Date: 20001215
Docket: T-366-98
BETWEEN:
AB HASSLE, ASTRAZENECA AB
and AASTRAZENECA CANADA INC.
Applicants
- and -
THE MINISTER OF NATIONAL
HEALTH AND WELFARE, RHOXALPHARMA INC.
and TAKEDA CHEMICAL INDUSTRIES, LTD.
Respondents
REASONS FOR ORDER
TREMBLAY-LAMER J.:
[1] This is an application by AB Hassle, Astra AB and Astra Pharma Inc. ("Astra") pursuant to thePatented Medicine (Notice of Compliance) Regulations ("Regulations")1 for an Order prohibiting the Minister of National Health and Welfare ("Minister") from issuing a Notice of Compliance ("NOC") to RhoxalPharma Inc. ("RhoxalPharma") in respect of omeprazole tablets, until after the expiration of Canadian Patent Nos. 1,234,118 ("`118"), 1,264,751 ("`751"), 1,292,693 ("`693"), 1,302,891 ("`891"), 1,338,377 ("`377"), 2,166,483 ("`483") and 2,166,794 ("`794") (collectively "Patents").
[2] Only two patents pertaining to the compositions are at issue in the present instance: `693 patent and `891 patent, both owned by AB Hassle. The other patents have been withdrawn from these proceedings by the Applicants.
[3] On February 19, 1998, the Respondent, RhoxalPharma sent Astra a Notice of Allegation with respect to omeprazole tablets. In the letter RhoxalPharma states as follows:
| This is a notice of allegation served pursuant to Section 5(3)(b) of the Patented Medicines (Notice of Compliance) Regulations. |
| With respect to patents 1,234,118, 1,264,751, 1,292,693, 1,302,891, 1,338,377, 2,166,483 and 2,166,794, we allege that 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 us of tablets containing omeprazole. |
| The legal and factual basis for the above allegation is as follows: |
| Patent 1,292,693 and Patent 1,302,891: |
| This patent is directed to and claims pharmaceutical preparations containing omeprazole and featuring a core region containing the active ingredient, an inert subcoating on the core region, and an outer enteric coating layer. We have available to us omeprazole tablets which will not contain a core region nor an inert subcoating. According, since at least one essential feature of each claim will not be found in our product, the patent will not be infringed. |
THE PATENTS
[4] Claim 1 of the `693 patent claims:
| 1. An oral pharmaceutical preparation comprising: (a) a core region comprising an effective amount of a material selected from the group consisting of omeprazole plus an alkaline reacting compound, an alkaline omeprazole salt alone; (b) an inert subcoating which is soluble or rapidly disintegrating in water disposed on said core region, said subcoating comprising one or more layers of materials selected from among tablet excipients and polymeric film-forming compounds; and (c) an outer layer disposed on said subcoating comprising an enteric coating. |
[5] Claim 1 of the `891 patent claims:
| 1. A Pharmaceutical preparation comprising |
| (a) an alkaline reacting core region comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance, an alkaline salt of an acid-labile pharmaceutically active substance, or an alkaline salt of an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance; |
| (b) an inert subcoating, which will rapidly dissolve or disintegrate in water, said subcoating being disposed on said core region and comprising one or more layers of materials selected from the group consisting of tablet excipients, film-forming compounds and alkaline compounds; and |
| (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced. |
[6] The claims in the omeprazole patents are directed to compositions in the form of enteric coated tablets which comprise of a core region containing the drug omeprazole, a subcoating disposed on the core region, and an enteric coating disposed on the subcoating. The purpose of the subcoating is to insulate the core from degradation caused by direct contact with the enteric coating.
[7] In essence, RhoxalPharma states that patents `693 and `891 would not be infringed because, amongst other things, its omeprazole tablets do not have a subcoating.
[8] By originating Notice of Motion dated March 5, 1998, Astra initiated these proceedings to prohibit the Respondent, the Minister of Health and Welfare from issuing a Notice of Compliance to RhoxalPharma with respect to its omeprazole tablets before the expiration of the Omeprazole Patents.
HISTORY OF THE PROCEEDING
[9] At the time the proceeding was initiated, the Applicants filed affidavits from Dr. James W. McGinity sworn March 3, 1998 ("first McGinity affidavit") and Phillippa Murphy sworn March 4, 1998.
[10] Further, to the issuance of a Protective Order, RhoxalPharma then delivered affidavits from Dr. Louis Cartilier sworn June 4, 1998 ("first Cartilier affidavit") and David Gardner sworn June 2, 1998. In response, the Applicants delivered a further affidavit of Dr. James McGinity sworn August 31,1998 ("second McGinity affidavit").
[11] Subsequently, RhoxalPharma filed affidavits sworn October 27,1998 from Dr. Louis Cartilier ("second Cartilier affidavit") and sworn December 17,1998 from Alain Leclerc.
[12] Finally, further evidence was filed by the Applicants; an affidavit from Dr. Jörgen Lindquist sworn June 24,1999 and Dr. James McGinity sworn June 29,1999 ("third McGinity affidavit").
[13] The affidavits' evidence can be summarized as follows. In the first McGinity affidavit, Dr. McGinity stated that the information in the notice of allegation was insufficient to be able to evaluate and test RhoxalPharma's allegations that it will not infringe the patents. Notwithstanding the lack of information, Dr. McGinity did indicate that even if RhoxalPharma does not specifically apply a subcoating as part of its process used to make its tablets, it is possible to have formed a subcoat during the process used to make the formulation. He further stated that the presence of a subcoat formed in situ during processing can be detected through physical and chemical analysis of samples of RhoxalPharma's tablets and its component parts in conjunction with disclosure of the formulation and process steps used to manufacture the RhoxalPharma tablets.
[14] In response, the Gardner and the first Cartilier affidavits disclose the pharmaceutical composition of RhoxalPharma's omeprazole tablets, including the complete list of ingredients, their relative proportions and process steps (the Exhibit B Composition). These affidavits conclude that RhoxalPharma's tablets do not have a subcoating and are therefore not in infringement of the omeprazole patents.
[15] In the second McGinity affidavit, Dr. McGinity states given that the list of ingredients does not provide sufficient information for a person of ordinary skill in the art of the Patents to conclude that they will not be infringed, he indicates that physical samples and/or more detailed process information would help him to decide whether RhoxalPharma's tablets infringe the omeprazole patents. Samples of RhoxalPharma's tablets were therefore forwarded to counsel for Astra.
[16] The second Cartilier affidavit contains the results of the experiments conducted by Dr. Cartilier on samples of RhoxalPharma's tablets in which he determined that the RhoxalPharma's tablets do not have a subcoating.
[17] In response, the Lindquist affidavit indicates the results of the experiments Dr.Lindquist conducted on samples of RhoxalPharma's tablets using two methods, a spectrometer, as well as a fluorescence microscope. He concludes to the presence of a subcoating generated spontaneously as a result of the reaction between the inner core and the enteric coating. Therefore, in his opinion, the RhoxalPharma tablet falls within the scope of claim 1 of each of the `693 and `891 patents.
[18] In the third McGinity affidavit, Dr. McGinity agrees with the conclusions put forth in the Lindquist affidavit.
| Theories of the Parties |
[19] Astra claims that the alleged subcoating in RhoxalPharma's product is spontaneously "generated" by a chemical reaction between one of the six ingredients in the core ("Substance X", unnamed in view of a Protective Order issued in this case) and one of the five ingredients in the enteric coating (hydroxy propylmethylcellulose phtalate, also referred to as HPMCP or HP-55).
[20] According to Astra's theory, this chemical reaction occurs when the enteric coating is disposed on the core of RhoxalPharma's tablet, a subcoating then spontaneously appears. Astra claims that the subcoating is an inert, water soluble salt, as per the essential requirements of the claims of the omeprazole patents.
[21] RhoxalPharma claims that the omeprazole patents cannot possibly cover what was disclosed as prior art--and specifically acknowledged in the introductory portion of these patents as constituting prior art--ie. a core containing omeprazole to which is applied an enteric coating. What is produced as a result of the application of the enteric coating on the core is old technology and cannot be covered by the Omeprazole patents. Further, RhoxalPharma submits that if its product contains a spontaneously generated subcoating, it is not covered by the patents because the wording of the claims clearly specifies that the subcoating must be "disposed" on the core. In the present context the term "disposed" implies an active intervention rather than a spontaneous generation.
[22] In response, the Applicants submit that there is no validity nor construction of the patent issue raised by RhoxalPharma in its detailed statement and hence the analysis entertained by RhoxalPharma is irrelevant. Further, RhoxalPharma initially argued its tablets were novel and inventive and is now estopped from asserting a contrary position.
ISSUE
| Is RhoxalPharma's allegation of non-infringement in respect of the `693 and `891 patents justified? |
| Discussion |
[23] Counsel for the Applicants submits that in considering whether the allegation of RhoxalPharma is justified, this Court is limited to considering whether the allegation is justified on the very limited factual and legal basis relied upon by RhoxalPharma in its letter. With respect to `693 and `891 patents, the factual and legal basis reads as follows:
| We have available to us omeprazole tablets which will not contain a core region nor an inert subcoating. |
[24] The Applicant therefore submits that the only remaining substantive issue in this proceeding is whether RhoxalPharma's proposed tablets will contain an inert subcoating. In this regard, in light of the evidence introduced by Drs. Lindquist and McGinity, counsel contends that it is clear that such a subcoating exists, and as a result, the allegation of non-infringement by the Respondent cannot be justified on the factual basis alleged.
[25] Considering Dr. Cartilier's admission in his second affidavit that the tablets contain a "core region", I agree with the Applicant the only remaining substantive issue in this proceeding is whether RhoxalPharma proposed tablets will contain an inert subcoating. In my opinion, this is a narrow issue which does not raise a validity issue nor the possibility of the presence of any subcoating which would not be covered by the patents.
[26] Considering the recent decision of the Federal Court of Appeal in Ab Hassle v. Canada2, it is clear that the Court is limited to consider only factual and legal basis relied upon in the detailed statement.
[27] In that decision, the respondent served on the appellant a NOC and a detailed statement pursuant to paragraph 5(3)(a) of the Regulations in which it denied infringement of the patent and alleged the claims of the patent were not valid for anticipation or obviousness in view of listed prior art references.
[28] The appellant commenced an proceeding pursuant to section 6 of the Regulations seeking an order prohibiting the Minister of Health from issuing a NOC to the respondent.
[29] The respondent filed expert evidence on the issue of obviousness which relied on prior art references, the majority of which were not listed in the detailed statement.
[30] The Federal Court of Appeal concluded that the detailed statement should be sufficiently complete to enable the patentee to assess its course of action in response to the allegation. As pointed out by Stone J., speaking for the Court, the intent appears to be that the entire factual basis be set forth in the statement rather than be revealed piecemeal when some need happens to arise in a proceeding pursuant to section 6 of the Regulations.
[31] That is exactly what is happening in the case at bar. RhoxalPharma is trying to introduce new matters based on an elaborate construction of the patents and on prior art which was not considered in the detailed statement. Further, I agree with the Applicants that RhoxalPharma initially argued that the composition of its tablets was novel and inventive and obtained a protective order on that basis. As such, it is now estopped from asserting that it is prior art.
[32] For these reasons, I am not ready to consider these new matters. I am unable to read the Court of Appeal's decision in Ab Hassle3 to allow any exception.
[33] Before starting the analysis of the evidence I would like to indicate that I find no merit in the argument made by the Applicants that RhoxalPharma has failed to demonstrate that it has available to it omeprazole tablets having the alleged characteristics described in its notice of allegation.
[34] I agree with RhoxalPharma that the product described in the Notice of Allegation must be assumed to be the one for which approval is sought.
[35] To submit that RhoxalPharma would seek approval and market a product different than that represented by the samples is tantamount to an allegation of fraud. As pointed out by counsel for RhoxalPharma once a second person's product reaches the market, the first person is in the position to test the accuracy of the detailed statement, if it was shown to be inaccurate the consequences for the second person could be very serious.4
| The Evidence |
[36] Has Astra shown that RhoxalPharma's notice of allegation is not justified? In other words, does the evidence support on a balance of probabilities that its tablets will not contain an inert subcoating which would be water soluble?
[37] RhoxalPharma's evidence was introduced by Dr. Cartilier, a pharmacist and scientist who was asked to review a novel omeprazole tablet developed by RhoxalPharma's supplier, Andrx.
[38] Dr. Cartilier conducted a scanning electron microscopy analysis. He relied upon a visual examination of the coated tablet cores and the uncoated tablet cores to conclude that there was no subcoating. No other technique was used that could have permitted him to identify the existence of an inert subcoating.
[39] Astra's evidence introduced by Dr. McGinity and more particularly by Dr. Lindquist clearly indicate that a subcoating is present.
[40] Dr. Lindquist, an analytical expert, used FT-IR spectrometer and fluorescence microscopy to analyse the samples.
[41] Fluorescence microscopy analysis involves the use of certain wave lengths of light to cause fluorescence in chemical materials. Different materials will fluoresce differently enabling a skilled analyst to identify different materials.
[42] From the cross-section of the coated tablet the photomicrograph showed three distinct layers: the upper portion or core region; a bright line (a subcoating) separating the tablet core and the enteric coating of approximately 3-4 microns in thickness; and the enteric coating.
[43] He also examined the cross-section of a coated tablet that had been washed with acetone [to remove the enteric coat], which showed two distinct regions, a tablet core region and a subcoating. The enteric coating (soluble in acetone) had been removed.
[44] Based on his analysis, Dr. Lindquist was of the opinion that there is a subcoating of approximately 3-4 microns in thickness between the enteric coating and the core region.
[45] Using FT-IR, he was of the opinion that the subcoating is a Substance X - HPMCP HP-55 salt which is inert.
[46] Using FT-IR, one can obtain an infrared spectrum from the surface of a solid object such as a tablet. By comparing the spectrum to the previously recorded spectra for known compounds, a skilled analyst can identify or learn information about compounds on the surface of the sample.
[47] As part of his employment duties, Dr. Lindquist has collected FT-IR spectra for a variety of pharmaceutical ingredients and could compare these reference spectra to a spectrum for an unknown material to assist in the identification of the material or to obtain useful information.
[48] He used FT-IR to obtain spectra on the following samples: (i) coated tablet, (ii) uncoated tablet, and (iii) coated tablet washed with acetone to remove the enteric coating.
[49] Based on spectra collected from the surface of the uncoated tablet, Dr. Lindquist concluded that the spectra showed the presence of Substance X.
[50] Based on a spectrum from the coated tablet, he concluded that the materials on the surface of the coated tablet were HPMCP HP-55 (hydroxypropylmethylcellulose phthalate 55, an enteric coating material also know as HPMCP 55) and possibly talc.
[51] Dr. Lindquist washed a coated tablet with acetone in order to remove the enteric coating and to reveal any existing subcoating. Subsequently, he conducted FT-IR scans to examine the surface of the washed tablet. The scans differed from the scan conducted on the coated tablet [which showed HPMCP 55] and from that conducted on the uncoated tablet [which showed Substance X] indicating that the material on the surface of the washed tablet (and therefore lying between the enteric coating and the core region of the coated tablet) was neither Substance X nor HPMCP HP-55.
[52] In his opinion, the scans indicated, based upon the location of the peaks, the likely presence of a Substance X - HPMCP HP-55 salt on the washed tablet surface. Moreover, the salt was likely to be water soluble given the conic nature of the salts. Finally, given the thickness of the subcoating it would likely be rapidly disintegrating.
[53] On the test conducted by Dr. Cartilier, Dr. Lindquist was of the opinion that the reliance upon SEM could not be determinative of the presence or absence of a subcoating as it would not necessarily discern materials having the same visual texture.
[54] Dr. McGinity confirmed in his third affidavit that based on the information available, he agrees with Dr. Lindquist's conclusion that the subcoating is likely Substance X - HPMCP HP-55 salt. He further agrees that the salt layer is inert and likely to be water soluble and rapidly disintegrating.
[55] Dr. McGinity further stated that Dr. Lindquist's analytical results and conclusions are consistent with the view he expressed in his second affidavit that Substance X could react with HPMCP 55 in the inert coat to form a subcoat.
[56] In his opinion, the RoxalPharma falls within the scope of claim 1 of each of the `693 and `891 patents. Dr. Linquist's evidence confirms the presence of a subcoating.
[57] I give great weight to the evidence of Dr. Lindquist. He has impressive qualifications as an analytical chemist.
[58] First, I am satisfied with his conclusion that, based on his experience, the technique used by Dr. Cartilier (SEM) is not determinative and that it is not one which would be used by an analytical chemist.
[59] I am satisfied that the evidence, on a balance of probabilities, supports his findings that there is an inert subcoating comprised on a Substance X -HPMCP HP-55 salt. He came to that conclusion prior to being shown the Exhibit B list of ingredients which makes his evidence more persuasive. I have reviewed carefully his extensive cross-examination and did not find any inconsistencies.
[60] Further, I do not agree with RhoxalPharma's assertion that the sub-layer, if any, is composed of degraded omeprazole. I accept Dr. Lindquist's evidence on that point that the absence of discolouration and the presence of peaks in the spectra showing a carboxylate confirm that the subcoat layer is not degraded omeprazole.
[61] With respect to RhoxalPharma's argument that there is no evidence that the Substance X - HPMCP HP-55 completely surrounds the core, I disagree. Dr. Lindquist's evidence indicates clearly that he observed a continuous subcoating. I didn't find evidence to the contrary.
[62] Finally, RhoxalPharma argues that there is no evidence that the salt is inert or that it will rapidly dissolve or disintegrate in water, again I disagree. I am satisfied that Dr. Lindquist has experience with Substance X salts and accept his conclusion that it is likely to be water soluble, given the conic nature of salts.
[63] In summary, I find that the evidence of Dr. Lindquist established on a balance of probabilities that RhoxalPharma's tablets will include an inert subcoating.
[64] As a result, the Applicants have established that the allegation of non-infringement, on the factual and legal basis provided in the detailed statement, cannot be justified.
[65] The application for judicial review is allowed. The Minister of National Health and Welfare is prohibited from issuing a notice of compliance to RhoxalPharma in respect of omeprazole tablets until after the expiration of Canadian patents `693 and `891. The whole with costs.
"Danièle Tremblay-Lamer"
JUDGE
OTTAWA, ONTARIO
December 15, 2000
__________________4 Hoffman-Laroche Ltd. v. Apotex Inc. (1996), 70 C.P.R. (3d) 206 at 213 (F.C.A.).