Date: 20051028
Docket: T-1070-04
Citation: 2005 FC 1458
BETWEEN:
BRISTOL-MYERS SQUIBB CANADA CO. and
KYORIN PHARMACEUTICAL CO. LTD.
Applicants
and
NOVOPHARM LIMITED and
THE MINISTER OF HEALTH
Respondents
INTRODUCTION
[1] By Notice of Application filed the 31st of May, 2004, Bristol-Myers Squibb Canada Co. ("Bristol-Myers") and Kyorin Pharmaceutical Co. Ltd. ("Kyorin"), (collectively the "Applicants"), seek the following relief:
1. An order in accordance with section 6(1) of the Patented Medicines (Notice of Compliance) Regulations, prohibiting the Minister of Health from issuing a notice under section C.08.004 of the Food and Drug Regulations (a Notice of Compliance) to Novopharm Limited in connection with 400 mg strength of oral tablets of the drug gatifloxacin until after the expiration of Canadian Patent 1,340,316;
2. Its costs of this Application; and
3. Such further and other order as to this Honourable Court seems just.
As noted, the Application was filed pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations[1] (the "Regulations"). It was responsive to a Notice of Allegation dated the 12th of April, 2004 and addressed to Bristol-Myers indicating that:
Novopharm intends to make, construct, use and/or sell gatifloxacin in tablet form for oral administration, in 400 mg strength (the "Novopharm Tablet"). Novopharm has filed with the Minister of National Health and Welfare (the "Minister") an Abbreviated New Drug Submission ("ANDS") that compares the Novopharm Tablet with the TEQUIN® gatifloxacin tablets in 400 mg strength for oral administration which is marketed in Canada by Bristol under the Drug Identification Number 02243182.
[2] The Notice of Allegation notes that Canadian Patent No. 1,340,316 (the " '316 patent") is the patent in issue and contains eight claims of which claims 2, 3, 5, 6, 7 and 8 are directed towards compounds other than gatifloxacin and are therefore irrelevant to the Notice of Allegation. It notes:
Only claims 1 and 4 are considered as being included on the Register in regard to [Bristol-Myers' TEQUIN® gatifloxacin tablets in 400 mg strength for oral administration], and therefore as being relevant to Novopharm's submission for a NOC... .
Novopharm alleges that the '316 patent is not valid, and that no relevant claim of the patent is valid on the sole ground that the relevant claims were, at the relevant time, obvious.
[3] An extensive "Detailed Statement Of The Legal And Factual Basis" for the allegation of obviousness follows in the Notice of Allegation and is reproduced as a schedule to these reasons.
THE PARTIES
[4] Kyorin is identified at paragraph 10 of the Notice of Application as the owner of the '316 patent which relates to "novel quinolonecarboxylic acid derivatives having excellent properties as antibacterial agents, the process for their preparation, and anti-bacterial agents containing these novel compounds".[2]
[5] Bristol-Myers is a Canadian innovator pharmaceutical manufacturer. It has permission from Kyorin under the '316 patent, to manufacture and sell TEQUIN® in Canada. Bristol-Myers is the manufacturer in Canada of TEQUIN®, an antibiotic. The material before the court indicates that TEQUIN® is sold in Canada under the authority of a Notice or Notices of Compliance in the name of Bristol-Myers, for 400 mg oral tablets of the drug gatifloxacin.
[6] Novopharm is a "generic drug company", that is to say, a manufacturer and marketer of drugs in Canada which, in the words of Justice Nadon in Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare)[3], "market[s] a drug without having to independently establish the safety and effectiveness of the drug...". As earlier noted, Novopharm seeks a Notice of Compliance from the Minister to enable it to market an equivalent of TEQUIN®.
[7] The Minister of Health is the Minister charged with the administration of the Regulations. No material filed on behalf of the Minister was before the Court at the hearing of this application. Further, the Minister was not represented at the hearing.
THE PATENT IN SUIT
[8] The '316 patent is entitled "8-Alkoxyquinolonecarboxylic Acid and Salts Thereof Excellent in the Selective Toxicity and Process of Preparing the Same". The application for the '316 patent was filed on the 19th of January, 1987 based upon a claimed priority date of the 21st of January, 1986. As earlier indicated in these reasons, the owner is Kyorin Pharmaceutical Co., Ltd. of Japan. It includes eight claims, only two of which are relevant for the purposes of this proceeding, those being claims 1 and 4. Those claims are in the following terms:
CLAIMS
1 An 8-alkoxyquinolonecarboxylic acid derivative represented by a general formula (I):
wherein R indicates a hydrogen atom or lower alkyl group, R' indicates a lower alkyl group, R² indicates a hydrogen atom, X indicates a halogen atom, and Z indicates a halogen atom, piperazino group, N-methyl-piperazino group, 3-methylpiperazino group, 3-hydroxypyrrolidino group, or pyrrolidino group of the following formula:
[9] The '316 patent notes early in the disclosure:
The compounds of this invention are characterized in having a cyclopropyl group at the 1-position and an alkoxy group at the 8-position of the quinolinecarboxylic acid.
[10] While the '316 patent claims a number of novel alkoxyquinolonecarboxylic acid derivatives stated to have excellent properties as anti-bacterial agents, as noted, only one such compound is at issue here, that being gatifloxacin which is included within the compounds claimed in claim 1 and which is specifically claimed in claim 4.
[11] The '316 patent purports to disclose antibacterial compounds that exhibit the following beneficial and unexpected properties: activity against a wide range of bacterial types including aerobic, Gram-negative, Gram-positive, anaerobic and atypical bacteria; significantly better activity as compared to other quinolones, including ciprofloxacin which is well known to this Court; low toxicity; excellent absorption; and low probability of inducing antibiotic resistance.
[12] Gatifloxacin belongs to the much larger class of antibacterial compounds known as quinolones.
THE EXPERT AFFIANTS
[13] The Applicants relied on the evidence of three expert affiants, each of whom was cross-examined with transcripts of the cross-examinations being before the Court. The following is a very brief description of the qualifications and experience of each of the Applicants' experts.
[14] Dr. Paul Bartlett is a Professor of Chemistry, Emeritus, at the University of California, Berkeley. He has been teaching at Berkeley since 1973. He obtained his A.B. in chemistry from Harvard University in 1969 and his Ph.D. in Organic Chemistry from Stanford University in 1972. Dr. Bartlett then pursued one year as a post-doctoral fellow at the University of California, San Diego.
[15] In addition to fulfilling his teaching duties, at the date his affidavit was sworn, Dr. Bartlett led a research group in the field of bioorganic chemistry and synthetic organic chemistry. The focus of his research had been on the design, synthesis and evaluation of biologically active compounds. He consulted broadly with industry and lectured extensively on drug design. He had co-authored more than 175 articles and abstracts in the field of organic chemistry and had filed, either as the inventor or as a co-inventor, a number of United States patent applications. He was a member of a number of technical societies, served on the editorial advisory boards of several technical journals, and had chaired a number of technical conferences. He had received a number of awards in his field.
[16] Dr. Ross Davidson was, at the time he swore his affidavit, Associate Director of the clinical microbiology laboratory and Director of Molecular epidemiology at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia. He was also an Assistant Professor in the Department of Microbiology and Immunology at Dalhousie University with a cross-appointment to the departments of Medicine and Pathology. Dr. Davidson completed his Ph.D. in 1995 at the University of Manitoba with his doctoral research focussed on the mechanisms of action and resistance to the fluoroquinolones in Staphylococcus aureus, a Gram-positive bacterium. Subsequent to obtaining his Ph.D., Dr. Davidson completed a fellowship in Medical Microbiology at the University of Toronto and Mount Sinai Hospital.
[17] Once again at the time he swore his affidavit, Dr. Davidson had published over 100 papers, book chapters and conference abstracts on the mechanisms of bacterial resistance, surveillance of antibacterial resistance and the appropriate use of antibiotics in the management of infectious diseases. He attests that many of his publications had focussed specifically on the fluoroquinolone class of antibiotics. He attests further that he had given several hundred invited lectures on the mechanisms of bacterial resistance, surveillance of antibacterial resistance and the appropriate use of antibiotics in the management of infectious diseases.
[18] Dr. Donald E. Low attests that, at the time he swore his affidavit, he was Microbiologist-in-Chief at Mount Sinai Hospital and a Professor of Microbiology and Medicine at the University of Toronto. He was head of the Division of Microbiology, Department of Laboratory Medicine at the University of Toronto, and the Chief of the Toronto Medical Laboratories and Mount Sinai Hospital Department of Microbiology. He was a fellow of the Royal College of Physicians and Surgeons of Canada and had completed his undergraduate and postgraduate training in medicine and infectious diseases.
[19] He attests:
I have been involved in research and clinical treatment of patients suffering from microbial infections with quinolones since as early as 1981. In this regard, I have published well over 200 articles in the field of medical microbiology and infectious diseases in international peer reviewed journals. I am in the top 1% of individuals cited in my field of publication. I am on the editorial boards of the journals entitled Antimicrobial Agents and Chemotherapy, The Journal of Infectious Diseases, and the Canadian Journal of Infectious Diseases. I am a regular reviewer for the New England Journal of Medicine, and Nature Medicine, and the Journal of Chemotherapy. I am one of 12 voting members of the National Committee for Clinical Laboratory Standards in the United States. This Committee sets standards for antimicrobial testing, interpretation and reporting. These guidelines are used by diagnostic laboratories and industry in North America as well as in most developed countries worldwide.
[20] Novopharm relied on the expert affidavit of only one affiant, Dr. Lester A. Mitscher who, at the time he swore his affidavit, was University Distinguished Professor in the Department of Medicinal Chemistry at the University of Kansas where he had been a professor in that Department since 1975. From 1975 to 1991, he was Chairman of the Department. He attests that he had also been an Adjunct Professor of Medicinal Chemistry at the University of Missouri since 1987.
[21] Dr. Mitscher attests that he graduated with a Bachelor of Science degree from Wayne University in 1953 and received his PhD. from Wayne State University in 1958. From 1958 to 1967, he was a research scientist and group leader at Lederle Laboratories "...working with their microbial products." In 1967, he became an Associate Professor of Natural Products Chemistry at Ohio State University. He became a full professor at the same University in 1969 and remained in that position until he joined the University of Kansas, in 1975.
[22] While at the University of Kansas, Dr. Mitscher held the position of Intersearch Professor, Victorian College of Pharmacy, Melbourne, Australia until 2000 and of Adjunct Professor of Molecular Biosciences at the University of Kansas from 1995 to 1999. He attests that he has held a number of other prestigious positions, has served on a number of editorial advisory boards and has received several awards.
[23] Dr. Mitscher attests:
The group I lead at the University of Kansas has a long-term interest in the quinolone antibacterial field, and I have published extensively in this field. We are exploring the molecular mode of action and resistance mechanisms of quinolones through their synthesis and evaluation against purified enzyme. We are also looking to identify through directed screening of pharmacologically active natural products, determining their structural formulae, evaluating their therapeutic potential and synthesizing (partial and total) analogues in attempts to improve their therapeutic potential.
[24] Counsel for Novopharm, before the Court, was critical of the expertise of the Applicants' witnesses alleging that Dr. Low and Dr. Davidson are both microbiologists whose involvement with new antibiotic compounds occurs after the compounds have been made and when they are asked to evaluate the effectiveness and other properties of such compounds. He argues that they have no experience in the development and synthesizing of new medicines. Counsel urges that while Dr. Bartlett is a medicinal chemist and has therefore been involved in developing and synthesizing new medicines, he has had no experience working with quinolones. By contrast, Novopharm's expert, Dr. Mitscher, is described by Novopharm's counsel as a medicinal chemist whose field of research has focussed on the development of new quinolone compounds. In the result, counsel urges, greater weight should be given to the expert testimony of Dr. Mitscher than to the combined expert testimony of the Applicants' expert witnesses.
[25] Counsel for the Applicants disputes the position taken by counsel for Novopharm.
[26] While I am satisfied that counsel for Novopharm's position is technically accurate, I am also satisfied that the combined experience and expertise of the Applicants' three expert witnesses should be given equal weight with the expert testimony of Dr. Mitscher.
THE PRIOR ART
[27] As earlier noted, the '316 patent was filed in Canada on the 19th of January, 1987 and thus, and this was not in dispute before the Court, the provisions of the Patent Act, as they read immediately before the 1st of October, 1989 apply for the purposes of determining obviousness. Equally, it was not in dispute before me that, under the "Old Act", the date for determination of obviousness is the date of invention which is the earlier of the filing date and the priority date. Here, once again as earlier noted, the priority date claimed is the 21st of January, 1986. Thus, that is the cut-off date for "prior art".
[28] In its Notice of Allegation, Novopharm lists six (6) patent documents and a further five (5) articles as prior art. Of the total of eleven (11) documents, only a limited number were significantly relied upon. A further prior art document, perhaps the fundamental prior art document, was put forward on behalf of the Applicants. The prior art documents primarily referred to before the Court are here briefly described.
[29] The "foundation document", not cited in the Notice of Allegation, is an article, described as the "Albrecht paper" entitled Progress in Drug Research[4], published in 1977. R. Albrecht was one of six authors. The opening paragraph under the heading "Introduction" reads as follows:
Nalidixic acid I...was introduced into therapy in 1963. This compound, which exhibits a good effect on gram-negative bacteria, is employed for treatment of urinary tract infections. At the time of its introduction into therapy nalidixic acid was the representative of a completely new structural type among chemotherapeutic agents. In the succeeding period, intensive work was carried out on the further development of analogous compounds. The present paper will summarize this work, which hitherto has not been reviewed.
[30] Novopharm's expert witness made no reference to the "Albrecht paper" in his expert affidavit. That being said, on cross-examination on his affidavit, while he described it as "relatively archaic", he acknowledged that it was still, in early 1986, not only part of the common general knowledge of persons skilled in the art, it was still probably the classic review and some things could be learned from it[5].
[31] With respect to the "Albrecht paper", at paragraph 80 of his expert affidavit, Dr. Bartlett attested:
There were additional reports from earlier work indicating that a methoxy substituent at the 8-position of the quinolone produced a deleterious effect on antibiotic activity. In their review..., Albrecht et al. note that
Substitution on the benzene nucleus is of decisive importance for the in vitro activity of quinolonecarboxylic acids. The unsubstituted compound IV, R=H, only has very slight activity... . The effect of this compound can be reduced still further by means of a substitution, e.g., by an 8-methoxy group, but a very considerable increase can also occur, e.g., as the result of a 7-methyl or 7-methoxy group.
Clearly, this authoritative statement and the data that back it up would lead a researcher away from any expectations of an 8-methoxy substituent as a way to improve the activity of a quinolone antibiotic.[6] [citations omitted]
[32] In 1980, Hiroshi Koga and others published a cited article entitled "Structure - Activity Relationships of Antibacterial 6,7- and 7,8-Distributed 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxcylic Acids"[7]. The "Koga article" was commented on by Dr. Mitscher in his expert affidavit[8].
[33] Counsel for the Applicants urged that Dr. Bartlett's opinion quoted above was confirmed by two European patent applications, the "Domagala application"[9] and the "Culbertson application"[10]. Those patent applications were published in April of 1984 and August of 1985 respectively and matured to patents under publication numbers referred to in the material before the Court as the "'489 patent" and the "'163 patent" respectively.
[34] As noted in the "Albrecht paper", in the years preceding its publication date and, perhaps more importantly, in the years following its publication date, extensive and intensive research in respect of quinolones was undertaken. In 1980, Norfloxacin was disclosed. Shortly thereafter, Ciprofloxacin was introduced into the market. The structure of Ciprofloxacin is as follows:
Ciprofloxacin, like Gatifloxacin is a fluoroquinolone. Only two structural differences exist between Ciprofloxacin and gatifloxacin: Ciprofloxacin does not have a methyl group at the 3-position of the piperazine ring, and Ciprofloxacin does not have the methoxy group at the 8-position.
[35] Ofloxacin, also a fluoroquinolone, came onto the market around 1985. Dr. Mitscher attests that he worked extensively on Ofloxacin.
[36] Early in 1985, Schentag and Domagala published a paper entitled "Structure-activity relationships with the quinolone antibiotics"[11]. The penultimate paragraph of the paper is in the following terms:
The activity of the quinolone agents against Gram-positive and anaerobic organisms has been increased through substitutions at position 8 with short 1-3 atom chains. The prototype compound for this type of modification is ofloxacin... . In this compound, the oxygen substitution at position 8 apparently enhances the activity against Gram-positive and anaerobic organisms while not substantially altering the activity against other organisms. Another recent modification at position 8 that results in increased activity against Gram-positive organisms is the addition of a fluorine atom...[citations omitted]
Much was made of this paragraph in the context of the argument regarding obviousness.
[37] Finally, U.S. Patent 4,556,658[12], the "'658 patent" entitled "7-amino-1-cyclopropyl-6,8-Difluoro-1,4-Dihydro-4-oxo-quinoline-3-carboxylic acids and antibacterial agents containing these compounds", issued the 3rd of December, 1985. Dr. Mitscher refers to one specific compound disclosed in the patent, example 3, which he dubs the "Grohe compound" and notes that it differs structurally from gatifloxacin in just one respect: the Grohe compound has fluorine at the 8-position while gatifloxacin has a methoxy group.
[38] Other cited prior art was not heavily relied upon. The medicines Ciprofloxacin, Norfloxacin and Ofloxacin, though not cited in the Notice of Allegation as prior art, were referred to by Dr. Mitscher in his review of the prior art.
THE EXPERT EVIDENCE
a) Dr. Bartlett
[39] Dr. Bartlett, in his expert affidavit, described the task assigned to him in the following paragraphs:
6. I have been asked by counsel for the Applicants to review a letter dated April 12, 2004, that is stated to be a "Notice of Allegation".
7. I have also been asked by counsel for the Applicants to review the 11 references that are referred to in the Notice of Allegation in order to comment on the allegation that Canadian Letters Patent 1,340,316 (the "'316 patent") is invalid on the grounds of obviousness.
8. I have also been advised that the Notice of Allegation alleges that both claim 1 and claim 4 are invalid due to obviousness. Thus I have been advised that in order for the allegation to be justified both claims 1 and 4 must be invalid. Therefore, even if claim 1 is invalid, but claim 4 is valid, the allegation is unjustified. Since claim 4 is narrower than claim 1, I will focus my comments on claim 4.
9. In order to provide this opinion, I initially reviewed the Notice of Allegation and the 11 references that Novopharm Ltd ("Novopharm") selected. In reviewing the 11 references, I noted that a number of these references cited or included additional references that relate to the state of the art in early 1986. I found one reference particularly useful for its comprehensive review of the state of the art, namely, R. Albrecht et al., "Development of Antibacterial Agents of the Nalidixic Acid Type"... .[13]... [cross-references omitted]
[40] Dr. Bartlett completed his analysis with the following opinion:
84. In its Letter of Allegation, Novopharm asserts that the 7-(3-methylpiperazinyl) and 8-methoxy substitutions of gatifloxacin were obvious to a technician skilled in the art as of 1986 and that by "combining these references" discussed above, he would "have come directly and without difficulty to the solution taught by the patent and claim[s] 1 [and 4]." The factual reasons why this statement is wrong are given above, but it is also refuted by the fact that none of the other research groups working on quinolone antibiotics had this idea prior to 1986, or even sought to exploit it in subsequent years. If a large number of motivated and creative researchers did not anticipate the beneficial properties of gatifloxacin, I do not believe that the technician skilled in the art, having no scintilla of inventiveness or imagination, would do so.
85. Novopharm has only provided references indicating that it was possible to make quinolone derivatives containing the 7-(3-methylpiperazinyl) and 8-methoxy groups of gatifloxacin, but has not provided any evidence as to why a technician skilled in the art would have ever considered these groups, let alone could have predicted that they would confer the beneficial properties possessed by gatifloxacin. With the very general directions provided by qualitative review articles, such as Schentag and Domagala, a researcher in this field would have had many possible modifications to consider in seeking a quinolone antibiotic with improved properties. There was no indication in the prior art that the specific modifications embodied by the structure of gatifloxacin were the most promising ones to make, in preference to many others. On the contrary, Novopharm's own references point unambiguously in the opposite direction by showing that the only comparative data available to a technician in 1986 showed that the compounds with 7-(3-methylpiperazinyl) and 8-methoxy substitutions had poorer activity than others with different substituents.
86. Based on the above analysis and based on the legal test that is set out above in paragraphs 11-14, I conclude that neither the structural changes that characterize gatifloxacin nor its beneficial properties would have been obvious in 1986 in light of the published information and knowledge of the quinolone antibiotics.
87. The improvements exhibited by gatifloxacin could not have been predicted prior to 1986. None of the data available in the art as of 1986 could have predicted its favourable biological and physiological characteristics.
88. In light of the above, in my opinion Novopharm is completely wrong in alleging that the invention embodied in the '316 patent was obvious.[14]
[emphasis added]
b) Dr. Davidson
[41] Dr. Davidson described the task assigned to him in the following paragraphs from his expert affidavit:
7. I have reviewed the letter submitted to Bristol-Myers Squibb Canada dated April 12, 2004 that purports to be a Notice of Allegation for gatifloxacin and the references cited in the letter.
8. I have been asked to provided my opinion on whether gatifloxacin as claimed in Canadian Patent number 1,340,316 possesses unexpected advantages over prior art compounds and whether these advantages could have been predicted without experimentation.
9. As part of my opinion, I have been asked to address whether the following advantages of gatifloxacin were unexpected:
1) the breadth of bacterial species for which gatifloxacin shows enhanced activity; and
2) the enhanced activity of gatifloxacin against Gram-positive species;[15]
[42] Dr. Davidson concludes his admirably brief expert affidavit with the following opinion:
20. In my opinion, gatifloxacin has greater activity against a broader spectrum of bacterial species compared to the cited prior art compounds. This is based on gatifloxacin's anaerobic coverage, lacking in prior art compounds.
21. In particular, gatifloxacin is an effective antibiotic against Gram-negative, Gram-positive, anaerobic, and atypical bacteria... .
22. In addition, gatifloxacin has also shown enhanced activity against Gram-positive bacteria such as Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Staphylococcus epidermidis. It has also been shown to select for resistance among Gram-positive bacteria much less than prior art compounds.[16]
[43] Interestingly enough, Dr. Davidson simply does not address the question of whether the advantages of gatifloxacin that he opines to could have been predicted in 1986, based on prior art, in the terms of the issue referred to him as quoted above, "...without experimentation."
c) Dr. Low
[44] In his expert affidavit, Dr. Low describes the task assigned to him by the Applicants in the following terms:
6. I have been asked by counsel for the Applicants to provide my opinion on the advantages that gatifloxacin, as claimed in Canadian Patent 1,340,316 ("the '316" patent), has over prior art compounds. Based upon the Notice of Allegation shown to me, for the purpose of this proceeding, I consider prior art compound [sic] as those compounds disclosed prior to January 21, 1986.
7. In this regard, I have been asked to provide my opinion as to whether the advantages that gatifloxacin possesses were unexpected and whether these advantages could have been predicted without experimentation.[17]
[45] Dr. Low concludes his expert affidavit and commences the summation of his opinion in the following paragraph:
61. In my opinion, gatifloxacin represents an improved antibacterial that has superior and unexpected benefits over the prior art compounds referred to in the Notice of Allegation.[18]
After describing certain of the "superior and unexpected benefits" or characteristics of gatifloxacin, Dr. Low continues:
64. This activity would not have been predictable as of 1986. Moreover, none of Novopharm's references suggest that the structure of gatifloxacin would exhibit this activity.
65. As such, the invention claimed within the '316 patent is not obvious because the advantages disclosed in the '316 patent could not have been accurately predicted in early 1986 without testing.
66. In addition, gatifloxacin has other advantages over earlier compounds such as lower photoxicity and less sensitivity to resistant strains. These additional benefits were unexpected and certainly not disclosed by data in Novopharm's references.
67. This, coupled with the number of quinolones that have failed due to toxicity problems reveals that the invention of gatifloxacin is unobvious and Novopharm's allegation to the contrary simply uses hind-sight to predict the advantages of this particular product.
68. In short, the benefits of gatifloxacin were completely unpredictable based on the prior art cited by Novopharm.[19]
[emphasis added]
d) Dr. Mitscher
[46] Dr. Mitscher attests that, on behalf of Novopharm, he reviewed the '316 patent, Novopharm's Notice of Allegation and the affidavits and related exhibits of Drs. Bartlett, Low and Davidson. He attests that he was asked by counsel for Novopharm to give his opinion with respect to: first what is the invention of the '316 patent; secondly, whether the subject matter of claims 1 and 4 of that patent would have been obvious at the relevant date to a person skilled in the art in view of the prior art and the common general knowledge; and finally, the affidavits of Drs. Bartlett, Low and Davidson.
[47] With respect to claim 1 of the '316 patent, Dr. Mitscher expresses the following opinion:
65. It is my opinion that the 8-alkoxy compounds of claim 1 of the '316 Patent would have been obvious in view of the teachings of the '658 Patent when combined with the teachings of Drs. Schentag and Domagala, and the '489 or '163 Application, and the common general knowledge. In my view, a person skilled in the art seeking to develop a non-toxic broad spectrum fluoroquinolone antibacterial agent active against Gram-positive, Gram-negative, aerobic and anaerobic bacteria would have easily thought to replace the 8-fluoro substituent of the Grohe Compound disclosed in the '658 Patent with a methoxy substituent. By combining these teachings of the prior art, the person skilled in the art would, as at January 1986, have come directly and without difficulty to gatifloxacin.[20]
[emphasis added]
[48] With respect to claim 4, of the '316 patent, Dr. Mitscher expressed his opinion in the following terms:
84. It is my opinion that gatifloxacin as claimed in claim 4 of the '316 Patent would have been obvious in view of the Grohe Compound shown in the '658 Patent, when combined with the teachings of Drs. Schentag and Domagala, the '489 or '163 Application and common general knowledge. For all the same reasons as set out above regarding claim 1, in my view, a person skilled in the art seeking to develop a non-toxic broad spectrum fluoroquinolone antibacterial agent active against Gram-positive, Gram-negative, aerobic and anaerobic bacteria would have replaced the 8-fluoro substituent of the Grohe compound with a methoxy substituent.
85. As I mentioned above, according to the teachings of Drs. Schentag and Domagala, the only remaining useful substitutions to the quinolone ring structure, in order to increase the spectrum of antibacterial activity, would be to the 8-position. They noted that compounds with a fluoro and a 1-3 atom group at the 8-position had greater activity against Gram-positive bacteria without losing activity against Gram-negative bacteria. Therefore, to increase activity against Gram-positive, one skilled in the art would be motivated to modify the substituent at the 8-position.[21]
[emphasis added]
[49] With respect to Dr. Bartlett's expert affidavit, Dr. Mitscher noted:
98. I reviewed Dr. Bartlett's affidavit and I note that he did not focus on the closest prior art known at the time in his analysis. In contrast, I began my analysis at the same point that is set out in Novopharm's letter of 12 April 2004, namely, the Grohe Compound. I assessed whether gatifloxacin would have been obvious in view of the 6,8 difluoro Grohe Compound. Dr. Bartlett has not addressed squarely the allegations made in the Novopharm letter.[22]
[50] Dr. Mitscher continues and concludes his general commentary on Dr. Bartlett's affidavit with the following paragraph:
101. Quinolones had already been well studied by January 1986. Many different quinolone compounds had been synthesized, evaluated and put on the market. Drug designers and medicinal chemists work by combining what is previously known. I agree that one cannot predict with certainty what effect a substituent will have, however, I believe that in many instances one can expect a particular effect. In other words, medicinal chemistry is a lot more predictable than Dr. Bartlett makes it out to be.[23] [emphasis added]
[51] Dr. Mitscher provides no specific opinion with respect to the expert affidavit of Dr. Davidson. With respect to Dr. Low's affidavit, he comments briefly in a general vein and provides only brief commentary on certain paragraphs of Dr. Low's affidavit. Dr. Mitscher's general commentary on Dr. Low's affidavit is in the following terms:
110. Generally, Dr. Low is right that gatifloxacin is a better antibacterial than ciprofloxacin. However, in view of Schentag and Domagala and the other prior art, this was not unexpected or unpredictable.[24]
e) Submissions and Preliminary Conclusions with Regard to the Expert Testimony
[52] Counsel for Novopharm urged that Dr. Bartlett had no relevant experience and that therefore, his opinions should be given little weight by the Court. While counsel acknowledged that Drs. Low and Davidson might have "formidable qualifications in some areas", the design and synthesis of quinolones was not among them. Counsel urged that Drs. Bartlett and Low were instructed to use a test for obviousness that would always result in a conclusion that a new compound was inventive. In the result, counsel urged that the expert testimony of the Applicants' witnesses should be given no weight and that the Court should, by contrast, rely upon the expert opinion of Dr. Mitscher.
[53] By contrast, counsel for the Applicants urged that the Applicants' expert witnesses were all persons skilled in the art with specialities in medicinal chemistry and microbiology and that therefore, their expert evidence, taken as a whole, should be given significant weight in determining the issue of obviousness.
[54] Counsel for the Applicants urged that Dr. Mitscher was over-qualified to provide an opinion on obviousness in the eyes of a person skilled in the art of quinolone synthesis in early 1986 and that therefore, his expert opinion should be viewed with some suspicion.
[55] Dr. Mitscher put forward in his expert affidavit his own definition of a person skilled in the art in the following terms:
30. In my opinion, the teachings of the '316 Patent are directed to a scientist with an undergraduate and perhaps a graduate (M.Sc. or Ph.D.) degree in organic, medicinal, pharmaceutical and synthetic chemistry, or biochemistry, who has several years of experience in the field of developing and synthesizing novel pharmaceutical compounds, and therefore knowledge in particular of the relationship between chemical structure and biological activity.[25]
Thus, at least in Dr. Mitscher's opinion, the ordinary person skilled in the art that is here at issue is far from an ordinary person on the "Clapham omnibus". In this I am in partial agreement with
Dr. Mitscher, but I would not place the bar as high as he does.
[56] In Halford et al. v. Seed Hawk Inc., et al[26], Justice Pelletier, then of this Court commented on the qualifications of an individual with a "...general background in mechanical engineering" as an expert witness in a matter involving the design of farm seeding equipment, soil science and soil dynamics. Justice Pelletier determined that the individual's training and experience as a mechanical engineer were such that his evidence "...would be of assistance to the court in understanding the design and operation of mechanical devices, including seeding devices." In the result, Justice Pelletier accepted the evidence of the individual as expert evidence. While the science at issue is here very different from the engineering, and perhaps science, that was before Justice Pelletier, I am satisfied that the expert evidence put forward on behalf of the Applicants, when taken as a whole, is of assistance to the Court and therefore deserves to be given significant weight. Equally, and I suspect this goes without saying, I am satisfied that the expert evidence of Dr. Mitscher should be given significant weight.
[57] More will be said on this subject shortly.
THE ISSUES
[58] Counsel for the Applicants urges that there is really only one issue on this application, that being whether Novapharm's allegation of invalidity of the '316 Patent by reason of obviousness is justified.
[59] Counsel for Novopharm further restricts the principle issue by relating it only to claims 1 and 4 of the '316 patent and, in the course of presentations before the Court, the issue was further restricted to focus on the validity or invalidity of claim 4 with the conclusion on that claim determining the issue of validity or invalidity of claim 1. Counsel for the Respondent urged that for the determination of the principle issue: first, claim 4 must be construed in the context of the '316 patent; secondly, the standard of proof in respect of the allegation of invalidity must be determined; thirdly, the weight to be given to the expert evidence before the Court must be assessed, and that has just been done, at least in a preliminary way; fourthly, the scope of the "prior art" must be defined; and finally, against the established jurisprudence and the evidence, including expert evidence before the Court, the Court must determine whether or not gatifloxacin would have been obvious as a "forward step in the art", at the relevant time, to a person skilled in the art.
ANALYSIS
a) Claim Construction, in General
[60] In Whirlpool Corp. v. Camco Inc.[27], Justice Binnie, for the Court, under the heading "The Principles of Patent Claims Construction", wrote at paragraphs 42 and 43:
The content of a patent specification is regulated by s. 34 of the Patent Act. The first part is a "disclosure" in which the patentee must describe the invention "with sufficiently complete and accurate details as will enable a workman, skilled in the art to which the invention relates, to construct or use that invention when the period of the monopoly has expired" ... . The disclosure is the quid provided by the inventor in exchange for the quo of a 17-year (now 20-year) monopoly on the exploitation of the invention. The monopoly is enforceable by an array of statutory and equitable remedies and it is therefore important for the public to know what is prohibited and where they may safely go while the patent is still in existence. The public notice function is performed by the claims that conclude the specification and must state "distinctly and in explicit terms the things or combinations that the applicant regards as new and in which he claims an exclusive property or privilege" ... . An inventor is not obliged to claim a monopoly on everything new, ingenious and useful disclosed in the specification. The usual rule is that what is not claimed is considered disclaimed.
The first step in a patent suit is therefore to construe the claims. Claims construction is antecedent to consideration of both validity and infringement issues. ...
[citations omitted, emphasis added]
[61] Claims construction is to be carried out in a purposive manner. Justice Binnie continued at paragraph 45 of his reasons:
The key to purposive construction is therefore the identification by the court, with the assistance of the skilled reader, of the particular words or phrases in the claims that describe what the inventor considered to be the "essential" elements of his invention.
The expert witnesses whose affidavits are before the Court and the transcripts of whose cross-examinations on those affidavits are also before the Court, are the "skilled readers" referred to in the foregoing brief quotation.
b) Person skilled in the art
[62] I have previously quoted Dr. Mitscher's opinion as to who is a "person skilled in the art" to which the '316 patent relates. That definition was essentially not in dispute except that, as earlier noted, counsel for the Applicants urged that the mythical "person skilled in the art" did not have to be as highly qualified and specialized and did not have to be a single individual but rather could be a group of scientists and researchers bringing their combined expertise to play. In support of the latter proposition, counsel cited the following brief passage from Bayer Aktiengesellschaft v. Apotex Inc.[28]:
The notional skilled technician can be a composite of scientists, researchers and technicians bringing their combined expertise to bear on the problem at hand: "This is particularly true where the invention relates to a science or art that transcends several scientific disciplines."... [citation omitted]
Thus, urges counsel, the expert witnesses put forward on behalf of the Applicants can, taken together, qualify as a person skilled in the art and, equally, as "skilled reader[s]" in the context of the second quotation from Justice Binnie's reasons in Free World Trust, immediately above. Dr. Mitscher's qualifications as a person skilled in the art and thus as a "skilled reader" were not in dispute before me. Indeed, as earlier noted, counsel for the Applicants expressed a concern that he was "over-qualified".
[63] I accept Dr. Mitscher's definition of "persons skilled in the art" to which the '316 Patent relates with the qualifications put forward on behalf of the Applicants. I am satisfied that Dr. Mitscher alone, and the Applicants' experts taken together, are persons skilled in the relevant art.
c) Construction of the claims in issue
[64] As earlier noted, the '316 patent contains eight (8) claims of which only the first and fourth are here at issue. It was not in dispute before the Court that claim 1 claims a small class of compounds, which includes gatifloxacin, and that claim 4 specifically claims gatifloxacin. Further, it was not in dispute that the '316 patent teaches that the claimed compounds have numerous excellent properties as antibacterial agents, those excellent properties including: first, activity against a broad bacterial spectrum; second, at least in the case of gatifloxacin, very good activity against Gram-positive and anaerobic bacteria, thus addressing a problem found in prior art antibacterials; third, low toxicity in contrast to other quinolone compounds that possess unacceptable toxicity levels; and fourth, excellent absorption, at least when administered orally to animals.
[65] The Applicants urge that the disclosed compounds are less likely to lead to the development and spread of resistant bacteria as compared to other antibacterials. Dr. Mitscher disagrees with this claimed advantage. I prefer the opinion of the Applicants' experts in this regard, at least as it relates to gatifloxacin, the only compound here directly at issue.
[66] For ease of reference, the terminology of claim 4 is repeated here.
4. The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
[67] I am satisfied that the quinoline compound claimed in claim 4, gatifloxacin, possesses all of the foregoing advantages and, on the evidence before the Court, is a novel antibacterial agent.
d) Obviousness
i) Standard of Proof
[68] In proceedings under the Patented Medicines Notice of Compliance Regulations, a patentee is entitled to rely on the statutory presumption of validity provided under the Patent Act. Counsel for Novopharm urges that that presumption only takes the Applicants so far. With this I agree. In Janssen-Ortho Inc. v. Novopharm Ltd.[29], my colleague Justice Mosley, relying on Bayer Inc. v. Minister of National Health and Welfare et al.[30] wrote at paragraph 20 of his reasons:
I read the Bayer decision as indicating that a second person's [here Novopharm's] evidence must not be clearly incapable of sustaining its allegations, and if it meets that threshold, then the statutory presumption will be spent and cannot aid the applicants for the purpose of a NOC summary proceeding. This interpretation is supported by the language of section 4 of the pre-1989 Patent Act, that the presumption is to apply "in the absence of any evidence to the contrary". I note, however, that simply succeeding in rebutting the presumption does not mean that a second person will be successful in a prohibition application, as it must still put sufficient evidence "in play" to challenge the validity of the patent as well as the applicant's expert evidence, while the overall legal burden remains with the applicant.
In Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health)[31], my colleague Justice Snider applied the Bayer decision, in the same manner. Justice Snider's decision was upheld by the Federal Court of Appeal[32].
[69] Applying the foregoing to this matter, the Applicants are able to start out relying on the statutory presumption of validity provided under the Patent Act. It thus falls to Novopharm to put forward evidence that is "not...clearly incapable" of sustaining its allegation of invalidity. I am satisfied that Dr. Mitscher's evidence is sufficient for at least this purpose with the result that Novopharm has met the threshold required and the statutory presumption is "spent" and cannot further aid the Applicants. Further, Dr. Mitscher's evidence is "sufficient evidence" to challenge the validity of the patent, as well as the Applicants' expert evidence, with the result that the "overall legal burden" rests with the Applicants.
ii) General Principles
[70] Counsel for the Applicants urges that a patent claim is unobvious unless a person skilled in the art would have come directly and without difficulty to the solution taught by the patent given the information disclosed in the cited prior art and the common general knowledge of persons skilled in the art as of the relevant date, here the priority date for the '316 patent, the 21st of January, 1986. In support of this submission, counsel cites the following oft-quoted passage from Beloit Canada Ltd. v. Valmet OY[33]:
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
On the facts of this matter, I have cast the definition of "technician skilled in the art" or "person skilled in the art" well above the concept of an individual having no scintilla of inventiveness or imagination but I am satisfied that my conclusion in this regard is justified in this particular field of "art" or science.
[71] The test for obviousness has been described in terms such as "plain as day" or "crystal clear"[34] and as requiring a mere "scintilla" or "spark" of inventiveness[35]. Traditionally, the concept of "worth a try" has been rejected as a test for obviousness; testing was not open to the person skilled in the art[36]. More recently, the "worth a try" test implying some experimentation, has been recognized as appropriate. Justice Wetston, in Apotex Inc. v. Wellcome Foundation Limited[37] wrote at paragraph [264] of his reasons:
I am satisfied that the prior art, individually or taken together would not have led an unimaginative skilled technician to the invention without undue experimentation.
[emphasis added]
The concept of "without undue experimentation" was adopted by my colleague Justice Dawson in Pfizer Canada Inc. v. Apotex Inc. et al.[38]. In Janssen-Ortho Inc. v. Novopharm Ltd.[39], my colleague Justice Mosley wrote at paragraph 54:
With regard to Janssen's contention that if experimentation or testing is required in order to determine the invention, the resulting invention cannot be said to be obvious, I am persuaded by Novopharm's submission that the test for obviousness does not exclude routine testing to determine characteristics of known compounds, not undertaken for the purpose of "searching for something novel", but rather for the purpose of verifying the actual attributes of already known compounds, where the results indicate no new uses or surprising results, or properties that are clearly superior to the already known parent compound. ...
In my view, Justice Mosley, who cited Justice Dawson's reference to "undue experimentation" was attempting to better define that concept. With great respect, I am concerned that he defined it too narrowly.
[72] The prior art before the Court clearly demonstrates that, for more than ten (10) years prior to 1986, research with respect to quinolones had been both intensive and extensive among highly qualified persons skilled in the art. The results of that research demonstrates that the impact flowing from introduction of new substituents is highly unpredictable, and that is reflected in the prior art before the Court. The prior art and expert evidence before the Court demonstrates that the breadth of activity against various bacterial types, level of toxicity, absorptive ability and likelihood of inducing antibiotic resistance are effectively impossible to predict without some degree of experimentation.
[73] What Justice Mosley referred to as "...routine testing to determine characteristics of known compounds, not undertaken for the purpose of "searching for something novel", but rather for the purpose of verifying the actual attributes of already known compounds,...", is, I am satisfied, appropriate . Where I differ from Justice Mosley is in his conclusion that the results of such routine testing should not indicate "...new uses or surprising results, or properties that are clearly superior to the already known parent compound". I am satisfied that such "surprising results" are not necessarily sufficient to take "routine testing" outside of the domain of routine and into the domain of "undue experimentation".
[74] In the area of research and development for more efficient and effective quinolones, I am satisfied that the concept of "obviousness" should not exclude the conduct of "routine testing" or "due experimentation" and where such testing or experimentation discloses "surprising results", such disclosure should not, of necessity, take the testing out of the realm of "routine testing" and into the realm of "undue experimentation". What will constitute "routine testing" or "due experimentation" in the context of any given challenge on the basis of obviousness should be dependant upon the evidence before the Court.
iii) The prior art and the expert opinions before the Court
[75] Counsel for the Applicants urged four (4) grounds on which the Court should find gatifloxacin, as claimed in claim 4 of the '316 patent, not to be obvious: first, on the ground that Novopharm had failed to meet its obligation of demonstrating that all of the prior art cited in its Notice of Allegation was known or would have been located by a person skilled in the art without the benefit of hindsight; secondly, since all that is required to establish inventive ingenuity is that there be a "scintilla" of inventiveness, and gatifloxacin demonstrated unexpected advantages which could not have been anticipated based on the cited prior art, the test for obviousness was not met; thirdly, that Novopharm's expert erred in law in relying on an hindsight analysis, considering improper art and relying on a "worth a try" test; fourthly, and inter-related with the allegation of reliance on the "worth a try" test, the test for obviousness was simply not met since the prior art "teaches away".
[76] I will deal with each of the foregoing allegations in turn.
[77] In Illinois Tool Works Inc. v. Cobra Fixations[40], Justice Pelletier, as he then was, wrote at paragraph [100]:
Consequently, when dealing with obviousness, one is not looking for prior disclosure of the invention in a single patent, for that would be anticipation. One is entitled to look at the patents which a skilled workman would discover in a reasonable and diligent search to determine whether the "mosaic" leads directly to the invention. ...What constitutes a reasonable and diligent search is a question of fact.
[citation omitted]
Counsel for the Applicants urges that Novopharm put forward no evidence whatsoever that the cited prior art would all be disclosed by a reasonable and diligent search conducted by a skilled
workman without the benefit of hindsight or ex post facto analysis.
[78] Prior art documents were introduced into the record under the affidavit of Laurie Kelly, a legal assistant at the firm of solicitors for Novopharm who attests that she was assisting counsel "responsible for this action." On cross-examination, Ms. Kelly indicated that she had no scientific background and that she could provide no information as to why the cited prior art was chosen or as to why any other art was omitted. Similarly, Novopharm's expert acknowledged on cross-examination that he did not know who had selected the references and had no idea how the particular references were selected.
[79] In response, counsel for Novopharm urged that the main prior art documents relied on, and that formed the basis of Dr. Mitscher's opinion, are the '658 Patent in which the Grohe compound is disclosed and the Schentag and Domagala paper. The '658 Patent was issued in the United States in December of 1985 to the maker of Ciprofloxacin, described as the "bench mark" quinolone on the market in the early 1980s, and therefore would clearly have come to the attention, without delay, of persons skilled in the art. With respect to the Schentag and Domagala paper, counsel for Novopharm urged that it is not an "obscure" reference but rather was published in a journal described by Dr. Bartlett, one of the Applicants' experts, as "...the premier - primary literature in medicinal chemistry..." and that therefore it would also have been well known before the relevant date, to persons skilled in the art.
[80] I am satisfied that the '658 Patent, the Schentag and Domagala paper and the patents for the well known quinolones Norfloxacin, Ciprofloxacin and Ofloxacin, and none of the latter three patents were cited as prior art but were nonetheless referred to in the expert evidence before the Court, are clearly relevant and would have been well known, before the relevant date, to persons skilled in the art. With respect to other cited prior art, I will simply not rely on it in reaching a conclusion with regard to obviousness.
[81] In general terms, it was not in dispute before the Court that gatifloxacin exhibits unexpected benefits that, by and large, could not be predicted on the basis of the '658 Patent, the Schentag and Domagala paper and the Norfloxacin, Ciprofloxacin and Ofloxacin patents. Counsel for Novopharm urges that the exception to the foregoing generalization flows from the '658 Patent's "Grohe compound", example 3 in the '658 Patent. Counsel for Novopharm notes that Dr. Mitscher began his analysis, in his expert affidavit, with the Grohe compound, a compound that is structurally very close to gatifloxacin in that it is identical to gatifloxacin except that, at the 8-position, it has a fluoro substituent rather than a methoxy substituent. Counsel notes that the Grohe compound was actually made and was tested for anti-bacterial activity and that it is said to have both low toxicity and a broad spectrum of activity, benefits similar to those provided by gatifloxacin.
[82] Further, counsel for Novopharm urged that Dr. Mitscher expressed his expert opinion that the Schentag and Domagala paper provided teachings and motivation to modify the 8-position of the Grohe Compound with an alkoxy group, in order to increase activity against anaerobic bacteria and Gram-positive bacteria.
[83] On cross-examination, Dr. Mitscher responded
...these clues in the literature that I led up to this paragraph with were sufficient for a person to hypothesize reasonably that such a combination could well be good, and if you were trying to solve a problem in this manner, that would motivate you to make the compound.
Counsel for the Applicants responded with the question: "Motivate you to make the compound, and then test it?" Dr. Mitscher responded "yes".[41]
[84] More will be said about Dr. Mitscher's expert opinion and the foregoing exchange in what follows on the questions of "hindsight analysis" and the "worth a try" test. As earlier indicated, counsel for the Applicants urges that Novopharm relies on errors of law in support of its analysis that, at the relevant time, gatifloxacin was obvious, in that the analysis amounts to hindsight analysis, is based on the consideration of improper art, and relies on the "worth a try" test. I have already dealt with the allegation of reliance on improper art and will say no more on that issue here. I will briefly comment on the allegation of "hindsight analysis" and reliance on a "worth a try" test together.
[85] In Beloit Canada Ltd. et al. v. Valmet OY[42], Justice Hugessen, for the Court, wrote at page 295:
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?"
I find the foregoing quotation determinative of this matter.
[86] On the cross-examination of Dr. Mitscher, the following exchange took place:
Q. ...Why did you start with the Grohe Compound,
A. Of the things that were provided to me and the things I had in my own collection and the things that I could find through my literature accessing services, that was the closest compound.
Q. The closest compound to gatifloxacin?
A. To gatifloxacin.
Q. Your actual starting point wasn't Grohe. It was gatifloxacin?
A. That is probably true. That was the context in which I was performing this particular activity.
Q. You started with gatifloxacin. When you look at the literature that was provided to you by Novopharm, and you found the compound in that literature that is the most similar to gatifloxacin?
A. That is correct. The Grohe compound differs from gatifloxacin simply in substituent of that carbonate.[43]
[87] I am satisfied that Dr. Mitscher, on behalf of Novopharm, engaged in a classic exercise in hindsight analysis. He did not start with the prior art which had been provided to him. Rather, he started with gatifloxacin and then went looking for what he could find in the prior art that, knowing what he did regarding the advantages of gatifloxacin, would lead him most directly and with the least difficulty to gatifloxacin. Example 3 in the '658 Patent, the Grohe compound, did not lead Dr. Mitscher directly and without difficulty to gatifloxacin. Rather, gatifloxacin led Dr. Mitscher to the Grohe compound and demonstrated that modification and testing of the Grohe compound was "worth a try".
[88] Based upon the foregoing conclusion, I am satisfied that Novopharm's expert erred in law in his analysis leading to the conclusion that gatifloxacin was obvious based upon the prior art that was properly before him.
[89] Finally, counsel for the Applicants urged that the test for obviousness could not be met based upon the prior art properly before the experts and the Court because that prior art "teaches away", which is to say, that the prior art teaches that gatifloxacin, as constituted, would produce a less favourable quinolone than those already known in the prior art.
[90] While I am inclined to agree with the conclusion urged on behalf of the Applicants in this regard, in light of my conclusion with regard to "hindsight analysis" and reliance on the "worth a try" test, even with that test allowing for the degree of experimentation that I have previously indicated I am satisfied is appropriate, is determinative and I need not go further.
CONCLUSION
[91] In summary, I conclude that the Applicants have met the burden on them to demonstrate that Novopharm's Notice of Allegation fails to fulfil the requirements of the Patented Medicines (Notice of Compliance) Regulations. The Applicants have demonstrated that the allegation, the prior art cited that is properly before the Court and the expert evidence filed in support of the allegation, when weighed against the expert evidence filed on behalf of the Applicants, do not sustain the allegation that gatifloxacin, as disclosed by claim 4 of the '316 patent and therefore the small family of compounds disclosed by claim 1 of the same patent, was and were obvious at the relevant date, that is to say the 21st of January, 1986.
[92] In the result, an order will go prohibiting the Respondent, the Minister of Health, from issuing to Novopharm a Notice of Compliance for its version of 400 mg strength of oral tablets of the drug gatifloxacin until after the expiration of Canadian Letters Patent 1,340,316.
COSTS
[93] As between the Applicants and Novopharm, except where otherwise provided by another Order of this Court, the Applicants are entitled to their costs. Given the cooperative and expeditious manner in which this Application proceeded to hearing, the costs in favour of the Applicants should be calculated on the ordinary scale.
[94] There will be no order as to costs either in favour of or against the Respondent, the Minister of Health.
"Frederick E. Gibson"
J.F.C.
Ottawa, Ontario.
October 28, 2005
SCHEDULE
2.0 DETAILED STATEMENT OF THE LEGAL AND FACTUAL BASIS
2.1 Canadian Patent No. 1,340,316 (the "'316 patent")
The '316 patent was filed in Canada on January 19, 1987, claiming priority to Japanese patent application no. 61-10880, filed January 21, 1986, and 61-220149, filed September 18, 1986. The '316 patent issued on January 12, 1999, and will expire on January 12, 2016.
According to the inventors, "the compounds of this invention are characterized in having a cyclopropyl group at the 1 position and an alkoxy group at the 8-position of the quinolonecarbocyclic acid" (page 2). The compounds are alleged to have "extremely high activity against gram-negative and gram-positive bacteria, and, besides, anaerobic bacteria and Mycoplasma" and to "not exhibit any toxicological effects after oral or parenteral administration" (page 4).
2.2 Prior Art
The '316 patent was filed in Canada on January 19, 1987. According to transitional provision 78.1 of the Patent Act, for patent applications filed before October 1, 1989 the provisions of the Patent Act as they read immediately before October 1, 1989 apply (the "Old Act").
Under the provisions of the Old Act and Canadian case law, the date for determination of whether an invention is obvious is the date of invention. The date of invention is presumed to be the filing date or the priority date, if any. Therefore, the earliest date of invention of the invention claimed in claims 1 and 4 would be January 21, 1986.
Therefore, all prior knowledge, literature, information and publications, which was made public in Canada or elsewhere prior to January 21, 1986, or prior to any date of invention of the invention claimed in claims 1 and 4, is relevant to the determination of the issue of obviousness.
The most frequently cited test for obviousness asks:
whether [the technician skilled in the art, having no scintilla of inventiveness or imagination] 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. (Beloit Canada Ltd. v. Valmet OY (1986), 8 C.P.R. (3d) 289 (F.C.A.), per Hugessen J.A.).
The '316 patent relates to antibacterial 1,4-dihydro-4-oxo-3-quinoline carboxylic acids (herein "Quinolones"). Prior to January 21, 1986, or any date of invention of the invention claimed in claims 1 and 4, it was known by those skilled in the art or science to which the '316 patent pertains that:
(qqqq) 6-fluoro-7-(1-piperazinyl)-substituted Quinolones, were potent antibacterial agents with an unusually wide spectrum that included aerobic and facultatively anaerobic Gram-positive and Gram-negative bacteria, anaerobic bacteria and mycoplasma: Van Caekenberghe and Pattyn (page 521); Sato et al; Osada and Ogawa.
(rrrr) the fluorine at position 6, and the piperazine ring with its double nitrogen configuration at position 7, were the most active substituents tested: Schentag and Domagala (page 12); Koga et al. (page 1358).
(ssss) substitution at the 8-position increased broad-spectrum activity against Gram-negative and Gram-positive bacteria and maintained low toxicity. More particularly:
• the activity against Gram-positive organisms was increased through substitution at position 8 with short 1-3 atom chains or fluorine atoms: Schentag and Domagala (page 12-13);
• compounds with an 8-fluoro or 8-alkyl substituent had good activity against both Gram-positive and Gram-negative bacteria: the '355 application (page 33); the '658 patent (Col. 17-18); the '440 application (page 1);'682 application (page 7);
• compounds with an 8-fluoro or an 8-alkyl substituent had low toxicity: the '355application (page 33); the '658 patent (Col. 17);'682 application (page 7);
• 8-alkyl Quinolones with a 7-(piperazin-1-y1) substituent had a broad spectrum of activity against Gram-positive and Gram-negative bacteria, and had low toxicity: '682 application (page 7);
• 1-cyclopropyl-6,8-difluoro Quinolones with a 7-(piperazin-1-y1) substituent, including 7-(3-methylpiperzin-l-y1), had broad-spectrum activity against Gram-positive and Gram-negative bacteria and against Mycoplasma, and had low toxicity: '355 application (page 33-34); the '658 patent (Col. 17-18).
(d) substitution at the 8-position of the 6-fluoro-7-(1-piperazino) Quinolones increased activity against anaerobic bacteria. More particularly:
• the activity against anaerobic organisms is increased through substitution at position 8, with short 1-3 atom chains: Schentag and Domagala (page 12);
• an oxygen substitution at position 8 enhances activity against Gram-positive and anaerobic organisms without affecting activity against other organisms: Schentag and Domagala (page 13)
(e) a 6-fluoro-7-heterocyclo-substituted Quinolone with an 8-methoxy substituent exhibited strong antibacterial activity against both Gram-negative and Gram-positive bacteria: '489 application (tables, pages 27-36), the '163 application (tables, pages 28-38).
(f) 8-fluoro and 8-alkoxy (specifically, methoxy) substituents are interchangeable and produce Quinolone compounds with similar biological activity: '489 application (tables, pages 27-36), the '163 application (tables, pages 28-38).
2.3 Detailed Obviousness Argument 2.3.1 Claim 1
An 8-alkoxyquinolonecarboxylic acid derivative represented by a general formula (I):
wherein R indicates a hydrogen atom or lower alkyl group, R1 indicates a lower alkyl group, R2 indicates a hydrogen atom, X indicates a halogen atom, and Z indicates a halogen atom, piperazino group, N-methyl-piperazino group, 3-methylpiperazino group, 3-hydroxy pyrrolidino group, or pyrrolidino group of the following formula:
>
wherein n is 0 or 1, R3 indicates a lower alkyl group, R4 indicates a hydrogen atom, a lower alkyl group, a hydroxy-substituted lower alkyl group or a halogenated lower alkyl group and R5 indicates a hydrogen atom, a lower alkyl group, an acyl group or an alkoxycarbonyl group; or a hydrate or a pharmaceutically acceptable acid addition or alkali salt there of.
2.3.1(a) Schentag and Domagala
6-Fluoro-7-(1-piperazino)-substituted Quinolones, were known to be antibacterial agents with a broad antibacterial spectrum. See also Van Caekenberghe and Pattyn; Sato et al.; Osada and Ogawa.
This article teaches that, with respect to quinolone antibiotics, the presence of a 2-carbon fragment, or a spatial equivalent (e.g., cyclopropyl), at the 1-position, is essential to antimicrobial activity (page 11). It also teaches that the link between the carboxylic acid and the ketone moiety at positions 3 and 4 is necessary for binding to DNA-gyrase, and that it is "unlikely that any markedly successful modifications of these sites will be achieved in the future." (page 11) It also teaches that modification at position 2 and 5 appears to offer few advantages.
With respect to the 6-fluoro substitution, this article and Koga et al., teach that fluorine, of all the halogens and a number of other substituents, optimizes antimicrobial activity. Further, this article and Koga et al. teach that the piperazine ring has been the most active substituent at position 7.
This article teaches that 8-fluoro and 8-alkyl compounds have greater activity against Gram-positive bacteria than non-substituted compounds, without losing activity against Gram-negative bacteria. In this regard, see also the '355 application, the '658 patent, the '440 application and the '682 application.
This article teaches that an oxygen substitution at position 8 enhances activity against Gram-positive and anaerobic organisms without substantially altering the activity against other organisms (page 13). In this regard, see also Sato et al., Osada and Ogawa, Van Caekenberghe and Pattyn, the '489 application and the '163 application.
2.3.1(b) The '355 application or the '658 patent
The '355 application and the '658 patent disclose 6,8-difluoro-substituted Quinolone antibacterial agents in which the 1-substituent is a cyclopropyl, and the 7-substituent is a (1-piperazine) ring that may further be substituted at the carbon atoms with C1-C4 alkyl groups. These compounds teach that a substituted piperazine ring at the 7-position combined with a substitution at the 8-position, in this instance fluoro, will provide compounds with low toxicity and good activity against Gram-positive bacteria and atypical bacteria (i.e., Mycoplasma), and against Gram-negative bacteria.
In this regard, see also the '682 application which teaches that a piperazine ring in combination with an 8-alkyl substituent will provide for compounds that are low in toxicity while having "excellent" antimicrobial activity against Gram-positive and Gram-negative bacteria.
2.3.1(c) Argument
Compared to the compounds of the '355 application or the '658 patent, the compounds of claim 1 differ in the substituent that is at the 8-position. There are also differences in the permissible substitutions at the 7-position, but there is a significant overlap at this position, as well.
It is a general motivation for those of skill in this art to design antibacterial agents that are more effective, that target a broader range of bacteria and that are less toxic than compounds that are already known. Given the teachings of Schentag and Domagala, one motivated to increase the spectrum of the Quinolone antibacterial activity taught by the '355 application or the '658 patent, including to increase activity against anaerobic bacteria, would have replaced the 8-fluoro substituent with an alkoxy substituent, to achieve this objective. This person would have expected that these compounds would have increased antibacterial activity and low toxicity.
The '489 application and the '163 application teach that an alkoxy substitution at position 8 is a permissible substitution in 6-fluoro-7-(heterocyclic)-substituted Quinolone compounds. These applications also teach the interchangeability of an 8-fluoro and an 8-alkoxy substituent on otherwise identical Quinolone compounds.
Therefore, the 8-alkoxy compound of claim 1 was obvious, at the date of invention, in view of the '355 application or the '658 patent (in respect of compounds in which there is an overlap in the 7-position substituent), when combined with the teachings of Schentag and Domagala and the '489 or '163 application, and common general knowledge relating to 6-fluoro-7-(1piperazino)-substituted Quinolones. By combining these references, the technician skilled in the art would, at the date of invention, have come directly and without difficulty to the solution taught by the patent and claim 1. The claim is therefore invalid.
2.3.2 Claim 4
The 8-alkoxyquinolonecarboxylic acid derivative as claimed in claim 1, wherein said derivative is 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
2.3.2(a) Schentag and Domagala
6-Fluoro-7-(1-piperazino)-substituted Quinolones were known to be antibacterial agents with a broad antibacterial spectrum. See also Van Caekenberghe and Pattyn, Sato et al; Osada and Ogawa.
This article teaches that, with respect to quinolone antibiotics, the presence of a 2-carbon fragment, or a spatial equivalent (e.g., cyclopropyl), at the 1-position is essential to antimicrobial activity (page 11). It also teaches that the link between the carboxylic acid and the ketone moiety at positions 3 and 4 is necessary for binding to DNA-gyrase, and that it is "unlikely that any markedly successful modifications of these sites will be achieved in the future." (page 11) It also teaches that modification at position 2 and 5 appears to offer few advantages.
With respect to the 6-fluoro substitution, this article and Koga et al., teach that fluorine, of all the halogens and a number of other substituents, optimizes antimicrobial activity. Further, this article and Koga et al. teach that the piperazine ring has been the most active substituent at position 7.
This article teaches that 8-fluoro and 8-alkyl compounds have greater activity against Gram-positive bacteria than non-substituted compounds, without losing activity against Gram-negative
bacteria. In this regard, see also the '355 application, the '440 application and the '682 application.
This article teaches that an oxygen substitution at position 8 enhances activity against Gram-positive and anaerobic organisms without substantially altering the activity against other organisms (page 13). In this regard, see also Sato et al., Osada and Ogawa, Van Caekenberghe and Pattyn, the '489 application and the '163 application.
2.3.2(b) The '355 application or the '658 patent
The '355 application or the '658 patent disclose a quinolone antibacterial compound 1cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-7(-3-methylpiperazin-l-yl)quinolone-carboxylic
acid (the "'Grohe compound") which has a 3-methyl-l-piperazinyl substituent in the 7-position and a fluorine substituent in the 8-position of the quinolone ring, respectively:
The Grohe compound differs from the compound of claim 4 (gatifloxacin) only in that it has an 8-fluoro rather than an 8-methoxy substitution.
This compound teaches that a 3-methyl substituted piperazine ring at the 7-position combined with a substitution at the 8-position, in this instance fluoro, will provide a compound with low toxicity and good activity against Gram-positive bacteria and atypical bacteria (i.e., Mycoplasma), and against Gram-negative bacteria.
In this regard, see also the '682 application which teaches that a piperazine ring in combination with an 8-methyl substituent will provide for compounds that are low in toxicity while having "excellent" antimicrobial activity against Gram-positive and Gram-negative bacteria.
2.3.2(c) Argument
Compared to the Grohe compound, gatifloxacin differs only with respect to the substituent at the 8-position.
It is a general motivation for those of skill in this art to design antibacterial agents that are more effective, that target a broader range of bacteria and that are less toxic than compounds that are already known. Given the teachings of Schentag and Domagala, one motivated to increase the spectrum of the Grohe compound, including to increase its activity against anaerobic bacteria, would have replaced the 8-fluoro substituent with a methoxy substituent to achieve this objective. This person would have expected that this 8-methoxy compound would have increased antibacterial activity and low toxicity.
The '489 application and the '163 application teach that a methoxy substitution at position 8 is a permissible substitution in 6-fluoro-7-(heterocyclic)-substituted Quinolone compounds. These applications also teach the interchangeability of an 8-fluoro and an 8-methoxy substituent on otherwise identical Quinolone compounds.
Therefore, the 8-methoxy compound of claim 4 (gatifloxacin) was obvious, at the date of invention, in view of the Grohe compound when combined with the teachings of Schentag and Domagala and the '489 or '163 application, and common general knowledge relating to 6-fluoro7-(1-piperazino)-substituted Quinolones. By combining these references, the technician skilled in the art would, at the date of invention, have come directly and without difficulty to the solution taught by the patent and claim 4. The claim is therefore invalid.
FEDERAL COURT OF APPEAL
NAMES OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-1070-04
STYLE OF CAUSE:
BRISTOL-MYERS SQUIBB CANADA CO.
and KYORIN PHARMACEUTICAL CO. LTD.
Applicants
and
NOVOPHARM LIMITED and
THE MINISTER OF HEALTH
Defendants
PLACE OF HEARING: Ottawa, Ontario
DATES OF HEARING: May 24, 25, 26, 2005
REASONS FOR JUDGMENT: GIBSON J.
DATED: October 28, 2005
APPEARANCES:
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For the Applicants
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For the Respondents |
SOLICITORS OF RECORD:
|
Gowling LaFleur Henderson LLP,
Ottawa, Ontario |
For the Applicants |
|
Bennett Jones LLP,
Toronto, Ontario |
For the Respondents
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[1] SOR/93-133.
[2]Notice of Application, paragraph 2 under the headings: "THE GROUNDS FOR THE APPLICATION ARE:" and "The '316 Patent".
[3] (1997), 74 C.P.R. (3d) 307 (F.C.T.D.) at 314.
[4]Applicants' Application Record, vol. I, tab 6.
[5]Applicants' Application Record, vol. III, tab 20, questions 130 and 131, page 566.
[6]Applicants' Application Record, vol. I, tab 4, page 81, paragraph 80.
[7]Novopharm's Application Record, tab 8.
[8]Applicants' Application Record vol. II, tab 15, pages 404-5, paragraphs 46-49.
[9]Novopharm's Application Record, tab 2.
[10]Novopharm's Application Record, tab 3.
[11]Novopharm's Application Record, tab 9.
[12]Novopharm's Application Record, tab 6.
[13]Applicants' Application Record, vol. I, tab 4, page 62.
[14]Applicants' Application Record, vol. I, tab 4, pages 83-84.
[15]Applicants' Application Record, vol. I, tab 11, page 223.
[16]Applicants' Application Record, vol. I, tab 11, page 226.
[17]Applicants' Application Record, vol. I, tab 13, page 249.
[18]Applicants' Application Record, vol. 1, tab 13, page 264.
[19]Applicants' Application Record, vol. I, tab, 13, pages 264-5.
[20]Applicants' Application Record, vol. II, tab, 15, page 410.
[21]Applicants' Application Record, vol. II, tab 15, page 415.
[22]Applicants' Application Record, vol. II, tab 15, page 419.
[23]Applicants' Application Record, vol. II, tab 15, pages 419-20.
[24]Applicants' Application Record, vol. II, tab 15, page 421.
[25]Applicants' Application Record, vol. II, tab 15, page 398.
[26]2002 FCT 764 (F.C.T.D.).
[27][2000] 2 S.C.R. 1067 at 1088-89.
[28](1995), 60 C.P.R. (3d) 58 at 79 (Ont. Gen. Div.).
[29][2004] F.C.J. No. 1968 (F.C.).
[30](2000), 6 C.P.R. (4th) 285 (F.C.A.).
[31][2004] F.C.J. No. 374 (QL), (F.C.T.D.).
[32][2004] F.C.J. No. 1973 (QL), (F.C.A.).
[33](1986), 8 C.P.R. (3d) 289 at 294 (F.C.A.).
[34]Apotex Inc. v. Wellcome Foundation (1998), 79 C.P.R. (3d) 193 at paragraph 245 (F.C.T.D.).
[35]Tye-Sil Corp. Ltd. v. Diversified Products Corp. et al. (1991), 35 C.P.R. (3d) 350 (F.C.A.).
[36]Bayer Aktiengesellschaft v. Apotex Inc., supra, note 26 at paragraphs 81 and 82.
[37] Supra, note 34, (1998), 79 C.P.R. (3d) 193 at paragraph 264 (F.C.T.D.).
[38](2002), 22 C.P.R. (4th) 466 (F.C.T.D.).
[39]Supra, note 29.
[40](2002), 20 C.P.R. (4th) 402 (F.C.T.D.).
[41]Applicants' Application Record, vol. 3, pages 674-5, questions and responses 567 to 569.
[42]Supra, footnote 33.
[43]Applicants' Application Record, vol. 3, tab 20, pages 558 to 560, questions and answers 104 to107.