Abbott Laboratories v. Canada (Minister of Health), 2005 FC 1093

Date: 20050810

Docket:T-1656-03

Citation: 2005 FC 1093

Ottawa, Ontario, this 10^th 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 (ANOC@) to Ratiopharm for Clarithromycin 250 mg and 500 mg tablets because it infringes Canadian Patent Nos. 2,258,606 (A > 606 Patent@), 2,386,527( A > 527 Patent@ ) 2,277,274 (A > 274 Patent@ ) 2,386,534 (A > 534 Patent@), 2,387,361 (A > 361 Patent@) and 2,387,356 (A > 356 Patent@) held by Abbott. Prior to the hearing, Abbott abandoned any claims regarding the 534 Patent and during the hearing, Abbott abandoned any claims for an application based on the > 527 or the > 356 Patent. Accordingly, these reasons will only deal with the > 606 Patent, > 274 Patent and > 361 Patent.

[2]                Abbott also brought a separate application (Court File T-1847-02) for an order prohibiting the Minister of Health from issuing a NOC to Ratiopharm for the production of Clarithromycin Form II because it infringes Canadian Patent No. 2,261,732 (A > 732 Patent@). While these two applications were heard together, they are based on different records and therefore separate reasons were issued with respect to the application based on the > 732 Patent.

Nature of Proceedings

[3]                These proceedings were initiated under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 (the ANOC 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 succinctly stated 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:

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 (ANOA@), which delimits the scope of the issues to be decided. Abbott, as the Applicant, must prove that Ratiopharm=s allegation ( that the > 606, > 274 and > 361 Patents are invalid) is not justified and that Ratiopharm=s allegation that its production of Clarithromycin Form II will not infringe any of these four patents is not justified.

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 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 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 recognized him as an expert in pharmaceutical chemistry, sold-state chemistry, industrial pharmacy, polymorphism, analytical techniques and crystallization.   

Ratiopharm Experts

Dr. Hollingsworth is an Associate Professor of chemistry at Kansas State University. He holds a Ph.D. in organic chemistry at Yale University where he used infrared (AIR@) spectroscopy to study different organic crystal forms. He completed his postdoctoral studies at the University of Cambridge where he focussed on characterizing chemical reactions of crystalline materials including polymorphs. The Court recognized him as an expert in the study of crystal forms and transformations between them and he has published extensively in the field of organic synthesis of crystal forms.

Dr. Eckhardt is a faculty member of the physical chemistry division of the Department of Chemistry at the University of Nebraska at Lincoln. He holds a Ph.D in physical chemistry from Yale University and has worked in the areas of single crystal X-ray diffraction settings, IR measurements, and crystal growth and characterization. The Court recognized him as an expert on the transformation of individual molecular properties into the bulk properties of a crystal. He has authored or co-authored 111 publications and two book chapters.

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. He explains that as crystallography often entails the use of x-ray powder diffraction (XRPD) as a method of analysis, he has developed considerable experience in this analytical method. The Court recognized him as an expert in the field of crystallography.

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 and will be dealt with in these reasons.

Burden of Proof

[7]                The burden of proof as to validity was succinctly set out in Biovail, supra, where Harrington J. stated at paragraph 12:

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.          

[8]              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] F.C.J. 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.

[9]                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

[10]            In Biovail, supra, Harrington J. succinctly summarized the rules for patent construction as laid down by the jurisprudence:

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.)

[11]            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. (4^th) 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 4^th ed Toronto: Carswell 169 at 184]

[12]            In this case the parties agree that a person skilled in the art on the priority date of the patents would have a B.Sc. degree in chemistry or chemical engineering and two to five years experience in pharmaceutical crystallization processes. The Court also accepts Ratiopharm=s contention that a person skilled in the art can be a team of individuals.

Construction of the > 606 Patent

[13]            In every patent case, the first step the court must take is to construe the patent. With respect to the > 606 Patent, all claims are in issue and thus this Court must construe claims 1 to 4. Attached hereto as Annex A are:

a) Relevant portions of the patent disclosure, entitled Summary of the Invention (ASummary@), and

b) Claims 1, 2, 3 and 4.

[14]            Applying the provisions set out in paragraphs 10 and 11 above to the > 606 Patent and reading claims 1 to 4 as a person skilled in the art, informed by the disclosure of the patent would, the Court notes that:

1. The claims are directed to a product per se. The product in claims 1 and 2 is Clarithromycin (also known as 6-O-methylerythromycin A) Form II. It is characterized by its XRPD pattern, (also known as PXRD). The XRPD pattern in claim 2 is the same as that of claim 1, it is merely stated more precisely to two digits after the decimal point instead of one digit.

2. Claims 3 and 4 claim Clarithromycin Form II substantially free of Form I. Again, it is characterized by its XRPD pattern. The XRPD pattern in claim 4 is the same as that of claim 3, it is merely stated more precisely to two digits after the decimal point, instead of one digit.

3. The disclosure informs one that Clarithromycin Form II has known therapeutic effect as an antibacterial treatment for infections of the upper respiratory tract. No argument was raised before me regarding the eligibility of this patent as a claim for a medicine or the use of a medicine within the meaning of the NOC Regulations.

[15]            Abbott urged me to interpret the term AForm II@ in the patent as it appears in each claim as referring to the identity of Clarithromycin defined by reference to the IR spectrum, the XRPD pattern and the differential scanning calorimetric (ADSC@). Abbott referred to lines 1 to 4 of the Summary which state^[1]:

We have discovered that 6-O-methylerythromycin A can exist in at least two distinct crystalline forms, which for the sake of identification are designated AForm I@ and AForm II@. The crystal forms are identified by their infrared spectrum, differential scanning calorimetric thermogram and powder x-ray diffraction pattern.

In Abbott=s view, the word Form II is superfluous unless it is interpreted as incorporating the IR, XRPD and DSC identifiers.

[16]            I cannot accept this interpretation for the following reasons:

a) The claims themselves only refer to the XRPD pattern. There is no reference at all in the claims to either IR or DSC.

b) Lines 19 to 26 of the Summary provide the characteristics of Clarithromycin Form II by providing A(t)his novel crystalline antibiotic may be characterized by peaks in the powder x-ray diffraction pattern having the following 2θ [theta] values: (...)@ Again, there is no reference to IR or DSC.                                   

c) Lines 1 to 4 of the Summary referred to by Abbott=s counsel refer to both Clarithromycin Form I and Clarithromycin Form II. This first paragraph of the Summary gives background to both these forms but it does not provide the characteristics of Clarithromycin Form II. To find the characteristics of Clarithromycin Form II, one needs to look at lines 19 to 26 of the Summary and in the claims themselves (where one finds no mention of IR or DSC). It would be an improper expansion of the claims to read this background information (relating to both forms of Clarithromycin) as characteristics of Clarithromycin Form II and import such a reading into the claims.

d) Example 1 on page 13 of the Patent deals with the preparation of Clarithromycin Form I. It provides in lines 9 to 11:

6-O methylerythromycin A Form I is characterized by its infrared spectrum, the differential scanning calorimetric (DSC) thermogram and the powder x-ray diffraction pattern.

Surely if the drafter had meant to characterize Clarithromycin Form II by the IR and DSC as well as the XRPD he would have used the same language in the claims as was used in respect of Form I in Example 1.

e) 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)

f) The word AForm II@ is the name Abbott assigned to this particular polymorph of clarithromycin. It is does not have any meaning per se, nor is it a defined term of art.

[17]       Accordingly, I will proceed on the basis that the > 606 Patent describes the invention of a new polymorph of Clarithromycin. This new polymorph is designated Form II and is characterized by specific 2 theta values. Claims 1 and 2 refer to Clarithromycin Form II, while claims 3 and 4 refer to Clarithromycin Form II, substantially free of Clarithromycin Form I. The 2 theta values for claims 1 and 3 are given at the one decimal level, while claims 2 and 4 are given at the two decimal level. While drawings of the IR and the DSC patterns are annexed to the patent and referred to in the disclosure they are provided for illustration only and do not form part of the invention as claimed in any of claims 1 to 4.

Ratiopharm=s NOA

[18]            Ratiopharm in its NOA questions the validity of the > 606 Patent on the basis of invalidity claiming:

a) it was anticipated by Salem;

b) it was anticipated by Iwasaki;

c) it was anticipated by the prior sale of BIAXIN; and

d) it was obvious.                    

[19]            The issue for this Court to decide is if any of Ratiopharm=s allegations are justified. If so, Abbott will not succeed in its application for a prohibition order. The Court will examine these issues in the order listed above.

Invalidity - Anticipation by Salem

[20]            Ratiopharm alleges that the invention set out in the > 606 Patent was anticipated by an article by I.I. Salem entitled AClarithromycin found in analytical profiles of drug substances and excipients@, Volume 24, published by Academic Press Inc., San Diego in 1996. The > 606 Patent was filed on July 25, 1997 and has a claim date of July 29, 1996.

[21]            Ratiopharm alleges that the Salem article anticipates the claim date of the > 606 Patent. The exact allegations in the NOA state:

Claims 1 to 4 BDescribed in or obvious in view of prior publications

Compositions comprising clarithromycin Form II and their uses as claimed in each of claims 1 to 4 of CA > 606 were described in patents, patent applications and printed publications that were published more than one year before the filing date or prior to the claim date of CA > 606 and clarithromycin Form II and processes for its preparation were obvious in view of such references. Ratiopharm relies on the disclosures contained in the documents listed in Schedule 1 hereto. By way of example, the reference to Salem (document 43) discloses clarithromycin in which the powder X-ray diffraction (PXRD) pattern (Figure 4) and the differential scanning calorimetry (DSC) thermogram (figure 6) are the PXRD pattern and DSC thermogram of clarithromycin crystal Form II).

The Schedule 1 referred to in the above quote lists the Salem article as no. 43 but merely gives 1996 as the publication date.

[22]            There is no dispute that Salem describes crystalline Clarithromycin and that the Clarithromycin analyzed and reported by Salem has XRPD 2 theta values that are identical to the ones set out in claim 1 of the > 606 Patent.

[23]            To be successful with this argument, Ratiopharm has to produce evidence to satisfy subsections 28.2(1)(a) and (b) of the Patent Act, R.S.C. 1985, c. P-4:

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;   

[24]            Ratiopharm produced no other evidence. Abbott produced the affidavit of one Daniel Artola, a lawyer with the firm representing Abbott. This affidavit purports to establish that the book Analytical Profiles of Drug Substances and Excipients, Volume 24 (in which the Salem article appears) has, according to the publisher=s record, a publication date of July 25, 1996. The publisher=s records also show that the first order for the book was placed on that date. There is no evidence provided as to who ordered the book, when it was shipped or when it was delivered. There is merely some conjecture that its normal deliveries were shipped through UPS and that its delivery would have taken 5 to 7 business days. (Artola Affidavit, Applicant=s Record, Volume 7, Tab 32, paras 5 to 9.)

[25]            However, this evidence was obtained by phone from an employee of the publisher. The publisher refused to let the employee appear as a witness or swear an affidavit. The Artola affidavit, being based on information relayed over the telephone from an employee who has no personal knowledge and is not prepared to swear an affidavit, is of no probative value to this Court. Accordingly, it will be disregarded.

[26]          In any NOC proceedings, the NOA has to set out a detailed statement of law and facts the person making the allegations intends to rely upon. As stated by Stone J.A. in AB Hassle v. Canada (Minister of National Health and Welfare) [2000] F.C.J. No. 855 at paragraphs 20 and 21:

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.

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.

[27]            I do not see how this standard has been met in this case. On the basis of the NOA, the date of the publication of Salem is not known. In my view, Ratiopharm failed to set out any facts in its NOA on which it relies to assert the Salem article was available prior to the filing or claim date of the > 732 Patent. There is no need for Abbott to disprove this allegation.

[28]            I would note that this application in respect of the > 606, > 274, > 527, > 356, > 534 and > 361 patents is separate from the application in respect of the > 732 Patent. Although the two applications were heard contemporaneously, they are each governed by their separate records. However, the conclusion reached on this record is no different than the conclusion reached on the basis of the evidence contained in the record related to the > 732 Patent.

Invalidity - Anticipation by Iwasaki

[29]            Ratiopharm also alleges that the > 606 Patent was anticipated by the article of H. Iwasaki published June 15, 1993 in ACrystal structure communications@, Volume 49, Part 6.

[30]            That article clearly predates the filing of the > 606 Patent. It describes the molecular structure of 6-O methylerythromycin A (Clarithromycin). Under the heading AExperimental@, it sets out the crystal data as C38H69NO13.CH40. The dot (.) before the CH40 denotes that this is a solvate.

[31]            Dr. Hollingsworth, Ratiopharm=s expert, testified that the 2 theta values of the Iwasaki molecule can be readily calculated from its crystal structure. He states in his affidavit:

It is evident from the foregoing that the 6-O-methylerythromycin A analyzed and reported by Iwasaki has the identical PXRD 2 theta values as claimed in claim 1 of the > 606 Patent. Although Iwasaki=s 2 theta value of 19.23 would appear to lie outside of the claimed range of 19.0__0.2 (number 15) in claim 1, it is, in fact, within this range when rounded to one decimal place, consistent with the manner in which the values in claim 1 are reported. The Iwasaki 2 theta values also fall within the more precise 2 theta values listed in claim 2 of the > 606 Patent. It is also evident that there is no detectable Form I in the Iwasaki sample, and so it also falls within the scope of claims 3 and 4 of the > 606 Patent, which require the Form II to be substantially free of Form I.

(Respondent=s Record, Volume 9, Tab 14, para 133)

[32]            Similarly, Abbott=s expert Dr. Byrn states in his affidavit:

For the reasons set out above, Iwasaki discloses a methanol solvate structure that it not claimed in any of the Abbott Patents, which is indistinguishable (to examination of the powder xray diffraction pattern) from Form II but which is very clearly not Form II (Byrn Affidavit, Applicant=s Record, Volume 12, Tab 41, para 59). (Underlining added)

Conclusion regarding the > 606 Patent

[33]            Abbott maintains that Clarithromycin Form II is not a solvate and therefore cannot have been anticipated by Iwasaki. While I found in the > 732 Patent proceedings that Clarithromycin Form II as referred to in that patent does not include a solvate, that is irrelevant for this application. Here we are dealing with the > 606 Patent which I have construed to be solely characterized by its XRPD pattern. The experts for both sides agree that the XRPD pattern which can be calculated from the Iwasaki molecule is identical to that of the > 606 Patent. Since the > 606 Patent did not claim any characteristics other than the XRPD pattern and as this pattern was already available to the public due to the Iwasaki publication, the > 606 Patent is anticipated by Iwasaki.

[34]            Given my findings regarding anticipation by Iwasaki, I see no necessity to deal with Ratiopharm=s allegation regarding invalidity due to the prior sale of BIAXIN or invalidity based on obviousness. In my view, Abbott has failed to disprove Ratiopharm=s allegations of invalidity, based on anticipation by Iwasaki.

> 274 Patent

Patent Construction

[35]            As noted previously, in every patent dispute, the first step the court must take is to construe the patent. Both sides agree that with respect to the > 274 Patent, only claims 1, 4, 5 and 16 are in issue. For ease of reference, Annex B attached hereto sets out:

a) the portion of the disclosure entitled Summary of the Invention, and

b) claims 1, 4, 5, and 16.

[36]            Applying the provisions set out in paragraphs 10 and 11 above to the > 274 Patent and reading the disclosure and claims 1, 4, 5 and 16 together as would a person skilled in the art, the Court notes that:

1. This is a product per se patent. The invention in claim 1 is the crystalline structure of an antibiotic designated as Clarithromycin Form 0. It is a solvate with the solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

2. Claim 16 is identical to claim 1 except that it claims Apure@ Clarithromycin Form 0, i.e. Form 0 substantially free of Form I or Form II.

3. Claims 4 and 5 are dependent on claim 1 and describe Clarithromycin Form 0, solvated from ethanol, by providing its XRPD pattern which shows 16 peaks in 2 theta values to one decimal and two decimals points respectively.

4. Claims 1 and 16 cover Clarithromycin Form 0 made from four solvents.

5. All the claims in issue are for an antibiotic. In reading the disclosure, we know that this is an antibiotic that has therapeutic utility to fight infections of the upper respiratory tract in children and adults. However, no claims regarding the use of this antibiotic are made and one has to refer to the disclosure to understand what is meant by the word Aantibiotic@.

[37]            Ratiopharm made four allegations at the hearing, namely:

1. All the claims in issue are for Form 0 used as an intermediate in the manufacture of Clarithromycin Form II, they are not a claim for the medicine itself, nor for the use of the medicine and therefore are not eligible under the NOC Regulations.

2. In the alternative, if the claims in issue are claims for Form 0 as the medicine itself, or for the use of the medicine, they cannot be asserted against an intermediate under the NOC Regulations.

3. Its manufacturing process (called CLX) does not involve the use, complex or suspension of Clarithromycin Form 0 as claimed.

4. The discovery of Clarithromycin Form 0 was inherent and obvious in light of the prior art.

Allegation 1 - Claim for the medicine

[38]            Ratiopharm alleges that the claims in issue regarding the > 274 Patent are claims for an intermediate and not claims for a medicine and thus, pursuant to Eli Lilly v. Apotex (1995) 63 C.P.R. (3d) 245, are not eligible for listing under the NOC Regulations. Abbott asserts that they are claims for a medicine within the meaning of the NOC Regulations.

[39]            Abbott=s expert, Dr. Byrn stated the following regarding Form 0 as a medicine in one of affidavits:

161.      However, after the invention of Form 0 and Form I, Abbott determined and disclosed in the Abbott Patents that Form 0 and Form I are less thermodynamically stable than Form II (see page 2, lines 12 and 13 of the > 606 Patent and lines 22 to 24, page 1 of the > 274 Patent).

162.      The fact that Form II is the most thermo-dynamically stable crystal form of

clarithromycin known at the date of the Abbott Patents necessarily entails that it is the least soluble of the three solid forms invented and claimed by Abbott in the patents.

163.      Once the antibiotic activity of the clarithromycin molecule in known, but only after they are determined to be less thermodynamically stable, it then follows that Form 0 and Form I must be useful as medicines to treat infections in the same way that Form II has been demonstrated to be useful.

164.      Once the crystals were identified and their thermodynamic stability relative to Form II was ascertained, one could conclude, with certainty, that crystal Form 0 and Crystal Form I of clarithromycin would be useful as medicines themselves.

165.      ratiopharm is incorrect to assert that Form 0 and Form I are anything but the medicine in issue in this case.

166.      The medicine in BIAXIN7 is clarithromycin and each Form 0, Form I and Form II are useful forms of the medicine in BIAXIN7. (Underlining added)

(Applicant=s Record, Volume 12, Tab 41, paras 161-166)

[40]            Abbott=s expert Dr. Atwood observed in his affidavit:

136.     The > 606 Patent identifies Form II as an antibiotic. An antibiotic is a medicine. The medicine is clarithromycin. Abbott has invented three crystal forms [forms 0, I and II] which are all an antibiotic medicine. (Underlining added)

(Applicant=s Record, Volume 10, Tab 35, para 136)    

[41]            Ratiopharm=s own expert Dr. Hollingsworth went further and suggested the word antibiotic signified that the > 274 Patent is a claim for Form 0 when used as a medicine. He stated:

57. Furthermore, in my opinion, a person skilled in the art would construe claim 1 as being directed to clarithromycin Form 0 when used as an antibiotic therapeutic agent. The wording of claim 1 is not directed to A6-O-methylerythromycin A Form 0" per se, but is instead directed to a Acrystalline antibiotic designated 6-O-methylerythromycin A Form 0".

58. In this regard, the disclosure of the > 274 Patent admits that 6-O-methylerythromycin A Form 0 per se is not new. The patent states at page 2:

6-O-methylerythromycin A prepared by the various methods described in the patent literature summarized below, in which the compound is purified by recrystallization from ethanol, result in initial formation of the crystalline form 0 ethanolate                  

(...)

Accordingly, the present invention in its principle embodiment provides a novel crystalline antibiotic designated 6-O-methylerythromycin A form 0 solvate (...)

59. From the foregoing, it is evident that the alleged invention is the apparent novel use of the known Form 0 solvate as an antibiotic. The inclusion of the word Aantibiotic@ in claim 1 seems directed to distinguishing the claim over the admitted prior art. Accordingly, on a proper construction, claim 1 must be construed as covering Form 0 as an antibiotic. (Underlining added)

(Respondent=s Record, Volume l9, Tab 14, paras 57-59)

[42]            The Court notes that the words Afor use as an antibiotic@ do not appear anywhere in the claims in issue of the > 274 Patent. By contrast, the divisional Patent > 356 (which was applied for and issued on the same dates as the > 274 Patent) specifically states both in the disclosure and in the claims portion that it is a patent for the use of Form 0 as an antibiotic. Merely employing the word Aantibiotic@ in the claim does make claim 1 or 16 claims for the use of Clarithromycin Form 0 as an antibiotic.

[43]            The Court rejects Dr. Hollingworth=s interpretation and finds Dr. Byrn=s interpretation more persuasive. The word antibiotic is used to identify the product of the invention as a medicine, but it would be excessive to suggest that this one word converts the claims in issue to claims for the use of the product as a medicine.

[44]          Recalling once again Binnie J.=s observation in Whirlpool, supra:

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)

Thus, in this case it is permissible to look at the disclosure to understand what is meant by Aantibiotic@ but it would be wrong to enlarge or contract the claim to import the notion of a claim Afor the use as@ from the disclosure.

[45]            As far as being restricted to intermediaries alone, the Court notes that the background information in the disclosure of the > 274 Patent states in line 21 on page 2: A6-O-methylerythromycin form 0 solvate is also a useful intermediate in the preparation of the nonsolvated 6-O-methylerythromycin A forms I and II@. The use of Aalso@ appears to negate any idea that Clarithromycin Form 0 is restricted to intermediaries and, on the contrary, suggests that it can be used both as an intermediary and as a medicine.

[46]            Accordingly, claims 1, 4, 5 and 16 of the > 274 Patent are claims for a medicine and are not restricted to claims as intermediaries. The > 274 Patent therefore qualifies as Aa patent containing a claim for the medicine itself@ within the meaning of section 4 of the NOC Regulations and thus is eligible to be listed pursuant to the NOC Regulations. Ratiopharrm=s allegation is not justified.

Allegation 2 - Assertion against intermediates

[47]            Ratiopharm, asserts in the alternative that even if Clarithromycin Form 0 is eligible for listing under the NOC Regulations, it can only be asserted against the final product produced by a second person, it cannot be asserted against an intermediate product used by the second person.

[48]            Abbott does not suggest that the final product resulting from Ratiopharm=s manufacturing process contains Form 0. Abbott=s experts, however, allege that Form 0 is produced in phase 5 of Ratiopharm=s CLX. This, in their view, constitutes infringement of Abbott=s > 274 Patent. They rely on Saccharin Corporation Ltd. v. Anglo Continental Chemical Works Ltd. (1900) 17 RPC 307 at 319 where Buckley J. stated:

If the patented process were the last stage in the production of the article sold, the importation and sale of the product would, in my opinion, plainly be an infringement. Does it make it any the less an infringement that the article produced and sold is manufactured by the use of the patented process which is subjected to certain other processes? In my opinion it does not. By the sale of saccharin, in the course of the production of which the patented process in used, the Patentee is deprived of some part of the whole profit and advantage of the invention, and the importer is indirectly making use of the invention. In my judgment, therefore, this contention fails.           

This so called Saccharin doctrine was recently affirmed by the Supreme Court of Canada in Montsanto v. Schmeiser (2004) 31 CPR (4^th) 161.

[49]            Abbott further relies on Pfizer Canada Inc v. Novopharm, 2004 FC 1633 where my colleague Gibson J. stated at paragraph 62:

To paraphrase portions of the quotation from Schmeiser, here Novopharm seeks to use what may well be a patented part that will be contained within something that is not patented, that is to say, Novopharm's 250 mg tablets strength azithromycin monohydrate product. The bulk azithromycin monohydrate that Novopharm proposes to import and to use would be a significant or important part of Novopharm's end product; indeed, it would appear that it would be by far the central part of that product. If this were allowed to happen, and if azithromycin dihydrate is formed in the intermediate steps for making Novopharm's bulk azithromycin, the Applicants would be deprived, indirectly, of the monopoly that the grant of the '876 Patent intends to be theirs. Its full enjoyment of the monopoly conferred would be substantially impaired.

[50]            Several points distinguish Pfizer, supra, from the present case:

First, I would note that Gibson J. did not decide that case on the basis of the Saccharin doctrine, but ruled that the NOA was insufficient.

Secondly, there is no evidence in this case that Ratiopharm=s manufacturing process will take place abroad, the central issue in Saccharin.

Thirdly, and in my view most importantly, Saccharin dealt with infringement of patent rights. The present case is not an infringement action but an application for prohibition under the NOC Regulations and, therefore, the exigencies of the NOC Regulations must be met. It is well established that the NOC Regulations are a self-contained code for dealing with allegations of infringement in the context of Notices of Compliance issued by the Minister of Health.

[51]            Subsection 5(1)(b)(iv) of the NOC Regulations 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 (...) another drug (...) and that other drug has been marketed in Canada pursuant to a notice of compliance issued to a first person and in respect of which a patent list has been submitted, the person shall, in the submission, with respect to each patent on the register in respect of the other drug,

(...)

(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)

[52]            Section 7 similarly states:

7 (1) The Minister shall not issue a notice of compliance to a second person before the latest of

(...)

(e) subject to subsections (2), (3) and (4), the expiration of 24 months after the receipt of proof of the making of any application under subsection 6(1), and

(f) the expiration of any patent that is the subject of an order pursuant to subsection 6(1).

(2) Paragraph (1)(e) does not apply if at any time, in respect of each patent that is the subject of an application pursuant to subsection 6(1),

(...)

(b) the court has declared that the patent is not valid or that no claim for the

medicine itself and no claim for the use of the medicine would be                                                            infringed.(Underlining added)

[53]            Thus, while I do not dispute that the Saccharin doctrine applies in Canada and any production of Form 0 in Ratiopharm=s production process could (if the necessary evidence can be adduced) constitute infringement in an infringement action on the basis of Pfizer, supra, that is not the issue here. This Court must determine if it is infringement under the NOC Regulations and they demand that there be infringement of the claim for the medicine itself or infringement of the claim for the use of the medicine. Clearly that is not the case here. At best, there could be infringement by the product resulting from stage 5 of Ratiopharm=s CLX. However, the result of stage 5 of the CLX is not Ratiopharm=s final product, but an intermediate product. This intermediate is not made, constructed, used or sold as a medicine but is merely a way station on the road to the final product. Thus, it defies logic to say the production of this intermediate product (assuming for argument=s sake that it is Form 0) infringes on the claims of the > 274 Patent for the medicine itself and/or for the use of the medicine.

[54]            I, therefore, find that Abbott has not disproven Ratiopharm=s second allegation with respect to the =274 Patent. While this finding is dispositive of the application for prohibition in favour of Ratiopharm, I will examine Abbott=s other allegations, in the event that my conclusion, as set out in paragraph 53, is reversed on appeal.

Allegation 3 - Infringement by Ratiopharm=s CLX

[55]            Abbott alleges that Ratiopharm=s CLX produces Clarithromycin Form 0. Stage 5 of

Ratiopharm=s process does not refer to Form 0. Instead it sets out the process as follows: ADescription of Production Process of CLX-V (Purification)@

01.        Charge absolute alcohol

02.        Prepare Hyflow bed in absolute alcohol

03.        Charge crush clarithromycin

04.        Apply heating and reflux for 30 minutes

05.        Filter the material and collect filtrate.

06.        Charge filtrate material and to 75 to 80EC.

07.        Cool slowly to 0 to 5EC and maintain for 2 hours.

08.        Filter the material and wash the cake with chilled absolute alcohol.

09.        Unload the material, weigh

10.        Charge absolute alcohol

11.        Charge 1st purified clarithromycin

12.        Apply heating and reflux for 30 minutes

13.        Filter the material in hot condition. Collect the filtrate.

14.        Charge filtrate material, heat to 75 to 80EC and cool slowly to 0 to 5EC and maintain for 2 hours.

15.        Filter the material and wash the cake with chilled absolute alcohol.

16.        Unload the material, weigh and send the sample to QC for related substances by the HPLC.

17.        If sample fails to meet the specifications, repeat steps 01 to 16.

18.        After analysis, dry the material at 115 to 120EC under a vacuum of not less than 550 mm Hg up to 12 hours.

19.        Send the sample for complete analysis.

(Applicant=s Record, Volume 9, Tab L, p. 1717)

[56]            Abbott relies on the affidavit of Dr. Atwood who reproduced Ratiopharm=s process in the laboratory and observed Clarithromycin Form 0 which fell within the 2 theta values of claims 4 and 5 of the > 274 Patent. (Applicant=s Record, Volume 10, Tab 35, para 169)

[57]            Dr. Atwood also reviewed an experiment conducted by a Dr. Chyall that simulated stage 5 of Ratiopharm=s CLX. In his view, this experiment confirms that step 16 of stage 5 of the CLX produces Form 0. (Applicant=s Record, Volume 10, Tab 37, para 2)

[58]            Similarly, Dr. Myerson, at paragraph 15 of his affidavit, comes to the conclusion that Ratiopharm produces Clarithromycin at step 5 of its CLX. (Applicant=s Record, Volume 12, Tab 40, para 115)

[59]            Even Ratiopharm=s expert Dr. Hollingsworth in his affidavit stated:

As the Form 0 in Ratiopharm=s process is not used as an antibiotic, it does not fall within the scope of claim 1 (...) as properly construed in the context of the specifications of the > 274 Patent as a whole. (Underlining added)

(Respondent=s Record, Volume 9, Tab 14, para 60)

[60]            In addition Dr. Eckhardt, on cross-examination, conceded that stage 5 of the CLX would more likely than not result in a solvate from solvent X. The exchange was as follows:

Q.         (By Mr. Reddon) But in case of solvent X, the thing like the Form II solvate is the Form 0 solvent X. Fair?

A.         All I could say is. I could safely say for you without too much trepidation that undoubtedly solvates formed. I am not convinced - - I mean, one of the problems, I=m sure, as you well know, in this industry is knowing all the solvates or polymorphs that are possible. In fact I=m working on that problem right now.

So it would be foolhardy to say that such things do not form. But I don=t think I could say exactly what- - what solvate forms.

Q.         But it would be equally foolhardy, though, in respect to multiple solvates to say in

            147062 that it=s necessarily the Form 0 solvent X solvate - -

A.         No. I don=t think I said necessarily. If I did, I will retract. I=ll say probably. But

            there again, I don=t have the multiplicity of procedures. I don=t have the plausible introduction of - - I don=t have the control of conditions in the sense that I do in the laboratory.       

I=m much more uncomfortable with this complicated a process that is going on here. In fact, even the multiple washings make me wonder exactly what=s happening. So I - - you know, I - - to my mind, there=s a world of difference between the - - what the bench chemist does and what - - the batch.                  

And this is one of the problems with chemical engineering, of course, is taking something from the bench and putting it into industrial processes. And when they do that, all kinds of nasty things can happen.

And I=m just - - you know, I mean, I may seem overly cautious, but I don=t think that I=m comfortable - - I=m comfortable with the basic science in saying, yes, something is going to form. Exactly what it is, I=m worried.

Q.         You=re comfortable saying it would be a solvate?

A.         Some kind of solvate.

Q.         You=re comfortable saying it=s a solvent X solvate, because they=re using solvent X?

A.         I=m saying any of these solvents could form a solvate.

Q.         Right. But you=re comfortable saying that at step - - at page 25, not with certainty, but with likelihood, it=s probably a solvate and probably a solvent X solvate?

A.         I=m saying it=s possibly a solvate if solvent X forms, yes.

Q.         More likely than not. Fair?

A.         More likely than not.

Q.         Do you know of any solvate of clarithromycin with solvent X that=s not a Form 0 solvent X solvate?

A.         That=s not Form 0? No. But that doesn=t mean there isn=t one. (Underlining added)

(Applicant=s Record, Volume 13, Tab 42, pages 80-83)

[61]            Ratiopharm, on the other hand, relies on its expert Dr. Eckhardt who suggests:

a) The first Atwood experiment cannot be trusted as he did not faithfully reproduce the CLX process, improperly drying the cake and reducing its weight by 20%. (Respondent=s Record, Volume 10, Tab 16, para 145)

b) The Chyall experiments also cannot be trusted as it is not clear whether he simulated steps 1 to 9 or steps 10 to 16 of the CLX. More importantly, the CLX process starts with Acrude clarithromycin@, while it is not clear what Dr. Chyall started with. The presence of impurities, however, is vital to the formation of polymorphs. (Respondent=s Record, Volume 10, Tab 17, paras 9-12)

c) The cross-examination of Dr. Hollingsworth confirmed the importance of impurities and the difference between the laboratory process and an industrial process. (Applicant=s Record, Volume 14, Tab 43, pp. 105, 112, 126 and 130).

[62]            While Dr. Eckhardt noted several shortcomings of the laboratory tests in his affidavit and these were not challenged or impugned on cross-examination, this is not dispositive of the issue. It is not surprising that the experimental laboratory process did not entirely duplicate the CLX. On the other hand, Dr. Atwood, Dr. Myerson and Dr. Hollingsworth all stated that Form 0 would be produced in the CLX. Dr. Eckhardt=s concession that more likely than not a solvent X solvate would be produced, coupled with his admission that he was unaware of any other solvent X solvate aside from Form 0, are tantamount to conceding this point.   

[63]            On the basis of these facts, the Court concludes that Abbott has, on a balance of probabilities, disproven Ratiopharm=s allegation that the CLX process does not infringe the > 274 Patent. The evidence establishes that Clarithromycin Form 0 is produced as an intermediate at Stage 5 of the CLX.

Allegation 4 - Obviousness

Inherency

[64]            Ratiopharm alleges that the > 274 Patent is invalid as the discovery of Form 0 was inherent in the discovery of Clarithromycin. It bases its argument on the following: Long before the claim date of the > 274 Patent, authors Morimoto, Watanabe, and Iwasaki found solvates of Clarithromycin. Ratiopharm also points out that US Patent 4,990,602 and EP 260,938 teach how to crystalize Clarithromycin from ethanol. It points to the evidence of Dr. Myerson (Applicant=s Record, Volume 12, Tab 40, para 177) and Dr. Byrn (Applicant=s Record, Volume 12, Tab 41, para 262) that Form 0 is produced whenever one produces either Form I or Form II.

[65]            Consequently, there is nothing new in the discovery of Form 0, it was inherent in previous crystallizations of Clarithromycin. It is Ratiopharm=s contention that the mere capping of the wet solvate amounts to nothing more than the use of a Tupperware container.

[66]            Ratiopharm relies on Merrell Dow Pharmaceuticals Inc. v. H. N. Norton & Co. Ltd., [1996] R.P.C. 76 (H.L.) for the often repeated dictum found on page 90:

In other words, if the recipe which inevitably produces the substance is part of the state of the art, so is the substance as made by the recipe.

Ratiopharm alleges that in this case the recipe for making Clarithromycin was known. Anyone producing either Clarithromycin (be it what is now known as From I or Form II) produced, albeit unwittingly, Form 0.

[67]            Ratiopharm argues that what Abbott did was verify the existence of Form 0. That is not an invention. Rather as established by SmithKline Beecham Pharma Inc. v. Apotex Inc. 21 C.P.R. (4th) 129, the mere verification of properties of a known substance does not involve any inventive skill.

[68]            Neither of these arguments is convincing. SmithKline Beecham dealt with anticipation, not obviousness and thus does not apply in these circumstances. As stated in that case at paragraph 22:

I do note, however, that anticipation and obviousness are distinct concepts (R. Hughes et al., supra, at 328). As Hugessen J.A. explained in Beloit, supra, obviousness alleges that "any fool could have done that", while anticipation alleges that "your invention, though clever, was already known".

[69]            As far as the principle of Merrell Dow, supra, is concerned, I fail to see how it applies here. Until Abbott discovered Form 0, its existence and its characteristics were unknown. Anyone following the Arecipe@ of the prior art would arrive at Clarithromycin in Form I or II. No one knew of the existence of an unstable polymorph that would disappear as a result drying.

[70]            As far as inherency is concerned, I am not aware of such a concept in Canadian patent law. It seems to me to be merely another label for anticipation. Ratiopharm really argues that anyone following the prior art would have produced Form 0. However, in order for such prior art to be anticipatory, it must meet the test in Beloit Canada v. Valmet (1986) 8 CPR (3d) 289 where Hugessen J. stated:

It will be recalled that anticipation, or lack of novelty, asserts that the invention has been made known to the public prior to the relevant time. The inquiry is directed to the very invention in suit and not, as in the case of obviousness, to the state of the art and to common general knowledge. Also, as appears from the passage of the statute quoted above, anticipation must be found in a specific patent or other published document; it is not enough to pick bits and pieces from a variety of prior publications and to meld them together so as to come up with the claimed invention. One must, in effect, be able to look at a prior, single publication and find in it all the information which, for practical purposes, is needed to produce the claimed invention without the exercise of any inventive skill. The prior publication must contain so clear a direction that a skilled person reading and following it would in every case and without possibility of error be led to the claimed invention.(Underlining added)

[71]            On cross-examination, Ratiopharm=s expert Dr. Eckhardt admitted that a person skilled in the art, applying conventional drying techniques, would be led directly and without difficulty to Form I, substantially free of Form II (Applicant=s Record, Volume 14, Tab 42, p. 150). There is no mention that it would lead to Form 0. Ratiopharm has not established that it was inherent that any skilled person producing Clarithromycin under the prior art would Ain every case and without possibility of error be led to the claimed invention [Form 0] without the exercise of any inventive skill@.

Obviousness

[72]            Ratiopharm=s other argument is that the invention of Form 0 was obvious in light of the prior art.

[73]            The test for obviousness was also spelled out by Hugesson J in Beloit, supra:

The test for obviousness is not to ask what competent inventors did or would have done to solve the problem. Inventors are by definition inventive. The classical touchstone for obviousness is the technician skilled in the art but having no scintilla of inventiveness or imagination; a paragon of deduction and dexterity, wholly devoid of intuition; a triumph of the left hemisphere over the right. The question to be asked is whether this mythical creature (the man in the Clapham omnibus of patent law) would, in the light of the state of the art and of common general knowledge as at the claimed date of invention, have come directly and without difficulty to the solution taught by the patent. It is a very difficult test to satisfy.

[74]            Furthermore, Hugesson J. suggested that in examining obviousness, the following classic question must be answered:

Every invention is obvious after it has been made, and to no one more so than an expert in the field. Where the expert has been hired for the purpose of testifying, his infallible hindsight is even more suspect. It is so easy, once the teaching of a patent is known, to say, "I could have done that"; before the assertion can be given any weight, one must have a satisfactory answer to the question, "Why didn't you?"

[75]            Here, Dr. Myerson testified that it was not intuitive to assume that:

a) there are different polymorphs of Clarithromycin;

b) some of these polymorphs are unstable; and

c) one should analyse first and dry later

(Applicant=s Record, Volume 12, Tab 40, para 145)

[76]            The inventive portion of Abbott=s discovery was to seal the wet Clarithromycin to prevent drying and analyse it. Dr. Myerson, under cross-examination, suggested that drying was standard practice to remove adhering solvent which might interfere with the analysis (Respondent=s Record, Volume 5, Tab 9, pp. 354, 359).

[77]            Dr. Byrn provided a good description of the inventive process concerning solvates in his affidavit:

While it is true to say that the laboratory and analytical techniques necessary to the

inventive process are routine, the adoption of an investigative approach, selection of conditions and solvents, the modification of the approach as different results are obtained, and ultimately the invention of polymorphic forms and processes to make them, is based on intuition, experience, and some times good luck. The process is not simple or unimaginative and, in my opinion, success often requires significant experience, ingenuity and inventive thought combined with a certain amount of good luck. Numerous experiments with many variables must usually be conducted just to find which solid forms will crystallize, let alone a solid form that will be suitable for use as a marketable pharmaceutical. Indeed, there are over a million possible different experiments if one conservatively assumes 60 different solvents, 60 possible co-solvents, 10 different temperatures, 10 different cooling rates, and 10 different concentrations. A failed experiment provides no information to a chemist as to what to try next. The chemist could just repeat the experiment and wait longer for a crystal to form. Whole departments have been created within pharmaceutical companies to carry out the search for solid forms of drug compounds having the desired qualities. Likewise, the company I founded, SSCI, along with several other companies, specializes in finding solid forms of drug substances. Once a solid form is discovered a method of isolation/drying must be found. This adds additional variables to the process.

(Applicant=s Record, Volume 12, Tab 41, para 100)

[78]            Abbott also points to Ratiopharm=s Dr. Eckhardt who under cross-examination stated:

Q.         So despite the fact that he had IR results, whatever deductive reasoning

was necessary to discover Form 0 of Form I does not have - - that appears from the article to have eluded Dr. Salem. Fair?

A.         It appears that is has eluded him, yes.

(Applicant=s Record, Volume 13, Tab 42, p. 186)     

He also conceded that for 15 years no one discovered Form 0 despite dozens of papers on the subject:

Q.         Well, the fact is, for whatever reason, whether they were uninterested or

not, there are dozens of references in Ratiopharm=s notice of allegation showing instances in which a person skilled in the art have crystallized clarithromycin between 1981 and 1996?

A.         Yes.

Q.         And none of them, including Salem in 1996 with a DSC and an IR in

hand, ever reported Form 0 or Form I. Is that fair?

A.         Correct.

(Applicant=s Record, Volume 13, Tab 42, p. 187)

[79]            By contrast, Ratiopharm notes that the capping of the wet solvate is not referred to in the claims of the > 274 Patent. It also refers to Dr. Eckhardt=s testimony that it is routine to cap if you want to maintain the solvate crystal(Respondent=s Record, Volume 10, Tab 16, para 158.)

[80]            Similarly, Dr. Hollingsworth noted in his affidavit that a person skilled in the art would follow the following procedure:

The skilled chemist would also expect that drying the solvate crystals might or

might not convert the solvate to some other unsolvated crystal form. Basic and routine of tests would have been followed by the person skilled in the art to analyze the solids obtained by filtration both before and after drying to determine the rate and extent of solvent loss. This would reveal that the Form 0 solvate loses solvent fairly readily when exposed to air. Recognizing this, any skilled chemist intent on analyzing the properties of the solvate would, without a doubt, take the appropriate steps to prevent exposure to air (e.g., by storing in a sealed container), thereby ensuring that the properties analyzed are those of the solvate, without risking conversion to some other polymorphic or pseudopolymorphic form. In short, the skilled chemist would store the solvate crystals in a sealed container. Not to do this would constitute negligence on the part of the skilled chemist.

(Respondent=s Record, Volume 9, Tab 14, para 159)

[81]            Dr. Hollingsworth also pointed out that researchers in the 1980s such as Morimoto and Iwasaki would be looking for solvates (Applicant=s Record, Volume 14, Tab 13, paras 224-226).

[82]            All of this then brings us to the key question: If capping and analysing the wet solvate was so obvious why did no one do it before Abbott? No answer was provided by Ratiopharm. Without answering that question, obviousness cannot be established.

[83]            The Court notes Ratiopharm=s failure to answer the Beloit, supra, question. It also accepts the logic of Dr. Myerson=s evidence that it is standard procedure to dry the solvate before analysing it, so as to avoid errors caused by adhering solvent. It finds the description of the inventive process by Dr. Byrn very persuasive which suggest more than deductive reasoning was required to find Form 0. Lastly, there is the indisputable fact that over 10 years had elapsed between the appearance of articles regarding the crystallization of Clarithromycin and the claim date for the =274 Patent, yet no one discovered Form 0.

[84]            Consequently, on a balance of probabilities, Abbott has disproved Ratiopharm=s allegation that the > 274 Patent is void for obviousness.

Conclusion with respect to the > 274 Patent

[85]            Having found in paragraph 53 above that Abbott cannot assert the > 274 Patent against Ratiopharm=s intermediate product under the NOC Regulations, Abbott is not entitled to the prohibition order it seeks as far as the > 274 Patent is concerned.

> 361 Patent

[86]            The > 361 Patent is a product-by-process patent providing for the production of Clarithromycin Form II from Clarithromycin Form 0, for use as an antibiotic.

[87]            Claim 1 of the > 361 Patent is the claim in issue. It is relatively straight forward and provides for:

A process for the preparation of 6-O-methylerythromycin A From II comprising heating 6-O-methylerythromycin A Form 0 solvate under vacuum at a temperature of between about 70_C and 110_C.

(Application Record, Volume 8, Tab 33F, p. 1604.)

[88]            The key to this invention is obviously the drying at Aa temperature of between about 70_C and 110_C@.

[89]            The process used by Ratiopharm to manufacture its final product is described at Step 18 of its production process as:

After analysis, dry the material at 115_C to 120_C under a vacuum of not less than 550 mm Hg up to 12 hours.

(Respondent=s Record, Volume 13, Tab 24, para 203.)

[90]            Ratiopharm alleges that the temperature used in its method of manufacture falls outside the range described in the patent and, therefore, there is no infringement of Abbott=s patent. It advances that Abbott=s invention is based on the temperature at which the solvate is dried. This drying temperature is the key variable in the claimed production process and, as a result, the temperature detailed in the patent should be strictly adhered to.   

[91]            Abbott asserts that the > 361 Patent is infringed because a person skilled in the art would understand, in reading the patent as a whole, that heating at 115_C to 120_C is either covered by the claims of the > 361 Patent or would be an obvious chemical equivalent.   

[92]            The > 361 Patent must be construed by reference to paragraph 10 set out above. The essential issue in this patent is whether or not the term Aabout@ in the > 361 Patent allows the upper range of 110_C to be extended to cover 115_C, given that 115_C is the low end of the temperature range used by Ratiopharm in the manufacture of its product.

[93]            Abbott=s expert, Dr. Myerson deposed that:

A person skilled in the art would understand the term Aabout@ used in claim 1 to mean within a range of 5 percent. In this case, this means plus or minus 5_C. Thus, a person skilled in the art would read claim 1 to include heating Form 0 at temperatures slightly higher than 115_C.

(Applicant=s Record, Volume 12, Tab 40, para 189.)

[94]            It is unclear to which base temperature Dr. Myerson is applying the 5%. A result of plus or minus 5_C would mean he is applying 5% to 100_C which is a rather imprecise choice of temperatures. If one uses a variation of 5% and applies it to the median temperature of 90_C, the variable amount would be 5% of 90_C which is 4.5_C and the range would be 65.5_C to 114.5_C. If, on the other hand, one applies the 5% to the range itself (being 70_C to 110_C or 40_C), this would only result in a 2_C variation and the range would be 68_C to 112_C. Either way, the upper end of Abbott=s stated range would not reach 115_C, being the lower end of Ratiopharm=s range of 115_C to 120_C. A temperature range of 65.5_C to 114.5_C or a temperature range of 68_C to 112_C obviously does not cover 115_C to 120_C as well.

[95]            Dr. Atwood deposed that:

The claims of the > 361 patent indicate a temperature for heating at Aabout 70_C and 110_C@. A person skilled in the art would know, upon reading the patent as a whole, that heating at 115_C to 120_C is either covered by the claims of the > 361 Patent (since temperature in an oven typically cycles by 10_C above and below the temperature it is set at), or be an obvious chemical equivalent. Heating at 115_C to 120_C would be known to a person skilled in the art to perform the exact same function in the exact same manner as heating at 110_C. A person skilled in the art would not think that the patentee intended to limit the scope of the claim to processes which heat below 110_C, and above 70_C since the claim uses the word Aabout@.

(Applicant=s Record, Volume 10, Tab 35, para 190.)

[96]            I find Dr. Atwood=s explanation of the heating temperature described in the patent is not tenable. Dr. Atwood=s construction of the patent is not commensurate with the well established principle that a patent must disclose to the public how the invention is made. It is reasonable to expect that the teachings of the patent in relation to the temperature are meant to be strictly adhered to in order to obtain the promised result.

[97]            Secondly, a person skilled in the art and knowing about the 10_C cycle above and below the temperature set, (as mentioned by Dr. Atwood) would surely select a temperature in the middle of the prescribed range of 70_C to 110_C. I would expect such a person to use 90_C, thus allowing the presumed cycle of 10_C to stay within the range. It is absolutely illogical to assume such a person, with the knowledge of cycling described by Dr. Atwood, would set the temperature at the high end of the range and still expect to obtain the promised result.

[98]            In Apotex Inc. v. Syntex Pharmaceuticals International Ltd. et al. 1 C.P.R. (4^th) 22 Reed J. dealt with a similar issue. In that case, the relevant portion of claim 1 read as follows:

1. A controlled release tablet (...) comprising a homogenous matrix comprising:

about 4-9 weight percent of hydroxypropylmethylcellulose (...)

[99]            Reed J. stated at paragraph 45 that if no specific definition is described in the patent, as is the case here, the ordinary meaning of the word applies. She said the word Aabout@ carries a dictionary definition of Anear@ or Aclose@ and that in the case before her this signified Aa flexibility no greater than half way to the next number@, ie. 3.5 to 9.5. She reasoned as follows:

A percentage below 3.5 or above 9.5 is not near or close to 4 or 9, respectively, but to 3 and 10. One would expect that the patentee would have described the permissible range as from about 3-10 had a range closer to 3 than 4 and closer to 10 than 9 been intended.

[100]        Of the three models suggested above, it strikes me that Dr. Myerson=s interpretation is the most reasonable (ie. _ 5%), even if I disagree with his mathematical calculations. However, applying his theory of a range of 5% to either of the two alternatives discussed in paragraph 9 above does not result in an overlap with the lower end of Ratiopharm=s range of 115_C to 120_C .

Conclusion regarding the > 361 Patent

[101]        Accordingly, I find that Abbott has not shown on a balance of probabilities that Ratiopharm=s process infringes claim 1 of the > 361 Patent.

Additional Comments

[102]        This application was argued for six days in Ottawa. As large portions of the record were confidential, the Court on July 11, 2005 send 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 Asolvent A@ and Asolvent X@. Accordingly, these reasons for judgment are issued in a redacted public version and an unredacted confidential version.   

[103]        However, counsel for Ratiopharm in a letter dated July 12, 2005 sent an unsolicited submission to the Court pointing out that with respect to the > 274 Patent the draft reasons did not accord with the draft order. The Court held a telephone conference with the parties on this issue and there being disagreement between counsel, ordered on July 15, 2005 that Abbott comment in writing, no more than three pages long, on Ratiopharm=s unsolicited submission. Abbott=s comments were sent to the Court on July 21.

[104]        Upon consideration of Ratiopharm=s unsolicited submission and Abbott=s reply, the Court amended its draft order. As Ratiopharm correctly pointed out, in the collation of the reasons the Court overlooked the fact that the finding in paragraph 53 is dispositive of the allegation respecting the > 274 Patent. The findings in paragraphs 55 to 84 are obiter and only come into play in the event that the Court of Appeal should reverse the finding in paragraph 53.

ORDER

THIS COURT ORDERS that this application be dismissed with costs to the Respondent Ratiopharm.

A Konrad von Finckenstein @

      F.C.J.

ANNEX A

> 606 Patent

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 designated AForm I@ and Form II@. The crystal forms are identified by their infrared spectrum, differential scanning calorimetric thermogram and powder x-ray diffraction pattern. Form I and Form II crystals have an identical spectrum of antibacterial activity, but Form I crystals unexpectedly have an intrinsic rate of dissolution about three times that of Form II crystals. Investigations in our laboratory have revealed that 6-O-methylerythromycin A when recrystallized from ethanol, tetrahydrofuranm, isopropyl acetate, and isopropanol, or mixtures of other common organic solvents results in exclusive formation of Form I crystals, not identified hitherto before.

Drugs currently on the market are formulated from the thermodynamically more stable Form II crystals. Therefore, preparation of the current commercial entity requires converting the Form I crystals to Form II. Typically this is done by heating the Form I crystals under vacuum at a temperature of greater than 80_C. Therefore, the discovery of a novel form of 6-O-methylerythromycin A which can be prepared without the high temperature treatment results in substantial processing cost savings. In addition, the favorable dissolution characteristics of Form I relative to Form II increases bioavailability of the antibiotic and provides significant formulation advantages.

The present invention in a principle embodiment provides a novel crystalline antibiotic designated 6-O-methylerythromycin A Form II. This novel crystalline antibiotic may be characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.5__0.2, 9.5__0.2, 10.8__0.2, 11.5__0.2, 11.9__0.2, 12.4__0.2, 13.7__0.2, 14.1__0.2, 15.2__0.2, 16.5__0.2, 16.9__0.2, 17.3__0.2, 18.1__0.2, 18.4__0.2, 19.0__0.2, 19.9__0.2, and 20.5__0.2 or by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.52__0.2, 9.48__0.2, 10.84__0.2, 11.48__0.2, 11.88__0.2, 12.36__0.2, 13.72__0.2, 14.12__0.2, 15.16__0.2, 16.48__0.2 16.92__0.2, 17.32__0.2, 18.08__0.2, 18.40__0.2, 19.04__0.2, 19.88__0.2, and 20.48__0.2.

In another embodiment, the present invention provides a novel crystalline antibiotic designated 6-O-methylerythromycin A Form II substantially free of 6-O-methylerythromycin A Form I. This novel crystalline antibiotic may be characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.5__0.2, 9.5__0.2, 10.8__0.2, 11.5__0.2, 11.9__0.2, 12.4__0.2, 13.7__0.2, 14.1__0.2, 15.2__0.2, 16.5__0.2, 16.9__0.2, 17.3__0.2, 18.1__0.2, 18.4__0.2, 19.0__0.2, 19.9__0.2, and 20.5__0.2 or 8.52__0.2, 9.48__0.2, 10.84__0.2, 11.48__0.2, 11.88__0.2, 12.36__0.2, 13.72__0.2, 14.12__0.2, 15.16__0.2, 16.48__0.2 16.92__0.2, 17.32__0.2, 18.08__0.2, 18.40__0.2, 19.04__0.2, 19.88__0.2, and 20.48__0.2.

The present invention also provides a novel crystalline antibiotic designated 6-O-methylerythromycin A Form I.

The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of 6-O-methylerythromycin A Form I in combination with a pharmaceutically acceptable carrier.

The invention further relates to a method of treating bacterial infections in a host mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of 6-O-methylerythromycin A Form I.

In another embodiment, the present invention also provides a process for preparing 6-O-methylerythromycin A Form I comprising

(a) converting erythromycin A to 6-O-methylerythromycin A;

            (b) treating the 6-O-methylerythromycin A with a solvent selected from the group consisting of (i) ethanol, (ii) isopropyl acetate, (iii) isopropanol, (iv) tetrahydrofuran, and (v) a mixture of a first solvent selected from the group consisting of ethanol, isopropyl acetate, isopropanol, and tetrahydrofuran and a second solvent selected from the group consisting of hydrocarbon of from 5 to 12 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, 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 solvent.

(c) isolating the crystalline 6-O-methylerythromycin A formed in step (b); and

(d) drying 6-O-methylerythromycin A isolated in step (c) at a temperature of between                              ambient temperature and about 70EC to form 6-O-methylerythromycin A Form I.

WE CLAIM:

1.          6-O-methylerythromycin A Form II characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.5__0.2, 9.5__0.2, 10.8__0.2, 11.5__0.2, 11.9__0.2, 12.4__0.2, 13.7__0.2, 14.1__0.2, 15.2__0.2, 16.5__0.2, 16.9__0.2, 17.3__0.2, 18.1__0.2, 18.4__0.2, 19.0__0.2, 19.9__0.2, and 20.5__0.2.

2.          6-O-methylerythromycin A Form II characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.52__0.2, 9.48__0.2, 10.84__0.2, 11.48__0.2, 11.88__0.2, 12.36__0.2, 13.72__0.2, 14.12__0.2, 15.16__0.2, 16.48__0.2 16.92__0.2, 17.32__0.2, 18.08__0.2, 18.40__0.2, 19.04__0.2, 19.88__0.2, and 20.48__0.2.                     

3.          6-O-methylerythromycin A Form II, substantially free of 6-O-methylerythromycin A Form I, characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.5__0.2, 9.5__0.2, 10.8__0.2, 11.5__0.2, 11.9__0.2, 12.4__0.2, 13.7__0.2, 14.1__0.2, 15.2__0.2, 16.5__0.2, 16.9__0.2, 17.3__0.2, 18.1__0.2, 18.4__0.2, 19.0__0.2, 19.9__0.2, and 20.5__0.2.

4.          6-O-methylerythromycin A Form II, substantially free of 6-O-methylerythromycin A Form I, characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 8.52__0.2, 9.48__0.2, 10.84__0.2, 11.48__0.2, 11.88__0.2, 12.36__0.2, 13.72__0.2, 14.12__0.2, 15.16__0.2, 16.48__0.2 16.92__0.2, 17.32__0.2, 18.08__0.2, 18.40__0.2, 19.04__0.2, 19.88__0.2, and 20.48__0.2.

ANNEX B

> 274 Patent

Summary of the Invention

6-O-methylerythromycin A can exist in a third crystal form, designated Aform 0@. Form 0, I, and II crystals have an identical spectrum of antibacterial activity. 6-O-methylerythromycin A prepared by the various methods described in the patent literature summarized below, in which the compound in purified by recrystallization from ethanol, result in initial formation of the crystalline form 0Aethanolate. Form 0 solvates are also formed with tetrahydrofuran, isopropanol, and isopropyl acetate. The form 0 solvate is converted to the non-solvated form I by removing the solvent from the crystal lattice by drying at a temperature of from about 0EC to about 50EC. Form 0 is converted to the non-solvated crystal form II by heating under vacuum at a temperature of between about 70EC and 110EC.

The 6-O-methylerythromycin A-carbomer complexes described above are prepared using 6-O-methylerythromycin A form II. Substantial savings in energy and material handling could be realized by forming the carbomer complexes from 6-O-methylerythromycin A form 0 solvate, thereby eliminating the vacuum drying step required to prepare form II crystals. 6-O-methylerythromycin A form 0 solvate is also a useful intermediate in the preparation of the non-solvated 6-O-methylerythromycin A forms I and II.

Accordingly, the present invention in its principle embodiment provides a novel crystalline antibiotic designated 6-O-methylerythromycin A form 0 solvate having the structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

6-O-methylerythromycin A form 0 solvate is characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 4.6__0.2, 6.5__0.2, 7.6__0.2, 9.2__0.2, 10.2__0.2, 11.0__0.2, 11.6__0.2, 12.5__0.2, 13.8__0.2, 14.8__0.2, 17.0__0.2, 18.2__0.2, 18.9__0.2, and 19.5__0.2 or 4.581__0.2, 6.498__0.2,7.615__0.2, 9.169__0.2, 10.154__0.2, 11.009__0.2, 11.618__0.2, 12.495__0.2, 13.772__0.2, 14.820__0.2, 16.984__0.2, 18.221__0.2, 18.914__0.2, and 19.495__0.2.

In one embodiment, there is provided a crystalline antibiotic designated 6-O-methylerythromycin A form 0Aethanolate which is characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.7__0.2, 6.6__0.2, 7.7__0.2, 9.3__0.2, 10.4__0.2, 11.1__0.2, 11.9__0.2, 12.7__0.2, 13.9__0.2, 15.0__0.2, 17.2__0.2, 18.5__0.2, 19.1__0.2, 19.7__0.2, 23.1__0.2, and 24.0__0.2 or 4.72__0.2, 6.60__0.2, 7.72__0.2, 9.30__0.2, 10.40__0.2, 11.10__0.2, 11.86__0.2, 12.72__0.2, 13.90__0.2, 15.02__0.2, 17.18__0.2, 18.50__0.2, 19.08__0.2, 19.68__0.2, 23.14__0.2, and 23.98__0.2.

In a further embodiment, there is provided a novel crystalline antibiotic designated 6-O-methylerythromycin A form 0Aisopropyl acetate which is characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.8__0.2, 6.7__0.2, 7.8__0.2, 9.1__0.2, 10.6__0.2, 12.0__0.2, 12.2__0.2, 12.4__0.2, 12.6__0.2, 12.8__0.2, 14.0__0.2, 15.2__0.2, 16.7__0.2, 17.3__0.2, 18.5__0.2, 19.2__0.2, 19.8__0.2, 20.6__0.2, 21.5__0.2, and 24.0__0.2 or 4.76__0.2, 6.70__0.2, 7.80__0.2, 9.128__0.2, 10.56__0.2, 11.96__0.2, 12.24__0.2, 12.36__0.2, 12.60__0.2, 12.84__0.2, 13.96__0.2, 15.16__0.2, 16.68__0.2, 17.28__0.2, 18.52__0.2, 19.18__0.2, 19.80__0.2, 20.56__0.2, 21.52__0.2, and 23.96__0.2.

In another embodiment, the present invention provides a composition comprising a therapeutically effective amount of 6-O-methylerythromycin A form 0 solvate in combination with a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides for the use of 6-O-methylerythromycin A form 0 solvate in the treatment of bacterial infections in a host mammal and in the preparation of an antibiotic medicament.

In yet another emobodiment (sic), the present invention provides a process for preparing 6-O-methylerythromycin form 0 solvate comprising

(a)         converting erythromycin A to 6-O-methylerythromycin A;

(b)         treating the 6-O-methylerythromycin A with a solvent selected from the group consisting of (i) ethanol, (ii) isopropyl acetate, (iii) isopropanol, and (iv) tetrahydrofuran; and

(c)         isolating the 6-O-methylerythromycin A form 0 solvate.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aethanolate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aisopropyl acetate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aisopropanolate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Atetrahydrofuran prepared according to the foregoing process.

In yet another embodiment, the present invention provides a composition comprising from about 25% to about 95% of 6-O-methylerythromycin A form 0 solvate and from about 5% to about 75% of a carbomer.

In yet another embodiment, the present invention provides for the use of 6-O-methylerythromycin A form 0 solvate-carbomer complex in the treatment of bacterial infections in a host mammal and in the preparation of an antibiotic medicament.

In yet another embodiment, the present invention provides a suspension for oral administration comprising 6-O-methylerythromycin A form 0 solvate-carbomer complex suspended in a pharmaceutically acceptable liquid medium.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form 0 solvate-carbomer complex of from about 25% to about 90% of 6-O-methylerythromycin A form 0 solvate and from about 5% to about 75% of a carbomer comprising

(a)         dispersing a carbomer in an organic solvent; and

(b)        mixing the dispersion of step (a) with 6-O-methylerythromycin A form 0 solvate to allow formation of the reaction product.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0 solvate-carbomer complex prepared according to the foregoing process.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form I comprising drying 6-O-methylerythromycin A form solvate at a temperature of from about 0EC to about 50EC.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form II comprising heating 6-O-methylerythromycin A form 0 solvate under vacuum at a temperature of between about 70EC and 110EC.

In further embodiments analogous to one or more of the above embodiments, the 6-O-methylerythromycin A form 0 solvate is substantially free of 6-O-methylerythromycin A form I and 6-O-methylerythromycin A form II.

WE CLAIM

1.          A crystalline antibiotic designated 6-O-methylerythromycin A Form 0 solvate having the

structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

4.          6-O-methylerythromycin A Form 0Aethanolate according to claim 1 characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.7__0.2, 6.6__0.2, 7.7__0.2, 9.3__0.2, 10.4__0.2, 11.1__0.2, 11.9__0.2, 12.7__0.2, 13.9__0.2, 15.0__0.2, 17.2__0.2, 18.5__0.2, 19.1__0.2, 19.7__0.2, 23.1__0.2, and 24.0__0.2.

5.          6-O-methylerythromycin A Form 0Aethanolate according to claim 1 characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.72__0.2, 6.60__0.2, 7.72__0.2, 9.30__0.2, 10.40__0.2, 11.10__0.2, 11.86__0.2, 12.72__0.2, 13.90__0.2, 15.02__0.2, 17.18__0.2, 18.50__0.2, 19.08__0.2, 19.68__0.2, 23.14__0.2, and 23.98__0.2.

16.        A crystalline antibiotic designated 6-O-methylerythromycin A Form 0 solvate, substantially free of 6-O-methylerythromycin A Form I and 6-O-methylerythromycin A Form II, having the structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

ANNEX C

> 274 Patent

Summary of the Invention

6-O-methylerythromycin A can exist in a third crystal form, designated Aform 0@. Form 0, I, and II crystals have an identical spectrum of antibacterial activity. 6-O-methylerythromycin A prepared by the various methods described in the patent literature summarized below, in which the compound in purified by recrystallization from ethanol, result in initial formation of the crystalline form 0Aethanolate. Form 0 solvates are also formed with tetrahydrofuran, isopropanol, and isopropyl acetate. The form 0 solvate is converted to the non-solvated form I by removing the solvent from the crystal lattice by drying at a temperature of from about 0EC to about 50EC. Form 0 is converted to the non-solvated crystal form II by heating under vacuum at a temperature of between about 70EC and 110EC.

The 6-O-methylerythromycin A-carbomer complexes described above are prepared using 6-O-methylerythromycin A form II. Substantial savings in energy and material handling could be realized by forming the carbomer complexes from 6-O-methylerythromycin A form 0 solvate, thereby eliminating the vacuum drying step required to prepare form II crystals. 6-O-methylerythromycin A form 0 solvate is also a useful intermediate in the preparation of the non-solvated 6-O-methylerythromycin A forms I and II.

Accordingly, the present invention in its principle embodiment provides a novel crystalline antibiotic designated 6-O-methylerythromycin A form 0 solvate having the structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

6-O-methylerythromycin A form 0 solvate is characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 4.6__0.2, 6.5__0.2, 7.6__0.2, 9.2__0.2, 10.2__0.2, 11.0__0.2, 11.6__0.2, 12.5__0.2, 13.8__0.2, 14.8__0.2, 17.0__0.2, 18.2__0.2, 18.9__0.2, and 19.5__0.2 or 4.581__0.2, 6.498__0.2,7.615__0.2, 9.169__0.2, 10.154__0.2, 11.009__0.2, 11.618__0.2, 12.495__0.2, 13.772__0.2, 14.820__0.2, 16.984__0.2, 18.221__0.2, 18.914__0.2, and 19.495__0.2.

In one embodiment, there is provided a crystalline antibiotic designated 6-O-methylerythromycin A form 0Aethanolate which is characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.7__0.2, 6.6__0.2, 7.7__0.2, 9.3__0.2, 10.4__0.2, 11.1__0.2, 11.9__0.2, 12.7__0.2, 13.9__0.2, 15.0__0.2, 17.2__0.2, 18.5__0.2, 19.1__0.2, 19.7__0.2, 23.1__0.2, and 24.0__0.2 or 4.72__0.2, 6.60__0.2, 7.72__0.2, 9.30__0.2, 10.40__0.2, 11.10__0.2, 11.86__0.2, 12.72__0.2, 13.90__0.2, 15.02__0.2, 17.18__0.2, 18.50__0.2, 19.08__0.2, 19.68__0.2, 23.14__0.2, and 23.98__0.2.

In a further embodiment, there is provided a novel crystalline antibiotic designated 6-O-methylerythromycin A form 0Aisopropyl acetate which is characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.8__0.2, 6.7__0.2, 7.8__0.2, 9.1__0.2, 10.6__0.2, 12.0__0.2, 12.2__0.2, 12.4__0.2, 12.6__0.2, 12.8__0.2, 14.0__0.2, 15.2__0.2, 16.7__0.2, 17.3__0.2, 18.5__0.2, 19.2__0.2, 19.8__0.2, 20.6__0.2, 21.5__0.2, and 24.0__0.2 or 4.76__0.2, 6.70__0.2, 7.80__0.2, 9.128__0.2, 10.56__0.2, 11.96__0.2, 12.24__0.2, 12.36__0.2, 12.60__0.2, 12.84__0.2, 13.96__0.2, 15.16__0.2, 16.68__0.2, 17.28__0.2, 18.52__0.2, 19.18__0.2, 19.80__0.2, 20.56__0.2, 21.52__0.2, and 23.96__0.2.

In another embodiment, the present invention provides a composition comprising a therapeutically effective amount of 6-O-methylerythromycin A form 0 solvate in combination with a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides for the use of 6-O-methylerythromycin A form 0 solvate in the treatment of bacterial infections in a host mammal and in the preparation of an antibiotic medicament.

In yet another emobodiment (sic), the present invention provides a process for preparing 6-O-methylerythromycin form 0 solvate comprising

(a)         converting erythromycin A to 6-O-methylerythromycin A;

(b)         treating the 6-O-methylerythromycin A with a solvent selected from the group consisting of (i) ethanol, (ii) isopropyl acetate, (iii) isopropanol, and (iv) tetrahydrofuran; and

(c)         isolating the 6-O-methylerythromycin A form 0 solvate.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aethanolate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aisopropyl acetate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Aisopropanolate prepared according to the foregoing process.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0Atetrahydrofuran prepared according to the foregoing process.

In yet another embodiment, the present invention provides a composition comprising from about 25% to about 95% of 6-O-methylerythromycin A form 0 solvate and from about 5% to about 75% of a carbomer.

In yet another embodiment, the present invention provides for the use of 6-O-methylerythromycin A form 0 solvate-carbomer complex in the treatment of bacterial infections in a host mammal and in the preparation of an antibiotic medicament.

In yet another embodiment, the present invention provides a suspension for oral administration comprising 6-O-methylerythromycin A form 0 solvate-carbomer complex suspended in a pharmaceutically acceptable liquid medium.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form 0 solvate-carbomer complex of from about 25% to about 90% of 6-O-methylerythromycin A form 0 solvate and from about 5% to about 75% of a carbomer comprising

(a)         dispersing a carbomer in an organic solvent; and

(b)        mixing the dispersion of step (a) with 6-O-methylerythromycin A form 0 solvate to allow formation of the reaction product.

In yet another embodiment, the present invention provides 6-O-methylerythromycin A form 0 solvate-carbomer complex prepared according to the foregoing process.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form I comprising drying 6-O-methylerythromycin A form solvate at a temperature of from about 0EC to about 50EC.

In yet another embodiment, the present invention provides a process for the preparation of 6-O-methylerythromycin A form II comprising heating 6-O-methylerythromycin A form 0 solvate under vacuum at a temperature of between about 70EC and 110EC.

In further embodiments analogous to one or more of the above embodiments, the 6-O-methylerythromycin A form 0 solvate is substantially free of 6-O-methylerythromycin A form I and 6-O-methylerythromycin A form II.

WE CLAIM

1.          A crystalline antibiotic designated 6-O-methylerythromycin A Form 0 solvate having the structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, iropropanol and tetrahydrofuran.

4.          6-O-methylerythromycin A Form 0Aethanolate according to claim 1 characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.7__0.2, 6.6__0.2, 7.7__0.2, 9.3__0.2, 10.4__0.2, 11.1__0.2, 11.9__0.2, 12.7__0.2, 13.9__0.2, 15.0__0.2, 17.2__0.2, 18.5__0.2, 19.1__0.2, 19.7__0.2, 23.1__0.2, and 24.0__0.2.

5.          6-O-methylerythromycin A Form 0Aethanolate according to claim 1 characterized by peaks in the powder x-ray diffraction pattern having the following 2θ values: 4.72__0.2, 6.60__0.2, 7.72__0.2, 9.30__0.2, 10.40__0.2, 11.10__0.2, 11.86__0.2, 12.72__0.2, 13.90__0.2, 15.02__0.2, 17.18__0.2, 18.50__0.2, 19.08__0.2, 19.68__0.2, 23.14__0.2, and 23.98__0.2.

16.        A crystalline antibiotic designated 6-O-methylerythromycin A Form 0 solvate, substantially free of 6-O-methylerythromycin A Form I and 6-O-methylerythromycin A Form II, having the structure

wherein S is a solvating molecule selected from the group consisting of ethanol, isopropyl acetate, isopropanol and tetrahydrofuran.

FEDERAL COURT

SOLICITORS OF RECORD

DOCKET:                               T-1656-03

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

DATE OF HEARING:           MAY 30, 2005

REASONS FOR

ORDER AND ORDER BY: The Honourable Mr. Justice von Finckenstein

DATED:                                  August 10, 2005

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 Ratiopharm Inc.)

Osler, Hoskin & Harcourt LLP

Ottawa Ontario