Abbott Laboratories v. Canada (Minister of Health)

Abbott Laboratories v. Canada (Minister of Health)
Court (s) Database
Federal Court Decisions
Date
2004-10-01
Neutral citation
2004 FC 1349
File numbers
T-1035-02
Notes
Digest
Decision Content
Date: 20041001
Docket: T-1035-02
Citation: 2004 FC 1349
BETWEEN:
ABBOTT LABORATORIES and
ABBOTT LABORATORIES LIMITED
Applicants
and
THE MINISTER OF HEALTH and
PHARMASCIENCE INC.
Respondents
APPLICATION UNDER Section 55.2 of the Patent Act, Section 6 of the Patented Medicines (Notice of Compliance) Regulations, am. by the Regulations Amending the Patented Medicines (Notice of Compliance) Regulations.
REASONS FOR ORDER
GIBSON J.:
INTRODUCTION
[1] By Notice of Application filed the 5th of July, 2002, Abbott Laboratories ("Abbott U.S.") and Abbott Laboratories Limited ("Abbott Canada"), (collectively "the Applicants"), seek the following relief:
1) an Order prohibiting the Respondent the Minister of Health (the "Minister") from issuing the Respondent Pharmascience Inc. ("Pharmascience") a notice of compliance for clarithromycin - 250 mg or 500 mg Tablets until after the expiry of Canadian Letters Patent No. 2,261,732;
2) costs of the application; and
3) such further or other relief as counsel might advise and this Court might deem just and reasonable.
[2] The Application was filed pursuant to section 6 of the Patented Medicines (Notice of Compliance) Regulations[1] (the "Regulations") and was responsive to a Notice of Allegation served by Pharmascience on Abbott Canada, pursuant to section 5 of the Regulations, on the 21st of May, 2002. The Notice of Allegation advised that Pharmascience had filed an Abbreviated New Drug Submission in respect of clarithromycin tablets 250 mg and 500 mg which makes reference to Abbott Canada's brand of clarithromycin in the same dosages for which Abbott Canada had received Notices of Compliance from the Minister.
[3] Pharmascience's Notice of Allegation sets out the following very brief "factual basis":
PMS' [Pharmascience's] clarithromycin is produced by a process which does not recrystallize or crystallize clarithromycin (in any form) directly to form II clarithromycin, and which does not use one solvent, or one solvent mixture. The process used to make form II clarithromycin is a slurrying of Form 0 crystals in water. The slurrying process is disclosed in PCT Application No. PCT/US 00/33845 (WO 01/44262).
[4] On the foregoing factual basis, Pharmascience's Notice of Allegation alleges that its form II clarithromycin is produced by a process that does not infringe Canadian Letters Patent No. 2,261,732 and that, alternatively, if its clarithromycin is covered by claims 16 to 21 of the Patent, then those claims are broader than the invention made and disclosed and thus the Patent is invalid.
[5] But for an extension of the twenty-four (24) month period provided in paragraph 7(1)(e) of the Regulations during which the Minister was prohibited from issuing a Notice of Compliance to Pharmascience, such twenty-four (24) month period running from the "...receipt of proof of the making..." of the Applicants' Application, the Minister would have been at liberty to issue a Notice of Compliance under the Regulations to Pharmascience on or after the 5th of July, 2004. Pursuant to paragraph 7(5)(b) of the Regulations, by Order dated the 25th of June, 2004, Prothonotary Aronovitch extended the twenty-four (24) month period by one hundred and five (105) days to the 18th of October, 2004. Prothonotary Aronovitch's Order was appealed. That appeal was dismissed by Order dated the 9th of July, 2004. In the result, the prohibition against the Minister issuing a Notice of Compliance to Pharmascience remains in force.
THE PARTIES
[6] Abbott U.S. is the owner of Canadian Letters Patent No. 2, 261, 732 (the "'732 Patent") which relates to specific pharmaceutical compounds when prepared or produced by certain methods or processes and to those methods or processes. The '732 Patent expires on the 28th of July, 2017. Abbott U.S. is the parent of Abbott Canada.
[7] Abbott Canada is a Canadian innovator pharmaceutical manufacturer. It has the permission of Abbott U.S., under the '732 Patent, to manufacture and sell BIAXIN BID® in Canada. Abbott Canada is the manufacturer in Canada of BIAXIN BID®, an antibiotic. BIAXIN BID® is sold in Canada in 250 mg and 500 mg tablets pursuant to Notices of Compliance originally issued to Abbott Canada on the 8th of May, 1992 and the 25th of August, 1994 respectively. The active medicinal ingredient in BIAXIN BID® is Clarithromycin. The '732 Patent has been listed by Abbott Canada on the Patent Register maintained pursuant the Regulations in respect of BIAXIN BID® .
[8] Pharmascience 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)[2] "...market[s] a drug without having to independently establish the safety and effectiveness of the drug...". As earlier noted, Pharmascience seeks a Notice of Compliance from the Minister to enable it to market an equivalent of BIAXIN BID®.
[9] The Minister of Health is the Minister charged with the administration of the Patented Medicines (Notice of Compliance) 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
[10] The application giving rise to the '732 Patent was filed on the 28th of July, 1997, claiming priority from the equivalent U.S. Patent as of the 29th of July, 1996. It is entitled "Preparation of Crystal Form II of Clarithromycin". The abstract of the Patent reads as follows:
The present invention provides a process for the preparation of 6-O-methylerythromycin A Form II comprising converting erythromycin A to 6-O-methylerythromycin A and treating the 6-O-methylerythromycin A with a number of common organic solvents or mixtures of common organic solvents.
It contains forty-four (44) claims. The claims that are relevant for the purposes of this matter are 1, 2 and 3 and 15 to 21. Those claims are set out in full in a Schedule to these reasons.
[11] In the disclosure of the Patent, the claimed invention is summarized in the following terms:
We have discovered that 6-O-methylerythromycin A can exist in at least two distinct crystalline forms, which for the sake of identification are designated "Form I" and "Form II". The crystal forms are identified by their infrared spectrum, differential scanning calorimetric thermogram and powder x-ray diffraction pattern. Investigations in our laboratory have revealed that 6-O-methylerythromycin A when recrystallized from ethanol, tetrahydrofuran, isopropyl acetate, and isopropanol, or mixtures of ethanol, tetrahydrofuran, isopropyl acetate, or isopropanol with other common organic solvents result in exclusive formation of Form I crystals, not identified hitherto before. 6-O-methylerythromycin A Form I is disclosed in the co-pending U.S. Patent 5,858,986, filed even-date on July 29, 1996.
Drugs currently on the market are formulated from the thermodynamically more stable Form II. Therefore, preparation of the current commercial entity requires converting the Form I crystals to Form II. Typically this is done by heating the Form I crystals under vacuum at a temperature of greater than 80 ° C. Therefore, a process for the preparation of 6-O-methylerythromycin A Form II which does not require the high temperature treatment would result in substantial processing cost savings.
Although recrystallization from ethanol, tetrahydrofuran, isopropanol or isopropyl acetate results in exclusive formation of Form I crystals, 6-O-methylerythromycin A Form II can be isolated directly by using a number of other common organic solvents, or mixtures of common organic solvents, thereby eliminating the additional conversion step.
Accordingly, the present invention provides a process for preparing 6-O-methylerythromycin A Form II comprising
(a) converting erythromycin A to 6-O-methylerythromycin A;
(b) treating the 6-O-methylerythromycin A prepared in step (a) with a solvent selected from the group consisting of (i) an alkanol of from 1 to 5 carbon atoms, provided said alkanol is not ethanol or isopropanol, (ii) a hydrocarbon of from 5 to 12 carbon atoms, (iii) a ketone of from 3 to 12 carbon atoms, (iv) a carboxylic ester of from 3 to 12 carbon atoms, provided said carboxylic ester is not isopropyl acetate, (v) an ether of from 4 to 10 carbon atoms,(vi) benzene, (vii) benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen, (viii) a polar aprotic solvent, (ix) a compound having the formula HNR1R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbons atoms, provided that R1 and R2 are not both hydrogen, (x) water and a second solvent selected from the group consisting of a water miscible organic solvent and a water miscible alkanol, (xi) methanol and a second solvent selected from the group consisting of a hydrocarbon of from 5 to 12 carbon atoms, an alkanol of from 2 to 5 carbon atoms, a ketone of from 3 to 12 carbon atoms, a carboxylic ester of from 3 to 12 carbon atoms, an ether of from 4 to 10 carbon atoms, benzene and benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen, and (xii) a hydrocarbon of from 5 to 12 carbon atoms and a second solvent selected from the group consisting of a ketone of from 3 to 12 carbons atoms, a carboxylic ester of from 3 to 12 carbon atoms, an ether of from 4 to 10 carbon atoms, benzene, benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen and a polar aprotic, and
c) isolating the 6-O-methylerythromycin A Form II crystals.
[12] For the purposes of this matter the terms "treating" in the first line of paragraph (b) of the fourth paragraph of the foregoing quotation and alternative (x) in that same paragraph reading "water and a second solvent selected from the group consisting of a water miscible organic solvent and a water miscible alkanol" are central. "Treating" is defined in the "detailed description" contained in the disclosure in the following terms:
The terms "treating" refers to crystallizing or recrystallizing 6-0-methylerythromycin A as defined above from any of the solvent systems described above.
[13] Alternative (x) referred to in the foregoing paragraph represents a combination of water and a water miscible organic solvent or water miscible alkanol that is, among other things, ethanol. A water-ethanol solvent is specifically referred to in Claim 15.
[14] Claims 15 and 16 specifically refer back to Claim 2. Claim 17 references a preparation according to Claim 3 which in turn references Claim 2. Similarly, claim 18 references a preparation according to Claim 9 which in turn references Claim 2. Also similarly, Claim 19 references a preparation according to the process of Claim 13 which in turn refers back to a method according to Claim 2.
THE PHARMASCIENCE PROCESS AND PRODUCT
[15] Pharmascience does not propose to manufacture its form of clarithromycin II but rather proposes to purchase it from an off-shore supplier. It was not in dispute before the Court that the end-product is the same. Rather, Pharmascience claims that the process by which the clarithromycin II for which it seeks approval is made outside the scope of the '732 Patent in that its supplier's process does not involve a crystallization or recrystallization but rather involves a "solid-state transformation" accomplished by slurrying in water. Put another way, Pharmascience's supplier's process is said not to involve the reduction of a crystalline form to a different form and then a recrystallization but rather to involve a direct transformation of a crystalline form to a different crystalline form, accomplished through slurrying.
[16] Earlier in these reasons, I reproduced a paragraph from Pharmascience's Notice of Allegation giving rise to this proceeding. That paragraph is repeated here for ease of reference. Under the heading "Factual basis", Pharmascience advised Abbott Canada as follows:
PMS' [Pharmascience's] clarithromycin is produced by a process which does not recrystallize or crystallize clarithromycin (in any form) directly to form II clarithromycin, and which does not use one solvent, or one solvent mixture. The process used to make form II clarithromycin is a slurrying of Form 0 crystals in water. The slurrying process is disclosed in PCT application No. PCT/US00/33845 (WO 01/44262).
[17] Further in its Notice of Allegation, under the heading "Legal basis" and the subheading "Claims 16 - 21", Pharmascience writes:
Claims 16 - 21 are not infringed because they cover clarithromycin crystal form II when prepared by a process of "treating" 6-0-methylerythromycin A with one solvent, or one solvent mixture. The '732 Patent defines "treating" to mean crystallizing or recrystallizing ... . The term 6-0-methylerythromycin A (or clarithromycin) is defined to mean a solid, a semisolid, or a syrup containing residual solvents (from the process for making the clarithromycin from erythromycin).
PMS' clarithromycin Form II is made by slurrying Form 0 clarithromycin in water to convert the crystals to form II.
...
PMS' process does not involve crystallizing Form II directly from clarithromycin, or recrystallizing Form I or mixtures of Form I and Form II. As is disclosed in the PCT Application, the PMS Form II is made from Form 0 that is stirred or slurried in water. The Form 0 is not dissolved and then crystallized or recrystallized.
...
Claims 16 to 21 cover Form II clarithromycin prepared by the process of Claim 1. The other process claims referred to in Claims 16 to 21, namely 2, 3, 9, 13, and 15 all depend upon Claim 1 either directly or indirectly.
Claim 1 covers a process for making clarithromycin Form II by first converting erythromycin A to 6-0-methylerythromycin; and then treating 6-0-methylerythromycin A (clarithromycin) with "a solvent selected from the group consisting of "listed groups (i) to (xii)".
The PMS process does not make Form II by treating clarithromycin with any of the solvent groups listed in Claim 1(b)(i) to (xii). For further certainty, the PMS process does not treat clarithromycin with any of the solvent groups which are listed in Claims 3, 9, 13 or 15 to prepare Form II clarithromycin.
[subheadings omitted]
[18] A more useful description of the process for making Pharmascience's clarithromycin II was disclosed to Abbott under cover of a letter dated the 19th of November, 2002. The enclosure with that letter consisted of three (3) pages from Pharmascience's Abbreviated New Drug Submission. Pharmascience claimed and continues to claim confidentiality in those pages.[3] While the disclosed pages elaborate to a significant degree on the foregoing description of the process for making Pharmascience's clarithromycin II, they also disclose that Pharmascience's supplier also makes clarithromycin II by a second process. It is not in dispute that that second process is within the terms of the '732 Patent. Pharmascience filed evidence in this proceeding to indicate the existence of an arrangement with its proposed supplier such that clarithromycin II supplied to Pharmascience would only be produced by the "slurrying" method described above. More will be said about this later in these reasons.
THE EXPERT AFFIANTS
[19] The Applicants relied on the evidence of three (3) 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 of each of the Applicants' experts.
[20] Dr. Jerry Atwood holds a BS degree in Chemistry and Mathematics from Southwest Missouri State University and a Ph.D. in Chemistry from the University of Illinois. Since 1994 he has been employed as Professor and Chairman of the Department of Chemistry at the University of Missouri-Columbia. From 1968 to 1994, he was employed by the University of Alabama, where he successively held the titles of Assistant Professor, Associate Professor, Professor, and University Research Professor. In 1999 he became Curators' Professor at the University of Missouri-Columbia.
[21] From 1985 to 1998, Dr. Atwood was Editor of the Journal of Chemical Crystallography. In 1999 he was named Consulting Editor for the Journal of Chemical Crystallography. He has edited the Journal of Supramolecular Chemistry since 2000, and he has been Associate Editor of Chemical Communications since 1996. From 1992 until 2000, he was editor of Supramolecular Chemistry.
[22] From 1985 to 1993, Dr. Atwood was Regional Editor for the Journal of Coordination Chemistry. He continues to be co-Editor of the Inclusion Compounds book series (five volumes) and Comprehensive Supramolecular Chemistry (ten volumes). He currently serves on the Editorial Boards of five journals. He attests that he has published more than 570 articles in refereed journals. He has authored ten patents.
[23] Dr. Atwood attests that he is an expert in the fields of crystal growth, crystal engineering, and polymer chemistry[4]. No challenge was recorded to that claim.
[24] Dr. Stephen Byrn received a Ph. D. in Chemistry from the University of Illinois in 1970 and was a post doctoral fellow at UCLA from 1970 to 1972. In 1972, he became a professor in the School of Pharmacy at Purdue University. He was Head of the Department of Medicinal Chemistry and Pharmacognosy at Purdue University in the School of Pharmacy and Pharmaceutical Sciences from 1988 to 1994. He was the Director of the Center for AIDS Research at Purdue from 1988 until 1998, and since 1994, he has been Head of the Department of Industrial and Physical Pharmacy. He became the Charles B. Jordan Professor of Medicinal Chemistry in 1992.
[25] Dr. Byrn has authored over 100 peer-reviewed publications in technical journals on topics relating to solid-state chemistry. He has also co-authored a book entitled "Solid Chemistry of Drugs", and is the author of two book chapters. As well, he has presented an extensive number of papers at conferences, and has taught numerous courses regarding polymorphism. He has taught at the U.S. federal Food and Drug Administration and has been an industrial consultant to a number of different innovator and generic pharmaceutical companies, in addition to serving as Chair of a number of prestigious committees.
[26] While Dr. Byrn does not attest in so many words that he is an "expert", he does attest that the opinions expressed in his affidavits before the Court "...are based on my background and experience including my thirty-three years of professional experience in the study, characterization and analysis of organic solids... ."[5] Dr. Byrn's qualifications and expertise were not challenged.
[27] Dr. Allan S. Myerson is a Professor of Chemical Engineering and Provost and Senior Vice-President at the Illinois Institute of Technology in Chicago. He has been in that position from January 2003. From January 2000 to December 2002, he served as Professor of Chemical Engineering and Dean of the Armour College of Engineering and Science at the Illinois Institute of Technology. From January 1985 to December 1999, he served on the Faculty of Polytechnic University (Brooklyn, NY) where he held various positions including Joseph and Violet J. Jacobs Professor of Chemical Engineering, Head of the Department of Chemical Engineering, Dean of the School of Chemical and Materials Science, and Vice Provost for Research and Graduate Studies. From September 1979 to December 1984, Dr. Myerson served on the Faculty at the Georgia Institute of Technology as an Assistant Professor of Chemical Engineering, and subsequently as an Associate Professor. Prior to his service at the Georgia Institute of Technology, Dr. Myerson served on the Faculty at the University of Dayton as an Assistant Professor of Chemical Engineering.
[28] Dr. Myerson received his Bachelors of Science in Chemical Engineering from Columbia University. He received a Masters and Ph. D. in Chemical Engineering from the University of Virginia. He is a registered Professional Engineer in the states of New York and Ohio.
[29] Dr. Myerson has published extensively and has taught courses in crystallization in the United States, Europe and Japan. He has consulted for major chemical and pharmaceutical companies in the United States, Europe and Japan.
[30] Dr. Myerson attests:
Based on my experience and qualifications, I consider myself to be an expert in the field of chemical engineering and crystallization, including industrial crystallization and polymorphism. These are precisely the issues raised in this proceeding.[6]
[31] Once again, Dr. Myerson's expert qualifications were not challenged.
[32] Pharmascience relied on the expert opinions of two (2) affiants. Their qualifications can be briefly summarized as follows.
[33] Dr. Frank Brown Jr. obtained a Ph.D. in Organic Chemistry from Purdue University in 1969. For most of his working career, he was employed by Lilly Research Laboratories, a division of Eli Lilly and Company, where he held a series of positions commencing with work as a technical service chemist, Research Scientist, Research Associate, Senior Research Scientist and Team Leader and Research Advisor which he attests to be the "...highest earned scientific level that can be achieved at Lilly."
[34] In 2000, Dr. Brown retired early from Eli Lilly to join Purdue University to pursue basic research in the Pharmaceutical Sciences. He became the Director of the Pharmaceutical Sciences Program at Purdue. Dr. Brown attests:
Based on my experience, I am an expert in industrial process chemistry, having scaled up numerous chemical processes at full scale associated with pharmaceutical manufacturing of human and animal health products. My experience has provided me the practical knowledge to carry out a pharmaceutical process and to troubleshoot any problems with a process at industrial scale. For example, my experience would enable me to solve crystallization problems on an industrial scale.[7]
[35] While Dr. Brown's experience and expertise was not challenged, counsel for the Applicants did express concern regarding his experience and expertise with regard to the processes and substances at issue in this proceeding.
[36] Dr. Mark D. Hollingsworth is an Associate Professor of Chemistry at Kansas State University. He received a Bachelor of Arts degree from Carleton College in 1979. From 1979 to 1985 he pursued his Ph. D. in Organic Chemistry at Yale University. From 1985 to 1987 he completed postdoctoral studies at the University of Cambridge where his research focussed on characterizing chemical reactions of crystalline materials including polymorphs. He commenced his work as a Professor of Chemistry in 1987 and has continued his work on solid state chemistry and polymorphs. He attests:
My research as a solid state organic chemist has focussed on the following areas:
(i) processes to isolate crystalline organic compounds;
(ii) analytical techniques for characterizing crystalline materials and the processes that occur within them;
(iii) solid state chemistry (defined as the study of various solid forms of chemical compounds);
(iv) mechanistic studies of crystal growth, including the effect of solvent used; and
(v) mechanistic studies of phase transitions and phase transformations in crystalline studies.
My area of expertise is in the study of crystal forms and transformations between them. For the past 22 years, I have regularly developed and conducted processes to crystallize chemical compounds. I have used crystallization as a technique of purification (to remove impurities from the desired compound) and isolation (to create a certain crystal form, where a compound may exist in one of many crystal forms).
[37] Dr. Hollingsworth has published extensively. He attests that he has acted as a consultant to pharmaceutical companies in the area of crystal analysis and in the preparation of crystal forms.
[38] Dr. Hollingsworth further attests:
As a result of my experience ..., I am familiar with (i) developing processes to make different crystal forms; (ii) studying the chemical and structural changes in a crystal during transformation from one crystal form to another; and (iii) characterizing and analyzing crystalline materials using normal laboratory techniques.[8]
[39] Once again, Dr. Hollingsworth's expertise was not challenged but, once again, counsel for the Applicants urged that his qualifications and experience were not equal to those of the Applicants' experts.
THE EXPERT EVIDENCE AND EVIDENCE OF EXPERIMENTATION
DR. JERRY ATWOOD
[40] Dr. Atwood attests in his first affidavit filed in this proceeding that, for the purposes of responding to Pharmascience's Notice of Allegation herein, he read the Notice of Allegation, the '732 Patent, six (6) United States Patents, related international publications and several unidentified journal articles related to the synthesis of clarithromycin as well as excerpts from the Abbreviated New Drug Submission of Pharmascience, including the Drug Master File of Pharmascience's proposed supplier. The summary of his opinion is in the following terms[9]:
The subject matter of the ['732 Patent] and the allegations of Dr. Neirinck (hereafter referred to as the "NoA") rely heavily on the discipline of organic chemistry. In order to make clear and concise opinions on the issues in this litigation, I have provided ... a brief overview of the relevant aspects of this area of chemistry.
It is alleged by Pharmascience that the '732 Patent is not infringed by its proposed process and processes and that, if there is infringement, the '732 Patent is invalid on the basis that the patent claims are broader that the invention made and disclosed.
In my opinion, the allegations set forth in the NoA are scientifically flawed and wholly without merit. In the following paragraphs, I provide the basis for my opinion, summarized as follows:
(a) the Disclosure suggests that Pharmascience' supplier makes Form II Clarithromycin ... the alleged slurry step is even commenced;
(b) the Pharmascience slurry step is a crystallization in ... and water;
(c) the Disclosure contains an alternate process which produces Form II ...;
(d) the claims of the '732 Patent as they would be read by a person skilled in the art are well supported by the disclosure in the '732 Patent and they clearly cover the process allegedly used by Pharmascience.[10]
[41] In the same affidavit, Dr. Atwood offered the following opinion:
A person of ordinary skill in the art of the '732 Patent is a chemist or chemical engineer with two to five years experience with crystallization processes.
First, it is normal practice, well known to a person skilled in the art of the '732 Patent, to use a slurry when one is practicing the art of industrial crystallization. Pharmascience is wrong to cite chemistry texts which deal with laboratory procedures for purification of organic compounds (i.e., Vogel's Textbook of Practical Organic Chemistry, pp. 105-113, published 1978) on this question. This is not an authority on industrial crystallization. A reading of pp. 105-113 of Vogel's book affords the conclusion that this reference is aimed at the synthetic organic chemist working at a laboratory bench with a small amount of impure compound. This is not the reference work to which one of ordinary skill in the art would refer when seeking information about the treatment of Clarithromycin to produce Form II crystalline material on an industrial scale.
More appropriate references would include commonly available references from which it is clear that slurrying is a common and well known method of crystallization.[11]
[42] In a supplementary affidavit sworn the 5th of September, 2003, Dr. Atwood notes that he has had the opportunity to review two (2) affidavits filed in this proceeding by Dr. Hollingsworth, an affidavit of Dr. Leonard Neirinck, Vice President, Scientific Affairs of Pharmascience, the affidavit of Dr. Frank Brown Jr., and two (2) affidavits of Patrick Taylor, a law clerk with Pharmascience's firm of solicitors. Collectively, he refers to the foregoing as the "Pharmascience evidence". He concludes his second affidavit in the following terms:
In my affidavit dated 1 May 2003, [earlier referred to] I offered the following summary opinion:
(a) The Pharmascience process uses crystallizations to make Form II Clarithromycin;
(b) In particular, the slurry step is a crystallization;
(c) The crystallizations in the Pharmascience process all take place in solvents comprised of ... and water;
(d) In particular, the "average" bulk concentration of ... in the slurry is as high as ... but the composition of ... in the solvent at the surface of the crystals is much higher;
(e) The use of ... in the solvents is a significant aspect of the Pharmascience crystallization process steps;
(f) A person skilled in the art would readily and clearly understand that the Abbott invention and disclosure of the '732 Patent include crystallization by a slurry method which was a well known crystallization technique as of publication date of the '732 Patent ..., and indeed, long before. The scope of the claims is no broader than the invention made and disclosed in the '732 Patent.
After careful review of the affidavits offered by the Pharmascience experts, I stand fully behind my original opinions.
Dr. Hollingsworth offers flawed, non-scientific experiments in an attempt to demonstrate that the slurry process used by the Pharmascience Clarithromycin supplier is a solid to solid phase transformation. It is not. Dr. Chyall's scientific experiments completely refute the experimental work done by Dr. Hollingsworth.[12]
[43] Dr. Atwood was subjected to an extensive cross-examination. While counsel for Pharmascience took me during the hearing of this application to a number of passages from the transcript of that cross-examination, I am satisfied that Dr. Atwood was not shaken in the opinions he expressed in his affidavit evidence. A reading of the whole of the transcript of his cross-examination leads me to conclude that there was no reason why he should have been. I choose to refer here to only one passage to which counsel took me from very close to the end of the transcript. That passage reads as follows:
Q. I take it had Dr. Chyall [who did testing on behalf of the Applicants] done tests, we might have seen that. You don't know. This is all a theoretical discussion. We could be discussing this based on fact; isn't that right?
A. I would like to have fact to base this on. But I'm not saying that the [Pharmascience supplier's] process, my understanding is - I'm unsure about the [Pharmascience supplier's] process. I think it may well be producing Form II [Clarithromycin]. However, it's not, in my judgment, doing it by a solid-to-solid transition, but rather it's doing it by a rolling crystallization.[13]
[44] Counsel for the Applicants took me to the following passage from the same cross-examination:
Q. Is it possible to have a solid-to-solid transformation take place in a slurry?
A. A solid-to-solid transformation could take place in a slurry. In order to verify that this is a solid-to-solid transformation, one would have to do some experiments.
First of all, if the compound is soluble to any extent in solution, one would have to rule out the fact that it's a simple recrystallization. In other words, it's a transformation which occurs in solution.
Solid-to-solid transformation is relatively uncommon. And much more common would be what I refer to in my affidavit as a rolling crystallization in which the solution or the solvent, mediates the transformation through a process of crystallization.[14]
[45] Both counsel for the Applicants and counsel for Pharmascience criticized the other side for the failure to carry out more extensive and more reliable testing or experimentation. I will return to this subject in the "Analysis" portion of these reasons where I will address the question of onus on an allegation of non-infringement.
DR. STEPHEN BYRN
[46] In his first affidavit, Dr. Byrn attests that he had been asked on behalf of the Applicants to review Pharmascience's Notice of Allegation underlying this application. He indicates that he had been asked to consider the allegations in the NOA and to provide his opinion about the allegations that the '732 Patent is not infringed or is invalid. He succinctly summarizes his opinion in the following words:
The PMS [Pharmascience] process, as set out in the NoA, is a crystallization process which is covered by the claims of the '732 Patent. In [sic] the PMS's process clearly infringes the '732 Patent.
PMS's allegations that the '732 Patent is invalid are without merit. The patent claims are not broader than the invention made or disclosed. PMS's "slurry" process is a crystallization process. Slurrying - as a method of crystallization - would be understood by those skilled in the art to be a method of "treating" as defined in the '732 Patent.[15]
[47] In two (2) subsequent affidavits filed in this proceeding, Dr. Byrn does not compromise the foregoing opinion.
[48] Like Dr. Atwood, Dr. Byrn was extensively cross-examined on his affidavits. During the course of the hearing of this matter, counsel took me to a number of extracts from his testimony on cross-examination. Having reviewed the transcript of his cross-examination as a whole, I draw only one global conclusion from it: like Dr. Atwood, he was not shaken in respect of the evidence put forward in his affidavits. To the contrary, he reconfirmed those opinions and the impression created by his training and experience as to his expertise.
DR. ALLAN MYERSON
[49] Dr. Myerson filed only one affidavit in these proceedings. In that affidavit, he summarized his opinion in the following terms:
The invention disclosed in Abbott's '732 patent relates to a method of preparing 6-0-methylerythromycin A Form II ("clarithromycin") directly by crystallization from a list of patented solvents.
For the reasons set out herein, it is clear that the processes of manufacturing clarithromycin, as proposed by PMS [Pharmascience] and [its supplier], clearly falls within the processes claimed in claims 1(b)(x), 2, 3 and 15 of [the] '732 Patent. Clarithromycin made in the processes by [Pharmascience] and [its supplier] is covered by claims 16, 17, 20, and 21 of the '732 Patent.
[Pharmascience's] allegations of non-infringement are directly contradictions [sic] by its own process information and are entirely unjustified.
[Pharmascience's] alternative allegation of invalidity is based on a fundamental misunderstanding of basic concepts in crystallization and is incorrect. The alternative allegation of invalidity is baseless and entirely unjustified.[16]
[50] With great respect, much of the foregoing, as with the paragraphs from Dr. Byrn's first affidavit quoted in paragraph [46] of these reasons, is an opinion as to the final issues in this matter and, whatever might or might not be the expertise of the Court in that regard, is a matter for determination by the Court. What the Court looks to from an expert such as Dr. Myerson or Dr. Byrn is professional opinion that will aid the Court in arriving at the determination which it is called upon to make, not opinion as to what that determination should be.
[51] The following paragraphs extracted from Dr. Myerson's affidavit are of much greater assistance:
As indicated above, the term solution mediated transformation refers to the transformation of a less stable (metastable) polymorph to a more stable polymorph when slurried in a solvent. In this case Form 0 and Form I are less stable than Form II.
Polymorphs (or solvates) of a given substance have different solubility. The most stable form has the lowest solubility. The least stable form has the highest solubility. Further, most substances have a finite solubility in all solvents (even if that solubility is very low). Accordingly, when material is slurried in a solvent, some of the substance dissolves until it forms a saturated solution; that is, a solution that cannot dissolve any more of the solid form initially added.
If the slurried substance is a metastable polymorph like Form I or Form 0, it is more soluble than Form II, in a given solvent. The solution is saturated with respect to the metastable polymorph because it dissolves into the solution more readily; however, the more stable form (like Form II) has a lower solubility in the same solvent: The solution (saturated with respect to Form I crystals) is at the same time supersaturated with respect to Form II crystals.
Put simply, a small amount of Form 0 (or Form I) dissolves into solution. Because of solubility difference between Form 0 and Form II, the dissolved molecules then come out of solution (crystallize) as Form II. This leaves "room" or "capacity" in the solvent for additional Form I to dissolve which, in turn, causes more Form II to crystallize out. The process continues until all Form I has converted to Form II. This is a solution mediated transformation.
It is important to note that a solution mediated transformation is a crystallization process. All of the metastable polymorph initially present in the slurry dissolves and then crystallizes as the stable polymorph.
The initial form does not dissolve all at once but does so over time. If, as is the case here, the initial slurry contains a mixture of both the stable (Form II) and the metastable (Form I) crystal forms, the process will occur at an accelerated rate since no primary nucleation step is required. The rate of this transformation depends on the difference in solubility between the two crystal forms in the chosen solvent and depends on their overall degree of solubility in the solution.
The [Pharmascience] slurry process is clearly a solution mediated transformating which is a crystallization or recrystallization.[17] [emphasis in original]
[52] As with Dr. Atwood and Dr. Byrn, Dr. Myerson was reasonably extensively cross-examined on his affidavit. While Counsel for Pharmascience took me to a limited number of passages from that cross-examination, I am satisfied that those passages, and the cross-examination in general, do not impact in any significant way on the expert opinions expressed by Dr. Myerson.
DR. FRANK BROWN JR.
[53] A single affidavit of Dr. Brown was filed in this matter on behalf of Pharmascience. In that affidavit, Dr. Brown speaks to a comparison of the '732 Patent and the process utilized by Pharmascience's supplier as disclosed in the Notice of Allegation and in greater detail in confidential disclosures that were before the Court. He also speaks to the issue of whether or not the claims of the '732 Patent are broader than the invention disclosed in that patent and replies to affidavits filed on behalf of the Applicants.
[54] After analysing the disclosure of the '732 Patent, the examples provided and the claims, as well as the process utilized by Pharmascience's supplier, Dr. Brown concludes:
In my opinion, the Abbott Patent [the '732 Patent] does not cover the [process utilized by Pharmascience's supplier] or the Form II [Clarithromycin] made by the [suppliers'] process. I have analyzed the claims below. The claims I have not specifically analyzed (namely claims 5, 6, 9-15, 18-19) are clearly not infringed as they used solvents other