Pfizer Canada Inc. v. Apotex Inc.

Pfizer Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2005-10-17
Neutral citation
2005 FC 1421
File numbers
T-1937-03
Decision Content
Date: 20051017
Docket: T‑1937‑03
Citation: 2005 FC 1421
Ottawa, Ontario, this 17th day of October, 2005
Present: The Honourable Mr. Justice Richard G. Mosley
BETWEEN:
PFIZER CANADA INC.
and PFIZER INC.
Applicants
and
APOTEX INC.
and THE MINISTER OF HEALTH
Respondents
REASONS FOR ORDER AND ORDER
[1] This application by Pfizer Canada Inc. and Pfizer Inc. (hereafter collectively "Pfizer") under section 6 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, as amended by SOR/98‑166 and SOR/99‑379, is for an order of prohibition against the Minister of Health to prevent the issuance of a notice of compliance to Apotex Inc. ("Apotex") until after the expiry of Canadian Letters Patent 2,148,071. The application is in response to a notice of allegation made by Apotex in a letter dated August 29, 2003. Pfizer’s notice of application was served on the Minister on October, 17, 2003.
Background
[2] The application addresses Apotex’ submission for a notice of compliance with respect to its apo‑azithromycin tablets. Pfizer’s azithromycin tablets are marketed in North America under the brand name ZITHROMAX. Apotex proposes to market tablets for oral administration comprising azithromycin isopropanolate monohydrate in a strength equivalent to 250 mg azithromycin. The ZITHROMAX formulation is azithromycin dihydrate.
[3] There is nothing novel about azithromycin itself. It was invented in the early 1980's in Europe and has long been approved for use in Canada. Azithromycin is the first macrolide antibiotic of the azalide group. Other macrolides include erythromycin, from which azithromycin was derived, and clarithromycin. Azithromycin is commonly used in the treatment of upper and lower respiratory infections, pneumonia, strep throat, and genitourinary infections such as chlamydia.
[4] Azithromycin has unique properties that make it a valuable instrument in treating microbial infections. While it has low oral bioavailability (absorption of the drug into the bloodstream for therapeutic effect) producing low blood serum concentrations, azithromycin goes directly to the site of the infection, has a long half‑life and does not need to be administered
as long or as often as other antibiotics. In contrast to erythromycin, it is acid stable, has decreased gastrointestinal tolerance and increased absorption capability.
[5] ZITHROMAX was initially marketed in North America in a capsule dosage form, beginning in the early 1990's. Tablets were not approved. It appears to have been available also in suspension form, at least to researchers, and to have been prescribed by physicians in tablet, powder and suspension forms in Europe. In the capsule form, the oral bioavailability of azithromycin was found to be adversely affected by the presence of food in the patient’s system. For that reason, ZITHROMAX product labelling required that the capsules should be taken at least one hour before or two hours after a meal. Compliance with the dosage instructions presented difficulties for some patients, particularly the young. Failure to follow them reduced the therapeutic effectiveness of the drug.
[6] Conducting research into the other dosage forms, Pfizer scientists found that azithromycin in tablets, powders or suspensions, could be taken with food without losing approximately 50% of its bioavailability. Pfizer sought protection for this claimed discovery. A patent application was filed in Canada on April 27, 1995 and the ‘071 patent was issued on October 17, 2000. The priority date, based on the U.S. filing, is April 29, 1994.
[7] The ‘071 Patent has 33 claims. Certain of the claims are limited to tablets made by wet granulation, a formulation Apotex says it does not use. Others are limited to dosages in the form of powders for oral suspension, or unit doses in packets or sachets, which again Apotex says it does not employ. The claims are set out in full in the attached Annex "A".
[8] The parties are agreed that the only claim at issue in this litigation is number 23 which reads:
Use of a therapeutically effective amount of azithromycin for the preparation of a pharmaceutical dosage form which does not exhibit an adverse food effect for administration, in the treatment of an antimicrobial infection, to a patient that has eaten.
[9] Apotex asserts in its notice of allegations and detailed statement that its product, Apo‑azithromycin, won’t infringe this claim because 1) its tablets are made in accordance with the prior art and thus satisfy the defence set out in Gillette Safety Razor Company v. Anglo‑American Trading Company Ltd., (1913) R.P.C. 465; and 2), that if claim 23 is found to be valid and to cover its tablets, they undertake not to market them as intended for administration to a patient that has eaten.
[10] Apotex further alleges that the invention claimed in the ‘071 Patent is obvious, anticipated, a method of treatment claim, ambiguous, overbroad, lacking in utility, and improperly on the patent register. Consequently, Apotex asks that I find that the ‘071 patent is invalid, that it is improperly listed on the register (either in addition to or alternatively to its invalidity), and that there is no bar to the Minister issuing a notice of compliance in respect of its apo‑azithromycin product.
Onus and Burden of Proof
[11] As recently reiterated by the Federal Court of Appeal in Pfizer Canada Inc v. Novopharm Limited [2005] F.C.J. No. 1318, 2005 FCA 270 at paragraph 20, Apotex has no evidentiary burden to support the allegations in its notice of allegations and detailed statement.
[12] The legal burden in these proceedings is on Pfizer to prove, on a balance of probabilities, that the allegations in Apotex’ notice were not justified; AB Hassle v.Canada (Minister of National Health and Welfare (2002), 22 C.P.R. (4th) 1, 2002 FCA 421 at paragraph 35 (AB Hassle 2) .
[13] In establishing that the allegations of invalidity are not justified, Pfizer is entitled to rely upon the statutory presumption of validity found in subsection 43(2) of the Patent Act R.S.C. 1985, c. P-4; Eli Lilly and Co. v. Apotex Inc. (1995), 60 C.P.R. (3d) 206 at 216 91 F.T.R. 181 at 216 (F.C.T.D.), aff’d (1996), 66 C.P.R. (3d) 329, 195 N.R. 378 (F.C.A.); Bayer Inc. v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 285, N.R. 238 (F.C.A.). Apotex has the evidentiary burden, on a balance of probabilities, to prove that the patent is invalid; Procter & Gamble Pharmaceuticals Canada Inc. v. Canada (Minister of Health) [2005] 2 F.C.R.269, 2004 FCA 393. If the allegations are not justified, the prohibition order is granted.
The Evidence
Pfizer’s principal witnesses
[14] Dr. Robert A. Rapp is a Professor of Pharmacy and Professor of Surgery at the University of Kentucky Colleges of Pharmacy and Surgery. He was tendered as an expert witness to provide opinion evidence as a person skilled in the art of clinical pharmacy. Dr. Rapp has experience in studying azithromycin in a clinical context, and has published papers related to its therapeutic applications. He is also familiar with food‑drug interactions and co‑authored his university hospital’s food‑drug interaction guidelines. He has no direct experience in pharmaceutical formulation but has served as an advisor to drug companies particularly Pfizer.
[15] His opinion is that the subject matter of claim 23 was neither anticipated nor obvious based on the general state of the knowledge among clinicians and researchers as of the priority date. In Dr. Rapp’s view the knowledge shared by most persons skilled in the art was that azithromycin in any dosage form exhibited a food effect. Consequently, the fact that it did not in tablets and suspensions was a surprising result.
[16] Dr. Vincent Andriole is a specialist in internal medicine and infectious diseases and Professor of Medicine at Yale University, New Haven, Connecticut. He has been the editor, served on the editorial boards, and acted as a reviewer for a large number of medical journals. He has also served on many advisory committees for pharmaceutical companies, including one related to azithromycin for Pfizer from 1989 until the early 1990s. Dr. Andriole provided opinion evidence on a fairly narrow question regarding the construction of claim 23. That is whether it suffers from overbreadth because, on its face, the claim is not limited to tablets but to all formulations of azithromycin that can be taken with food.
[17] Madelaine Pesant is an employee of Pfizer Canada and attaches to her affidavit documents related to the litigation, with a view to establishing that the ‘071 patent is properly listed on the register in connection with the 250 and 500 mg tablets. She also attests to the commercial success of the ZITHROMAX 250 mg tablets. She was not cross‑examined on her affidavit but was asked to respond to written interrogatories.
Apotex’s principal witnesses
[18] Dr. Robert S. Langer is a Professor of Chemical and Biomedical Engineering at MIT, the Department of Chemical Engineering, Whitaker College of Health Sciences, Technology and Management, and the Harvard‑MIT Division of Health Sciences and Technology. He is tendered as an expert in pharmaceutics and pharmaceutical formulation technology. He has been awarded a great number of honours including many of the highest awards in medicine, such as the highest Canadian prize in that field. He has published over 700 articles and is a named inventor of hundreds of patents.
[19] In Dr. Langer’s opinion, the Apotex azithromycin tablets made by non‑wet granulation will not infringe the ‘071 claims. He attests that the azithromycin tablets made by Apotex are in accordance with the prior art and will not infringe because of the Gillette defence. Even if claim 23 is valid, the tablets will not be identified as administrable to a patient who has eaten. He also supports Apotex’ position that the ‘071 patent is anticipated and that it was also obvious in light of the state of the knowledge in 1994. He also believes that claim 23 is ambiguous, overbroad, and lacks utility.
[20] Professor Jonathan S. Dordick is a Professor of Chemical and Biological Engineering at Rensselaer Polytechnic Institute in Troy, New York. He has conducted research on the delivery of drugs in the body, serves as a consultant to numerous companies in the pharmaceutical and chemical industries and is tendered as an expert in pharmaceutical formulations, biosynthetic chemistry and bioanalytical chemistry.
[21] Dr. Dordick states the opinion that claim 23 is anticipated by the prior art because formulations prepared according to the prior art meet the requirements of claim 23. He discusses dissolution tests and asserts that the formulations tested were anticipated by several north american and european patents. He refers in particular to the Canadian 2,101, 466 patent (the ‘466 or Catania patent) which taught the use of azithromycin in a taste‑masked form by grinding up a tablet or using a powder to sprinkle on food. He thinks that the ‘071 patent was obvious as well, in light of the ‘466 patent.
[22] Dr. Michael Mayersohn is Professor of Pharmaceutical Sciences in the College of Pharmacy at the University of Arizonan and a former member of the Pharmaceutical Sciences Advisory Committee to the US Federal Drug Administration. Dr. Mayersohn has prior but not recent experience as a pharmacist advising patients. He is tendered as an expert in pharmacokinetics, biopharmaceutics and pharmaceutics.
[23] Dr. Mayersohn also reviewed the results of dissolution tests. He concludes that the ‘071 patent is anticipated, so does not deal with any of the other allegations. In his view, formulations disclosed in prior art patents anticipate the very same rapid dissolution formulations that are described in the ‘071 patent. He is also of the opinion that the ‘466 patent discloses the taking of azithromycin with food.
[24] Dr. Eli Shefter is a Doctor of Pharmaceutics and Professor of Pharmacy at the University of Colorado and Adjunct Professor at the University of California at San Diego. He is the Chief Scientific Director for IriSys Research and Development LLC and also works as a consultant to pharmaceutical and biotech companies on matters pertaining to formulation, stability and regulatory issues. He too was a consultant to the FDA for over five years and also served on the USP Committee of Experts. He has experience in formulating antimicrobial dosage forms. Dr. Shefter’s evidence was similar to that of Dr. Mayersohn.
[25] Stephen Levine is a formulation scientist at Emerson Pharma Services. He prepared three formulations based on the US 4,963,531 (Remington) patent for azithromycin suspension
and two weights of tablets. He contracted an analytical laboratory (Chemir Pharma Services) to conduct dissolution tests (as described in the ‘071 patent) comparing the formulations. The tests showed that for each dosage form, at least 90% of the azithromycin dissolved within 30 minutes and also within 15 minutes. He includes as Exhibit 4 the results of the tests. Lev Fridman is the employee of Chemir Pharma Services who conducted the dissolution tests. He also attaches the results of the tests. He attests that the instructions he followed were the same as those in the ‘071 patent. Neither Mr. Levine nor Mr. Fridman were cross‑examined.
[26] Pfizer’s experts, Dr’s Rapp and Andriole, have expertise in the clinical applications of drugs such as azithromycin and both were involved in its development in a consultative capacity.They do not have expertise in drug formulation. Pfizer submits that their evidence, as that of a practising pharmacist and physician with direct experience with the drug should be given greater weight than that of the Apotex witnesses. Apotex claims, in turn, that the opinions of pharmaceutical scientists such as Dr. Mayersohn and drug formulation experts such as Drs Langer and Dordick should be preferred over that of clinicians, however eminent they may be.
[27] While all of the experts tendered by the parties in this case have impressive qualifications, I do have reservations about Dr. Rapp’s evidence. It is clear from his evidence that, despite his long experience with the therapeutic applications of azithromycin, he did not become fully aware of the revised dosing instructions until he was instructed for this litigation in 2003. His university’s drug interaction guidelines, of which he is co‑author, did not reflect the change until that year. As stated by Justice Binnie in Camco Inc.et al v. Whirlpool Corp.et al,
[2000] 2 S.C.R. 1067, (2000) 9 C.P.R. (4th) 129 at paragraph 74 [Camco],, the skilled worker is thought to be reasonably diligent in keeping up with advances in the field to which the patent relates. It is open to question how diligent Dr. Rapp was in keeping up with advances in the field.
[28] On cross‑examination, it emerged that Dr. Rapp has significant ties to Pfizer, including owning stock in the company, doing promotional talks for it, serving on consulting boards and receiving research grants that, indirectly at least, contribute to the level of compensation he receives from the university. He stated that this is typical of those in his position, at least at his university. While that may be the case, in my view such close links to one of the parties compromises the independence expected of a witness tendered as an expert by that party in litigation. I have also concluded from reviewing his cross‑examination that Dr. Rapp seemed defensive and appeared to cross the line at times from independent expert to advocate for the Pfizer position.
[29] I had no difficulty with the manner in which Dr. Andriole and the Apotex experts provided their evidence. While Pfizer counsel took me to several portions of the transcript of Dr. Langer’s cross‑examination where he stated a lack of knowledge or that he would need to review the evidence in question, I was satisfied that was entirely consistent with what is to be expected from an independent and objective expert.
[30] Having carefully reviewed the experts’ affidavits and cross‑examinations, where there is a conflict between Dr. Rapp’s evidence and that of the Apotex experts, I generally preferred the latter as appearing to be more thorough, objective and grounded in the scientific literature.
Issues
[31] At issue in these proceedings is whether the Court should grant an order prohibiting the Minister from issuing a notice of compliance to Apotex. That requires a determination of whether the allegations of invalidity and non‑infringement set out in Apotex’ notice of allegation and detailed statement are justified. Following construction of the claim at issue, the specific questions I will address are whether the ‘071 Patent is invalid on the grounds that the invention claimed was anticipated or obvious by reason of the prior art, whether claim 23 is ambiguous or overbroad, whether the claimed invention is not properly the subject of a patent and, as further alleged by the respondent, whether the patent was improperly listed and whether the Apotex product will not infringe.
Claim Construction
[32] The first step before addressing the issues is to construe the claims through eyes educated by a person or persons skilled in the art. In conducting my analysis, I have had regard to the principles enunciated by the Supreme Court of Canada decisions in Free World Trust v. Électro-Santé Inc., [2000] 2 S.C.R. 1024, 2000 SCC 66 [ Free World Trust] and Camco, supra.
[33] The object of claim construction is to fairly and reasonably define the purpose of the invention. The assistance of experts may be necessary, but is not determinative. I am not bound by the suggested constructions put forward by the parties or their experts. The words of the claims themselves are to be the focus of the analysis: Novartis Pharmaceuticals Canada Inc. v. RhoxalPharma Inc. (2005) 38 C.P.R. (4th) 193, 2005 FCA 11 at para. 45, 53.
[34] As noted above, Claim 23 is the contentious portion of the ‘071 patent. It reads as follows:
Use of a therapeutically effective amount of azithromycin for the preparation of a pharmaceutical dosage form which does not exhibit an adverse food effect for administration, in the treatment of an antimicrobial infection, to a patient that has eaten.
[35] Claims 1‑22 are claims to dosage forms, that is tablets, powders for oral suspension and unit dose packets. Claims 24 to 27 are formulation claims for specific tablets. Claims 28 and 32 are a therapeutic package claim. Claims 29‑31 refer to powders, 32 to a unit dose packet. The claims are set out in full in Annex "A" to these reasons.
[36] There is some common ground between the parties as to the appropriate construction of Claim 23. For instance, they agree that the reference to "antimicrobial" infections is simply a typographical error and is of no moment. Clearly, the intended wording was "microbial". There is also no serious argument about the meaning of the words "a patient that has eaten." These words are understood by the skilled person to be a patient who has eaten in the hour prior to taking the dose of oral azithromycin or who will eat in the two hours following taking that dose. There is also general agreement that none of the dosage forms contain a significant amount of an alkaline earth oxide or hydroxide (referred to in the claims), and, finally, that capsules are excluded from the claim.
[37] I interpret the words "a therapeutically effective amount of azithromycin" in claim 23 to mean simply, as several of the experts suggested, "enough of the drug to treat the infection". Nothing of importance in these proceedings turns on this in my view.
[38] Pfizer’s position is that claim 23 is a "use to treat" claim. Pfizer’s reading emphasises the following parts of the claim:
Use of a therapeutically effective amount of azithromycin for the preparation of a pharmaceutical dosage form which does not exhibit an adverse food effect for administration, in the treatment of an antimicrobial infection, to a patient that has eaten. [Emphasis added]
[39] In other words, Pfizer’s position is that the claim is for a new use of azithromycin (in particular dosage forms) in a particular manner – the treatment of microbial infections in a patient who has eaten. In its submission, the essential elements in claim 23 are:
(I) the oral administration of a dosage form of azithromycin;
(ii) to treat a microbial infection;
(iii) where the oral dosage form does not exhibit an adverse food effect in a patient who has eaten.
[40] Apotex criticises this reading of claim 23 because it says it ignores a large part of the language of the claim. Apotex emphasises the importance of the words underlined below:
Use of a therapeutically effective amount of azithromycin for the preparation of a pharmaceutical dosage form which does not exhibit an adverse food effect for administration, in the treatment of an antimicrobial infection, to a patient that has eaten.
[41] The words regarding the preparation of the dosage form should not have been included if their meaning was simply going to be ignored, Apotex contends. Experts cannot read in words, and neither should they be able to read them out of a claim: GlaxoSmithKline Inc. v. Canada (Attorney General) (2005) 40 C.P.R.(4th) 93, 2005 FCA 197 at paragraph 13.
[42] Apotex’s position on claim construction, therefore, is that the emphasis in construing the essential elements of claim 23 must be placed on the formulation of azithromycin dosage forms (that can then be used in a particular way) rather than for the use of the dosage form itself.
[43] Apotex finds support for this position in the terms of claim 27:
A tablet as defined in any one of claims 22 to 26, which is coated with a film of hydroxypropylmethylcellulose, hydroxypropylcellulose or acrylate‑methacrylate copolymer.
If claim 23 defines a tablet (rather than the use of a tablet), as suggested by claim 27, this gives some support to Apotex’s theory that claim 23 is a formulation claim. However, I do not find this to be conclusive.
[44] Pfizer submits that the experts also read claim 23 as a use to treat claim. Its witness, Dr. Rapp, deposes that a person skilled in the art would understand that the invention described in claim 23 is to administer a pharmaceutical form of azithromycin to a patient who has eaten in a way to overcome the adverse food effect observed with capsules. Dr. Andriole provided a similar opinion.
[45] Pfizer also finds support for its interpretation in the evidence of Apotex’ witnesses. In Dr. Dordick’s affidavit, at paragraph 40, he states that the key issue in respect of Claim 23 is "...the use of an azithromycin formulation which does not exhibit an adverse food effect and administration of such to a mammal that has eaten" (emphasis added). Further, at paragraph 41 where he breaks down the elements of claim 23 for an anticipation analysis, his description is similar to that urged on the court by Pfizer.
[46] While Dr. Mayersohn initially stated that one of ordinary skill in the art would have no way of interpreting what was disclosed in claim 23, the scope of the claim or the invention that it reflects, he agreed on cross‑examination that one aspect disclosed was a method of treating a microbial infection.
[47] On the other hand, Pfizer’ s witness Dr. Andriole, at paragraph 47 of his affidavit, seems to have agreed with Apotex’ position in stating that "...what was claimed in claim 23 is the use of ‘pharmaceutical formulations’ ..." Dr. Rapp also, at paragraph 61 of his affidavit, seems to put the emphasis in construing claim 23 on the making of the dosage form.
[48] Dr. Langer, Apotex’ expert pharmaceutical chemist, was clear in his evidence at paragraphs 11 and 64 that he reads claim 23 as claiming the use of azithromycin in pharmaceutical dosage forms that do not exhibit an adverse food effect upon administration to fed patients.
[49] Notwithstanding the assistance of the experts, I do not find that the correct reading of claim 23 is plain on its face, as argued by both Pfizer and Apotex. A purposive construction thus requires that it be interpreted in light of the whole of the disclosure: Schmeiser v.Monsanto Canada Inc., [2004] 1 S.C.R. 902, 2004 SCC 34 at paragraph 18.
[50] The title of the Patent is "Method of Administering Azithromycin". The first paragraph of the disclosure section reads:
This invention relates to a dosage form of azithromycin, and also to a method of treating a microbial infection which involves administering azithromycin in the fed state to a mammal, including a human patient, in need of such treatment. [emphasis added]
Thus, it is reasonable to expect that the individual claims of the patent will apply to either the dosage form of azithromycin or the administration of azithromycin as a method of treatment.
[51] The "Summary of the Invention" section of the patent disclosure provides for four aspects of the invention: an oral dosage form of azithromycin that does not exhibit an adverse food
effect, specific oral azithromycin dosage forms (i.e., tablets, powders), a method for treating a microbial infection, and a therapeutic package containing the dosage forms.
[52] An oral dosage form that does not exhibit an adverse food effect, paraphrasing the disclosure, would be one in which there is substantially no inhibition of the rate at which the azithromycin is absorbed into the blood stream for therapeutic purposes.
[53] The inventors assert at page 5 of the patent that they found it surprising that a dosage form of azithromycin did not exhibit an adverse food effect because, they state, azithromycin is unstable at low acid levels such as are found in stomach acid. Apotex argues that this is clearly erroneous as the literature does not support that conclusion with respect to azithromycin as opposed to other related azalide antibiotics. Pfizer did not dispute this.
[54] The inventors further say in the detailed description at page 7 that "[it] is believed that the dosage forms of the invention do not exhibit a food effect in large part because they either provide azithromycin ready for dissolution in the GI tract, essentially immediately following ingestion (suspensions), or they disintegrate rapidly following ingestion (tablets) and thereby provide azithromycin rapidly for dissolution."
[55] They conclude, on page 7, that "[w]hile not wishing to be bound by theory, it is believed that if an azithromycin dosage form provides azithromycin immediately following ingestion for dissolution in the GI tract, or at least...within a certain time period following ingestion, the azithromycin will be absorbed into the bloodstream at a rate which results in substantially no adverse food effect."
[56] The disclosure discusses how the rate of absorption into the blood stream is measured and how to determine whether there is no food effect. For an adequate rate of absorption to occur, at least 90% of the azithromycin in the dosage form should dissolve within 30 minutes of ingestion, preferably within 15 minutes. Rapid dissolution alone, however, is not enough to establish bio‑availability. There are fast‑dissolving capsule formulations which continue to exhibit an adverse food effect in testing of the blood samples of human subjects. The object, according to the disclosure, is to strive for a high degree of statistical confidence that the mean rate of absorption in the general population would fall within specified values. The evidence of the expert witnesses was generally in agreement with this proposition.
[57] An adverse food effect is said not to exist if the ratio of the areas under the azithromycin plasma concentration‑time curve in a subject ingesting the drug orally in the fed state (AUCfed) compared to the fasted state (AUCfast), AUCfed/AUCfast, is less than 0.8 and the lower 90% confidence limit for this ratio is not less than 0.75. According to the '071' patent disclosure, an adverse food effect will not occur as measured in in vitro dissolution tests if at least 90% of the azithromycin in the dosage form dissolves within about 30 minutes and, preferably, within about 15 minutes.
[58] The parameters required for dissolution are set out in claims 1, 3, and 6 for the different dosage forms as follows:
...the dosage form effecting at least about 90% dissolution of azithromycin within about 30 minutes when an amount of the dosage form equivalent to 200 mg of azithromycin is tested as set forth in USP test <711> in a USP‑2 dissolution apparatus under conditions at least as stringent as the following: 900 ml sodium phosphate buffer, pH 6.0, 37oC, with paddles turning at 100 rpm, provided that the dosage form contains less than a taste‑masking amount of an alkaline earth metal oxide or hydroxide.
[59] The inventors state, at page 7 line 9‑10 of the detailed description, that if a non‑capsule dosage form of azithromycin satisfies the in vitro dissolution requirements specified, they consider it to fall within the scope of the claims. Thus you can determine whether a particular non‑capsule dosage form exhibits an adverse food effect in two ways. Either through absorption testing or through dissolution testing.
[60] This conflicts with Dr. Rapp’s evidence, at paragraph 63 of his affidavit, in which he says that dissolution alone cannot be used to predict food effect. The patent disclosure is supported by Dr. Shefter’s affidavit in which he states at paragraph 31 that
It was well established that prior to 1995 that in vitro dissolution provides a correlation with in vivo dissolution. In other words, the rate at which a dosage form dissolves in a dissolution test is a reflection of how that dosage form will perform in the gastrointestinal tract fluids. The ‘071 Patent was clearly aware that this type of correlation existed for tablets...
[61] Having carefully reviewed the whole of the specifications and the evidence of the expert witnesses, I conclude that the purpose of the invention claimed in the ‘071 patent was to offer a solution to the problem of the adverse food effect caused by azithromycin capsules. It was not a new use for azithromycin but a new method of administering azithromycin. The essential elements are:
1. the use of "enough" azithromycin
2. in an oral pharmaceutical dosage form, excluding capsules;
3. to treat microbial infections;
4. in patients who have eaten;
5. which does not result in an adverse food effect;
6. as measured within the parameters of standard scientific tests for dissolution or absorption.
Validity of the patent
Anticipation
[62] Apotex alleges anticipation by prior publication and by prior use and sale. As anticipatory prior art, the notice of allegation cites United States Patents No. 4, 963,531 (the ‘531 or Remington patent), No.4,474, 768 (the Bright or ‘ 768 patent), Canadian Patent No. 2,101,466 (the ‘466 or Catania patent), European Patent EP‑A‑307128 (equivalent to the ‘531 patent), excerpts from the Gazetta Ufficiale Della Repubblica Italiana, an Italian data sheet on ZITHROMAX dated in 1992 and a Spanish invoice for a 250 mg azithromycin formulation dated December 1993.
[63] In asserting that a patent claim has been anticipated, the argument is that the invention has already been disclosed to the public and is therefore not novel. The well‑established approach to anticipation is found in Justice Hugessen’s decision in Beloit Canada Ltd.,v. Valmet Oy, (1986) 8 C.P.R. (3d) 289, [1986] F.C.J. No. 87 at page 297 [Beloit cited to C.P.R.]:
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...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. Where, as here, the invention consists of a combination of several known elements, any publication which does not teach the combination of all the elements claimed cannot possibly be anticipatory.
[Emphasis added]
[64] This approach was cited with approval by the Supreme Court of Canada in Free World Trust, supra at paragraph 26. Justice Binnie, in that decision, also cautioned against the use of ex post facto deduction in evaluating whether an invention was anticipated by a particular publication, since assembling a dossier of prior art with the benefit of hindsight is "all too easy after an invention has been disclosed" (Free World Trust, supra at para. 25).
[65] The priority date for the assessment of anticipation as determined by subsection 28.2 of the Patent Act, is a year before the Canadian filing date, hence April 27, 1994. Nothing turns on the two day difference between that date and the date of the US filing, April 29, 1994.
Disclosure by publication
[66] The Remington or ‘531 patent, cited as prior art, was issued in 1990 and assigned to Pfizer. The abstract describes it as a method of use of azithromycin or its derivatives in the treatment of a microbial infection (toxoplasma gondii). Apotex argues that two of the examples provided in Remington are of formulations that fall within the scope of claim 23 of the ‘071 patent as they are identical in all significant respects to two examples in the ‘071 patent and must therefore, exhibit the same properties. Further, formulations made by Apotex’ experts following the two Remington examples were shown to meet the in vitro dissolution criteria specified in the ‘071 patent.
[67] Apotex submits that the Remington patent anticipates the ‘071 patent as it teaches and discloses powders for suspension and fast‑dissolving tablets made using azithromycin that, upon administration to fed patients, would not exhibit adverse food effects as defined in the ‘071 patent. This was supported by and addressed at length by Dr. Langer in his affidavit at paragraphs 77‑81, by Dr. Shefter at paragraphs 21‑24 to his affidavit, by Dr. Dordick at paragraphs 61 ‑ 66 and by Dr. Mayersohn at paragraphs 13‑18.
[68] Shefter and Langer both agreed on cross‑examination that there is no mention in Remington that any of these oral dosage forms exhibit an adverse food effect. Further, there is no discussion of dissolution rates.
[69] The base azithromycin patent for antibacterial use is the ‘768 patent issued in 1984 to Gene Bright, a Pfizer research scientist. Related to the ‘768 patent, for the purpose of Apotex’ prior art submission, is a 1989 international patent application by Allen et al for a new form of azithromycin. The Allen application, also assigned to Pfizer, incorporates Bright. There is no restriction in either to the administration of the formulations disclosed with or without food. However, neither discuss a food effect.
[70] In his affidavit, Dr. Langer states at paragraph 71 that the inventors of the ‘768 patent (referred to as the ‘071 patent in error) teach the formulation of azithromycin with pharmaceutically acceptable carriers by conventional methods for the production of tablets, suspensions and solutions. A person skilled in the art would understand that to mean, among other things, fast dissolving tablets made via direct compression, dry or wet granulation containing azithromycin and a disintegrant. As a result, Langer says, while the ‘768 tablet does not explicitly discuss the absence of adverse food effects, it teaches the use of azithromycin for the production of oral dosage forms that include solution, suspension and fast‑dissolving tablet dosage forms that would not exhibit an adverse food effect when administered to a fed patient. He reaches a similar conclusion with respect to the Allen application.
[71] Further cited as anticipatory prior art is the Canadian ‘466 or Catania patent. Catania has a priority date of July 30, 1992 and a publication date of January 31, 1994. Catania addresses the reduction of the bitter taste of pharmaceutical compositions, including azithromycin, through the addition of a taste masking component. Azithromycin, apparently, has a particularly bitter
flavour. Catania discusses the use of chewable tablets or suspension oral dosage forms for azithromycin. It suggests that the tablets may be ground up, mixed with, placed in or sprinkled on cereals, ice cream or other food and drinks. Alternatively they may be swallowed whole without chewing or mixing. The suspension may be mixed with food and drinks. No concern about an adverse food effect is mentioned. What it teaches, Apotex submits, is the use of azithromycin in a dosage form to be administered to a patient who has eaten with no food effect to treat microbial infections. Precisely one of the alternative constructions for claim 23 of the ‘ 071 patent.
[72] Again, Apotex relies on the evidence of Drs. Langer, Shefter, Mayersohn and Dordick in support of this interpretation of Catania. They all say that the formulations being virtually identical in both Catania and the ‘071 patent, the results should be identical. The only difference being the inclusion of taste‑masking agents in the formulations disclosed in the Catania patent. Dr. Langer, at paragraph 99 of his affidavit, says that in his experience he would not expect those agents to make any difference on the dissolution behaviour of the dosage forms or the lack of a food effect.
[73] Dr. Dordick notes first at paragraph 51 of his affidavit that the taste‑masking agent in Catania would have no effect on dissolution rates as its purpose is solely to mask the taste in the mouth. He goes on to say, at paragraphs 57, that it is clear to anyone skilled in the art of drug formulation, that Catania teaches that azithromycin can be used in conjunction with food. He concludes at 59 that it is clear that rapidly dissolvable azithromycin formulations existing as powders for oral suspension or tablets were known and formed part of the state of the art prior to
the priority date of the ‘071 patent. Further, because there were teachings correlating in vitro dissolution to in vivo bio‑availability, claims in the ‘071 patent directed towards bio‑availability are also anticipated by the prior art. Finally, because azithromycin could be administered with solid food, its use as a purported new medical indication was anticipated by the prior art. Again, there is no specific reference to whether the dosage forms referenced exhibit an adverse food effect. Dr. Mayersohn stated on cross that he knew they would not because of the results of the tests disclosed in the ‘071 patent.
[74] Incidentally, all of the claims in the ‘071 patent, save for claim 23, exclude a taste‑masking amount of an oxide. There is no exclusion in claim 23.
[75] Dr. Rapp, at paragraph 53 of his affidavit, states that it had always been possible to administer an azithromycin compound that does exhibit a food effect (such as capsules) with food. He suggests that a person skilled in the art would know to administer a higher dose because of the food effect. But that is not what Catania teaches. There is no suggestion in the patent that excessive amounts of the drug be administered to counter a food effect. On cross‑examination, Dr. Rapp conc