the evidence of Professors
Davies and Clark on the difficulties involved. My comments with respect to
Professor Davies are scattered throughout these reasons.
[110] There is no
basis for believing that as part of routine testing, Mosher’s acid, which had
been known as a shift reagent, would be used in a preparative solution and
would play a major role in the ring closure reaction. This was not of the
common general knowledge or of the prior art. Although spoken in the context of
a process claim in Ciba Limited v. Commissioner of Patents, [1956-1960] Ex.C.R.142,
27 C.P.R. 82, President Thorson stated at page 152:
…[W]hen a process consists in the
application of a known method to known materials but it has not previously been
applied to them and the use of the process results in the production of a
substance that is not only new but also valuable for its unobvious useful
qualities, the process by which such substance is produced is patentable.
In dismissing the appeal, Mr. Justice Martland
added at [1959] S.C.R. 378, page 383:
…The method may be known and the
materials may be known, but the idea of making the application of the one to
the other to produce a new and useful compound may be new, and in this case I
think it was.
[111] Professor
Clark dealt with chiral HPLC, which was not the resolution method disclosed in
the patent. I have found his analysis of the difficulties involved to be well
balanced. In particular, he was careful to distinguish what was known and
available in 1988 as compared to later developments, with new generations of
columns, with better packing material which improved resolution capacity and
preparative scales. These improvements, he explained, allowed for the
separation of sufficient quantities of material to allow for biological testing
and not simply detection.
Rochat
[112] Post-1988, reference
has also been made to two papers by Rochat published in 1995, lab experiments
commissioned by Lundbeck in 2002, a paper by Elati et al., in 2007 and
Apotex commissioned a Dr. Kellogg to attempt to resolve citalopram in 2007. These
papers and work cannot be considered prior art. The respondents assert however that
these are examples of what could also have been done in 1988. Rochat did
achieve some separation of citalopram in 1995 using an analytical HPLC column. However,
there are three reasons Rochat cannot be relied upon. The first is that an
analytical column at best will give very little of the desired product. To get
a sufficient quantity to carry out tests one would have had to use the column
some 40,000 times and would lose resolution. The second is that there is no
evidence that the type of column used by Rochat was available in 1988. It is
clear that even small changes could make a huge difference in resolution. The
third is that Rochat did not get substantially pure citalopram, although that
might have been overcome, but one would literally end up with a pool of solvent
in order to obtain a few milligrams.
[113] Certainly,
basing oneself on Rochat, the experimentation would have been prolonged and
arduous and not considered routine.
Rhodia ChiRex Inc.
[114] In 2002,
Lundbeck retained Rhodia ChiRex Inc. to resolve citalopram and its diol
precursors. They purchased 77 different resolving agents all told and tested
the respective racemates to promote diastereomeric salt formations in the hope
of finding something that would give resolution in a chiral HPLC analysis.
There was no real success which lead to their conclusion that resolution was
only possible on diol precursors. The study was only a screening. Optimization
of the best candidates identified would thereafter be necessary.
[115] Needless to
say the respondents did not take kindly to this study. It is interesting that
one of the resolving agents used was later used by Elati. Dr. Chong, for one,
also notes that the study only used ethanol and acetone as solvents. He said: “…I
would have expected a person skilled in the art who wished to achieve success
in directly resolving citalopram to not limit themselves to two solvents, but
rather conduct a routine and methodical solvent screen on the salts which
formed crystals…” If anything, this proves the point that there were a myriad
of possibilities and that the use of Mosher acid had been fortuitous.
Elati
[116] In January
2007, Elati and others published an article in Organic Process Research
& Development which disclosed successful resolution of citalopram using
di-p-toluoyltartaric acid. This article is relied upon by the
respondents as this acid was available in 1988. Lundbeck moved for leave to
file additional evidence in the Genpharm and Apotex cases but was unsuccessful
before Prothonotary Morneau, on appeal to the Federal Court, and in the case of
Apotex on appeal to the Court of Appeal. The basis of Prothonotary Morneau’s
decisions was that, save in special circumstances, these matters should be left
to the judge who hears the case on the merits.
[117] Shortly
before the hearing on the merits, Lundbeck brought on further motions in all
three cases in an effort to bring to my attention the fact that subsequent articles
in the same journal challenged Elati’s findings and that Elati himself had
admitted an error. These motions were strongly opposed.
[118] In my opinion
it would be open to me to allow further evidence, particularly since Elati’s
partial admission, was very recent. Indeed, in Kent Trade and Finance Inc.
v. JP Morgan Chase Bank, 2008 FCA 399, the Federal Court of Appeal allowed new
expert evidence in appeal. However, in this case the motions are moot because I
give no weight whatsoever to the Elati article. Reply evidence would not assist
the Court (Atlantic Engraving Ltd. v. Lapointe Rosenstein,
2002 FCA 503, (2002), 23 C.P.R. (4th) 5).
[119] The article lists
various ways to resolve racemates. There is no reference whatsoever to any
article published before 1990 and Elati even claims a patent on his process.
Assertions by experts called by the respondents that this could have been done
in 1988 are simply that: assertions. It is certainly not plain and obvious that
such a step would have been taken or that the Elati process would have been
used. Even on the basis that the particular solvent was available in 1988, it
was simply one of a great number and no cogent evidence was advanced as to why
it would have been obvious to use it in 1988, rather than one of the many
others. In any event, there were flaws in the Elati article as admitted by Drs.
Newton and McClelland.
DR. RICHARD KELLOGG
[120] Dr. Richard
Kellogg was retained by solicitors for Apotex (not the solicitors of record)
and given a mandate to resolve citalopram. However, he was called as a factual
witness. The report prepared by his laboratory in the Netherlands reports the
resolution of a diol precursor of citalopram with a resolving agent called
phencyphos as well as separation of citalopram by a chiral HPLC column namely, a
chiralcelOD-H column. Dr. Kellogg’s report was issued after Apotex’s Notice of
Allegation and so is neither referred to in the text of the allegation nor in
the literature cited. Apotex had alleged that “testing results have confirmed
that separation of citalopram using conventional techniques (as described
herein) available prior to June 13, 1987 results in substantially pure (+)
citalopram.”
[121] Lundbeck
moved to have Dr. Kellogg’s affidavit struck as well as those portions of the
affidavits of others who referred to them or, in the alternative, to be given
leave to file reply evidence. Their motion was dismissed by Prothonotary
Morneau but on appeal I struck the affidavit in its entirety and those portions
of the other affidavits which referred to the lab report. In turn, the Court of
Appeal reinstated Prothonotary Morneau’s decision which left the matter to the
applications judge which, as it turns out, is me. One of the rationales for taking
a cautious approach to interlocutory motions in applications is that these
matters may be successfully resolved by cross-examination and, in any event the
applications judge, after hearing the entire case, is in a better position to
consider relevance and to render a ruling.
[122] Apparently,
Dr. Kellogg’s aim was to carry out his experiments as if he were back in 1988. This
is a very difficult task. His report falls short of the mark and does not make
it more or less self-evident that resolution ought to have worked in 1988. I
consider it unfortunate that Dr. Kellogg was put forth as a factual rather than
an expert witness given that he and his company have done this type of work. This
limited cross-examination.
[123] The mandate Dr.
Kellogg was given in late 2006 was to resolve the citalopram diol. Immediately
one realizes that a number of other possible starting points had been
eliminated. Although phencyphos was in existence prior to 1988, the only relevant
paper published, that of Wolter ten Hoeve and Hans Wynberg, does not identify
it as a likely candidate. There is no explanation as to why phencyphos was
selected. In cross-examination, Dr. McClelland admitted that he had not used phencyphos
prior to 1988 and that it was not commercially available from the most
important supplier of such compounds before 1995. With respect to the chiral
HPLC column resolution, the column used, a chiralcel OD-H, came on the market
after 2000. It has smaller particle sizes which, as admitted by Dr. Ward, have a
direct impact on its resolution capacity. Dr. Kellogg did not successfully
recreate what would have happened in 1988.
[124] To conclude
on this point, the resolution of citalopram was not obvious. It was not more or
less self-evident that resolution ought to work. There were almost an infinite
number of parameters known to persons skilled in the art. The only trials
carried out up to 1988 were by Lundbeck. They certainly were not routine. They
were prolonged and arduous. They succeeded in inventing escitalopram.
ANTICIPATION BY PRIOR
USE
[125] In addition
to anticipation by prior publication, all the respondents alleged in their NOAs
that escitalopram had been previously used. The theory is that the body resolves
citalopram into its two enantiomers on its own. Neither Cobalt nor Apotex pursued
this allegation. As Professor Jenner stated at paragraph 23 of his affidavit
for Apotex: “…The enantiomers do not physically separate when ingested but
interact with molecules in the body in different lock and key ways…”. However
this evidence does not form part of the Genpharm application.
[126] Dr. Newton,
speaking as a witness called by Genpharm, was of the opinion that when a
racemic drug, such as citalopram, is ingested, the two enantiomers exist as two
separate compounds in solution. They react with receptors within the body at
different rates. It is only the biologically active enantiomer that binds to
the receptor to produce a drug receptor complex and a biological response. The
inactive enantiomer, R-citalopram, has little or no affinity for the receptor
and does not bind to it.
[127] The legal
inspiration for this hypothesis is the decision of the House of Lords in Merrell
Dow Pharmaceuticals Inc. v. N.H. Norton and Co. Ltd., [1996] UKHL 14,
[1996] R.P.C. 76. In that case, Merrell Dow had obtained a patent for
terfenadine, an anti-histamine. Following the expiry of the patent, other
companies began to make and market their generic versions. However, Merrell Dow
discovered that when the drug passed through the stomach it was metabolised in
the liver. They analyzed the chemical composition of the acid metabolite formed
in the liver, patented it and then alleged that the generic versions of
terfenadine infringed.
[128] In essence, knowledge
of the acid metabolite was held to have been available to the public by means
of the terfenadine specification under the description “a part of the chemical
reaction in the human body produced by the ingestion of terfenadine and having
an anti-histamine effect.” Technically it was held that this was anticipation
by disclosure, not anticipation by use.
[129] The evidence
in this case is not evidence at all; it is outright conjecture. The precise
configuration of the receptors within the body is not known, and there is no
reason to believe that the R-enantiomer is completely inactive. The tests
disclosed in the ‘452 patent suggest there is some activity within the
R-enantiomer, albeit even though it is some 60 to 130 times less potent than
escitalopram. Furthermore, Rochat obtained his partially resolved citalopram by
drawing human blood samples which suggests that the body does not resolve
citalopram into substantially pure escitalopram and R-citalopram. The
distinction between conjecture and inference is most important. In Minister of Employment and Immigration v. Satiacum
(1989), 99 N.R. 171 (F.C.A.) at paragraphs 34 and 35, Mr. Justice MacGuigan
wrote:
The common law has long recognized the difference between
reasonable inference and pure conjecture. Lord Macmillan put the distinction
this way in Jones v. Great Western Railway Co. (1930), 47 T.L.R. 39, at
45, 144 L.T. 194, at 202, (H.L.):
“The dividing line between conjecture and inference is often a
very difficult one to draw. A conjecture may be plausible but it is of no legal
value, for its essence is that it is a mere guess. An inference in the legal
sense, on the other hand, is a deduction from the evidence, and if it is a
reasonable deduction it may have the validity of legal proof…”
AMBIGUITY
[130] The Patent
Act requires the specification to correctly and fully describe the
invention. However it must be read by a mind willing to understand, not a
nit-picking mind, and should not be defeated on a mere technicality. It has
been alleged that the patent is ambiguous because claim 1 is directed to
substantially pure (+) citalopram, a term not defined. However there is no
ambiguity. The examples given show purity in excess of 99% and Professor Davies
was of the view that “substantially pure” would mean at least 95% as a standard
method for measuring purity can only reliably detect impurities if they are
present at a level of 5%. Likewise, a proper reading of the patent indicates
“substantially pure” refers to optical purity. This lack of definition did not
bother Justices Mosley and Hughes in the Janssen-Ortho cases cited at
paragraph 11 of these reasons.
[131] Apotex makes
the point that different solvents may rotate light in a different way so that
the (+) and (-) designations are ambiguous. I find no merit in this allegation
as the solvents were fully described.
[132] As Mr.
Justice Hughes noted in Pfizer Canada Inc. v. Canada (Minister of
Health),
2005 FC 1725, 46 C.P.R. (4th) 244 at paragraphs 49-53, “…ambiguity is
truly a last resort, rarely, if ever, to be used.”. I hold that patent is
not invalid for ambiguity.
OTHER ALLEGATIONS OF
INVALIDITY
[133] The
usefulness of an invention need not be demonstrated in the patent. A sound
prediction will suffice. As noted by the Supreme Court in Apotex Inc. v.
Wellcome Foundation Ltd., [2002] 4 S.C.R. 453, , 21 C.P.R. (4th) 499, sound
prediction is dependent upon a factual basis, the inventor must have an
articulate and sound line of reasoning from which the desired result can be
inferred from that factual basis and there must be proper disclosure. One must
carefully consider what the inventor promised. As noted above, the inventor did
not promise that escitalopram was better than citalopram as an antidepressant,
although there are now indications that it is indeed the case. Although there is
no evidence that escitalopram had been tested on humans that is not a condition
precedent to obtaining a patent, as opposed to obtaining food and drug
administration approvals. The testing disclosed was on rodents, the same
testing which had been done on citalopram. Since citalopram was a useful
antidepressant and escitalopram was more potent with no indication of adverse
side effects, it follows that the prediction was a sound one. This allegation,
particularly pursued by Apotex, fails.
[134] Usefulness
was promised, usefulness was predicted and usefulness was delivered. Only a
scintilla of utility was required (Laboratoires Servier v. Apotex Inc., 2008
FC 825, 67 C.P.R. (4th) 241 as per Madam Justice Snider at paragraph 270, quoting
the edition of Fox referred to at paragraph 32 hereof, at page 153).
[135] A failure to
define the way an invention is produced or built would invalidate a patent on
the grounds of insufficiency (Pioneer Hi-Bred Ltd. v. Canada (Commissioner
of Patents), [1989] 1 S.C.R. 1623, 25 C.P.R. (3d) 257). A patent is
sufficient as long as the patentee describes what the invention is, its
usefulness and describes how a person skilled in the art could put it into
practice by producing it (Pfizer Canada Inc. v. Canada (Minister of
Health),
2008 FCA 108, 67 C.P.R. (4th) 23). Apotex submitted that the ‘452 patent is
invalid because it discloses that escitalopram might be useful in the treatment
of obesity and alcoholism, but provides no particulars thereof. However, the
patent makes no promise or claim in this regard and so supporting data was not
required. The claim portion of the patent specification takes precedence over
the disclosure portion.
[136] Likewise,
Apotex also submits that the ‘452 patent is invalid because even if it
established that escitalopram is useful as an anti-depressant, it did not do so
with respect to R-citalopram. Indeed, the disclosure begins “the present
invention relates to the two novel enantiomers of [citalopram].” Again, in the
claim portion of the specification no promise whatsoever was made that
R-citalopram was useful as an anti-depressant. Maybe it is. Maybe it is not.
However, the patent cannot fall because of something which was not claimed. At
most, the patent disclosed R-citalopram and so it would be much too late for
anyone to now seek patent protection.
[137] Cobalt
alleges inutility because of the wide dosage range in claim 5 of 0.1 to 100
milligrams, especially when compared to a narrower range in the citalopram
patent, citalopram being less potent. This, surely, is a lawyer’s point. Cobalt
has not put in play any evidence that at the lower extremities the unit dosage
would not be useful.
[138] I said
earlier that only claims 1, 3 and that portion of 5 dependent on 3 are at
issue. In its NOA, Apotex said that claim 2, including claims 4 and 5 as dependent
thereon, are irrelevant. However, in its argument it submitted that all of claims
1 through 5 were invalid. Claim 2, 4 and 5 read:
- 2 -
A compound of Claim 1 being the pamoic
acid salt of (+)-1-(3-dimethylaminopropyl)-1-(4’-fluorophenyl-1, 3-dihydro-isobenzofuran-5-carbonitrile.
- 4 -
A pharmaceutical composition in unit
dosage form useful as an antidepressant comprising a
pharmaceutically-acceptable diluent or adjuvant and, as an active ingredient,
an effective amount of the compound of claim 2.
- 5 -
A pharmaceutical composition in unit
dosage form, useful as an antidepressant according to claim 3 or 4, wherein the
active ingredient is present in an amount from 0.1 to 100 milligram per unit
dose.
[139] Apotex
alleges that the pamoic acid addition salt of escitalopram is toxic. The basis
of this allegation is a Lundbeck patent application in 2004 which refers to the
free base of escitalopram as an oil, not as salt. Pamoic salt or pamoate salts
were commercially approved in 1988 (McClelland, cross-examination at pp.
200-205). In any event, claim 1 only covers escitalopram and non-toxic
additional salts thereof and does not include pamoic salt. In Burton Parsons
Chemicals Inc. v. Hewlett Packard (Canada) Ltd., [1976] 1 S.C.R.
555 at 563, 17 C.P.R. (2d) 97, it was held that the knowledge the skilled
addressee is expected to possess is to be taken into consideration in
construing a patent. To such an addressee it is obvious that one is not to
devise a compound with ingredients that are toxic.
[140] That
rationale also applies to the allegation that some of the salts may not be
useful. The characteristics of unsuitable salts would be avoided by application
of the knowledge expected of the skilled addressee. Thus the allegations as they
may pertain to claims 2, 4 and 5 are not justified.
[141] Apotex and
Cobalt assert the specification is insufficient since the resolution methods
disclosed were not economically and environmentally feasible for industry
production. Apart from lack of evidence, the argument is irrelevant as
commercial utility was not promised and was not required. The question is
whether the invention works and does what the specification promises it will
do: act as an antidepressant.
[142] Dr. Keana
found so much linguistic imperfection in the patent that it could not be
understood. For instance, there was a reference to a compound 20 which, on
cross-examination, he had to concede to be a clerical error and had to refer to
escitalopram. As well, there was failure to mention a phenol, but it was
impossible to work the invention without it. Dr. McClelland, also called by
Apotex, had no problem understanding the invention.
[143] Genpharm criticized
the patent for not providing margins of error, for stating that most of the
activity resided in escitalopram rather than R-citalopram without giving sufficient
particulars and for setting out test results which had to be a compilation
drawn from more than one test. The test results nevertheless gave sufficient
detail. Even allowing for a margin of error, the worst possible situation was
that escitalopram was only nearly sixty times as potent as R-citalopram. The
point was that escitalopram was far more potent and every chemist called by the
respondents assumed that one enantiomer would be more potent than the other.
[144] The
respondents allege that the claims are broader than the invention made. For
instance, Cobalt alleges that if there is any invention, it should be limited
to the specific resolution methods disclosed in the ‘452 patent and that escitalopram
cannot be claimed regardless of how it is made. This point is going to the
House of Lords as noted earlier in these reasons. However, I take the law to be
as stated by Lord Hoffman who came down from the House of Lords to hear the Generics
(U.K.) Ltd. case in appeal:
26. The judge held that
claim 1 and claim 3 (which is dependent on claim 1) were insufficient. His
reasoning was that claim 1, being a claim to the (+) enantiomer as a product,
was a claim to a monopoly of that product however made: see section 60(1)(a) of
the 1977 Act. But Lundbeck's inventive idea was not to discover that the
enantiomer existed and had a medicinal effect. Everyone knew that the two
enantiomers existed and that one or other or both had a medicinal effect. What
Lundbeck discovered was one way of making it. But that did not entitle them to
a monopoly of every way of making it.
27. I can understand
and sympathise with the judge's instinctive reaction to the inherent breadth of
a product claim. Indeed, as I shall in due course show, he is not the first to
have registered such a protest. But in my opinion his reasoning is not
justified either by the statute or the authorities. In an ordinary product
claim, the product is the invention. It is sufficiently enabled if the specification
and common general knowledge enables the skilled person to make it. One method
is enough.
[145] Cobalt
alleges that section 53 was breached because the patentee failed to disclose
the prior art which revealed the importance of stereochemistry and the
likelihood that one enantiomer would have better pharmaceutical activity than
the other, and in failing to bring those facts to the attention of the patent examiner.
However, there is no provision in the Patent Act or Rules that an
omission to disclose prior art has any effect on the validity of a patent. In
any event, the closest prior art was U.S. patent ‘193 which had
been disclosed.
[146] This argument
runs counter to the accepted proposition that even an undergraduate organic
chemistry student would have appreciated the stereochemistry aspects of the
patent. While this case does not go into the qualities expected of a patent
examiner, there is certainly no reason to suppose that he or she is a dolt.
[147]
Section
53 provided that a patent might be invalidated if any material allegation was untrue
and wilfully made for the purpose of misleading. Both Cobalt and Apotex made
much of the fact that the patent states “…Results upon administration to human
beings have been very gratifying.” At that point in time, as confirmed by Dr. Bøgesø, escitalopram had not been
administered to human beings. Lundbeck led evidence from Peter Davies who spent
37 years with the Canadian Patent Office culminating in his appointment as
Chairman of the Patent Appeal Board. Had he been the examiner in looking for
utility, he would have examined the reported data and would have thought that
the statement referred to the racemate. With all respect to Mr. Davies, the
language was not technical and the Court does not need his assistance in reading
that portion of the patent, although I do note that some pages earlier the
following statement appears “…All work in the development of this compound has
been made with the racemate…” However Mr. Davies’ evidence is helpful in that
he points out the file history does not indicate that the examiner requested an
explanation for or correction of this statement. Given that the patent has two
full pages of evaluation of escitalopram upon rodents together with a table of
pharmacological test results, I do not consider that the one-liner misled
anyone. Furthermore, there is no evidence of an effort to mislead.
INTERLOCUTORY MATTERS
[148] Mention has
been made in these reasons of efforts by Lundbeck to strike affidavits or
portions thereof, to adduce new evidence or both. Counsel for the respondents on
occasion directed witnesses who were being cross-examined not to answer
questions and some answers were given under reserve of objections. The motions
will be dismissed and rulings on objections and refusals are not necessary as no
new evidence is needed, answers are not needed to questions which were not
answered and no reliance was placed on the evidence taken under reserve. No
useful purpose would be served.
SUMMATION
[149] To summarize,
patent ‘452 is not a selection patent. If I am wrong on that score then it is
an invalid selection patent. The other allegations of invalidity asserted by
the respondents, be they with respect to anticipation, obviousness, ambiguity,
or otherwise, are not justified. Lundbeck has made its case and the Minister
shall be prohibited from issuing Notices of Compliance to the respondents prior
to the expiry of the patent.
COSTS
[150] Lundbeck Canada Inc. and H. Lundbeck A/S are entitled to one set of
costs in each of the three applications. Failing agreement, the parties have 30
days to move for directions, and may seek an order for lump sum costs in whole
or in part. As the Minister did not participate, the prohibition orders shall
issue against him without costs.
“Sean Harrington”
Toronto,
Ontario
February
25, 2009