2012 FC, 2012 FC 1189

Federal Court Cour fédérale Date: 20121011 Docket: T-1652-10 Citation: 2012 FC 1189 Ottawa , Ontario , October 11, 2012 PRESENT: The Honourable Mr. Justice O'Keefe BETWEEN: ASTRAZENECA CANADA INC. and ASTRAZENECA AB Applicants and PHARMASCIENCE INC. and THE MINISTER OF HEALTH Respondents REASONS FOR JUDGMENT AND JUDGMENT [ 1 ] In this application, the applicants, AstraZeneca Canada Inc. and AstraZeneca AB, collectively referred to as AstraZeneca, address allegations of patent invalidity made by the respondent, Pharmascience Inc. (Pharmascience) in its notice of allegation dated August 27, 2010 (the NOA). The NOA was filed pursuant to

section 5 of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133 (the NOC Regulations) for Canadian Patent No. 2,290,531 (the ‘531 Patent) and Canadian Patent No. 2,346,988 (the ‘988 Patent). In an order dated August 8, 2011, Prothonotary Mireille Tabib dismissed the application with respect to the ‘ 988 Patent. The scope of this application is therefore limited to the ‘ 531 Patent. [ 2 ] AstraZeneca requests a declaration that the NOA is neither a valid notice of allegation nor a detailed statement as contemplated by the NOC Regulations .

In the alternative, AstraZeneca requests an order prohibiting the Minister of Health (the Minister) from issuing a notice of compliance (NOC) to Pharmascience for its 20 and 40 mg dosage esomeprazole magnesium capsules (the Pharmascience capsules) until the expiry of the ‘531 Patent. Background

[ 3 ] Pharmascience filed an Abbreviated New Drug Submission (ANDS) with the Minister seeking an NOC for its Pharmascience capsules. These capsules are intended to treat duodenal ulcer disease associated with Helicobacter pylori infection.

In its ANDS , Pharmascience compared the Pharmascience capsules to AstraZeneca’s 20 and 40 mg dosage capsules of NEXIUM to demonstrate bioequivalence under subsection 5(1) of the NOC Regulations . [ 4 ] In its NOA, Pharmascience alleged that the claims made in the ‘531 Patent were irrelevant and/or invalid on the following grounds: - Insufficient disclosure/lack of support; - Claims broader than invention made or disclosed; - Lack of novelty and anticipation by prior use; - Double-patenting; - Lack of inventive step/obviousness; - Not an invention (under

section 2 of the Patent Act , RSC, 1985, c P-4); - Lack of sound prediction and lack of utility; - Not a valid selection patent; and - Fraud on the patent officer (under subsection 34(1) and

section 53 of the Patent Act ). [ 5 ] The main polymer at issue is hydroxypropyl methylcellulose (HPMC). HPMC has different properties depending on its molecular weight. The molecular weight of HPMC is proportional to the viscosity of an aqueous solution of HPMC; thus, as the molecular weight of HPMC increases, so does the viscosity of an aqueous solution of HPMC. High molecular weight HPMC has a viscosity greater than 4,000 cps and dissolves slowly in water which makes it advantageous for controlled release formulations that require slow release of drugs.

Conversely, low molecular weight HPMC has viscosity ranging from 5 to 15 cps and is often used in film coatings due to its faster dissolution in water. ‘531 Patent [ 6 ] The ‘ 531 Patent , entitled Pharmaceutical Formulation of Omeprazole , issued on December 12, 2006 from an international patent application filed in Canada on May 18, 1998. The ‘ 531 Patent claimed priority from Swedish patent application No. 9702000-2 filed on May 28, 1997.

The ‘ 531 Patent was published on December 3, 1998 and expires on May 18, 2018. [ 7 ] The inventors of the ‘ 531 Patent are Magnus Erikson (Sweden) and Lars Josefsson (Sweden).

The patent is owned by AstraZeneca AB and is listed on the Minister’s Patent Register for AstraZeneca’s NEXIUM brand of 20 and 40 mg esomeprazole magnesium trihydrate tablets. [ 8 ] Specific terms are defined as follows in the ‘ 531 Patent : Omeprazole, an alkaline salt thereof, the (-)-enantiomer of omeprazole and an alkaline salt of the (-)-enantiomer of omeprazole […] Cloud point is the temperature at which this polymer phase separation occurs.

Cloud point is determined by measuring the light transmission through the polymer solution. [ 9 ] The ‘ 531 Patent is directed at the use of low viscosity HPMC of a specific quality (as reflected by its CP) in an enteric- coated omeprazole immediate release formulation. The enteric coating, an acid, is used to withstand the omeprazole, an acid labile compound, from the acidic conditions of the stomach. The HPMC layer serves as a binder and/or separating layer between the

omeprazole-containing core and the enteric coating. The inventors stated that they surprisingly found that different batches of a single low viscosity HPMC product, as gauged by the cloud point (CP), may have different abilities to influence the rate of release of omeprazole from an enteric-coated formulation.

The “Claimed CP” [ 10 ] The patent’s claimed CP for low viscosity HPMC is as follows: - CP of not less than 45.6˚C at 96% light transmission measured with a Mettler FP90/FP81C instrument, where the CP is determined by dissolving the HPMC in a concentration of 1.2% (w/w) in a mixed solution of phosphate buffer 0.235 M and simulated gastric fluid pH 1.2 in the proportions 4:5 at a pH of 6.75 to 6.85; and - CP of not less than 44.5˚C at 95% light transmission measured with a spectrophotometer, where the CP is determined by dissolving the low viscosity HPMC in a concentration of 1% (w/w) in a mixed solution of phosphate buffer 0.235 M and simulated gastric fluid pH 1.2 in the proportions 4:5 at a pH of 6.75 to 6.85. [ 11 ] The patent states that this claimed CP ensures sufficient drug release from the formulation.

Thus, by following the ‘ 531 Patent , the amount of product discarded from insufficient release is reduced, which results in a significant advantage. Claims [ 12 ] The ‘531 Patent has 20 claims. [ 13 ] The first claim is for an enteric coated oral pharmaceutical formulation comprising the following three layers: 1. Core material consisting of an active ingredient (omeprazole, as defined above, in admixture with one or more pharmaceutically accepted excipients and an optional binding agent) and optionally an alkaline reacting compound; 2. Separating layer on the core material; and 3.

Enteric coating layer on the separating layer. [ 14 ] The optional binding agent and/or constituent of the separating layer are comprised of low viscosity HPMC with at least the claimed CP. [ 15 ] Claims 2 to 8 add the following specifications: Claim 2: subset of Claim 1 where the constituent of the separating layer is low viscosity HPMC. Claim 3: subset of Claim 2 where the enteric coating layer is methacrylic acid copolymer. Claim 4: subset of Claim 1 where the binding agent is low viscosity HPMC.

Claim 5: subset of Claims 1 to 4 where the low viscosity HPMC has a viscosity of less than 7.2 cps in 2% aqueous solution. Claim 6: subset of Claims 1 to 5 where the active ingredient is omeprazole. Claim 7: subset of claims 1 to 5 where the active ingredient is magnesium salt of omeprazole.

Claim 8: subset of Claims 1 to 5 where the active ingredient is magnesium salt of the (-)-enantiomer of omeprazole. [ 16 ] Claims 9 and 10 specify an enteric coated oral pharmaceutical formulation manufactured with an optional binding agent and a separating layer of low viscosity HPMC at the claimed CP of 45.6˚C and 44.5˚C, as described above, respectively.

Similarly, Claims 11 and 12 specify an enteric coated oral pharmaceutical formulation that does not contain a separating layer but is manufactured with at least a binding agent of low viscosity HPMC at the claimed CP of 45.6˚C and 44.5˚C, as described above, respectively. Claim 13 pertains to any of the Claims 9 to 12, wherein the low viscosity HPMC has a viscosity of less than 7.2 cps in 2% aqueous solution.

[ 17 ] Claims 14 to 17 describe the process for the manufacture of an enteric coated oral pharmaceutical formulation in accordance with Claims 9 to 12, respectively. [ 18 ] Claims 18 and 19 describe the use of a pharmaceutical formulation as defined in any one of the Claims 1 to 8 for the manufacture of a medicament in the treatment of gastrointestinal diseases and in the treatment of gastrointestinal diseases, respectively. [ 19 ] Finally, Claim 20 describes a commercial package comprising a pharmaceutical formulation as defined in any one of Claims 1 to 8, with instructions for the use thereof in the treatment of gastrointestinal diseases.

Experiments [ 20 ] Three experiments (examples) were presented in the ‘531 Patent. Two different batches of low viscosity HPMC were tested in these experiments: Type A and Type B. [ 21 ] Examples 1 and 2 tested the rate of release of omeprazole from omeprazole pellets layered with two different batches of low viscosity HPMC used as a constituent of the separating layer. The omeprazole pellets were prepared according to the description in EP 247 983. The test methodology was described as follows: The pellets were pre-exposed to simulated gastric fluid USP (without enzyme) at 37˚C for 2 hours.

Thereafter the drug release in buffer solution pH 6.8 at 30 minutes was determined by liquid chromatography. The buffer solution pH 6.8 was a mixture of 100.0 parts of simulated gastric fluid USP (without enzyme) and 80.0 parts of 0.235 M disodium hydrogen phosphate solution, pH should be between 6.75 and 6.85. The simulated gastric fluid USP (without enzyme) was prepared by dissolving 2.0 g NaCl and 7.0 ml conc. HCl and add water to 1000 ml.

The 0.235 M disodium hydrogen phosphate solution was prepared by dissolving 41.8 g Na 2 HPO 4 .2H 2 0) and add water to 1000 ml. [ 22 ] The composition of the core material, separating layer and enteric coating layer of the tested omeprazole pellets was set out at pages 10 and 11 of the ‘531 Patent. The separating layer included Type A or Type B HPMC at 6 cps. [ 23 ] The CP determinations were performed with two different apparatus: a commercial equipment from Mettler (example 1) and a spectrophotometer equipped with a heating coil and stirring function (example 2).

The results were presented in a table on page 11 of the ‘531 Patent (the page 11 table), as follows: Pellets containing HPMC Cloud Point (˚

C) Release of omeprazole from enteric coated pellets [%] Ex. 1 (n=2) Ex. 2 (n=1) Type A 44.4 42.5 69 (60-84) Type B 47.5 47.2 93 (93-94) [ 24 ] The results of examples 1 and 2 were depicted on figures 1 and 2, respectively.

Compared to the marketing approval for the Losec® capsule formulation of at least 75% release of omeprazole within 30 minutes in a buffer solution (the marketing standard), the results on the tests on the Type A and Type B separating layers showed, respectively, unacceptable (i.e., 69% below 75%) and acceptable (i.e., 93% above 75%) release of omeprazole for a pharmaceutical product. [ 25 ] The patent also stated that: Results from a number of experiments with different batches of HPMC indicate that HPMC with a cloud point of at least 45.6˚C is desirable in fulfilling the regulatory requirements on rate of release of omeprazole, when the cloud point determination is performed in a commercial Mettler instrument. [emphasis added]

[ 26 ] Example 3 tested the two types of low viscosity HPMC when used as a binding agent in the preparation of core material for pellets. The pellets were not coated with a separating layer or an enteric coating layer. The core material was prepared by spray leaching omeprazole magnesium salt and HPMC on sugar spheres in a fluidized bed. The composition of the core material was indicated on page 13 of the ‘531 Patent.

The prepared pellets were then tested to determine the rate of release of omeprazole in a buffer solution of pH 6.8 with identical composition as used in example 1 at 37˚C with a paddle speed of 100 rpm. The release of omeprazole was determined with a spectrophotometer. [ 27 ] The results of example 3 were presented on figure 3. The graphs shows that the release of omeprazole was delayed for Type A compared with Type B. Evidence [ 28 ] The witnesses whose evidence is on the record are as follows: For Pharmascience – Dr. Colombo, Dr. Miller, Dr. Desbrières, Mr. Alderman. For AstraZeneca – Dr. Bodmeier.

Pharmascience’s Experts [ 29 ] Dr. Paolo Colombo is a professor in the Department of Pharmacy at the University of Parma, Italy. Dr. Colombo has worked in academia since receiving his Pharm. D. in 1968. Dr. Colombo has published extensively and has been involved in research related to cellulose polymers such as HPMC since 1983. Dr. Colombo was asked to provide background information on delayed release pharmaceutical dosage forms and the use of HPMC in delayed release formulations. [ 30 ] Dr.

Colombo provided a background on delayed release formulations, noting that the dosage form of a pharmaceutical product is chosen based on the intended site of administration and the time period over which a therapeutic agent is to be administered. A delayed release dosage form delivers the therapeutic agent in the gastrointestinal tract. Dr. Colombo explained that delayed release formulations typically contain an acid resistant outer layer, termed an enteric coating, to protect the drug.

This layer dissolves in the neutral-to-basic conditions of the intestine such that the drug is immediately released when the dosage form enters the intestine. Some polymers conventionally used as enteric coatings contain acidic groups that can cause degradation of sensitive drugs and Dr. Colombo noted that he had encountered such problems with omeprazole tablets. [ 31 ] Turning to HPMC, Dr. Colombo noted that this polymer has been widely employed as a thin film coating on conventional tablets since the 1980s.

Low viscosity HPMC dissolve under both acidic and basic conditions and are suitable for preparing films that dissolve rapidly at the target site. Dr. Colombo referred to an

article by Rowe that indicated that the disintegration time of tablets coated in HPMC is directly related to the polymer molecular weight. At paragraphs 20 and 22 to 24 of his affidavit, Dr. Colombo discussed high molecular weight/high viscosity HPMC, which is commonly used to form controlled release matrixes that allow slow release of a drug. [ 32 ] Based on his familiarity with formulations containing omeprazole and esomeprazole, Dr.

Colombo reviewed Canadian Patent No. 1,292,693 and WO 95/01783 at paragraphs 26 to 38 of his affidavit. [ 33 ] Canadian Patent No. 1,292,693 involved a separating layer, such as low viscosity HPMC, to protect omeprazole formulation discolouring arising from the interaction of the enteric coating and the active ingredient. The rate of drug release would be dictated by the type and thickness of the enteric coating and the amount and type of excipients used in the core, not the type of HPMC film used which Dr.

Colombo stated only functions as a physical barrier between the omeprazole and the material of the enteric coating. Dr. Colombo noted that a person skilled in the art (PSA) would know that low viscosity HPMC would be required to fulfill this role of requiring quick dissolution in water. [ 34 ] WO 95/01783 pertained to the same formulation as Patent No. 1,292,693, but focused on a novel physical form of omeprazole magnesium salt. Dr.

Colombo noted that the reported rate of dissolution would be considered an immediate release (93% dissolution within 30 minutes) and this rate was not reduced by the thickness of the enteric coating.

[ 35 ] Turning to the ‘531 Patent, Dr. Colombo noted that the formulation described therein was the same as that described in the two patents discussed above. At paragraphs 39 to 44, Dr. Colombo summarized the information contained in the ‘531 Patent. Dr. Colombo noted that the different release profiles for two core pellets (one made of Type A and the other of Type

B) depicted in figure 3 appeared to be by chance as the pellets were both manufactured by spray layering and both dissolved over 90% in 30 minutes. This was consistent with the fact that the amount of HPMC in the core would not affect the release rate. With regards to the experiment set out on pages 10 and 11 that suggested different release rates for Type A and Type B, Dr. Colombo noted that this difference could not be attributed to the low viscosity HPMC, which would dissolve immediately, unless there was a problem with the amount of polymer deposited on the pellet that was not directly controlled. Dr.

Colombo stated that the difference would not be caused by a difference in CP. [ 36 ] In addressing whether there was enough information in the ‘531 Patent for the PSA to understand the nature of the invention and how it works, Dr. Colombo noted the naming of HPMC used in the patent as “Type A” and “Type B”. As commercially available HPMC is well characterized in terms of viscosity and levels of methoxyl and hydroxypropyl substitution, Dr. Colombo found this naming approach questionable. To reproduce the formulation and understand whether there was actually a difference between the two types of HPMC, Dr.

Colombo stated that a PSA would require more detailed information on the types of HPMC tested. [ 37 ] Dr. Colombo also stated that the data did not support a finding that there was an actual difference between the two types of HPMC used. Rather than showing replicated results (typically 12 tests), there was only one acceptable value provided in the page 11 table for the Type A sample. Dr.

Colombo concluded that without a strict characterization of the film applied, it was not possible to assign an effect on drug dissolution to the small difference measured in CP of the two batches of HPMC having nominally the same viscosity. [ 38 ] With regards to whether the invention would achieve what the patent promised, Dr. Colombo noted that the thickness of the film deposited remained unspecified. [ 39 ] Dr.

Colombo noted that the low viscosity (7.2 cps or lower) HPMC separating layer described in the ‘531 Patent was neither intended to exert control over the rate of drug release, nor capable of exerting such control. To exert any control over the rate of drug release, high viscosity (greater than 4,000 cps) HPMC that leads to strong polymer gel formation would need to be employed. Dr. Colombo stated that it is well known to formulators that low viscosity HPMC is most suitable for preparing thin films that dissolve rapidly and completely. [ 40 ] At paragraph 56 of his affidavit, Dr.

Colombo explained that another critical parameter to determining whether any control over the rate of drug release could be achieved was the thickness of the coating layer surrounding the core unit. In light of existing test results and the general knowledge of a PSA, Dr. Colombo stated that the low viscosity HPMC described in the ‘531 Patent was too thin to exert any control over the rate of drug release. After reviewing the formulations described in pages 10 and 11 of the patent, Dr.

Colombo found at paragraph 59 of his affidavit that the amount of low viscosity HPMC polymer described in the ‘531 Patent could not function to control the rate of drug release from the omeprazole containing core units described therein. [ 41 ] At paragraphs 60 to 67, Dr.

Colombo highlighted information missing in the patent, including: - the dosage form tested; - the strength of the final dosage form; - the conditions under which the dissolution studies were carried out; - which apparatus was used for conducting dissolution testing; - number of samples tested; and - the thickness or uniformity of the separating layer produced with the two types of HPMC. [ 42 ] Dr.

Colombo commented that the most glaring oversight of the numbers reported on page 11 was the assertion that they represented a release of omeprazole from a formulation because rather than representing a release, these numbers represented dissolution of omeprazole in the buffer solution at a particular time. [ 43 ] At paragraphs 69 to 73, Dr. Colombo also criticized the dissolution testing reported in Figure 3 of the ‘531 Patent, stating that when used as a binding agent, HPMC cannot exert control over the rate of drug release.

[ 44 ] Finally, Dr. Colombo considered whether a PSA would consider that the ‘531 Patent disclosed an invention. Dr. Colombo highlighted that the prior art disclosed the identical formulation to that found in the ‘531 Patent, including the use of low viscosity HPMC for the film separating layer. Dr. Colombo noted that: 80. […] The addition of an irrelevant parameter, namely Cloud Point, does not create a difference between the formulations of the ‘531 Patent and those of the prior art. 81.

Low viscosity HPMC (having a viscosity lower than 7.2 cps) applied as a thin separating layer or as binder cannot control the rate of release of omeprazole. The bioavailability of omeprazole will be determined by the rate of dissolution of omeprazole within the gastrointestinal tract. This is independent of the cloud point of low viscosity HPMC. [ 45 ] For these reasons, Dr. Colombo concluded that the ‘531 Patent cannot be considered an invention. [ 46 ] Dr.

Robert Miller is the president of MPD Consulting, a consulting company to the pharmaceutical industry in the areas of dosage form formulation and manufacturing process design. Dr. Miller received his Ph.D. in Pharmaceutics in 1977. He was employed in the pharmaceutical industry from 1978 to 1994. From 1994 to 2002, Dr. Miller was employed as an assistant professor and also provided technical pharmaceutical services to private industry. [ 47 ] At paragraphs 15 to 22 of his affidavit, Dr. Miller provided a background

summary on the use of HPMC in pharmaceutical formulations. Dr. Miller noted that no specifications for CP were provided in the 1995 edition of the United States Pharmacopeia (USP) for low viscosity HPMC. CP was not something that a pharmaceutical formulator would consider when designing a formulation in 1997 or today; rather, the primary governing factors are molecular weight and viscosity. Dr. Miller noted that a low molecular weight HPMC would provided an immediate release.

As well, when used as a binder in a formulation, HPMC would not impact the release rate of the formulation. [ 48 ] At paragraphs 23 to 63 of his affidavit, Dr. Miller considered the following prior art patents on omeprazole: Canadian Patent No. 2,025,668; Canadian Patent No. 1,292,693; Canadian Patent No. 1,302,891; WO 94/27988; WO 95/01783; WO 96/01623; Canadian Patent No. 2,184,842; and Canadian Patent No. 2,184,037. [ 49 ] From this review, Dr. Miller listed various factors that the PSA would learn from formulations of benzimidazoles such as omeprazole and esomeprazole at paragraph 64 of his affidavit.

These findings included the following: HPMC is recommended as a separating layer to be used in between the active and the enteric coating; and the recommended thickness of the separating layer is 2-4 μm (which would be a thin film coating) […] the separating coating must be water soluble or in water rapidly disintegrating – which would mean a low viscosity/low molecular weight HPMC as this type of HPMC will dissolve in water; … [ 50 ] A PSA would take these factors into account and use a grade of HPMC as a binder or separating layer that would not impact the release rate of the formulation.

The delayed release of the active ingredient would be determined by the enteric coating, which would withstand the stomach acid but dissolve immediately in the alkaline intestine. [ 51 ] Dr. Miller then considered the ‘531 Patent at paragraph 66 of his affidavit. Dr. Miller noted that the testing reported in the patent and the clinical use of the capsules was at 37˚C. This was below the claimed CP of both types of HPMC referred to in the patent. Dr.

Miller also noted that the following information was missing on the tests reported in the patent: the specific grade of HPMC, the number of hydroxypropyl groups, the number of methoxy groups and which specific HPMC was tested. Dr. Miller found that prior art provided teachings on the appropriate thickness and weight of the HPMC layer to ensure an acceptable release rate.

[ 52 ] With regards to whether there was sufficient information for a PSA to understand the invention and how it works, Dr. Miller noted that the patent did not disclose sufficient information on what Type A and Type B HPMC was; thus, key information was missing to allow the PSA to obtain the correct quality of HPMC. In addition, Dr. Miller stated that the testing in the ‘531 Patent did not show that the CP of HPMC affects drug release. Based on his own experience, Dr. Miller was skeptical that CP in and of itself has any effect on release. Dr.

Miller noted that no information was provided on the coating amounts on the spheres or the size of the spheres; differences in the amount of coating could account for the numbers provided in the page 11 table. Dr. Miller found that a PSA could not put the invention into practice without difficulty in light of the lack of information on what type of HPMC to purchase. [ 53 ] With regards to the patent’s suggestion that different batches of HPMC may differ in their abilities to influence the rate of release of omeprazole in simulated intestinal fluid, Dr.

Miller noted that, in his experience, there were no obvious differences in 1997 in different batches of a particular grade of HPMC. The overall characteristics of a certain grade of HPMC are and were the same from batch to batch. At paragraph 93 of his affidavit, Dr. Miller also noted that the differences in release rates reported in the testing of HPMC as a separating layer could not be attributed to CP because that temperature was not reached in the course of the testing (which was done at 37˚C). In conclusion, Dr.

Miller found that “[t]here is no invention in adding parameters to the specifications for HPMC – i.e. cloud point, particularly when the parameters are irrelevant to the use of the formulation in the body”. [ 54 ] Dr. Jacques Desbrières is a professor at the University of Pau, France. Dr. Desbrières obtained a degree in chemical engineering in 1980. He worked as a research engineer and project leader at a pharmaceutical company between 1981 and 1988. In 1990, he entered academia where he remains today. Dr.

Desbrières has published extensively and teaches in the areas of physical chemistry and polymer science. [ 55 ] At paragraphs 15 to 24 of his affidavit, Dr. Desbrières provided a

summary on HPMC polymers and their physical properties, including thermal gelation and CP. Dr. Desbrières highlighted the findings of a study published by Sarkar in 1979. In this study, the thermal gelation temperatures and CPs of numerous HPMC polymers produced by Dow Chemical Corporation (Dow) under the trade- mark METHOCEL were determined experimentally. A significant finding in this study was that the thermal gelation temperatures and CPs are predominantly determined by the percentage of methoxyl groups present on the polymer.

However, where methoxyl groups and hydroxypropyl groups were similar, the CP was found to be within a narrow range for HPMC polymers having vastly different molecular weights. [ 56 ] At paragraphs 25 to 31 of his affidavit, Dr. Desbrières discussed his experiments on low viscosity HPMC to determine CPs. He conducted these tests on samples of METHOCEL E5, E6 and E15 from Dow and on Pharmacoat 603 and 606 from Shin-Etsu Chemical Corporation (Shin-Etsu). In Table 1 of his affidavit, Dr.

Desbrières presented the results of his experiments as follows: Sample IPT* buffer C=1% CP* buffer CP=1% %** Methoxyl %** Hydroxypropyl Viscosity (cP)** M n * (g/mol) M w * (g/mol) Pharmacoat 603 47.8 49.2 28.9 9.1 3.09 12100 15600 Pharmacoat 606 45.8 47 28.7 9.0 5.96 19100 24600 Dow E5 47.7 49.3 28.5 8.9 4.4 15900 19000 Dow E6 46.6 48 29.5 8.0 5.6 18600 22700 Dow E15 45.2 46.2 28.7 9.1 15 30300 38200 * = Determined Experimentally ** = Provided by Manufacturer [ 57 ] The first column, entitled IPT, provides the results that correspond with the CP as defined in the ‘531 Patent (i.e., the temperature where light transmission is reduced to 95% when measured using a spectrophotometer with an ultraviolet detector).

The second column, entitled CP, provides the results that correspond with the temperature at which light transmission was reduced to 50% (i.e., the true CP; namely the definition that Dr. Desbrières stated is prevalent in the literature and understood by a PSA). Dr. Desbrières noted that for polymers having viscosities below 7.2 cps, both these data returned narrow temperature ranges.

In tests on buffer solutions containing phosphate salts, results of which were presented in Table 2 of his affidavit (not reproduced here), the IPTs and CPs were depressed and remained within narrow temperature ranges for polymers of low viscosity. [ 58 ] Dr. Desbrières considered the ‘531 Patent at paragraphs 33 to 37 of his affidavit. He noted that CP values obtained using a

Mettler FP90/FP81C instrument would be slightly higher than values obtained using a spectrophotometer, which explained why the curves in Figures 1 and 2 were slightly different. In addition, Dr. Desbrières noted that these figures showed that the two types of HPMC used in the patent would be fully dissolved at body temperature. [ 59 ] In considering whether a PSA would understand the nature of the invention and how it works, Dr.

Desbrières stated that “claiming a low viscosity HPMC with a specific cloud point appears to be an indirect way of claiming a low viscosity HPMC with a certain degree of methoxyl groups and hydroxypropyl groups” (at paragraph 38). Thus, to put the invention into practice without difficulty, Dr. Desbrières noted that the patent should have specified the degree of substitution for the methoxyl groups and the molar substitution for hydroxypropyl groups; information provided by manufactures on their certificates of analysis. [ 60 ] Finally, Dr.

Desbrières noted that he did not see a scientific reason for choosing HPMC at the claimed CP because, when used as an excipient in a pharmaceutical formulation, HPMC would not be exposed to temperatures above body temperature (37˚C). Thus, the CP would not affect the polymer’s solubility under physiological conditions. [ 61 ] Mr. Daniel Alderman obtained a chemical engineering degree in 1975. From graduation through to 2000, Mr. Alderman held increasingly senior positions at Dow in the areas of emulsion polymers and cellulose ethers. Between 2000 and 2002, Mr. Alderman worked in the Dow automobile division.

Between 2002 and his retirement in 2008, Mr. Alderman was the corporate research and new business development intellectual asset manager at Dow. [ 62 ] At paragraphs 11 to 20 of his affidavit, Mr. Alderman provided a background on the HPMC products sold by Dow. Dow’s HPMC products for pharmaceutical application as film formers were the low viscosity METHOCEL E5 Premium and E6 Premium. These were designed to dissolve quickly in water or gastric fluids. They were not designed to nor did they affect the performance or release of the active ingredients in the tablet. Mr.

Alderman noted that when used as a film former, it is important that the low viscosity HPMC be applied in a continuous film, without holes or cracks. Mr. Alderman stated that, to the best of his recollection, Dow did not receive any complaints from their customers (including AstraZeneca) on batch-to-batch performance variation of their low viscosity HPMC products. Mr. Alderman also remarked that the HPMC products produced by Dow under the trade-mark METHOCEL in 1997 and 1998 are the same HPMC polymers produced today. [ 63 ] At paragraphs 14 to 17 of his affidavit, Mr.

Alderman explained the chemical structure of Dow’s METHOCEL HPMC polymers. Mr. Alderman also explained that Dow has developed innovative processes to prepare HPMC polymers with controlled physical properties. The HPMC monograph in the USP was created according to Dow’s specifications. The USP specifications relating to methoxyl content and hydroxypropyl content have not changed in the last 25 years. In addition, methods for testing HPMC polymers were developed by Dow and the American Standards Association for Testing and Materials. [ 64 ] Mr.

Alderman considered the ‘531 Patent at paragraphs 21 to 25 of his affidavit. He noted that although it is highly unlikely that significant differences exist between different lots of HPMC, a reason for such differences could relate to differences in the continuity of the separating layers formed by the Type A and Type B HPMC described in the patent. Mr. Alderman observed that the formulation described on page 11 for the separating layer did not contain a plasticizer. Plasticizers are important for creating defect-free continuous films.

This is particularly true for very thin films, where cracks or imperfections would have a greater deleterious effect and for films made of low viscosity polymers that tend to be more brittle and prone to cracking. [ 65 ] At paragraphs 29 to 30 of his affidavit, Mr. Alderman explained the HPMC manufacturing process. Mr. Alderman noted that it is known that the apparent viscosity of an aqueous solution of a HPMC polymer is proportional to its molecular weight. Similarly, it is known that the dissolution of HPMC varies directly with the molecular weight. Mr.

Alderman explained that the viscosity of HPMC polymers produced by Dow is controlled through the manufacturing process. [ 66 ] At paragraphs 34 to 38, Mr. Alderman described the results of studies on the thermal gelation and CP temperatures of HPMC polymers. He explained that HPMC polymers possess a unique property of decreased solubility in water above a critical temperature; thus, where a solution of HPMC is dissolved in water and heated above that critical temperature, the decreasing solubility of HPMC is manifested as an increase in viscosity and an onset of cloudiness or turbidity of the solution.

The temperature at which the amount of light transmitted through the solution is reduced to 50% is termed the CP temperature and is dependent on the percentage of methoxyl groups present in the polymer. The molecular weight and viscosity of a polymer has a very small effect on the CP. The process of increasing cloudiness or turbidity is reversible by cooling the solution. At paragraph 35 of his affidavit, Mr.

Alderman explained that this phenomenon has been attributed to an association of methoxyl groups along the same polymer chain and the association of methoxyl groups on different polymer chains. [ 67 ] At paragraph 43 of his affidavit, Mr. Alderman noted the following regarding the CP of a solution of HPMC:

The cloud point of a solution of a given HPMC is a property of the polymer that arises from its physical properties, in particular, the percentage of methoxyl groups present on the polymer chain. If the physical properties of a given HPMC polymer are known, such as percentage methoxyl groups, the cloud point of an aqueous solution of the polymer can be predicted within a very narrow temperature range. Methocel E5 and E6 have had the same percentage of methoxyl groups (and viscosity/molecular weight) since at least 1997 to today. [ 68 ] At paragraphs 47 to 49 of his affidavit, Mr.

Alderman considered the claims contained in the ‘531 Patent and whether the alleged invention would have been obvious to a PSA. As low viscosity HPMC having a specific CP was essentially a claim to an inherent property of a known material, Mr. Alderman concluded that the ‘531 Patent would be obvious to a PSA. [ 69 ] Finally, Mr. Alderman considered whether there was sufficient information in the ‘531 Patent for a PSA to understand the nature of the invention and how it works.

However, as the patent did not disclose information that would have been found in HPMC specifications in 1998, namely, the percentage of methoxyl groups or the molecular weight, Mr. Alderman concluded that a PSA would not be able to choose the correct HPMC with the specified cloud point. Thus, the results in the patent would not be reproducible by a PSA and could not be relied on for practical applications. AstraZeneca’s Expert [ 70 ] Dr. Roland Bodmeier is a professor at the Institute für Pharmazie Freie Universität Berlin, Germany. Dr.

Bodmeier obtained his Ph.D. in pharmaceutics in 1986 and a post-doctorate degree in 1993. Since 1994, he has been employed in his current position. Dr. Bodmeier has published extensively and consulted to the pharmaceutical industry in the areas of drug dosage forms and controlled drug delivery systems. [ 71 ] At paragraphs 11 and 12, Dr. Bodmeier provided a background on the terminology of HPMC and CP. Dr. Bodmeier noted that there is no generally accepted level of light transmission that defines a CP; a percentage between 50 and 97.5 is typically chosen. [ 72 ] Turning to the ‘531 Patent, Dr.

Bodmeier noted that in December 1998, the inventors’ finding that different batches of low viscosity HPMC differ in their ability to influence the rate of release of omeprazole from an enteric coated formulation; a difference that can be gauged by reference to the CP and would have been surprising to a PSA for two reasons. [ 73 ] First, the use of low viscosity HPMC in a pharmaceutical formulation was not generally known to be capable of influencing release rate. The opposite would have been believed because low viscosity HPMC dissolves quickly in water.

Thus, if a PSA saw that their omeprazole enteric formulations were being released at different rates, the PSA would have considered other process or formulation parameters rather than investigating variability of different batches of subtypes of a specific product family of HPMC. As such, Mr. Alderman’s statement that he did not recall receiving any complaints on batch-to-batch variation from customers was not surprising. Dr.

Bodmeier also highlighted that a PSA would have understood that the reference to different batches in the patent is a reference to different batches of one subtype of HPMC, not different batches of different subtypes. Second, CP was not a factor considered in selecting a low viscosity HPMC for use as a binder and/or separating layer. [ 74 ] Dr. Bodmeier further noted that CP of low viscosity HPMC is primarily affected by the level of methoxyl and hydroxypropyl substitution of a given HPMC polymer.

As categories of HPMC are defined in the USP by reference to specific ranges of percent methoxyl and hydroxypropyl substitution, there are an infinite number of possible combinations, each of which will affect CP. Dr. Bodmeier noted that CP is also affected by other variables, such as the nature of substitution along a given cellulose backbone and molecular weight/viscosity of the polymer. Further, as HPMC polymers consist of dozens to hundreds of repeating glucose units, the assigned percent methoxyl and hydroxypropyl substitution is simply an average of the substitution of all glucose units in the polymer.

Thus, even when batches have identical viscosity and methoxyl and hydroxypropyl content, the pattern of substitution and distribution can vary which will affect CP. [ 75 ] As it is highly improbable that different lots will have identical substitution patterns because the number of substitution sites on the polymer chain far exceeds the number of possible substituents, the CP of an HPMC batch can only be obtained from direct measurement. Dr.

Bodmeier further highlighted that the allowable ranges for viscosity and percentage substitution of methoxyl and hydroxypropyl, as indicated in Dow’s certificate of analysis for METHOCEL E5, highlights the infinite number of variations of HPMC

for one subtype. This can be further complicated by the distribution of substituted groups along the polymer chain and on individual glucose units. By characterizing HPMC by reference to its CP, Dr. Bodmeier explained that the inventors of the ‘531 Patent provided an elegant and objective proxy to assess the sum effect of the infinite combination of these variables. Concurrently, the inventors determined that when the CP exceeded a certain value when measured with a specific instrument, there was greater release of omeprazole within 30 minutes. [ 76 ] At paragraphs 35 to 50 of his affidavit, Dr. Bodmeier provided a

summary of the claims contained in the ‘531 Patent. In the remainder of his affidavit, Dr. Bodmeier responded to the affidavits of Pharmascience’s experts. [ 77 ] At paragraphs 51 to 55 of his affidavit, Dr. Bodmeier responded to Dr. Desbrières’ affidavit. Dr. Bodmeier disagreed with Dr. Desbrières’ characterization of CP as the temperature at which light transmission is reduced to 50%. Rather, Dr. Bodmeier stated that there was and is no common understanding as to what light reduction level defines a CP. Dr. Bodmeier stated that the testing reported in Dr.

Desbrières’ affidavit was premised on an incorrect understanding of the invention of the ‘531 Patent. Rather than comparing batches of a single low viscosity HPMC subtype, Dr. Desbrières’ testing compared different subtypes of HPMC products. Dr. Desbrières’ testing results are thus not informative. [ 78 ] Dr. Bodmeier also stated that even though HPMC is expected to be fully dissolved at 37˚C, this does not mean that all HPMC batches dissolve at the same rate. Dr. Bodmeier states that Dr.

Desbrières ignored the date in the table at page 11 of the ‘531 Patent that explicitly shows that when tested in simulated gastric conditions at 37˚C, two batches of HPMC resulted in different average omeprazole release rates; one within the marketing standard and one that was not. Thus, different batches of one subtype of HPMC interact differently with water, which results in the release of omeprazole at different rates. [ 79 ] At paragraphs 56 to 68 of his affidavit, Dr. Bodmeier responded to Mr. Alderman’s affidavit. At the outset, Dr. Bodmeier noted that Dr. Desbrières, Dr. Miller, Dr. Colombo and Mr.

Alderman provided several of the same statements. Where that was the case, his comments on one affidavit applied equally to the others. [ 80 ] Dr. Bodmeier noted Mr. Alderman’s suggestion that low viscosity HPMC would not affect the release of the active ingredient in the tablet. However, Dr. Bodmeier noted that Mr. Alderman concurrently contradicted that statement by noting that HPMC dissolution varies with molecular weight and that there is a clear correlation between increasing viscosity and increasing time of disintegration.

Based on the data on viscosity and tablet disintegration time presented in the Rowe study and the range for viscosity stated in the certificate of analysis for METHOCEL E5 (4.0 to 6.0 mPas), Dr. Bodmeier showed that batch-to-batch variation in viscosity for METHOCEL E5 correlated with an approximately 30 second difference in disintegration times between batches. Thus, Dr. Bodmeier stated that Mr. Alderman’s statement that HPMC would not affect release rate of the active ingredient was incorrect. [ 81 ] In response to Mr.

Alderman’s suggestion that a possible reason for the difference in release rates between different batches of HPMC (as reported in the page 11 table) could be imperfections in the film from lack of plasticizer use, Dr. Bodmeier noted that this appeared to merely be an unfounded guess. In addition, neither batches included a plasticizer. [ 82 ] Dr. Bodmeier also noted that Mr. Alderman incorrectly stated that methoxyl groups, rather than hydroxypropyl groups, are responsible for turbidity. The Sarkar

article clearly showed that both groups are responsible for the turbidity caused by phase transition. In addition, Dr. Bodmeier disagreed with Mr. Alderman’s statement that if the physical properties of a given HPMC polymer were known, the CP of an aqueous solution of the polymer could be predicted within a very narrow range. Rather, CP is influenced by the nature of the substitution and distribution of both methoxyl and hydroxypropyl along the polymer chain and on the individual glucose units and by the molecular weight/viscosity of the polymer. [ 83 ] Turning to the sufficiency of disclosure, Dr.

Bodmeier disagreed with Mr. Alderman’s statement that a PSA would not be able to choose the correct HPMC with the specified CP without having the percentage of methoxyl groups provided. Dr. Bodmeier noted that methoxyl groups are not the only determinant of CP. In addition, this statement ignored the invention of the ‘531 Patent, which improved on prior art omeprazole formulations by providing a means (HPMC at the claimed CP) to avoid having to know physical properties of a given batch of HPMC in selecting an HPMC batch that would result in the required levels of omeprazole release within 30 minutes.

Thus, the ‘531 Patent clearly teaches a PSA how to select a specific quality of HPMC for omeprazole enteric formulation. [ 84 ] At paragraphs 69 to 76 of his affidavit, Dr. Bodmeier responded to Dr. Miller’s affidavit. Dr. Bodmeier noted that none of the patents cited by Dr. Miller as prior art discussed concerns with batch-to-batch variation in HPMC, nor did they direct the PSA towards selecting an HPMC above the claimed CP. The invention of the ‘531 Patent was not obvious in light of any or all the prior art cited. Dr. Bodmeier noted that Dr.

Miller’s critique on the absence of information on the specific grade of HPMC being tested and the coating

amounts of HPMC on the spheres or size of the spheres missed the point of the invention. Based on the ‘531 Patent, the PSA would understand that any suitable grade or coating amount of low viscosity HPMC could be used to prepare an enteric omeprazole formulation as long as it meets the claimed CP. [ 85 ] Dr. Miller’s observation that the release for Type A HPMC was acceptable for at least one of the coated pellet batches because the range of release reached 84% also missed the point. What the patent teaches is a means of selecting a specific quality HPMC to avoid variation. In addition, Dr.

Bodmeier disagreed with Dr. Miller’s statement that the dissolution results for the two cores in Type A and Type B listed in Figure 3 do not vary greatly. Rather, there is a difference of approximately six minutes between the two profiles, which is equivalent to approximately 20% of the total release time of approximately 30 minutes; a significant difference for immediate release, uncoated pellet cores. [ 86 ] In addition, contrary to Dr. Miller’s statement that the ‘531 Patent does not indicate what type of HPMC a PSA should purchase, Dr.

Bodmeier stated that the patent clearly provides that the PSA should purchase a low viscosity HPMC at the claimed CP. Where the HPMC is selected at the claimed CP, the patent teaches that all batches will sufficiently release 75% of the active ingredient in 30 minutes (in accordance with the marketing standard), thereby reducing product discard due to failed formulations. [ 87 ] Finally, at paragraphs 77 to 88 of his affidavit, Dr. Bodmeier responded to Dr. Colombo’s affidavit. Dr. Bodmeier noted Dr.

Colombo’s statement that the amount of HPMC in the core would be less than 3% thereby not affecting the release rate. However, Dr. Bodmeier stated that this calculation was incorrect. Rather, there is approximately 15% HPMC which is a significant amount in the drug and would be expected to affect the drug release rate. In addition, although low viscosity HPMC is commonly understood to dissolve quickly, there are differences in the dissolution rates of HPMC and low viscosity HPMC used as a coating does affect the rate of immediate release of the active ingredient. [ 88 ] Dr. Bodmeier also noted that Dr.

Colombo’s statement that dissolution tests require 12 replicate dissolutions was incorrect. Rather, as per scientific literature, a maximum of three to six replicates are generally used. Dr. Bodmeier highlighted that the patent indicates that the findings are based on a “number of experiments”. Dr. Bodmeier critiqued several of Dr. Colombo’s claims on the basis that they pertained to controlled release formulations and not to immediate release formulations, the subject matter of the ‘531 Patent. [ 89 ] Dr. Bodmeier further noted Dr.

Colombo’s statement that the ‘531 Patent did not specifically state what final dosage form and strength was tested which would cause the PSA to not know which USP standards to compare the tests to and what apparatus was used for conducting the dissolution testing. However, Dr. Bodmeier stated that the PSA, on reading the patent as a whole, would clearly understand that the tests should be compared to 75% release in 30 minutes (the marketing standard) and that the apparatus used was the Dissolution Apparatus 2 (paddle). Dr. Bodmeier also stated that Dr.

Colombo’s critique of the word “release” as opposed to “dissolve” was incorrect and stemmed from confusion between controlled release and immediate release. Dr. Bodmeier finally stated that Dr. Colombo’s calculation of the similarity factors between the two release profiles for the core pellets shown in Figure 3 of the ‘531 Patent was error prone and unfounded. Issues [ 90 ] AstraZeneca submits the following point at issue: Are Pharmascience’s allegations of invalidity of the ‘ 531 Patent justified? [ 91 ] Pharmascience submits the following points at issue: 1. Is the patent invalid for inutility? 2.

Does the patent meet the requirements of sufficiency? 3. Is the claimed invention obvious? [ 92 ] I would rephrase the issues as follows: 1. Is the ‘531 Patent not an invention as defined in

section 2 of the Patent Act because it merely ascertains the properties of a known substance? 2. Does the ‘531 Patent meet the validity requirements for utility?

3. Does the ‘531 Patent meet the validity requirements of sufficient disclosure? 4. Does the ‘531 Patent meet the validity requirements for obviousness? AstraZeneca’s Written Submissions Evidence [ 93 ] AstraZeneca submits that Pharmascience is strictly limited to making submissions on those invalidity allegations for which it filed evidence, namely: obviousness, insufficiency and lack of demonstrated utility.

Thus, Pharmascience cannot rely on its other allegations of invalidity that it did not address in its evidence, namely: lack of novelty, claims broader, double patenting, lack of sound prediction, not a valid selection patent and fraud on the Patent Office. [ 94 ] AstraZeneca also notes that the order of evidence was reversed by Prothonotary Tabib’s order dated February 15, 2011. A reversal of evidence is intended to define more narrowly the allegations of invalidity that will be argued by the generic company, thereby limiting the issues at play.

Patent Construction [ 95 ] AstraZeneca submits that when the ‘ 531 Patent was published in December 1998, the inventors’ discovery that different batches of low viscosity HPMC, as reflected by their CP, may have different abilities to influence the rate of release of omeprazole from an enteric coated formulation would have been very surprising to a PSA. This was because the use of low viscosity HPMC in a pharmaceutical formulation was not generally known to be capable of influencing release rate.

Moreover, a PSA would actually have believed the opposite to be true because low viscosity HPMC is a polymer that dissolves quickly in water. AstraZeneca also notes that the reference to different batches in the patent would be clearly understood by a PSA to mean different batches of the same subtype of low viscosity HPMC. [ 96 ] AstraZeneca notes that experts for both sides agreed that in December 1998, a PSA would not have referred to or categorized HPMC by reference to its CP.

However, on reading the patent, it would have become apparent to a PSA that by selecting low viscosity HPMC in accordance with its CP, the inventors had provided a proxy by which to assess the sum effect of the infinite combinations of different variables that were understood to affect the CP and the release rate of omeprazole. [ 97 ] AstraZeneca highlights the statement in the patent that an upper limit for the CP is not critical and must therefore not be specified.

From this, a PSA would understand that when selecting a low viscosity HPMC, the upper limit is not important as long as the requirements defined in phamacopoeial monographs and the claimed CP are fulfilled. As a higher CP reflects higher water solubility, it would not be expected to decrease the rate of release of omeprazole.

Thus, it is the specification for the lower limit, not the upper limit, that is critical to achieving the desired rate of release. [ 98 ] In addition, the inventors stated in the patent that the reduction of product discard was a real economic advantage resulting from selecting a low viscosity HPMC in accordance with the claimed CP.

On following the patent, a PSA would also learn how to reduce unpredictable variations in release rates between different batches of formulations, further reducing product discard. [ 99 ] Finally, AstraZeneca notes that none of Pharmascience’s experts provided a discussion on the understanding of the PSA of the batch-to-batch variation described in the ‘ 531 Patent . This is fundamental to an understanding of the patent invention.

Although the experts stated their general disbelief that differences in low viscosity HPMC as gauged by reference to the CP can affect the release of a drug, they did not provide evidence disproving the correlation or any credible basis for their disbeliefs. Invention under

Section 2 of the Patent Act [ 100 ] AstraZeneca submits that Pharmascience’s allegation that the ‘ 531 Patent is not an invention is fundamentally flawed as it is premised on an incorrect construction of the patent. When properly construed, the patent does not merely contribute a verification of the

CP but also teaches that by selecting low viscosity HPMC above the claimed CP, a pharmaceutical formulator can reduce the amount of product discard that does not meet omeprazole release specifications. This was a surprising and unexpected teaching offering a substantial advantage. [ 101 ] Furthermore, Pharmascience’s evidence that the ‘ 531 Patent claims an inherent property of a known compound is flawed as it is premised on testing that purportedly indicates that low viscosity HPMC in 1998 and today would have a CP above the claimed CP. This testing failed to consider the batch-to-batch variation in CPs.

Concurrently, it provided a clear admission that the CP of some batches of the same low viscosity HPMC product can in fact be below the claimed CP. Utility [ 102 ] AstraZeneca submits that the patent’s inventors demonstrated that by selecting low viscosity HPMC at the claimed CP for use in the omeprazole enteric formulation, at least 75% of the omeprazole would be released in a buffer solution in the first 30 minutes (as per the marketing standard). In reading this in the context of the whole patent, a PSA would clearly understand that different batches of a subtype of HPMC can differ in CPs.

This difference can result in one batch with a certain CP releasing omeprazole within the prescribed 30 minutes while another batch with a different CP does not. [ 103 ] AstraZeneca notes that the Federal Court of Appeal has explicitly rejected the notion that utility must be demonstrated in the patent disclosure. Nevertheless, AstraZeneca highlights the patent’s reference to results from a number of experiments.

These experiments demonstrated that selecting a batch of HPMC with at least the claimed CP is desirable for achieving the marketing standard. [ 104 ] AstraZeneca submits that the Pharmascience experts’ disbelief, which relies on Dr. Desbrières’ testing, is pure conjecture and is not based on evidence. In support, AstraZeneca notes that Dr. Desbrières’ testing does not address the invention of the ‘ 531 Patent and whether there is batch-to-batch variation of CPs in a given subtype of low viscosity HPMC.

Moreover, these experts’ disbelief is directly contradicted by actual data in the ‘ 531 Patent and in a table produced by Pharmascience at page 60 of its allegation. [ 105 ] AstraZeneca notes that Pharmascience did not share this information with its witnesses, including Dr. Desbrières, before he conducted the testing described in his affidavit. After considering this information, AstraZeneca submits that Dr. Desbrières admitted in cross-examination that test results showed some batches of low viscosity HPMC with a CP below 44.5˚C.

This contradicted his affidavit evidence that all HPMC would have a CP above the claimed CP. Similarly, AstraZeneca notes Mr. Alderman’s affidavit evidence that, based on Dr. Desbrières’ testing, the CP of METHOCEL E5 in 1996 and today would have exceeded 45˚C. However, on cross- examination, Mr. Alderman admitted that he had not seen the data from Dr.

Desbrières’ testing when he provided his opinion, nor did he write that particular sentence in his affidavit. [ 106 ] AstraZeneca also notes that Pharmascience’s experts agree that within a subtype of low viscosity HPMC, there are allowable ranges of methoxyl and hydroxypropyl content and that both of these have an effect on CP. In addition, when a particular HPMC subtype is manufactured, it is highly improbable that one lot will have an identical distribution of substitutes as another because the number of sites on the polymer chain where the substitution occurs far exceeds the number of possible substituents.

Dr. Desbrières admitted that in a heterogenous industrial process, the distribution of substituents of the HPMC will vary from batch to batch. Dr. Desbrières’ evidence also shows that the distribution of substituents can affect gelation temperature, which can lead to differences of at least 20˚C for CP. [ 107 ] AstraZeneca further notes that the experts agree that within a given subtype of low viscosity HPMC, there are allowable ranges of molecular weight and viscosity. Albeit to a lesser extent, CP is also affected by the molecular weight or viscosity of the polymer.

These unpredictable differences will affect the CP and AstraZeneca notes that it is unchallenged that the CP of a low viscosity HPMC batch can only be obtained from direct measurement. [ 108 ] AstraZeneca highlights that Pharmascience directed Dr. Desbrières to conduct testing on certain HPMC samples in support of its invalidity allegations. Dr. Desbrières admitted that he did not compare the CP of different batches of a given subtype of HPMC, rather, he compared the CP of different subtypes. As Dr.

Desbrières’ testing did not address the batch-to-batch variation addressed by the patent and is premised on a fundamentally incorrect understanding of the patent, AstraZeneca submits that his test results are not informative. [ 109 ] AstraZeneca also submits that Dr. Desbrières’s testing should be disregarded as he was unaware of the chain of custody of some of the HPMC samples he tested, particularly with what happened to the samples between the time they were shipped from Dow to his counsel and ultimately to him. AstraZeneca also notes the following in support of its submission that Dr.

Desbrières’ evidence should be treated with circumspection. Dr. Desbrières:

1. is not an expert in the formulation of enteric coatings and has never conducted a gastric acid release test; 2. gave an opinion that the differences in release rates disclosed in the gastric acid release tests in the ‘ 531 Patent could be erroneous even though he did not know the margin of error of these tests and has never conducted such a test; 3. suggested that the claimed CP was not a true CP because it was not designated as the temperature at which light transmission is reduced to 50%.

However, he later admitted that CP does not have a fixed definition and gave no explanation as to why he defined CP at 95% in a 1997 publication; 4. gave affidavit evidence that low viscosity HPMC would have a minimum CP of 44.5˚C.

However, he later admitted that he had no data as to whether the CP of multiple batches of one subtype of HPMC would fall below this temperature and admitted that the data provided by Pharmascience in its NOA shows several batches of the same subtype of HPMC with CPs below this temperature; and 5. approached the ‘ 531 Patent improperly as he applied all his knowledge gained up until drafting his affidavit rather than focusing on the understanding of a PSA reading the patent at the publication date. [ 110 ] AstraZeneca also notes that although Pharmascience’s experts provided affidavit evidence that CP does not affect release rate, Dr.

Desbrières admitted that gelation properties (related to CP) have an effect on release and the heterogeneity of substitution provides a poor predictability of release. On Mr. Alderman’s suggestion that a possible reason for the difference in release rates could be imperfections in the film caused by a lack of use of plasticizer, AstraZeneca notes that this appears to be a guess without basis. In addition, Mr. Alderman’s experience with pharmaceutical formulations pertains to controlled release formulations rather than immediate release formulations and Mr.

Alderman has also not been actively engaged in the field of controlled release since about 1988. [ 111 ] AstraZeneca submits that Dr. Miller’s statement that the release for Type A HPMC was acceptable for at least one of the coated pellet batches misses the point. The fact that one example has a release rate within the required limits is irrelevant. The patent teaches that the variation in release rates can be avoided by selecting an HPMC exceeding the claimed CP. [ 112 ] In response to Dr.

Colombo’s statement that differences in the release rates for different types of HPMC cannot be attributed to differences in CPs because the HPMC would dissolve immediately, AstraZeneca notes that low viscosity HPMC are commonly understood to dissolve quickly. However, it is not true that there are no differences in the dissolution rates of HPMC or that low viscosity HPMC, when used as a coating, does not affect the rate of release of the active ingredient.

Rather, prior to the release of the ‘ 531 Patent , a PSA would have generally believed that there were no relevant differences in the release characteristics of low viscosity HPMC designed for immediate release. [ 113 ] The ‘ 531 Patent surprisingly and clearly shows that differences in low viscosity HPMC, as gauged by reference to the CP, do result in difference in release rate of omeprazole. Thus, selecting batches of low viscosity HPMC that exceed the claimed CP ensures that omeprazole release is consistently within the marketing standard. AstraZeneca submits that Dr.

Colombo’s statement on the quick dissolution of low viscosity HPMC and that is not used in preparing controlled release formulations confuses the matter because neither of these situations are taught in the ‘ 531 Patent. The ‘531 Patent pertains to avoidance of variations in immediate release formulations. [ 114 ] With regards to Example 3, where low viscosity HPMC was used as a binder rather than a separating layer, AstraZeneca notes that in stating that the dissolution rates for the two cores did not vary greatly, Dr.

Miller ignored that this test pertained to the release from uncoated pellet cores, for which there is a significant difference in immediate release. In addition, in his calculation of the similarity factor between the two release profiles, Dr. Colombo did not have the necessary information from the patent, nor did he indicate what assumptions he made in his calculation. Nevertheless, the figure that Dr. Colombo’s calculation was based on (Figure 3) was developed from an experiment related to the use of low viscosity HPMC as a binder.

The low viscosity HPMC was not exposed to gastric acid in that experiment as would have been the case for enteric formulation with the separating layer containing the low viscosity HPMC. [ 115 ] AstraZeneca highlights that Pharmascience’s own evidence shows that the least important cause of differences in CP, namely viscosity, also has an effect on the release.

This data indicates that batch-to-batch variation in viscosity for METHOCEL E5 correlates with an approximately 30 second difference in disintegration times between batches at either end of the allowable range. [ 116 ] Finally, AstraZeneca notes that although HPMC is expected to be fully dissolved at 37˚C, this does not mean that HPMC batches dissolved at the same rate. In fact, as admitted by Dr. Miller, different batches of HPMC dissolve at different rates and these rates are important to the release from a dosage form.

AstraZeneca submits that Pharmascience’s argument on body temperature also considers HPMC solubility in isolation. This is not the subject of the ‘ 531 Patent which is directed to the effect of HPMC on the release of the active ingredient. In fact, the data in the patent shows that when tested in simulated gastric conditions at 37˚C, two batches of HPMC resulted in different average omeprazole release rates, only one of which met the marketing standard.

This shows that different batches of one subtype of HPMC in formulations that are otherwise identical interact differently with water, resulting in the release of omeprazole at different rates.

Sufficiency [ 117 ] AstraZeneca notes that an attack on the basis of insufficiency is a technical attack and will only succeed where the PSA, equipped with common general knowledge, could not put the invention into practice. Here, AstraZeneca submits that all the allegedly missing information would be clearly known to a PSA on reading the patent as a whole. Thus, the allegations of insufficiency are not justified. [ 118 ] AstraZeneca notes that Pharmascience’s evidence acknowledges that use of low viscosity HPMC in a separating layer and as a binding agent was well known at the date of publication.

The ‘ 531 Patent adds to this prior art by teaching that the CP of HPMC should be above a certain limit (the claimed CP) to ensure desirable release characteristics. As there is no question that CP as defined in the patent is understood and can be determined, there is no insufficiency of disclosure. [ 119 ] With regards to the statement by Pharmascience’s experts that the ‘ 531 Patent does not indicate what type of HPMC a formulator should choose or purchase, AstraZeneca notes that the patent, on its face, could not be clearer.

AstraZeneca submits that a PSA would understand that any suitable grade of low viscosity HPMC can be used to prepare an enteric omeprazole formulation, as long as it exceeds the claimed CP. The patent also clearly explains how to determine the CP. Thus, a PSA could put the invention into practice by testing that it exceeds the claimed CP. [ 120 ] AstraZeneca further submits that contrary to the evidence from Dr. Colombo, a dissolution test need not be run in replicates of 12. Rather, in scientific literature, three to six replicates is the standard. Thus, it is not credible for Dr.

Colombo to suggest a lack of understanding of the patent data based on the number of replicates run. [ 121 ] In response to Dr. Colombo’s statement that the apparatus used for conducting dissolution testing was not disclosed in the patent, AstraZeneca states that a PSA, upon seeing the reference to the requirement of 75% release in 30 minutes (the marketing standard) and the reference to the use of a paddle in the patent, would clearly know that the inventors used the Dissolution Apparatus 2 (paddles). The patent also clearly states that enteric pellets were used in the testing. AstraZeneca notes that Dr.

Colombo resiled from this position on cross-examination. [ 122 ] With regards to Dr.

Miller’s statement that there is no information in the patent on the coating amounts of HPMC on the spheres or the size of the spheres, AstraZeneca submits that a PSA would understand that any suitable amount of coating of low viscosity HPMC can be used to prepare an enteric omeprazole formulation as long as it exceeds the claimed CP. [ 123 ] AstraZeneca further submits that the allegation by Pharmascience’s witnesses that a PSA would not be able to choose the correct HPMC without knowing the percentage of methoxyl groups highlights their misunderstanding or mischaracterization of the ‘ 531 Patent .

This patent improves on prior art omeprazole formulations by ensuring adequate release without having to know or determine specific physical properties of a given batch of low viscosity HPMC. Moreover, as admitted by Pharmascience’s experts, certain characteristics cannot be readily determined. Thus, the patent provides an elegant means for incorporating all the various physical properties of low viscosity HPMC that affect release by reference to CP as a proxy. [ 124 ] Finally, AstraZeneca notes that Dr.

Colombo alone took issue with the fact that the ‘ 531 Patent does not specifically state which final dosage form and strength was tested in the release studies. Dr. Colombo alleged that as a result, a PSA would not know to which USP-stipulated standards to compare the release tests of the patent. However, AstraZeneca submits that a PSA, having read the patent and seen the numerous references to USP and Losec®, would have understood that the release tests should be compared to 75% release in 30 minutes (the marketing standard). AstraZeneca highlights that Dr.

Colombo also resiled from this evidence on cross-examination. Obviousness [ 125 ] AstraZeneca notes Pharmascience’s reference to other patents as indicative of prior art. However, AstraZeneca highlights that none of these patents discuss the concerns with batch-to-batch variations in HPMC. In addition, the other patents do not direct a PSA towards selecting and using HPMC above a particular CP to reduce product discard during manufacturing. [ 126 ] AstraZeneca submits that the invention of the ‘ 531 Patent would not be obvious from all or any of the prior art cited.

In fact, prior to 1998, a PSA would not have considered the low viscosity HPMC on seeing that omeprazole enteric formulations were being

released at different rates. Rather, a PSA might have considered other formulation or process parameters to solve his or her problems. [ 127 ] All experts also agreed that CP was not a factor considered in selecting low viscosity HPMC for use as a binder and/or separating layer. In fact, this information was not included in low viscosity HPMC sold commercially in December 1998 nor was it considered by PSAs in their selection or design of a formulation.

The nexus between the CP of low viscosity HPMC and release rate was an important and counter-intuitive innovation born out of the differential release data in the ‘ 531 Patent . [ 128 ] In conclusion, AstraZeneca submits that Pharmascience’s invalidity allegations are not justified. AstraZeneca therefore requests that this Court prohibit the Minister from issuing a NOC for the Pharmascience capsules until the expiry of the ‘ 531 Patent . Pharmascience’s Written Submissions [ 129 ] Pharmascience submits that the ‘531 Patent does not disclose an invention or a useful contribution to the science of formulations.

Rather, a clear reading of the ‘531 Patent indicates that there is no invention at all. Evidence [ 130 ] Pharmascience notes that it is settled law that the ultimate burden of proof rests on AstraZeneca to disprove Pharmascience’s allegations of invalidity on a balance of probabilities. Conversely, Pharmascience merely has an evidentiary burden to present sufficient evidence to give its allegations of invalidity an air of reality. [ 131 ] Pharmascience highlights that it provided evidence from four separate experts, all of whom were straightforward in giving their evidence.

Conversely, AstraZeneca only filed evidence from one expert (Dr. Bodmeier) and none from the patent inventors. In giving his evidence, Dr. Bodmeier acted as an advocate for AstraZeneca. Pharmascience therefore submits that, to the extent that there is any conflict between the evidence from the two parties, the evidence from their witnesses must be preferred. [ 132 ] Pharmascience notes that the viscosity of HPMC is controlled through the manufacturing process. Pharmascience submits that the

article by Rowe shows that the disintegration time of tablets coated with HPMC is directly related to the molecular weight. The sole batch-to-batch variation that AstraZeneca’s expert identified from this

article was a 30 second variation for METHOCEL E5. [ 133 ] Further, a paper by Sangalli shows that a coating of METHOCEL E5 is not thick enough to induce control over the rate of drug release. Notably, the coating of METHOCEL E5 in that testing was 30 times greater than the thickness of the separating layer used in the ‘531 Patent. [ 134 ] Thus, Pharmascience submits that the literature supports a finding that low viscosity HPMC, when used as a binder or as a separating layer in a pharmaceutical formulation, does not delay the release of the drug.

Pharmascience notes that AstraZeneca has not provided any scientific literature that indicates that low viscosity HPMC will impact drug release. In addition, Dr. Bodmeier either did not report any effect of HPMC on the release of the drug or in fact reported that low viscosity HPMC increased the release rate of drugs in the papers he authored. Prior Art Patents [ 135 ] Pharmascience submits that prior art patents on formulations of omeprazole have consistently disclosed the following three layer formulation: 1. Core with omeprazole and an alkaline compound or an alkaline salt of omeprazole; 2.

Coating layer that is soluble in water or rapidly disintegrating in water and that consists of non-acidic inert substances such as HPMC; and 3. Enteric coating.

[ 136 ] Pharmascience submits that a PSA would understand that the HPMC used as a binder in the core and in the coating layer would be a low viscosity HPMC. In addition, most prior art patents disclose that rapid dissolution of the formulation in the intestine is needed and the formulation that provides such dissolution is this three layer formulation.

This is the formulation described in the ‘531 Patent. [ 137 ] Pharmascience summarizes the basic teaching of prior art patents as follows: - Omeprazole is susceptible to degradation in acid reacting and neutral media; - A fully bioavailable dosage form of omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal canal; - Omeprazole must be protected from the acidic juice of the stomach by enteric coating; - Enteric coatings are made of acidic compounds and if applied directly to omeprazole, the omeprazole will become badly discoloured; and - The three layer formulation is used to protect omeprazole with the separating layer protecting omeprazole from the enteric coating. [ 138 ] Pharmascience submits that the teaching of prior art patents is to use the three layer formulation when formulating benzimidazoles such as omeprazole and esomeprazole and that HPMC is used in the separating layer as part of a rapidly dissolving formulation.

A skilled formulator would know that low viscosity HPMC used as a separating layer or as a binder would not impact on the release rate of the formulation. Further, no problems with the dissolution of HPMC were indicated in the prior art patents and no problems with batch-to-batch variation were reported by AstraZeneca to its supplier, Dow. Pharmascience submits that the CP of HPMC would not be considered when designing a formulation either in 1997 or today. Rather, the primary governing factors are molecular weight and viscosity.

Cloud Point (CP) [ 139 ] Pharmascience submits that the two main manufacturers of HPMC (Dow and Shin-Etsu) manufacture HPMC using the same technology and their products meet the same pharmacopeial specifications. The HPMC polymers that were commercially available in 1997 are the same HPMC polymers that are available today. These are: METHOCEL E3, E5 and E15 and Pharmacoat 603, 606 and 615. [ 140 ] Pharmascience submits that the CP of a solution of HPMC is an inherent property of the polymer that arises from its physical properties. In particular, the percentage of methozyl groups present on the polymer chain.

This percentage is determined through the manufacturing process. As METHOCEL E5 and E6 have had the same percentage of methozyl groups, they would have CPs within a narrow range. Further, the specifications of METHOCEL E6 and Pharmacoat 606 are identical and they can therefore be considered two batches of the same subtype. Pharmascience notes that the CPs for Pharmacoat 606, METHOCEL E6 and METHOCEL E5 range from 45.8˚C to 47.7˚C, all of which exceed the claimed CP. [ 141 ] In response to AstraZeneca’s attack on the chain of title for the samples sent to Dr.

Desbrières, Pharmascience notes that the samples came either from counsel or directly from the manufacturer, both of which are reliable sources. [ 142 ] Further, although AstraZeneca submits that the differences in the substitution of methoxyl and hydroxypropyl groups along the backbone of HPMC has significant effects on the CP, these submissions were unsupported by scientific evidence. In addition, although AstraZeneca seeks to rely on the gelation properties of HPMC and their correlation to the release of the drug, these were not covered by the ‘531 Patent.

Patent Construction [ 143 ] Pharmascience highlights that the ‘531 Patent admits that extensive information about the ingredients at issue therein was already known. The main qualification that this patent adds pertains to the CP of HPMC. [ 144 ] Contrary to AstraZeneca’s assertion that the formulation is an immediate release formulation, Pharmascience submits that it is a delayed release formulation since the drug is not released until the formulation travels through the stomach and into the intestine.

[ 145 ] Pharmascience submits that the patent does not present any tests or supporting evidence as to why the claimed CPs were selected. As such, they are arbitrary choices. Further, Pharmascience notes that the ‘531 Patent does not disclose that the CP of HPMC has any effect on drug release. Rather, it discloses the opposite as the tests included therein pertained to only one batch of low viscosity HPMC at the claimed CP. These tests can therefore not show batch-to-batch variation.

In addition, Pharmascience notes that the three tests in the ‘531 Patent purport to compare two unidentified types of HPMC, one above and one below the claimed CP. As AstraZeneca admits that these two types are equivalent, Pharmascience notes that they could be one batch of METHOCEL E6 and one batch of Pharmacoat 606. [ 146 ] Pharmascience further notes that Figures 1 and 2 in the ‘531 Patent indicate full dissolution of both types of HPMC at body temperature. Thus, the patent does not teach anything on a cause and effect relationship between the CP of the

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