Date: 20070622
Docket: A-546-03
Citation: 2007 FCA 243
CORAM: SEXTON
J.A.
SHARLOW
J.A.
MALONE
J.A.
BETWEEN:
APOTEX INC.
Appellant
(Respondent)
and
BAYER AG and BAYER INC.
Respondents
(Applicants)
and
THE MINISTER OF HEALTH
Respondent
(Respondent)
REASONS FOR JUDGMENT
SHARLOW J.A.
[1]
This is an
appeal by Apotex Inc. from a Federal Court judgment dated October 17, 2003
granting the application of Bayer AG and Bayer Inc. (collectively, “Bayer”) for
an order under the Patented Medicines (Notice of Compliance) Regulations,
SOR/93-133 (the “NOC Regulations”) prohibiting the Minister of Health
from issuing a notice of compliance to Apotex for ciprofloxacin hydrochloride
tablets until after the expiry of Canadian Patent No. 1,218,067 (the “067
patent”).
[2]
Most of
the record in this case was presented in the form of documents in respect of
which a protective order had been made under Rule 151 of the Federal Courts
Rules. At the hearing of this appeal, counsel for both parties agreed that
they no longer consider any of the information in the record to be
confidential.
[3]
The 067
patent was issued on February 17, 1987 and expired on February 17, 2004. A
notice of compliance was issued before this appeal was heard, rendering the
appeal moot. However, the appeal was allowed to continue because the outcome of
the appeal may affect the rights of Apotex under section 8 of the NOC
Regulations: see Bayer AG v. Apotex Inc., 2004 FCA 242, leave to
appeal refused [2004] S.C.C.A. No. 408 (QL).
The 067 patent
[4]
The 067
patent relates to a number of compounds described by the term
“1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylic acids”, which are said
to be useful as antibacterial agents. Ciprofloxacin is one of the compounds
described by that term.
[5]
Claim 8
and claim 14 of the 067 patent are “product by process claims”. They claim
“1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic
acid” made by certain methods. The quoted term includes four specific compounds
of which one component may be hydrogen, methyl, ethyl or β-hydroxy ethyl.
If that component is hydrogen, the compound is ciprofloxacin, so that both
claim 8 and claim 14 include claims for ciprofloxacin. Only the claims for
ciprofloxacin in claim 8 and claim 14 are in issue in this appeal.
[6]
The
difference between claim 8 and claim 14 relates to the process by which the
claimed compound is made. Claim 8 claims the named compound “of Formula I as
defined in claim 1 or a pharmaceutically acceptable salt or hydrate thereof
when prepared by a process according to claim 1 or an obvious chemical
equivalent thereof”. Claim 14 claims the named compound “when prepared by a
process according to claim 10, 11 or 12 or an obvious chemical equivalent
thereof”. Thus, both claim 8 and claim 14, read literally, include claims for
ciprofloxacin prepared by a specified process.
[7]
The
prohibition application in issue in this appeal was a response to a notice of
allegation dated October 4, 2001. The Judge says, at paragraph 3 of his
reasons, that the notice of allegation alleges that claims 8 and 14 of the 067
patent as they relate to ciprofloxacin are invalid for obviousness, and that
the process described in claims 10, 11 and 12, are also invalid for
obviousness. The Judge’s description of the notice of allegation is
unchallenged. That is fortunate because the copy of the notice of allegation in
the record (Appeal Book, Volume VII, pages 1918 to 1927) contains only the odd
numbered pages of the original notice of allegation. The Judge concluded that
the allegation of invalidity was not justified, and granted the prohibition
order.
Construction of claims 8 and 14
[8]
Apotex
argues that the Judge erred in failing to construe the patent claims. Bayer
argues that Apotex cannot raise this argument because it does not appear in its
notice of appeal and because, in any event, it was not necessary for the Judge
to construe the patent claims because there was no dispute between the parties
as to the construction of the claims.
[9]
In this
case, no evidence was submitted by either party dealing directly with the
construction of the patent claims. Although the record of this case consists of
seventeen volumes of material, including 13 affidavits and a transcript of
cross-examination for each affidavit, no witness directly addressed the
construction of the patent claims. In addition, as far as I can tell, no issue
of patent construction was raised in argument in the Federal Court. There is
merit in Bayer’s submission that Apotex should be precluded from arguing claims
construction for the first time on appeal.
[10]
However,
it is now established in the jurisprudence that in every judicial decision in
which the validity or infringement of a patent claim is in issue, the
construction of the claim is an essential starting point: Whirlpool Corp. v.
Camco Inc., [2000] 2 S.C.R. 1067 at paragraph 43. Normally, the task of
construing a patent claim requires the Judge to consider and analyze expert
evidence as to how a person skilled in the art would interpret the language of
the claims and specification. Appellate review of a decision on the validity or
infringement of a patent claim is difficult, if not impossible, unless it is
possible to discern the starting point of the analysis.
[11]
I note
that this case involves proceedings under the NOC Regulations, which do
not and cannot involve a final determination of the validity of the patent in
issue. The lack of an authoritative pronouncement on the correct construction
of claims 8 and 14 of the 067 patent will have no importance outside this case.
Also, this appeal is being heard despite its mootness only because Apotex has a
potential claim for damages if the appeal succeeds. In these circumstances, it
seems preferable to address the question of claims construction as well as I
can based on the appeal record, rather than return this case to the Federal
Court for reconsideration on the basis that the patent claims must be
construed.
[12]
How should
I deal with the issue of the construction of the patent claim, which is an
essential step in the analysis of an allegation that a patent claim is invalid
for obviousness, when the record contains no direct evidence on that question?
Fortunately, there is no dilemma.
[13]
It is
apparent to me that the arguments of both parties in the Federal Court were
based on the premise that, in so far as this case is concerned, claim 8 and
claim 14 as they relate to ciprofloxacin are to be construed literally, so that
they are simply claims to ciprofloxacin itself when made by one of a number of
processes. The utility of ciprofloxacin is said to relate to its antimicrobial
effect, but the inventors do not assert a claim for ciprofloxacin of any
particular quality or for any particular use. Neither party argues that any
particular quality or effect of ciprofloxacin is an aspect of claim 8 or claim
14, or that there is any claim to a particular use of ciprofloxacin.
[14]
Therefore,
I will assume for the purposes of this appeal that claim 8 and claim 14 are to
be construed on the basis of the apparent shared premise of the parties. In
that regard, Apotex suggested in argument that certain comments made by the
Judge could indicate that he had implicitly adopted a different construction of
the claims. I do not read any of the Judge’s cited comments that way. In my
view, the cited comments were related either to undisputed facts (such as the
commercial success of ciprofloxacin) or were part of his discussion of the
factors relevant to the question of obviousness. Reading the Judge’s reasons in
their entirety, it seems to me reasonable to assume that the Judge implicitly
adopted the same patent construction as the parties.
[15]
In dealing
with the issue of patent construction in this manner, I have avoided the need
to resolve the issue as to whether the absence of expert evidence dealing
specifically with the issue of patent construction is or should be fatal to
Bayer’s application for a prohibition order under the NOC Regulations,
or whether it was incumbent on Apotex to address patent construction in its
notice of allegation in the context of its allegations of invalidity. These
remain open questions. Perhaps the best practice is for both parties to address
claims construction in their evidence and in argument, even if they agree on
what it should be.
Obviousness
[16]
The policy
of the Patent Act, R.S.C. 1985, c. P-4, is to reward an inventor with a
monopoly on the right to exploit the invention provided the claimed invention
is properly disclosed and fulfils the statutory requirements of novelty,
utility and ingenuity: Whirlpool (cited above) and Free World
Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024. The element of
ingenuity is implicit in the definition of “invention” in the Patent Act which
reads as follows:
|
“invention” means any
new and useful art, process, machine, manufacture or composition of matter,
or any new and useful improvement in any art, process, machine, manufacture
or composition of matter.
|
«invention » Toute
réalisation, tout procédé, toute machine, fabrication ou composition de
matières, ainsi que tout perfectionnement de l’un d’eux, présentant le
caractère de la nouveauté et de l’utilité.
|
[17]
If there
is not a sufficient element of ingenuity to warrant a monopoly, the claimed
invention is said to be “obvious” and no patent will issue, or a patent that
has been issued may be invalidated, or the holder of the patent will be unable
to succeed in a claim for infringement.
[18]
The determination of an allegation that a
claimed invention is obvious is essentially a factual exercise, informed by the
policy of the Patent Act as summarized above. Hugessen J.A. stated the accepted legal
test for obviousness in Beloit Canada Ltd. et al. v. Valmet OY (1986),
8 C.P.R. (3d) 289 (F.C.A.) at page 294:
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.
[19]
The
inquiry mandated by the Beloit test must be guided by expert
evidence about the relevant skills of the hypothetical person of ordinary skill
in the art, and the state of the art at the relevant time. The expert evidence
must be carefully assessed by the trier of fact as to its credibility and
reliability. There is no single factual question or a set of questions that
will determine every claim of obviousness.
[20]
It is
undisputed in this case that, for the purposes of determining obviousness, the
person of ordinary skill in the art is a highly trained and experienced
scientist, and that the state of the art is to be determined as of the priority
filing date for the 067 patent, which is October 29, 1981.
[21]
The main
allegation of Apotex is that claims 8 and 14, insofar as they relate to ciprofloxacin,
are obvious because ciprofloxacin would have been obvious as of the relevant
date to the person of ordinary skill in the art. If that argument is valid,
then the claims for ciprofloxacin in claims 8 and 14 are invalid for
obviousness, regardless of the process by which ciprofloxacin may be made.
Therefore, I will deal first with the claims for ciprofloxacin itself and
ignore for the moment the problem of how to make it.
[22]
There is
little controversy about what material comprises the relevant prior art. The
argument of Apotex essentially walks through the prior art in chronological
fashion to demonstrate what a person of ordinary skill in the art could and
would have done to discern that a substance with the chemical structure of
ciprofloxacin would be a better antimicrobial agent than the previously known
substance norfloxacin, and to synthesize ciprofloxacin from norfloxacin. The
argument of Apotex on this point is supported by expert evidence submitted by
Apotex and contradicted by expert evidence submitted by Bayer.
[23]
Each of
the expert witnesses who expressed an opinion on obviousness is highly
qualified. The Judge made no adverse comments on the credibility or reliability
of any of the expert evidence that is relevant to the question of the obviousness
of ciprofloxacin.
[24]
The Judge
noted at paragraph 90 of his reasons that “much of the expert testimony
presented on behalf of Apotex reflects hindsight analysis.” I agree with that
assessment of the Apotex evidence but I do not regard it as necessarily fatal
to the position of Apotex. The traditional warning about hindsight is found in Beloit (at page 295, per Hugessen
J.A.):
Every invention is obvious after it has
been made, and to no one more so than an expert in the field. Where the expert
has been hired for the purpose of testifying, his infallible hindsight is even
more suspect. It is so easy, once the teaching of a patent is known, to say,
"I could have done that"; before the assertion can be given any
weight, one must have a satisfactory answer to the question, "Why didn't
you?"
[25]
This does not mean that the trier of fact is
required as a matter of law to reject an expert’s hindsight analysis. After
all, the evidence of a party alleging invalidity for obviousness is necessarily
based to some degree on hindsight because it is addressed to a hypothetical
question about a point of time in the past. However, as a factual matter, an
allegation of obviousness may be weakened if the evidence does not explain,
directly or by inference, why the claimed invention was not discovered by
others.
[26]
In this
regard, I observe that in this case there is evidence that during the relevant
period well known companies around the world were engaged in synthesizing
quinolone, naphthyridine and pyridopyrimidine compounds but did not synthesize
ciprofloxacin (Affidavit #1 of Dr. Paul Actor, Appeal Book, Volume III,
paragraph 27, pages 640-641). In my view, that evidence weighs against but does
not necessarily defeat the argument that ciprofloxacin was obvious.
[27]
I now turn
to the submissions of Apotex as to what the prior art would have taught the
person of ordinary skill in the art at the relevant date about ciprofloxacin. I
summarize those submissions as follows:
a.
The term
“quinolone” may be used in a broad sense to include any fused two-ring compound
containing a nitrogen at the N1 position of the right ring and 0, 1 or 2
nitrogens in the left ring.
b.
The term
“quinolone” may also be used in a narrow sense to mean a fused two-ring
compound containing a nitrogen at the N1 position of the right ring and no
nitrogen in the left ring.
c.
A
“naphthyridone” contains a nitrogen at the N1 position of the right ring and a
nitrogen in the left ring.
d.
A
“pyridopyrimidone” contains a nitrogen at the N1 position of the right ring and
2 nitrogens in the left ring.
e.
In a
quinolone (using that term in the broad sense), the use of a piperazine
substituent at the C7 position of the left ring is desirable to obtain good
antibacterial activity.
f.
Optimization
of N1 for antibacterial activity does not depend on other substituent groups
present on the rings.
g.
The
substitution of a fluorine at the C6 position of the left ring improves
antibacterial activity.
h.
Norfloxacin,
a quinolone (used in the narrow sense) and a proven antibacterial compound, was
invented in 1978. Norfloxacin differed from other known quinolones by the
introduction of a fluorine at the C6 carbon position in conjunction with a
piperazine at the C7 carbon position.
i.
The
substitution of cyclopropyl for ethyl at the N1 position of the right ring of a
quinolone (used in the broad sense) improves antibacterial activity across a
broad spectrum of bacteria.
j.
The only
difference between norfloxacin and ciprofloxacin is that norfloxacin contains
an ethyl at the N1 position while ciprofloxacin contains a cyclopropyl at the
N1 position. One obtains ciprofloxacin merely by substituting cyclopropyl for
ethyl at the N1 position. (For the purposes of this part of the analysis, it is
assumed that the method for making such a substitution was known.)
[28]
Based on
this line of reasoning, Apotex argues that as of October 29, 1981, it would
have been obvious to a person of ordinary skill in the art that an
antimicrobial compound better than norfloxacin would result from starting with
norfloxacin and substituting a cyclopropyl for an ethyl at the N1 position in
the right ring. Apotex cannot succeed unless this argument is correct. In that
sense, it is a threshold question.
[29]
The Judge
did not expressly ask himself this question, but moved directly to a
consideration of some of the factors that are traditionally considered in the
context of an allegation of obviousness. Given the other conclusions expressed
by the Judge, it seems to me that he likely would have answered this question
in Bayer’s favour. Nevertheless as he did not deal with this question
expressly, I will consider it based on my own review of the relevant evidence.
[30]
I do this
with considerable hesitation, because the affidavit material is lengthy,
detailed and technical, and I am compelled to read it with the limited
assistance afforded by the submissions of counsel on appeal which are
necessarily general and brief. I do not have the benefit, as the Judge did, of
several days of oral explanation. As a consequence, my review will be general
in nature, focussing where I think necessary on specific factual points on
which I have been able to discern a clear dispute between the experts that I
can assess based on their supporting explanations.
[31]
The
question of the obviousness of starting with norfloxacin and substituting ethyl
with cyclopropyl was addressed in the evidence of expert witnesses for both
parties, who of course reached opposite conclusions. The evidence is detailed
and in many respects repetitive. It is far from clear why the parties thought
it necessary to present so many affidavits saying largely the same things.
Nevertheless, having carefully reviewed the entire record, it seems to me that
the most cogent evidence on this question (including many but not all
unnecessary duplications) appears in the following documents listed below. They
are presented for convenience in chronological order, followed by my
observations about what appear to me to be the most telling points.
1.
Affidavit
#1 of Dr. Paul Actor (Bayer) sworn December 27, 2001 (Appeal Book Volume III,
Tab 7)
Dr.
Paul Actor, a professor of microbiology and immunology, was given the notice of
allegation filed by Apotex, as well as the prior art references upon which
Apotex relied, and addressed the obviousness theory presented by Apotex. Dr.
Actor opined that at the relevant date, it was generally accepted that for
quinolones, the optimal chemical substituent at the 1-position for
antimicrobial activity was ethyl, not cyclopropyl. Even the named inventor of
norfloxacin wrote during the relevant period that ethyl is the best substituent
at the 1-position of quinolones.
Dr.
Actor further opined that there was nothing in the prior art cited by Apotex
that would lead a person of ordinary skill in the art away from the accepted
preference for ethyl at that position, and in particular there was nothing to
indicate that anyone had studied the effect of substituting cyclopropyl at that
position. He noted that some of the prior art made general statements about the
superiority of cyclopropyl in relation to pyridopyrimidones and naphthyridones,
but contained no data. He opined that a person of ordinary skill in the art
would not rely on such general statements without supporting data, especially
in relation to a discussion about a compound that is not norfloxacin or another
quinolone (using that term in the narrow sense).
Dr.
Actor addressed in detail each item of prior art cited by Apotex, and provided
a full explanation as to why in his opinion it would not lead a person of
ordinary skill in the art to substitute cyclopropyl for ethyl in norfloxacin.
Having
been instructed by Bayer’s counsel that one response to an allegation of
obviousness is to ask why no one else had hit upon the invention, Dr. Actor
commented (at paragraph 25 of his affidavit) that “a number of other
pharmaceutical research and development companies were heavily involved in
synthesizing quinolone, naphthyridone and pyridopyrimidone compounds (e.g.
Warner Lambert, Sterling Drug, Kyorin Pharmaceutical Co., Dainippon
Pharmaceutical Co.) in the seventies and early eighties and none the companies,
all of whom employed highly trained expert synthetic chemists and
microbiologists, synthesized ciprofloxacin.”
2.
Affidavit
#1 of Dr. Robin D.G. Cooper (Bayer) sworn December 27, 2001 (Appeal Book Volume
V, Tab 11)
Dr.
Robin Cooper, an organic chemist, was given a mandate that was similar to that
given to Dr. Actor, and made substantially the same points as Dr. Actor. He
added that the state of the art at the relevant time would have taught the
person of ordinary skill in the art that a substituent at the 1-position would
have deleterious results in anti-bacterial activity. As cyclopropyl is bulkier
than ethyl, that person would not have chosen cyclopropyl for that position.
Dr.
Cooper, like Dr. Actor, presented a detailed analysis of the prior art cited by
Apotex. His analysis, which generally parallels that of Dr. Actor, supports his
conclusion that nothing in those references would have displaced the
conventional wisdom that ethyl, not cyclopropyl, was the optimal substituent.
Dr.
Cooper refers specifically to German Patent application 2808070 (the 070
application), an important foundation for the Apotex position, and opines that
it is not scientifically possible to predict from this work the effect of a
cyclopropyl on a quinolone molecule, “given the thousands of molecules
disclosed in the publication with such significant differences in the core
structures and substituent groups contemplated and disclosed therein”.
3.
Affidavit
#1 of Dr. George A. Olah (Apotex) sworn February 1, 2002 (Appeal Book Volume
XI, Tab 24)
Dr.
George Olah, winner of the 1994 Nobel Prize for chemistry and numerous other
awards, supported the argument of Apotex. He was provided with the notice of
allegation and the cited prior art, but not the affidavits of Dr. Actor and Dr.
Cooper. He opined that a person of ordinary skill in the art looking for a more
effective analog of norfloxacin would have replaced ethyl with cyclopropyl. He
presented a detailed and cogent explanation in support of his opinion.
4.
Affidavit
#1 of Dr. Robert M. Williams (Apotex) sworn February 1, 2002 (Appeal Book
Volume XI, Tab 29)
Dr.
Williams, a professor of chemistry, was given the notice of allegation, the
cited prior art, and the affidavits of Dr. Actor and Dr. Cooper. His opinion
supports the analysis and conclusion of Apotex, and includes a detailed
explanation in support of his opinion that a person of ordinary skill in the
art would have been led directly and without difficulty to ciprofloxacin as of
the relevant date. I will not reproduce his cogent analysis, but I will quote
the strongly worded summary from paragraph 48 of his affidavit:
[…] It is crystal clear that the literature
taught that substituting the N-1-ethyl group for a cyclopropyl group in the
nalidixic acid structure resulted in improved antibacterial activity.
Similarly, substituting the N-1-ethyl group for a cyclopropyl group in
pipemidic acid structure resulted in improved antibacterial activity. The
unimaginative skilled technician, who would have been aware of the norfloxacin
structure, did not need to invent or invest energy in creative thought to
perform the same cyclopropyl for ethyl substitution on the norfloxacin
structure. One can hardly imagine more prominent road signs pointing directly to
exercising this same cyclopropyl for ethyl substituent change on the
norfloxacin structure and the obvious result expected is improved antibacterial
activity. The logic and teachings of the literature prior to October 29, 1981
flow explicitly and unmistakably to the ciprofloxacin structure from
norfloxacin.
5.
Affidavit
#1 of Dr. Robert A. McClelland (Apotex) sworn February 5, 2002 (Appeal Book
Volume XI, Tab 22)
Dr.
Robert A. McClelland, a professor of chemistry, was also provided with the
notice of allegation, the cited prior art, and the affidavits of Dr. Actor and
Dr. Cooper. Like Dr. Williams, Dr. McClelland supports at every step the
analysis of Apotex. His affidavit contains a careful and detailed explanation as
to why he believed that a person of ordinary skill in the art would discover ciprofloxacin
from the cited prior art.
Dr.
McClelland replies to the comment of Dr. Actor on the question of why no one
else had hit upon ciprofloxacin. He points out that other companies were indeed
doing similar work, and some discovered useful compounds, suggesting that their
attention was elsewhere. He also argues that, since a person of ordinary skill
in the art would have recognized that the disclosure in the 070 application
included ciprofloxacin within its broadest aspects, they would have avoided
synthesizing ciprofloxacin “for reasons of patenting, not for a scientific
reason. They would not want to reinvent the wheel”. (I discuss this point following
this summary of the evidence, under the heading “Observation #1”.)
6.
Affidavit
#2 of Dr. Paul Actor (Bayer) sworn December 12, 2002 (Appeal Book Volume IV,
Tab 8)
Dr.
Actor’s second affidavit is intended to answer the affidavits of Dr. Olah, Dr.
Williams and Dr. McClelland. An important point made by Dr. Actor in this
affidavit is that the teaching in the prior art relating to naphthyridone and
pyridopyrimidone would not have been understood as directly applicable to
norfloxacin, which is a quinolone (used in the narrow sense). He points out
that there is nothing in the cited prior art that would lead a person of
ordinary skill in the art to conclude that the improved antibacterial activity
of a cyclopropyl substituent in a naphthyridone or a pyridopyrimidone would
result from a cyclopropyl substituent in a quinolone. He also opines that,
given the state of the art, a person of ordinary skill in the art seeking a
foundation for a cyclopropyl substituent would likely have chosen a
naphthyridone molecule such as enoxacin, not norfloxacin.
7.
Affidavit
#2 of Dr. Robin D.G. Cooper (Bayer) sworn January 2, 2003 (Appeal Book Volume
VI, Tab 12)
The
second affidavit of Dr. Cooper is also a response to the affidavits of Dr.
McClelland, Dr. Williams and Dr. Olah. His principal point is that their
position is based on the premise that norfloxacin was the target and an obvious
starting point for an improved antibacterial agent. He opines that this
characterization is overly simplistic and not realistic. In his view,
norfloxacin would not be an obvious starting point for a person of ordinary
skill in the art. Rather, such a person would first identify a suitable core
structure and then consider systematic alterations of varying degree to the
chemical substituents. This would entail preparing a list of many potential
target compounds, and would choose first the “low hanging fruit”, or the
easiest substitutions, a long and tedious process which is far from the
hypothetical process proposed by Apotex that would easily and without
difficulty produce ciprofloxacin from norfloxacin.
Dr.
Cooper also points out that it the substitution of cyclopropyl for ethyl on a
quinolone core structure were obvious in 1981, one would have expected patent
applications for such a structure after the publication of the 070 application
in 1979 and the publication of ciprofloxacin in 19892, but there are none.
Dr.
Cooper raises a number of other criticisms of the evidence of the Apotex
experts, which I will not summarize. It is sufficient to say that it is a
cogent and detailed attack on the bases of their analysis.
8.
Affidavit
#2 of Dr. George A. Olah (Apotex) sworn January 15, 2003 (Appeal Book Volume
XI, Tab 25)
Dr.
Olah’s second affidavit contains a response to the second affidavits of Dr.
Actor and Dr. Cooper. Most notably, Dr. Olah disagrees with Dr. Cooper’s analogy
of the “low hanging fruit” to describe how a person of ordinary skill in the
art would approach the question, but then he simply repeats what he said in his
first affidavit. The inference I draw from this exchange is that Dr. Olah
attributes a higher degree of sophistication to the person of ordinary skill in
the art than Dr. Cooper. (I discuss this point following this summary of the
evidence, under the heading “Observation #2”.)
9.
Affidavit
#2 of Dr. Robert A. McClelland (Apotex) sworn January 19, 2003 (Appeal Book
Volume XI, Tab 23)
The
second affidavit of Dr. McClelland contains a response to the affidavits of Dr.
Actor and Dr. Cooper. Most of it is simply a bare expression of disagreement.
However, Dr. McClelland does provide some support for disagreeing with the
suggestion made by Dr. Cooper that the hypothetical skilled person would have
chosen enoxacin as a starting point rather than norfloxacin. He cites the fact
that it was the publicly available information about norfloxacin that
encouraged the inventors of ciprofloxacin to continue their work. (I discuss
this point following this summary of the evidence, under the heading
“Observation #3”.)
10.
Affidavit
#2 of Dr. Robert M. Williams sworn January 21, 2003 (Appeal Book Volume XII,
Tab 30)
The
second affidavit of Dr. Williams also contains a response to the affidavits of
Dr. Actor and Dr. Cooper. A great deal of his affidavit consists of a defence
of his credentials and experience, in response to an attack on his credentials
and experience made by the Bayer affiants. Both the attack and the defence are
unnecessary and irrelevant because all of the experts are supposed to opine on
what a person of ordinary skill in the art would know or would do, not what the
experts themselves would know or would do.
Another
substantive disagreement relates to whether a person of ordinary skill in the
art would have started with enoxacin rather than norfloxacin. Dr. Williams
supports this rebuttal of Dr. Cooper’s evidence on this point with extensive
references to material from 1979 indicating that the antibacterial activity of
enoxacin would have been considered inadequate as a starting point, as compared
to norfloxacin, the antibacterial activity of which was known. (This point is
discussed below under the heading “Observation #3).
[32]
I also
reviewed the transcripts of the cross-examinations of the experts, paying
particular attention to the references made in the parties’ memoranda of fact
and law. In my view, there is nothing in the cross examinations that adds
substantially to the evidence summarized above.
[33]
The record
includes many affidavits in addition to those listed above. I have not
disregarded them. I have not referred to them because in my view they do not
significantly advance the debate on the threshold question of whether, at the
relevant time, a person of ordinary skill in the art would have been led
directly and without difficulty to synthesize ciprofloxacin from norfloxacin.
Observation #1: the
debate about whether the 070 application effectively discloses ciprofloxacin
[34]
Dr.
McClelland opined that because persons of ordinary skill in the art would have
recognized that the 070 application included ciprofloxacin within its broadest
aspects, they would have avoided synthesizing ciprofloxacin because they “would
not want to reinvent the wheel”. This comment invites a closer look at the 070
application, which cannot be understood without the assistance of expert
evidence. Would the 070 application have led a person of ordinary skill in the
art to the structure of ciprofloxacin?
[35]
The Bayer
experts are of the view that a person of ordinary skill in the art would not
have realized that the 070 application discloses the structure of
ciprofloxacin. Dr. Actor does not expressly deny that the structure of
ciprofloxacin is included within the general statements made in the 070
application, but he says that nothing in the 070 application points to a
compound with the structure of ciprofloxacin as having superior antimicrobial
properties (affidavit #1 of Dr. Actor, paragraphs 26, 29 and 30). Dr. Cooper
opines that nothing in the 070 application would have displaced the
conventional wisdom that ethyl, not cyclopropyl, was the optimal substituent.
He reaches that conclusion because none of the examples in the 070 application
are quinolones (in the narrow sense), and because the statements about the
properties of the cyclopropyl compounds are broad and unsupported by data
(affidavit #1 of Dr. Cooper, paragraph 23 and 25).
[36]
The Apotex
experts are of the view that a person of ordinary skill in the art would have
realized that the 070 application discloses the structure of ciprofloxacin. It
seems to me that they reach that conclusion, not because the structure of
ciprofloxacin appears expressly in the 070 application, but because the person
of ordinary skill in the art would infer the existence of ciprofloxacin from
certain general statements in the 070 application. First, Dr. Olah cites the
similarities between the structure of ciprofloxacin and the structure of the
compounds referred to in the 070 application (affidavit #2 of Dr. Olah,
paragraph 6). Second, Dr. McClelland relies on the phrase “optionally
substituted carbon atom” which he says would include a piperazinyl carbon
atom (affidavit #2 of Dr. McClelland, paragraph 18). Third, Dr. Williams
opines that the 070 application covers “most sub-families” in the quinolone
field including quinolones (in the narrow sense), although he also says that
the specific examples disclosed in the 070 patent did not include quinolones
(affidavit #1 of Dr. Williams, paragraphs 34 and 35). Dr. Williams
also responds to the suggestions of Dr. Cooper and Dr. Actor that the
statements in the prior art (including the 070 application) about the
superiority of cyclopropyl over ethyl were “vague”. That response appears to me
to be somewhat misdirected, because what Dr. Cooper and Dr. Actor said was that
the statements were unsupported by data, a point that Dr. Williams does not
refute.
[37]
Having
carefully reviewed what appears to be the most relevant evidence on this point,
it seems to me that Bayer has the better side of this argument. The Bayer
experts cast significant doubt on the proposition that the structure of
ciprofloxacin is disclosed in the 070 application well enough to lead a person
of ordinary skill in the art to recognize it as a compound that should be
synthesized because of the likelihood of its improved antibacterial properties.
This weakens the suggestion of Dr. McClelland as to the reason ciprofloxacin
was not discovered by anyone other than the inventors named in the 067 patent,
and leaves no persuasive answer to the question posed by Beloit: If the
invention of ciprofloxacin was so obvious, why didn’t someone else find it?
Observation #2 – Dr.
Olah’s comments on Dr. Cooper’s analogy of the low hanging fruit
[38]
Dr.
Olah’s disagreement with Dr. Cooper’s analogy of the “low hanging fruit”
suggests that Dr. Olah attributes a higher degree of sophistication to the
person of ordinary skill
in the art than Dr. Cooper. In that regard, it is unfortunate that Dr. Olah
does not elaborate in his affidavit on the skills he believed the hypothetical
person of ordinary skill in the art would possess. This suggests that he may
not have correctly differentiated a person of ordinary skill from a person like
himself, whose skills are extraordinary by any measure.
[39]
It seems
to me unlikely that Dr. Cooper would have made a similar error. In paragraph 6
of his first affidavit, he defines the notional skilled person as someone with
“a Ph.D. in chemistry or microbiology, or an MD with similar education and
experience and with several years of work experience in the pharmaceutical
industry, with an emphasis in drug development and evaluating new antibacterial
compounds.” The undisputed finding of the Judge is that, for the purposes of
this case, the notional skilled person is “a highly trained and experienced
scientist”, a description that accords reasonably well with what Dr. Cooper
described.
[40]
I infer
that Dr. Cooper was likely to have had a more accurate view of the skill level
required of the hypothetical person of ordinary skill in the art. This
conclusion weakens the evidence of Dr. Olah and therefore the case for Apotex,
and strengthens the evidence of Dr. Cooper and therefore the case for Bayer.
Observation #3 – the available
information about norfloxacin
[41]
Dr.
McClelland, disagreeing with Dr. Cooper, opines that a person of ordinary skill
in the art would not have chosen enoxacin as a starting point rather than
norfloxacin because there was publicly available information about norfloxacin
that encouraged the inventors of ciprofloxacin to continue their work. In my
view, this is not a strong rebuttal to the point made by Dr. Cooper that
enoxacin would have been the more logical starting part for the person of ordinary
skills. The named inventors of ciprofloxacin are acknowledged and experienced
inventors. The decisions they made on the basis of publicly available
information about norfloxacin cannot establish the decision that an inventive
person of ordinary skill might have made with the same information. I would
assess Dr. McClelland’s rebuttal of Dr. Cooper’s opinion on this point as weak.
On the other hand, Dr. Williams’ rebuttal of Dr. Cooper’s opinion on this point
is based on material from 1979 indicating persuasively that the antibacterial
activity of enoxacin would have made it inadequate as a starting point, as
compared to norfloxacin. I would assess Dr. Williams’ rebuttal on this point as
strong. However, the point is a narrow one (the choice of enoxacin versus
norfloxacin as a starting point), and by itself does not go far in advancing
the position of Apotex that the invention of ciprofloxacin was obvious.
Discussion
[42]
I note in
passing that the debate disclosed in this evidence indicates that there is some
potential for misunderstanding based on the two meanings of the term
“quinolone”. As indicated above, the word “quinolone” maybe used in a narrow
sense to refer to a fused two-ring compound containing a nitrogen at the N1
position of the right ring and no nitrogen in the left ring. It may also be
used in a broader sense to refer to any fused two-ring compound containing a
nitrogen at the N1 position of the right ring and 0, 1 or 2 nitrogens in the
left ring. In that broad meaning, the word “quinolone” would include a
“naphthyridone” (a nitrogen at the N1 position of the right ring and a nitrogen
in the left ring) and a “pyridopyrimidone” (a nitrogen at the N1 position of
the right ring and 2 nitrogens in the left ring). I mean no criticism of either
party when I note that using “quinolone” in the broader sense as Apotex has
done in most of its argument tends to minimize the distinctions between
quinolones (in the narrow sense), naphthyridones and pyridopyrimidones, while
using “quinolone” in the narrower sense as Bayer has done in its argument tends
to emphasize those distinctions. The first affidavit of Dr. Williams explains
(at paragraph 20) that the broader meaning of the term “quinolone” became
common after norfloxacin and ciprofloxacin became prominent (presumably, after
1981). If that is so, then most pre-1981 uses of the word “quinolone” should be
presumed to reflect the narrow meaning, especially since much of the prior art
relates to naphthyridones and pyridopyrimidones. In the final analysis, this dual
usage of the word “quinolone” does not strengthen or weaken the case for either
party to any substantial degree, but it does make the evidence and the argument
more difficult to understand. I acknowledge Dr. Williams as the only expert who
expressly made and explained the distinction.
[43]
Based on
this evidence and my observations about the strengths and weaknesses of the
debate between the experts, I conclude that as of October 29, 1981,
ciprofloxacin would not have been obvious to a person of ordinary skill in the
art. A review of the evidence discloses a picture of a field of research that,
during the relevant period, was highly complex and changing rapidly. Indeed,
the cited prior art spans a period of only four years, and the length of time
between the publication of the last item of prior art cited by Apotex and
October 29, 1981 is only 2.5 months. Throughout the relevant period many
pharmaceutical companies employing skilled and experienced scientists were
actively engaged in the search for better antimicrobial agents among the many
thousands of potential quinolone, naphthyridone and pyridopyrimidones
compounds. It is generally recognized that ciprofloxacin was a successful
result of that search, and there is no convincing explanation as to why the ciprofloxacin
solution was found only by the claimed inventors of ciprofloxacin, and not by
any of the other scientists engaged in the same or similar work Both parties
presented the evidence of highly qualified experts, who gave full and cogent
explanations as to why they believed that a person of ordinary skill in the art
would or would not have been led directly and without difficulty from
norfloxacin to ciprofloxacin. However, on a number of key points at which the
experts engaged in a specific factual debate, the evidence of the Bayer experts
was more persuasive. The weight of the evidence compels me to reject the
submission of Apotex on this threshold question. That is a sufficient ground on
which to find that Bayer has met its burden of establishing the allegations of
invalidity based on obviousness are not justified.
[44]
The Judge
reached the same conclusion on the basis of a different analysis. He focussed
his attention, in relation to the claims for ciprofloxacin itself (as opposed
to the method for making it) on some of the traditional obviousness factors,
“No motivation to combine”, “The prior art teaches away”, “Unexpectedly
improved properties”, “Secondary considerations” and “Hindsight analysis”.
[45]
With
respect to the Judge’s comments under the heading “No motivation to combine”,
Apotex argued that the Judge misinterpreted and therefore misapplied certain
statements from Wellcome Foundation Ltd. et al v. Apotex Inc. (1991), 39
C.P.R. (3d) 289 (F.C.T.D.). In particular, it is argued that the Judge erred in
concluding that ciprofloxacin’s “unexpected utility” was an answer to a claim
of obviousness. It is also argued that the Judge erred in failing to articulate
why he preferred the expert evidence submitted by Bayer on this point to the
expert evidence submitted by Apotex, particularly the portions he quoted. I
agree that the Wellcome case is not particularly relevant to this point,
and that the Judge should have offered better reasons for his assessment of the
evidence. However, based on my own analysis of the evidence, I agree with the
Judge that the evidence he quotes from the Bayer experts effectively refutes
the evidence he quotes from the Apotex experts.
[46]
With
respect to the Judge’s comments under the heading “The prior art teaches away”,
Apotex argues that the Judge did not provide adequate reasons for preferring
the expert evidence submitted by Bayer to that of the expert evidence submitted
by Apotex. I agree that the Judge should have offered a better explanation,
particular since he appears to have misconstrued certain comments made by Dr.
Williams in his cross-examination. However, given the conclusions I have
reached on the basis of my own review of the evidence, I cannot regard this
issue as consequential.
[47]
Apotex
also argued that the Judge gave undue weight to the unexpected utility and
commercial success of ciprofloxacin. I am inclined to agree with Apotex on this
point. The utility of ciprofloxacin was not in dispute and was not particularly
relevant to the obviousness debate. The subsequent commercial success of
ciprofloxacin says little, if anything, about the degree of inventive ingenuity
required to invent it, particularly since there is no dispute that there was a
recognized need in the market for better antibacterial agents. Again, however,
in the circumstances I cannot regard this issue as consequential.
Conclusion
[48]
I conclude
that there is no basis for interfering with the conclusion of the Judge that
the allegations of obviousness in relation to the claim for ciprofloxacin in
claim 8 and claim 14 of the 067 patent are not justified. I agree with the
Judge that this conclusion makes it unnecessary to consider the obviousness of
the stipulated methods. It follows that the Judge was correct to issue a
prohibition order.
[49]
It is also
unnecessary to deal with the other grounds of appeal.
[50]
I would
dismiss this appeal with costs.
“K.
Sharlow”
“I
agree
J.
Edgar Sexton J.A.”
“I
agree
B.
Malone J.A.”
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