Bayer AG v. Apotex Inc.

Bayer AG v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2004-02-02
Neutral citation
2004 FC 177
File numbers
T-877-02
Notes
Digest
Decision Content
Date: 20040202
Docket: T-877-02
Citation: 2004 FC 177
BETWEEN:
BAYER AG AND BAYER INC.
Applicants
and
APOTEX INC.
and
THE MINISTER OF NATIONAL HEALTH AND WELFARE
Respondents
REASONS FOR ORDER
CAMPBELL J.
[1] Since 1987, the Applicant Bayer AG has held Canadian Patent 1,218,067 ("the Patent" or "the '067 patent") for the antibacterial medicine ciprofloxacin hydrochloride ("ciprofloxacin") when made by the processes claimed in the Patent or by their obvious chemical equivalents. Ciprofloxacin is sold by the Applicant Bayer Inc. (formerly Miles Canada Inc.) in Canada under a Notice of Compliance (NOC) granted by the Minister of National Health and Welfare (the "Minister") under s.C.08.004 of the Food and Drug Regulations, C.R.C. 1985, c. 870 ("Food and Drug Regulations"). The '067 patent was issued February 17, 1987, on an application filed in August 1982, and expires February 17, 2004. Since 1993, the Respondent Apotex Inc. ("Apotex") has filed several Notices of Allegation (NOA) claiming invalidity or non-infringement of the Patent. The NOA at issue in the present case is Apotex' eighth NOA with respect to ciprofloxacin, and its second non-infringement allegation regarding the '067 patent. Apotex' eighth NOA alleges that no claim for the medicine itself and no claim for use of the medicine would be infringed by the manufacture or sale of ciprofloxacin when prepared by Apotex' proposed process.
[2] As a preliminary matter, the Applicants Bayer AG and Bayer Inc. ("Bayer") seek an order declaring that Apotex' NOA is invalid for non-compliance with s.5 of the Patent Medicines (Notice of Compliance) Regulations, SOR/93-133 as amended (the "NOC Regulations") on the basis that Apotex failed to file a submission for a NOC with respect to the Apotex process for ciprofloxacin prior to serving its non-infringement NOA on Bayer. Bayer also argues that Apotex' NOA does not "relate to" its new drug submission and, as a result, Apotex has failed to comply with s.5(3)(c)(i). Bayer therefore asserts that the Court does not have jurisdiction to render a decision on the merits of Apotex' non-infringement NOA.
[3] In the alternative, Bayer seeks an order pursuant to s.6(1) of the NOC Regulations prohibiting the Minister from issuing a NOC under s.C.08.004 of the Food and Drug Regulations to Apotex in respect of ciprofloxacin tablets of 100 mg, 250 mg, 500 mg, and 750 mg dosage strengths for oral administration, until after the expiration of the '067 patent. In these proceedings, Bayer seeks to demonstrate that step 2 of the six-step Apotex process for producing ciprofloxacin is an obvious chemical equivalent of the process claimed in claims 8(1) and 14(10) of the '067 patent and that Apotex' allegation of non-infringement is, therefore, not justified.
[4] The legislative scheme and the detailed procedures relevant to these proceedings have been explained in many cases and need not be repeated here (see for example Hoffman LaRoche v. Canada (1996), 67 C.P.R. (3d) 484 (F.C.T.D.), affd (1996), 70 C.P.R. (3d) 206 (F.C.A.)). It is important to note, however, that the burden of proof rests with Bayer to demonstrate on a balance of probabilities that Apotex' allegation of non-infringement is not justified. In order to discharge that burden, Bayer must disprove some or all of the allegations in the NOA, which are presumed to be true, and which, if left unchallenged, would allow the Minister to issue a NOC.
[5] The two main questions to be answered in the present application are as follows:
I. The jurisdictional question: Does the Court lack jurisdiction to render a decision on the merits on the basis that Apotex failed to comply with s.5 of the NOC Regulations?
II. The non-infringement question: Is step 2 of the six-step Apotex process for producing ciprofloxacin an obvious chemical equivalent of the process claimed in claims 8(1) and 14(10) of the '067 patent? If the answer to this question is "no", Apotex' allegation of non-infringement is justified.
I. The Jurisdictional Question
[6] In the course of oral argument, it was agreed that the abuse of process and "sham submission" arguments raised by Bayer in its written submissions be considered merged into the following jurisdictional argument.
[7] Bayer argues that Apotex has failed to comply with s.5 of the NOC Regulations, and as a result, Apotex' NOA is a nullity, leaving the Court with no jurisdiction to render a decision on the merits.
[8] First, Bayer contends that the modification of Apotex' Abbreviated New Drug Submission by way of a "notifiable change" is a "submission for a NOC" within the meaning of s.5 of the NOC Regulations, and consequently, under s.5(3)(c)(i), Apotex was obliged to file its notifiable change prior to serving its non-infringement NOA; Bayer argues that Apotex failed to comply with this timing requirement.
[9] Second, Bayer advances an alternative argument in the event of a finding that a notifiable change update is not a "submission for a NOC", being that the "submission for a NOC", within the meaning of s.5, is Apotex' underlying Abbreviated New Drug Submission. Bayer argues that, pursuant to s.5(3)(c)(i), where a second person, in this case Apotex, has filed a submission for a NOC, and the person alleges non-infringement, that person is required to serve on the first person, in this case Bayer, a NOA "relating to" the submission for a NOC filed with the Minister. Bayer states that Apotex'Abbreviated New Drug Submission contains a previously-prohibited process, and does not contain the current Apotex process which is the subject of Apotex' NOA in the present proceedings. Bayer, therefore, argues that Apotex' NOA does not "relate to" its Abbreviated New Drug Submission and, as a result, Apotex has failed to comply with s.5(3)(c)(i).
A. Has Apotex failed to comply with the timing requirements in s.5(3)(c)(i)?
[10] Under s.5(1) of the NOC Regulations, where a second person, in the present case Apotex, files or has filed a "submission for a NOC" in respect of a drug, and compares that drug with, or makes reference to, another drug for the purpose of demonstrating bioequivalence, and that other drug has been marketed in Canada pursuant to a NOC and in respect of which a patent list has been submitted, the second person must either state that it accepts that a NOC will not issue until the patent expires or make an allegation of non-infringement (or one of the other allegations set out in s.5(1)(b)).
[11] Section 5(3)(c)(i) provides that a submission for a NOC must be filed with the Minister before, or at the same time as, a non-infringement NOA is served. Subparagraph 5(3)(c)(i) of the NOC Regulations, reads in part:
(3) Where a person makes an allegation pursuant to paragraph (1)(b) [...], the person shall
...
(c) if the allegation is made under subparagraph (1)(b)(iv)...,
(i) serve on the first person a notice of the allegation relating to the submission filed under subsection (1) [...] at the time that the person files the submission or at any time thereafter
...
3) Lorsqu'une personne fait une allégation visée aux alinéas (1)b) [...], elle doit:
...
c) si l'allégation est faite aux termes des sous-alinéas (1)b)(iv)...:
(i) signifier à la première personne un avis de l'allégation relative à la demande déposée selon les paragraphes (1) [...], au moment où elle dépose la demande ou par la suite
...
[12] With respect to these requirements, certain features of the present case are not in dispute. Apotex originally filed its Abbreviated New Drug Submission for ciprofloxacin in 1993 and, therefore, this submission was before the Minister at the time when the NOA at issue in these proceedings was served. The parties agree that on April 25, 2002, Apotex filed information with the Minister with respect to a "notifiable change" containing the Apotex process, which process is the subject of the non-infringement NOA in the present proceedings. The parties further agree that Apotex' notifiable change updates the Abbreviated New Drug Submission for ciprofloxacin previously filed by Apotex. The Minister acknowledged receipt of the information with respect to the notifiable change on April 26, 2002. Apotex sent its NOA with respect to its process to Bayer by registered mail on April 22, 2002, and under s.9(2) of the NOC Regulations, the NOA is deemed to have been served on Bayer five days after mailing, namely, April 27, 2002.
[13] With respect to this fact pattern, Bayer argues that Apotex' Abbreviated New Drug Submission, as amended by the notifiable change in 2002, is a "submission for a NOC" within the meaning of s.5 of the NOC Regulations, and, therefore, the timing requirements in s.5(3)(c)(i) were engaged by the filing of the notifiable change in 2002. Accordingly, Bayer argues that s.5(3)(c)(i) required Apotex to have submitted its notifiable change prior to, or at the same time as, serving the non-infringement NOA on Bayer.
[14] Apotex responds that a notifiable change is not a "submission for a NOC" within the meaning of s.5 of the NOC Regulations, and, therefore, the requirement in s.5(3)(c)(i) that a submission for a NOC be filed with the Minister before, or at the same time as, the NOA is served does not apply to Apotex' notifiable change.
[15] An important fact which drives Bayer's argument is that the information filed as the subject matter of the notifiable change was at first found to be deficient by Health Canada, and a number of months went by before it was found to be acceptable; on April 26, 2002, Apotex attempted to file the notifiable change relating to its process, but the subject matter of it was not found to be acceptable until June 28, 2002. Thus, Bayer contends that Apotex' filing did not become a "submission" until June 28 2002, and, therefore, was filed after the service of the NOA on Bayer on April 27, 2002. Therefore, Bayer argues that Apotex failed to comply with the timing requirements set out in s.5(3)(c)(i).
[16] In order to determine whether Apotex has complied with the timing requirements set out in s.5(3)(c)(i), it is first necessary to determine the legal force and effect of a "notifiable change", and then to determine whether the modification of an abbreviated new drug submission by way of notifiable change is a "submission for a NOC" within the meaning of s.5 of the NOC Regulations.
[17] Bayer relies on the Management of Drug Submissions Policy, Therapeutic Products Directorate ("Management of Drug Submissions Policy") to argue that if a notifiable change is deficient upon filing, it does not constitute a "submission for a NOC" until all appropriate documents are filed and are accepted for review by the Minister.
[18] The stated purpose of the Management of Drug Submissions Policy is to outline the way in which the Therapeutic Products Directorate will manage information and material submitted by sponsors in accordance with the Food and Drugs Act, R.S. 1985, c. F-27 and the Food and Drug Regulations. The policy applies "to all submission types", including notifiable changes.
[19] The Management of Drug Submissions Policy reads in part as follows (note that "notifiable change" is abbreviated as "NC"):
2.1 Acceptable Original Information and Material
If original information and material is found to be acceptable on screening, it will be accepted for review and considered to be a submission. All submission types will be considered workload from the date of acceptance.
For NDSs, SNDs, ANDs, SANDSs, NCs, and those DINAs with a submission fee greater than $10,000 the sponsor will be notified of the acceptability by mail.
The date of acceptance for INDs will be considered the date of receipt in the Therapeutic Products Directorate, provided the information and material is accepted on screening. The days allocated to the screening of INDs are considered part of the days allocated for the submission review.
2.2 Unacceptable Original Information and Material
If deficiencies are identified during screening of original information and material the sponsor will be issued a Screening Deficiency Notice identifying the deficiencies. The sponsor will be required to submit all of the requested information and material identified in the Screening Deficiency Notice, within 45 calendar days from the date of request. As a general rule, submissions containing interim analyses of pivotal trial data or safety studies will be considered deficient on screening (unless otherwise specified in 3.2.2).
If the sponsor fails to provide all requested information within 45 calendar days, or the submitted information is incomplete, deficient or contains unsolicited information, the original information and material will be rejected and returned to the sponsor at the sponsor's expense. A Rejection Letter will be issued by the Therapeutic Products Directorate. If the sponsor wishes to resubmit the information and material at a future time, it will be processed as new information and material, and will be assigned a new control number.
After receipt of the information requested in the Screening Deficiency Notice, a new screening period commences (with a new performance target), and the requested material and information will be screened for completeness. The original information and material will be considered a submission when all requested information is found to be acceptable. The sponsor will be notified of the acceptability as delineated in 2.1.
DINAs may be rejected during screening for several reasons, without the issuance of a Screening Deficiency Notice. e.g. if an NDS is required, if a proposed ingredient is a prohibited substance, or if a monograph attestation is found not to reflect the submission content. If the sponsor wishes to resubmit the information at a future time, it will be processed as new information and material and will be assigned a new control number. [Emphasis added]
(Application Record (A.R.), v. V, 9F, pp. 865-866)
[20] Thus, on the basis of the emphasised statements in the passage just quoted, Bayer argues that there is no "submission" until Health Canada gives its approval to the filings made. Bayer argues that the Management of Drug Submissions Policy and the NOC Regulations are linked and, therefore, the definition of "submission" in the Management of Drug Submissions Policy and the definition of "submission for a NOC" in s.5 of the NOC Regulations are the same, and both definitions include a notifiable change; thus, "a notifiable change" is a "submission" that modifies a pre-existing submission for a notice of compliance".
[21] The term "submission for a notice of compliance" is not defined in the NOC Regulations, however s.2 does define "notice of compliance" as "a notice under section C.08.004 of the Food and Drug Regulations."
[22] Section C.08.004 of the Food and Drug Regulations provides that a NOC shall be issued after a review of a "new drug submission", an "abbreviated new drug submission", or a "supplement" to a new drug submission or to an abbreviated new drug submission, and a determination that the submission or supplement complies with other requirements in the Food and Drug Regulations. As Apotex argues, a notifiable change is not mentioned in the Food and Drug Regulations, and in particular, in Division 8, which pertains to "new drugs"; that is, a NOC is only issued in respect of a new drug submission, an abbreviated new drug submission, or a supplement to either of those.
[23] Subsection C.08.002(1) of the Food and Drug Regulations provides that no person shall sell or advertise a new drug unless the manufacturer of the new drug has filed with the Minister a new drug submission or an abbreviated new drug submission that is satisfactory to the Minister and has been issued a NOC in respect of the new drug submission or abbreviated new drug submission.
[24] Section C.08.003 of the Food and Drug Regulations addresses the situation where a NOC has been issued to a manufacturer, but where the manufacturer must file with the Minister a supplement to the new drug submission or a supplement to the abbreviated new drug submission, and a notice of compliance must be issued in response to the supplementary submission before the new drug can be sold (See Apotex Inc. v. Canada (Minister of Health) (1999), 87 C.P.R. (3d) 271 (F.C.T.D.) affd (2001), 11 C.P.R. (4th) 538 (F.C.A.)).
[25] The expression "notifiable change" does not appear in the Food and Drug Regulations, nor is it found in the NOC Regulations. The only mention of "notifiable change" important to the present application is in the policy guidelines of the Management of Drug Submissions Policy. In my opinion, this distinction means that a notifiable change is merely a notice-giving document required for administrative purposes by Health Canada. Therefore, I find that a notifiable change has no force and effect in law.
[26] Further support for Apotex' argument that the definition of a "submission for a NOC" within the meaning of s.5 of the NOC Regulations does not include a notifiable change is found in a line of authority concluding that the expression "submission for a NOC" as used in s.4 and s.5 of the NOC Regulations means, only, a new drug submission, an abbreviated new drug submission, and a supplement to a new drug submission or to an abbreviated new drug submission.
[27] In Apotex Inc. v. Canada (Minister of Health) (1999), 87 C.P.R. (3d) 271 (F.C.T.D.) affd (2001), 11 C.P.R. (4th) 538 (F.C.A.) at para. 36, Justice McGillis defined the term "submission for a NOC" as follows:
In considering the expression "submission for a NOC" in sections 4 and 5 of the Patented Medicines (Notice of Compliance) Regulations, the mechanisms which trigger the issuance of a notice of compliance are, by virtue of the definition of "notice of compliance" in section 2, those specified in section C.08.004 of the Food and Drug Regulations, namely a new drug submission, an abbreviated new drug submission, and a supplement to a new drug submission or to an abbreviated new drug submission. In the circumstances, the expression "submission for a NOC" in sections 4 and 5 of the Patented Medicines (Notice of Compliance) Regulations, means a new drug submission, an abbreviated new drug submission, and a supplement to a new drug submission or to an abbreviated new drug submission.
[28] While the main issue before Justice McGillis was whether a supplement to a new drug submission constitutes a "submission for a NOC" within the meaning of s.4, she analysed, in a comprehensive manner, the legislative scheme contained in the Food and Drug Regulations and the NOC Regulations and arrived at the conclusion that the definition of the expression "submission for a NOC" is the same for both s.4 and s.5 of the NOC Regulations.
[29] Justice McGillis was quoted with approval by Justice Russell in Glaxo Smith Kline Inc. v. Apotex Inc. 2003 FC 1055 at para. 46, as follows:
In the circumstances, the expression "submission for a Notice of Compliance", as used in Sections 4 and 5 of the Regulations means a new drug submission, an abbreviated new drug submission and a supplement to a new drug submission or to an abbreviated new drug submission as was clearly established in Apotex Inc. v. Canada (Minister of Health) (1999), 87 C.P.R. (3d) 271 at 287 (F.C.T.D.), affirmed (2001), 11 C.P.R. (4th) 538 (F.C.A.)
[30] In Bristol Myers Squibb Co. v. Canada (Attorney General) (2003), 24 C.P.R. (4th) 417 (F.C.A.) at para. 15, the Federal Court of Appeal cited with approval another decision of Justice McGillis (Merck & Co. v. Canada (Attorney General) (1999), 176 F.T.R. 21 at para. 59 (T.D.), affd (2000), 5 C.P.R. (4th) 138 (F.C.A.)) and held that, for the purposes of s.5(1.1) of the NOC Regulations, "submission" means a new drug submission, an abbreviated new drug submission, or a supplement to either.
[31] In Merck & Co. v. Canada (Attorney General), supra, Justice McGillis considered whether s.5(1) of the NOC Regulations requires a generic manufacturer to provide an allegation and, in particular, whether the generic manufacturer Nu-Pharm had filed a submission for a NOC comparing its drug product to a drug product marketed in Canada by a first person pursuant to a NOC for which a patent list had been filed. Justice McGillis held at para. 59 that the expression "submission for a notice of compliance" in s.5 of the NOC Regulations "means a new drug submission, an abbreviated new drug submission, and a supplement to either of those submissions."
[32] Given this line of authority, together with my finding that a notifiable change has no force and effect in law, I find that a notifiable change is not a "submission for a NOC" within the meaning of s.5 of the NOC Regulations and cannot trigger s.5(3)(c)(i). Thus, I find that the requirement in s.5(3)(c)(i) that a submission for a NOC be issued prior to, or at the same time as, the service of a non-infringement NOA does not apply to a notifiable change.
[33] The evidence is clear that Apotex originally filed its Abbreviated New Drug Submission for ciprofloxacin in 1993 and subsequently filed its NOA respecting the present application on April 27, 2002. On the basis of the analysis just concluded, I find that this Abbreviated New Drug Submission is the "submission for a NOC" contemplated by s.5, and it is this new drug submission which fulfils the requirement that a "submission for a NOC" be on file with the Minister before, or at the same time as, the service of a non-infringement NOA.
[34] Therefore, my answer to the question posed in this section of these reasons is "no".
B. Has Apotex failed to comply with s.5(3)(c)(i) because its NOA does not "relate to" its submission for a NOC?
[35] Unders.5(3)(c)(i), where a second person, in this case Apotex, has filed a submission for a NOC, and the person alleges non-infringement, that person is required to serve on the first person, in this case Bayer, a NOA "relating to"the submission for a NOC filed with the Minister. Bayer correctly states that Apotex' Abbreviated New Drug Submission contains a previously-prohibited process, and does not contain the current Apotex process which is the subject of Apotex' NOA in the present proceedings. Therefore, Bayer submits that Apotex' Abbreviated New Drug Submission is not "related to"its NOA as the Abbreviated New Drug Submission does not contain the entire basis for Apotex' non-infringement allegation. Bayer contends that as Apotex' NOA does not "relate to" its New Drug Submission, Apotex has failed to comply with s.5(3)(c)(i).
[36] This issue has been addressed in AB Hassle v. RhoxalPharma Inc. (2002), 21 C.P.R. (4th) 298, wherein the Applicants argued that RhoxalPharma had failed to comply with s.5(3)(c)(i) of the NOC Regulations because it did not have a submission filed with the Minister that "related to" its non-infringement NOA. The Applicants had contended that it was incumbent on the Court to ensure that RhoxalPharma's new drug submission, upon which the prohibition proceeding was based, fully corresponded to the NOA before the Court. Justice Gibson rejected the Applicant's argument on this point and held as follows at para. 31:
...I favour the position advocated by counsel for RhoxalPharma. If those who framed the relevant amendments to the Regulations on which the Applicants rely had intended to place an obligation on this Court to satisfy itself of the concordance between an underlying new drug submission and a relevant notice of allegation, they could have done so much more clearly and directly. It is worthy of note that the amended Regulations place no onus on a second person such as RhoxalPharma to file its new drug submission with this Court and that the authority of the Court to order production of relevant portions of a new drug submission is discretionary, not mandatory where a first person such as the Applicants here seeks such production. I regard the interpretation of the amendments to the Regulations that counsel for the Applicants urges on the Court as imaginative, but unduly strained.
[37] Although Bayer submits that I am not bound by Justice Gibson's reasoning and I should find to the contrary, I can find no serious reason to do so. Indeed, I agree with Justice Gibson's finding.
[38] Therefore, my answer to the question posed in this section of these reasons is "no".
[39] Accordingly, I find that Apotex has complied with s.5 of the NOC Regulations, and this Court has jurisdiction to render a decision on the merits.
II. The Non-Infringement Question
A. Principles of patent construction
[40] While the purpose of these proceedings is not to decide whether the '067 patent has been infringed, the approach that has been adopted in similar cases considers established patent infringement considerations (see Janssen Pharmaceutica Inc. v. Apotex Inc. (2000), 5 C.P. R. (4th) 53 at para. 59 (F.C.T.D.), affd [2002] 1 F.C. 393 (F.C.A.)).
[41] The first objective in deciding whether a patent has been infringed is to construe the claims of the patent to determine what exactly lies within the scope of the monopoly granted by the patent. Once that has been determined, the second objective is to consider whether, for example, an impugned pharmaceutical process falls within the scope of the claims (for the principle see: Mobil Oil Corp. et al. v. Hercules Canada Inc. (1995), 63 C.P.R. (3rd) 473 at 489 (F.C.A.)). Determining the scope of a patent involves giving it a purposive construction (Catnic Components Ltd. v. Hill & Smith Ltd., [1989] R.P.C. 183 at 242-243 (H.L.)). In Free World Trust v. Électro Santé Inc. , [2000] 2 S.C.R. 1024, Justice Binnie explored the principles of patent construction at paras. 14-15 as follows:
Patent claims are frequently analogized to "fences" and "boundaries", giving the "fields" of the monopoly a comfortable pretense of bright line demarcation....
...
In reality, the "fences" often consist of complex layers of definitions of different elements (or "components" or "features" or "integers") of differing complexity, substitutability and ingenuity. A matrix of descriptive words and phrases defines the monopoly, warns the public and ensnares the infringer. In some instances, the precise elements of the "fence" may be crucial or "essential" to the working of the invention as claimed; in others the inventor may contemplate, and the reader skilled in the art appreciate, that variants could easily be used or substituted without making any material difference to the working of the invention. The interpretive task of the court in claims construction is to separate the one from the other, to distinguish the essential from the inessential, and to give to the "field" framed by the former the legal protection to which the holder of a valid patent is entitled. [Emphasis added]
[42] The significance of distinguishing essential from non-essential elements is that the substitution or omission of an essential element of a patent invention will defeat an allegation of infringement, whereas the substitution or omission of a non-essential element will not necessarily foreclose a patentee's claim of infringement (see Janssen, supra at paras. 46-47).
[43] The claims of a patent are to be read from the perspective of a person skilled in the art to whom the patent is addressed, and who applies his or her knowledge in the field to which the patent relates (Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 at paras. 48, 52-53). In the present proceedings, a person skilled in the art is someone who has advanced knowledge in the field of organic chemistry.
B. The evidence on construction of the '067 patent
[44] The '067 patent is a product by process patent, as was required by s.39(1) of the Patent Act, R.S.C. 1985, c. P-4 (the "Patent Act") when the Patent was issued in 1987. At the relevant time, s.39(1) read as follows:
39.(1) In the case of inventions relating to substances prepared or produced by chemical processes and intended for food or medicine, the specification shall not include claims for the substance itself, except when prepared or produced by the methods or processes of manufacture particularly described and claimed or by their obvious chemical equivalents.
39.(1) Lorsqu'il s'agit d'inventions portant sur des substances préparées ou produites par des procédés chimiques et destinées à l'alimentation ou à la médication, le mémoire descriptif ne peut comprendre les revendications pour la substance même, sauf lorsque la substance est préparée ou produite par les modes ou procédés de fabrication décrits en détail et revendiqués, ou par leurs équivalents chimiques manifestes.
[45] As stated in the '067 patent, the Patent relates to 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acids, to a process for their production, and to their use in feed additives and as antibacterial agents; "1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid" is the chemical name for ciprofloxacin.
[46] The last of three claimed steps in the '067 patent is the reaction of piperazine and "7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid"; the latter compound is abbreviated to "6-FQA". This third step is embodied in claims 1, 8, 10 and 14, which are the only claims at issue in the present proceedings. Claims 1, 8, 10 and 14 are best understood by reference to the written and diagrammatic descriptions in the '067 patent cited in Appendix I to these reasons.
[47] Claims 1 and 10 disclose the process itself, while claims 8 and 14 are product by process claims for the compound ciprofloxacin as prepared by the process defined in the process claims, or an "obvious chemical equivalent thereof". Claim 8 of the Patent claims ciprofloxacin (and three other compounds), as made by the process of claim 1 or an obvious chemical equivalent of this process ("claim 8(1)"). Where R is a hydrogen atom, the compound of this formula is ciprofloxacin. Claim 14 is a claim specifically for ciprofloxacin, when made by the process of claim 10 (or two other processes) or an obvious chemical equivalent of this process ("claim 14(10)"). For the purpose of making ciprofloxacin, claim 8(1) and claim 14(10) are effectively the same and are referred to as the "Bayer process"; in argument, counsel for Bayer focussed primarily on claim 14(10).
[48] Both Bayer and Apotex adduce the evidence of expert witnesses with respect to construction of the '067 patent, and the nature of both the Bayer and the Apotex processes for producing ciprofloxacin. The professional qualifications of these experts are detailed in Appendix II. On behalf of Bayer, Dr. Overman filed two Affidavits: one sworn August 5, 2002 (A.R. v. 1, p. 12), and another sworn December 11, 2002 (A.R. v. 1, p. 151). Dr. Wuest filed an Affidavit sworn September 5, 2002 (A.R. v. IV, p. 602). On behalf of Apotex, Dr. McClelland filed two Affidavits: one sworn October 18, 2002 (A.R. v. VIII, p. 1751), and another sworn January 10, 2003 (A.R. v. IX, p. 2074). Finally, Dr. Meth-Cohn filed two Affidavits: one sworn October 18, 2002 (A.R. v. X, p. 2264), and another sworn January 21, 2003 (A.R. v. XI, p. 2525).
1. The interaction between piperazine and 6-FQA
[49] Bayer argues that the Patent has wide scope. Dr. Overman, in the August 5, 2002
Affidavit at para. 15, and Dr. Wuest, in the September 5, 2002 Affidavit at para. 14, share the opinion that claims 8(1) and 14(10) describe and claim a process by which hydrogen from the piperazine compound, and chlorine from the 6-FQA, are eliminated thereby forming a bond between the piperazine compound and 6-FQA. Apotex argues that the process in the Patent requires a fully built, or intact piperazine and a fully built, or intact 6-FQA.
[50] In cross examination, Bayer's expert Dr. Overman agreed that the relevant claims describe piperazine being added to an otherwise fully-built molecule to make ciprofloxacin:
173 Q. Dr. Overman, with respect to the '067 patent, I wanted to ask you whether you would agree with me that in each instance, either in the disclosure or in the claims where ciprofloxacin is made as illustrated or described, piperazine is added to an otherwise fully-built molecule to make ciprofloxacin?
A. Are you referring specifically and only to ciprofloxacin or in the '067 patent, ciprofloxacin is among the compounds that are referred to in the patent?
174 Q. Let's begin with ciprofloxacin.
A. I believe it is true.
(A.R. v. XIII, Tab 25, p. 2884, questions 173-174)
He further answered that an intact piperazine is used in the process claimed in the '067 patent:
192 Q. Still with the '067 patent, can you tell me whether there is any discussion or illustration of the building of the piperazine moiety or whether in all instances the piperazine moiety that is employed is intact?
A. The piperazine moiety that is employed, the piperazine or substituted piperazine is intact at the time of use.
(A.R. v. XIII, Tab 25, p. 2885, question 192)
[51] Therefore, on Dr. Overman's evidence, I find that both the piperazine and the 6-FQA must be fully built.
[52] A second dispute exists as to whether piperazine is essential to Bayer's process claims. On this point, in cross-examination, Dr. Wuest analyzed "example 4", which is an example in the disclosure of the '067 patent, to make the point that piperazine is not essential:
109 Q. Can you just tell me whether any of these examples illustrate the making of the compounds which are the subject of the invention, the compounds of Formula I, and if so, whether they illustrate that by utilization of compound II reacted with piperazine or piperazine derivatives?
A. My reading of the examples is that all of them refer to compounds of the invention, that is of general type I, and they all involve reactions of 6-FQA with a piperazine or piperazine derivative, except possibly Example 4 which I will have to look at more carefully because I am not quite sure what it talks about just yet.
110 Q. Okay
- A Short Pause
A. Example 4 relates to compounds of type I, but I do not see a reaction in which 6-FQA is made to react with a piperazine.
111 Q. Am I not correct that Example 4 in its starting materials starts with ciprofloxacin as one of the reactants?
A. Yes, it does.
112 Q. This is an example that actually starts with a compound that is within the compounds of the invention and then is manipulated in a way to alter it by altering one of the substituents on the piperazine group. Is that right.
A. That is true, although as far as I can tell in my reading of Example 4, it does not say how the ciprofloxacin was obtained.
113 Q. Right.
A. It could have been by a different route altogether.
114 Q. It is silent on the route by which the starting material for Example 4, one of the starting materials, cipro, was prepared.
A. Exactly.
115 Q. Then having looked through the entire disclosure, am I right that the only discussion and the only illustrations of the making of the compounds of Formula I, the process by which that is illustrated and discussed in each instance involves a 6-FQA compound or derivative reacted with piperazine or a piperazine derivative?
MR. BELLMORE: How are you defining "derivative" when you use that term in relation to either piperazine and 6-FQA?
MR. RADOMSKI: Compound II is COOR1, so it is whatever is permitted for R1 as part of compound II and for piperazine or piperazine derivative. Those are the words that are used by the disclosure on page 2 at the top. That is all I meant by my choice of the words -
THE WITNESS: I have become confused by what your question is. Would you mind repeating it, please?
116 Q. Not at all. Having now gone through the disclosure, my question is, am I right that the only process or processes that are discussed and illustrated are those which involve compound II, 6-FQA or its derivative, and piperazine or a piperazine derivative?
A. If you are limiting yourself to what is explicitly disclosed in the '067, I would agree with you. However, it is my understanding that someone of normal skill in the art would recognize that if this particular reaction can be carried out with piperazine, then conceivably it could also be carried out with ammonia itself by the same type of substitution reaction, and the NH2 group that results from that could be converted by conventional chemistry into a piperazine. That is one of the things that would occur to a reader of '067 of normal skill in the art because we do not know exactly how the ciprofloxacin in Example 4 was made. It seems to me that that leaves open the possibility that some alternative route was actually used for its construction.
...
120 Q. What you describe for me, though, takes 6-FQA or one of its derivative compounds with chlorine at the 7 position and then reacts that with ammonia and then requires further manipulation in order to convert the 7 position into a piperazine having had ammonia at that position in place of the chlorine. Is that correct?
A. I think that is a possibility suggested immediately to someone of normal skill in the art who reads '067.
(A.R. v. XII, Tab 24, pp. 2676-77, questions 109-116 and 120)
It appears from this evidence that Dr. Wuest did not know how ciprofloxacin is formed through the example, but he postulated one alternative whereby the same type of reaction could be carried out with ammonia, instead of piperazine, which could then be converted into piperazine by conventional chemistry.
[53] In oral argument, counsel for Bayer referred to this ammonia reaction to show that the '067 patent covers not only piperazine reacting with 6-FQA, but also something that becomes piperazine. Counsel for Apotex, however, pointed out that Dr. Wuest did not assert that either Bayer's or Apotex' process uses chemistry similar to this "ammonia reaction." Apotex argued that while Dr. Wuest claimed that this "ammonia reaction" is based upon Example 4 of the '067 patent, this example does not make ciprofloxacin, let alone mention ammonia, and is, therefore, not relevant to the present case (Exhibit R-3, "Response to Bayer Hand-ups", p. 7).
[54] I give weight to Apotex' argument and find that piperazine is essential.
2. The nature of the nucleophilic substitution reaction
[55] Dr. Wuest states that the reaction of 6-FQA with piperazine in the Bayer process is a nucleophilic substitution reaction (September 5, 2002 Affidavit at para. 25, and cross-examination, A.R. v. XII, Tab. 24, p. 2680, question 149). On cross-examination, Dr. Wuest responded to questioning regarding the nucleophilic substitution reaction as follows:
146 Q. That nucleophilic substitution, as per what Mr. Belmore said, is more particularly described as a nucleophilic aromatic substitution. Would you agree with that?
A. It is described in the paragraph you referred me to in Exhibit J to nucleophilic substitution.
147 Q. Right, and I am asking you whether that is more particularly described, the substitution that occurs, 6-FQA plus piperazine, as a nucleophilic aromatic substitution?
A. It could be done that way because the leaving group is attached to an aromatic ring.
148 Q. I don't know what you mean by "it could be done that way", but that is in fact what happens; right? The leaving group is attached to an aromatic ring and, hence, the reaction is more particularly described as a nucleophilic aromatic substitution. Is that right?
A. It could be done that way.
149 Q. I don't know what you mean by "it could be done that way". I am asking you whether that descriptor, "nucleophilic aromatic substitution", correctly describes what occurs when you react 6-FQA with piperazine. Is that a nucleophilic aromatic substitution?
A. It is a aromatic substitution because a group that serves as a leaving group is displaced in a reactio