Allergan Inc. v. Apotex Inc.

Allergan Inc. v. Apotex Inc.
Court (s) Database
Federal Court Decisions
Date
2022-02-23
Neutral citation
2022 FC 260
File numbers
T-794-19
Decision Content
Date: 20220223
Docket: T-794-19
Citation: 2022 FC 260
Ottawa, Ontario, February 23, 2022
PRESENT: The Honourable Madam Justice Kane
BETWEEN:
ALLERGAN INC. AND ALLERGAN PHARMACEUTICALS
INTERNATIONAL LIMITED
Plaintiffs
and
APOTEX INC.
Defendant
P|||||||||||||||||||||||||| PUBLIC JUDGMENT AND REASONS
Table of Contents
I. Background 4
II. Overview 7
A. Summary of Allergan’s Position 7
B. Summary of Apotex’s Position 13
C. Summary of the Court’s Findings 16
III. The ‘188 Patent 17
IV. The Evidence 23
A. Expert Witnesses for Allergan 23
B. Fact Witnesses for Allergan 30
C. Expert Witnesses for Apotex 32
D. Fact Witnesses for Apotex 37
E. Observations Regarding the Experts’ Evidence 40
V. The Person of Skill in the Art 42
A. Allergan’s Position on the Skilled Person 43
B. Apotex’s Position on the Skilled Person 44
C. The Experts’ Evidence regarding the Skilled Person 44
D. The Skilled Person for the Purpose of this Application 46
VI. The Invention 48
A. The Construction of the Claims 50
B. The Issue in Dispute Regarding the Construction of the Claims 53
C. Allergan’s Submissions 53
D. Apotex’s Submissions 56
E. The Relevant Jurisprudence Regarding Construction of the Claims 58
F. Overview of the Experts’ Evidence on the Construction of the Claims 59
G. The Court’s Construction of the Claims 63
VII. The State of the Art 67
A. BR 601 67
B. Food Effect in Small Intestine 68
C. Bisphosphonates 69
D. Absorption Enhancers, including EDTA 71
E. Safety of EDTA 74
F. Enteric Coating/Delayed Release 75
G. Post Art ‒ Publications after 2005 78
VIII. The Common General Knowledge 80
A. Overview of the Experts’ Evidence on the Common General Knowledge 80
B. The Court’s Finding on the Common General Knowledge 82
IX. Is the ‘188 Patent Anticipated by the BR 601? 83
A. Apotex’s Submissions 83
B. Allergan’s Submissions 88
C. The Relevant Jurisprudence on Anticipation 93
D. BR 601 97
E. Overview of the Experts’ Evidence on Anticipation 102
(1) Dr. Yates 102
(2) Dr. Parr 105
(3) Dr. Cremers 106
(4) Dr. Sinko 108
F. BR 601 Does Not Disclose and Does Not Enable the Asserted Claims of the ‘188 Patent 109
(1) BR 601 is an Anticipatory Reference 109
(2) BR 601 Does Not Provide Sufficient Disclosure of the Claims of the ‘188 Patent 109
(a) The Problem Addressed by BR 601 111
(b) BR 601 Does Not Seek to Solve the Food Effect 112
(c) BR 601 and the Essential Elements of the ‘188 Patent; No Clear Direction 119
(d) BR 601 Does Not Disclose Pharmaceutically Effective Absorption 125
(3) BR 601 Does Not Enable the Claims of the ‘188 Patent 127
G. Conclusion on Anticipation 130
X. Is the ‘188 Patent Obvious? 131
A. Apotex’s Submissions 131
(1) The State of the Art 133
(2) No Differences between the State of the Art and the Subject Matter of the Claims 137
(3) Bridging Any Differences Did Not Require Inventive Ingenuity 138
(4) If BR 601 is Not Part of the Mosaic, the Claims of the ‘188 Patent are Still Obvious 139
(5) The Invention was Obvious to Try 141
B. Allergan’s Submissions 144
(1) BR 601 is Not Part of the Mosaic of Prior Art 147
(2) BR 601 Does Not Render the ‘188 Patent Obvious 147
(3) The State of the Art and “Teach Aways” 149
(4) The Differences between the State of the Art and the Subject Matter of the Claims 153
(5) The Invention was Not Obvious to Try 154
C. The Relevant Jurisprudence on Obviousness 157
D. Overview of the Experts’ Evidence 162
(1) Dr. Yates 162
(2) Dr. Parr 165
(3) Dr. Dillberger 168
(4) Dr. Cremers 169
(5) Dr. Sinko 171
(6) Dr. Burgio 172
(7) Dr. Dansereau 174
E. The ‘188 Patent is Not Obvious ‒ Overview 176
F. The Skilled Person 179
G. The Common General Knowledge 179
H. The Subject Matter of the Claims 180
I. The State of the Art 180
(1) BR 601 is Part of the Mosaic of Prior Art 181
(2) The Prior Art 183
(a) BR 601 184
(b) The Use of EDTA 188
(i) Conclusions on EDTA 196
(c) The Use of Enteric Coatings 198
(i) Conclusions on Enteric Coatings 202
J. Differences between the State of the Art and the Subject Matter of the Claims 203
K. Bridging the Differences Required Inventive Ingenuity; it was Not Obvious to Try to Obtain the Invention 206
(1) Not Self-Evident to Try to Obtain the Invention and Not Self-Evident that it would Work 207
(2) Motive 210
(3) The Nature, Extent and Effort Required to Achieve the Invention 212
(4) The Inventors’ Course of Conduct 213
XI. Is the ‘188 Patent Invalid Due to Lack of Utility, Insufficient Disclosure and/or Overbreadth? 219
A. Apotex’s Submissions 219
B. Allergan’s Submissions 220
C. The Relevant Jurisprudence on Utility, Sufficiency and Overbreadth 222
D. The Claims are Not Invalid due to Lack of Utility, Insufficiency of Disclosure or Overbreadth 225
XII. Does Apotex Infringe the Asserted Claims of the ‘188 Patent? 228
A. Allergan’s Submissions 228
B. Apotex’s Submissions 233
C. The Relevant Jurisprudence on Infringement 236
D. Overview of the Experts’ Evidence on Infringement 239
E. The Apotex Product Does Not Infringe the Asserted Claims of the ‘188 Patent 242
(1) The Claims and the Essential Elements 243
(2) The Jurisprudence Relied on by the Parties 245
(3) “Suitable For” Use 253
(4) The Product Monograph 255
(5) The Product Monograph Does Not Indicate Use With Or Without Food 257
(6) The Risk of Abdominal Pain 259
(7) No Direct Infringement 259
(8) No Inducement of Infringement 260
XIII. Costs 262
A. The Parties’ Submissions 262
B. Costs to the Successful Party 264
I. Background
[1] Osteoporosis is a common condition in women over 50, characterized by weakening of the bone, leading to fractures. Bisphosphonates are widely used in the treatment of osteoporosis. There are several bisphosphonates available for the treatment of osteoporosis in different formulations and with different dosing instructions. This patent infringement action [Action] focusses on one of the bisphosphonates ‒ risedronate ‒ taken weekly as a 35 mg dosage and known as ACTONEL DR® [ACTONEL DR]. ACTONEL DR is said to differ from other formulations of risedronate and from formulations of other bisphosphonates in that it can be taken either with food or without food, at the preference of the patient.
[2] The Plaintiffs have established (by way of the affidavit of Mr. FooLim Yeh) that Allergan Inc. holds a Notice of Compliance [NOC] or ACTONEL DR and that it lists Canadian Patent 2,602,188 [the ‘188 Patent, the ‘188 or the Patent] on the Patent Register for that product (granted on October 13, 2009).
[3] ACTONEL DR is a weekly oral dosage (tablet), the key ingredient of which is sodium risedronate, used for the treatment of osteoporosis in post-menopausal women. ACTONEL DR is an enteric-coated delayed release tablet at a strength of 35 mg risedronate and contains ethylene‑daimine-tetraacetic acid [EDTA]. (Allergan also makes and markets ACTONEL, which is an immediate release dosage administered daily as a 5 mg dosage, weekly as a 35 mg dosage or monthly as a 150 mg dosage).
[4] The Plaintiffs have also established its ownership of the ‘188 Patent. The Patent was originally granted to Proctor and Gamble [P&G]. P&G assigned the Patent and its rights to WarnerChilcott in October 2009. Warner-Chilcott subsequently assigned the Patent to Allergan Pharmaceuticals International Limited in December 2015. The Plaintiffs have established that Allergan Inc. is an innovative pharmaceutical company. The Plaintiffs are collectively referred to as Allergan.
[5] Pursuant to section 42 of the Patent Act, RSC 1985, c P-4 [Patent Act], Allergan has the exclusive right, privilege and liberty of making, constructing, using and selling to others to be used the invention claimed in the ‘188 Patent.
[6] The ‘188 Patent (Dosage Forms of Risedronate) was filed in Canada on November 23, 2005 and claims a priority date of April 15, 2005. The Patent was issued on October 13, 2009. The Patent has 137 claims. The asserted claims are described more fully below.
[7] Apotex Inc. [Apotex] is a generic pharmaceutical company. In March 2019, Apotex submitted an Abbreviated New Drug Submission [ANDS] to Health Canada seeking an NOC for its generic product, an orally administered delayed release tablet containing 35 mg sodium risedronate [APO-RISEDRONATE DR or the Apotex product]. Apotex compares its product to ACTONEL DR.
[8] On May 16, 2019, Apotex served a Notice of Allegation [NOA] on Allergan in respect of ACTONEL DR regarding the ‘188 Patent.
[9] Allergan, now brings this Action pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [PMNOC Regulations]. Allergan seeks a declaration that Apotex will infringe, directly or indirectly, at least one of the claims of the ‘188 Patent by making, constructing, using and selling the Apotex generic product.
[10] Apotex disputes that its product will infringe the ‘188 Patent. Apotex also alleges that the ‘188 Patent is invalid on the grounds of anticipation, obviousness, inutility, insufficiency of disclosure and overbreadth.
[11] The parties agree that relevant dates for the determination of the issues in this Action are: for claims construction, the date of the publication of the patent, October 26, 2006; for anticipation and obviousness, the priority date, April 15, 2005; and, for the assessment of utility, the Canadian filing date, November 23, 2005.
II. Overview
A. Summary of Allergan’s Position
[12] Allergan submits that its product, ACTONEL DR, is unique among the several bisphosphonates currently available to treat osteoporosis because it overcomes the “food effect”.
[13] Allergan notes that this “food effect” for bisphosphonates was known well before the 1990s and many pharmaceutical companies were grappling with how to solve this problem, but did not succeed.
[14] Allergan notes that the experts explained the scientific basis for the “food effect”. In layman’s terms, this means that the food in the stomach, which includes calcium and other cations, attaches to the bisphosphonate and prevents its absorption.
[15] Absorption relates to the availability of the drug to treat the underlying condition. Allergan notes (as do all the experts) that bisphosphonates are very poorly absorbed. This poor absorption (also referred to as bioavailability) is made even worse if the bisphosphonate is taken with food, to the extent that drug absorption is almost completely eliminated.
[16] Allergan submits that ACTONEL DR remains the only oral bisphosphonate “suitable” for use with or without food or beverage intake. The tablet provides “pharmaceutically effective absorption” in either state – fed or fasted ‒ and will treat a patient’s osteoporosis. Other oral bisphosphonates, including Allergan’s earlier product, ACTONEL® [ACTONEL], must be taken before breakfast on an empty stomach, with only water and no food for at least 30 minutes. This fasted administration of ACTONEL (and other bisphosphonate products) is essential to ensure that a sufficient amount of the bisphosphonate is absorbed.
[17] Allergan submits that the rigid dosing requirements for the other bisphosphonates, including its own precursor, ACTONEL, were inconvenient for some patients and almost impossible to comply with for others. For example, patients who take several medications and/or rely on others to administer their medication may not be able to adhere to the proper dosing instructions. This inconvenience contributes to poor compliance in taking the medication and leads to impairment in the treatment of the patient’s osteoporosis.
[18] Allergan notes that other pharmaceutical companies attempted to reduce the inconvenience of the food effect problem, but only Allergan overcame it. For example, some pharmaceutical companies developed a once weekly, or once monthly dose, to reduce the inconvenience of taking the medication in a fasted state daily. Others pursued intravenous administration. The inventors of the ‘188 Patent were the first to provide a direct solution to overcome the food effect as it discloses an oral dosage form of risedronate that provides pharmaceutically effective absorption ( i.e., similar absorption in the fed or fasted state) whether taken with or without food.
[19] Allergan notes that the ‘188 teaches how the invention works to overcome the food effect and also clearly teaches what does not work. The ‘188 Patent provides targeted release of just the right amount of the chelating agent in the small intestine with risedronate. The amount is high enough to bind ions and minerals in food, but low enough not to significantly alter fasted absorption. The ‘188 Patent also teaches that slow or prolonged delivery of the chelating agent and risedronate in the small intestine does not overcome the food effect; rather, in addition to targeted release in the small intestine, that release must be immediate.
[20] Allergan submits that the ‘188 is not anticipated or obvious, meets the requirements of the Patent Act with respect to utility and sufficiency of disclosure, and is not overbroad.
[21] Allergan disputes that Brazilian Patent Application 0106601 [BR 601], cited by Apotex as prior art, anticipates the ‘188. Allergan submits that BR 601 would not have been found by the skilled person and, in the unlikely event that it did come to the attention of the skilled person, BR 601 does not disclose or enable a bisphosphonate suitable for use with or without food that provides pharmaceutically effective absorption in either the fed or fasted state.
[22] Allergan acknowledges that the ‘188 Patent cites BR 601, and as a result, it is an anticipatory reference but submits that it should not be considered as part of the mosaic of prior art for the purpose of analysis of the allegations of obviousness.
[23] Allergan asserts that the ‘188 Patent is inventive ‒ i.e., not obvious. Allergan argues that the prior art taught away from the use of enteric coatings for risedronate as this was shown to reduce absorption. With respect to the use of EDTA, Allergan notes that the prior art taught that the amounts of EDTA required to overcome the food effect were too high for clinical use. It was not obvious that the low amounts of EDTA used in combination with the enteric coatings, to provide for release of risedronate and EDTA in the small intestine (bypassing release in the stomach) as claimed in the ‘188 Patent, would overcome the food effect.
[24] Allergan argues that the prior art relied on by Apotex is so broad that it cannot be found to teach the invention claimed in the ‘188 Patent.
[25] Allergan submits that there was strong motivation to address the food effect, but other pharmaceutical companies did not pursue the inventive approach of the ‘188 Patent. Allergan notes that there remains no other oral dosage form that addresses the food effect. Allergan adds that if this invention were obvious, as Apotex alleges, it is curious that no other pharmaceutical company, despite their research efforts, has come up with this approach.
[26] Allergan also points to the work of the inventors, Drs. Richard Dansereau and David Burgio, over many years, which ultimately resulted in the invention.
[27] Allergan explains that the P&G researchers sought to develop a formulation to allow risedronate to be taken “anytime”. The initial approaches were not successful and after several setbacks, the inventors arrived at the formulation disclosed in the ‘188 Patent; oral dosage forms of risedronate that are suitable for use with or without food or beverage intake because they provide pharmaceutically effective absorption either way.
[28] With respect to the allegation of inutility, Allergan submits that the evidence of Drs. Burgio and Dansereau, and that of the experts, Drs. Serge Cremers and Patrick Sinko, show that utility was demonstrated as of the Canadian filing date, November 23, 2005, by the P&G Pilot Bioavailability Study No. 2004132 [‘132 Study] results.
[29] Allergan further submits that there was sufficient disclosure of the invention. The evidence of Drs. Cremers and Sinko establishes that the skilled person could make and use the invention without undue burden and without exercising any inventive ingenuity based on the disclosure of the ‘188 Patent and their common general knowledge.
[30] Allergan submits that Apotex will infringe the asserted claims for the oral dosage forms by making and selling the Apotex product and will infringe the claims related to use given that the Apotex product is also intended to be used to treat osteoporosis.
[31] Allergan describes the first set of claims as product claims, which includes Claim 1 and several dependant claims. Allergan argues that Apotex’s intentions and how the proposed product will ultimately be used are irrelevant. The claims only require that Apotex’s proposed product be “suitable for” use with or without food or beverage intake.
[32] Allergan notes that the Apotex product has nearly identical ingredients, and its proposed product monograph is a copy of the ACTONEL DR product monograph. Allergan submits that the Apotex product has all the essential elements of the ‘188 Patent, noting that it is suitable for use both with food and without food and will provide pharmaceutically effective absorption with or without food or beverage intake, therefore, it will infringe the ‘188 Patent.
[33] Allergan disputes Apotex’s argument that it will not infringe because its proposed product monograph and package insert instruct users not to take the tablet without food. Allergan submits that the dosing instruction to take the tablet with food is only to avoid a potential side effect of abdominal pain and has nothing to do with pharmaceutically effective absorption.
[34] With respect to the evidence, Allergan submits that its experts were candid and neutral and made concessions where called for and did not advocate for a particular interpretation or outcome.
[35] Allergan submits that, in contrast, Apotex’s experts – Drs. John Yates, Alan Parr, and John Dillberger – were evasive in some of their responses and aimed to support Apotex’s position. In addition, Allergan suggests that the prior art selected by Apotex and provided to its experts led their experts to rely on hindsight. Allergan notes that where the plain words in references conflicted with Apotex’s invalidity theory, the experts then disagreed with the prior art.
[36] Allergan also notes that Mr. Duane Terrill, Apotex’s Director of Regulatory Affairs (Canada and Caribbean), initially stated that Apotex sought ||||| ||||| from Health Canada ||| ||| |||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||| due to concerns about the safety of its biostudy participants. Allergan alleges that this concern was ||||||||||||||||||||||| ||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||
B. Summary of Apotex’s Position
[37] Apotex submits that it will not infringe the claims of the ‘188 Patent because its product is not for use with or without food, rather only for use with food. Apotex also submits that it will not infringe because the ‘188 Patent is invalid on the basis of anticipation, obviousness, inutility, insufficiency of disclosure and overbreadth.
[38] With respect to invalidity, Apotex submits that the subject matter of the ‘188 Patent was previously disclosed and enabled by BR 601. Apotex notes that BR 601 is cited in the ‘188 Patent, and as a result, Allergan cannot resile from BR 601 as prior art or that it was publicly available.
[39] Apotex argues that the ‘188 Patent does not claim anything new or inventive; all the essential elements were disclosed in BR 601. Apotex submits that BR 601 taught the combination of bisphosphonates (of which risedronate is one), a chelating agent (of which EDTA is one), and an enteric coating – all of which are the essential elements of the ‘188 Patent.
[40] Apotex further submits that BR 601 disclosed the solution to the problem of low bioavailability of bisphosphonates by the use of the chelating agent and an enteric coating to permit the bisphosphonate to bypass the stomach and release immediately in the small intestine. Apotex submits that BR 601 addresses the food effect and, if performed, would result in pharmaceutically effective absorption in both the fed and fasted states.
[41] Apotex further submits that BR 601 enabled the skilled person to make the formulations in the ‘188 Patent with the information from BR 601.
[42] Apotex also argues that the claims of the ‘188 Patent were obvious. Apotex adds that even if the claims are not anticipated by BR 601, BR 601 is part of the mosaic of prior art for the purpose of the obviousness analysis.
[43] Apotex notes that by April 2005, the prior art was well developed with respect to bisphosphonates, including risedronate, and it was well known that bisphosphonates had low absorption, which was even lower if taken with food.
[44] Apotex argues that there were no differences between the state of the art in 2005 and the subject matter of the claims. The only possible small gap between the prior art and the subject matter of the claims would be that the art did not specifically combine risedronate and EDTA in an enteric coating for use with or without food and explicitly teach that this dosage would provide pharmaceutically effective absorption. Apotex submits that this small gap would easily be bridged by the skilled person using their common general knowledge.
[45] Apotex submits that the invention was obvious to try and the relevant factors support this determination. Among other things, Apotex submits that there was a general motivation to overcome the food effect and a specific motivation to do so by combining EDTA and the bisphosphonate in an enteric-coated form.
[46] Apotex disputes that the work of the inventors was long or arduous. Apotex submits that the inventors identified the possible use of EDTA early in their project. However, the inventors wasted effort by pursuing colonic delivery that the skilled person would have known would fail. Apotex submits that once the inventors were on the right track, the invention came easily.
[47] Apotex adds that the comparable patent in the United States for the product ATELVIA® [ATELVIA] was found to be obvious in the United States.
[48] Apotex also argues that the ‘188 Patent is invalid for inutility, insufficiency of disclosure and overbreadth.
[49] With respect to infringement, Apotex submits that Allergan’s allegations are based on distorting the plain words of the claims and of Apotex’s proposed product monograph for APO‑RISEDRONATE DR.
[50] Apotex focuses on the clear requirement in the claims of the ‘188 Patent that the oral dosage form of risedronate is for use “with or without food or beverage intake” at the preference of the person taking the medication. Apotex disputes that the asserted claims are product claims, rather characterizes the asserted claims as “product for use” claims.
[51] Apotex argues that the essential element of Claim 1, “for use with or without food or beverage intake”, will not be satisfied by Apotex because APO-RISEDRONATE DR is not an oral dosage form for use with or without food. It is only for use with food.
[52] Apotex submits that the evidence is clear; the proposed product monograph for APO‑RISEDRONATE DR (which is identical to that of ACTONEL DR) instructs persons taking the medication to take it with food and to not take it while fasting as it may cause abdominal pain. Therefore, Apotex does not infringe and does not induce others to infringe the claims of the ‘188 Patent.
[53] Apotex notes that it obtained ||||| ||||| from Health Canada ||||||||||||||||||| ||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| because of the safety concerns of testing the product on human subjects who may experience abdominal pain.
[54] Apotex submits that, to the extent physicians prescribe the product without food or beverage, this would be an off-label use and would not be based on any guidance from Apotex’s label.
C. Summary of the Court’s Findings
[55] The parties have tendered a vast amount of evidence and have extensively cited passages in the jurisprudence to support their respective arguments. It is important to focus on the principles established in the jurisprudence rather than the application of the principles to the particular facts of the cases cited. No two cases are identical; the facts differ, the evidence differs, and the allegations made and arguments advanced differ. I have not addressed every case cited by the parties in these Reasons. I have considered the key cases and I have focussed on the well established principles and how they relate to the issues in this case. I have considered all the evidence, some of which is applicable to more than one issue, but I have not referred to every aspect of the evidence in these Reasons.
[56] For the reasons that follow I find that Apotex has not established on a balance of probabilities that the asserted claims of the ‘188 Patent are invalid. I find that the asserted claims are not anticipated by BR 601 and are not obvious in light of the prior art, including BR 601. I also find that the asserted claims are not invalid due to lack of demonstrated utility, insufficiency of disclosure or overbreadth.
[57] I also find that Allergan has not established on a balance of probabilities that Apotex will infringe the asserted claims of the ‘188 Patent either directly or indirectly. The Apotex product is only for use with food. It is not for use with or without food, which is an essential element of the asserted claims.
III. The ‘188 Patent
[58] The title of the Patent is “Dosage Forms of Risedronate”.
[59] The Abstract states:
Oral dosage forms of risedronate comprised of a safe and effective amount of a pharmaceutical composition comprising risedronate, a chelating agent, and, means for effecting delayed release of the risedronate and the chelating agent in the small intestine provide immediate release of the pharmaceutical composition to the small intestine of the mammal subject and pharmaceutically effective absorption of the bisphosphonate with or without food or beverages. The present invention substantially alleviates the interaction between risedronate and food or beverages, which interaction results in the bisphosphonate active ingredient not being available for absorption. The resulting oral dosage may thus be taken with or without food. Further, the present invention effects delivery of risedronate and the chelating agent to the small intestine, substantially alleviating the upper GI irritation associated with the bisphosponate (sic) therapies. These benefits simplify previously complex treatment regimens and can lead to increased patient compliance with bisphospanate (sic) therapies.
[60] The Patent describes the field of invention in the same manner as the Abstract, adding that “the invention further relates to a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism comprising administering to a human or other mammal in need thereof the oral dosage form described herein”.
[61] In the Background to the Invention, the Patent notes that bisphosphonates were first developed to improve the performance of detergents in hard water. They were subsequently found useful in the treatment and prevention of conditions characterized by abnormal calcium and phosphate metabolism. These conditions fall into two categories: those which cause or result from deposition of calcium and phosphate in the body, referred to as pathological calcifications, which includes osteoporosis; and, those which are manifested by anomalous calcium and phosphate deposition, which include arthritis, neuritis, bursitis and other inflammatory conditions.
[62] The Patent describes osteoporosis as a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Bone strength is weakened and bone becomes less dense and fragile.
[63] The Patent notes that bisphosphonates tend to inhibit the resorption of bone tissue. However, the administration of bisphosphonates sometimes results in heartburn, esophageal burning, pain or difficulty swallowing or pain in the mid-sternum. The Patent notes that this is thought to be due to the bisphosphonate adhering to mucosal tissues, which leads to their irritation. To avoid this irritation, patients were instructed to take the medication with a full glass of water and to remain upright for a half hour.
[64] The Patent states that oral bisphosphonates are poorly absorbed in the gastrointestinal [GI] tract. The Patent also notes that absorption enhancers, such as EDTA, were proposed to increase absorption of bisphosphonates, but were thought to be impossible due to their effect on mucosal integrity. The Patent cites a publication by Ezra, Aviva et al, “Administration Routes and Delivery Systems of Bisphosphonates for the Treatment of Bone Resorption” (2000) Advanced Drug Delivery Reviews 42:175-195 [Ezra] (discussed in these Reasons in the context of prior art). The Patent also cites Janner, Marco et al, “Sodium EDTA enhances intestinal absorption of two bisphosphonates” (1991) Calcified Tissue International 49:280-283 [Janner] (also discussed in the context of prior art) for its conclusion that the high amount of EDTA required to increase absorption excludes EDTA as a candidate for use with oral bisphosphonates.
[65] The Patent notes that the primary site of absorption of bisphosphonate is in the small intestine and that similar absorption occurs throughout the small intestine regardless of where the bisphosphonate is delivered (citing Mitchell, David Y et al, “Risedronate gastrointestinal absorption is independent of site and rate of administration” (1998) Pharmaceutical Research 15(2):228-232 [Mitchell 1998]). The Patent notes that for this reason, delivery of the bisphosphonate alone to the small intestine would not increase absorption or efficacy.
[66] The Patent further notes that “others have attempted to increase the absorption of bisphosphonates by increasing the permeability of the intestinal mucosa through delivery of microparticles of chelating agents and bisphosphonate to the reported site of absorption” (citing BR 601).
[67] The Patent further notes that, although bisphosphonates have been approved by some regulatory agencies as effective for the treatment of various bone pathologies, interactions with foods and minerals cause less of the bisphosphonate to be available for absorption. This is referred to as the “food effect”. The Patent cites Mitchell, David Y et al, “The effect of dosing regimen on the pharmacokinetics of risedronate” (1999) Br J Clin Pharmacol 48:536-542 [Mitchell 1999] as demonstrating that administration of risedronate within 30 minutes of a meal reduced its absorption by 50% compared to administration in a fasted state. The Patent explains that as a result of the food effect, dosing instructions direct the patient to take the medication at least 30 minutes prior to the first food of the day. The Patent adds that dosing instructions can be complex and inconvenient, resulting in poor compliance.
[68] The Patent then notes the ongoing need to develop an oral dosage form of bisphosphonate that can be taken with or without food or beverages (i.e., having the same pharmaceutically effective absorption regardless) at the preference of the patient and which does not produce upper GI irritation.
[69] The Patent asserts that:
…it has been found that a pharmaceutical composition comprising risedronate, a sufficient amount of a chelating agent to bind the ions and minerals in food, and a means for effecting delayed release of risedronate and the chelating agent in the small intestine is useful in providing an oral dosage form which provides immediate release of risedronate to the small intestine, as well as pharmaceutically effective absorption of risedronate when administered with or without food or beverage intake.
[70] The Patent adds that the oral dosage forms of the invention can be taken with or without food or beverages, which simplifies the treatment and increases patient compliance and convenience. In addition, the oral dosage form provides for delayed release in the small intestine, which may alleviate upper GI tract irritation experienced with other oral bisphosphonates and the need to remain upright after ingestion.
[71] The Summary of the Invention describes several aspects. One broad aspect is the oral dosage form of risedronate for use with or without food or beverage intake. This includes a pharmaceutical composition comprising: from 1 mg to 70 mg of bisphosphonate (which includes risedronate), EDTA, wherein the EDTA is at least 50% as soluble in water as the bisphosphonate, and an enteric coating.
[72] In the Detailed Description of the Invention the relevant terms are defined. Of note, “pharmaceutically effective absorption” is defined as “an amount of a chelating compound high enough to significantly bind the metal ions and minerals in food but low enough not to significantly alter absorption of risedronate as compared to absorption in the fasted state. That is, absorption is similar with or without food. Given the high variability of bisphosphonate absorption, fed exposure within about 50% of fasting exposure is expected to be pharmaceutically effective absorption”.
[73] With respect to “kits”, the Patent states that the invention comprises kits that are useful for administering the oral dosage forms according to a continuous dosing schedule of daily, weekly, three times per month, twice per month or monthly. The kits include instructions, packaging and dispensing means and other memory aids.
[74] The Patent includes 12 examples. Examples I-VIII are of enteric-coated tablets containing risedronate and EDTA. Example IX is of a soft gel capsule containing risedronate and EDTA. Examples X-XII describe patients who take dosage forms of Examples I and IV.
[75] The ‘188 Patent has 137 claims. There are two independent claims, Claims 1 and 98. Other dependent claims narrow the ranges of the bisphosphonate or EDTA or other elements, address use and treatment and the kits.
[76] Allergan has narrowed the asserted claims, described more fully below. The key claim is Claim 1, as other claims depend on it via other dependant claims.
[77] Claim 1 of the 188 Patent states:
1. An oral dosage form of a bisphosphonate for use with or without food or beverage intake, comprising a pharmaceutical composition comprising:
(a) from about 1 mg to about 70 mg of the bisphosphonate, the bisphosphonate being risedronate, an acid, salt, ester, hydrate, polymorph, or solvate thereof, or a combination of two or more of the foregoing;
(b) EDTA wherein the EDTA is at least 50% as soluble in water as the bisphosphonate; and
(c) an enteric coating,
wherein the enteric coating provides for release of the bisphosphonate and the EDTA in the small intestine and the molar ratio of EDTA to bisphosphonate is at least 2, to provide for pharmaceutically effective absorption of the bisphosphonate with or without food or beverage intake.
[78] Other claims: Claims 1-63 and 98-132 are to oral dosage forms; Claims 64-77 and 133‑136 are to use to treat with those oral dosage forms; Claims 79 and 137 are to a kit.
IV. The Evidence
A. Expert Witnesses for Allergan
[79] Dr. Jonathan Adachi is a Canadian practicing medical physician and expert in the diagnosis, treatment and care of patients suffering from osteoporosis, including with the use of bisphosphonates. Dr. Adachi is the only expert qualified as a Canadian physician. He has treated patients with osteoporosis for over 35 years and was the past president of Osteoporosis Canada, the only national organization dedicated to osteoporosis. His evidence in chief focused on claims construction and infringement from the perspective of a skilled physician. He also responded to Dr. Yates invalidity report.
[80] Dr. Adachi described the common general knowledge of the skilled physician as of April 2005, including that bisphosphonates were a well-known class of drugs to treat osteoporosis and several were on the market. He explained that bisphosphonates suffered from low oral bioavailablity, which was significantly reduced if taken with food. He also noted that the strict dosing requirements – to take the drug on an empty stomach, with a full glass of water, to avoid food or beverages for at least 30 minutes and to remain upright ‒ posed challenges to patients and doctors. He noted that patients did not always follow the dosing instructions which impaired their treatment.
[81] In Dr. Adachi’s opinion, the claims of the ‘188 Patent will be infringed by Apotex because the Apotex product is for use both with and without food. Dr. Adachi explained that the Apotex product ponograph must be read holistically and would inform physicians that whether taken with or without food, the product would provide pharmaceutically effective absorption. Dr. Adachi stated that the skilled physician would understand that the dosing instructions that state that the product should be taken with food is only to minimize the risk of abdominal pain, and would know that the product would be effective whether taken with food or without food. Dr. Adachi explained that in his experience, only a minority of patients experienced abdominal pain.
[82] In Dr. Adachi’s opinion, the Apotex product infringes the claims of the ‘188 Patent and the Apotex product monograph will induce physicians to prescribe the Apotex product to patients in a manner that will infringe the asserted claims.
[83] Dr. Adachi stated that the instruction that ACTONEL DR “should” be taken with food is to minimize the risk of upper abdominal pain, which is noted in the product monograph. Dr. Adachi stated that the skilled physician would understand that taking it with food may lower the risk of abdominal pain, but it will still be effective if taken without food. He reiterated that only a minority of patients, in his experience, suffered from upper abdominal pain to the extent that they discontinued treatment. The most important thing is that the patient takes the medication. Dr. Adachi stated that taking it with or without food are both “on label” uses.
[84] Dr. Adachi opined that physicians treating osteoporosis would know that ACTONEL DR can be taken with or without food, despite the dosing instructions, as this is what the ACTONEL DR product monograph instructs when read as a whole. Dr. Adachi stated that the skilled physician would be confident that the same formulation can be taken with or without food and it will provide similar absorption either way.
[85] Dr. Fakhreddin Jamali is an expert in pharmacokinetics in human clinical studies and the assessment and approval of generic drug submissions, including for enteric-coated dosage forms and related Health Canada guidance documents. Dr. Jamali holds a PharmD and PhD. He was a member of the Scientific Advisory Committee on Bioavailability & Bioequivalence for Health Canada’s Therapeutic Products Program. He has acted as a consultant for both brand and generic pharmaceutical companies. His evidence focussed on Apotex’s submissions to Health Canada on bioequivalence of the Apotex product as compared to ACTONEL DR.
[86] Dr. Jamali explained that Health Canada would not simply accept a generic drug manufacturer’s statement that a drug “should” be taken with food as justification for not conducting a bioequivalence stud