Apotex Inc. v. Bayer AG

Apotex Inc. v. Bayer AG Court (s) Database Federal Court of Appeal Decisions Date 2007-06-22 Neutral citation 2007 FCA 243 File numbers A-546-03 Decision Content 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) Heard at Toronto, Ontario, on May 15, 2007. Judgment delivered at Ottawa, Ontario, on June 22, 2007. REASONS FOR JUDGMENT BY: SHARLOW J.A. CONCURRED IN BY: SEXTON J.A. MALONE J.A. 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” J.A. “I agree J. Edgar Sexton J.A.” “I agree B. Malone J.A.” FEDERAL COURT OF APPEAL NAMES OF COUNSEL AND SOLICITORS OF RECORD DOCKET: A-546-03 (APPEAL FROM THE ORDER OF THE HONOURABLE MR. JUSTICE GIBSON DATED OCTOBER 17, 2003, FROM THE FEDERAL COURT OF CANADA, FILE NO. T-2052-01) STYLE OF CAUSE: Apotex Inc. v. Bayer AG and Bayer Inc. and The Minister of Health PLACE OF HEARING: Toronto, Ontario DATE OF HEARING: May 15, 2007 REASONS FOR JUDGMENT BY: Sharlow J.A. CONCURRED IN BY: Sexton J.A. Malone J.A. DATED: June 22, 2007 APPEARANCES: H.B. Radomski N. Deluca R. Tuzi N. Belmore L. Neidrauer N. Rizkalla-Kamel FOR THE APPELLANT APOTEX INC. FOR THE RESPONDENTS BAYER AG and BAYER INC. E. Peterson FOR THE RESPONDENT THE MINISTER OF HEALTH SOLICITORS OF RECORD: Goodmans LLP Toronto, Ontario Gowlings Lafleur Henderson LLP Toronto, Ontario FOR THE APPELLANT APOTEX INC. FOR THE RESPONDENTS BAYER AG and BAYER INC. John H. Sims, Q.C. Deputy Attorney General of Canada Ottawa, Ontario FOR THE RESPONDENT THE MINISTER OF HEALTH