Pfizer Canada Inc. v. Canada (Minister of Health)

Pfizer Canada Inc. v. Canada (Minister of Health)
Court (s) Database
Federal Court Decisions
Date
2005-09-28
Neutral citation
2005 FC 1205
File numbers
T-1633-03
Notes
Digest
Decision Content
Date: 20050928
Docket: T-1633-03
Citation: 2005 FC 1205
Ottawa, Ontario, September 28, 2005
Present: The Honourable Madam Justice Heneghan
BETWEEN:
PFIZER CANADA INC.
WARNER-LAMBERT COMPANY LLC
and PARKE, DAVIS & COMPANY LLC
Applicants
and
THE MINISTER OF HEALTH
and APOTEX INC.
Respondents
PUBLIC REASONS FOR ORDER
(Confidential Reasons for Order were issued on September 2, 2005)
[Edited] - Words Deleted to Preserve Confidentiality
INTRODUCTION
[1] Pfizer Canada Inc., Warner-Lambert Company LLC and Parke, Davis & Company LLC (the "Applicants or "Pfizer"") bring this application pursuant to the Patented Medicines (Notice of Compliance) Regulations (the "NOC Regulations"), SOR/93-133 for an order prohibiting the Minister of Health (the "Minister") from issuing a Notice of Compliance ("NOC") pursuant to section C.08.004 of the Food and Drug Regulations, C.R.C., c. 870, until after the expiry of Canadian letters patent 1,341, 330 (the " '330 Patent") and 1,331,615 (the " '615 Patent"). This application arose in response to two Notices of Allegation ("NOA") served by Apotex Inc. ("Apotex" or the "Respondent"), the first dated July 18, 2003 in respect of the '615 Patent and Canadian letters patent 1,291,999 (the " '999 Patent") and the second, dated July 24, 2003 in respect of the '330 Patent. Generally, Apotex alleges that the '615 Patent is not infringed by its activities in manufacturing and marketing its drug product Apo-Quinapril and that the '330 Patent is invalid.
[2] The Applicants are multinational drug companies. The '330 Patent was issued to Parke, Davis & Company LLC and the '615 Patent was filed by the assignee, Warner-Lambert Company LLC. Pursuant to the NOC Regulations, the Applicants filed a patent list relating to those pharmaceutical products for which they hold an NOC. The Applicants are the "first person" for the purpose of the within prohibition proceeding.
[3] Apotex is a Canadian corporation that manufactures generic pharmaceutical products. The NOC Regulations allow a generic drug manufacturer to rely on prior approval of related pharmaceutical products in applying for marketing approval of its generic form of the product. A manufacturer who produces the same drug may apply for an NOC that refers to and relies on the fact that approval has already been granted for the brand-name version of the drug. Apotex is a "second person", pursuant to section 2 of the NOC Regulations.
[4] The Minister is responsible for the review of applications by drug companies for the issuance of an NOC. The NOC Regulations prohibit the Minister from issuing an NOC until all relevant product and use patents in the earlier approved medicine, as described in the patent list, have expired. This means that a second person must either wait until the patent in issue has expired before obtaining an NOC or it may submit an NOA to the Minister with its new drug submission. Following review of an NOA upon the first person, the party may seek, pursuant to subsection 6(1) of the NOC Regulations, an order prohibiting the Minister from issuing the NOC. The Minister, although a party to this proceeding, is not actively participating in it.
QUINAPRIL HYDROCHLORIDE
[5] Quinapril Hydrochloride is an angiotensin-converting Enzyme ("ACE inhibitor"). ACE facilitates the conversion of angiotensin I, which is benign, to the activated form, called angiotensin II, which raises blood pressure, allowing it to function as a potent vasoconstrictive agent that causes hypertension. Quinapril hydrochloride is an ACE-inhibitor which inhibits the formation of angiotensin II, used for treating high blood pressure, congestive heart failure and for preventing kidney failure due to hypertension and diabetes.
[6] The patent that first disclosed the medicine quinapril hydrochloride was U.S. Patent No. 4,344,949 (the " '949 Patent" or the "Hoefle Application") issued on August 17, 1982 to Dr. Milton L. Hoefle and Dr. Sylvester Klutchko and assigned to Warner-Lambert Company LLC. This patent discloses a class of compounds generated by the substitution of acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids ("THIQ") and salts thereof, produced by coupling a suitably substituted THIQ with a suitably substituted amino acid, for therapeutic use as anti-hypertensive agents.
[7] The chemical structure of a molecule of quinapril consists of a THIQ "head", that is a double-ring structure, combined with a "side chain." In quinapril, there are three chiral centres, which occur where a carbon atom has four bonds attached to four different constituents and which may be arranged in one of two different ways, where one is the mirror image of the other. One of these configurations is identified using the "S,S,S" notation, while the mirror image, or enantiomer, of this molecule would be "R,R,R".
[8] The Applicants market a line of products containing quinapril hydrochloride in Canada under the trade name "ACCUPRIL®", in 5, 10, 20 and 40 mg oral tablets. Apotex identifies its intended product, Apo-Quinapril, as a generic version of quinapril hydrochloride composed of [Edited], which it refers to as [Edited]. Pursuant to section 5 of the NOC Regulations, Apotex served the July 18 and July 24, 2003 NOAs on the Applicants in respect of the '615 and '330 Patents, listed by the Applicants pursuant to section 4 of the NOC Regulations. These two patents, that are the subject of this prohibition application, are described below.
THE '330 PATENT
[9] The '330 Patent is entitled "Substituted Acyl Derivatives of 1,2,3,4 - tetrahydroisoquinoline -3 - Carboxylic Acids." The patent relates to compounds having two parts, a "head" that is made up of a particular chemical structure THIQ, and a "side-chain". Together, these parts are useful as ACE-inhibitors for the treatment of hypertension. The claims of the '330 Patent are broad, covering a genus of chemical compounds that include quinapril and other ACE-inhibitors, all of which share a common structure, that is a THIQ head and an enalapril tail asserted to be useful in the treatment of hypertension. The compounds have three chiral centres and all the stereoisomers sharing this common structure, that is both the S- and R-configuration stereoisomers, are within the scope of the claims.
[10] The '330 Patent was filed in the Canadian Patent Office on September 30, 1981 with a priority date of October 3, 1980. Since the '330 Patent issued from an application filed in Canada prior to October 1, 1989, this patent is, for most purposes governed by the provisions of the Patent Act, R.S.C. 1985, c. P-4, as amended (the "Act"), as it read immediately before the October 1, 1989 amendments (the "pre-1989 Act"). The '330 Patent claimed priority from U.S. Patent Applications 193,767 (the " '767 U.S. Patent") and 236,397 (the " '397 U.S. Patent"), filed on October 3, 1980 and February 20, 1981 respectively.
[11] From the date of filing the application to the issuance of the '330 Patent to Parke, Davis & Company LLC on January 1, 2002, a number of obstacles were encountered, the main obstacle being the initiation of conflict proceedings by the Commissioner of Patents. When pending applications contain one or more claims defining substantially the same invention, or one or more claims of one application describe the invention disclosed in another application, section 43 of the Pre-1989 Act provided a conflict procedure to determine the prior inventor to whom the Commissioner will allow the claims. Under the scheme provided by the Pre-1989 Act, no patent could be issued until the conflict proceedings were resolved.
[12] The '330 Patent claims were placed into conflict with a German patent owned by Hoechst Aktiengessellschaft ("Hoechst") and the Commissioner of Patents determined that Hoechst was the first to invent and thus awarded it the patent. However, a consent judgment was entered on December 22, 1999, whereby the claims of the '330 Patent were issued, in Canada only, to the Applicants. The '330 Patent was not issued until this obstacle was resolved, almost 21 years after the application was filed.
[13] The claims of the '330 Patent that are relevant to this application are as follows:
_ Claim two (2) relates to substituted acyl derivatives of formula II set out therein and pharmaceutically acceptable acid addition salts or solvated forms thereof. Formula II includes a compound having the structure of quinapril but without restriction as to stereochemical configuration.
_ Claim three (3) of the '330 Patent claims quinapril, quinaprilat, and a quinapril analogue with a methyl (CH3) substituted for ethyl (C2H5) on the side chain's COO-group. All possible stereoisomers are included within the scope of this claim. This claim relates to substituted acyl derivatives of Formula IIa set out therein and pharmaceutically acceptable and addition salts or solvated forms thereof including a compound having the structure of quinapril but without restriction as to stereochemical configuration.
_ Claim four (4) relates to a pharmaceutical composition comprising a substituted acyl derivative as claimed in claim 2 or 3 or a pharmaceutically acceptable salt or solvated form thereof, and a pharmaceutically acceptable carrier.
_ Claim five (5) claims all of these compounds, as well as larger carbon groups in two positions. All possible stereoisomers are included within the scope of this claim. This claim relates to a further class of compounds of the general Formula A set out therein, which includes a compound having the structure of quinapril but without restriction as to stereochemical configuration, and includes the pharmaceutically acceptable salts thereof.
CANADIAN PATENT 1,331,615 (the " '615 Patent")
[14] The second patent which is the subject of this application is the '615 Patent, entitled "Substituted Acyl Derivatives of 1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acids." An application was filed for the patent on June 23, 1992 by the then assignee Warner-Lambert Company LLC, who filed two divisional patent applications derived from the patent application form from which the '330 Patent issued. The divisional applications related to particular "species," including quinapril in various solid forms. The divisional applications were allowed on August 23, 1994; one of the resulting patents was the '615 Patent and the second was Canadian patent 1,331,614 (the " '614 Patent"). Both the '615 and the '614 Patents have the same filing date, same priority dates, and substantially the same disclosure because they derive from a divisional application, divided from the patent application of the '330 Patent. The claims relevant to this application are as follows:
_ Claim one (1) claims, among other things, a substituted acyl derivative of THIQ in the form of the (S,S,S) isomer, with a hydrogen atom or an ethyl radical in one of the following acid salt forms: the hydrochloride, hydrate; the hydrochloride; and the hydrochloride hemihydrate.
_ Claim two (2) relates to a specific compound, namely, a particular benzyl ester, maleate (S,S,S) isomer.
_ Claim three (3) relates to a specific compound, namely a particular dimethylethyl ester (S,S,S) isomer.
_ Claim four (4) relates to a specific compound namely quinapril hydrochloride hydrate (S,S,S).
_ Claim five (5) relates to a specific compound, namely quinaprilat hydrochloride hemihydrate (S,S,S).
THE NOTICES OF ALLEGATION
[15] By letter dated July 18, 2003, Apotex served an NOA upon the Applicants pursuant to subsection 5(3) of the NOC Regulations regarding its Apo-Quinapril tablets. Apotex alleged that none of the relevant claims of the '999 Patent and the '615 Patent would be infringed because, among other things, the process claims of those patents are not relevant under the NOC Regulations and further, that its tablets would not comprise any of the compounds set out in the relevant claims of the '999 and '615 Patents. Specifically, the NOA describes the legal and factual grounds for the allegation of non-infringement as follows:
Claims 1 and 2 of the '999 Patent and all claims of the '615 Patent are limited to specific compounds. Our tablets will not comprise any such compounds, nor will any such compounds be made, constructed, or used in the manufacture of our tablets. Hence, none of these claims will be infringed.
Moreover, none of the claimed compounds is the medicine contained in our tablets, nor is it the medicine contained in your AccuprilÔ tablets. Hence, none of the claims is a claim for the medicine itself or for the use of the medicine.
[16] By letter dated July 24, 2003, Apotex served another distinct NOA upon the Applicants, alleging that all of the relevant claims of the'330 Patent are invalid on a number of grounds. Specifically, the legal and factual basis for the alleged invalidity are set out in the NOA as follows:
Double Patenting
...
As an admission that the subject-matter of the claims of the '330, '614 and '615 Patents relate to a single invention or do not cover subject-matter which is patentably distinct from each other, we also rely on United States Patent No. 4,344,949 [the Hoefle Application].
...
Claims broader than the invention disclosed
...
Since the disclosure of the '330 Patent teaches that the (S) configuration on the chiral centre of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety is a requirement for biological activity in the compounds of the invention, the claims are broader than the invention disclosed since they include within their scope compounds which have an (R) configuration at the chiral centre of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety.
Claims broader than the Invention and Inutility
...
By the relevant date, which we allege in this case to be the earliest priority filing date of the '330 Patent (October 3, 1980), the purported inventors of the '330 Patent did not make, isolate, characterize or test each of the compounds included within the scope of the Claims in Issue, including the compounds Quinapril and Quinaprilat, nor could they have soundly predicted the scope of the compounds contained within the Claims in Issue.
...
We also allege that each of the Claims in Issue is invalid on the basis of inutility since they include within their scope compounds which do not possess the requisite level of activity and the requisite pharmacological and toxicological profile which would allow for their use as an ACE inhibitor which is suitable for oral or parenteral administration to provide compositions useful to reduce or relieve hypertension in mammals.
...
Anticipation
...
We allege nonetheless, that the Claims in Issue are anticipated, as having been previously known or used by the Hoechst Inventors who had filed Canadian Patent Application No. 384, 787 upon which a conflict was declared, and that the consent judgment of December 22, 1999 is not binding on Apotex since Apotex was not a party to those proceedings, and in light of the clear evidence set out above that the purported inventors of the '330 Patent had not invented the subject-matter of the Claims in Issue prior to the priority filing date of Hoechst's 384,78 Application (i.e., the filing date of DE 30 32 709 Application - August 30, 1980).
Lack of Invention - Obviousness
...
As an indicia of lack of inventiveness, we will rely on the fact that at least three separate inventors, or group of inventors, independently arrived at subject-matter contained within the scope of the [sic] each of the Claims in Issue.
...
Claims broader than invention made or disclosed
...
As such, the Claims in Issue include subject-matter which the purported inventors did not invent and in which an exclusive property or privilege has been previously granted. With the issuance of the '330 Patent the public will be precluded from practising subject-matter claimed within Canadian Patent No. 1,292,999, thereby effectively extending the monopoly granted under Canadian Patent No. 1,292,999 until the expiry of the '330 Patent on January 1, 2019.
Apotex referenced 119 articles, patents and other materials as representing the state of the art in support of its assertions about the invalidity of the '300 Patent. Included as part of this prior art were two patents which preceded the '330 Patent, that is, the enalapril patent, published June 25, 1980, and the Tanabe patent, published July 9, 1980.
[17] On September 5, 2003, the Applicants filed an application pursuant to the Federal Court Rules, 1998, SOR/98-106, as amended, the Act, and the NOC Regulations, seeking an Order prohibiting the Minister from issuing an NOC to Apotex for its product Apo-Quinapril.
THE EVIDENCE
A) The Applicants
[18] Both the Applicants and Apotex filed affidavits from a number of expert and factual witnesses. The qualifications of the experts ae not contested and a brief description of the opposing parties' witnesses follows.
[19] The Applicants filed an affidavit sworn by Ms. Madeleine Pesant, Associate Director, Regulatory Intelligence and Information Drug Regulatory Affairs and Safety-Canada, for Pfizer. Ms. Pesant appended to her affidavit copies of the patent lists filed with Health Canada in respect of, among others, the '615 and '330 Patents.
[20] The Applicants also filed the affidavits of Ms. Rose Lombardi, a law clerk, appending copies of the file history of the '330 and '615 Patents, documentation pertaining to the Commissioner of Patents' determination of the conflict proceedings in relation to the '330 Patent and the subsequent consent order that, in Canada only, the claims subject to that conflict proceeding may issue to the Applicants. In addition, Ms. Lombardi appended copies of Apotex's Abbreviated New Drug Submission ("ANDS") for its Apo-Quinapril tablets.
[21] Affidavit evidence was also provided by Dr. John G. Topliss, former Director of Chemistry at Warner-Lambert Company LLC, as well as by Dr. Clifton J. Blankley, a former chemist with Warner-Lambert Company LLC and member of the development team who worked on certain anti-hypertensive compounds, including quinapril. The transcript of the cross-examination of Dr. Blankley was also filed.
[22] The Applicants filed affidavits of the inventors of the patents in issue, specifically the affidavit of Dr. Milton L. Hoefle, former chemist and Section Director of Cardiovascular Research at Warner-Lambert Company LLC and Dr. Sylvester R. Klutchko, former chemist and Research Associate with Warner-Lambert Company LLC.
[23] The Applicants submitted expert evidence from the following expert witnesses:
1. Edward G. Fiorito, Intellectual Property Consulting Attorney residing in Dallas, Texas. Mr. Fiorito was the former Chair of the IP section of the American Bar Association (the "ABA") (2000-2001), Chair of the IP section of the Texas State Bar (1990-1991), and Chair of the Science and Technology section and the Expert Witness Committee of the ABA (1984-1985, 1995-1998). Pfizer filed his affidavit, sworn on October 13, 2003 (the "Fiorito Affidavit"), together with a transcript of the cross-examination thereon dated January 20, 2005.
2. Dr. Paul S. Anderson, medicinal chemist and former Senior Research Chemist and later, Vice President for Chemistry, at Merck Sharpe & Dohme ("Merck"), obtained his doctorate in chemistry from the University of New Hampshire in 1963 and was most recently employed as Vice President of Drug Discovery for Bristol Myers Squibb ("BMS") in Wilmington, Delaware. He swore two affidavits, the first on January 13, 2004 (the "First Anderson Affidavit") and the second, a reply affidavit, on September 10, 2004 (the "Second Anderson Affidavit"). He was cross-examined on the contents of these affidavits on April 5, 2005.
3. Dr. Gerald S. Brenner, pharmaceutical consultant and former Senior Director of Pharmaceutical Research and Development, and former Department Head for Pharmaceutical Research at Merck. Dr. Brenner obtained his doctorate in organic chemistry from the University of Wisconsin in 1961 and worked in the pharmaceutical industry for 33 years. He has extensive experience in pre-formulation research and in formulation development and has been involved with the pre-formulation and formulation of several hundred pharmaceuticals. Dr. Brenner has over fifty publications and presentations to his credit. He swore two affidavits, the first on January 14, 2004 (the "First Brenner Affidavit") and the second, a reply affidavit, on September 10, 2004 (the "Second Brenner Affidavit"). He was cross-examined on the contents of those affidavits on January 5-6, 2005.
4. Dr. Jan Wasley, medicinal chemist formerly employed by Ciba-Geigy and former Director of Chemistry and Vice President of Business Development at Neurogen Corporation in Branford, Connecticut. Dr. Wasley obtained his doctorate in chemistry from the University of Nottingham in 1962. His affidavit, filed in reply to Apotex's evidence, was sworn on September 9, 2004 (the "Wasley Affidavit") and he was cross-examined on its contents on March 11, 2005.
B) Apotex
[24] Apotex filed the affidavit of Francis Ng-Cheng-Hin, Patent Agent Trainee, which attaches copies of the 119 prior art references named in the NOA dated July 24, 2003, as well as the affidavit of John Hems, Director of Regulatory Affairs for Apotex. Mr. Hems described the new drug submission for Apo-Quinapril and the preparation and filing of the ANDS for Apo-Quinapril tablets.
[25] The opinion evidence relied on by Apotex was provided by a number of affiants, as follows:
1. Dr. Regis Leung-Tong, Manager of Medicinal Chemistry at ApoPharma Inc. Dr. Leung-Tong received his doctorate in chemistry from the University of Toronto in 1989. His affidavit was sworn on April 22, 2004 (the "Leung-Tong Affidavit") and cross-examination on the contents thereof was conducted on December 10, 2004.
2. Dr. Sergei M. Danilov, Researcher at the University of Chicago, Department of Anaesthesiology Research Centre. Dr. Danilov received his doctorate in medical sciences (pharmacology) from the National Cardiology Research Centre in Moscow, Russia in 1980, and his doctorate in Cardiology and Biochemistry in 1994. He swore two affidavits, the first on April 28, 2004 (the "First Danilov Affidavit") and the second on October 14, 2004 (the "Second Danilov Affidavit"). Cross-examination of Dr. Danilov was conducted on December 10, 2004.
3. Matthew Alexander Buck, Research and Development Associate at Brantford Chemicals Inc. Mr. Buck received his master of science degree from the University of Waterloo in 2003. His affidavit was sworn on May 4, 2004 (the "Buck Affidavit") and cross-examination thereon was held on January 14, 2005 and April 1, 2005.
4. Dr. David Coffin-Beach, former President of TorPharm Inc., an affiliate of Apotex which was amalgamated with Apotex in 2004. Dr. Coffin-Beach obtained his doctorate in pharmaceutics from the University of Maryland in 1982. His affidavit was sworn on May 10, 2004 (the "Coffin-Beach Affidavit"), and cross-examination thereon was held on February 18, 2005.
5. Dr. Garland Ross Marshall, Full Professor of Biochemistry and Molecular Biophysics and of Biomedical Computing at the Washington University School of Medicine in St. Louis, Missouri since 1976. Dr. Marshall obtained his doctorate from Rockefeller University in 1966. He swore two affidavits, the first on May 11, 2004 (the "First Marshall Affidavit") and the second on October 13, 2004 (the "Second Marshall Affidavit"). Cross-examination of Dr. Marshall was conducted on March 8-9, 2005.
6. Dr. Robert S. Langer, Professor of Chemical and Biomedical Engineering at MIT. Dr. Langer obtained his doctorate in chemical engineering from MIT in 1974. He swore two affidavits, the first on May 12, 2004 (the "First Langer Affidavit") and the second on October 14, 2004 (the "Second Langer Affidavit"). Cross-examination on those affidavits was conducted on March 2, 2005.
7. Dr. Robert Allan McClelland, Full Professor in the Department of Chemistry at the University of Toronto since 1983. Dr. McClelland obtained his doctorate in chemistry from the University of Toronto in 1969. He swore two affidavits, the first on May 12, 2004 (the "First McClelland Affidavit") and the second on October 13, 2004 (the "Second McClelland Affidavit"), upon which he was cross-examined
8. Dr. Martin Kurt Ehlert, Director of Manufacturing and Process Scale-up for Apotex Pharmachem Inc., formerly known as Brantford Chemicals Inc. Dr. Ehlert obtained his doctorate in chemistry from the University of British Columbia in 1992 and presently oversees the production process of [Edited]. His affidavit was sworn on May 13, 2004 (the "Ehlert Affidavit") and cross-examination thereon was held on January 12, 2005.
9. Dr. Jianguo Wang, Manager, Preformulation Research Lab in the Department of Pharmaceutical Research for Apotex. Dr. Wang obtained his doctorate in organic chemistry from the University of Montreal in 1993. His affidavit was sworn on May 13, 2004 (the "Wang Affidavit") and cross-examination was held on March 23, 2005.
10. Dr. Michael J. Cima, Full Professor of Materials Science and Engineering at MIT since 1995. Dr. Cima obtained his doctorate in chemical engineering from the University of California at Berkeley in 1986. His affidavit was sworn on May 14, 2004 (the "Cima Affidavit") and cross-examination thereon was conducted on January 10, 2005.
C) The Expert Evidence
(i) The Applicants' Expert Evidence
[26] Pfizer filed the affidavits of Dr. Anderson and Dr. Wasley to respond to the allegations of invalidity raised in respect of the '330 Patent. Dr. Anderson, a medical chemist with particular expertise in designing molecules that could be delivered to the body to produce a therapeutic effect, was asked to provide an opinion respecting the allegations of invalidity raised by Apotex concerning the '330 Patent. In preparing his report, he reviewed various materials including the July 24, 2003 NOA, the prior art referred to in that NOA and the '615, '614 and '330 Patents. His opinion was based upon an assumed invention date for the '330 Patent of June 18, 1980, as opposed to the date given by Apotex in its July 24, 2003 NOA, that is October 3, 1980.
[27] Dr. Anderson considered the issue of invalidity of the '330 Patent on the grounds of obviousness, anticipation, lack of utility and overbreadth and commented on certain pieces of prior art relied on by Apotex in that regard. He expressed the opinion that a person of ordinary skill in the art, as of June 18, 1980 would have been led directly and without difficulty only to a proline head and that inventive ingenuity would have been required to advance beyond proline as the head group for an ACE inhibitor. He also opined that the invention disclosed in the '330 Patent was not anticipated and that the compounds demonstrate activity.
[28] Dr. Wasley is also a medicinal chemist. He is currently a consultant to the pharmaceutical industry. He prepared a detailed statement concerning the '330 Patent and in doing so, reviewed the reports and affidavits of Dr. Marshall and Dr. Danilov, expert witnesses on behalf of Apotex, as well as the affidavits of Dr. Anderson, Dr. Klutchko, Dr. Topliss, Dr. Blankley and Dr. Hoefle filed on behalf of Pfizer.
[29] Dr. Wasley expressed the opinion that, as of June 18, 1980, there was a sound basis for the inventors of the '330 Patent to predict that all of the compounds claimed in claims two (2), three (3), and five (5), would have some level of activity. By extension, the same could be said of claim four (4). This view was contrary to the opinion given by Dr. Marshall on behalf of Apotex. Dr. Wasley also expressed the opinion that Apotex had failed to show that any compounds within those claims lacked activity and further, that no claims at issue in the '330 Patent are broader than the invention disclosed.
[30] Dr. Wasley also commented on the ACE inhibition test results for Quinapril-type compounds and Lisinopril-type compounds as found by Dr. Danilov. He criticized Dr. Danilov's test methodology and conclusions. Specifically, Dr. Wasley noted that Dr. Danilov reported lower values for the in vitro tests than other reported values for the same compounds and concluded that Dr. Danilov's tests were less sensitive than other reported tests. Accordingly, Dr. Wasley opined that Dr. Danilov's testing resulted in under-representation of activity in relation to the other reported tests.
[31] Dr. Wasley observed that Dr. Danilov used a spectrophotometric method that, to his knowledge, is generally less sensitive than the radiometric method as used by the inventors to obtain the results referred to in the '330 Patent. Dr. Wasley also commented on the sample size and timing of the in vivo tests as causing potential problems with Dr. Danilov's methodology, and suggested that these methodological problems serve to weaken the reliability of Dr. Danilov's test results.
[32] In regard to the '615 Patent, Pfizer submits the evidence of Dr. Brenner, an organic chemist and industrial formulation expert. He was asked to provide an opinion about the allegations of non-infringement raised by Apotex in its NOA dated July 18, 2003. In preparing his opinion, Dr. Brenner reviewed various documents including Apotex's Drug Master File ("DMF"), its ANDS that was submitted relative to Apo-Quinapril, as well as Apotex's formulation process. He concluded that Apotex's allegation of non-infringement was incorrect for these reasons.
[33] First, he expressed the view that Apotex is using the acid salt form of quinapril hydrochloride through its use of [Edited]. He interpreted claim one (1) of the '615 Patent as follows:
It is my opinion that when the patentee/inventor used the word "hydrochloride" in claim I, he intended to capture quinapril hydrochloride in its organic [Edited], non-hydrated, and amorphous forms. [Emphasis in original]
[34] Second, he concluded that it is possible that quinapril hydrochloride is present in the material made through the process of making Apo-Quinapril. Dr. Brenner referred to the description of the manufacturer of Apo-Quinapril in Apotex's ANDS, in other words the reaction of [Edited] to yield what Apotex describes as "Intermediate Drug Product", described as [Edited]. He expressed the opinion that there could be as much as 20% quinapril hydrochloride in the final Apotex drug product. However, he noted that since Pfizer had only been able to obtain 5 mg of the Apotex product, for testing, he had been unable to confirm whether Apo-Quinapril did in fact contain this amount of quinapril hydrochloride.
[35] Third, Dr. Brenner noted that Apotex admits that quinaprilat, which is also covered by the '615 Patent, is a by-product of its drug production process. He said that claim one (1) of the '615 Patent refers to both quinapril and quinaprilat in the hydrochloride, hydrochloride hydrate and hydrochloride hemihydrate acid salt forms.
(ii) Apotex's Expert Evidence
[36] Apotex responded to the expert evidence tendered by Pfizer with the evidence of parallel experts. In addressing the allegations of invalidity relative to the "330 Patent, Apotex relies on the evidence of Dr. Marshall and Dr. Danilov. Dr. Marshall, a biochemist and molecular biophysicist with particular experience researching angiotension II antagonists, was asked to provide an opinion with respect to the allegation of invalidity of the '330 Patent and in particular, on the issue of obviousness. In preparing his opinion, Dr. Marshall reviewed, among other things, the July 24, 2003 NOA, the affidavits filed on behalf of Pfizer and Apotex, and the '330 Patent.
[37] Dr. Marshall expressed the opinion that the disputed claims of the '330 Patent include within their scope compounds that were obvious as of June 1980. He said his opinion on the issue of obviousness would remain unchanged even if he were to assume a later invention date of October 3, 1980. Further, he opined that the '330 Patent is overly broad, on the basis that while that patent clearly requires that the THIQ moiety must be in the (S) configuration, the claims of the Patent do not specify the correct chiralities as S-configuration and consequently, include many compounds with no therapeutic utility as ACE inhibitors. Additionally, Dr. Marshall concluded that the inventors of quinapril hydrochloride, as at October 3, 1980, did not have an articulable and sound line of reasoning from which the desired result could have been inferred from those facts.
[38] As well, Apotex conducted both in vitro and in vivo tests of two series of compounds in order to assess their ability to inhibit ACE. The first series of these compounds were 200 mg samples of six compounds, [Edited] and five other compounds that were structurally related to Quinapril; these samples were provided by Mr. Buck. The second series of compounds were structurally related to Lisinopril and were provided by Dr. Leung-Tong.
[39] The two series of compounds were tested by Dr. Danilov, using a spectrophotometric technique. For the in vitro testing, the compounds were tested for inhibition of human kidney ACE and rat lung ACE, both pre-hydrolysis and post-hydrolysis. For the in vivo testing, the compounds were administered at a concentration of 10 mg/kg and tested for inhibition of ACE activity in rat serum, lung and kidney.
[40] Dr. Danilov concluded that testing of the Quinapril-like compounds demonstrated varying degrees of ACE inhibition in vitro after hydrolysis, generally there was no inhibitory potency in vivo, with the exception of the [Edited] which demonstrated excellent ACE inhibition potency both in vitro and in vivo. With respect to the Lisinopril-like series of compounds, he found that none of the compounds demonstrated any pharmacological properties as an ACE inhibitor and could not be used as medicinal agents.
[41] Dr. David-Coffin Beach, a pharmaceutical formulation chemist currently employed by Apotex, was involved in the development of the tablet formulation for Apo-Quinapril. He commented on the preparation and composition of Apo-Quinapril tablets, [Edited] and stated that this process does not involve a chemical reaction in which the [Edited]. In his view, the granulation and tableting processes followed by Apotex, as well as its film-coating processes, do not involve a reaction in which [Edited].
[42] Dr. McClelland and Dr. Langer addressed the '615 Patent, specifically claim one (1). In their opinion, that claim should not be read as concluding that "the hydrochloride" includes a [Edited] form of quinapril hydrochloride. According to these experts, claim one (1) of the '615 Patent contains clear wording capable of interpretation without relying upon the patent's disclosure. Both Dr. McClelland and Dr. Langer expressed the opinion that this claim covers the anhydrous, [Edited] form of the claimed compounds.
[43] Apotex also submitted the affidavits of Dr. Cima and Dr. Wang, who concluded, on the basis of their testing that the material contained in an ACCUPRIL® tablet is consistent with [Edited]and inconsistent with [Edited] quinapril hydrochloride hydrate, or quinapril hydrochloride. Consequently, these witnesses concluded that the ACCUPRIL® tablets contain some form of [Edited] rather than quinapril hydrochloride
ISSUES
[44] This application raises several issues. With respect to the '330 Patent, the following issues were addressed by the parties:
1) the construction of claims three (3) and five (5);
2) the justification of Apotex's allegation that the patent is invalid on the following grounds:
a) lack of actual utility
b) lack of sound prediction of utility
c) anticipation
d) obviousness
e) claims broader than invention or disclosure; and
f) double patenting
[45] In relation to the '615 Patent, two issues were raised, first, whether the July 18, 2003 NOA is sufficient and second, whether Apotex's allegation of non-infringement is justified.
DISCUSSION AND DISPOSITION
A. Nature of this Proceeding
[46] This application seeks to prohibit the issuance of an NOC to the Respondent for its product which contains a generic version of quinapril hydrochloride composed of [Edited]. The Applicants challenge the Respondent's NOAs on the grounds that the allegations of invalidity of the '330 Patent and non-infringement of the '615 Patent are not justified.
[47] An NOC grants marketing approval for drugs in Canada. It is issued by the Federal Government, indicating that all requirements have been met pursuant to the Food and Drug Regulations, supra for the protection of public health and safety. The NOC Regulations authorize owners of existing patents for pharmaceutical products to file a "patent list" relative to those products for which they hold a NOC. The NOC Regulations refer to the person filing such a list as the "first person". In this case, the Applicants are the "first person".
[48] The framework of the NOC Regulations allows generic drug manufactures to rely on prior approval of related pharmaceutical products in applying for marketing approval of their generic form of the products. Manufacturers who produce the same drug may file an application for an NOC that refers to and relies on the fact that prior approval has been granted for the brand-name version of the drug. Such a manufacturer is known to as the "second person" and that is the Respondent's status.
[49] The NOC Regulations prohibit the Minister of Health from issuing an NOC until all relevant product and use patents in the earlier approved medicine, as described in the patent list, have expired. Consequently, a second person must either wait until patent expiry before receiving an NOC or it may submit an NOA to the Minister with its ANDS.
[50] The NOC Regulations require service of the NOA upon the first person. Section 5 sets out the grounds upon which an NOA is to be based. Briefly, the NOA must assert either that the first person is not the patentee, that the patent is expired or invalid, or that it would not be infringed if a NOC were issued.
[51] Following service of the NOA, the Minister may issue an NOC to the second person, unless the first person avails of its right, pursuant to section 6(1) of the NOC Regulations, to seek an order from the Federal Court of Canada prohibiting the Minister from issuing the NOC. Any such step must be taken by the first person within 45 days after receipt of the NOA and once such a proceeding is commenced, the issuance of a NOC to the second person is stayed for a maximum period of twenty-four months. In the present proceeding, the twenty-four month period will expire on September 5, 2005.
B. Burden of Proof
[52] In Smith Kline Beecham Pharma Inc. v. Apotex Inc., [2001] 4 F.C. 518 (T.D.), aff'd. [2003] 1 F.C. 118 (F.C.A.), Justice Gibson considered the evidentiary burden in proceedings under the NOC Regulations where invalidity of a patent is alleged. At pages 533 to 534 he wrote the following:
Against the foregoing, I conclude that while an "evidential burden" lies on Apotex to put each of the issues raised in its Notice of Allegation "in play", if it is successful in doing so, the "persuasive burden" or "legal burden" then lies with SmithKline. Assuming Apotex to be successful in putting the issue of validity of the '637 Patent "in play", SmithKline is entitled to rely on the presumption of validity of the patent created by subsection 43(2) of the Act.
The "persuasive burden" or "legal burden" that lies with SmithKline in the circumstances described in the preceding paragraph is, however, impacted by the nature of the proceeding here before the Court. In Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare), [(1994), 55 C.P.R. (3d) 302 (F.C.A.)] M