ALLERGAN INC. v. ALLERGAN PHARMACEUTICALS, 2022 FC 260

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 study in the fasted state, given the strict requirements of Health Canada’s bioequivalence guidance document. Dr. Jamali first stated that it was likely that Apotex did, in fact, conduct bioequivalence testing between the two drugs in both the fasted and fed states. Following his review of additional documents, Dr. Jamali confirmed that Apotex sought ||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||| on the basis of safety concerns when the product is taken in fasted state. [ 87 ] Dr.

Serge Cremers is a pharmacologist with expertise in the clinical and translational pharmacology of bisphosphonates, including for treatment of metabolic bone diseases such as osteoporosis. Dr. Cremers received his PharmD and PhD in the Netherlands. He has published extensively and is currently a professor at the Columbia University Irving Medical Center in New York. His evidence focused on claims construction and infringement from the perspective of a pharmacologist. He also responded to the reports of Dr. Yates and Dr. Parr regarding the allegations of invalidity. [ 88 ] Dr.

Cremers noted that it has long been known that oral formulations of many bisphosphonates suffered from a " “food effect.” " Failure to follow the strict dosing instructions resulted in lowered absorption and poorer clinical outcomes. Dr. Cremers noted that many patients found it difficult to follow the dosing regime. [ 89 ] Dr. Cremers emphasized that the ‘188 Patent was focussed on tackling the food effect which relates to the absorption of the bisphosphonate and that the bioavailability was the most important factor. [ 90 ] Dr.

Cremers stated that the skilled person would understand that the ‘188 Patent relates to a solution to the food effect problem with bisphosphonate drugs: pharmaceutical compositions comprising risedronate, a sufficient amount of 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.

The skilled person would understand the Patent to be disclosing that these oral dosage forms overcome the food effect problem because they provide for " “pharmaceutically effective absorption of risedronate when administered with or without food or beverage intake.” " [ 91 ] Dr. Cremers compared the Apotex product to the reference product ACTONEL DR and concluded that the Apotex product contains all the essential elements of the asserted claims of the ‘188 Patent and would infringe those claims. [ 92 ] Dr.

Cremers acknowledged that the dosing instructions for ACTONEL DR and also for APO-RISEDRONATE DR were specific but added that a product monograph should be read holistically. [ 93 ] In Dr. Cremers’ opinion the ‘188 Patent was not anticipated by BR 601 and was not obvious. [ 94 ] With respect to the allegation of obviousness, Dr. Cremers stated that as of April 15, 2005, to his knowledge, the prior art contained no direct solution to the food effect problem for oral bisphosphonate formulations. [ 95 ] Dr.

Cremers stated that the state of the art did not provide the claimed risedronate dosage forms that overcame the food effect and also provided similar absorption when taken with or without food. Inventive ingenuity would be required to bridge the differences and arrive at the invention. [ 96 ] Dr. Patrick Sinko is an expert in pharmaceutics, including the pharmacokinetics of pharmaceutical products, drug formulation, drug delivery systems, and toxicology. He received his PhD in the United States and has been a professor in the Department of Pharmaceutics at Rutgers University, New Jersey, since 1991.

He has published extensively and has served as editor and reviewer for many scientific journals. He is also a member of the Society of Toxicology. His evidence responded to the reports of Dr. Parr and Dr. Dillberger on the allegations of invalidity. Counsel for Apotex objected to Dr. Sinko’s qualification as an expert in toxicology, however the Court is satisfied, based on Dr. Sinko’s curriculum vitae and his explanation of his expertise, including his role at Rutgers University, that he is indeed an expert in toxicology. [ 97 ] Dr.

Sinko stated that the invention of the ‘188 Patent overcomes the food effect and has the additional benefit of not significantly increasing small intestinal membrane permeability when taken without food. Dr. Sinko notes that this is important because significantly altering the small intestine membrane can lead to irreversible damage. In his view, the ‘188 Patent achieves two things: it provides for an oral dosage form of risedronate that can be taken with or without food, and it does so in a safe way. [ 98 ] In Dr.

Sinko’s opinion, the ‘188 Patent is not anticipated by BR 601 and is not obvious. [ 99 ] With respect to obviousness, Dr. Sinko stated that none of the prior art taught to combine a specific amount of risedronate, a specific amount of EDTA, or a specific enteric coating that could achieve " “pharmaceutically effective absorption” " , as defined in the ‘188 Patent. [ 100 ] Ms. Maria Margarida Rodrigues Mittelbach is the former Director of the Patents Registry of the Brazilian patent office (i.e., National Institute of Industrial Property) with expertise in its practice and procedures including as of 2005.

She is a lawyer and legal consultant in Brazil. From 1970 to 1999, she was employed by the Brazilian patent office as a patent examiner and then as the Director of the Patents Registry for over 12 years. In 2002, she started her own intellectual property law firm. Ms. Mittelbach continues to be familiar with patent practice and procedures in Brazil. She explained how a patent application could be found, in particular, the likelihood that BR 601 would be found and accessed. [ 101 ] Ms. Mittlebach explained the process to search for a patent or patent application in Brazil. Ms.

Mittelbach acknowledged that the Brazilian patent office’s online database was publically available in 2005, but noted that it was not as reliable or accurate as it is today. Ms. Mittlebach opined that experienced practitioners could not rely solely on the database to search for published patent applications because of the substantial delay in the first publication of the application in the Brazilian Gazette. She also noted that the Gazette was not available digitally until June 14, 2005 (two months after the relevant date). Ms.

Mittlebach explained that the Brazilian Gazette is published weekly and includes hundreds of abstracts which would require review of the whole document. Ms. Mittlebach noted that a search for a patent must be conducted in Portuguese and only the title, application number and abstract could be searched by key words. The full text of the patent application is not searchable by key words. Requesters must attend in person at the Brazilian patent office to obtain a copy of a patent.

[ 102 ] Ms. Mittlebach also noted that the database shows that the first time a copy of BR 601 was requested from the Brazilian patent office was in April 2013, although she agreed that a simple (unofficial) copy could have been obtained previously by an in-person request. B. Fact Witnesses for Allergan [ 103 ] Dr. David Burgio is one of the inventors of the ‘188 Patent. He is the current senior vice president of Research and Development for Global Personal Health Care at P&G. Dr. Burgio was the pharmacokineticist and pharmacologist on the team that developed ACTONEL DR. Dr.

Burgio attached to his affidavit confidential documents related to the development of the invention at P&G. [ 104 ] Dr. Burgio described his work and that of Dr. Dansereau which, after five years, resulted in the invention of an oral dosage form to overcome the food effect. He described, among other things, the obstacles faced, the concern about the use of EDTA, increasing intestinal permeability, the Enterion studies which led to a new strategy to target release in the small intestine, the testing of prototype formulations and the clinical development of the formulation. Dr.

Burgio also explained various P&G documents that chronicled their project. [ 105 ] Dr. Burgio explained that he did not recall how he became aware of BR 601, but noted that this occurred after he and Dr. Dansereau had developed their invention. He opined that BR 601 was likely provided by someone in P&G’s patent prosecution team. [ 106 ] Dr. Richard Dansereau is one of the named inventors of the ‘188 Patent. Prior to retirement, he was employed by P&G as a scientist and research fellow for 35 years. He was the lead formulator on the team that developed ACTONEL DR. Dr.

Dansereau attached to his affidavit confidential documents related to the development of the invention at P&G. [ 107 ] Dr. Dansereau described the work he conducted with Dr. Burgio and others at P&G to address the food effect of risedronate, which had inconvenient dosing instructions, particularly for elderly women, who are the main patient population for osteoporosis. He noted that P&G had identified the food effect as the biggest unmet need for bisphosphonates.

He explained that it was not known at that time, what caused the food effect, and various hypotheses were identified along with various options to address the food effect. [ 108 ] Dr. Dansereau described the work of the inventors in a similar manner as Dr. Burgio, including the setbacks and challenges, the Enterion studies and the testing of prototype formulations. He explained that the original hypothesis of colonic delivery was not successful. With respect to the use of chelating agents, he noted that he focussed on EDTA due to its strong binding characteristics compared to risedronate.

At that time, EDTA had been used as a stabilizer or preservative, not for this type of pharmaceutical application. [ 109 ] With respect to BR 601, Dr. Dansereau did not recall how this came to his attention but, like Dr. Burgio, opined that it may have been provided by the patent department at P&G. Dr. Dansereau stated that his impression upon reviewing BR 601 was that one of its objectives was to use a chelating agent to increase the permeability of the intestinal mucosa and thus increase the capacity to absorb the bisphosphonate. He explained that he and Dr. Burgio did not want to alter intestinal permeability.

In his view, BR 601 was about providing lower doses of the bisphosphonate active ingredient, not about solving the food effect. [ 110 ] Mr. Foo-Lim Yeh is the Director of Regulatory Affairs at Allergan, responsible for overseeing the regulatory approval and maintenance of Allergan’s pharmaceutical products with Health Canada. Mr. Yeh attested to Allergan’s NOC for ACTONEL DR. C. Expert Witnesses for Apotex [ 111 ] Dr.

John Yates is an expert in pharmacology, including the pharmacology and chemistry of bisphosphonates, bone and mineral metabolism, the development of pharmaceutical products for treating disorders of the bone, including osteoporosis, and the use of bisphosphonates to treat disorders of the bone, including osteoporosis. He holds degrees in the United Kingdom, which are equivalent to an MD and PhD in Canada. Dr. Yates led a team of researchers at Merck & Co Inc. [Merck] from 1990 to 2003, which focussed on the development of alendronate, a bisphosphonate. Dr.

Yates addressed the allegations of invalidity of the ‘188 Patent, including the state of the art as of April 15, 2005, from the perspective of a pharmacologist. Dr. Yates also responded to Dr. Adachi’s opinion on the infringement allegations. [ 112 ] Dr. Yates’ view is that the Apotex product will not infringe the ‘188 because it is not a product that can be taken with or without food or beverage. [ 113 ] Dr.

Yates stated that the claims of the ‘188 Patent require that the oral dosage form provides " “pharmaceutically effective absorption” " regardless of whether the dosage form is administered in the fed or fasted state. Dr. Yates notes that the patent provides that it is at the preference of the patient whether to take the dosage fed or fasted, and the intention is to simplify the treatment therapy and lead to increased compliance. [ 114 ] In Dr. Yates’ opinion, the ‘188 Patent is anticipated by BR 601 and it is obvious based on the prior art, including BR 601. [ 115 ] With respect to obviousness, Dr.

Yates stated that there were no differences between the state of the art in 2005 and the subject matter of the claims. Dr. Yates adds that any possible differences would have been bridged by the skilled person using their common general knowledge and would have readily combined several other prior art references to develop the subject matter of the asserted claims. [ 116 ] Dr. Yates emphasized the teaching of BR 601, which in his view teaches every element of the claims.

He opined that BR 601 disclosed an enteric-coated bisphosphonate and EDTA that will provide pharmaceutically effective absorption because it does not require that it must be taken fasted or must be taken fed. Dr. Yates added that even without BR 601, the claims of the ‘188 Patent would be obvious. Dr. Yates provided his opinion of the teaching of several prior art references. Among other things, he did not agree with the

Allergan experts that the prior art discouraged the use of EDTA. [ 117 ] Dr. Alan Parr is an expert in pharmaceutical formulation, including pre-formulation of solid dosage forms (both conventional and delayed/controlled release) and the biopharmaceutics of pharmaceuticals, including their design and evaluation and including for drugs having poor absorption and/or solubility. He received his PharmD and PhD in the United States. He has 30 years of experience in the pharmaceutical industry, of which 28 years were with GlaxoSmithKline. Dr. Parr is currently an independent consultant in biopharmaceutics. Dr.

Parr addressed the validity issues, including the teaching of the state of the art as of April 15, 2005, and the common general knowledge from the perspective of a pharmacologist. [ 118 ] Dr. Parr’s view is that the ‘188 Patent is anticipated by BR 601 and is obvious based on BR 601 and the teaching of the prior art. [ 119 ] Dr.

Parr explained the teaching of the prior art from his perspective, noting among other things that formulations of EDTA and bisphosphonates had been described in the prior art and that EDTA was known to be safe at particular levels, including those exceeding the amounts set out in the ‘188 Patent. Dr. Parr disagreed with Dr. Sinko’s opinion regarding possible adverse impacts of EDTA on the intestine. [ 120 ] Dr. Parr also opined that BR 601 enables the skilled person, using the common general knowledge, to prepare the subject matter of the claims. He pointed to the example of the alendronate formulation in BR 601.

Dr. Parr noted that a pharmaceutical formulator would have experience using the excipients and enteric coatings set out in BR 601 and the dosage forms claimed in the ‘188 Patent would not be difficult to prepare. Dr. Parr added that the prior art included disclosure of this combination (citing BR 601, PCT Patent Application WO 00/61111 [WO 111], U.S. Patent 5,462,932 [the ‘932 Patent] and U.S. Patent 5,730,715 Patent). [ 121 ] Dr. Parr’s view is that there is no difference between the state of the art in April 2005 and the subject matter of the ‘188 Patent.

The only possible difference is that there was no specific example in the prior art of making an enteric-coated tablet containing risedronate and EDTA. Dr. Parr stated that this difference would be easily bridged without inventive ingenuity. [ 122 ] Dr. John Dillberger is an expert in toxicology and the application of toxicology, pathology and pharmacology to the safety evaluation of drugs and the preparation of safety evaluation packages for regulatory submissions. He received his Doctor of Veterinary Medicine degree and PhD in pathology and environmental toxicology in the United States.

He has been certified as an expert in veterinary pathology and toxicology by American professional bodies and is a fellow in the International Academy of Toxicologic Pathology. Dr. Dillberger’s evidence focussed on the safety of EDTA and its use in food and pharmaceuticals as of April 15, 2005. [ 123 ] Dr. Dillberger disagreed that the prior art noted in the ‘188 Patent and other prior art taught away from the use of EDTA. He disagreed with Dr. Sinko that EDTA, particularly together with a bisphosphonate, has a toxic effect on the intestinal membrane. Dr.

Dillberger stated that there was extensive use of EDTA in food and pharmaceuticals as of April 15, 2005. [ 124 ] Dr. Lélio Denicoli Schmidt is an expert in Brazilian intellectual property law, including patent law and practice, including before the Brazilian patent office. He holds a PhD in intellectual property. Dr. Schmidt is currently a senior partner at a Brazilian intellectual property law firm, and is a patent and trademark agent enrolled at the Brazilian Patent and Trademark Office. He has acted as an expert to assist Brazilian judges in several intellectual property cases.

His evidence focussed exclusively on the filing and publication of BR 601 and whether and how it could be found and accessed. [ 125 ] Dr. Schmidt confirmed that BR 601 was filed on December 21, 2001 and published on the Brazilian patent office’s Official Gazette No. 1705 on September 9, 2003. He noted that the Gazette provided the application number, application filing date, title of the invention, abstract of the invention, applicant name, inventor name, and patent agent name. [ 126 ] Dr.

Schmidt opined that prior to April 2005, BR 601 would have been publicly available on the online database of the Brazilian patent office, created in 1997, which includes Brazilian issued patents and published patent applications. He explained that to obtain a complete copy of BR 601, a person must attend at the Brazilian patent office; the request cannot be made in writing or online. [ 127 ] With respect to how he had located BR 601, Dr. Schmidt acknowledged that he was provided with the application number by counsel for Apotex.

He explained that he found BR 601 in the database by inputting the application number, which led him to Official Gazette No. 1705. He also acknowledged that he had never searched for BR 601 prior to April 2005 and, in fact, the first time he did so was in 2020. [ 128 ] Dr. Schmidt acknowledged that over 300 patent applications are published in each weekly edition of the Official Gazette and that BR 601 was published in a volume of that length. D. Fact Witnesses for Apotex [ 129 ] Mr. Duane Terrill is the Director of Regulatory Affairs Canada and Caribbean at Apotex.

He has been employed by Apotex since 1990 with a focus on Regulatory Affairs since 2005. Among other responsibilities, he oversaw the regulatory submissions to Health Canada for the Apotex product. Mr. Terrill attached to his affidavit documents filed with Health Canada in relation to the Apotex product. [ 130 ] Mr. Terrill explained that Apotex submitted a Supplemental Abbreviated New Drug Submission [SANDS] for APO- RISEDRONATE DR to Health Canada.

He noted that Apotex only conducted a comparative bioavailability study on the APO- RISEDRONATE DR tablets and ACTONEL DR tablets |||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||| .

Apotex sought ||||| ||||| from Health Canada ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||| |||||||||||||||||||||| , submitted to Health Canada, cited the safety concerns associated with administration of the product in the fasted state (i.e., upper abdominal pain), the position of the United States Food and Drug Administration [U.S. FDA], which conducted only a fed study, and the labelling instructions that ACTONEL DR be consumed after breakfast. Health Canada granted ||||||||| ||||||||| .

[ 131 ] On cross examination, when presented with |||||||||||||||||| |||||||||||||||||| a ||| ||| study conducted in 2016 at the request of Apotex, Mr. Terrill testified that he was not aware that Apotex had conducted |||||||||||||||| |||||||||||||||| studies with 35 mg delayed-release risedronate tablets. Mr. Terrill acknowledged that it appeared that Apotex had conducted such a ||| ||| study in 2016. [ 132 ] Mr. Terrill stated that Apotex did not conduct a ||| ||| study on the specific formulation which was ultimately submitted to Health Canada. [ 133 ] Mr.

Terrill did not dispute the suggestion by counsel for Allergan that Apotex sought to ||||||||||||| pursue a course of action for other reasons ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||| ||| [ 134 ] Dr. Martin Bonenfant is the Director of Legal and Intellectual Property at Medicago Inc., a biopharmaceutical company. He holds a PhD in Reproductive Biology.

Between 2002 and 2005, he was employed as a scientific analyst by Chemical Abstracts Service, a division of the American Chemical Society and a provider of scientific information. Between 2005 and 2008, Dr. Bonenfant was employed by Canadian law firm Ogilvy Renault as a technical advisor in patents. [ 135 ] Dr.

Bonenfant explained that during his time at Chemical Abstracts Service he was responsible for reviewing scientific documents and inputting the relevant information into the " “STN” " database, a database that provides worldwide coverage of scientific documents including international journals, patents, and patent applications.

He noted that given the team of over 800 analysts, who spoke various languages, publications in a foreign language were reviewed and the relevant information was put into the database, including the title, abstract, date of publication, type of publication (scientific or patent), language and entry date. [ 136 ] Dr. Bonenfant was retained by Apotex to carry out a search on the STN search engine for scientific documents, including patent applications, which included the words " “composition” " and " “bisphosphonates” " in their titles. Dr.

Bonenfant attested that on January 21, 2021 he conducted a search on the STN database for publications using specific search terms that had " “composition” " and " “bisphosphonates” " in the title. This yielded 27 scientific documents, one of which was information about BR 601. On cross examination, Dr. Bonenfant agreed that access to the STN database requires a paid subscription. E. Observations Regarding the Experts’ Evidence [ 137 ] Both parties submit that the evidence of their experts is more credible and based on greater or more relevant experience.

Both parties cast aspersions on the opposing experts for various reasons, including their participation in analogous litigation in the United States, their advocacy for a particular position, and their sometimes contrived and other times vague answers. [ 138 ] Allergan submits that the Apotex experts had predetermined views about the teaching of the art. Allergan notes that Dr. Yates and Dr.

Dillberger had both testified in the U.S. litigation for the analogous product and both acknowledged that they were confirming the same opinions from the previous litigation. [ 139 ] Allergan also cautions against relying on opinions based on hindsight by the Apotex experts, noting that Apotex selected the prior art and provided it to the experts. Allergan adds that the Apotex experts did not conduct any further searches for relevant prior art that would support a different view. [ 140 ] As I stated at the hearing, I review all the evidence, including the testimony of the experts in its entirety.

I am sceptical of being pointed to extracts of examination and cross examination which points in a particular direction to support a particular argument without the full context being considered. [ 141 ] The experts all brought their expertise and perspectives to bear on the issues and mandates given to them and provided detailed evidence and responses to questions. [ 142 ] However, despite that all the experts were highly qualified and some had similar expertise, their opinions differed on several key issues.

They interpreted the prior art differently and some disagreed with the underlying statements in some of the art, while taking other statements at face value, without any scrutiny or based on assumptions. For example, despite his considerable expertise and the high regard that other experts expressed, Dr. Yates’ evidence was not persuasive on several issues due to his

interpretations, assumptions and rigidity. [ 143 ] With respect to Allergan’s submission that Dr. Parr’s blinded evidence is not deserving of any greater weight given the contrived manner his opinion was procured, I note that the jurisprudence is mixed on the treatment of blinded evidence. I favour the approach noted in Janssen Inc v Apotex Inc , 2019 FC 1355 at paras 58-59 [ Janssen 2019 ], that blinded opinions are not necessarily given greater weight just because they are blinded. As noted by the Court: [58] There is some authority in this Court that favours blinded witnesses.

However, I am of the view that blinding can be overrated. It may be a factor in giving weight but the Court is more interested in the substance of the opinion and the reasoning behind the conclusions. In that respect my conclusion is similar to that in Shire Canada Inc v Apotex Inc , 2016 FC 382 , 265 ACWS (3d) 456. [59] Blinding may in some cases be unhelpful because the opinion lacks proper context. In other cases blinding will produce a less cluttered opinion. In the present case I do not favour Apotex’s experts simply because they were blinded.

I would favour their opinions on the POS and common general knowledge because they offered stronger reasons for their position. Some of Apotex’s witnesses, Nam for example, provided confusing and at times contradictory statements on utility and non- infringement. [ 144 ] Similar reasoning applies here. I have considered the opinions of Dr. Parr in their overall context, including his responses on cross

examination. [145] The weight attached to particular evidence and my preference for the opinion of one expert over that of another is addressed in theanalysis of the issues. V. The Person of Skill in the Art [146] The person of skill in the art [the skilled person] is not a real person, rather a notional person or team of persons with anamalgamation of different skills and attributes.

The skilled person provides the lens or perspective through which the patent is construed,the teaching of the prior art is considered, and the allegations, in this case, of invalidity and infringement are assessed (Pfizer Canada Incv Pharmascience Inc, 2013 FC 120 at para 28; Teva Canada Limited v Janssen Inc, 2018 FC 754 at para 66, aff’d 2019 FCA 273; TevaCanada Innovation v Pharmascience Inc, 2020 FC 1158 at para 232). [147] There is an abundance of jurisprudence about the skilled person. [148] In Janssen Inc v Teva Canada Ltd, 2020 FC 593 at para 98 [Janssen 2020], the Court considered the jurisprudence andsummarised the skilled person as follows: The POSITA is a worker of ordinary skill to which the invention relates who possesses the ordinary amount of knowledgeincidental to the particular trade (Consolboard Inc v Macmillan Bloedel (Saskatchewan) Ltd, (SCC), [1981]1 SCR 504 at 523).

The POSITA may be a team of persons with different skills (Teva Canada Limited v Janssen Inc, 2018FC 754 at para 66 [Teva Canada], aff’d 2019 FCA 273). [149] In Valeant Canada LP/Valeant Canada SEC v Generic Partners Canada Inc, 2019 FC 253 at para 44 [Valeant], the Courtdescribed the skilled person in much the same way: The PSA is unimaginative and uninventive, but reasonably diligent in keeping up with advances (Pfizer Canada Inc v TevaCanada Ltd, 2017 FC 777 at para 185).

The PSA is not incompetent, and brings background knowledge and experience tothe workbench (AstraZeneca Canada Inc v Apotex Inc, 2015 FC 322 at para 276). The PSA is not stripped of the ability topursue reasonable and logical enquiries, and can make deductions based on the information available (Jay-Lor InternationalInc v Penta Farms Systems Ltd, 2007 FC 358 at para 75 [Jay-Lor], citing Beloit Canada Ltd v Valmet Oy (1986), 8 CPR (3d)289 at 294 (FCA) [Beloit]). A.

Allergan’s Position on the Skilled Person [150] Allergan submits that for this Patent, some aspects are directed to a skilled physician and others to a skilled person having a rangeof experience, including pharmacology (and formulation). [151] With respect to the aspects of the ‘188 Patent directed to a skilled physician, Allergan submits that this person is a physician withactual experience treating patients with osteoporosis. [152] Allergan submits that with respect to the aspects of the ‘188 Patent directed to a skilled pharmacologist (a part of the "“skilledperson”" team) ‒ as opposed to the skilled physician ‒ the level of expertise expected is that of the ordinary pharmacologist.

Allergansubmits that Dr. Yates’ perspective and evidence was based on the skill set of an entire drug development team, such as the team he ledat Merck, a leading industry player in the bisphosphonates field. Allergan submits that the opinions of Dr. Yates and Dr. Parr reflect theirview that the skilled pharmacologist would possess skills superior to those of the person of ordinary skill and should be considered inthis light. B. Apotex’s Position on the Skilled Person [153] Apotex submits that there is no real disagreement about the attributes of the skilled person.

Apotex submits that the ‘188 Patent isdirected to a team familiar with the oral dosing of bisphosphonates, including their side effects, bioavailability when fasting and fed, andhow bisphosphonates are administered. The team includes a drug formulator having a graduate degree in a relevant discipline and at leasta few years experience developing oral formulations, including delayed-release formulations.

The team also includes clinical researcherswith relevant scientific backgrounds, such as an MD, and several years experience designing, conducting and interpreting clinical trials,and with familiarity with animal studies, including toxicology and pharmacology. C. The Experts’ Evidence regarding the Skilled Person [154] Allergan’s expert, Dr. Cremers, opined on the attributes of the skilled person or team taking into account the subject matter of the‘188 Patent. [155] Dr. Cremers stated that the ‘188 Patent is directed to a team that includes a skilled physician and a skilled person.

The skilledperson could have a PhD degree in pharmacy, pharmaceutical sciences, or pharmacology, and some related work experience; or amaster’s degree in such disciplines and more related work experience (about 3 years); or a bachelor’s degree in such disciplines and agreater amount of related work experience (about 5 years). This skilled person would have a general understanding of formulations,including dosage forms and coatings, and a general understanding of the clinical pharmacology of bisphosphonates. [156] Dr.

Cremers added that the skilled physician would have an MD in a relevant field for the treatment of diseases described in the‘188 Patent along with some practical work experience in the treatment of such diseases.

[ 157 ] Allergan’s expert, Dr. Adachi, also considered the subject matter of the Patent in setting out his opinion on the attributes of the skilled physician. Dr. Adachi agreed that the Patent is directed to a team of skilled individuals. [ 158 ] In Dr. Adachi’s view, the aspects of the Patent relating to the treatment of osteoporosis and other bone diseases would be directed to a skilled physician with experience in diagnosing and treating diseases characterized by abnormal calcium and phosphate metabolism, including osteoporosis.

The skilled physician would have an MD and clinical and practical experience using bisphosphonates, including risedronate, to treat diseases characterized by abnormal calcium and phosphate metabolism such as osteoporosis. [ 159 ] Apotex’s expert, Dr. Yates, described his view of the skilled person noting his own extensive qualifications and his own experience, including his 13 years as clinical researcher at Merck, where he led teams that included scientists in many different disciplines, including drug formulation, drug manufacturing, and basic and clinical research. Dr.

Yates opined that " “[i]t is to just such a team that the 188 Patent is directed.” " [ 160 ] Dr. Yates elaborated, based on the qualifications of the team he had led at Merck, that the skilled person would include a drug formulator with a PhD or master’s degree in a relevant discipline, such as formulation science, and at least a few years of experience in developing oral formulations, including delayed-release formulations.

The team would also include a clinical researcher with an MD, a strong scientific background and several years of experience in designing, conducting and interpreting the results of clinical trials. Dr. Yates added that the same clinical researcher or another scientist on the team would also be familiar with relevant studies conducted in animals, including toxicology and pharmacology studies.

All members of the team would be familiar with the oral dosing of bisphosphonates, including their side effects, bioavailability under fasting and fed conditions, and conditions under which bisphosphonates were administered. [ 161 ] Dr. Parr stated that the skilled person is a team that would include a formulator, with a graduate degree (e.g., MSc or PhD), such as a pharmaceutical formulator with several years of experience developing pharmaceutical dosage forms in industry. The team would also include clinicians, preclinical pharmacologists, and toxicologists. D.

The Skilled Person for the Purpose of this Application [ 162 ] With respect to Allergan’s submission that the Apotex experts elevated the attributes and expertise of the skilled person beyond that of the ordinary skilled person, this view is reflected to some extent in Dr. Yates’ evidence. Dr. Yates stated that the skilled person or team is the type of team he led at Merck. However, Dr.

Yates disputed that his team members were more expert or knowledgeable than those that other pharmaceutical companies would hope to retain for similar projects. [ 163 ] There is really not much disagreement on the attributes of the skilled person or team of persons. Whether the Apotex experts applied a higher than ordinary standard of knowledge, skill and experience to their perspective as a skilled person or skilled physician will be assessed in the context of their opinions and evidence. For example, in several instances, Dr.

Yates disagreed with statements in the prior art, noting that the skilled person would not agree. Dr. Yates also was reluctant to praise the inventors or members of his own team for their knowledge and expertise. Whether his opinion of others or on the teaching of the prior art is due to an application of a higher standard will be considered in that context. In my view, this does not change the characterization of the skilled person.

As noted in the jurisprudence, the skilled person is not imaginative or inventive and possesses ordinary knowledge and skill in their field, albeit that the field may be highly specialized.

The skilled person or team of persons, given the attributes and experience required, is hardly " “ordinary” " as that term is generally understood, but among their peers, they are just that; neither exceptionally brilliant nor dull. [ 164 ] I find that the skilled person is a two part team: a skilled physician and a skilled person (other than the skilled physician), that is also a team. [ 165 ] The skilled physician is a physician with experience in diagnosing and treating diseases characterized by abnormal calcium and phosphate metabolism, including osteoporosis.

The skilled physician would have practical experience using bisphosphonates, including risedronate, to treat diseases characterized by abnormal calcium and phosphate metabolism such as osteoporosis. The skilled person would, of course, have an MD and several years experience in a clinical practice which includes the diagnosis and treatment with bisphosphonates of such conditions.

The skilled person would include family physicians, endocrinologists, rheumatologists, geriatricians, or a resident in those fields where they meet these criteria. [ 166 ] The skilled person, or team of persons (apart from the skilled physician) would be familiar with the oral dosing of bisphosphonates, including their side effects, bioavailability when fasting and fed, and how bisphosphonates are administered.

The team includes a drug formulator or other scientist with a master’s or PhD degree in pharmacy, pharmaceutical sciences, or pharmacology, and related work experience, with an understanding of or experience with formulations, including dosage forms, coatings and the clinical pharmacology of bisphosphonates, including delayed-release formulations. The team also includes clinical researchers with relevant scientific backgrounds, and experience designing, conducting and interpreting clinical trials, including familiarity with animal studies, including toxicology and pharmacology. VI.

The Invention [ 167 ] With respect to the disclosure of the ‘188 Patent, the experts described the invention in a similar manner, basically reiterating the words in the Patent as set out above and offering little in the way of a layman’s explanation. [ 168 ] For example, Apotex’s expert, Dr. Yates, noted that the invention pertains to a solid dosage form of risedronate, which also contains EDTA in an enteric-coated dosage form that is designed to remain intact in the stomach.

Once the intact dosage form passes through the pylorus (the exit valve of the stomach) and into the higher pH environment of the small intestine the enteric coating dissolves allowing the contents of the dosage form to become available for absorption. Dr. Yates explained that enteric-coated dosage forms are also referred to as delayed-release dosage forms because the release is delayed until the dosage form is in the small intestine.

[ 169 ] Dr. Yates added that the ‘188 Patent states that once the dosage form is in the small intestine, it is designed to release both the risedronate and the EDTA rapidly, with consequent absorption of the risedronate. Dr. Yates explained that this approach differs from the earlier immediate-release formulati

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