Janssen-Ortho Inc. v. Novopharm Ltd.

Janssen-Ortho Inc. v. Novopharm Ltd.
Court (s) Database
Federal Court Decisions
Date
2006-10-17
Neutral citation
2006 FC 1234
File numbers
T-2175-04
Decision Content
Date: 20061017
Docket: T-2175-04
Citation: 2006 FC 1234
Toronto, Ontario, October 17, 2006
PRESENT: The Honourable Mr. Justice Hughes
BETWEEN:
JANSSEN-ORTHO INC. and
DAIICHI PHARMACEUTICAL CO., LTD.
Plaintiffs
and
NOVOPHARM LIMITED
Defendant
REASONS FOR JUDGMENT AND JUDGMENT
[1] This action concerns the infringement and validity of a Canadian Patent relating to an antimicrobial drug known as levofloxacin. There is only one claim of the Patent at issue, claim 4. The Defendant has admitted infringement of that claim. Validity of claim 4 and remedies are the contested issues. For the reasons that follow, I find that claim 4 is valid and infringed. The Plaintiffs are entitled to damages and interest. An injunction, with a certain delay and conditions, and delivery up, is granted.
The Parties
[2] The Plaintiff, Daiichi Pharmaceutical Co. Ltd., is a Japanese company to which the Patent was granted. The Patent names the grantee as Daiichi Seiyaku Co. Ltd., but the parties are agreed that this is the same entity as the Plaintiff Daiichi. Daiichi remains the owner of the Patent.
[3] The Plaintiff Janssen-Ortho Inc. is a Canadian company. It is a licensee of Daiichi under the Patent. It markets and sells levofloxacin products in Canada.
[4] The Defendant, Novopharm Limited, is a Canadian-based corporation. Since about December 2004, it has been marketing and selling levofloxacin products in Canada.
The Patent
[5] The Patent at issue is Canadian Patent Number 1,304,080 entitled “Optically Active Pyridobenzoxazine Derivatives and Intermediates Thereof”. The application for that Patent was filed in Canada on June 19, 1986 thus the Patent is to be governed by the provisions of the Patent Act, R.S.C. 1985, c. P-4, pertaining to Patents applied for before October 1, 1989. That is, the “old” Patent Act.
[6] The Patent claims priority from three separate Patent application filed in Japan, the first on June 20, 1985; the second on October 11, 1985; and the third on January 28, 1986. Named as inventors are Isao Hayakawa, who appeared as a witness at trial, and six others. The Patent includes 19 claims in all, some claims are directed to processes, other claims are directed to compounds, other claims are directed to a salt of a compound, other claims to a compound and salt, and other claims to a pharmaceutical composition. Only claim 4 is at issue, it reads:
4. S(-)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
[7] The Patent was issued and granted to Daiichi on June 23, 1992 and, unless held to be invalid, will expire on June 23, 2009.
Issues
[8] The issues for decision by this Court are as follows:
1. What is the proper construction of claim 4 of the Patent?
2. Is claim 4 invalid on the basis of one or more of the following grounds:
a.) Anticipation having regard to the prior disclosure of Ofloxacin in, for example, Canadian Patent 1,547,840 (the 840 patent) and a 1983 publication by Daiichi employees Osada and Ogawa;
b.) Obviousness, having regard to the prior knowledge, including Ofloxacin, the nature of racemic compounds, the methods for obtaining enantiomers (optical isomers) from racemic compounds and the Gerster 1982 and 1985 abstracts and posters;
c.) Is claim 4 ambiguous in failing to specify what level of purity, if any, is required;
d.) Has the patent, in as much as claim 4 is concerned, failed to provide a correct, full and clear description as required by section 34(1) of the old Patent Act particularly in respect of the disclosures as to toxicity and solubility?
3. If Claim 4 is valid, infringement having been admitted, what remedies will the Court provide:
a.) Damages;
b.) An election as to profits;
c.) A permanent injunction;
d.) Delivery up;
e.) Aggravated, punitive or exemplary damages;
f.) Pre and/or post judgment interest;
g.) Costs;
h.) Other relief?
This Court has, in a previous Order, directed that monetary remedies be the subject of a subsequent hearing.
The Evidence - Witnesses
[9] I commend counsel for having done much to define the issues and agree as to much of the evidence in this case. The pleadings were clear and precise. Admissions were made in the pleadings as to several matters. Through the Request to Admit process the parties further agreed as to evidence and, by a document filed at trial, the issues were further reduced essentially to the validity of claim 4 of the Patent. An Order providing for separate determination of the monetary remedies has been previously made. The documents filed at trial further provided admissions as to all documents save one, the 1982 Gerster poster, and provided that all expert reports be deemed to be read in and that all persons who provided expert reports and were called as witnesses be deemed to be qualified as experts, subject to later argument if needed. This co-operation between counsel and parties is exemplary.
Called as expert witness for the Plaintiff were in Order of appearance:
Dr. Mark P. Wentland: A professor of chemistry and organic chemistry at Rensselaer Polytechnic Institution, Troy, N.Y.. He specializes in quinolones, a class of compounds that includes those at issue. He was active in quinolones in the 1980’s, a period in which the subject matter of the Patent was developed. He was actively working as a medicinal chemist in the quinolone area at the relevant time in the early 1980’s.
Dr. Alexander M. Klibanov: A professor of Chemistry and Bioengineering at Massachusetts Institute of Technology. He has researched, lectured and written extensively in the area of synthesis and evaluation of optically active compounds. Dr. Klibanov returned as a supplemental witness to address the Gerster 1982 poster.
Dr. David C. Hooper: A medical doctor and antimicrobial researcher. A medical doctor, Associate Professor of Medicine, Harvard Medical School. He teaches in the area of antimicrobial agents and infectious diseases and has written extensively, particularly in the area of quinolones. He is a practising physician in a clinical hospital in the infectious diseases division and the infection control unit. He also was working as a physician in the quinolone area in the early 1980’s.
Dr. Frank A. Bucci: An ophthalmologist specializing in ocular diseases including surgery of the eye. He is the director of an eye surgery centre and has done thousands of surgical and other procedures related to the eye. He has also lectured, given presentations and written extensively in the area of ophthalmology.
Dr. Charles Chan: A medical doctor, professor of medicine at the University of Toronto. His main clinical and research interests are in infectious complications of the lungs. He has evaluated many compounds for the purpose of listings on the Ontario drug formulary.
Dr. George G. Zhanel: Professor in Medical Microbiology and Infectious Diseases with the Faculty of Medicine, University of Manitoba. He has focused on the study of antibiotics in the treatment of infectious diseases, particularly in respect of antibiotic resistant organisms. A major focus has been on quinolones.
Dr. Joseph V. Rodricks: A consultant in toxicology with focus in safety and human health risk assessment and a visiting professor at Johns Hopkins University, Baltimore, where he teaches courses in toxicology and risk analysis. He has lectured and written extensively in the area of toxicology.
Dr. Allan S. Myerson: Is the Provost and Senior Vice President and Philip Danforth Armour Professor of Engineering at the Illinois Institute of Technology, Chicago. He specializes in the area of crystallization and solubility and has written and taught extensively on the subject.
Dr. Marion B. Stewart: An economist and vice president of an independent economic research organization. He has focused on the area of intellectual property, the calculation of damages and measurement of commercial success. He appeared as a witness, filed a report, but was not cross-examined.
Dr. Ronald Grossman: A medical doctor, Professor of Medicine at the University of Toronto and Chief of Medicine, Credit Valley Hospital, Mississauga. He specializes in respiratory infections and the use of antibiotics in treating such conditions. He has contributed to national Guidelines in that area. He appeared as a witness, filed a report, but was not cross-examined.
Dr. Paul A. Bartlett: A retired Professor Emeritus of Chemistry at the University of California, Berkeley. He has lectured and written extensively in medicinal chemistry and the area of drug design. He also filed a supplemental report as to the 1982 Gerster poster.
Dr. John J. Partridge: A consultant to the drug industry, having previously worked in organic chemistry in the pharmaceutical industry for many years. He testified as to searches conducted in an endeavour to locate the 1982 Gerster poster.
The evidence of other expert witnesses on behalf of the Plaintiffs was, by agreement, presented by the filing of their reports in evidence without calling the witnesses in person. These were:
John C. Jarosz: A principal of an independent economic analysis firm. He specializes in the area of economics relating to intellectual property.
Anne Langley: Has a Masters degree in library science. Head Librarian at the Duke University Chemical Library.
The Plaintiffs also called three fact witnesses. They were:
Dr. James B. Kahn: A medical doctor. He joined Ortho-McNeil, now Janssen-Ortho, in July 1992. He was responsible for setting up a unit to support the flow of scientific information respecting FLOXIN, the company’s Ofloxacin product and subsequently LEVAQUIN the company’s levofloxacin product. He has since that time been closely associated with that company’s efforts in respect of Ofloxacin and levofloxacin.
Dr. Isao Hayakawa: One of the named inventors of the patent in suit. He joined Daiichi in 1969 and in 1972 became involved in researching anti-infectives. In 1985 he became the supervisor of the quinolones group. From 1991 and thereafter he continued in a progression of more senior positions in Daiichi’s research area. Dr. Hayakawa continues working at Daiichi full-time as a special research advisor. Dr. Hayakawa has limited abilities to understand and speak the English language. His evidence was conducted through the aid of an interpreter. Questions were put to this witness in English and translated into Japanese. The witness’s answered in Japanese and the interpreter translated that answer to English. The transcript records the question as posed in English and the answer as translated into English. At the request of the Plaintiffs a second interpreter was provided as a “check” on the first. On occasion the second translator would indicate to the official court translator that some correction could be made in the translation. Where the official translator accepted that indication, the record reflected that agreed upon translation. Where not so accepted, the translation provided by the official interpreter prevailed.
Jeff Enstrom: Business Unit Director for Janssen-Ortho in charge of launching the Canadian levofloxacin product (LEVAQUIN) since June 1997.
The Defendant called several expert witnesses and one factual witness. Called as expert witnesses were:
Dr. Donald E. Low: A medical doctor, Head of the Department of Microbiology at Mount Sinai Hospital in Toronto. He is a Professor at the University of Toronto and Director of the Ontario Public Health Laboratories. He specializes in the area of microbiology and infectious diseases where he has written and taught extensively.
Dr. Adam J. Matzger: Associate Professor of Chemistry at the University of Michigan. He specializes in the area of crystallization of organic materials. He has won awards in that area.
Dr. John Caldwell: Dean of the Faculty of Medicine of the University of Liverpool. He was the founder of an important journal, CHIRALITY and has written and lectured extensively in the area of medicinal chemistry and drug chirality.
Dr. Roland Collicott: A senior consultant to the pharmaceutical industry by providing analytical chemistry and training services. He specializes in chromatography, HPLC, and particularly in chiral analysis, chiral separations and polymorphic analysis. He has extensive experience in the resolution of quinolones.
Dr. Peter G. Wells: A Professor of Toxicology at the University of Toronto. He specializes in toxicology, clinical pharmacy and clinical pharmacology. He has extensive experience in the areas of toxicology, drug metabolism and animal modelling.
Dr. Michael Chong: A professor of chemistry at the University of Waterloo. He specializes in the area of asymmetric synthesis of chiral compounds where he has written extensively. I permitted the Defendant to introduce the evidence of Dr. Chong so as to address the supplemental reply evidence of Dr. Klibanov and Bartlett, which I in turn had permitted the Plaintiffs to introduce to address the Gerster 1982 poster. It was appropriate to allow Dr. Chong’s evidence as other expert witnesses previously selected to testify for the Defendant did not have expertise in this area. Dr. Chong confined his evidence to that of replying to the supplemental evidence of Drs. Klibanov and Bartlett.
Also introduced into evidence by the Defendant by agreement were reports of experts who were not called as witnesses in person. They were:
Dr. Jake J. Thiessen: A Professor in the Faculty of Pharmacy at the University of Toronto. He specializes in pharmokinetics including the bioavailability of drugs in the body.
Dr. Lea Prevel Katsanis: Chair of and Professor in the Department of Marketing at Concordia University. She specializes in pharmaceutical marketing.
The Defendant called one factual witness, namely:
Dr. John Gerster: A retired scientist who was engaged by the 3M Company’s Riker division, now 3M Pharmaceuticals, from 1967 until his retirement in 1999. He testified as to the posting of his paper during a conference held in Toronto in 1982, dealing with his research in separating the isomers of flumequine.
[10] The Plaintiffs resisted the calling of Dr. Gerster on the basis that they had not been provided adequate discovery and that there was a breach of an undertaking on discovery. I invited Plaintiffs counsel to indicate such undertaking. There was none. As to inadequate discovery, I found that the Plaintiffs were well aware of the Defendant’s position that the 1982 paper was posted at the Toronto conference. A review of the Plaintiffs’ expert reports demonstrates that the Plaintiffs were fully aware of the fact that the Defendant asserted the posting of the1982 paper. Dr. Gerster’s evidence dealt with that matter. Several of the Plaintiffs expert witnesses addressed that poster paper. Discovery relates to facts, not the evidence by which it may be proven. There is no provision in the Federal Courts Rules for examination of a factual witness, by way of discovery, before trial. The Plaintiffs themselves could have called Dr. Gerster as a witness and, if he did not attend voluntarily, used letters rogatory to compel that evidence. Dr. Gerster in cross-examination was asked why he declined to speak with the Plaintiffs’ lawyers. He answered that he felt uncomfortable doing that as he had never been a witness before. Having observed Dr. Gerster, I accept completely his credibility and testimony. I have every sympathy with any reluctance he may have had in testifying. The Plaintiffs had a battery of lawyers in the courtroom, six gowned and several Canadian and foreign lawyers, in the audience. It would be intimidating to a person unaccustomed to being in Court or dealing with lawyers. I gave the Plaintiffs an opportunity to receive a “will say” of Dr. Gerster’s proposed evidence from the Defendant before he testified and an opportunity to amend and expand upon their expert evidence if so advised, which they did by supplementary evidence of Drs. Klibanov and Bartlett.
[11] In addition, each of the Plaintiffs and Defendant introduced into evidence excerpts of the examination for discovery of the other, including transcripts and documents.
[12] As to the factual witnesses, I have already addressed Dr. Gerster. Dr. Hayakawa had the disadvantage of giving his evidence though an interpreter which may have caused some discrepancies. I found his evidence, on the whole, to be credible except where he was confronted with documents authored by others at Daiichi, which contained statements that may have been construed as unfavourable to Daiichi. When so confronted he distanced himself from these statements, claiming them to be written by others, such as his superiors, and not reflecting his views. I am troubled by this. Thus, when considering such documents, I will prefer what the documents say to Dr. Hayakawa’s testimony. These documents were, after all, written at or about the relevant time by persons involved with the events in circumstances before any litigious significance as to the events or their interpretation, had arisen. No issue arises as to any other factual witness.
[13] As to the expert witnesses, no challenge was raised as to the qualifications of any of them as being person qualified to testify as experts, and I find them all to be so qualified. The differences in their opinions were largely those of degree. I find particular assistance from Dr. Wentland, a quinolone chemist working in the area at the relevant time. I have found the Defendant’s witnesses Drs. Low, Caldwell, Collicott, Wells and Chong to be particularly candid and forthcoming. I was troubled by Dr. Klibanov in the manner in which he gave his evidence, particularly in cross-examination. He was quarrelsome, dogmatic and sought to accuse cross-examining counsel frequently of “misrepresenting” what he was saying. Dr. Klibanov’s evidence was sprinkled with legal buzz words such as “motivated” and “worth a try”. I give less weight to the evidence of Dr. Klibanov particularly where it conflicts with evidence of other experts. Dr. Bartlett was largely candid and forthcoming although I detected that he has become highly skilled as a witness and could avoid giving answers and deflect questions where he perceived that difficulty may arise. I have not mentioned the other experts, particularly the medical doctors, by name, however I have found them all to be credible.
Background
[14] The Patent in general deals with a particular type of antimicrobial compound, levofloxacin. It falls within a general class of such compounds known as quinolones.
[15] The treatment of infections by antimicrobial substances, has been common for a long time. Many such substances, such as penicillin, were derived from materials which occurred naturally. As matters progressed, antimicrobial compounds were developed artificially.
[16] Consideration must be given to the risks of toxicity in the administration of antimicrobial substances. Much evidence was presented at trial as to the measurement of antimicrobial activity and of toxicity and the balancing of antimicrobial activity on the one hand and toxic effects on the other in administering various dosage levels of these substances. A drug must be effective, it must also be safe.
[17] The effectiveness of an antimicrobial drug is measured in several ways. The drug can be subjected to an MIC test. That test is conducted in vitro, that is, in glass in a laboratory and measures the Minimum Inhibitory Concentration (MIC) of a drug that is needed to kill a stated percentage of the microbes being examined. Hence a subscript MIC50 means that a stated concentration of the drug was needed to kill fifty percent of the microbes. The smaller the concentration number, the more effective the drug.
[18] In measuring antimicrobial activity, attention is paid to whether a compound is Gram positive or Gram negative. These expressions arise from a test developed long ago in which microbes were divided into two classes depending upon the colour of the stain they produced under certain circumstances. It was found that antimicrobial compounds could, in a rough way, be considered as those which dealt with one class or the other. The most desirable were those that could deal with both classes.
[19] The toxicity of a drug is measured in several ways. A quantity can be administered to animals such as mice or rats to a point where effects such as convulsions are observed, or death of the animal occurs. Measurements such as LD50 are provided which indicate the minimum Lethal Dose required to kill fifty percent of the animals tested. The higher the required dose, the less toxic is the drug in question. Measurements of toxicity are highly variable and depend, among other things, on the strain and sex of the animals tested, the rate at which the drug is administered, and whether administration is oral or by injection.
[20] Other factors are of interest: one is solubility. A more soluble drug is desirable as a greater concentration can be provided in liquid form to facilitate injection. Solubility is measured by determining how much of the drug will go into solution in a solvent, usually water, at a given temperature, usually room temperature, until the solution is saturated. A debate as to the time required to achieve saturation arose; Daiichi often used 30 minutes in their tests. Expert evidence suggested four hours. Some evidence indicated that several days may be required.
Quinolones
[21] In the early 1960’s quinolones emerged as a laboratory-developed drug. A sub-class, which incorporated fluorine into the molecular structure was known as fluroquinolones. Levofloxacin is a fluroquinolone.
[22] Quinolone drugs are said to operate by attaching themselves to substances called gyrases that are found with or associated with the DNA of the microbes to be killed or at least prevented from reproducing. The molecular structure of the quinolone compounds is such that it fits at
certain locations on the gyrase so as to do its work. The nature of the fit is debated. It may be as rigid as a lock and key or somewhat more flexible, called an inducted fit, as in a rubber spoon in a bowl of Jell-O. The more flexible approach would allow changes in the molecular structure to be made, which would affect the degree to which the quinolone works. A simple change may, therefore, not result in a simple mathematical increase or decrease in effectiveness. One always has to try it out.
[23] Early quinolones entering the market in the 1970’s were seen essentially to be limited to treatment of urinary tract infections, a Gram negative infection. Subsequently, newer quinolones such as Norofloxacin came to market which had broader activity to deal with microbes that were Gram positive. Among the most successful was Ciprofloxacin (Cipro) which continues to this day to be used in the treatment of several types of infections.
[24] Daiichi’s research in the quinolone area led to a drug known as Ofloxacin (Oflo). Ofloxacin was discovered by Daiichi researchers, including Dr. Hayakawa, in about June 1980. A scientific paper by Daiichi employees, Osada and Ogawa, was published in March 1983. It described Ofloxacin in terms of its (±) structure. An application for a patent pertaining to Ofloxacin was filed in Japan September 2, 1980 and a corresponding application was filed in Canada on September 2, 1981. The Canadian application matured to Patent number 1,167,480 (the ’480 patent) issued on May 22, 1984.
[25] The formula for Ofloxacin can be written as follows:
9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
It can be seen that this differs from claim 4 of the Patent at issue only in that claim 4 adds “S(-)-” at the beginning.
[26] The molecular structure of Ofloxacin can be depicted as:
Ofloxacin
[27] Chemists as of the early 1980’s would have realized that Ofloxacin has what is known as a chiral centre at the point where the CH3 (methane) joins the ring structure at the lower right hand corner of the structure shown above. Ofloxacin is thus known as a racemic compound or as it is sometimes called, a racemate. At this point it is necessary to discuss the concept of racemic compounds.
Racemic Compounds
[28] Molecular compounds although often written out as a series of letters, number and symbols or depicted on a flat sheet of paper, do not exist that way in reality. They are three dimensional structures. Some compounds only assume one three dimensional shape, others such as those that are racemic, do not.
[29] Racemic compounds, also called racemates, exist as comprising the same atoms in the same sequence, but bent at joints called chiral centres so as to assume what has been called left handed (levo) or right handed (dextro) configurations. Levo is sometimes simply depicted as (-) and dextro as (+). The left handed configuration is the mirror image of the right.
[30] A racemate is said to contain an equal number of left and right handed configurations of the molecule. This concept is sometimes depicted (±) although that is unnecessary when a competent chemist would be able to detect a chiral centre.
[31] Knowing that a compound is racemic is to know that, if there is only one chiral centre as there is in this case of Ofloxacin, there is a left hand and a right hand version of the molecule. Each version can be detected optically by a device such as a polarimeter. That device will detect which of the two configurations turns light to the left (levo or -) and which turns light to the right (dextro or +). Depending on the prevailing conditions different researchers may detect the molecules differently.
[32] Having detected left and right molecules, called enantiomers or optical isomers, one can go further however, and identify which of the two configurations is that which produces the left or right. For illustrational purposes, the configuration where the molecule attached at the chiral centres come “out of” the page is illustrated by a solid wedge and where they go “into” the page is illustrated by a dotted wedge. These configurations are designated as S and R. Once the left or right compound has been identified and isolated, it can be subjected to techniques such as X-ray diffraction whereby a determination as to whether the – is S or R or the + is R or S. For instance a designation S(-) means that the molecule attached at the chiral centre comes out of the page and exhibits left handed optical rotation. Once a substance is designated as S or R, it is unnecessary to add (-) or (+) in order to identify the structure of the compound as being a particular enantiomer although (-) or (+) will give added information.
[33] To put matters into the context of the facts of this case, Ofloxacin was a known compound. A competent chemist would readily detect that it had a chiral centre and thus was a racemate.
[34] When levofloxacin was isolated it was seen that one configuration produced optically detected left handed enantiomers levo or (-); the other, of course, was dextro or (+). When the levo or (-) configuration was analysed further it was confirmed that it existed in the S configuration. Thus the levo configuration could be written:
S Ofloxacin
or
S(-) Ofloxacin
or
S-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
or
S(-)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
[35] Prior to the isolation of levofloxacin it was known that Ofloxacin had a (+) and a (-) component but until levofloxacin was isolated and examined it was not known whether the (+) was R or S or the (-) was R or S. Thus, there could be products to exist any of:
R(+) Ofloxacin
together with
S(-) Ofloxacin
or
R(-) Ofloxacin
together with
S(+) Ofloxacin
What was determined to exist in reality was:
R(+) Ofloxacin
together with
S(-) Ofloxacin
These are shown with solid or dotted wedges at the lower right of the depiction where CH3 joins the ring structure as:
levofloxacin
(S(-) Ofloxacin)
R(+) Ofloxacin
[36] A racemate contains equal quantities of (+) and (-) thus may be written as (±) but often this symbol is omitted as unnecessary. As the two components (enantiomers) are separated and one or the other is isolated, the process of isolation will mean that any given sample will have an excess of one enantiomer over the other. This is sometimes called enantiomeric excess (ee) and is a measure of the purity of the sample. Thus if a sample (100%) contains 95% of the (-) enantiomer and 5% of the (+) enantiomer the enantiomeric excess of the (-) enantiomer over the (+) enantiomer is 90% (95 – 5 = 90). The earliest example of separation of enantiomers is said to be an exercise conducted by Louis Pasteur in the mid 1800’s when he detected by a simple optical microscope of the day, that tartaric acid comprised two crystal forms which displayed light differently. He separated them manually with the aid of tweezers.
Arriving at Levofloxacin
[37] Daiichi is in the business of discovering, marketing and licensing drugs to others. It has over a thousand employees engaged in drug research. In June 1980, Daiichi researchers, including Dr. Hayakawa, discovered the compound Ofloxacin which was subsequently the subject of patents in Japan, Canada and elsewhere. Ofloxacin was the first compound in the quinolone class developed by Daiichi that proved to have the necessary qualities to be marketed as an antimicrobial drug. It enabled Daiichi to enter into the market and compete with other quinalones such as Ciprofloxacin marketed by Bayer.
[38] Daiichi, having arrived at Ofloxacin sought to expand the scope of possible derivatives. The purpose was, as stated in its business plan for the first half year 1981, “for patent protection”. The stated theme of the research was to seek optical resolution of Ofloxacin (called DL-8280), research metabolism and other related work. Patent protection meant that Daiichi wanted to secure patent protection from compounds related to Ofloxacin in order to maintain a competitive advantage and ward off competitors.
[39] During 1981 Daiichi researchers endeavoured to isolate the optical isomers of Ofloxacin. Some success was achieved in isolating the (+) form but further work was needed to obtain an isolate of the (-) form. A report dated August, presumably 1981, indicates that a Mr. Ebata, through repeated recrystalization through four rounds, obtained 200 mg of material which contained the (-) form in a 5:1 ratio over the (+) form, that is about 83% (-). This was not the (-) form of Ofloxacin as a further molecule had been attached to the compound to aid the process of isolation. The evidence is that it would have been routine to remove that molecule so as to obtain the (-) enantiomer of Ofloxacin.
[40] There is no clear evidence as to what was done with this product. Dr. Hayakawa says that, knowing his personality, he would have instructed that the product be further refined if at all possible and, since there is no record that a further refined product was obtained, then he assumes that it could not be obtained and the project was abandoned. Dr. Collicott says that 200 mg of product of this purity would have been sufficient to conduct some microbial and other tests. Dr. Bartlett describes this activity as a failure. There simply is no clear record as to what happened at this time.
[41] In about November 1982, Daiichi reports it was able to obtain some of the (+) form of optical isomers from Ofloxacin but indicated that the matter was under further study.
[42] A report concerning the period of research at Daiichi from August 1983 to March 1984 indicates that Daiichi had obtained some commercial Pirkle type chiral HPCL columns to assist in their endeavour to isolate the optical isomers of Ofloxacin. One such column was that known as BAKERBOND. Daiichi also prepared its own version of such a column. The report indicates that further investigation was needed.
[43] In April 1985, Daiichi reported that since Hoechst and J&J who were licensees of Daiichi in respect of Ofloxacin, had requested data on the optical isomers, presumably because government regulatory bodies were pressuring them, Daiichi would attempt to reach a conclusion as early as possible. I take this to be the motivation that spurred on the final push by Daiichi to isolate the enantiomers. Two methods were tried, the HPLC column, called Process A in the Patent, and, an enzymatic process, called Process B in the Patent. Using the HPLC columns that it had previously acquired, Daiichi was successful in obtaining (-) and (+) optical isomers of 100% optical purity. Code number DR-3355 was assigned to the (-) form and DR-3354 to the (+) form. This was the first isolation of a substantially pure substance. However, it was not ascertained at this time whether the (-) was an S or R configuration or the (+) was R or S. Further, at that time, no testing as to antimicrobial activity or toxicity or solubility had been conducted. Thus, while the (-) form was isolated it was not determined that it was S(-) as claimed in claim 4 at that time nor, were any of its properties ascertained.
[44] A May 1985 Daiichi report indicates that up to 10 mg of (+) and (-) had been obtained by the HPLC method in April and that tests indicated that the (-) form DR-3355 showed almost double the antimicrobial activity of Ofloxacin DL-8280. This is the first test as to antimicrobial activity. An Interim Report of May 1985 describes the isolation of the (-) and (+) forms and determination of activity as a “really big finding”.
[45] In June 1985 the first of the Japanese Patent Applications, this one directed to the HPLC method, Process A, was filed.
[46] In June and July 1985, work continued on the enzymatic process for separation, called Process B. In August 1985, Daiichi reported “astonishing separation”. In October 1985 the second of the Japanese Patent Applications was filed and was directed to this enzymatic process. No tests had yet been conducted as to determine the S or R configuration, nor had any toxicity or solubility tests been conducted.
[47] In a report dealing with the period from August to October 1985, Daiichi shows that it had conducted initial screen toxicity tests on mice. A chart appears giving the same information as that that now appears in Table 3 of the 080 patent except that the LD50 values are not given. In the same report a solubility of 22500 mg/ml or 10 times as much as Ofloxacin is reported, just as set out in Table 4 of the Patent. The LD50 value for Ofloxacin of 203 (or 208 as there may have been a misprint) appears to have been simply an accepted number at Daiichi. The LD50 value of 244 (243.8) mg/kg for the (+) and (-) optical isomers is first reported January 1986.
[48] In December 1985, Daiichi reports that last month (November) an X-ray diffraction analysis had been conducted on the (-) optical isomer and that the absolute configuration of S had been determined.
[49] In January 1986 the third of the Japanese Patent Applications was filed. It is the first to disclose the S configuration.
[50] It can been seen through this course of development that the final element of claim 4, determination of the S configuration, had been made by December 1985. I find therefore, that December 1985 is the relevant date of invention for consideration of issues as to inventive ingenuity and obviousness with respect to claim 4.
The Gerster Papers
[51] Papers in poster form authored by Dr. John Gerster, one in 1982 and one in 1985, both relating to processes for obtaining a quinolone drug known as flumequine, are significant to the arguments of the parties. The fact of publication and availability of the 1985 poster paper is not at issue. It is admitted that the 1985 paper was the subject of a poster presentation at a convention in the fall of 1985. That convention was attended by scientist interested in the area of drugs such as quinolones. Dr. Hayakawa admitted that he attended that convention, made notes from the poster as presented and returned to Japan where he adapted the process to produce levofloxacin. He said that this process went well. This process is a version of what the Patent describes as Process C and is set out in the third of the Japanese patent applications filed on January 28, 1986.
[52] The 1982 poster differs from the 1985 poster only in that the 1982 paper is directed to flumequine itself whereas the 1985 paper is directed to a flumequine derivative.
[53] It is the publication of the 1982 paper in poster form that is in contention. Dr. Gerster’s evidence, which I accept completely, was that there was a convention of drug scientists such as himself, held in Toronto in June 1982. Prior to or at the convention attendees were given a book which contained a list of attendees and abstracts of papers presented including abstracts of those presented in poster format. Exhibit D-97 was a copy of a portion of that material which included an abstract of Dr. Gerster’s poster. A copy of the poster itself may have been sent by Dr. Gerster to the chairman of the conference prior to the opening of that conference, but the evidence on this point is unclear as to whether the poster or the abstract was sent. At the convention, Dr. Gerster attached a full copy of his poster to a four by eight fact board in an area where those attending would pass by and could examine the poster and speak to Dr. Gerster. Dr. Gerster could not remember if anyone had actually requested a copy of the poster but said he would have provided a copy, if asked. There is no evidence that any person was ever provided with a copy of the poster or examined the paper as posted.
[54] Dr. Hayakawa testified that in the fall of 1985 he attended a conference and examined Dr. Gerster’s 1985 poster and made notes from it. He testified that the 1985 poster made reference to the 1982 poster which Dr. Hayakawa had never seen. He asked Daiichi’s New York office to endeavour to obtain a copy of the 1982 Gerster poster but apparently they were unsuccessful in doing so.
[55] The expert evidence of Dr. Partridge, a consultant to the drug industry and a person who had worked for many years in that industry and Ms Langley, Head Librarian at Duke University Chemical Library, is that the 1982 Gerster poster could not be located by means of any available searching facility whether using 1985 or 2006 techniques. The Defendants’ evidence, through Dr. Collicott is that the 1982 abstract, but not the poster, was available at the British Library.
[56] The 1982 poster deals with flumequine, not Ofloxacin, not levofloxacin. While the scientific experts argued as to how closely relevant flumequine may have been to levofloxacin, it is clear that the 1982 poster makes no specific disclosure as to levofloxacin. To that extent therefore, the 1982 poster does not “anticipate” levofloxacin since in order to anticipate it must disclose levofloxacin itself, as will be discussed more fully in these Reasons. Thus the 1982 paper can only be relevant to the issue of obviousness. The law respecting the availability of printed publications pertaining to issues of novelty (anticipation) is different from the law respecting invention or obviousness.
[57] In order to be relevant to the issue of invention or obviousness, the 1982 poster must be something which, on the evidence, was available to a person skilled in the art or could reasonably be assumed to have knowledge of in 1985 (Mahurkar v. Vas-Cath Canada Ltd. (1988), 18 C.P.R. (3d) 417 at 432-36 (F.C.), aff’d 32 C.P.R. (3d) 409 (F.C.A.)). There was no evidence that anyone other than Dr. Gerster, perhaps the chair of the conference and a