Astrazeneca Canada Inc. v. Apotex Inc.

Astrazeneca Canada Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2015-03-16
Neutral citation
2015 FC 322
File numbers
T-1409-04, T-1890-11
Decision Content
Date: 20150316
Dockets: T-1409-04
T-1890-11
Citation: 2015 FC 322
Ottawa, Ontario, March 16, 2015
PRESENT: The Honourable Mr. Justice Barnes
Docket: T-1409-04
BETWEEN:
ASTRAZENECA CANADA INC. AND AKTIEBOLAGET HÄSSLE
Plaintiffs
and
APOTEX INC.
Defendant
Docket: T-1890-11
AND BETWEEN:
ASTRAZENECA AB AND AKTIEBOLAGET HÄSSLE
Plaintiffs
and
APOTEX INC.
Defendant
JUDGMENT AND REASONS
Table of Contents
Page
I. The Patent 2
II. The Expert Evidence. 8
A. Dr. Martyn Davies. 8
B. Dr. Roland Bodmeier 23
C. Dr. Frank Bright 31
D. Dr. Peter Griffiths. 40
E. Dr. Arthur Kibbe. 46
F. Dr. William Amos. 55
III. Claims Construction. 60
A. Principles of Claims Construction. 60
B. The Construction Issues. 64
C. Does Claim 1 Cover Subcoatings That Form in Situ?. 65
D. What is the Meaning of the Term Inert?. 76
E. What are the Essential Structural Features of the Claimed Subcoat?. 78
IV. Validity. 84
A. Anticipation. 84
B. Obviousness. 88
V. Overbreadth, Inutility and Ambiguity. 115
VI. Infringement 125
A. Criticisms of Dr. Davies’ Testing Methods. 125
B. What Are the Constituent Elements and Structural Makeup of the Apotex Subcoating and to What Extent is it Compromised by Holes, Gaps or Other Anomalies?. 133
C. Thickness. 150
VII. Standing. 160
VIII. Foreign Issue Estoppel 163
IX. Remedies. 166
A. Deception. 166
B. Conclusions Re Infringement 169
C. Limitations. 172
D. Is AstraZeneca Entitled to an Elect an Accounting of Profits?. 174
X. Conclusion Re Relief. 175
I. The Patent [1] In these proceedings AstraZeneca Canada Inc., Aktiebolaget Hässle and AstraZeneca AB assert that Apotex Inc. [Apotex] has infringed Canadian Letters Patent 1,292,693 [the 693 Patent] – in which they all claim an interest. Except where otherwise expressly or contextually indicated, any reference to AstraZeneca in these reasons will apply collectively to the Plaintiffs.
[2] The proceedings have been bifurcated so that this decision concerns only the issue of liability.
[3] The 693 Patent sets out 19 claims pertaining to a formulation for omeprazole but only Claims 1, 5, 6, 13 and 19 are in issue. Apotex challenges the validity of the 693 Patent on several grounds. It also argues that its omeprazole formulation does not infringe any of the asserted claims. Much of its infringement defence is built around the construction of the language of Claim 1 with a view to establishing essential differences with its omeprazole formulation.
[4] The 693 Patent describes the field of the invention as the discovery of a new stable pharmaceutical preparation containing omeprazole for oral use and a method for its manufacture. This formulation has been successfully marketed by AstraZeneca under the trade name LOSEC.
[5] In the Background of the Invention, the inventors describe what was generally known about omeprazole. Omeprazole had been shown to be a powerful inhibitor of gastric acid secretion and was useful to treat gastric and duodenal ulcers. The 693 Patent cites Pilbrant and Cederberg Scand. J. Gastroenterology 1985; 20 (suppl. 108) p 113-120 [hereafter referred to as the Pilbrant reference] for the knowledge that omeprazole is susceptible to degradation in acid reacting and neutral media and can be stabilized in solution in the presence of higher pH values. Pilbrant is also cited for the proposition that a conventional enteric coat doseage form of omeprazole had been shown to provide sufficient stability for clinical studies. This approach was, however, later found to provide inadequate stability in long term storage. Following the Pilbrant citation, the inventors state “the stability profile [of omeprazole] is similar in solid phase”.
[6] The stability problem associated with conventional enterically coated omeprazole formulations is described in the 693 Patent as follows:
In order to obtain a pharmaceutical dosage form of omeprazole which prevents omeprazole from contact with acidic gastric juice, the cores must be enteric coated. Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, omeprazole rapidly decomposes by direct or indirect contact with it, with the result that the preparations become badly discolored and lose in omeprazole content with the passage of time.
In order to enhance the storage stability the cores which contain omeprazole must also contain alkaline reacting constituents. When such an alkaline core is enteric coated with an amount of a conventional enteric coating polymer such as, for example, cellulose acetate phthalate, that permits the dissolution of the coating and the active drug contained in the cores in the proximal part of the small intestine, it also will allow some diffusion of water of gastric juice through the enteric coating into the cores, during the time the dosage form resides in the stomach before it is emptied into the small intestine. The diffused water of gastric juice will dissolve parts of the core in the close proximity of the enteric coating layer and there form an alkaline solution inside the coated dosage form. The alkaline solution will interfere with the enteric coating and eventually dissolve it.
[7] At page 4 of the 693 Patent, the object of the invention is said to be the development of an omeprazole formulation which provides acceptable gastric acid resistance that dissolves rapidly in neutral to alkaline media (ie. the intestine), and that has good stability during long term storage. This object is said to be fulfilled with a new doseage form made up of three structural elements:
a. Cores of neutral or alkaline salts of omeprazole optionally mixed with alkaline compounds;
b. A separating sublayer coating or coatings soluble or rapidly disintegrating in water consisting of non-acidic, otherwise inert pharmaceutically acceptable substances; and
c. An outer layer consisting of an enteric coating.
The final doseage form is then treated in a suitable way to reduce the water content to a very low level in order to obtain good stability during long term storage.
[8] In the Detailed Description of the Invention, the omeprazole cores are further described. Gelatine capsules are said to be “used as cores for further processing”. The separating layer and its purpose are described in detail in the following way:
The omeprazole containing alkaline reacting cores must be separated from the enteric coating polymer(s) containing free carboxyl groups, which otherwise causes degradation/discolouration of omeprazole during the coating process or during storage. The subcoating layer, in the following defined as the separating layer, also serves as a pH-buffering zone in which hydrogen ions diffusing from the outside in towards the alkaline core can react with hydroxyl ions diffusing from the alkaline core towards the surface of coated articles. The pH-buffering properties of the separating layer can be further strengthened by introducing in the layer substances chosen from a group of compounds usually used in antacid formulations such as, for instance, [examples omitted] or similar compounds; or other pharmaceutically acceptable pH-buffering compounds such as, for instance the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric, citric or other suitable, weak, inorganic or organic acids.
The separating layer consists of one or more water soluble inert layer, optionally containing pH-buffering compounds.
The separating layer(s) can be applied to the cores - pellets or tablets - by conventional coating procedures in a suitable coating pan or in a fluidized bed apparatus using water and/or conventional organic solvents for the coating solution. The material for the separating layer is chosen among the pharmaceutically acceptable, water soluble, inert compounds or polymers used for film-coating applications such as, for instance sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethyl-aminoacetate or the like. The thickness of the separating layer is not less than 2 μm, for small spherical pellets preferably not less than 4 μm, for tablets preferably not less than 10 μm.
In the case of tablets another method to apply the coating can be performed by the drycoating technique. First a tablet containing omeprazole is compressed as described above. Around this tablet a layer is compressed using a suitable tableting machine. The outer, separating layer, consists of pharmaceutically acceptable, in water soluble or in water rapidly disintegrating tablet excipients. The separating layer has a thickness of not less than 1 mm. Ordinary plasticizers colorants, pigments, titanium dioxide, talc and other additives may also be included into the separating layer.
In case of gelatin capsules the gelatin capsule itself serves as separating layer.
[9] Much of the expert evidence presented in this case was concerned with the language of Claim 1. At the heart of the infringement dispute is whether Claim 1, properly construed, has been infringed by the manufacture and sale of Apotex’s omeprazole formulation, Apo-Omeprazole. A key aspect of the dispute is whether Apo-Omeprazole contains a subcoating layer meeting the criteria described in Claim 1. Apotex’s challenges to the validity of the 693 Patent were similarly directed at Claim 1. Among other issues, Apotex and its experts maintain that the formulation described in Claim 1, however construed, was anticipated, obvious and overbroad.
[10] Claim 1 of the 693 Patent describes the formulation in the following terms:
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 plus an alkaline reacting compound and 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 material selected from among tablet excipients and polymeric film forming compounds; and (c) an outer layer disposed on said subcoating comprising an enteric coating.
[11] Claims 5, 6 and 13 are all directly or indirectly dependant on Claim 1. Claim 19 covers the use of the formulation according to any of the Claims 1 to 16 for the treatment of gastrointestinal diseases.
[12] The 693 Patent has a priority date of April 30, 1986, a Canadian filing date of April 29, 1987 and a date of issuance of December 3, 1991. It is common ground that the relevant date for construing the patent claims is December 3, 1991 and the relevant date for assessing obviousness is April 30, 1986.
II. The Expert Evidence [13] In order to more fully understand the construction, validity and infringement issues arising in these proceedings, it is helpful to first consider the scientific evidence presented by the expert witnesses and, in particular, the few points where they agreed and the many where they disagreed.
[14] AstraZeneca’s case was advanced by Dr. Martyn Davies and Dr. Roland Bodmeier. Apotex led evidence from Dr. Peter Griffiths, Dr. William Amos, Dr. Frank Bright and Dr. Arthur Kibbe.
[15] I accept that all of these witnesses were appropriately qualified. My assessments of their credibility and the weight I have attributed to their evidence are set out later in these reasons.
A. Dr. Martyn Davies [16] Dr. Davies has a record of extensive work, research and professional recognition in the areas of pharmaceutical testing analysis and characterization of drug formulations. He has widely employed advanced analytical techniques in his work. He has been qualified to testify as an expert witness on 12 occasions and, in particular, his evidence was accepted in the United States patent infringement proceedings involving the equivalent to the 693 Patent. He was qualified as an expert in pharmaceutical formulation, particularly the formulation of coated oral doseage forms, including enteric coatings.
[17] Dr. Davies was retained by AstraZeneca to ascertain the composition of the Apotex omeprazole pellets. His precise mandate is set out at paragraph 23 of his initial report. He had previously been retained by AstraZeneca in the United States in connection with patent infringement litigation between AstraZeneca and a number of competitors, including Apotex.
[18] Dr. Davies subjected the Apotex pellets to a number of tests including various forms of microscopy, infrared spectroscopy, visual inspection, video micro-imaging, pH measurement, and water content analysis. Some of his testing was conducted in 2004 in support of his opinions in the United States’ litigation concerning the equivalent patent. That testing was replicated, in part, in 2011 in connection with this proceeding.
[19] Dr. Davies designed and oversaw the 2004 and 2011 experiments that were carried out in his laboratory. He gave evidence that he observed the vast majority of the experiments and the recording of data. He was responsible for reviewing the data and formulating the opinions he provided in the United States and in Canada.
[20] Dr. Davies was provided with samples of the Apotex uncoated omeprazole cores, capsules containing fully formulated enterically coated omeprazole pellets and the Apotex excipients.
[21] Dr. Davies removed the enteric coating from some of the Apotex pellets by dissolving the MACP coating in acetone/isopropanol [IPA] solvent. IPA is known to dissolve MACP. The solvent wash procedure was conducted for 2 minutes in 2004 and for 4 minutes in 2011. This was followed by a solvent rinse and drying on paper. A number of washed pellets were then randomly sectioned near their equators and fixed to metal discs using adhesive UV curable resin for microscopic examination.
[22] In 2004, Dr. Davies combined MACP and PVP in solution and observed that a precipitate readily formed. That precipitate was washed three times in water and kept for further analysis. This procedure was not repeated in 2011.
[23] The imaging techniques that Dr. Davies used involved Confocal Laser Scanning Microscopy [CLSM] and wide-field-UV fluorescence microscopy (2004 only) at 10X and 50X magnification.
[24] Dr. Davies also exposed his samples to Attenuated Total Reflectance Fournier Transfer Infrared Spectroscopy [ATIR] as a means of detecting their molecular “fingerprints”.
[25] In 2004 and in 2011 Dr. Davies exposed washed pellets to a water bath and video-imaged the reaction that took place.
[26] Finally, in 2004 Dr. Davies carried out pH and water content measurements on the Apotex samples.
[27] In 2004 Dr. Davies examined over 20 bisected enteric coated Apotex pellets and over 20 washed pellets with UV fluorescence and CLSM fluorescence and reflectance microscopy. Many individual and “representative” CLSM optical slices were examined for each pellet. The same process was followed in 2011 with CLSM imaging. According to Dr. Davies, all of the images he obtained showed the presence of a distinct and continuous brightly fluorescing ring or corona at the interface of the pellet cores and the enteric coating. No gaps in the fluorescent ring could be seen. The ring was detected both within the enterically coated pellets and at the surface of the washed pellets. When Dr. Davies examined some 20 bisected Apotex pellet cores using CLSM and UV fluorescence microscopy, he found the cores to be weakly fluorescent but there was no bright fluorescent ring at the surface of the samples [see Schedule 27 to Exhibit 6]. According to Dr. Davies, the fact the fluorescent ring remained intact after the enteric coating was washed off in solvent indicates the chemical solubility of each structure was different.
[28] When Dr. Davies measured the thickness of the fluorescent layer in 2004 from individual CLSM images, he obtained a range of between 2 and 6 microns. His thickness measurements from 2011 fell between 1 micron and 6.8 microns. On a recorded sample size of 50, the average thickness measurement came to 3 microns.
[29] In 2004 and in 2011, Dr. Davies performed ATIR analysis on the surface of the Apotex enteric coated pellets, on the fluorescing layer of the washed pellets and on the uncoated cores. He then compared the spectra obtained to the known spectra for the components used by Apotex (omeprazole, povidone [PVP], mannitol, MACP and the known omeprazole degradation products) and to the MACP-PVP complex he had prepared.
[30] When Dr. Davies scanned the Apotex cores, he observed spectral peaks he attributed to omeprazole, mannitol and PVP. In particular, he found PVP to be present on the surface of the cores. The spectra he took from the enteric coating of the Apotex pellets matched the spectrum for a sample of MACP supplied by Apotex.
[31] Dr. Davies then examined the fluorescing layer. In 2004 he assessed ten washed pellets and recorded spectra from five. The ATIR spectra he obtained disclosed differences from the spectra for MACP. In particular, the spectra for the fluorescing layer disclosed an additional absorption peak that he attributed to a complex that had formed in a reaction between the MACP enteric coating and PVP in the pellet cores. Dr. Davies noted that those two polymers are known to complex with each other due to hydrogen bonding. He described the complex as a methacrylic acid copolymer-PVP complex chemically distinct from the enteric coating. To confirm this finding, Dr. Davies compared a spectrum taken from the fluorescing layer to a spectrum taken from the MACP-PVP complex precipitate he prepared. The two spectra were comparable.
[32] In addition to finding the complex in the Apotex sublayer, Dr. Davies found evidence of the presence of MACP magnesium salt. This compound, he said, formed from a reaction with magnesium hydroxide during the enteric coating process. Mannitol peaks that appeared in the washed pellet spectra were said by Dr. Davies to arise from the detection of mannitol immediately below the sublayer. No evidence of omeprazole or its degradation products was observed.
[33] The ATIR data led Dr. Davies to conclude that both the complex and MACP magnesium salt in the fluorescing sublayer formed from a reaction between MACP and PVP and magnesium hydroxide during the Apotex enteric coating process.
[34] Dr. Davies’ visual inspection of the Apotex pellets revealed no discolouration as an indication of degradation.
[35] After submerging 20 washed pellets in a water bath, Dr. Davies observed a film-like layer peeling away from the cores. The loss of the sublayer was complete at about 7 minutes and the pellets fully disintegrated within 10 minutes. Time-lapse videos of this reaction were recorded.
[36] Dr. Davies’ 2004 pH measurements disclosed values of between 8.81 and 9.39. Similar results were obtained in 2011. When Dr. Davies compared the pH values for MACP and PVP to the values for the complex, he observed that the complex was 2 pH units higher. This indicated to Dr. Davies that the complex was chemically distinct from either of its constituent compounds. His measurement of water content in the Apotex pellets resulted in a range from between 1.52% to 1.97%.
[37] From the above test results, Dr. Davies drew the following conclusions:
a. The cores of the Apotex pellets contain omeprazole.
b. The presence of a subcoating outside of the Apotex pellet cores had been demonstrated by CLSM fluorescence and reflectance microscopy. The fluorescing ring that he observed conformed to the contours of the cores.
c. The subcoating layer has different chemical properties from the enteric coating. This was demonstrated by its continued presence after the enteric coating was removed with acetone/IPA solvent, by the different ATIR spectra that were obtained from both regions and by differences in their acidity levels.
d. Neither the MACP-PVP complex nor the MACP salt present in the sublayer appeared to degrade omeprazole. The pellets showed no evidence of discolouration and the ATIR data did not disclose omeprazole degradation products in the sublayer.
e. Although Dr. Davies did not rule out the presence of acidic functional groups from the enteric coating in the sublayer, he concluded that most would have been taken up in the MACP-PVP reaction. To the extent that unreacted acidic functional groups did remain in the sublayer, they were likely to be segregated away from the cores and not available to degrade the omeprazole at the surface of the cores.
f. In water, the subcoating does not dissolve but it rapidly disintegrates. This was evident from the water disintegration tests.
g. The ATIR data showed that the sublayer does not contain omeprazole or an alkaline salt of omeprazole.
h. The complex and MACP salt are polymeric film forming compounds. The film-like character of the complex is evident in the disintegration videos.
i. The enteric coating layer of the Apotex pellets is composed of MACP and is distinct from the sublayer containing the complex.
j. The Apotex cores exhibit pH values of between 8.81 and 9.39.
[38] In reply to the responding expert reports from Dr. Griffiths and Dr. Bright, Dr. Davies offered additional justification for his testing conclusions. Dr. Davies disagreed that he had attempted to use fluorescence data to identify the complex in the sublayer region. He acknowledged that fluorescence is not a suitable technique to identify a chemical composition but could be used to study the structure of pharmaceutical compositions. Fluorescence was only one technique he used to assess the presence and structure of the sublayer. Dr. Davies stated that he had not conflated the observed fluorescent ring with the complex nor had he concluded the complex was the only constituent compound in the sublayer.
[39] Dr. Davies confirmed that his ATIR interrogations consistently disclosed the presence of the complex in the sublayer and his multiple UV and CLSM examinations all exhibited a continuous bright fluorescent layer.
[40] Dr. Davies asserted again that the detection of mannitol bands in some of the ATIR spectra resulted from the detection of mannitol sitting below the sublayer in the omeprazole cores. According to Dr. Davies the suggestion that the presence of mannitol bands indicated gaps in the sublayer was based on a flawed assumption about the depth of penetration of his ATIR signal. He also observed that Dr. Griffiths’ analysis of sublayer thickness was very indirect and that no attempt was made to replicate his direct measurements using a standard technique.
[41] Dr. Davies did not agree that omeprazole degradants were more likely to be the sources of the observed fluorescence. There was no reliable empirical evidence produced to show degradants in the sublayer and, even if they were present below levels of ATIR detection, they would be insignificant.
[42] In responding to ATIR spectra obtained by Dr. Hawker, Dr. Davies noted an anomalous and significant signal from the starting control (the blank). According to Dr. Davies this rendered all of the Hawker data unreliable. Dr. Davies also criticized the method employed at Temple University to obtain CLSM images. He said the pellets were crudely cracked and not, as he had done, carefully sliced and, unlike his Z series of CLSM images, only one image was taken for each pellet examined.
[43] Dr. Davies’ response to Dr. Griffiths’ comment that he had not directly ascertained the chemical composition of the fluorescent layer is set out at paragraph 35 of his reply report and further discussed at pages 433-434 of his testimony:
Q. So to begin with, Dr. Davies, I would like to ask you about part of your reply report which starts at page 12, under the heading "Experiments Conducted to Directly Analyze Composition of Fluorescent Subcoating Layer".
In paragraph 35 of your reply report you note that Dr. Griffiths states that you carried out no experiments to elucidate directly the composition of the intense fluorescing layer observed in Apotex's enteric coated pellets. You say that that is untrue. Could you please explain your basis for saying so?
A. My basis is that I employed ATR FTIR analysis on that subcoating layer on the surface of the solvent washed pellets to elucidate the composition of that layer to demonstrate that it contained the MACP PVP complex and the MACP salt.
I also undertook the UV CLSM fluorescence and reflectance data on the bisected pellets which were enteric coated pellets, the washed pellets, the uncoated cores, to identify the presence of that layer and confirmed that it remained after washing. So it had different properties to that of the enteric coating.
I then went on to make the complex to show that the complex had the same chemical signals, diagnostic signals for the complex in the ATR FTIR analysis.
I then compared that spectra to the spectra I saw for the washed pellets. And, again, I showed that what I saw in the complex that I had made in the test tube was the same signal that I saw for the complex that I saw on Apotex's washed pellet.
So I took a number of steps to show that, in fact, that I had done a number of experiments to show that I was directly analyzing the composition of that layer.
[44] Dr. Davies addressed Dr. Griffiths’ identification of carboxylic acid groups (MACP that had not reacted with PVP) in the sublayer by pointing out that any unreacted MACP was unlikely to be in contact with the cores and that Dr. Griffiths had not tested his hypothesis. If these acid groups were available to react with omeprazole at the surface of the cores measurable degradation products ought to have been present. Apotex’s own sensitive HPLC tests of its finished products showed only insignificant or undetectable levels of degradation products.
[45] The Apotex criticisms about the representativeness of Dr. Davies’ testing were addressed. It was acknowledged that the area of ATIR interrogation carried out by Dr. Davies was 44 microns in diameter from a total pellet diameter of about 1000 microns. Dr. Davies examined at least 15 washed pellets and recorded 10 spectra for each. All of the spectra disclosed the presence of the complex. This was said to be consistent with Dr. Davies’ UV and CLSM fluorescence microscopy where over 25 bisected coated pellets and 25 bisected washed pellets were imaged. In every case a bright fluorescent ring was observed. Dr. Davies noted that Dr. Bright had not attempted to conduct his own testing to challenge the representativeness of Dr. Davies’ data.
[46] In a further response to the suggestion that he had assumed the fluorescent band to be the complex, Dr. Davies answered in the following way:
56. However, merely because fluorescence is not a suitable technique for identifying the MACP-PVP complex does not mean that it cannot be used in combination with other tests to show where the complex is located. As set out in my 2011 Report, I used wide-field UV and CLSM fluorescence in combination with reflectance microscopy to show that a continuous brightly fluorescent layer is present in Apotex’ s pellets on the outside of the pellet core where the enteric coating is first applied. I then used ATR-FTIR spectroscopy to show that the fluorescent subcoating layer contains an MACP-PVP complex, which is not present in either the core or enteric coating. In combination, these tests show that the MACP-PVP complex and the subcoating layer are located together.
[47] To Dr. Griffiths’ postulation that omeprazole degradants were more likely than the complex to be the source of the fluorescent ring, Dr. Davies pointed out that the complex was actually detected in the sublayer and omeprazole degradants were not. In the absence of data to show the presence of omeprazole degradants in the sublayer and in the face of an acknowledgement that fluorescence alone cannot identify a particular molecule, Dr. Griffiths’ opinion was described as speculation.
[48] The representativeness of Dr. Davies’ sublayer thickness measurements was defended in the following way in his reply report:
72. First, the thickness data for the fluorescent subcoating layer was obtained using a standard analytical technique. Second, the thickness data was consistent across multiple pellets in both 2004 and 2011. In particular, all the pellets examined in 2011 had a fluorescent subcoating layer with an average thickness of at least 2 microns, which was consistent with the range of thickness measured in 2004. Third, this thickness data is consistent with both CLSM reflectance microscopy and ATR-FTIR spectra of bisected washed pellets.
[49] Dr. Davies confirmed his thickness measurements were not conducted from maximum intensity images but, rather, from individual CLSM Z-slice images. This point was advanced to displace the suggestion that Dr. Davies’ thickness measurements had been taken from maximum intensity images.
[50] Dr. Davies dealt with Dr. Griffiths’ opinion concerning the presence of mannitol bands in some of the ATIR washed pellet spectra. Much of the debate focussed on the assessment of the depth of the penetration of the beam generated by Dr. Davies’ ATIR spectrometer. According to Dr. Davies, Dr. Griffiths had significantly understated the depth of signal penetration and thus underestimated the thickness of the subcoating layer. A key point of disagreement between Dr. Davies and Dr. Griffiths concerned the angle of the spectrometer beam inherent to Dr. Davies’ instrument. Dr. Griffiths assumed a median angle of incidence of 45º and Dr. Davies said it fell in a range of between 27º and 45º. I will say more about this later in these reasons.
[51] In response to Dr. Griffiths’ doubt that the film-like layer falling away from the Apotex washed pellets when immersed in water was the complex and, instead, could be residual MACP, Dr. Davies said the MACP readily dissolved in a solvent wash and was unlikely to have remained except in minute amounts. Since the ATIR spectra of the washed pellets consistently showed the complex to be present, it was the only film-like compound that could plausibly remain.
[52] The Apotex criticisms of Dr. Davies’ testing methods were addressed in Dr. Davies’ reply report. Dr. Bright’s concern about possible contamination by Dr. Davies’ use of drying paper and adhesive resin was countered in the following ways:
a. The fluorescent ring was present in both the washed and unwashed pellet and therefore could not have resulted from paper residue.
b. Paper contamination would have been localized. The fluorescent ring formed a corona around the pellet cores.
c. The pellets were never embedded in resin but instead were affixed at the base well away from the area under inspection.
[53] To Dr. Bright’s concerns that Dr. Davies bisected the Apotex pellets only near their equators and otherwise failed to obtain representative data, Dr. Davies said that he wanted to avoid a plane that intersected the sublayer at an angle and that, unlike Dr. Rez Fassihi, he took numerous CLSM images through each pellet sample. Having regard to the uniformity of Apotex’s manufacturing methods, the location of pellet analysis would not be expected to allow for significant coating anomalies.
[54] Dr. Davies challenged Dr. Bright’s opinion that the CLSM images showed discontinuities in sublayer fluorescence. He noted that the bisected pellets had irregular surfaces such that portions of the image will typically be out of focus. According to Dr. Davies, in order to properly analyze the entire surface of a non-planar pellet, a series of CLSM sections is required to discern which portions of each image are in focus. With a non-transparent sample, the intensity of fluorescence diminishes as the focal plane moves into the interior. This attenuation effect means that the fluorescent image obtained from the in-focus surface of a partially opaque sample imparts the most reliable information. Multiple Z-scan images of each sample are thus required to accurately determine the continuity of any observed fluorescence. According to Dr. Davies, Dr. Bright failed to appreciate these points and took his discontinuity observations from single and unrepresentative CLSM Z-scan images from well above and below the pellet surface. For those CLSM images where the focal plane intersected the pellet surface, no discontinuities in sublayer fluorescence could be observed.
[55] Dr. Davies expressed the same concern about Dr. Bright’s use of 3D images reconstructed from individual CLSM images. His reply report at paragraphs 167-169 addressed the problem as follows:
167. Based on my CLSM three dimensional (“3D”) images for Apotex’s enteric coated pellets, capsule Lot FD9104B and the 3D montages Dr. Bright created using my 2011 CLSM data, Dr. Bright concludes that discontinuities in the subcoating layer are “many and obvious”. I disagree for the following reasons.
168. It is improper to assess continuity of the subcoating layer by visual inspection of the 3D images reconstructed from the CLSM sections of the bisected pellet. The image formed using CLSM reflects the intensity of the fluoresced light detected in the focal plane. However, as previously explained, the intensity depends on the depth and orientation of the focal plane in relation to the bisected pellet surface. CLSM images with focal planes taken above or below the bisected pellet surface will not accurately reflect the level of fluorescence at the surface. Even when a focal plane intersects a bisected pellet surface, some portions of the surface may be out of focus if the focal plane is not exactly parallel with the pellet surface. A 3D stack of such CLSM images suffers from the same limitations. Dr. Bright did not account for this effect when analyzing the 3D CLSM images. As a result, he misinterpreted the dark areas in the images as discontinuities.
169. Moreover, had there been actual discontinuities in the subcoating layer, they would have presented themselves as gaps in portions of the 2D CLSM images where the bisected pellet surface is in focus. However, no such gaps were evident. [Footnotes omitted]
[56] To Dr. Bright’s opinion that the overall intensity of fluorescence emanating from the sublayer was not appreciably different from the surrounding areas, Dr. Davies observed that when intensity was assessed from in-focus areas at the sample surface it was appreciably brighter than its surroundings. In those areas a distinct bright fluorescing layer could be seen resting on the weakly fluorescing cores. In contrast, fluorescence arising from background noise would be random and would not be represented in the images as a bright continuous corona.
[57] Dr. Davies took umbrage at Dr. Bright’s allegation that many of his CLSM images had been artificially altered to highlight specific regions. He pointed out that the images were automatically generated by his CLSM instrument and not altered by any operator manipulation.
[58] In commenting on the Temple University CLSM 10X fluorescence images, Dr. Davies pointed out that the pellets were crudely bisected and therefore difficult to clearly image. Because each sample was only imaged once, the images were insufficient to support any meaningful conclusions. Multiple images are required to determine which areas are in focus.
[59] In response to Dr. Amos’ opinion that Dr. Davies’ CLSM images were saturated, Dr. Davies stated that he took the steps necessary to avoid this problem.
B. Dr. Roland Bodmeier [60] Dr. Bodmeier was qualified as an expert in pharmaceutical formulation, particularly the formulation of coated oral doseage forms, including enteric coatings. He has extensive experience as an academic and in working with different coating technologies including the application of coatings in drug formations (often to obtain specific release profiles). He is a prolific scientific author and researcher. He also frequently acts as a consultant to the pharmaceutical industry.
[61] Dr. Bodmeier was initially retained by AstraZeneca to construe the relevant claims of the 693 Patent as read by the notional person of skill and to assess whether, in view of Dr. Davies’ test results, the Apotex omeprazole capsules infringe Claims 1, 5 and 6 of the 693 Patent. In a subsequent responding report [Exhibit 67] Dr. Bodmeier addressed Apotex’s invalidity evidence bearing on anticipation, obviousness, overbreadth, utility, sufficiency, claims broader and ambiguity. In a final report [Exhibit 68], he addressed a few specific evidentiary points raised by the Apotex experts mainly concerning the degradation of omeprazole.
[62] Dr. Bodmeier described the object of the 693 Patent as the provision of a storage stable and gastric acid resistant omeprazole formulation. Because omeprazole was known to be unstable in acidic aqueous environments, it required a protective enteric coating to pass through the stomach for release in the intestine. However, in that formulation, long term storage stability was compromised as evidenced by discolouration.
[63] Dr. Bodmeier noted that when the inventors addressed the storage instability problem by adding either an alkaline reacting compound [ARC] to the omeprazole cores or by using an alkaline omeprazole salt, a new problem arose in the form of a decrease in gastric acid resistance. This was caused by the premature degradation of the enteric coat. What was found to be happening was that some gastric juice would diffuse through the enteric coat into the cores, forming an alkaline solution. The alkaline solution caused the enteric coat to dissolve from the inside leading to premature failure after administration.
[64] According to Dr. Bodmeier, the inventors’ solution to the formulation problem lay in the inventive combination of an alkaline core separated from the enteric coat with a water soluble or rapidly disintegrating subcoating layer. With the use of a subcoating layer the alkalinity of the cores could be reduced without compromising the long term storage stability of the formulation.
[65] Dr. Bodmeier was asked to construe Claims 1, 5 and 6. In particular, he was asked to determine whether Claim 1 included within its ambit a subcoating that formed in situ as the product of a chemical reaction between the enteric coat and an alkaline omeprazole core. He was also asked to interpret the term “inert” as it related to the subcoating.
[66] Dr. Bodmeier interpreted Claims 1, 5 and 6 as formulations per se without any limitation to the process of manufacture. He construed the words “disposed on” as describing only the location of the subcoating. His conclusion is set out in the following passage from his initial report:
48. In response, as noted above, claims 1, 5 and 6 of the ‘693 patent are not limited to a particular method of formation of the composition, provided that the subcoating achieves the goals of the patent, namely a storage stable and gastric resistant dosage form. In particular, the advantages of the invention arise from the finished dosage form structure and not from any particular process by which the structure is made. Contrary to what Apotex suggests, the patent is not directed to avoiding all possible reaction products. In certain circumstances, a reaction product may provide the necessary subcoating layer which will assist in achieving gastric resistance and storage stability. For example, the application of an enteric coating material to a core can, depending upon process conditions and ingredients, lead to a subcoating layer which is formed in situ. This subcoating can comprise material distinct from the core and the enteric coating. There is nothing in the disclosure teaching that such a reaction product must be avoided. The skilled person would not read such a limi