Docket: T-1847-02
Ottawa, Ontario, this 10th day of August, 2005
Present: THE HONOURABLE JUSTICE von FINCKENSTEIN
BETWEEN:
ABBOTT LABORATORIES
and ABBOTT LABORATORIES LIMITED
Applicants
and
THE MINISTER OF HEALTH
and RATIOPHARM, A DIVISION OF RATIOPHARM INC.
Respondents
REASONS FOR ORDER AND ORDER
(Public Version)
[1] This is an application brought by Abbott for an order prohibiting the Minister of Health from issuing a Notice of Compliance ("NOC") to Ratiopharm for the production of Clarithromycin 250 or 500 mg because such production would infringe Canadian Patent No. 2,261,732 (the " '732 patent") held by Abbott. The active medicinal ingredient in these tablets is 6-O-methylerythromycin A Form II (also referred to as Clarithromycin Form II).
[2] Abbott also brought a separate application (Court File T-1656-03) for an order prohibiting the Minister of Health from issuing a NOC to Ratiopharm for the production of Clarithromycin 250 or 500 mg tablets because such production would infringe Canadian Patent Nos. 2,258,606 (" '606 Patent"), 2,386,527 (" '527 Patent" ), 2,277,274 (" '274 Patent" ), 2,386,534 (" '534 Patent"), 2,387,361 (" '361 Patent") and 2,387,356 (" '356 Patent") held by Abbott. While these two applications were heard together and involve the same parties, they are based on different records and therefore separate reasons were issued with respect to the applications based on the application record for the '606, '527, '274, '534, '361 and '356 patents. Any evidence contained in Court File T-1656-03 could not be referred to in Court File T-1847-02 and vise versa.
Nature of Proceedings
[3] These proceedings were started under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the "NOC Regulations"). The nature of these proceedings was summarized by Layden Stevenson J. in Fournier Pharma Inc. v. Canada (Minister of Health), 2004 FC 1718 as follows:
6 As noted, this proceeding is brought under the Regulations. The history and scheme of the Regulations have been delineated in various decisions of the Federal Court of Appeal and need not be repeated here. See: Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.); AB Hassle v. Canada (Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.); Novartis AG et al. v. Abbott Laboratories Ltd. et al. (2000), 7 C.P.R. (4th) 264 (F.C.A.). Basically, issues of non-infringement and validity between the patent holder (first person) and the person seeking a NOC from the Minister (second person) originate with a NOA, served on the first person by the second person, setting out the second person's allegations, including the legal and factual basis in support. The first person may disagree and apply to the court for an order prohibiting the Minister from issuing a NOC to the second person until after expiration of the patent. (...)
8 Section 6 proceedings are not to be likened to actions for determining validity or infringement. They are proceedings in judicial review, to be held expeditiously, whose aim is to determine whether the Minister is free to issue the requested NOC. Their scope is confined to administrative purposes: Apotex Inc. v. Canada (Minister of National Health and Welfare) (1997), 76 C.P.R. (3d) 1 (F.C.A.). The determination must turn on whether there are allegations by the second person sufficiently substantiated to support a conclusion for administrative purposes (the issuance of a NOC) that an applicant's patent would not be infringed if the second person's product is put on the market: Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 (F.C.A.).
9 By merely commencing the proceeding, the applicant obtains what is tantamount to an interlocutory injunction without having satisfied any of the criteria a court would require before enjoining issuance of a NOC: Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1998), 80 C.P.R. (3d) 368 (S.C.C.); Bristol-Myers Squibb Canada Inc. v. Canada (Attorney General) (2001), 11 C.P.R. (4th) 539 (F.C.A.). The Regulations allow a court to determine summarily, on the basis of the evidence adduced, whether the allegations are justified. Section 6 proceedings are not adjudicative and cannot be treated as res judicata. The patentee is in no way deprived of all the recourses normally available to enable it to enforce its rights. If a full trial of validity or infringement issues is required, this can be obtained in the usual way by commencing an action: Pfizer Canada Inc. v. Apotex Inc. (2001), 11 C.P.R. (4th) 245 (F.C.A.); SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001), 14 C.P.R. (4th) 76 (F.C.T.D.) aff'd. (2002), 21 C.P.R. (4th) 129 (F.C.A.); Novatis A.G. v. Apotex Inc. (2002), 22 C.P.R. (4th) 450 (F.C.A.)
[4] As to the findings the court must make, these were stated succinctly by Harrington J. in Biovail Pharmaceuticals Inc. v. Canada (Minister of National Health and Welfare), [2005] F.C.J. No. 7 at paragraph 10 as follows:
The only question is whether the Court should grant an order prohibiting the Minister from issuing Novopharm an NOC until after the expiration of one or both of the two underlying patents. Subject to the comment above as to the limited nature of the proceeding, it is inherent in a decision to grant a prohibition order that the Court form the view that Novopharm's allegations are not justified, i.e. the Court must form the view that the patents are valid and that Novopharm would infringe them. There must be a finding on both points. However, if the Court refuses to grant a prohibition order, it must have formed the view that Novopharm would not infringe or that the patents are invalid. It is not necessary to find on both points. (Underlining added)
[5] In this case, Ratiopharm served Abbott with a Notice of Allegation ("NOA"), which delimits the scope of the issues to be decided. Abbott, as the Applicant, must disprove Ratiopharm's allegations that the '732 Patent is invalid or that Ratiopharm's production of Clarithromycin Form II will not infringe the '732 Patent.
Experts
[6] As in all litigation under the NOC Regulations, there were several expert opinions in evidence throughout the hearing of this matter. Harrington J. described the role of expert witnesses in Biovail Pharmaceuticals, supra, at paragraph 16 as follows:
Expert evidence presented to a court should be the independent product of the expert uninfluenced as to form or content by the exigencies of litigation. The expert should provide independent assistance to the Court (National Justice Companion Riviera SA v. Prudential Assurance Co. Ltd. [1993] 2 Lloyd's Rep. 68, reversed on other grounds, [1995] 1 Lloyd's Rep. 455, and Merck Frosst Canada Inc. v. Apotex Inc. and Minister of Health, [2004] F.C.J. No. 684, 2004 FC 567, at paragraph 16.)
Abbott Experts
Dr. Atwood is a professor and Chairman of the Department of Chemistry at the University of Missouri-Columbia. He holds a Ph.D. in chemistry from the University of Illinois and has held and holds numerous editorial positions. He has published over 500 articles in refereed journals and has authored nine patents. The Court has recognized him as an expert in the fields of crystal growth, crystal engineering and polymer chemistry.
Dr. Myerson is a professor of chemical engineering and Provost and Senior Vice-President at the Illinois Institute of Technology in Chicago. Previous to that, he served as Professor of Chemical Engineering and Dean of the Armour College of Engineering and Science at the Illinois Institute of Technology. He holds a Ph.D. in chemical engineering from the University of Virginia and has edited five books and published approximately 120 papers in refereed journals, many of which deal with crystallization and related subjects. The Court has recognized him as an expert in the fields of chemical engineering and crystallization, including industrial crystallization and polymorphism.
Dr. Byrn is the head of the Department of Industrial and Physical Pharmacy at Purdue. He holds a Ph.D. in chemistry from the University of Illinois and has authored over 100 peer-reviewed publications in technical journals on topics relating to solid-state chemistry and is co-author of a book entitled Solid Chemistry of Drugs. The Court has recognized him as an expert in pharmaceutical chemistry, sold-state chemistry, industrial pharmacy, polymorphism, analytical techniques and crystallization.
Ratiopharm Experts
Dr. Clive is a professor in the Department of Chemistry at the University of Alberta. He holds a Ph.D. from Imperial College, D.H.R., Barton in organic chemistry and is the author or co-author of 159 publications, principally in the area of chemical synthesis and synthetic methods. The Court has recognized him as an expert in the areas of organic synthesis (the construction of complex organic compounds, usually natural products with important medical or biological properties) and the development of new synthetic methods.
Dr. Lee-Ruff is a professor of chemistry at York University. He holds a Ph.D. in organic chemistry from McGill University and has authored or co-authored 111 publications. The Court has recognized him as an expert in synthetic and mechanistic organic chemistry and, more particularly, works in areas involving methods developed in organic synthesis and physical organic chemistry.
Dr. Petrov is a research associate at the Department of Chemistry, University of Toronto who has been involved in crystallography for the past 30 years. He holds a Ph.D. in mineralogy and crystallography from Sofia University in Bulgaria. The Court has recognized him as an expert in crystallography and the use of x-ray powder diffraction (XRPD or PXRD) as a method of analysis.
The qualification of both parties' experts was not in issue, however the varying weight to be assigned to their testimony was argued by both sides.
Preliminary Issue
[7] The first step in any patent case involves the construction of the patent. In paragraph 34 of its Memorandum of Fact and Law, Abbott has limited its case in this matter to claim 15 of the '732 patent. During oral argument, Abbott asked for permission to retreat from that position to also include claim 20. Without claim 20, Abbott would solely be arguing for a process, and thus would be outside the scope of the NOC Regulations (see Deprenyl Research Ltd. v. Apotex Inc., [1994] F.C.J. No. 542). As Ratiopharm addressed all issues regarding a product by process patent and as it is obvious that the retreat in paragraph 34 was merely an oversight, (after all, Abbott would have no claim if it only relied on the process claim in claim 15, given that process claims cannot be addressed under the NOC Regulations,) the Court granted such permission.
[8] Thus, in order to deal with this case, this Court must construe claims 15 and 20 of the '732 Patent. Claim 15 refers to claim 2, which refers to claim 1. Attached hereto as Annex A are:
a) The relevant parts of the patent disclosure, entitled Summary of the Invention and Reference Example as well as
b) Claims 1, 2, 15 and 20.
Burden
[9] The required burden of proof was succinctly set out in Biovail Pharmaceuticals, supra, where Harrington J. stated at paragraphs 12 and 13:
Much has been said with respect to the burden of proof as to patent validity. The burden is on Biovail to disprove Novopharm's assertions as set forth in its Notice of Allegation. Like any plaintiff or applicant, Biovail has the overall legal burden of proof. However, since the purpose of the application is to disprove Novopharm's allegations, rather than to prove its own allegations, Novopharm, as respondent, has an obligation to put the allegations set out in its notice "in play". Obviously, it knows better than Biovail what it intends to do and how it will go about it. There is also a rebuttable presumption that a patent is valid. See for example Merck Frosst Canada Inc. v. Canada (Minister of National Health & Welfare), [1994] 55 C.P.R. (3d) 302 FCA, and the recent commentary thereon by Mosley J. in Janssen - Ortho Inc. et al. v. Novopharm Ltd., et al., [2004] F.C.J. No. 1968, 2004 FC 1631, at paragraphs 13 and following, as well as Pfizer Canada Inc. v. Canada (Minister of Health), 2004 FCA 402, [2004] F.C.J. No. 2033 (QL) per Sharlow J.A. at paragraph 8.
[10] With respect to the rebuttable presumption that a patent is valid, Rothstein J.A. stated in Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health) [2004] FCJ No. 1973 at paragraphs 15 and 16:
Noël J., in Glaxo, relied on this Court's decision in Bayer v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285 (F.C.A.) which, on this point, is the governing authority. In Bayer, Sharlow J.A. dealt with the burdens of proof on the patentee and the generic in proceedings under the Regulations. She explained that the patentee, being the applicant for the order of prohibition, bears the burden of establishing its entitlement to the order sought. Subsection 43(2) of the Patent Act, R.S., c. P-4, s. 1, as amended, provides that, "After the patent is issued, it shall, in the absence of any evidence to the contrary, be valid and avail the patentee..." Sharlow J.A. observed that because of that presumption of validity, the generic, as the party responding to the application for a prohibition order, has the burden of proof to displace the presumption.
As to the standard of proof, at paragraph 9, she wrote:
The operation of the statutory presumption in the face of evidence of invalidity depends upon the strength of the evidence. If the evidence proves, on a balance of probabilities that the patent is invalid, the presumption is rebutted and is no longer relevant. [Emphasis added.]
Therefore, the standard of proof applicable to proving invalidity has been found to be proof on a balance of probabilities.
[11] With regard to the burden of proof for non-infringement, Gauthier J. precisely summarized the issue in AstraZeneca v. Apotex [2004] F.C.J. No 1078 at paragraphs 72 and 73:
A proceeding under subsection 6(1) of the Regulations is not an action for infringement. In the present case, the Court does not have to determine whether or not the second person's product would infringe a valid patent. It only needs to determine whether the facts assumed or proven and the legal assertions made justify the specific allegation of non-infringement made by Apotex. (Hoffmann-La Roche Ltd. v. Canada (1996), 70 C.P.R (3d) 206 (F.C.A.) and Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) at p. 302).
This means that Astrazeneca has the burden of convincing the Court that the specific allegation of non-infringement contained in the NOA is unjustified. It need not otherwise prove that Apotex' tablet would infringe the '377 Patent because it contains all the essential elements of a claim in the said patent.
Patent Construction
[12] In Biovail Pharmaceuticals, supra, Harrington J. succinctly summarized the rules for patent construction at paragraph 15:
It is a pre-requisite to considerations of both patent validity and infringement that the language of what is claimed in the patent be properly considered. The Court can do no better than to take the same approach in an NOC proceeding, keeping in mind the restricted purpose of the proceeding. The Supreme Court has done much to codify and clarify patent claim construction in two recent cases handed down the same day: Free World Trust v. Électro-Santé Inc., [2000] 2 S.C.R. 1024 and Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067. The reasons in both were given by Mr. Justice Binnie. I take the following principles as having particular relevance to this case:
1. A patent is construed as a bargain between the inventor and the public. In consideration of disclosing the invention, the inventor is given a temporary monopoly to exploit it.
2. It is a statutory requirement that the patent contain a specification and end with a claim or claims "defining distinctly and in explicit terms the subject-matter of the invention for which an exclusive privilege or property is claimed". The specification must be sufficiently full, clear, concise and exact "as to enable any person skilled in the art or science to which it pertains, or to which it is most closely connected, to make, construct, compound or use it". (Patent Act, R.S.C. 1985, c. P-4, as amended, s. 27)
3. The patent is notionally addressed to a person skilled in the art or science of the subject-matter and is to be read as such a person would have read it when it first became public. (More will be said about this skilled reader.)
4. The claims are to be read in an informed and purposive way to permit fairness and predictability and to define the limits of the monopoly "[I]ngenuity of the patent lies not in the identification of the desired result but in teaching one particular means to achieve it. The claims cannot be stretched to allow the patentee to monopolize anything that achieves the desired result" (Free World Trust, paras. 31, 32).
5. The claim portion of the patent specification takes precedence over the disclosure portion in the sense that the disclosure is read to understand what was meant by a word in the claims "but not to enlarge or contract the scope of the claim as written and thus understood" (Whirlpool, para. 52).
6. It is only such novel features that the inventor claims to be essential that constitute the "pith and marrow" of the claim. "The key to purposive construction is therefore the identification by the Court with the assistance of the skilled reader, of the particular words or phrases in the claims that describe what the inventor considered to be the "essential" elements of his invention" (Whirlpool, para. 45).
7. Some elements of the claimed invention are essential and others are not, based either on common knowledge when the patent was published or according to the intent of the inventor, expressed or inferred from the claims. This lies at the heart of Biovail's position that Novopharm's allegation that it will not infringe the '320 patent is not justified. Put another way, was it obvious at the time the patent was published that the substitution of a variant would make a difference?
8. To overclaim is to lose everything. If the inventor underclaims, the court will not broaden the monopoly in the interests of the "spirit" thereof. This often, as in this case, results in layers of claims, each limitation serving as a potential safety net so that if the broadest claims fall, the monopoly may be saved in part by the more modest claims.
9. Yet a patent is not an ordinary writing. It meets the definition of a "regulation" in the Interpretation Act, and must be read to assure the attainment of its objects. "Claims construction is a matter of law for the judge, and he was quite entitled to adopt a construction of the claims that differed from that put forward by the parties." (Whirlpool, para. 52.)
[13] The person skilled in the art has been described by Binnie J. in Free World Trust v. Electro Sante Inc. (2000), 9 C.P.R. (4th) 168, at paragraph 44, as follows:
The courts have traditionally protected a patentee from the effects of excessive literalism. The patent is not addressed to an ordinary member of the public, but to a worker skilled in the art described by Dr. Fox as:
a hypothetical person possessing the ordinary skill and knowledge of the particular art to which the invention relates, and a mind willing to understand a specification that is addressed to him. This hypothetical person has sometimes been equated with the "reasonable man" used as a standard in negligence cases. He is assumed to be a man who is going to try to achieve success and not one who is looking for difficulties or seeking failure. [Fox, H.G. The Canadian Patent Law and Practice relating to Letters Patent for Inventions 4th ed Toronto: Carswell 169 at 184]
[14] Applying these rules to the '732 Patent and reading claims 1, 2, 15 and 20 as a person skilled in the art, informed by the disclosure of the patent would, the Court notes that:
1. This is a product by process patent. The product is designated as Clarithromycin Form II (also known as 6-O-methylerythromycin A) and can appear in Form 0, Form I or Form II. The disclosure reveals that it has known therapeutic effect as an antibacterial treatment for infections of the upper respiratory tract. Parenthetically, it was not disputed before me that this patent contains a claim for the medicine or the use of the medicine within the meaning of the NOC Regulations.
2. Claim 1 teaches a three step process for producing Clarithromycin Form II by:
a) converting erythromycin A to 6-O-methylerythromycin A;
b) treating 6-O-methylerythromycin A prepared in step a) with a solvent selected from a group of 12 solutions; and
c) isolating the Clarithromycin Form II crystals.
3. Claim 2 teaches an alternate route. It employs the same three step process as in claim 1 except that it substitutes for step 1(a) a four step process consisting of:
i) converting erythromycin A into an erythromycin A-9 oxime derivative;
ii) protecting some of the erythromycin A-9 oxime derivative prepared in step (i);
iii) reacting the product of step (ii) with a methylating agent; and
iv) deprotecting and deoxidating the product of step (iii) to form 6-O-methylerythromycin A.
Steps b) and c) remain the same as in claim 1.
4. Claim 15 builds on claim 2. It teaches the same three step process as claim 2 but in step b) of claim 2, it substitutes the use of 17 solvents in lieu of the use of 12 groups of solvents formerly prescribed in step b) of claim 2. Step c) of claim 2 (which is the same as step c) of claim 1) remains unchanged.
5. Claim 20 claims the product resulting from employing the process described in claim 15.
[15] The Court notes that 6-O-methylerythromycin A crystal Form II is not defined, nor are any of its characteristics provided anywhere in the claims. The disclosure informs us that Clarithromycin Form II is identified by three characteristics:
a) its infrared spectrum ("IR");
b) its differential scanning calorimetric thermogram ("DSC"); and
c) its powder x-ray diffraction pattern ("XRPD" or "PXRD").
Diagrams showing the IR, DSC and XRPD of Clarithromycin Form II are attached for illustration in the disclosure but are not referred to in the claims. The disclosure also points out that one of the key advantages of the invention is that it skips the step of converting Clarithromycin Form 0 to Clarithromycin Form I and instead provides a method of progressing from Clarithromycin Form 0 directly to Clarithromycin Form II, thereby requiring less heat.
[16] While a court should look at the disclosure to understand the patent, the disclosure should not be used to enlarge or contract the scope of the claim. As Binnie J. stated in Whirlpool Corp. v. Camco Inc., [2000] 2 S.C.R. 1067 at paragraph 52:
More recently, Hayhurst, supra, at p. 190, cautioned that "[t]erms must be read in context, and it is therefore unsafe in many instances to conclude that a term is plain and unambiguous without a careful review of the specification". In my view, it was perfectly permissible for the trial judge to look at the rest of the specification, including the drawing, to understand what was meant by the word "vane" in the claims, but not to enlarge or contract the scope of the claim as written and thus understood. (underlining added)
[17] Using the IR, DSC or XRPD to identify the product obtained from the process taught by the '732 Patent would violate this rule and would contract the claim as written and understood. Accordingly, the IR, DSC and XRPD will not be used by this Court to construe claims 1,2,15 and 20 of the '732 Patent.
Ratiopharm's Allegation
[18] The product by process described in claims 15 and 20 is the subject of this case. Ratiopharm alleges in its NOA that:
1) The patent is invalid as:
a) claim 15 lacks utility; it covers 17 solvents, yet there is proof that the use of five of the specified solvents will not result in Clarithromycin Form II;
b) it is anticipated by the prior use and sale of Abbott's drug BIAXIN which contains Clarithromycin Form II;
c) it is anticipated by the publication of a paper by Iwasaki; and
d) it is anticipated by the publication of a paper by Salem.
2) The Ratiopharm process does not infringe the '732 patent as:
e) the Ratiopharm process does not use a 9-oxime process; and
f) there is no proof that Clarithromycin Form II is used in the Ratiopharm process, and even if used, it is used only as an intermediary product and not a final product and the NOC Regulations do not apply to intermediate products.
[19] The issue for this Court to decide is if any of Ratiopharm's allegations can be disproven. If not, Abbott will not succeed in its application for a prohibition order. The Court will look at these issues in the order listed above.
Claim 15 - Invalidity by reason of lack of utility
[20] As mentioned above, Abbott has resiled to defend the '732 Patent by relying on claims 15 and 20. Claim 20 refers to Clarithromycin Form II, prepared according to the process described in claim 15. Claim 15 reads as follows:
A method according to Claim 2 wherein the solvent is selected from the group consisting of: acetone, heptane, toluene, methyl tert-butyl ether, N, N-dimethylformamide, ethyl acetate, xylene, isopropanol-water, tetrahydrofuran-water, ethanol-water, ethyl ether, amyl acetate, isopropyl acetate-methanol, diisopropyl ether, isopropyl butyrate, isopropylamine, and methanol-ethanol.
[21] Abbott, in its Memorandum of Fact and Law, retreated to the position that it only relies on claim 15 in respect of solvent A. It points to section 27(5) of the Patent Act which, in its view, allows it to assert claims in the alternative. Ratiopharm counters that claim 15 is a "Markush claim" and therefore it applies to all members of a genus and one cannot claim utility in respect of only one member. It is undisputed that the process in claim 15, when employing solvent A, results in Clarithromycin Form II as claimed.
[22] Section 27(5) of the Patent Act ( R.S. 1985, c. P-4 ) provides that:
27(1) The Commissioner shall grant a patent for an invention to the inventor or the inventor's legal representative if an application for the patent in Canada is filed in accordance with this Act and all other requirements for the issuance of a patent under this Act are met.
(...)
(5) For greater certainty, where a claim defines the subject-matter of an invention in the alternative, each alternative is a separate claim for the purposes of sections 2, 28.1 to 28.3 and 78.3.
[23] A Markush claim has been defined in the Manual of Patent Office Practice ("MOPOP") in Chapter 11 at Section 11.11 as:
In chemical cases, a claim directed to a genus expressed as a group consisting of
certain specified materials is allowable (Ex parte Markush 1925, 340 U.S.O.G. 839) provided it is clear from the known nature of the alternative materials or from the prior art that the materials in the group possess at least one property in common which is mainly responsible for their function in the claimed relationship. Therefore, a Markush claim will generally be construed with a generic expression covering a group of two or more different materials (elements, radicals, compounds) as illustrated in the following examples:
A solvent selected from the group consisting of alcohol, ether and acetone...
A strip of a conductive metal selected from the group consisting of copper, silver and aluminium...
Occasionally, the Markush format may be used in claims directed to subject matter in the mechanical or electrical fields in a manner such as that illustrated in the example below:
A means for attaching a wall panel to a framework wherein the attaching means is selected from group consisting of nails, rivets and screws... (underlining and emphasis from the original)
Further in Chapter 14, Section 14.03.02 provides:
Markush Claims
A Markush claim is a claim which covers selected members of a genus as contrasted to all the members of a genus, so as to exclude inoperative members of the group.
Markush groupings will be considered to be directed to one invention when all of the members of the group have a common basic structure and/or common property or activity is present. In those cases where a common property or activity is present, all of the members are expected to behave in the same way in the context of the claimed invention. (Underlining added)
[24] The expression "Markush" originated in the U.S., as indicated in the above quote. The court in the recent case of Abbott Labs. v. Baxter Pharm. Prods., (2003) 334 F.3d 1274 at paragraph 16 quoted the following definition from Robert C. Faber "Landis on Mechanics of Patent Claim Drafting", para 50, 5A, VI-5-6 (4th edition 2002):
A Markush group is a sort of homemade generic expression covering a group of two or more different materials (elements, radicals, compounds etc), mechanical elements, or process steps, any one of which would work in the combination claimed. (Underlining added)
The reason for Markush claims apparently was to reduce the number of claims and the costs given that under US law there was a limitation on the number of claims that could be made in a patent and a fee per claim. Regardless of its origin, the concept of a Markush claim has been adopted in Canadian practice, as witnessed by the above quotes from the MOPOP.
[25] Given the Commissioner's guidance, given the wording of the above cited definition and given the fact that claim 15 uses the exact words "selected from the group consisting of", as well as the word "and" instead of "or" before enumerating the last solvent, in my mind there can be no doubt that claim 15 is a Markush claim.
[26] The key to a Markush claim is that it defines a homemade genus, all the members of which can be used interchangeably. By stating in claim 15 "a method according to Claim 2 wherein the solvent is selected from the group consisting of: acetone (...), and methanol-ethanol",
one can only conclude that any one of these solvents can be used to obtain the desired result. It is a claim to this group of solvents, it is not a claim to each of the solvents in the alternative.
[27] I cannot accept that these listed solvents were meant as alternatives and that section 27(5) of the Patent Act applies. Section 27(5) of the Patent Act is of no help as it only applies "where a claim defines the subject-matter of an invention in the alternative". That is not the case here. By using the specific language suggested by the Commissioner and by using the word "or" instead of "and" as the penultimate word of the claim, the drafter clearly made a Markush claim and asserted that the use of all of the specified solvents would produce the desired result.
[28] While there is no dispute about claim 15 when using solvent A, there is considerable dispute with regard to the other substances. Ratiopharm hired a Dr. Brown to carry out experiments in accordance with the specifications of the '732 Patent, following the method set out in the patent disclosure, in accordance with the manner appropriate to a person skilled in the art. Dr. Brown is Project Manager at Dalton Chemicals Labs Inc. and holds a Ph.D. in chemistry. He has authored or co-authored over 20 scientific publications. Inter alia, he performed Example 1 (acetone), Example 5 (N,N Dimethylformamide), Example 11 (ethyl ether) and Example 17 (isopropylamine) of the '732 Disclosure.
[29] The results of the tests performed Dr. Brown were subjected to XRPD and DSC analysis by Dr. Petrov, an expert in crystallography. It was Dr. Petrov's undisputed evidence, as shown in the table on p. 8 of his affidavit, (Respondents Record, Volume 4, Tab 5) that not all of the samples contain Clarithromycin Form II. For instance, Example 5 (N, N-Dimethylformamide) produced no crystallization, Example 11 (ethyl ether) produced only Clarithromycin Form I and Example 16 (isopropylamine) also produced no crystallization.
[30] Dr. Brown was criticized by Abbott's experts Drs. Atwood, Myerson and Byrn for the way he followed the procedures set out in the'732 Patent and for being generally unappreciative of the art of crystallization. (Dr. Atwood - Applicant's Record, Volume 3, Tab 18, paras 5 - 7, 11, 12 - 16, 20, 31, 34 - 36, Dr. Myerson - Applicant's Record, Volume 3, Tab 20, paras 10, 23, 25, 31, 33 - 35; Dr. Byrn - Applicant's Record, Volume 3, Tab 22, paras 5, 7, 26)
[31] Abbott, in turn, hired a Dr. Chyall to perform the crystallizations of clarithromycin from N, N-Dimethylformamide, ethyl ether and isopropylamine. Dr. Chyall is a scientist employed by SSCI Inc. He is an organic chemist who holds a Ph.D. in chemistry. He works primarily in the area of crystallization of pharmaceuticals and has authored 18 scientific publications and three patents. He was successful in obtaining Clarithromycin Form II from all three solvents. His procedures were roundly criticized by Dr. Brown for not following the examples prescribed in the '732 Patent (Respondent's Record, Volume 4, Tab 8, paras 6 - 7). Dr. Lee-Ruff also criticized Dr. Chyall's methodology (Respondent's Record, Volume 3, Tab 4, paras 13, 17, 33 - 43). Most importantly, on cross-examination Dr. Chyall admitted that he did not read the '732 Patent before performing his experiments, but rather followed a protocol furnished by Abbott's counsel when he attempted to carry out the examples set out in the '732 Patent (Respondent's Record, Volume 6, Tab 12, pp. 11, 12, 86, 87). During cross-examination, Abbott's counsel even went so far as to suggest that Dr. Chyall is not a person skilled in the art (Respondent's Record, Volume 6, Tab 12, pp. 24, 25).
[32] Evidently there is conflicting expert opinion with regard to claim 15 in so far as it concerns N, N-Dimethylformamide, ethyl ether and isopropylamine. The Court however takes note that:
a) Dr. Brown performed the examples regarding N, N-Dimethylformamide, ethyl ether and isopropylamine following the teachings of the disclosure of the '732 Patent, as set out in examples 5, 11 and 16 respectively;
b) Dr. Brown 's evidence was not shaken on cross-examination;
c) there is no evidence that Dr. Chyall performed all the examples taught by the '732 Patent. By his own admission, he followed a protocol furnished by Abbott's counsel; said protocol is not part of the record;
d) Dr. Chyall was unaware of the teachings of the '732 Patent until after he had performed his experiments; and
e) none of the criticism of Dr's Atwood, Myerson or Byrn accused Dr. Brown of not following the examples of the '732 Patent, but rather disputed whether a person skilled in the art would have employed certain practices or procedures or followed the Patent the way he did.
As a result, the Court prefers the evidence of Ratiopharm's experts, based on experiments following the teachings of the '732 Patent and finds that Ratiopharm, on a balance of probabilities, has proven that claim 15 has no utility with respect to three of the 17 solvents claimed, namely N, N Dimethylformamide, ethyl ether and isopropylamine.
[33] This finding combined with the earlier interpretation of claim 15 as a Markush claim means that Abbott has not disproven Ratiopharms's allegation that claim 15 is invalid for lack of utility.
Invalidity - Prior Sale of BIAXIN
[34] It is an undisputed fact that Abbott has sold BIAXIN since 1989. BIAXIN contains Clarithromycin Form II. Ratiopharm relies on Hoffmann-La Roche Ltd. v. Canada (Minister of National Health and Welfare), (1955) 23 C.P.R.1 where Kerwin C.J.C. laid down the following proposition:
" There being nothing new about a product, an applicant is not entitled to obtain a patent therefor, even on the basis of a process dependent product claim".
Hoffmann was decided under the former Patent Act (S.C. 1935 c.32) which in section 26(1)(a), used the expression "known or used". Abbott argues that the principle of Hoffmann is premised on a provision that is now repealed and, accordingly, is inapplicable. Alternatively, if Hoffmann is still good law, it must be "translated" into the present Patent Act, i.e. one applies subsections 28.2(1)(a) and (b) of the present Patent Act, rather than section 26(1)(a) of the former Patent Act.
[35] Subsections 28.2(1)(a) and (b) provide:
The subject-matter defined by a claim in an application for a patent in Canada (the "pending application") must not have been disclosed
(a) more than one year before the filing date by the applicant, or by a person who obtained knowledge, directly or indirectly, from the applicant, in such a manner that the subject-matter became available to the public in Canada or elsewhere;
(b) before the claim date by a person not mentioned in paragraph (a) in such a manner that the subject-matter became available to the public in Canada or elsewhere;
[36] In Canwell Enviro-Industries Ltd. v. Baker Petrolite Corp. et al., (2002) 17 C.P.R. (4th) 478, Rothstein J.A., at paragraph 42, provided eight principles with regard to how subsection 28.2(1)(a) should be interpreted and stated in reference to chemical products:
3. The prior sale or use of a chemical product will constitute enabling disclosure to the public if its composition can be discovered through analysis of the product. The Board of Appeal for the European Patent Office in Bisons PLC v. Packard Instrument BV, E.P.O. case number T0952/92-3.4.1, August 17, 1994, stated at p. 21:
(...) in the Board's view it is the fact that direct and unambiguous access to information concerning the composition or internal structure of a prior used product is possible, for example by means of analysis, which makes such composition or internal structure "available to the public" and thus part of the state of the art for the purpose of Article 54(2) EPC. [Emphasis added.]
[37] I agree with Abbott that the principle discussed in Hoffman, supra, needs to be translated to the present Patent Act. Thus, one must apply subsection 28(5) as interpreted by Canwell, supra, which means, in this case, there must be evidence regarding any analysis "which would make such composition or internal structure available to the public".
[38] Ratiopharm presented no evidence of reverse engineering. Nor does Ratiopharm explain in its NOA how the prior sale of BIAXIN would allow a person skilled in the art to obtain knowledge, directly or indirectly, in accordance with known analytical techniques available at the relevant time, in such a manner that the subject matter of the '732 Patent would become available to the public in Canada or elsewhere. In fact, there is no discussion of BIAXIN in the NOA. The argument regarding BIAXIN is only developed in the Respondent's Memorandum of Fact and Law (Respondent's Record, Volume 13, Tab 24, p. 63, para 275).
[39] The standard for sufficiency of NOAs was established in AB Hassle v. Canada (Minister of National Health and Welfare), (2000) 7 C.P.R. (4th) 272, referred to above, where Stone J.A. observed:
17 (...) Section 5(3)(a) of the Regulations requires that the applicant for the NOC provide a detailed statement of the basis in fact and law of his statement of allegation. It seems intended that the patentee be fully aware of the grounds on which the applicant says issuance of an NOC will not lead to an infringement of the patent before the patentee decides whether or not to apply to a court for a determination. Such disclosure would define the issues at a very early stage. (...)
19 The detailed statement is not a pleading per se but represents a pivotal step in the process leading up to the issuance of an NOC. By taking that step the second person puts the patentee on notice of the grounds on which he or she considers that the making, constructing, using or selling of the drug will not infringe the second person's patent rights during the unexpired term of the patent. In theory, this procedure ought to enable the patentee to confidently decide within the 45-day time limit whether to resist the issuance of an NOC. It is to be noted that, subject to business exigencies, the second person had no obligation to make its allegation and provide its detailed statement by an imposed deadline. As much time as the second person deems necessary is available under the scheme of the Regulations.
20 While it is true that the detailed statement is not filed in a section 6 proceeding, it nevertheless casts a long shadow over that proceeding. Indeed, it is upon the content of that statement that the patentee must decide whether or not to commence a section 6 proceeding and to assess its chances of success or failure. In this sense the allegation and detailed statement assist in an important way in framing the issues and facts to be determined in the section 6 proceedings for in seeking prohibition the patentee is obliged to show that, contrary to what is stated in the detailed statement, the patentee's patent right will be infringed if an NOC for the drug is issued prior to the expiration of the listed patent.
21 In my view, all of these considerations suggest that a second person must do what, in fact, paragraph 5(3)(a) requires, i.e. set forth in the detailed statement "the legal and factual basis" for the paragraph 5(1)(b) allegation and to do so in a sufficiently complete manner as to enable the patentee to assess its course of action in response to the allegation.
[40] Regarding the prior sale and use of BIAXIN, I am of the view that the NOA is deficient and does not meet the standards referred to in AB Hassle, supra. Accordingly, there is no need for Abbott to disprove this allegation.
Invalidity - Anticipation by Salem
[41] Ratiopharm alleges that the invention set out in the '732 Patent was anticipated by an article by I. I. Salem entitled "Clarythromycin found in analytical profiles of drug substances and excipients", Volume 24, published by Academic Press Inc., San Diego in 1996. The exact date of publication is not clear. The application for the '732 Patent was filed in the Canadian Patent Office on July 28, 1997 and has a priority date, and thus a claim date of July 29, 1996.
[42] Ratiopharm alleges that the Salem article anticipates the claim date of the '732 Patent. To be successful with this argument, Ratiopharm has to produce evidence to satisfy subsections 28.2(1)(a) and (b) which I will reproduce again for ease of reference:
28.2 (1) The subject-matter defined by a claim in an application for a patent in Canada (the "pending application") must not have been disclosed
(a) more than one year before the filing date by the applicant, or by a person who obtained knowledge, directly or indirectly, from the applicant, in such a manner that the subject-matter became available to the public in Canada or elsewhere;
(b) before the claim date by a person not mentioned in paragraph (a) in such a manner that the subject-matter became available to the public in Canada or elsewhere;
[43] Ratiopharm must establish that the Salem article was available to the public in Canada or elsewhere prior to the claim date of July 29, 1996.
[44] Dr. Atwood, Abbott's expert, attested to the fact that the University of Missouri, Columbia Library had a standing order for volumes of the series. However, it did not barcode its copy (and consequently did not place it in its library) before August 19, 1996. Given its standing order, it should have received the copy as quickly as any other library (Atwood affidavit, Applicant's Record, Volume 3, Tab 17, para 32).
[45] Ratiopharm points to the following quote from Canwell, supra, at para 96:
To prove anticipation under para. 28.2(1)(a), it is not necessary to demonstrate that a particular purchaser did or would have conducted an analysis of the product. It is sufficient that the purchaser could have done so (see Lux, supra, at p. 133).
[46] The passage referred to in Lux Traffic Controls Ltd. v. Pike Signals Ltd., [1993] R.P.C. 107 provides at p. 133:
Further it is settled law that there is no need to prove that anybody actually saw the disclosure provided the relevant disclosure was in public. Thus an anticipating description in a book will invalidate a patent if the book is on a shelf of a library open to the public, whether or not anybody read the book and whether or not it was situated in a dark and dusty corner of the library. If the book is available to the public, then the public have the right to make and use the information in the book without hindrance from a monopoly granted by the State. [emphasis added]
[47] In any NOC proceedings, the NOA has to set out a detailed statement of facts. Reference was already made to the standard set out in AB Hassle, supra, which was reiterated by Gibson J. in Abbott Laboratories v. Canada (Minister of Health), [2004] F.C.J. No. 1644 which incidentally involved the same patent. The court pronounced at paragraph 72:
A Notice of Allegation served by a "first person", here Pharmascience, on a "second person", here Abbott Canada, must provide all of the facts the second person intends to rely upon in the event that a proceeding such as that now before the Court is instituted. A first person cannot rely on facts that are not reflected in the Notice of Allegation, which is required to include a detailed statement of facts. [See Note 24 below] Absent a detailed statement of facts in compliance with the Regulations, the Applicants are entitled to rely on the presumption of infringement. [See Note 25 below]
Note 24: See: Proctor & Gamble Pharmaceuticals Canada, Inc. v. Canada (Minister of Health) [2003] 1 F.C. 402 at paragraphs [21] to [26] (F.C.A.).
Note 25: See: AB Hassle v. Canada (Minister of National Health and Welfare), (2000), 7 C.P.R. (4th) 272 (F.C.A.).
[48] I fail to see how Ratiopharm met the standard stated in the cases listed in the preceding paragraph with respect to the Salem article. The claim date for the '732 Patent is July 29, 1996. There is no evidence on the '732 record of the exact date of publication of the Salem article. There is also no evidence that the material was actually available to the public before July 29, 1996 or put on a shelf (to meet the Lux, supra, standard). In my view, Ratiopharm failed to set out any facts in its NOA on which it relies to assert that the Salem article was available prior to the filing or claim date of the '732 Patent. There is thus no need for Abbott to disprove the allegation.
Invalidity - Anticipation by Iwasaki
[49] Ratiopharm also alleges that the '732 Patent was anticipated by the article of H. Iwasaki published June 15, 1993 in "Crystal structure communications", Volume 49, Part 6.
[50] That article clearly predates the claim of the '732 Patent. It describes the molecular structure of 6-O-methylerythromycin A (clarithromycin). Under the heading "Experimental", it sets out the crystal data as C38H69NO13.CH40. The dot (.) before the CH40 denotes that this is a solvate.
[51] There is nothing in the '732 Patent to indicate that it is a solvate. Neither the text, nor the formula indicate that it deals with a solvate. Page 8 of the Disclosure of the '732 Patent states:
6-O-methylerythromycin A crystal form II is isolated by filtration and dried in a vacuum oven at a temperature of between ambient temperature and about 50 C and a pressure of between about 2 inches of mercury and atmospheric pressure to remove any remaining solvent. (Underlining added)
[52] In addition, all of Abbott's experts and even Ratiopharm's own expert Dr. Clive agree that the crystal resulting from Iwasaki's process is not Clarithromycin Form II. As Dr. Clive states at page 23, paragraph 81 of his affidavit:
The use of methanol taught by Iwasaki et al. teaches everything that a person skilled in the art would need to know in order to carry out the invention claimed in the patent, yet the resulting crystal is not Form II, but a methanol solvate, i.e. a crystal lattice which includes both clarithromycin and methanol, as stated by Professor Myerson at paragraph 49, and Professor Atwood at paragraph 20. Therefore, the crystallization taught by the patent is incorrect, and the patent lacks utility, in that in fact crystallization from methanol results in something other than Form II.
[53] The expert evidence suggests that it is customary for chemists to indicate in the formula and in the text if they are dealing with solvates. Even Dr. Petrov (Ratiopharm's expert who claims that the '732 Patent includes solvates) admitted that if he produced a solvate, he would so indicate in the formula or in the text (Dr. Petrov, cross-examination, Applicant's Record, Volume 6, Tab 26, pp. 1295-96).
[54] Nevertheless, Dr. Petrov maintains that the Iwasaki methanol solvate is included in what Abbott claims as Clarithromycin Form II. However, Dr. Petrov is a crystallographer, not a chemist. Under cross-examination, he displayed a limited understanding of stereo chemistry. His credibility was further weakened in cross-examination when he admitted that methanol solvate is a larger unit cell than the material claimed in the '732 Patent. He refused to concede on cross-examination that the larger unit cell of the methanol solvate could not fit within the smaller unit cell of Clarithromycin Form II (Dr. Petrov, cross, Applicant's Record, Volume 6, Tab 26, pp. 1224-1227).
[55] For the foregoing reasons, I prefer the evidence of Abbott's three experts and Dr. Clive and conclude that the '732 Patent does not include solvates. Therefore, it cannot have been anticipated by the Iwasaki paper.
Non-infringement - 9-oxime
[56] Ratiopharm alleges that its manufacturing process does not include an erythromycin A 9-oxime derivative ("9-oxime"). The synthetic pathway used by Ratiopharm's supplier, which was supplied to Abbott under a confidentiality order, makes this abundantly clear. No Abbott expert suggested that 9-oxime was used by Ratiopharm. Yet step a)(i) of claim 2 (which is used in claim 15) specifically states "converting erythromycin A into erythromycin A 9-oxime derivative". (Underlining added)
[57] There is no reference to the 9-oxime in Ratiopharm's NOA. Ratiopharm explains this omission by pointing out that it could not, for reasons of confidentiality, release the synthetic pathway until a confidentiality order was issued. It relies on Pfizer Canada Inc. et al. v. Apotex Inc. et al., (2004) 31 CPR (4th) 214 at paragraph 32 in support of this proposition.
[58] While I do not dispute the applicability of Pfizer and I find that Ratipopharm did not have to set out the issue in detail prior to obtaining the confidentiality order, it behoved Ratiopharm to alert Abbott that one of the steps employed in the '732 Patent was not used in its manufacturing process. Once the confidentiality order issued, it should have explained its allegation regarding the 9-oxime issue in more detail. However, subsequent to the order being issued, Ratiopharm conveyed its Detailed Process Description and Drug Master File ("DMF") to Abbott, yet still failed to make any references regarding 9-oxime.
[59] Ratiopharm's failure to raise this issue in the NOA or when making the confidential disclosure, meant that no expert evidence was produced on this point by either side, nor did the cross-examinations deal with the 9-oxime issue in anything but a cursory manner. The only reference that Ratiopharm could point to was a single reply of Dr. Clive on cross-examination regarding the route taken, which did not even involve the expression "9-oxime" (Applicant's Record, Volume 5, Tab 24, page 972, lines 6 - 12).
[60] The 9-oxime issue is of fundamental importance to the allegation and could potentially be dispositive of this case. By not mentioning it in either the NOA, nor calling attention to it when providing the confidential disclosure, Ratiopharm did not comply with subsection 5(3)(a) of the NOC Regulations, nor with the standard set out in A.B. Hassle, supra, to:
set forth in the detailed statement "the legal and factual basis" for the paragraph 5(1)(b) allegation and to do so in a sufficiently complete manner as to enable the patentee to assess its course of action in response to the allegation.
[61] Accordingly, there is no requirement for Abbott to disprove this portion of Ratiopharm's allegations.
Non-infringement - Intermediates
[62] Ratiopharm alleges that the fifth and final step in its manufacturing process does not produce Clarithromycin Form II from solvent A but Clarithromycin Form II from solvent X. Solvent X is not one of the substances claimed in the '732 Patent. Abbott, however, asserts that steps 13 to 16 of stage 4 of Ratiopharm's DMF infringe the '732 Patent as they involve dissolving in solvent A. These steps provide:
13. Charge acetone, distill out acetone completely and degas by applying vacuum.
14. Repeat step number 13.
15. Charge acetone and reflux for 1 hour. Cool to 8 to 12_C, maintain the reaction mass between 8 to 12_C for 1 hrs. filter [sic] through hyflow bed in nutch filter. Charge filtrate to another reactor and wash the cake with acetone. Add the filtrate to the previous filtrate.
16. Unload the cake weigh.
(Applicant's Record, Volume 2, Tab G, p. 205.)
[63] The "cake" referred to in step 16 is also called crude 6-O-methylerythromycin A. The crude 6-O-methylerythromycin A is then dissolved at stage 5 in solvent X and recrystallized and heated to produce Clarithromycin Form II.
[64] Two issues arise:
1. Does the cake obtained at the end of stage 4 contain Clarithromycin Form II (thereby infringing the '732 Patent, given that it is obtained from a solvent A solution)?
2. Do the NOC Regulations cover intermediate products or only the final product (it being undisputed that the final Ratiopharm product is obtained from dissolving in solvent X not solvent A)?
Does the "cake" contain Clarithromycin Form II?
[65] There is conflicting expert evidence on this point. Ratiopharm's experts make the following statements in their affidavits:
Dr. Clive states that there are too many impurities at this stage to predict the outcome of the crystallization (Respondent's Record, Volume 1, Tab 1, page 12, paras 41 - 44); and
Dr. Lee-Ruff suggests that no conclusion can be reached without experimental verification (Respondent's Record, Volume 2, Tab 3, p. 19, paras 58 - 59).
[66] Abbott's own experts differ as well:
Dr. Atwood asserts that steps 13 to 16 are recrystallizations from solvent A and such steps infringe claims 1 (b)(iii), 15 and 20 of the '732 Patent (Applicant's Record, Volume 3, p. 30, para 82);
Dr. Myerson asserts that steps 13 to 16 and 19 to 23 involve crystallization or recrystallization from solvent A and thus infringe claims 1 (b)(iii), 15 and 20 of the '732 Patent (Applicant's Record, Volume 3, Tab 19, p. 38, paras 120 - 121); and
Dr. Byrn asserts that steps 13 to 17 and 18 to 25 of the DMF infringe claims 1(b)(iii), 2, 15, 16, 18, 20 and 21 of the '732 Patent (Applicant's Record, Volume 3, Tab 21, p. 49 para 202); he goes further and suggests:
Based on the data we have in hand there is no apparent scientific reason for any of the steps in stage 5 [of the DMF] because the numerous previous separations, purifications and crystallizations should produce purified Form II Clarithromycin.(underlining added) (Applicant's Record, Volume 3, Tab 21, p. 49, para 193).
[67] None of the Abbott experts did any actual experimentation, notwithstanding that they had Ratiopharm's DMF which sets out the whole manufacturing process. These are assertions based on their knowledge and experience, not the results of actual testing. No allegations have been made by Abbott that stage 5 of the Ratiopharm DMF is unnecessary and has been added merely to avoid infringement.
[68] The cross-examinations of these experts is of little help. None were shaken in their assertions. The only way to conclusively resolve the conflicting expert testimony as to whether the "cake" obtained in the step at the end of steps 16 and 24 contains Clarithromycin Form II would be through experimental testing simulating Ratiopharm's industrial process. Unfortunately, this was not carried out.
[69] The bottom line is that Ratiopharm's experts question whether the "cake" at the end of stage 4 contains Clarithromycin Form II, while Abbott's experts assert that it does but cannot prove it. In effect, Abbott's experts produced evidence of the possibility of infringement but no proof. That is not enough for proceedings of this kind where the applicant has the burden of proof to disprove allegations of non-infringement. As McGillis J. stated in SmithKline Beecham Inc. v. Apotex Inc. (1999) 1 C.P.R. (4th) 99 at paragraph 39:
Apotex has alleged in its notice of allegation that its tablets will not infringe the '060 patent. That allegation is presumed to be true, ". . . except to the extent that the contrary has been shown . . ." by SmithKline. (See Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) at 319.) In my opinion, the evidence adduced by SmithKline, including the two experiments, raises no more than a possibility of infringement by Apotex, and does not establish, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified.
[70] The same reasoning would appear appropriate for this case. In light of the conflicting testimonies of the experts, I find that Abbott has only established the possibility of infringement but has not disproven, on a balance of probabilities, Ratiopharm's allegation of non-infringement (i.e. that Clarithromycin Form II is not produced at the end of stage 4 of the DMF).
Do the NOC Regulations apply to intermediates?
[71] Ratiopharm makes the argument that in any event the "cake" at the end of stage 4 of the DMF is only an intermediate product. It will be completely dissolved in solvent X and the final Clarithromycin Form II will be crystallized out of solvent X. Dr. Clive, (who was not challenged on this point) stated that the dissolution and recrystallization has the following effect:
In any event, when the crude clarithromycin resulting in stage 4 is dissolved in solvent X in stage 5, any crystal resulting from stage 4 is destroyed. A crystal by definition no longer exists after dissolution in solution. The form any crystal will take after such a dissolution depends on what solvent is used (in this case, solvent X), and what temperature is applied during the subsequent heating (in this case, the high temperature treatment the patent teaches a way to avoid). (Respondent's Record, Volume I, Tab 1, p. 13, para 45.)
[72] It is well established that intermediates that have no therapeutic value are not covered by the NOC Regulations (see Eli Lilly and Co. v. Apotex Inc. et al., 63 C.P.R. (3d) 245). In this case, however, the intermediate that is produced at stage 4 is Clarithromycin Form II, the very medicine covered by the '732 Patent. The question therefore becomes: Do the NOC Regulations cover an intermediate that has therapeutic value but is only used as an intermediate?
[73] I would have thought the answer is clear by the wording of subsection 5(1)(b)(iv) of the NOC Regulations which provides:
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 (...) the person shall, in the submission, with respect to each patent on the register in respect of the other drug,
...
(b) allege that
(...)
(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. (Underlining added)
[74] If stage 4 results in producing Clarithromycin Form II, it would appear, at first blush, that it is "made" within the meaning of the NOC Regulations. However, as I have held that Abbott has not proven on a balance of probabilities that Clarithromycin Form II is produced at stage 4, there is no need to make a ruling on this point.
Conclusion
[75] Given that Abbott has not disproven:
a) Ratiopharm's allegation that claim 15 is a Markush claim, nor has it disproven Ratiopharm's allegation that three of the 17 solvents mentioned in claim 15 do not yield Clarithromycin Form II; and
b) Ratiopharm's allegation that Clarithromycin Form II is not produced in stage 4 of Ratiopharm's DMF;
this application cannot succeed.
Additional Comments
[76] This application was argued for five days in Toronto. As large portions of the record were confidential, the Court on July 11, 2005 sent a draft copy of its reasons for judgment to the parties asking them to point out if any portions of the reasons should be blacked out to maintain confidentiality. Pursuant to the response of the parties dated July 19, several paragraphs were partially blacked out. In addition, the names of two solvents were deleted and replaced by "solvent A" and "solvent X". Accordingly, these reasons for judgment are issued in a redacted public version and an unredacted confidential version.
ORDER
THIS COURT ORDERS that this application be dismissed with costs to the Respondent Ratiopharm.
" Konrad von Finckenstein"
F.C.J.
ANNEX
Summary of the Invention
We have discovered that 6-O-methylerythromycin A can exist in at least two distinct crystalline forms, which for the sake of identification are designed " Form I" and "Form II". The crystal forms are identified by their infrared spectrum, differential scanning calorimetric thermogram and powder x-ray diffraction pattern. Investigations in our laboratory have revealed that 6-O-methylerythromycin A when recrystallized from ethanol, tetrahydrofuran, isopropyl acetate, and isopropanol, or mixtures fo ethanol, tetrahydrofuran, isopropyl acetate, or isopropanol with other common organic solvents result in exclusive formation of Form I crystals not identified hitherto before. 6-O-methyl erythromycin A Form I is disclosed in the co-pending U.S. Patent 5,858,986, filed even-date on July 29, 1996.
Drugs currently on the market are formulated from the thermodynamically more stable Form II. Therefore, preparation of the current commercial entity requires converting the Form I crystals to Form II. Typically this is done by heating the Form I crystals under vacuum at a temperature greater than 80 º C. Therefore, a process for the preparation of 6-O-methylerythromycin A Form II which does not require the high temperature treatment would result in substantial processing cost savings.
Although recrystallization from ethanol, tetrahydrofuran, isopropanol or isopropyl acetate results in exclusive formation of Form I crystals, 6-O-methylerythromycin A Form II can be isolated directly by using a number of other common organic solvents, or mixtures of common organic solvents, thereby eliminating the additional conversion step.
Accordingly, the present invention provides a process for preparing 6-O-methylerythromycin A Form II comprising
(a) converting erythromycin A to 6-O-methylerythromycin A;
(b) treating the 6-O-methylerythromycin A prepared in step (a) with a solvent selected from the group consisting of (i) an alkanol of from 1 to 5 atoms, provided said alkanol is not ethanol or isopropanol, (ii) a hydrocarbon of from 5 to 12 carbon atoms, (iii) a ketone of from 3 to 12 carbon atoms, (iv) a carboxylic ester of from 3 to 12 carbon atoms, provided said carboxylic ester is not isopropyl acetate, (v) an ether of from 4 to 10 carbon atoms, (vi) benzene, (vii) benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen, (viii) a polar aprotic solvent, (ix) a compound having the formula HNR1R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms, provided that R1 and R2 are not both hydrogen, (x) water and a second solvent selected from the group consisting of water miscible organic solvent and a water miscible alkanol, (xi) methanol and a second solvent selected from the group consisting of a hydrocarbon of from 5 to 12 carbon atoms, an alkanol of from 2 to 5 atoms, a ketone of from 3 to 12 carbon atoms, a carboxylic ester of from 3 to 12 carbon atoms, an ether of from 4 to 10 carbon atoms, benzene, and benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen, and (xii) a hydrocarbon of from 5 to 12 carbon atoms and a second solvent selected from the group consisting of a ketone of from 3 to 12 carbon atoms, a carboxylic ester of from 3 to 12 carbon atoms, an ether of from 4 to 10 carbon atoms, benzene, benzene substituted with one or more substituents selected from the group consisting of alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, nitro, and halogen, and a polar aprotic; and
(c) isolating the 6-O-methylerythromycin A Form II crystals.
Claims 1, 2, 15 and 20 of Canadian Patent No. 2,261,732:
1. A method of preparing 6-O-methylerythromycin A crystal Form II comprising:
(a) converting erythromycin A to 6-0-methylerythromycin A;
(b) treating 6-O-methylerythromycin A prepared in step a with a solvent selected from the group consisting of:
(i) an alkanol of from 1 to 5 carbon atoms, provided said alkanol is not ethanol or isopropanol,
(ii) a hydrocarbon of form 5 to 12 carbon atoms,
(iii) a ketone of from 3 to 12 carbon atoms,
(iv) a carboxylic ester of from 3 to 12 carbon atoms, provided said carboxylic ester is not isopropyl acetate,
(v) an ether of from 4 to 10 carbon atoms,
(vi) benzene,
(vii) benzene substituted with one or more substituents selected from the group consisting of:
alkyl of from one to four carbon atoms
alkoxy of from one to four carbon atoms,
nitro, and
halogen,
(viii) a polar aprotic solvent,
(ix) a compound having the formula HNR1R2 where R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms, provided and R1 and R2 are not both hydrogen,
(x) water and a water miscible solvent selected from the group consisting of;
a water miscible organic solvent, and
a water miscible alkanol,
(xi) methanol and a second solvent selected from the group consisting of:
a hydrocarbon of from 5 to 12 carbon atoms, an alkanol of
from 2 to 5 carbon atoms,
a ketone of from 3 to 12 carbon atoms,
a carboxylic ester of from 3 to 12 carbon atoms,
an ether of from 4 to 10 carbon atoms,
benzene, and
benzene substituted with one or more substitutents selected
from the group consisting of;
alkyl of from one to four atoms,
alkoxy of from one to four carbon atoms,
nitro, and
halogen, and
(xii) a hydrocarbon of from 5 to 12 carbon atoms and a second
solvent selected from the group consisting of:
a ketone of from 3 to 12 carbon atoms,
a carboxylic ester of from 3 to 12 carbon atoms,
an either of from 4 to 10 carbon atoms,
benzene,
benzene substituted with one or more substituents
selected from the group consisting of:
alkyl of from one to four carbon atoms,
alkoxy of from one to four carbon atoms,
nitro, and
halogen, and
a polar aprotic; and
(c) isolating the 6-O-methylerythromycin A crystal Form II crystals.
2. The process of Claim I wherein steps (a) comprises
(c) converting erythromycin A into an erythromycin A 9-oxime derivative;
(b) protecting the 2' and 4" hydroxy groups of the erythromycin A 9-oxime
derivative prepared in step (I);
(c) reacting the product of step (ii) with a methylating agent; and
(d) deprotecting and deoximating the product of step (iii) to form
6-O-methylerythromycin A.
15. A method according to Claim 2 wherein the solvent is selected from the group consisting of:
acetone,
heptane,
toluene,
methyl tert-butyl ether,
N, N-dimethylformamide,
ethyl acetate,
xylene,
isopropanol-water,
tetrahydrofuran-water,
ethanol-water,
ethyl water,
amyl water,
isopropyl acetate-methanol,
diisopropyl ether,
isopropyl butyrate,
isopropylamine, and
methanol-ethanol
20. 6-O-methlerythromycin A crystal Form II prepared according to the process of Claim 15.
FEDERAL COURT
SOLICITORS OF RECORD
STYLE OF CAUSE: ABBOTT LABORATORIES and
ABBOTT LABORATORIES LIMITED
- and -
THE MINISTER OF HEALTH and
RATIOPHARM, A DIVISION OF
RATIOPHARM INC.
PLACE OF HEARING: OTTAWA, ONTARIO
ORDER AND ORDER BY: The Honourable Mr. Justice von Finckenstein
APPEARANCES:
Andrew J. Reddon FOR THE APPLICANTS
Steven G. Mason
Marcus A. Klee
F.B. (Rick) Woyiwada FOR THE RESPONDENT
(For The Minister of Health)
David W. Aitken FOR THE RESPONDENT
J. Bradley White (For Ratiopharm, a Division of
Ratiopharm Inc.)
SOLICITORS OF RECORD:
ANDREW J. REDDON FOR THE APPLICANTS
STEVEN G. MASON
MARCUS A. KLEE
McCarthy Tétrault LLP
Toronto Ontario
JOHN H. SIMS, Q.C. FOR THE RESPONDENT
Deputy Attorney General of Canada (For The Minister of Health)
Ottawa Ontario
DAVID W. AITKEN FOR THE RESPONDENT
J. BRADLEY WHITE (For Ratiopharm, a Division of
Osler, Hoskin & Harcourt LLP Ratiopharm Inc.)
Ottawa Ontario