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.)] Mr. Justice Hugessen, for the Court, wrote at pages 319-20:
As I understand the scheme of the regulations, it is the party moving under s. 6, in this case Merck, which, as the initiator of the proceedings, has the carriage of the litigation and bears the initial burden of proof. That burden, as it seems to me, is a difficult one since it must be to disprove some or all of the allegations in the notice of allegation which, if left unchallenged, would allow the Minister to issue a notice of compliance.
...
In this connection, it may be noted that, while s. 7(2)(b) [of the Regulations] seems to envisage the court making a declaration of invalidity or non-infringement, it is clear to me that such declaration could not be given in the course of the s. 6 proceedings themselves. Those proceedings, after all, are instituted by the patentee and seek a prohibition against the Minister; since they take the form of a summary application for judicial review, it is impossible to conceive of them giving rise to a counterclaim by the respondent seeking such a declaration. Patent invalidity, like patent infringement, cannot be litigated in this kind of proceeding.
Thus, the burden on SmithKline is only to disprove the allegations in the notice of allegation, not to justify declarations of validity and infringement or conversely to negative claims for declarations of invalidity and non-infringement.
[53] The burden lies on Pfizer, as the Applicant, to refute the allegations set forth by Apotex in its NOAs dated July 18, 2003 and July 24, 2003. Therefore, like any plaintiff or applicant, Pfizer has the overall legal burden of proof. Apotex, as the Respondent, has an obligation to put the allegations set out in its NOAs "in play".
[54] Pfizer accepts that it carries the legal burden with respect to the allegation of non-infringement. However, it argues that Apotex carries the burden of proof in relation to the allegation of invalidity, on the basis of the presumption of validity that arises under section 45 of the Pre-1989 Act. In this regard, Pfizer relies on the recent decision of the Supreme Court of Canada in Apotex Inc. v. Wellcome Foundation Ltd., [2002] 4 S.C.R. 153 in support of its argument that the burden of showing invalidity lies on the person challenging the patent, that is the second person, in a prohibition proceeding. They argue that the argument used by the Supreme Court in Apotex v. Wellcome, supra, indicates that a finding of invalidity can only be made if the Court is satisfied that the Commissioner of Patents was "clearly wrong" or made an unreasonable decision by initially granting the patent. They argue that the reasoning applied by the Supreme Court in the context of a patent infringement action is equally applicable to these prohibition proceedings.
[55] Apotex disputes this approach and, relying on the decision in Bayer Inc. v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285 (F.C.A.), argues that the presumption of validity is spent when the second person presents evidence that is capable of establishing the invalidity of the patent. Rebutting the presumption of validity will depend upon the weight of the evidence addressing that issue.
[56] In Janssen-Ortho Inc. v. Novopharm Ltd. (2004), 35 C.P.R. (4th) 353 (F.C.T.D.), Justice Mosley concluded that as long as the second person adduces evidence that is not clearly incapable of establishing its allegation of invalidity, then the statutory presumption is spent and cannot assist the first person for the purpose of a prohibition proceeding.
[57] In my opinion, the Applicants' reliance on Apotex v. Wellcome, supra, in relation to the question of the burden of proof is not well-founded. That decision came from an action involving issues of patent impeachment and infringement. The present proceeding is a summary proceeding pursuant to the NOC Regulations and the Federal Court Rules, 1998, supra governing application for judicial review. Again, a finding of invalidity or infringement, for the purposes of this kind of proceeding is not determinative of that issue in any subsequent action; see Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.) at page 216 where the Court said as follows:
..these proceedings are not actions for determining validity or infringement: rather they are proceedings to determine whether the Minister may issue a notice of compliance. That decision must turn on whether there are allegations by the generic company sufficiently substantiated to support a conclusion for administrative purposes (the issue of a notice of compliance) that the applicant's patent would not be infringed if the generic's product is put on the market....
[58] I conclude that Pfizer bears the burden of establishing that Apotex's allegations of invalidity are not justified.
C. Construction of Claim Three (3) and Claim Five (5) of the '330 Patent
[59] The first step in assessing the allegations of invalidity is to construe the disputed claim of the patent. In Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 and Free World Trust v. Électro Santé Inc., [2000] 2 S.C.R. 1024 the Supreme Court of Canada held that the patent claim is to be construed in a "purposive" way and that the Court must consider the entire specification of the patent in order to understand the words as stated in a disputed claim. In Free World Trust, supra, at pages 1043-1044, Justice Binnie identified a list of principles that guide the purposive approach to the construction of a claim, as follows:
a. The Patent Act promotes adherence to the language of the claims.
b. Adherence to the language of the claims in turn promotes both fairness and predictability.
c. The claim language must, however, be read in an informed and purposive way.
d. The language of the claims thus construed defines the monopoly. There is no recourse to such vague notions as the "spirit of the invention" to expand it further.
e. The claims language will, on a purposive construction, show that some elements of the claimed invention are essential while others are non-essential. The identification of elements as essential or non-essential is made:
i. on the basis of the common knowledge of the worker skilled in the art to which the patent relates;
ii. as of the date the patent is published;
iii. having regard to whether or not it was obvious to the skilled reader at the time the patent was published that a variant of a particular element would not make a difference to the way in which the invention works; or
iv. according to the intent of the inventor, expressed or inferred from the claims, that a particular element is essential irrespective of its practical effect;
v. without, however, resort to extrinsic evidence of the inventor's invention.
f. There is no infringement if an essential element is different or omitted. There may still be infringement, however, if non-essential elements are substituted or omitted.
[60] The decisions in Whirlpool, supra and Free World Trust, supra provide clear instructions that claims are to be interpreted in light of the patent specification. In following the purposive approach to interpreting the words or phrases of a claim, the Court should stay within the "four corners of the specification" and limit itself to the words of the claim interpreted in the context of the specification as a whole, avoiding reliance on extrinsic evidence of intent; see Whirlpool, supra at page 1095. Expert evidence is admissible, but only to assist the Court in interpreting the claim in a knowledgeable way; see Whirlpool, supra at page 1102.
[61] The '330 Patent contains seven (7) claims. Claims one (1), six (6) and seven (7) are process claims and the parties agree that they are irrelevant under the NOC Regulations. Claims two (2), three (3), four (4) and five (5) were alleged to be invalid in the NOA dated July 24, 2003. These claims concern classes of compounds deemed to be useful for the treatment of hypertension. However, only claims three (3) and five (5) are addressed by Pfizer in its submission in this application and Apotex has inferred that Pfizer is conceding claims two (2) and four (4).
[62] Pfizer argues that a purposive construction of the relevant claims, including reference to the specifications, discloses that the invention of the '330 Patent relates to ACE inhibition.
[63] On the other hand, Apotex argues that all of the claims of the '330 Patent promise compounds useful in reducing or relieving hypertension, which is distinct from ACE inhibition. It submits that not all ACE inhibitors have sufficient inhibition activity to be capable of acting as an anti-hypertensive useful in the treatment of hypertension.
[64] In my opinion, the claims of the '330 Patent here in issue would be read by a person skilled in the art as referring to compounds useful for the relief of hypertension. In the abstract of this patent, the following words are found:
The compounds of the invention, their salts and pharmaceutical compositions thereof are useful as antihypertensive agents.
[65] Further, the specification of the '330 Patent confirms this construction of the claim:
The compounds of this invention intervene in the renin - > angiotensin I - > angiotensin II sequence by inhibiting angiotensin I converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II, and therefore are useful in reducing or relieving hypertension. Thus by the administration of a composition containing one or a combination of compounds of formula I or pharmaceutically acceptable salts thereof, hypertension in the species of mammal suffering therefrom is alleviated.[...]
The compounds of the invention can be utilized to achieve the reduction of blood pressure by formulating in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. [...] [Emphasis added]
[66] Claims three (3) and five (5) of the '330 Patent must be construed on the basis of the common knowledge of the worker skilled in the art, at the time the patent was issued, that is January 1, 2002. I agree with the submissions of Apotex on this issue, that the '330 Patent claims a family of compounds with a shared common structure, that is having three chiral centres, and claiming all possible stereoisomers thereof. I conclude that the purpose of the inventions described in claims three (3) and five (5) of the '330 Patent is to use the described compounds as the active ingredient in medicine for the treatment of hypertension.
D. Invalidity of the '330 Patent
[67] The parties agree that the Pre-1989 Act governs the analysis of the alleged invalidity of this patent. Subsection 61(1) is relevant and provides as follows:
| 61. (1) No patent or claim in a patent shall be declared invalid or void on the ground that, before the invention therein defined was made by the inventor by whom the patent was applied for, it had already been known or used by some other person, unless it is established that
(a) that other person had, before the date of the application for the patent, disclosed or used the invention in such manner that it had become available to the public;
(b) that other person had, before the issue of the patent, made an application for patent in Canada on which conflict proceedings should have been directed; or
(c) that other person had at any time made an application in Canada which, by virtue of section 28, had the same force and effect as if it had been filed in Canada before the issue of the patent and on which conflict proceedings should properly have been directed had it been so filed.
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61. (1) Aucun brevet ou aucune revendication dans un brevet ne peut être déclaré invalide ou nul pour la raison que l'invention qui y est décrite était déjà connue ou exploitée par une autre personne avant d'être faite par l'inventeur qui en a demandé le brevet, à moins qu'il ne soit établi que, selon le cas :
a) cette autre personne avait, avant la date de la demande du brevet, divulgué ou exploité l'invention de telle manière qu'elle était devenue accessible au public;
b) cette autre personne avait, avant la délivrance du brevet, fait une demande pour obtenir au Canada un brevet qui aurait du donner lieu à des procédures en cas de conflit;
c) cette autre personne avait à quelque époque fait au Canada une demande ayant, en vertu de l'article 28, la même force et le même effet que si elle avait été enregistrée au Canada avant la délivrance du brevet et pour laquelle des procédures en cas de conflit auraient dû être régulièrement prises si elle avait été ainsi enregistrée.
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In this proceeding, Apotex has alleged that claims three (3) and five (5) of the '330 Patent are invalid on the basis that, as of its priority date, that is October 3, 1980, the inventors had demonstrated neither the utility of, nor were they able to soundly predict the utility of the claimed compounds. As well, Apotex alleges that the relevant claims are invalid on the grounds of anticipation, lack of inventiveness, over-breadth and double-patenting.
(i) Lack of Utility
[68] The definition of "invention" in the Pre-1989 Act includes the requirements of novelty and utility. Section 2 provides as follows:
| "invention" means any new and useful art, process, machine, manufacture or composition of matter, or any new and useful improvement in any art, process, machine, manufacture, or composition of matter;
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« invention » Toute réalisation, tout procédé, toute machine, fabrication ou composition de matières, ainsi que tout perfectionnement de l'un d'eux, présentant le caractère de la nouveauté et de l'utilité.
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The inventor must be able to establish utility as of the date the patent is applied for, on the basis of either demonstration or sound prediction based on the information and expertise then available.
[69] In [1981] 1 S.C.R. 504">Consolboard Inc. v. MacMillan Bloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504 , Justice Dickson (as he then was) discussed "utility" at page 525, as follows:
There is a helpful discussion in Halsbury's Laws of England, 3rd ed., vol. 29, p. 59, on the meaning of "not useful" in patent law. It means "that the invention will not work, either in the sense that it will not operate at all or, more broadly, that it will not do what the specification promises that it will do." There is no suggestion here that the invention will not give the result promised. The discussion in Halsbury's Laws of England, ibid, continues:
... the practical usefulness of the invention does not matter, nor does its commercial utility, unless the specification promises commercial utility, nor does it matter whether the invention is of any real benefit to the public, or particularly suitable for the purposes suggested ...
and concludes [at p. 60]:
... it is sufficient utility to support a patent that the invention gives either a new article, or a better article, or a cheaper article, or affords the public a useful choice.
[70] In my view, Apotex has submitted evidence that is capable of establishing the invalidity of the '330 Patent, and consequently, sufficient to rebut the statutory presumption of validity. It relies upon the evidence of Dr. Danilov, Dr. Marshall, the Klutchko article and the Blankley declaration attached to the Fiorito Affidavit, to support its allegation that as of October 3, 1980, that is the priority date, no compounds covered by the scope of claims three (3) or five (5) had been synthesized or tested in vivo or in vitro, for ACE inhibition activity or tested to determine if they were pharmacologically useful to reduce or relieve hypertension in mammals.
[71] As noted above, the purpose of the inventions described in claims three (3) and five (5) of the '330 Patent is the use of these compounds as the active ingredients in medicine for the treatment of hypertension, not merely inhibition of ACE activity. Since I have found that Apotex has presented sufficient evidence capable of rebutting the presumption of validity, the burden of proof shifts to Pfizer to disprove the allegation of lack of utility made in the NOA dated July 24, 2003.
[72] Pfizer argues that, according to the specification and the evidence submitted, it is clear that the utility requirement of the '330 Patent is ACE inhibition. Alternatively, it argues that even if anti-hypertensive activity is required, then it is reasonable to expect such activity from effective ACE inhibition. I am not persuaded by this argument.
[73] It appears that ACE inhibition of a sufficient level is required to make a compound useful for reducing hypertension. It follows that not all ACE inhibition will result in relieving hypertension, but all reduction of hypertension will be the result of adequate levels of ACE inhibition. Since I have construed claims three (3) and five (5) as encompassing compounds useful for the relief of hypertension in mammals, Pfizer's arguments in this regard do not assist.
[74] Pfizer bears the burden of refuting Apotex's allegation of lack of actual utility. On the basis of the evidence submitted, I am not satisfied that Pfizer has discharged the onus of showing that the allegation of lack of utility is not justified. The Applicants have not provided evidence that, at the relevant time, there was demonstrated utility of claims three (3) and five (5) of the '330 Patent.
[75] However, as acknowledged by Apotex, claims three (3) and five (5) may still be upheld if Pfizer can demonstrate that the inventors could have soundly predicted that these compounds, if made, would prove to be useful for their stated purpose; see [1979] 2 S.C.R. 1108">Monsanto Co. v. Canada Commissioner of Patents), [1979] 2 S.C.R. 1108.
(ii) Lack of Sound Prediction of Utility
[76] In Apotex v. Wellcome, supra, the Supreme Court of Canada reviewed the doctrine of sound prediction. The doctrine has three components: first, there must be a factual basis for the prediction; second, the inventor must have, at the date of the patent application, an articulable and "sound" line of reasoning from which the desired result can be inferred from the factual basis; and third, there must be proper disclosure.
[77] As a preliminary matter, the parties dispute the date of invention for the '330 Patent. Pfizer argues that the date is June 18, 1980; Apotex submits that the relevant date is October 3, 1980, that is the priority date. In this regard, Apotex argues that as of June 18, 1980, the inventors had only "conceived" of a single member of the purported invented class of compounds, had no basis to extrapolate different stereoisomers to various classes of compounds and to bulky compounds, and were unable to predict anti-hypertensive properties of the claimed compounds.
[78] In my opinion, these arguments are sound. I note that the inventors themselves referred to June 18, 1980 as the date on which they "conceived" of an idea that would "probably" be useful as an ACE inhibitor. I am not persuaded that a "conceived" idea is synonymous with an invention. I conclude that the appropriate date for the date of the invention is October 3, 1980, the priority date of the '330 Patent.
[79] Once more, since the statutory presumption of validity arises, Apotex must provide sufficient evidence to substantiate its allegation to rebut that presumption. I am satisfied that Apotex has done so and accordingly, the burden shifts to Pfizer to disprove Apotex's allegation of invalidity on the basis of a lack of sound prediction.
[80] In this regard, Pfizer refers to a number of prior art references, including the enalapril patent and the Tanabe patent, as well as journal articles published before the date of October 3, 1980. It argues that this evidence is sufficient to soundly base a prediction of utility of the compounds claimed in the '330 Patent.
[81] Where a challenge is made to the validity of a patent and the proponents of the patent rely on the doctrine of sound prediction, the challenge will succeed if the prediction was not sound at the date of prediction or, regardless of the soundness of prediction, "there is evidence of lack of utility in respect of some of the area covered"; Monsanto, supra at page 1117.
[82] Apotex, relying on the trial judgment in Apotex v. Wellcome, supra, reported at (1998), 145 F.T.R. 161 (T.D.), argues that the doctrine of sound prediction does not apply here since the inventors never demonstrated the utility of the claimed class of compounds. However, this argument must fail in light of the decision of the Supreme Court of Canada in Apotex v. Wellcome, supra, where the Court said the following at page 185:
With respect, I think Parliament intended to get something more than speculation in exchange for the grant of a patent monopoly (a point which is further discussed below). On the other hand, I do not think, with respect, that the doctrine of sound prediction is limited to the narrow ambit ascribed to it by the trial judge. Once it is accepted that in appropriate circumstances utility can be predicted in advance of complete testing (whether of untested chemical compounds or otherwise), there seems no reason in principle why the doctrine should not be applied more generally, depending, of course, on the expert evidence. There is no doubt that care must be taken that the doctrine is not abused, and that sound prediction is not diluted to include a lucky guess or mere speculation. The public is entitled to obtain a solid teaching in exchange for the patent rights.
Accordingly, I conclude that Pfizer has satisfied its burden of disproving Apotex's allegation of lack of sound prediction with respect to the '330 Patent.
(iii) Anticipation
[83] Apotex argues that the '330 Patent was anticipated by a German patent owned by Hoechst, the subject of conflict proceedings initiated by the Commissioner of Patents in Canada. Pfizer submits that this patent does not meet the legal test for anticipation as set out by the Federal Court of Appeal in Beloit Canada Ltd. v. Valmet Oy (1986), 8 C.P.R. (3d) 289 (F.C.A.) where the prior publication must contain so clear a direction that a skilled person reading and following it would be led directly to the claimed invention.
[84] Pursuant to the Pre-1989 Act, an anticipatory prior art reference must have described the subject matter of a particular claim two years prior to the filing date of the patent in issue. Subsection 27(1) of the Pre-1989 Act, provides as follows:
| 27. (1) Subject to this section, any inventor or legal representative of an inventor of an invention that was
(a) not known or used by any other person before he invented it,
(b) not described in any patent or in any publication printed in Canada or in any other country more than two years before presentation of the petition hereunder mentioned, and
(c) not in public use or on sale in Canada more than two years prior to his application in Canada, may, on presentation to the Commissioner of a petition setting out the facts, in this Act termed the filing of the application, and on compliance with all other requirements of this Act, obtain a patent granting to him an exclusive property in the invention.
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27. (1) Sous réserve des autres dispositions du présent article, l'auteur de toute invention ou le représentant légal de l'auteur d'une invention peut, sur présentation au commissaire d'une pétition exposant les faits, appelée dans la présente loi le « dépôt de la demande » , et en se conformant à toutes les autres prescriptions de la présente loi, obtenir un brevet qui lui accorde l'exclusive propriété d'une invention qui n'était pas :
a) connue ou utilisée par une autre personne avant que lui-même l'ait faite;
b) décrite dans un brevet ou dans une publication imprimée au Canada ou dans tout autre pays plus de deux ans avant la présentation de la pétition ci-après mentionnée;
c) en usage public ou en vente au Canada plus de deux ans avant le dépôt de sa demande au Canada.
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[85] The Applicants submit that Apotex has not shown that the cited prior art, that is the Hoechst patent, is anticipatory, as required by subsection 27(1). They argue that only patents issued or articles published on or before September 30, 1979, fall within paragraph 27(1)(b).
[86] The test for anticipation was described in Beloit, supra and adopted by the Supreme Court in FreeWorld Trust, supra at page 1041. At page 297 of Beloit, supra the Court of Appeal said the following:
One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention.
[87] The words "in every case and without possibility of error" are important. The mere possibility that one piece of prior art could be within the claim is not sufficient to establish anticipation. As noted above, the test for anticipation requires the Court to consider independently each item of prior art cited by the Respondent. That means that, in this case, the Respondent must show that the prior art, that is the Hoechst patent that was the subject of conflict proceedings with the '330 Patent, must have contained "so clear a direction that a skilled person" would inevitably find the invention.
[88] Having regard to the relevant date, that is September 30, 1979, I find that the Respondent has not referred to any evidence that the Hoechst patent was issued on or before that date. Further, no evidence was submitted to show that a Canadian patent was filed in respect of Hoechst's German patent, and that it was filed on or before September 30, 1979. Accordingly, I conclude that Apotex has not put its allegation of invalidity on the basis of anticipation "in play", as that allegation is not supported by sufficient evidence.
(iv) Obviousness
[89] The question of obviousness must be assessed as of the date of the invention. This date is contested by the parties. The '330 Patent claims priority from October 3, 1980. Apotex submits that the Applicants have not adduced evidence to establish the date of invention and consequently, the relevant date for evolutionary obviousness must be accepted as being no earlier than the earliest possible priority date.
[90] The choice of the date is a consequence of the fact that the '330 Patent was issued under the statutory scheme of the Pre-1989 Act. In light of sections 28 and 29 of the Pre-1989 Act, I accept that the date of invention is the priority date of October 3, 1980, and not the date on which the patent was issued. An allegation of obviousness requires the Court to examine the claims of the patent which arise from the date of invention, and not from the grant of a patent; see Janssen-Ortho, supra.
[91] The Pre-1989 Act does not specifically provide a test for obviousness. The test for obviousness is established by jurisprudence and is succinctly stated by the Federal Court of Appeal in Beloit, supra as follows at page 294:
The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical create (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.
[92] Hindsight must not be used in assessing whether a patent is obvious. The question is whether the solution taught by the patent would be "plain as day" to the skilled technician who is seeking something new, without the necessity of conducting experiments or research. Justice Hugessen, writing for the Court in Beloit, supra, sounded a cautionary note in this regard at page 295, where he said the following:
Every invention is obvious after it has been made, and to no one more so than an expert in the field. Where the expert has been hired for the purpose of testifying, his infallible hindsight is even more suspect. It is so easy, once the teaching of a patent is known, to say, "I could have done that"; before the assertion can be given any weight, one must have a satisfactory answer to the question, "Why didn't you?"
[93] A patent is obvious only if the solution to the problem is clearly apparent. Suggestions in the prior art are not enough to render a patent invalid on the basis of obviousness; see Apotex v. Wellcome, supra; Bayer Aktiengesellschaft v. Apotex Inc. (1995), 60 C.P.R. (3d) 58 (Ont. Gen. Div.); and [1979] 2 S.C.R. 929">Hoechst v. Halocarbon (Ontario) Ltd., [1979] 2 S.C.R. 929. The person skilled in the art must be able to say that he or she would know that the invention would work and would have the benefits associated with the invention in light of publicly available information. The person skilled in the art must know that the solution or benefits would exist without testing, excluding verification of established information.
[94] In the case of obviousness, the invention need not be disclosed in one single patent or piece of prior art, as is the case for anticipation. The Court is entitled to look at all the patents and other publications that a skilled technician would discover in a "reasonable and diligent search", to determine whether the resulting "mosaic" leads directly to the invention; see Illinois Tool Works Inc. et al. v. Cobra Anchors Co. (2002), 221 F.T.R. 161, aff'd. (2003), 312 N.R. 184 (F.C.A.).
[95] Further, prior art that is relied upon in support of an allegation of obviousness must have been in the public domain; see Janssen-Ortho, supra. The Respondent's NOA dated July 24, 2003 cites a number of alleged prior art references with respect to obviousness, including European Patent Application No. EP 12,845, as well as a number of scientific articles demonstrating that others working in the art arrived at the subject matter of the disputed claims, at the same time.
[96] The Applicants, relying on the evidence of Dr. Anderson, argue that this prior art does not suggest that a person skilled in the art could have predicted the existence of quinapril hydrochloride prior to the date of its invention. In his affidavit, Dr. Anderson states that the replacement of proline with something hydrophobic-like THIQ was completely unpredictable as of June 18, 1980. However, he does not address the issue of obviousness on the basis of the October 3, 1980 date.
[97] In my opinion, the evidence about the state of the knowledge at the date of invention, that is the discovery of quinapril hydrochloride, does not show that others skilled in the art would have known the way to create, notice and document the benefits of this compound as an anti-hypertensive. While it is true that other ACE inhibitors effective in relieving hypertension may have existed before October 3, 1980, the fact remains that no one else, up to that time, had detected and created a compound similar to quinapril hydrochloride.
[98] As noted above, the test for obviousness is stringent. It requires the capable but non-imaginative skilled person to look at the common knowledge in the art at the date of the invention and immediately, without inventive ingenuity, reach the described invention. In my opinion, the cited art referred to by Apotex does not meet that test. I conclude that Pfizer has met its burden of showing that this allegation is not justified.
(v) Claims Broader than Invention or Disclosure
[99] Apotex alleges that claims three (3) and five (5) are broader than either the invention or the disclosure. Relying on Farbwerke [1979] 2 S.C.R. 929">Hoechst AG v. Commissioner of Patents (1966), 50 C.P.R. 220 (S.C.C.) and Xerox of Canada Ltd. v. IBM Canada Ltd. (1977), 33 C.P.R. (2d) 24 (F.C.T.D.), Apotex says that the doctrine of over breadth has two branches: a claim will be considered overly broad and accordingly, invalid, if it asserts an exclusive property or privilege in something the inventor did not actually invent; or something that the inventor did not fully disclose in the patent.
[100] Apotex argues that the relevant claims of the '330 Patent are broader than the disclosure, saying that the disclosure limits the invention to compounds in which the chiral centre on the THIQ is in the S-configuration, while claims three (3) and five (5) claim all stereoisomers. In this regard, Apotex refers to the disclosure of the '330 Patent which states as follows:
The [THIQ] used in this invention has the L(S) configuration. This configuration has been shown to be required for biological activity [...]
[101] Apotex argues that any skilled reader would understand that the statement made by the purported inventors was consistent with the literature that demonstrated that the S-configuration for the proline in captopril and enalapril was an absolute requirement for biological activity. As well, the inventors had only ever worked with the S-configuration of the THIQ in their earlier work.
[102] However, contrary to the disclosure, claims three (3) and five (5) do not impose any limitation on the chiralty of the THIQ head. Consequently, Apotex submits that these claims are broader than the invention claimed. It argues that there is an obvious contradiction between the paragraph cited above and the following paragraph:
The 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid used in this invention has the L (S) configuration. This configuration has been shown to be require for biological activity [...]
Optical and diastereo isomers arising from the chirality at the centers marked with an asterisk in formula I and racemates and mixtures thereof are within the scope of the invention. The S configuration at these centres is preferred.
[103] The Applicants' position is that the claims of the patent must be given an ordinary and logical construction by the person skilled in the art at the date of issuance of the patent, reading the patent specification as a whole. In this regard, the Applicants rely on [1976] 1 S.C.R. 555">Burton Parsons Chemicals, Inc. v. Hewlett-Packard (Canada) Ltd., [1976] 1 S.C.R. 555; Xerox, supra; Whirlpool, supra and Free World Trust, supra.
[104] As well, Pfizer submits that the Supreme Court of Canada has held that "reasonably broad cover" is both appropriate and necessary to protect research and innovation; see Whirlpool, supra and Free World Trust, supra.
[105] Pfizer relies on the evidence of Dr. Anderson and Dr. Wasley who each expressed the opinion that, when reading the patent as a whole, they recognized that the disclosure specifically indicated that all stereoisomers are within the scope of the invention. As no stereochemistry is specified in the claim language, both Dr. Anderson and Dr. Wasley were required to consider the disclosure to determine what stereoisomers were being claimed. They relied on the disclosure to confirm their opinion that all stereoisomers were claimed.
[106] The Applicants also note that, upon cross-examination, Dr. Marshall, a witness for Apotex, admitted that the patent specifies that all stereoisomers are within the scope of the invention. The Applicants rely on this evidence, as well, to argue that the claims cannot be broader than the invention disclosed.
[107] In my opinion, these arguments are to be assessed relative to the construction of the patent. Since I have concluded that claims three (3) and five (5) should be construed so as to include compounds useful for reducing hypertension and having regard to the expert evidence that the S-configuration is the optimal configuration for high level ACE inhibition leading to anti-hypertensive results, I conclude that the claims encompassing all possible stereoisomers are overly broad.
[108] The aim of the purposive approach is to give meaning to the claims of a patent. Those claims which exceed the scope of the invention or the description in the patent's specification are invalid; see Farbwerke [1979] 2 S.C.R. 929">Hoechst v. Commissioner of Patents, supra. Accordingly, I am satisfied that the Applicants have failed to show that the allegation of invalidity, on the basis of overly broad claims, is not justified.
(vi) Double Patenting
[109] The final allegation of invalidity raised by Apotex is double patenting. Apotex alleges that the '330 Patent is invalid on the basis of obvious-type double patenting. This was discussed in Whirlpool, supra where Justice Binnie said the following at pages 1105-1106:
There is, however, a second branch of the prohibition which is sometimes called "obviousness" double patenting. This is a more flexible and less literal test that prohibits the issuance of a second patent with claims that are not "patentably distinct" from those of the earlier patent. In [1964] S.C.R. 49">Commissioner of Patents v. Farbwerke Hoechst Aktiengesellschaft Vormals Meister Lucius & Bruning, [1964] S.C.R. 49, 41 C.P.R 9, the issue was whether Farbwerke [1979] 2 S.C.R. 929">Hoechst could obtain a patent for a medicine that was a diluted version of a medicine for which it had already obtained a patent. The claims were neither identical nor coterminous. Judson J. nevertheless held the subsequent patent to be invalid, explaining at p. 53:
A person is entitled to a patent for a new, useful and inventive medicinal substance but to dilute that new substance once its medicinal uses are established does not result in further invention. The diluted and undiluted substance are but two aspects of exactly the same invention. In this case, the addition of an inert carrier, which is a common expedient to increase bulk, and so facilitate measurement and administration, is nothing more than dilution and does not result in a further invention over and above that of the medicinal itself.
In Consolboard, supra, Dickson J. referred to Farbwerke [1979] 2 S.C.R. 929">Hoechst as the "main authority on double patenting" (p. 536) which stood for the proposition that a second patent could not be justified unless the claims exhibited "novelty or ingenuity" over the first patent:
Judson J. for the Court said that the second process involved no novelty or ingenuity, and hence the second patent was unwarranted.
[110] This second type of double patenting is in issue in this application. The question that arises is whether the claims of one of the patents in issue are patentably distinct over the claims of the other. The answer depends upon the relationship between the claims to quinapril hydrochloride as set out in the two patents, that is the '330 Patent and the '615 Patent.
[111] The Applicants argue that both the Canadian and American Patent Offices have determined that the claims of the '614 and '615 Patents are patentably distinct from the claims of the '330 Patent. They submit that Apotex has failed to lead any evidence to the contrary.
[112] As well, Pfizer points out that the '615 Patent was not involved in the conflict proceeding between the '330 Patent and the [1979] 2 S.C.R. 929">Hoechst patent, although the issue was raised at the time.
[113] Apotex, for its part, argues that moving from the '330 Patent to the '615 Patent was not inventive since it was well known and understood, at both the June and October dates, that the S-configuration of the stereoisomers would be the most effective in inhibiting ACE. As well, it was not inventive to move from the '615 Patent to the '330 Patent since changing the chirality of the compound from the S-configuration was expected to create compounds with reduced rather than enhanced activity.
[114] Further, Apotex submits that the issuance of the '614 and '615 Patents, prior to the issuance of the '330 Patent, is not dispositive of the claim for validity of the '330 Patent.
[115] I accept the Applicants' arguments on the issue of double patenting. The fact that the '615 Patent was not engaged in the conflict proceedings between the '330 Patent and the [1979] 2 S.C.R. 929">Hoechst patent is persuasive evidence that the '615 Patent does not give rise to obvious-type double patenting. I note, as well, that the record shows that the [1964] S.C.R. 49">Commissioner of Patents suggested that a divisional application be made in respect of the '615 Patent. I am satisfied, on the basis of the evidence in the record, that the Applicants have shown that the allegation of invalidity on the basis of double patenting is not justified.
E. The '615 Patent
(i) Adequacy of the NOA
[116] The Applicants challenge the adequacy of the NOA dated July 18, 2003 and submit that it fails to comply with the NOC Regulations due to its lack of detail in respect of both its factual and legal grounds. In particular, Pfizer submits that Apotex's allegation of non-infringement is not justified because it fails to assert adequate facts to explain how no claim for the medicine itself, or for the use of the medicine, would be infringed.
[117] The Applicants argue that the bald allegation in the July 18, 2003 NOA that quinapril hydrochloride is "not the medicine contained in your ACCUPRIL® tablets" does not serve the purpose of the detailed statement, that is to provide the first person with the entire basis upon which the allegation rests. Since Apotex failed to make the allegation in its NOA that ACCUPRIL® tablets contain [Edited], the Applicants argue that it is precluded from relying on that allegation in this application. In this regard, the Applicants refer to and rely on the decision in Merck Frosst Canada Inc. v. Canada (Minister of Health) (2001), 12 C.P.R. (4th) 447 (F.C.A.).
[118] In response, Apotex says that the Applicants' arguments about the sufficiency of the July 18, 2003 NOA are misplaced. It submits that it is appropriate for a second person to withhold certain information until a confidentiality order is in place. Further, the NOA will meet the legal tests for sufficiency. The NOA will be adequate if further disclosure elaborates on the basis for which the allegation of non-infringement was made such that there is sufficient information upon which to assess the allegation and respond to it.
[119] In this case, Apotex submits that it provided that information to Pfizer as part of its ANDS, following the issuance of a protective order. In this regard, it relies on the decision in Aventis Pharma Inc. v. Pharmascience Inc. (2005), 38 C.P.R. (4th) 441 (F.C.T.D.); Pfizer Canada Inc. et al. v. Apotex Inc. et al. (2004), 245 F.T.R. 243 (T.D.); Bayer AG v. Canada (Minister of National Health and Welfare) (1993), 51 C.P.R. (3d) 329 (F.C.A.).
[120] Apotex further argues that Pfizer was fully aware at the time of filing its expert evidence that Apotex was asserting that the medicine ACCUPRIL® did not contain quinapril hydrochloride but rather [Edited]. In any event, Apotex submits that it was unnecessary to tell Pfizer the identity of the medicine in the ACCUPRIL® tablets since that information was, or should have been, known by Pfizer itself.
[121] Section 5(1) of the NOC Regulations details the requirements of an NOA as follows:
| 5. (1) Where a person files or has filed a submission for a notice of compliance in respect of a drug and compares that drug with, or makes reference to, another drug for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics and that other drug has been marketed in Canada pursuant to a notice of compliance issued to a first person and in respect of which a patent list has been submitted, the person shall, in the submission, with respect to each patent on the register in respect of the other drug,
(a) state that the person accepts that the notice of compliance will not issue until the patent expires; or
(b) allege that
(i) the statement made by the first person pursuant to paragraph 4(2)(c) is false,
(ii) the patent has expired,
(iii) the patent is not valid, or
(iv) no claim for the medicine itself and no claim for the use of the medicine would be infringed by the making, constructing, using or selling by that person of the drug for which the submission for the notice of compliance is filed.
|
|
5. (1) Lorsqu'une personne dépose ou a déposé une demande d'avis de conformité pour une drogue et la compare, ou fait référence, à une autre drogue pour en démontrer la bioéquivalence d'après les caractéristiques pharmaceutiques et, le cas échéant, les caractéristiques en matière de biodisponibilité, cette autre drogue ayant été commercialisée au Canada aux termes d'un avis de conformité délivré à la première personne et à l'égard de laquelle une liste de brevets a été soumise, elle doit inclure dans la demande, à l'égard de chaque brevet inscrit au registre qui se rapporte à cette autre drogue :
a) soit une déclaration portant qu'elle accepte que l'avis de conformité ne sera pas délivré avant l'expiration du brevet;
b) soit une allégation portant que, selon le cas:
(i) la déclaration faite par la première personne aux termes de l'alinéa 4(2)c) est fausse,
(ii) le brevet est expiré,
(iii) le brevet n'est pas valide,
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[122] In AB Hassle v. Canada (Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.) the Federal Court of Appeal discussed the purpose of the NOA, at page 288 as follows:
The respondent suggests that the list of prior art in the detailed statement was not intended to be exhaustive, hence the presence of the word "including", so that the way was left open to add to that list in the section 6 proceeding. I am of the view, however, that paragraph 5(3)(a) does not contemplate such possibility. The intent appears to be that the entire factual basis be set forth in the statement rather than be revealed piecemeal when some need happens to arise in a section 6 proceeding. This Court has cautioned persons in the position of the respondent that they assume a risk that a particular allegation may not be in compliance with the Regulations and that the deficiency cannot be cured by the Court in a section 6 proceeding [...].
[123] The requirements of a legally sufficient NOA were recently reviewed by the Federal Court of Appeal in Pfizer Canada Inc. v. Novopharm Ltd., [2005] F.C.J. No. 1318 (F.C.A.)(Q.L.). The Court stated the test in the following terms at paragraphs 14-15:
The purpose for Novopharm providing the detailed statement of the legal and factual basis for the non-infringement allegations was to notify the patentee (Pfizer) of the reasons why its patent would not be infringed or was invalid (see AB Hassle 1 at paragraph 16). At paragraph 17 of that decision Stone J.A. stated:
... the detailed statement must be such as to make the patentee fully aware of the grounds for claiming that the issuance of an NOC would not lead to infringement of a listed patent for, otherwise, the patentee would be unable to decide whether or not to initiate a section 6 proceeding.
Similarly, in SmithKline Beecham Pharma Inc. v. Apotex Inc., Noël J.A. stated the following at paragraph 24:
The detailed statement ... is intended to place the patentee in the position of deciding whether to oppose the issuance of a notice of compliance by instituting a section 6 proceeding or to stand aside.
[124] In the present case, I am satisfied that the NOA dated July 18, 2003 partially complies with the legal test for adequacy. A plain reading of paragraph 5(1)(b)(iv) of the NOC Regulations supports the view that the second person, here Apotex, need only address the issue of non-infringement of claims for the medicine. The medicine here in issue is quinapril hydrochloride.
[125] When the July 28, 2003 NOA was served on Pfizer, no confidentiality order was in place relative to the composition of Apotex's product. In these circumstances, it was appropriate for Apotex to withhold information concerning the formulation of its Apo-Quinapril and its manufacturing process until such an order was obtained. The confidentiality order was issued on November 25, 2003. I conclude that the NOA meets the legal requirements insofar as the elements of its product are concerned.
[126] However, I do not agree that the NOA is sufficient with respect to the alleged contents of the Applicants' ACCUPRIL® product. If Apotex is alleging that the Applicants' product contains [Edited] rather than quinapril hydrochloride, Apotex should have so specified in its NOA.
[127] Nonetheless, I am satisfied that this defect is not fatal. Apotex clearly raised the issue of non-infringement in relation to Apo-Quinapril and the '615 Patent. The broad issue of non-infringement was "put in play" and Pfizer carried the burden to show that the allegation is not justified.
(ii) Non-Infringement of the '615 Patent
[128] The remaining issue is that of infringement. The Applicants argue that any evidence of the presence of quinapril hydrochloride in Apotex's product, regardless of intention or reasonable attempts to avoid, will amount to infringement of the '615 Patent.
The Applicants argue that the product monograph for Apotex's Apo-quinapril tablets is the same as the inventor's monograph.
[129] The Applicants submit that, upon the evidence submitted, they have demonstrated infringement by Apotex of all claims of the '615 Patent. The Applicants argue that the issue of infringement requires construction of claim one (1) of the '615 Patent. Among other things, claim one (1) claims quinapril hydrochloride. The disclosure specifically states that [Edited] forms are "equivalent" to the [Edited] forms, although the claims themselves are silent on this issue. Relying on the principles of claim construction outlined in Whirlpool, supra, the Applicants submit that claim one (1) should be construed to include [Edited] forms of quinapril hydrochloride for the following reasons.
[130] The '615 Patent contains a claim for quinapril or quinaprilat in the following forms: the hydrochloride; the hydrochloride, hydrate; and the hydrochloride hemihydrate. The disclosure of the '615 Patents provides as follows:
... in general, the hydrated forms and the solvated forms with pharmaceutically acceptable solvents are equivalent to the anhydrous, or unsolvated form for the purposes of this invention.
[131] Pfizer submits that a reading of the claims of the '615 Patent to exclude [Edited] forms leads to the unreasonable conclusion that the patentee intended to disclose a manner in which its patent claim could be circumvented.
[132] Apotex uses [Edited] forms of quinapril hydrochloride known as [Edited]. It has named [Edited] as its "drug substance" for regulatory purposes, even though [Edited] is the substance that is formulated into tablets. Apotex's proposed product monograph refers to its tablets as containing quinapril hydrochloride.
[133] According to Dr. Brenner, an expert witness who provided evidence on behalf of the Applicants, the words "the hydrochloride" in light of the specification indicating that [Edited] forms are "equivalent", encompasses the hydrochloride, hydrate, the hydrochloride, and the hydrochloride hemihydrate. He also interpreted the words broadly, on the basis that the inventers did not intend the word "the" to denote a single compound. Finally, he applied the standard of the person of ordinary skill in the art, rather than on the standard of an expert chemist. In his view, the person of ordinary skill in the art would conclude that the claim one (1) on the "615 Patent includes [Edited].
[134] The Applicants argue that the evidence of Dr. Brenner is to be preferred over the evidence of both Dr. McClelland and Dr. Langer. They criticize the impartiality of Dr. McClelland, who has frequently testified on behalf of Apotex and further, pursuant to an order dated August 18, 2004, and upheld on October 14, 2004, a portion of his affidavit was struck as constituting inadmissible hearsay evidence.
[135] Dr. Langer has also been retained by Apotex on a regular basis. According to the Applicants, he was given incorrect instructions with respect to interpreting a Canadian patent and his evidence in that regard, is unreliable. Specifically, he appeared to be of the view that if a term in a claim is capable of construction from the claims alone, there is no need to refer to the specification. The Applicants submit this approach is contrary to the purposive construction advocated by the Supreme Court in Whirlpool, supra and Free World Trust, supra.
[136] The Applicants challenge the tests that were conducted by Apotex to demonstrate that there is no quinapril hydrochloride in ACCUPRIL®. Specifically, the Applicants argue that the gas emission tests done by Dr. Wang are unreliable, the mass spectral analysis was inconclusive, and the FTIR tests have been differentially interpreted. The Applicants also sought a court order to strike statements made by Dr. Wang in his affidavit as constituting inadmissible hearsay evidence, however, by Order dated October 14, 2004 this Court found that it was a question of weight to be accorded to this evidence rather than inadmissibility.
[137] The Applicants also argue that Apotex has failed to establish on a balance of probabilities that there is only [Edited] in its drug product, not quinapril hydrochloride. Quinapril hydrochloride was approved by Health Canada as the active pharmaceutical ingredient in ACCUPRIL®. Dr. Brenner testified that he would expect some quinapril hydrochloride to remain in the ACCUPRIL® tablets, even if Apotex is correct that a reaction is occurring, despite the limitation of the tests relied upon by Apotex.
[138] Apotex argues that the medicine in the Applicants' tablets is [Edited], not quinapril hydrochloride as claimed by the '615 Patent. Accordingly, the '615 Patent is not applicable to Apo-Quinapril since the '615 Patent does not contain a claim to the medicine within Apo-Quinapril, or to ACCUPRIL®, for the same reason.
[139] Alternatively, Apotex submits that it will not infringe the relevant claims of the '615 Patent as the patent does not claim [Edited], the substance used as an intermediate in the formulation of its medicine [Edited].
[140] In support of its first argument, Apotex refers to the NOC Regulations which permit a patentee who obtains an NOC for a drug that contains a medicine to add a patent to the patent list where that patent has a claim to the medicine. The essential requirement is that the medicine contained in the drug must be the same medicine that is claimed in the patent; see subsections 4(1) and 4(2) of the NOC Regulations. Apotex takes the position that since neither ACCUPRIL® nor Apo-Quinapril contains any of the compounds claimed in the '615 Patent, Apotex is not required to address the '615 Patent.
[141] Apotex relies on Merck Frosst v. Canada (Minister of Health) (2000), 7 C.P.R. (4th) 522 (F.C.T.D.), aff'd (2001), 12 C.P.R. (4th) 383 (F.C.A.), where the Court considered whether an active metabolite of the drug zocor could be included on the Register. The Court held that since the active metabolite was not contained in the zocor tablets approved by Health Canada, the patents were ineligible for listing. In affirming that decision, the Federal Court of Appeal agreed that what is present in the final dosage form is the relevant material in determining the "medicine".
[142] As well, Apotex argues that a similar conclusion was reached by the Court in Aventis v. Pharmascience, supra, where the patent in issue contained claims to both ramipril and its active metabolite, ramiprilat. The Court concluded that the "medicine" includes only that which is present in the dosage form. Apotex also relies on the recent decision of Justice von Finckenstein in Abbott Laboratories v. Ratiopharm, 2005 FC 1093, where he concluded that the intermediate product in Ratiopharm's clarithromycin Form II is not made, constructed, used or sold as a medicine and accordingly, cannot be said to infringe Abbott's patent for the purposes of the NOC Regulations.
[143] In any event, Apotex argues that Pfizer has not filed any evidence to satisfy its burden with respect to the issue of infringement. Further, Pfizer relies upon its Form IV filed with Health Canada relative to the '615 Patent. This form identifies quinapril hydrochloride as the medicine and active ingredient.
[144] Apotex notes that Dr. Brenner, the key witness for the Applicants on this point, admitted that the listing does not always correspond to the identity of the compound in the final dosage form. Apotex relies on the evidence of its witnesses, Dr. Cima and Dr. Wang, who concluded on the basis of testing that the material contained within an ACCUPRIL® tablet is consistent with [Edited] and is not consistent with [Edited], quinapril hydrochloride hydrate or quinapril hydrochloride.
[145] Finally, Apotex argues that the Applicants did not raise in its Notice of Application the argument that its ACCUPRIL® tablets contain trace amounts of quinapril hydrochloride relative to the amount of [Edited]. In any event, it submits that Pfizer has failed to discharge its burden of proving this assertion.
[146] Apotex, in any event, argues that its allegation of non-infringement is justified because its product will not infringe any of the claims of the '615 Patent. Since that patent does not cover the compound [Edited], the material used as an intermediate for the preparation of its tablets, Apotex submits that its product does not infringe. In this regard, Apotex relies on Hoffman-La Roche Ltd. v. Canada (Minister of National Health and Welfare) (1996), 67 C.P.R. (3d) 484 (T.D.), aff'd (1996), 70 C.P.R. (3d) 206 (F.C.A.), aff'd (1996), 70 C.P.R. (3d) 1 (F.C.A.) and AB Hassle v. Apotex Inc. (2003), 29 C.P.R. (4th) 23 (F.C.A.). It argues that these decisions support the argument that where the claims of the patent appear to be clear, it is not appropriate to refer to the disclosure to construe the claim and in particular, to vary the ambit of the claims.
[147] Apotex submits that only claim one (1) of the '615 Patent is at issue. It claims the following:
A substituted acyl derivative [...] in the form of the (S,S,S) isomer [...] in one of the following acid salt forms: the hydrochloride, hydrate; the hydrochloride; and the hydrochloride hemihydrate.
[148] Apotex argues that the claims of the '615 Patent are facially clear and that Pfizer cannot look to the disclosure to expand the scope of the claims. In this regard, Apotex relies on the evidence of Dr. Langer and Dr. McClelland. These two experts concluded that the term "the hydrochloride", as used in claim one (1), covers the anhydrous, [Edited] form of the claimed compounds. Consequently, claim one (1) does not cover [Edited] claimed compounds, [Edited]. Claim one (1) specifically includes two [Edited] forms, that is "the hydrochloride hydrate" and "the hydrochloride hemihydrate". Apotex submits that if the inventors had intended to include other [Edited] forms, they would have clearly said so.
[149] In any event, Apotex argues that there is doubt as to whether claim one (1) includes [Edited], and consequently Pfizer has not discharged its legal burden and a prohibition order should not issue.
[150] The burden lies on the Applicants to show that the Respondent's product infringes all claims of the '615 Patent. In my opinion, the Applicants have failed to discharge it.
[151] The Applicants were provided with a sample of Apotex's Apo-quinapril product, in the amount of 5 grams, pursuant to an Order of the Court dated November 25, 2003, which provides as follows:
5. Apotex is to produce:
(a) 5 grams of the active ingredient used in the manufacturing of Apotex' Apo-Quinapril tablets;
without prejudice to the applicants' right to bring the production motion back on for a greater amount should 5 grams be insufficient
The Applicants elected not to test this material, although Dr. Brenner gave evidence about testing that could be done.
[152] These were x-ray powder diffraction, density, thermal gravimetric analysis, Karl Fisher analysis, gas chromatography, differential scanning calorimetry, and elemental analysis. In the course of his cross-examination, Dr. Brenner was questioned about the quantities required to conduct some of these tests, as appears from the following:
196. Q. Now, you say, in paragraph 58 for x-ray powder diffraction you would run two tests, each requiring 200 milligrams of active ingredient; do you see that?
A. Yes
197. Q. So you are estimating that you would need for x-ray powder diffraction testing, 400 milligrams of material?
A. To do it in duplicate, yes.
198. Q. Then the next section deals with density testing?
A. Right
...
200. Q. And you say you would run two tests for density; do you see that in 60?
A. Yes.
201. Q. So that would be two times 500 milligrams you would need?
A. Yes.
202. Q. So that is 1,000 milligrams?
A. Correct.
...
204. Q. If you go over the page to page 23, you are talking about thermal gravimetric analysis, TGA?
A. Yes.
205. Q. And you say that test could determine whether the compound is [Edited]?
A. Correct.
206. Q. And in 62, you say you would run three tests using 5 milligrams each?
A. Yes.
207. Q. So the total there would be 15 milligrams?
A. Correct.
208. Q. Then the next section deals with Karl Fisher analysis, KF?
A. Correct
209. Q. And this is a test that determines specific water content?
A. Correct.
210. Q. For this you say in 65, you would require 100 to 200 milligrams of active and you would like to run the test twice?
A. Correct.
211. Q. So taking the upper limit you would need, 2 times 200, would be 400 milligrams?
A. Correct.
...
214. Q. Then you go over the page, you have differential scanning calorimetry, DSC. In the fourth line you say:
"... The unique data provided by the DSC test provides information akin to a fingerprint on the nature of the sample tested ..."
And you accept that?
A. Correct.
215. Q. And you say that you would do two tests of 2 to 5 milligrams of active in paragraph 68?
A. Correct.
216. Q. So using the upper limit, you would have 2 times 5 milligrams or 10 milligrams?
A. Correct.
217. Q. Then in 69 you talk about elemental analysis. And I gather this would determine the total amount of carbon, hydrogen, nitrogen and chlorine in the material?
A. Correct.
218. Q. And this would allow you to determine the exact type of chemical compound used in Apotex' process?
A. Correct.
219. Q. And you would need 10 to 20 milligrams run twice?
A. Correct.
220. Q. So using the upper limit, you would need 40 milligrams for that?
A. Correct.
221. Q. So if you will accept my math, I took all of the upper limits and all of the numbers we talked about, to which you made reference in this affidavit, for the bulk testing, and I came up with 1,865 milligrams; do you have any reason to think that is not correct?
A. I assume your calculation is correct.
222. Q. You haven't done the addition?
A. I haven't done them myself.
[153] It is clear that the amount of product required for the testing described by Dr. Brenner was less than the amount which Apotex was ordered to make available. If it were not sufficient, the Applicants were authorized to seek a further order for production.
[154] Later in his cross-examination, Dr. Brenner was questioned about the ability to detect quinapril hydrochloride in [Edited], as follows:
717. Q. The issue is not that you can't identify quinapril hydrochloride. The issue is that you may not be able to identify it when the amounts are so small as to be beyond the detectable capabilities of existing equipment. That is what you are talking about?
A. That equipment is tied into certain methodologies. Different methodologies have different capabilities.
718. Q. Okay, but ...
A. Bearing that in mind.
719. Q. Assuming one employs the best available methodology with the best available equipment ...
A. Equipment, yes.
720. Q. ... you are saying it may be possible that there may be undetectable amounts of quinapril hydrochloride even beyond the best equipment and best methodologies that could be employed?
A. Yes, I couldn't guarantee success.
[155] In my opinion, the inability to guarantee the success of a chosen testing process is no answer to the Applicants' burden relative to the allegation of non-infringement. The '615 Patent claims quinapril hydrochloride as the medicine. The presence of that substance in Apotex's product would amount to infringement. One means of establishing that presence is testing and according to the Applicants' evidence, no testing was done. In these circumstances, I conclude that the Applicants have failed to show that the allegation of non-infringement is not justified.
[156] It is not necessary to decide whether ACCUPRIL® in fact contains quinapril hydrochloride since I have concluded that the NOA is insufficient in respect of that argument.
CONCLUSION
[157] In conclusion, the application for a prohibition order is dismissed. The Applicants have not shown that the allegation of invalidity in respect of the '330 Patent, on the basis of overly broad claims, is not justified. The Applicants have not discharged their burden to show that the allegation of non-infringement, with respect to the '615 Patent, is not justified. This application is dismissed, with costs to the Respondent, Apotex Inc., the Respondent Minister of Health not having participated.
"E. Heneghan"
J.F.C.
FEDERAL COURT
NAME OF COUNSEL AND SOLICITORS OF RECORD
DOCKET: T-1633-03
STYLE OF CAUSE: PFIZER CANADA INC., WARNER-LAMBERT
COMPANY LLC and PARKE, DAVIS & COMPANY
LLC
Applicants
and
THE MINISTER OF HEALTH and APOTEX INC.
Respondents
PLACE OF HEARING: Toronto, Ontario
DATE OF HEARING: May 30 - June 2, 2005
Additional Written Submissions received from the Applicants and Apotex Inc., on August 29 and 30, 2005, respectively
PUBLIC REASONS
FOR ORDER AND ORDER: HENEGHAN J.
DATED: September 28, 2005
(Confidential Reasons for Order were issued on September 2, 2005)
APPEARANCES:
Sheila Block
Andrew Shaughnessy
Andrew Bernstein FOR APPLICANTS
H.B. Radomski
Andrew Brodkin
Sorelle Simmons FOR RESPONDENT,
Rick Tuzi APOTEX INC.
No appearance FOR RESPONDENT,
MINISTER OF HEALTH
- 2 -
SOLICITORS OF RECORD:
Torys LLP
Toronto, ON FOR APPLICANTS
Goodmans LLP
Toronto, ON FOR RESPONDENT,
APOTEX INC.
John H. Sims, Q.C.
Deputy Attorney General of Canada FOR RESPONDENT,MINISTER OF HEALTH
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