JANSSEN INC. v. ACTELION PHARMACEUTICALS LTD, 2022 FC 996

Date: 20220706 Docket: T-555-20 Citation: 2022 FC 996 Toronto, Ontario, July 6, 2022 PRESENT: Madam Justice Pallotta BETWEEN: JANSSEN INC. AND ACTELION PHARMACEUTICALS LTD Plaintiffs and APOTEX INC. Defendant PUBLIC REASONS FOR JUDGMENT (Judgment issued May 20, 2022 – 2022 FC 995 ) (Confidential Judgment and Reasons issued May 20, 2022) Table of Contents I. Overview 3 II. Background 5 A. The Parties and the Nature of this Proceeding 5 B. The 770 Patent 7 C. PAH and Diseases Involving Vasoconstriction 8 III. Issues 9 IV. Witnesses 12 A. Dr. Mielniczuk (Plaintiffs’ Expert Witness) 13 B. Dr.

Kapasi (Plaintiffs’ Expert Witness) 14 C. Dr. McIvor (Apotex’s Expert Witness) 16 D. Ms. Picard (Apotex’s Expert Witness) 17 V. The Skilled Person and Their Common General Knowledge 23 VI. Claim Construction 28 A. Legal Principles 28 B. The Asserted Claims 30 C. Experts’ Opinions on Claim Construction 33 D. Parties’ Positions on Claim Construction 36 E. Analysis on Claim Construction 42 (

a) Claims 1-5 43 (

b) Claims 10-20 46 (

c) Claims 21-31 49 VII. Infringement 50 A. Direct Infringement 51

(1) Parties’ Submissions 51

(2) Analysis 52 B. Inducing Infringement 54

(1) Parties’ Submissions 55

(2) Analysis 62 (

a) Corlac Test: Prong 1 62 (

b) Corlac Test: Prong 2 64 (

c) Corlac Test: Prong 3 74 VIII. Conclusion 75 IX. Postscript 76

SCHEDULE A 79 I. Overview [ 1 ] The plaintiffs, Janssen Inc. (Janssen) and Actelion Pharmaceuticals Ltd (Actelion), bring this patent infringement action against Apotex Inc. (Apotex) pursuant to subsection 6(1) of the Patented Medicines (Notice of Compliance) Regulations , SOR/93-133 [ PMNOC Regulations ], made under the Patent Act , RSC 1985, c P-4 [ Patent Act ]. [ 2 ] Janssen markets a prescription medication in Canada known as OPSUMIT®, a film-coated tablet containing 10mg of macitentan as the active ingredient, to treat patients afflicted with pulmonary arterial hypertension (PAH).

PAH is a serious and incurable condition of high blood pressure in the blood vessels of the lungs, caused by changes to the arteries that transport deoxygenated blood from the heart to the lungs for reoxygenation. If left untreated, the high blood pressure strains the heart, leading to heart failure and death. [ 3 ] OPSUMIT belongs to a class of drugs known as endothelin receptor antagonists (ERAs). ERAs work by binding to endothelin receptors within the walls of blood vessels, preventing endothelin from binding to these receptors.

Endothelin binding is one of the steps in the endothelin pathway, a biological pathway that causes smooth muscle cells in blood vessel walls to constrict and proliferate, forcing the heart to work harder to push blood through the narrowed and thickened arteries. By blocking the endothelin binding step, ERAs interfere with the vasoconstricting and proliferative effects of the endothelin pathway. [ 4 ] OPSUMIT can be prescribed alone or in combination with another class of drugs known as phosphodiesterase type-5 inhibitors (PDE5-Is).

Like ERAs, PDE5-Is affect blood pressure, but they do so by enhancing the vasorelaxation and anti-proliferative effects of the nitric oxide pathway. Sildenafil and tadalafil are two PDE5-Is prescribed for PAH. [ 5 ] Currently, Janssen is the only company authorized by Health Canada to sell macitentan as a prescription medication.

Apotex seeks Health Canada’s approval to sell a generic prescription medication containing 10mg of macitentan as the active ingredient (APO- MACITENTAN). [ 6 ] The plaintiffs allege that if Apotex sells APO-MACITENTAN, it will infringe claims 1-5, 10-20, and 21-31 (Asserted Claims) of Actelion’s Canadian Patent No. 2,659,770 titled " “Therapeutic Compositions Comprising a Specific Endothelin Receptor Antagonist and a PDE5 Inhibitor” " (770 Patent). [ 7 ] Claims 1, 10, and 21 are independent claims of the 770 Patent that relate to macitentan in combination with a PDE5-I to treat a disease wherein vasoconstriction is involved.

The other Asserted Claims depend directly or indirectly on claims 1, 10, or 21, and they are narrower in scope. The dependent claims include limitations on the specific PDE5-I, the specific disease, or both. [ 8 ] According to the plaintiffs, Apotex will infringe certain Asserted Claims directly, or indirectly by making statements in the APO- MACITENTAN product monograph (PM) that will induce others to infringe, notably prescribing physicians. With respect to inducement, the plaintiffs allege that the APO-MACITENTAN PM communicates that APO-MACITENTAN should not be used any differently than OPSUMIT.

They allege the APO-MACITENTAN PM includes bioequivalence data and results from a multicentre, double blind, placebo-controlled Phase 3 clinical trial (SERAPHIN) involving 742 PAH patients that established the safety and efficacy of macitentan as a monotherapy and as combination therapy with a PDE5-I. As such, the APO-MACITENTAN PM will encourage physicians to use APO-MACITENTAN just as OPSUMIT is used, in combination with PDE5-Is. [ 9 ] For the purposes of this proceeding only, Apotex concedes that the Asserted Claims are valid.

Apotex defends the plaintiffs’ allegations on the basis that it will not infringe any of the Asserted Claims. Apotex alleges that it will not infringe any Asserted Claims directly because it will not perform all of the essential elements of the claims, and it will not infringe any Asserted Claims indirectly because the " “Indications and Clinical Use” "

section of the APO-MACITENTAN PM states that |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| and the PM does not suggest that physicians or patients should use APO-MACITENTAN in combination with a PDE5-I.

[ 10 ] For the reasons below, the plaintiffs have not established that Apotex will directly infringe any of the Asserted Claims. The plaintiffs have established that Apotex will induce infringement of claims 1-5 and 21-31. II. Background A. The Parties and the Nature of this Proceeding [ 11 ] Janssen is a pharmaceutical company with a head office in Toronto, Ontario. Actelion is a pharmaceutical and biotechnology company with a head office in Allschwil, Switzerland. Janssen is wholly owned by Johnson & Johnson, which acquired Actelion in 2017.

Both Janssen and Actelion are members of the Johnson & Johnson group of companies. Janssen is a " “first person” " within the meaning of subsections 4(1) and 6(1) of the PMNOC Regulations . Actelion is the registered owner of the 770 Patent and is a necessary party to this action under subsection 6(2) of the PMNOC Regulations . [ 12 ] Apotex is a pharmaceutical corporation with its head office in Toronto, Ontario.

Apotex is a " “second person” " within the meaning of subsections 5(1) and 6(1) of the PMNOC Regulations . [ 13 ] Apotex filed an Abbreviated New Drug Submission (ANDS) with Health Canada, seeking authorization to market APO- MACITENTAN tablets based on their equivalent pharmaceutical and bioavailability characteristics, when compared to OPSUMIT. [ 14 ] The Minister of Health maintains a list of patents related to drugs that have been authorized for sale under a notice of compliance (NOC).

As a condition of obtaining market authorization for its macitentan product, the PMNOC Regulations required Apotex to address the patent list for OPSUMIT. Apotex served a Notice of Allegation on April 6, 2020 and the plaintiffs commenced this action in response. [ 15 ] When this action was commenced, three patents were listed in relation to OPSUMIT: Canadian Patent No. 2,437,675, Canadian Patent No. 2,621,273, and the 770 Patent. Canadian Patent No. 2,437,675 has expired, and Canadian Patent No. 2,621,273 is not at issue in this action.

Only the 770 Patent is at issue. [ 16 ] By commencing this action, the plaintiffs triggered a stay that prevents the Minister of Health from issuing an NOC to Apotex for up to 24 months in order to allow time for the action to be heard and decided. B. The 770 Patent [ 17 ] The 770 Patent was issued on November 18, 2014. It relates to a specific compound, referred to throughout the patent as " “formula (I)” " , in combination with a PDE5-I to treat diseases wherein vasoconstriction is involved. Formula (

I) is identified by the following diagram of its chemical structure: [ 18 ] There is no dispute that formula (

I) is the compound now known as macitentan, the active ingredient in OPSUMIT, and that formula (I)/macitentan is an ERA. [ 19 ] The first paragraph of the 770 Patent specification describes the invention as relating to a product containing a compound of formula (

I) in combination with at least one compound having PDE5-inhibitory properties for therapeutic use in the treatment of a disease wherein vasoconstriction in involved. The specification states that " “disease wherein vasoconstriction is involved” " means in particular hypertension, pulmonary hypertension (including PAH), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris.

Some of the Asserted Claims do not include a limitation on the particular disease wherein vasoconstriction is involved, while others are limited to: the particular diseases of vasoconstriction listed above, hypertension and pulmonary hypertension, pulmonary hypertension (PH) specifically, or PAH specifically. [ 20 ] The patent specification defines " “compound having PDE5-inhibitory properties” " to be a compound that meets or exceeds a threshold measurement of its ability to inhibit PDE5 according to an experimental test protocol described in the patent, and it provides four examples of PDE5-Is: sildenafil, vardenafil, tadalafil, and udenafil.

Some of the Asserted Claims do not include a limitation on the PDE5-I, and others are limited to: the four example PDE5-Is, sildenafil or tadalafil, sildenafil specifically, or tadalafil specifically. C. PAH and Diseases Involving Vasoconstriction [ 21 ] Vasoconstriction is the constriction of the vasculature (arteries and veins) of the circulatory system. The vasculature can be divided into two systems that circulate blood between the body, heart, and lungs. The systemic circuit involves the left side of the heart, which pumps oxygenated blood from the heart to the rest of the body (except the lungs).

The pulmonary circuit involves the right side of the heart, which pumps deoxygenated blood from the heart to the lungs for reoxygenation.

[ 22 ] Although some of the Asserted Claims cover other diseases of vasoconstriction and are not limited to PAH, PAH is the only disease that is relevant to the issues in this action because the allegations of direct and indirect infringement are restricted to PAH. [ 23 ] PAH is a subtype of PH, a general term that describes abnormally high blood pressure in the pulmonary circulatory system.

As noted above, PAH is a progressive and incurable disease where the artery walls in the lungs constrict and thicken, increasing vascular resistance to blood flow and making the right side of the heart work harder to push blood through narrowed arteries. The extra stress causes the right ventricle of the heart to enlarge and dilate. Over time, the changes become unsustainable. The right ventricle weakens, its ability to push blood out of the heart to the lungs is compromised, and eventually, the heart fails. III.

Issues [ 24 ] The issues in this action relate to claim construction and infringement of the Asserted Claims. As noted above, validity of the 770 Patent is not an issue that is before the Court. [ 25 ] The Asserted Claims of the 770 Patent must be construed—that is, interpreted—before there is an assessment of whether they are infringed: Whirlpool Corp v Camco Inc , 2000 SCC 67 at para 43 [ Whirlpool ] .

Doing so requires that the claims be read in an informed and purposive way, from the perspective of a notional person of ordinary skill in the art or science to which the patent relates, and to whom the patent is addressed (skilled person): Free World Trust v Électro Santé Inc , 2000 SCC 66 at para 44 [ Free World ] . [ 26 ] While the parties in this case and their expert witnesses largely agree (with some variation) on the qualifications of the skilled person and the relevant experience and knowledge that person would bring to bear on the issues in the action, the first issue for the Court is to define the skilled person. [ 27 ] The parties filed a joint claim chart.

Despite their identical proposed constructions of the essential elements of the Asserted Claims, the parties do not agree on what the claims mean. Two aspects of claim construction are in dispute: (

i) whether claims 1, 10 and their dependent claims are, in substance, claims to the use of macitentan to treat a disease including PAH; and (ii) for all Asserted Claims, whether " “combination” " contemplates the use of macitentan and a PDE5-I as something that a physician intended at the outset of a patient’s treatment. [ 28 ] The Court’s claim construction analysis is not confined to the aspects of claim construction that are in dispute. The Court is not required to accept the parties’ or the experts’ proposed claim construction. Claim construction is a matter of law for the Court to decide: Whirlpool at para 61 ; Zero Spill Systems (Int'

l) Inc v Heide , 2015 FCA 115 at para 41 [ Zero Spill ] . The construction of the Asserted Claims is the second issue. [ 29 ] The application for the 770 Patent was published on March 6, 2008. This is the relevant date for construing the claims: Free World at paras 53-54 . The skill and knowledge that the skilled person brings to bear when interpreting the claims is their skill and knowledge as of March 6, 2008.

For simplicity, I will sometimes refer to the 770 Patent’s publication date as March 2008 or I will refer to the year only. [ 30 ] The plaintiffs bear the burden of proving infringement on a balance of probabilities.

The parties’ joint statement of issues frames the infringement issue as follows: The Court will be required to decide whether, if approved, the making, constructing, using, or selling of APO- MACITENTAN 10 mg film-coated tablets, by Apotex Inc. in accordance with its Abbreviated New Drug Submission No. 2365227 constitutes infringement of any of the Asserted Claims of the 770 Patent, either directly or indirectly by inducing others to infringe. [ 31 ] As the third issue, the Court must decide whether the plaintiffs have established that Apotex would directly infringe claims 1-5 and 10-20, if it is authorized to market APO-MACITENTAN. [ 32 ] As the fourth issue, the Court must decide whether the plaintiffs have established that Apotex would indirectly infringe claims 1-5 and 21-31 by inducing others, notably prescribing physicians, to infringe.

As noted above, the plaintiffs assert that statements made in the APO-MACITENTAN product monograph (PM) will induce prescribing physicians to infringe the Asserted Claims. [ 33 ] At the outset of trial, the plaintiffs stated that they were alleging Apotex would infringe claims 10-20 indirectly, however, their written closing argument did not address indirect infringement of claims 10-20. In view of my construction of claims 10-20, I would not have found indirect infringement for these claims. IV.

Witnesses [ 34 ] Each of the parties introduced expert evidence in support of their respective positions on claim construction and infringement. The plaintiffs relied on the expert opinion evidence of Dr. Mielniczuk and Dr. Kapasi. Apotex relied on the expert opinion evidence of Dr. McIvor and Ms. Picard. [ 35 ] The parties agree on a number of facts. As a result, neither party called fact witnesses. They provided a joint scientific primer and an agreed statement of facts. [ 36 ] That said, the plaintiffs submit that Apotex should have called a fact witness from the company.

They argue an adverse inference should be drawn because the only evidence regarding Apotex’s actions and intentions—which are centrally important to the issue of infringement—was Dr. McIvor’s and Ms. Picard’s speculation. The plaintiffs therefore argue that this Court should infer that Apotex did

not call a company witness because their evidence would not have been helpful to Apotex’s position. [ 37 ] I decline to draw an adverse inference based on Apotex’s alleged failure to call a company witness. According to the joint statement of issues, the question on infringement is whether the making, constructing, using or selling of APO-MACITENTAN in accordance with Apotex’s ANDS would constitute direct or indirect infringement. In this regard, the plaintiffs asked Drs. Mielniczuk and Kapasi to review the proposed APO-MACITENTAN PM and product label that Apotex submitted as part of its ANDS, and opine on: (

i) how APO-MACITENTAN will be used by physicians and patients if it is approved, sold, and used in Canada; and (ii) what Apotex’s influence will be on the use of APO-MACITENTAN in Canada by physicians and patients. Both experts opined that Apotex would represent that APO-MACITENTAN can be used in place of OPSUMIT through the information within the proposed APO- MACITENTAN PM. [ 38 ] The following provides a brief description of each expert witness’ qualifications and testimony. A. Dr. Mielniczuk (Plaintiffs’ Expert Witness) [ 39 ] Dr.

Mielniczuk is a Staff Cardiologist and Medical Director of the Pulmonary Hypertension Clinic at the University of Ottawa Heart Institute. She has been in this role since 2007. Dr. Mielniczuk received her M.D. from McMaster University in 1998. She completed a residency in internal medicine at Queen’s University in 2001, and a fellowship in cardiology at the University of Ottawa Heart Institute in 2004. Dr. Mielniczuk also completed a fellowship in advanced heart failure and cardiac transplantation at the Brigham and Women’s Hospital in Boston, Massachusetts in 2006.

She received a Master of Science degree in Clinical Science and Epidemiology from the Harvard School of Public Health in 2007. [ 40 ] Dr. Mielniczuk’s research activities focus on heart failure, clinical outcomes relating to heart failure associated with PH, and the evaluation of myocardial energetics in right heart failure. [ 41 ] Apotex did not object to Dr. Mielniczuk’s proposed qualifications. I was satisfied Dr. Mielniczuk was qualified to provide expert evidence according to the proposed qualifications that were put forward by the plaintiffs: Dr.

Mielniczuk is a medical doctor, researcher, and professor of cardiology with expertise in (

i) pulmonary hypertension (“PH”) (including pulmonary arterial hypertension (“PAH”)); (ii) the development and science of treatment of PH (including PAH); and (iii) the treatment of PH (including PAH) in Canada, past and present. [ 42 ] Dr. Mielniczuk prepared an expert witness report dated July 15, 2021. The report sets out Dr.

Mielniczuk’s opinions on mandates related to the qualifications and knowledge of the skilled person, construction of the Asserted Claims, how PAH is treated today, how APO-MACITENTAN will be used by physicians and patients in Canada, and what Apotex’s influence will be on the use of APO- MACITENTAN by physicians and patients. Dr. Mielniczuk’s report was taken as read. B. Dr. Kapasi (Plaintiffs’ Expert Witness) [ 43 ] Dr. Kapasi is an Associate Professor of Medicine at the University of British Columbia. Dr.

Kapasi received his M.D. from the University of Alberta in 2003 and completed a residency in family medicine in 2004. He also completed a residency in internal medicine at the University of Manitoba in 2006, a respirology subspeciality training program in 2008, and a fellowship in lung and heart/lung transplantation in 2009. Dr. Kapasi received a Masters in Pulmonary Vascular Disease from the Università di Bologna in 2012. [ 44 ] Since the beginning of his practice of medicine in 2009, Dr.

Kapasi’s focus has been on treating cardiovascular diseases, with a particular interest in diseases affecting the pulmonary circulatory system. [ 45 ] The plaintiffs proposed that Dr. Kapasi be qualified to testify as an expert as follows: Dr. Kapasi is a medical doctor, researcher, and professor of pulmonary medicine with expertise in (

i) pulmonary hypertension (“PH”) (including pulmonary arterial hypertension (“PAH”)); (ii) the development and science of treatment of PH (including PAH); and (iii) the treatment of PH (including PAH) in Canada, past and present. [ 46 ] Apotex did not object to the proposed qualifications, and I was satisfied that Dr. Kapasi was qualified to provide expert testimony in accordance with the proposed qualifications. [ 47 ] Dr. Kapasi prepared an expert witness report dated July 15, 2021. Dr. Kapasi’s report covered his opinions on the same mandates as Dr. Mielniczuk’s report. Dr.

Kapasi’s report was taken as read. [ 48 ] Prior to Dr. Kapasi’s testimony at trial, Apotex registered an objection to Dr. Kapasi’s expert opinion evidence on the ground that his evidence is duplicative of Dr. Mielniczuk’s expert opinion evidence. Having noted the objection, Apotex stated that it would provide its submissions on the objection in the context of closing arguments. [ 49 ] Apotex did not provide submissions on the objection in its written or oral closing arguments.

Following a question from the Court, asking whether the objection was withdrawn, Apotex stated it was not objecting to the admissibility of Dr. Kapasi’s expert opinion evidence but it reserved the right to speak to the issue on costs. Apotex then added that the duplicative nature of the evidence should be a factor considered in assigning weight to Dr. Kapasi’s evidence, and the plaintiffs raised an objection. The plaintiffs’ position was that, having made no submissions in its closing arguments (and in fact, Apotex relied on both Dr. Kapasi’s and Dr.

Mielniczuk’s evidence on various points), and having withdrawn the objection, it was not open to Apotex to argue that Dr. Kapasi’s opinion should be given less weight because it is duplicative. In any event, the plaintiffs submit Dr. Kapasi’s and Dr. Mielniczuk’s opinions are corroborative rather than duplicative.

[50] Apotex argued that an opinion from a second, similarly-situated PAH expert does not assist the Court according to the frameworkset out in R v Mohan, (SCC), [1994] 2 SCR 9. In my view, that is a question of admissibility, and Apotex stated it wasnot objecting to the admissibility of Dr. Kapasi’s evidence. Apotex also argued that the Court should not decide issues on the basis thattwo experts are better than one. In my view, that caution was unnecessary. I have not given "“extra weight”" to the opinions of either ofthe plaintiffs’ experts simply because there were two of them. C. Dr.

McIvor (Apotex’s Expert Witness) [51] Dr. McIvor is a respirologist (also referred to as a pulmonologist, especially in the United States) whose clinical practice andresearch focuses on a range of respiratory disorders. Dr. McIvor was trained in internal medicine in the United Kingdom from 1984 to1989, and enrolled in the Respirology Training Program at the University of Toronto from 1990 to 1992. Dr. McIvor received his M.D.from Queen’s University in Belfast, Northern Ireland in 1994 and a Master of Science degree in clinical epidemiology from McMasterUniversity in 1995.

Since 2005, he has been a Staff Respirologist at the Firestone Institute for Respiratory Health (FIRH) of St. Joseph’sHealthcare Hamilton and a Professor of Medicine at McMaster University. FIRH is a referral centre for patients in the Hamilton Areawith asthma and chronic respiratory disease, including patients with PAH. [52] Dr. McIvor was qualified to testify as an expert as follows: Dr. McIvor is a respirologist with expertise in the diagnosis, management and treatment of respiratory conditions includingPulmonary Arterial Hypertension. [53] Dr. McIvor prepared an expert witness report dated October 12, 2021.

The report sets out Dr. McIvor’s opinions on mandatesrelated to the qualifications and knowledge of the skilled person, construction of the Asserted Claims, how PAH is treated today, how aphysician would understand the instructions from the APO-MACITENTAN PM, whether the PM would result in direct infringement orinduce physicians to infringe the Asserted Claims, and responses to Dr. Mielniczuk and Dr. Kapasi’s reports. Dr. McIvor’s report wastaken as read. D. Ms. Picard (Apotex’s Expert Witness) [54] Ms.

Picard is a pharmacist and President of SPharm Inc., a regulatory consulting firm that provides strategies and consultancy topharmaceutical companies. She has a Master’s degree in hospital pharmacy and 30 years of experience in regulatory affairs. [55] Ms. Picard prepared an expert report dated October 12, 2021. Ms. Picard was asked to provide her opinion on whether Apotexwould be permitted to market or promote that APO-MACITENTAN can be used as a combination therapy with PDE5-Is, based on theAPO-MACITENTAN PM provided to her. She was also provided with copies of Dr. Kapasi’s and Dr.

Mielniczuk’s reports and asked tocomment on those portions of their expert reports relevant to her expertise, and advise whether she agreed or disagreed. [56] Apotex proposed the following qualifications for Ms. Picard: Susanne Picard is a licensed pharmacist and an expert in Canadian pharmaceutical regulatory affairs, including thepreparation, filing and management of new and abbreviated new drug submissions. She has particular expertise in: (

a) thepreparation and filing and

interpretation of brand and generic Product Monographs (“PMs”); (

b) the relevant regulations andguidelines for preparing PMs; (

c) Health Canada’s evaluation of PMs; and (

d) the regulations applicable to the marketing ofapproved pharmaceuticals. [57] At trial, the plaintiffs objected to Ms. Picard’s proposed qualifications. After hearing the parties’ arguments, I revised the proposedqualifications offered by Apotex by deleting the word "“particular”" from the second sentence and adding a proviso. These changes wereintended to make it more explicit that Ms. Picard’s opinions offer one perspective of PMs, the regulations and guidelines, and HealthCanada’s evaluation of PMs, and her opinions do not go further than that perspective.

The revised statement of qualifications is asfollows: Susanne Picard is a licensed pharmacist and an expert in Canadian pharmaceutical regulatory affairs, including thepreparation, filing and management of new and abbreviated new drug submissions. She has particular expertise in: (

a) thepreparation and filing and

interpretation of brand and generic Product Monographs (“PMs”); (

b) the relevant regulations andguidelines for preparing PMs; and (

c) Health Canada’s evaluation of PMs; and (

d) the regulations applicable to themarketing of approved pharmaceuticals, provided that the expertise noted as (a), (b), (c), and (

d) is within Ms. Picard’sexpertise as a pharmacist or in Canadian pharmaceutical regulatory affairs. [58] The plaintiffs also argued that most parts of Ms. Picard’s expert report (paragraphs 23, 24, 53, 55-60 and 62-80) are inadmissible.These are almost all of the paragraphs in Ms. Picard’s report that provide an opinion on the APO-MACITENTAN PM. The remainingparagraphs in the report provide information about Ms.

Picard’s qualifications, or information about the regulations made under theFood and Drugs Act and other aspects of the regime that governs drug marketing in Canada. [59] The plaintiffs do not take issue with Ms. Picard’s qualifications as an expert in the area of regulatory affairs; however, they say herexpertise in this regard is irrelevant to the issues in this case and does not support most of the opinions within her expert report. Theplaintiffs object to the above-noted paragraphs principally on two bases: (

i) Ms. Picard provides opinions that are outside her expertise;and (ii) Ms. Picard provides opinions on domestic law, which should be excluded for that reason and also for being unnecessary. [60] According to the plaintiffs, Ms. Picard is not a properly qualified expert whose opinion is relevant and necessary to assist the Court:White Burgess Langille Inman v Abbott and Haliburton Company Limited, 2015 SCC 23. All drafts of the PM that were submitted toHealth Canada are already in evidence, Ms. Picard’s

interpretation of them from the perspective of a regulatory affairs expert are notrelevant to inducement, and she cannot provide the perspective of a PAH physician. Also, Ms. Picard is not a lawyer and the Court does

not need her evidence to take judicial notice of the Food and Drugs Act or the regulations thereunder. The plaintiffs further note that Ms. Picard’s opinions on what Apotex can and cannot do from a regulatory perspective are not grounded in fact evidence from Apotex, and she does not know its marketing plans. [ 61 ] The plaintiffs say the situation is analogous to Bell Helicopter Textron Canada Limitée v Eurocopter , 2013 FCA 219 .

In that case, the Court ruled that an expert’s opinion on the patent examination process before the Patent Office was irrelevant because the expert had no expertise on the technology in question, the patent examination history was already in evidence, a patent examiner’s perspective was irrelevant to the Court’s assessment of validity from a skilled person’s perspective, and expert opinion on domestic law was unnecessary. [ 62 ] Apotex’s responding position was that the Court should reserve on the question of admissibility, but if the Court were inclined to rule on admissibility during the trial, Ms.

Picard’s evidence met the test for admissibility as expert opinion. [ 63 ] On the first point, Apotex argued that a determination of admissibility at trial would be premature. There was insufficient reason to rule that parts of Ms. Picard’s report should be excluded based on the threshold requirements of admissibility, and no reason to engage the Court’s discretionary gatekeeper role of balancing the potential risks and benefits of admitting her evidence. A central issue in this action relates to Apotex’s intentions as gleaned from an objective reading of the PM, and Ms.

Picard’s experience allows her to opine on what can be inferred from the PM based on the purpose of a PM and the regulatory framework that applies to it. Apotex argued it would be efficient to allow Ms. Picard to testify under reserve of objection, and doing so would also promote fairness because Apotex did not have advanced notice of the challenged paragraphs and the bases for objecting to them. [ 64 ] On the second point, Apotex argued that Ms. Picard’s evidence meets the threshold requirements for admissibility, and the plaintiffs’ objections should be considered as a matter of weight.

The regulatory perspective of an expert who provides advice to pharmaceutical companies on PMs and the marketing of a drug product is helpful to assist the Court in understanding the PM. Although guided by legislation, Ms. Picard’s evidence is not a legal opinion and her evidence should not be excluded on this basis. Ms. Picard can assist the Court to navigate a complex regime that involves an interplay between legislation, standards, guidance documents, and other considerations. [ 65 ] I agreed with Apotex that it was premature to rule on admissibility at trial.

It was not clear to me that all of the impugned paragraphs should be excluded as inadmissible on the basis of relevance or necessity, and I reserved my ruling on admissibility. [ 66 ] As noted above, as her first mandate Ms. Picard was asked to provide her opinion on whether Apotex would be permitted to market or promote that APO-MACITENTAN can be used as a combination therapy with PDE5-Is, based on the APO-MACITENTAN PM provided to her. As her second mandates she was provided with copies of Dr. Kapasi’s and Dr.

Mielniczuk’s reports and asked to comment on those portions of their expert reports relevant to her expertise, and advise whether she agreed or disagreed. [ 67 ] With respect to the second mandate, I find Ms. Picard’s expert report and testimony to be inadmissible because her opinions are outside of her expertise. For example, Ms. Picard offered opinions on whether or not the references to SERAPHIN found in the APO- MACITENTAN PM would support the use of macitentan as a monotherapy or as combination therapy. Ms.

Picard is not qualified to do so as she is not a physician, she has no expertise regarding PAH, and she is not qualified to opine on whether the APO-MACITENTAN PM " “omits any discussion of efficacy as it relates to the use of combination therapy” " . Her opinion in this regard was based on a side- by-side comparison of words deleted from the APO-MACITENTAN PM. This is an exercise of form over substance that is potentially misleading from an expert witness with no PAH expertise. [ 68 ] With respect to the first mandate, and to the extent that Ms.

Picard’s evidence fell within the scope of her expertise as a pharmaceutical regulatory expert, I find the opinions have marginal relevance to the issues that the Court must determine in this case. For example, Ms. Picard provided a generalized opinion that generic pharmaceutical companies are not free to omit clinical and pre-clinical studies that are included in a PM for the " “reference product” " (the brand company’s PM) because these studies are typically conducted to establish the safety and/or efficacy of the drug in question. However, Ms.

Picard has no knowledge about what Apotex was or was not required to include from SERAPHIN in particular. As another example, Ms. Picard opined that Apotex would not be permitted to market or promote that APO-MACITENTAN can be used as a combination therapy with PDE5-Is, based on the APO-MACITENTAN PM provided to her. However, the issue in this case is whether the contents of the APO-MACITENTAN PM itself would induce physicians to infringe. I accord these opinions little weight. V.

The Skilled Person and Their Common General Knowledge [ 69 ] The notional person of skill in the art or " “skilled person” " is a legal construct embodying a number of concepts that inform a proper approach to resolving issues of claim construction, infringement, and validity in a patent action. [ 70 ] The skilled person possesses a level of skill and knowledge necessary to appreciate the nature and description of the invention at a technical level: Whirlpool at para 53 . This is the ordinary level skill of and knowledge of the particular art or science to which the patent relates: Free World at para 44 .

The skilled person embodies the " “common general knowledge” " (CGK) that is generally known and accepted in the field, and they are reasonably diligent in keeping up with advances: Pfizer Canada Inc v Teva Canada Limited , 2017 FC 777 at para 185 . [ 71 ] Where a patent relates to multiple scientific or technical fields, the skilled person can comprise a team of people: Amgen Inc v Pfizer Canada ULC , 2020 FC 522 at para 172 .

However, the skilled person is not defined on a claim-by-claim basis: Teva Canada Limited v Janssen Inc , 2018 FC 754 at para 236 , aff’d 2019 FCA 273 , leave to appeal to SCC refused, 39007 (7 May 2020). [ 72 ] Expert witnesses assist the Court by opining on the qualifications, relevant experience and knowledge of the notional skilled person, and how to assess the issues in dispute from the skilled person’s frame of reference in view of the relevant experience and knowledge they would bring to bear: Tetra Tech EBA Inc v Georgetown Rail Equipment Company , 2019 FCA 203 at para 88 , citing Free World at para 51 .

[ 73 ] Drs. Mielniczuk and Kapasi opine that the 770 Patent focuses on the use of macitentan in combination with a PDE5-I to treat a disease where vasoconstriction is involved, particularly PH and PAH. Therefore, the skilled person would be a cardiologist, pulmonologist, or general internist who is capable of identifying and diagnosing PH and PAH, and is capable of either providing direct treatment or referring patients to the appropriate specialist. Dr.

Kapasi adds that the skilled person may be part of a larger team that includes those with expertise in pre-clinical animal studies and pharmacology, and an interest in researching diseases related to the circulatory system. [ 74 ] Dr. McIvor opines that the skilled person is a physician with experience in treating patients in diseases wherein vasoconstriction is involved, including PAH. Since severe respiratory diseases, such as PAH, are treated by specialists, the skilled person would have specialized training.

The skilled person would have several years of practical clinical experience, as well as experience with or knowledge of the design of clinical trials and the

interpretation of their results. [ 75 ] While Dr. McIvor notes that parts of the 770 Patent are directed to those with experience in formulating pharmaceutical products and/or preclinical experiments, he adopted the perspective of the skilled person having the skill set of a physician. [ 76 ] Ms. Picard did not provide an opinion on the skilled person. In these Reasons, references to " “physician experts” " mean Drs.

Mielniczuk, Kapasi, and McIvor. [ 77 ] In this case, the parties and the physician experts have focused on the skilled person’s qualifications as a physician who would treat PH and PAH and in this regard, they do not materially disagree on the skilled person’s qualifications. While the 770 Patent is not limited to PH or PAH, based on statements in the specification that the disease intended to be treated is " “more preferably” " selected from hypertension and PH, " “in particular” " PH, and " “notably” " PAH, I accept that the 770 Patent is more focused on hypertension and PH.

Furthermore, I accept that treatment decisions and the management of patients with PAH are made by specialists having an understanding of PH and PAH. In my view, the skilled addressee of the 770 Patent would have knowledge and skills related to the treatment of diseases of vasoconstriction generally, but the skilled person would also have the specialized knowledge about PH or PAH and its treatments. [ 78 ] Dr. Mielniczuk’s and Dr.

Kapasi’s reports summarize the skilled person’s CGK as of 2008 regarding PH and PAH, including diagnosing and treating PAH in view of the diagnostic methods and treatments that were available at the time. Their main points are:

a) PAH is a subgroup of PH, characterized by elevated blood pressure in the pulmonary arteries due to a progressive remodeling and narrowing of the arterial walls;

b) The severity of a patient’s symptoms were graded according to a functional classification scheme developed by the World Health Organization (WHO); functional classes I-IV described progressive levels of incapacity and served to monitor disease progression and to inform the therapeutic approach;

c) PAH was rarely diagnosed early: patients often delayed seeking treatment because symptoms progress gradually; the diagnosis was often delayed because PAH symptoms can be attributed to more common cardiorespiratory diseases, and co-morbidities (particularly in older patients) can mask the disease; as a result, PAH was often diagnosed after other possibilities had been ruled out, and it was typically diagnosed in younger patients, particularly otherwise healthy young women;

d) By the time most patients began receiving treatment for PAH, their disease had progressed to WHO functional class III (fatigue, chest pain and other symptoms are experienced with less than ordinary activity) with a median survival of about five years;

e) As of 2008, there remained significant gaps in knowledge about the root causes of PAH and the efficacy and safety of potential treatments;

f) Due to the complexity of the disease, PAH patients were referred to specialized PAH clinics to initiate a therapeutic plan;

g) The therapeutic plan could include supportive medications (e.g., anticoagulants or diuretics); a small percentage of patients were treated with high-dose calcium channel blockers (calcium channel blockers were not approved for PAH in Canada so this was an " “off-label” " use); the vast majority of patients were considered for treatment with medications developed specifically for PAH;

h) As of 2008, there were three classes of PAH medications: prostacyclin analogues, ERAs, and PDE5-Is; the approved drugs in these classes were approved for late stage patients in WHO functional classes III or IV only, partly because clinical trials focused on patients in these classes and there was a lack of understanding of long-term prognosis;

i) As of 2008, epoprostenol, a prostacyclin analogue, was considered the most effective treatment but it had to be continuously infused into the pulmonary arteries using a pump and an intravenous (IV) catheter; treprostinil was another approved prostacyclin analogue, administered by IV or subcutaneous injection; the inhaled prostacyclin analogue iloprost was approved in the U.S. and Europe but not in Canada;

j) The three known ERAs were: bosentan (approved in Canada in 2001), sitaxsentan (approved in Canada in 2007, subsequently withdrawn from the market in 2010 due to concerns about liver toxicity), and ambrisentan (approved in the U.S.); all were orally administered drugs;

k) In 2008 (and today), ERAs were only approved for PAH; their " “off-label” " use for other disease states was (and is) extremely limited;

l) The PDE5-I sildenafil was approved to treat PAH in 2006; tadalafil had not yet been approved for PAH but was on the market as a treatment for erectile dysfunction; prior to their approval for PAH, both sildenafil and tadalafil were sometimes used " “off- label” " to treat PAH; both were orally administered drugs;

m) The 2008 treatment approach was to begin with monotherapy;

n) WHO functional class III patients would typically be prescribed an ERA or PDE5-I; class IV patients would typically beprescribed epoprostenol;

o) If the initial treatment failed, the patient would stop taking that intervention and progress to the next available treatment option;combination therapy was used in limited cases as a last resort, because there was no clinical trial evidence to support this approachand the drugs were costly and not covered by provincial programs or private drug plans. [79] Dr. McIvor’s report includes a background

section that describes vasoconstriction, PH and PAH, available drug treatments, andtreatment approaches (monotherapy versus combination therapy). Dr. McIvor acknowledges that he did not distinguish between whatwas known before and after March 2008, except in a general way. Dr. McIvor’s report states that the skilled person would have knownthe following as of 2008: information about vasoconstriction, PH and PAH, knowledge about different subtypes of PAH based onetiology, and knowledge of the WHO functional classes.

As a general matter, the skilled person was aware of the categories of drugs thatcould be used to treat diseases of vasoconstriction and in particular, PH and PAH; however, with respect to available drug treatments andtreatment approaches, the specific details about the drugs, and strategies relating to their use, would have continued to evolve afterMarch 6, 2008. In particular, Dr. McIvor notes that the SERAPHIN trial, a clinical trial designed to assess the effects of macitentan inpatients with PAH, was completed well after March 6, 2008. [80] Dr. McIvor did not disagree with Dr. Mielniczuk’s or Dr.

Kapasi’s description of the CGK as of 2008. [81] I accept that all the information described above (except the SERAPHIN trial, which was completed after 2008) was part of theskilled person’s CGK as of 2008. VI. Claim Construction A. Legal Principles [82] Claims are to be read in an informed and purposive way through the eyes of the skilled person: Free World at para 44. A purposiveconstruction will determine whether claim elements are essential or non-essential: Free World at para 50; Tearlab Corporation v I-MEDPharma Inc, 2019 FCA 179 at paras 30-34 [Tearlab].

If an essential element of a claim is different or omitted, there is no infringement:Free World at para 31. [83] Paragraphs 30-34 of Tearlab summarize key principles of claim construction: [30] The general principles of claim construction are now well established and were set out by the Supreme Court in threecases (Whirlpool at paras. 49-55; Free World Trust v. Électro Santé Inc., 2000 SCC 66, [2000] 2 S.C.R. 1024 at paras. 31-67[Free World Trust]; Consolboard Inc. v. MacMillan Bloedel (Sask.) Ltd., (SCC), [1981] 1 S.C.R. 504 at p.520 [Consolboard]).

These principles can be summarized as follows. [31] The Patent Act promotes adherence to the language of the claims, which in turn promotes fairness and predictability(Free World Trust at paras. 31(a), (

b) and 41). The words of the claims must, however, be read in an informed and purposiveway (at para. 31(c)), with a mind willing to understand (at para. 44). On a purposive construction, it will be apparent thatsome elements of the claimed invention are essential while others are non-essential (at para. 31(e)).

The interpretative taskof the court, in claim construction, is to separate and distinguish between the essential and the non-essential elements, and togive the legal protection to which the holder of a valid patent is entitled only to the essential elements (at para. 15). [32] To identify these elements, the claim language must be read through the eyes of a [skilled person], in light of thelatter’s common general knowledge (Free World Trust at paras. 44-45; see also Frac Shack at para. 60; Whirlpool at para.53).

As noted in Free World Trust: [51] …The words chosen by the inventor will be read in the sense the inventor is presumed to have intended,and in a way that is sympathetic to accomplishment of the inventor’s purpose expressed or implicit in the text ofthe claims. However, if the inventor has misspoken or otherwise created an unnecessary or troublesomelimitation in the claims, it is a self-inflicted wound.

The public is entitled to rely on the words used provided thewords used are interpreted fairly and knowledgeably. [Emphasis in the original.] [33] Claim construction requires that the disclosure and the claims be looked at as a whole “to ascertain the nature of theinvention and methods of its performance, … being neither benevolent nor harsh, but rather seeking a construction which isreasonable and fair to both patentee and public” (Consolboard at p. 520; see also Teva Canada Ltd. v. Pfizer Canada Inc.,2012 SCC 60, [2012] 3 S.C.R. 625 at para. 50).

Consideration can thus be given to the patent specifications to understandwhat was meant by the words in the claims. One must be wary, however, not to use these so as “to enlarge or contract thescope of the claim as written and … understood” (Whirlpool at para. 52; see also Free World Trust at para. 32). TheSupreme Court recently emphasized that the focus of the validity analysis will be on the claims; specifications will berelevant where there is ambiguity in the claims (AstraZeneca Canada Inc. v.

Apotex Inc., 2017 SCC 36, [2017] 1 S.C.R. 943at para. 31; see also Ciba at paras. 74-75). [34] Finally, it is important to stress that claim construction must be the same for the purpose of validity and for the purposeof infringement (Whirlpool at para. 49(b)). [84] As noted above, the material date for construing the claims is March 6, 2008.

[ 85 ] The parties introduced a joint claim chart outlining the plaintiffs’ and defendant’s proposed construction of the Asserted Claims, and it is attached as

Schedule A to these Reasons. As noted above, claim construction is a question of law for the Court to decide: Whirlpool at para 61 ; Zero Spill at para 41 . B. The Asserted Claims [ 86 ] The Asserted Claims in the 770 Patent read as follows (independent claims are in bold text): 1. A product containing the compound of formula (

I) below or a pharmaceutically acceptable salt of this compound, in combination with at least one compound having PDE5- inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved. 2. A product according to claim 1, wherein the compound having PDE5-inhibitory properties is sildenafil, vardenafil, tadalafil or udenafil. 3. A product according to claim 2, wherein the compound having PDE5-inhibitory properties is tadalafil. 4.

A product according to claim 2, wherein the compound having PDE5-inhibitory properties is sildenafil. 5. A product according to claim 2, wherein the disease wherein vasoconstriction is involved is hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris. … 10. A use of the compound of formula (

I) as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one compound having PDE5-inhibitory properties, or a pharmaceutically acceptable sale thereof, for the manufacture of a medicament intended to treat a disease wherein vasoconstriction is involved. 11. The use according to claim 10, wherein the compound having PDE5-inhibitory properties is sildenafil, vardenafil, tadalafil or udenafil. 12. The use according to claim 11, wherein the compound having PDE5-inhibitory properties is sildenafil or tadalafil. 13.

The use according to claim 12, wherein the compound having PDE5-inhibitory properties is sildenafil. 14. The use according to claim 12, wherein the compound having PDE5-inhibitory properties is tadalafil. 15. The use according to claim 10, wherein the disease intended to be treated is hypertension or pulmonary hypertension. 16. The use according to claim 15, wherein the disease intended to be treated is pulmonary hypertension. 17. The use according to claim 16, wherein the disease intended to be treated is pulmonary arterial hypertension. 18.

The use according to claim 17, wherein the compound having PDE5-inhibitory properties is sildenafil or tadalafil. 19. The use according to claim 17, wherein the compound having PDE5-inhibitory properties is sildenafil. 20. The use according to claim 17, wherein the compound having PDE5-inhibitory properties is tadalafil. 21. A use of the compound of formula (

I) as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one compound having PDE5-inhibitory properties, or a pharmaceutically acceptable sale thereof, for treating a disease wherein vasoconstriction is involved. 22. The use according to claim 21, wherein the compound having PDE5-inhibitory properties is sildenafil, vardenafil, tadalafil or udenafil. 23. The use according to claim 22, wherein the compound having PDE5-inhibitory properties is sildenafil or tadalafil. 24. The use according to claim 23, wherein the compound having PDE5-inhibitory properties is sildenafil.

25. The use according to claim 23, wherein the compound having PDE5-inhibitory properties is tadalafil. 26. The use according to claim 21, wherein the disease is selected from hypertension and pulmonary hypertension. 27. The use according to claim 26, wherein the disease is pulmonary hypertension. 28. The use according to claim 27, wherein the disease is pulmonary arterial hypertension. 29. The use according to claim 28, wherein the compound having PDE5-inhibitory properties is sildenafil or tadalafil. 30. The use according to claim 28, wherein the compound having PDE5-inhibitory properties is sildenafil. 31.

The use according to claim 28, wherein the compound having PDE5-inhibitory properties is tadalafil. C. Experts’ Opinions on Claim Construction [ 87 ] The physician experts, Dr. Mielniczuk, Dr. Kapasi, and Dr. McIvor, provided opinions on claim construction. Ms. Picard did not opine on claim construction. [ 88 ] Dr. Mielniczuk opined that the skilled person would read claim 1 as having two main components: (

i) a product containing macitentan in combination with at least one PDE5-I; (ii) for therapeutic use to treat a disease involving vasoconstriction. The skilled person would understand that the combination of macitentan and PDE5-I can be administered: (

i) by the same route and at the same time; (ii) by different routes at the same time; (iii) sequentially through the same or different route of administration. Dr. Mielniczuk’s report includes an appendix that summarizes the essential elements of claims 1-5 and 10-31. According to her opinion, the essential elements of claim 1 are:

a) a product containing macitentan (or its salt);

b) administered in combination with at least one PDE-5 inhibitor (or its salt);

c) where (

i) the product containing macitentan, and (ii) the PDE-5 inhibitor, are administered simultaneously, separately or sequentially; and

d) for therapeutic use in the treatment of a disease involving vasoconstriction. [ 89 ] Dr. Kapasi’s opinion on claim 1 is similar. Dr. Kapasi’s report attached an appendix that summarized the essential elements of claims 1-5 and 10-31. According to his opinion, the essential elements of claim 1 are:

a) a product containing macitentan (or its salt);

b) in combination with at least one PDE-5 inhibitor (or its salt);

c) for therapeutic use in the treatment of a disease where vasoconstriction is involved; and

d) administration of (

i) the product containing macitentan and (ii) the PDE-5 inhibitor simultaneously, separately or over a period of time. [ 90 ] Dr. McIvor opined that claim 1 covers macitentan where it is to be used in combination with a PDE5-I to treat a disease associated with the narrowing of blood vessels. The product may include both macitentan and a PDE5-I in the same dosage form, or only macitentan, provided it is used in combination with a PDE5-I to treat a disease involving vasoconstriction. Dr.

McIvor opined that the skilled person would understand the reference to using macitentan in combination with a PDE5-I for therapeutic use contemplates the two drugs being used together as part of the same treatment regime to treat the same disease, which differs from the mere concomitant use of two drugs without a recognition that they would be acting in concert to treat a disease. Dr. McIvor also opined that the skilled person would refer to the

definitions of " “simultaneously, separately and over a period of time” " in the 770 Patent disclosure, and he disagrees with Drs. Mielniczuk and Kapasi that " “over a period of time” " is synonymous with " “one after the other” " .

The skilled person would consider " “over a period of time” " to mean that the physician establishes an administration plan at the outset of treatment and this is distinguishable from the case where a second drug is started after first based on a physician’s evaluation of the patient’s condition, rather than a pre-defined treatment plan. [ 91 ] The physician experts agree that claims 2-4 limit the PDE5-I to specific compounds, and claim 5 limits the diseases to hypertension, PH, diabetic arteriopathy, heart failure, erectile dysfunction, or angina pectoris. [ 92 ] Dr.

Mielniczuk opined that independent claims 10 and 21 claim the use of macitentan in combination with a PDE5-I for a particular purpose. Claim 10 is for use to manufacture a medicament for treating vasoconstrictive diseases. Claim 21 is for use in treating a vasoconstrictive disease. The skilled person would understand that the macitentan and the PDE5-I would be in dosage form for administration to the patient. According to the table appended to Dr. Mielniczuk’s report, the essential elements of claim 10 are:

a) use of macitentan (or its salt);

b) for the manufacture of a medicament;

c) in combination with at least one PDE5-I (or its salt); and

d) where the medicament is intended to treat a disease involving vasoconstriction.

[ 93 ] Dr. Kapasi provides a similar opinion, and echoes that there is no limitation within claim 10 on how or when the combination is to be administered, but the 770 Patent as a whole is clear that various options are available. He summarizes the essential elements of claim 10 as follows:

a) use of macitentan (or its salt) for the manufacture of a medicament;

b) in combination with at least one PDE5-I (or its salt); and

c) where the medicament is intended to treat a disease where vasoconstriction is involved. [ 94 ] Dr. McIvor opined that the subject matter of claim 10 is analogous to claim 1—while claim 1 refers to a product, claim 10 refers to the preparation of a medication for the same purpose. Therefore, like claim 1, claim 10 covers the use of macitentan in combination with PDE5-Is to treat diseases involving vasoconstriction. [ 95 ] The physician experts agree that claims 11-14 are dependent on claim 10 and limit the PDE5-I to specific compounds.

Claims 15-20 are also dependent on claim 10 and specify the disease being treated and/or the PDE5-I. [ 96 ] Drs. Mielniczuk and Kapasi opine that claim 21 is for the use of macitentan in combination with a PDE5-I in treating a disease involving vasoconstriction. They state that the essential elements of claim 21 are:

a) use of macitentan (or its salt);

b) in combination with at least one PDE5-I (or its salt); and

c) for treating a disease where vasoconstriction is involved. [ 97 ] Dr. McIvor provides the same opinion and notes that the skilled person would understand claim 21 (like claims 1 and 10) to cover the use of macitentan to treat a disease involving vasoconstriction when used in combination with a PDE5-I. [ 98 ] Similar to the structure of claims 11-20, dependent claims 22-31 narrow the specific diseases and/or PDE5-Is. D. Parties’ Positions on Claim Construction [ 99 ] According to the joint claim chart, the parties’ proposed constructions for Asserted Claims appear to comprise identical essential elements.

Their proposed constructions for independent claims 1, 10, and 21 are set out below. Claim 1

a) a product containing macitentan (or its pharmaceutically acceptable salt);

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) for therapeutic use in the treatment of a disease where vasoconstriction is involved; and

d) administration of (

a) the product containing macitentan and (

b) the PDE5-I, simultaneously, separately or over a period of time. Claim 10

a) use of macitentan (or its pharmaceutically acceptable salt) for the manufacture of a medicament;

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) where the medicament is intended to treat a disease where vasoconstriction is involved. Claim 21

a) use of macitentan (or its pharmaceutically acceptable salt);

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) for treating a disease where vasoconstriction is involved. [ 100 ] Despite this apparent agreement, the parties disagree on the fundamental nature of the claims, and they disagree on the purposive construction of certain claim elements. [ 101 ] The first point of disagreement relates to the meaning of " “combination” " . Apotex asserts that " “combination” " would be understood to mean that macitentan and the PDE5-I are working in concert to treat the disease in question, and also, it would contemplate the use of macitentan and a PDE5-I where this is something a physician intended at the outset of treatment.

Apotex states that simultaneously, separately, and over a period of time would receive the

interpretation in the 770 Patent disclosure (at page 2), namely: “Simultaneously” or “simultaneous”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients by the same route and at the same time.

“Separately” or “separate”, when referring to a therapeutic use, means in the present application that the therapeutic use concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes. By therapeutic administration “over a period of time” is meant in the present application the administration of two or more ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins.

In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. [ 102 ] Based on these

definitions, Dr. McIvor opined that " “over a period of time” " means the physician establishes a combination administration plan for a patient at the outset of their treatment. [ 103 ] The plaintiffs do not dispute that " “combination” " would be understood to mean that macitentan and the PDE5-I are working in concert to treat the disease in question; however they disagree " “combination” " is limited to a combination treatment plan that is contemplated at the outset of treatment.

They argue that such limitation is inconsistent with the definition of " “over a period of time” " , which refers to two or more active ingredients administered at different times, including administration of the second ingredient several months after the first. The definition does not suggest that combination therapy is contemplated at the outset of treatment. Furthermore, limiting " “combination” " as Apotex suggests is inconsistent with a purposive construction in view of the CGK.

As of March 2008, monotherapy was the standard of care, and a physician typically did not establish a combination administration plan at the outset of treatment. If the initial treatment failed, another PAH medication would be considered; combination therapy was used in limited cases as a last resort. The skilled person would not interpret " “combination” " so as to exclude this primary method of administering two PAH therapies in 2008. [ 104 ] Furthermore, the parties disagree on the fundamental nature of the three claim sets.

Their dispute on this point affects whether, for claims 1-5, the Court is required to engage in an analysis of direct infringement or only an analysis of indirect infringement by inducement. Apotex’s position is that the 770 Patent is a use patent and all of the Asserted Claims are effectively use claims, which means it would not infringe any of the Asserted Claims directly, since pharmaceutical manufacturers do not use medications. The plaintiffs state Apotex’s position ignores the product and medicament elements of claims 1-5 and 10-20.

They say Apotex’s approach is similar to " “spirit of the invention” " approach that was rejected by the Supreme Court of Canada in Whirlpool and Free World . According to the plaintiffs, the Asserted Claims clearly fall into three, distinct claim sets: product claims (claims 1-5), Swiss-style use for the manufacture of a medicament claims (claims 10-20), and use claims (claims 21-31). Claims 21-31 have no product or medicament element, and they are the only claims to " “just the use” " of macitentan in combination with a PDE5-I to treat diseases involving vasoconstriction.

While claims 1-5 and 10-20 have use elements, this does not " “convert” " them into use claims. With respect to claim 1, the plaintiffs state that the fourth element

d) only requires that the product is for administration to a patient, and it does not require that administration to a patient take place. As a result, the plaintiffs assert that Apotex would infringe claims 1-5 directly, as well as by inducing others to infringe. They allege that Apotex would also infringe claims 10-20 directly, and infringe claims 21-31 indirectly, by inducing others to infringe. [ 105 ] The plaintiffs note that Apotex’s expert witness, Dr. McIvor, does not dispute the claim construction that was put forward by Drs. Mielniczuk and Kapasi. Dr.

McIvor does not dispute claim 1 to be a product claim, and he describes claim 10 as being related to the use of macitentan not merely as a treatment, but rather, for the manufacture of a medicament. [ 106 ] Apotex states the experts recognized that the subject matter of claims 21-31 is largely indistinguishable from the subject matter of claims 1-5 and 10-20, and none of the experts suggest that the 770 Patent is focused on a new product, new medicament, or new formulation.

Notwithstanding the reference to a " “product” " in claim 1 (and in dependent claims 2-5), the expert witnesses agreed that an essential element of these claims is the use of macitentan in combination with a PDE5-I and its administration to a patient (whether separately, sequentially, or over a period of time).

Similarly, though claim 10 states " “the manufacture of a medicament” " , claims 10-20 are fundamentally " “use claims” " directed at the use of macitentan in combination with a PDE5-I and how it is administered to patients. [ 107 ] Apotex submits the plaintiffs’ approach seeks to have the Court redraft the claims, and ignores that all of the Asserted Claims are fundamentally directed at the use of macitentan as a combination therapy. The plaintiffs’ approach is without foundation, as the law is clear that the claims of a patent are tethered to what has purportedly been invented: Patent Act , s 27(4).

A claim is not an " “added description of the invention, but a limitation of the description of the invention contained in the body of the specification” " : Merck & Co Inc v Pharmascience Inc , 2010 FC 510 at para 44 . [ 108 ] According to Apotex, a purposive claim construction orients the analysis at what has actually been invented. This logic was applied in Hoffman-La Roche Limited v Sandoz Canada Inc , 2021 FC 384 (at paragraphs 97-98 ) [ Hoffman-La Roche ] to reject the patentee’s attempt to enlarge the scope of " “use” " claims by recasting them as product claims.

In Hoffman-La Roche , Justice Manson rejected an argument that the asserted claims could be categorized into three distinct claim forms (German-style claims, Swiss-style claims, and " “product for use” " -style claims) as being an argument of form over substance: [97] Roche’s approach seeks a finding of claim form over substance . In doing so, it obscures the proper approach to claims construction. As discussed above, the claims construction exercise emphasizes a purposive construction.

In this case, the 654 and 997 Asserted Claims have been properly construed as use claims, as provided above. […] The alleged invention in this case resides in the use of pirfenidone, whether in the context of the 654 or 997 Patent, and not in the manufacture or composition of pirfenidone, a known compound. [Emphasis in original.] [ 109 ] According to Apotex, all of the physician experts opined that the use of macitentan to treat certain diseases is an essential element of the claims, and there is no reason for this Court—either as a matter of law or based on expert opinion—to rewrite the claims of the 770 Patent and thereby engage in an analysis of direct infringement.

E. Analysis on Claim Construction [ 110 ] On the first point of the parties’ disagreement, I find that claim 1 is not limited to the use of macitentan with a PDE5-I that is contemplated by the physician at the outset of treatment. [ 111 ] The 770 Patent specification does not indicate that any of the alternatives for therapeutic administration are tied to the timing of a prescribing physician’s decision. The

definitions of " “simultaneously, separately or over a period of time” " in the 770 Patent specification reflect a broad range of ways that the two or more active ingredients could be administered in combination. They are not limited to simultaneous administration, and could be administered at the same time via the same route, separately via different routes, or one after the other. [ 112 ] The skilled person would construe the claim in light of the CGK, including that: (

i) ERAs were only approved for PAH; (ii) monotherapy was the standard of care for PAH in 2008; (iii) combination therapy was used in limited cases as a last resort, when treatment with a single medication failed. Dr. Mielniczuk opined that physicians took a deterioration approach to PAH, only escalating therapy once the patient’s condition had worsened. Dr.

McIvor’s testimony in cross-examination was that monotherapy was the standard of care for PAH in 2008, and the most likely situation for combination treatment at that time would be an approach of giving a patient a drug, monitoring how they were doing, and if they did not improve, either move the patient to a different drug (sequential monotherapy) or add a second drug (combination therapy).

He agreed that this would fall within the meaning of " “combination” " in the 770 Patent. [ 113 ] For these reasons, I find that the skilled person would not read claim 1 so as to exclude what the skilled person would have considered to be a likely way that the claimed combination would be administered to PAH patients in 2008. [ 114 ] I will now turn to the parties’ dispute regarding the fundamental nature of the three claim sets of the Asserted Claims. For ease of reference, I have reproduced the language of each independent claim and the essential elements as proposed by the parties in the joint claim chart. (

a) Claims 1-5 Claim 1 Parties’ proposed construction 1. A product containing the compound of formula (

I) below or a pharmaceutically acceptable salt of this compound, in combination with at least one compound having PDE5-inhibitory properties, or a pharmaceutically acceptable salt thereof, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved

a) a product containing macitentan (or its pharmaceutically acceptable salt);

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) for therapeutic use in the treatment of a disease where vasoconstriction is involved; and

d) administration of (

a) the product containing macitentan and (

b) the PDE5-I, simultaneously, separately or over a period of time. [ 115 ] With respect to claim element d), the plaintiffs state that the Court must determine whether the element requires that administration to a patient take place, or solely that the product be for that administration. According to the plaintiffs, if the Court determines that element

d) requires only that the product be for that administration, Apotex would infringe claim 1 directly. [ 116 ] It is apparent that the word " “administration” " does not appear in claim 1, and the physician experts do not fully explain why they considered administration of the combination to be a separate, essential element. The 770 Patent specification defines simultaneously, separately or over a period of time as ways to administer the combination.

However, a plain reading of claim 1 ties " “simultaneously, separately, or over a period of time” " to " “for therapeutic use” " , while the parties’ proposed construction breaks that connection by identifying administration as a separate essential element. [ 117 ] The focus of purposive claim construction is on the language of the claims, which define the monopoly: Patent Act , s 27(4). The disclosure should not be used to enlarge or contract the scope of the claims as written and understood: Tearlab at para 33 , citing Whirlpool at para 52 and Free World at para 32 .

When the words of claim 1 are read in the order that they appear, the elements would be:

a) a product containing macitentan (or its pharmaceutically acceptable salt);

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved. [ 118 ] A plain reading of claim 1 does not suggest that administration to a patient is an essential element. I find that the skilled person would not consider administration to a patient to be an essential element. [ 119 ] I agree with the parties and their experts that " “in combination” " is an essential element.

I also agree with the parties and their experts that the claim language does not tie the element of " “in combination” " to the product that contains macitentan (the first essential element). Dr. McIvor opined that claim 1 covers a product that includes both macitentan and a PDE5-I, or a product that includes only macitentan provided it is used in combination with a PDE5-I. It necessarily follows that, in his opinion, the product of claim 1 is not limited to a product that contains both macitentan and a PDE5-I.

Although the plaintiffs’ experts did not expressly address whether claim 1 covers a product that contains macitentan and a PDE5-I, they opined that it covers a product that includes only macitentan provided it

is used in combination with a PDE5-I. Therefore, like Dr. McIvor, they did not tie " “in combination” " to the product. [ 120 ] In my view, the skilled person would read claim 1 to cover an embodiment where two active ingredients—macitentan and a PDE5- I—are combined either in the same dosage form or in a package that has two dosage forms, but would not read claim 1 to be limited to such embodiment. Claim 1 also covers a product that only contains macitentan, provided that the other claim elements are satisfied.

Where a product does not contain macitentan in combination with a PDE5-I, there must be a combination of the product and a PDE5-I. [ 121 ] The plain reading is consistent with the disclosure. The first paragraph of the 770 Patent, describing what the invention relates to, is a verbatim recitation of claim 1. In my view, claim 1 would therefore be a broad claim. [ 122 ] I find the elements of claim 1 are: Claim 1

a) a product containing macitentan (or its pharmaceutically acceptable salt);

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) for therapeutic use, simultaneously, separately or over a period of time, in the treatment of a disease wherein vasoconstriction is involved. [ 123 ] Claim elements are presumed to be essential: Mediatube Corp v Bell Canada , 2017 FC 6 at para 33 . On a purposive construction, I find that they are all essential elements. [ 124 ] The limitations that are added by the dependent claims 2-4 are straightforward and non-controversial. On a purposive construction, claims 2-5 add the following limitations: Claim 2 : the PDE5-I is sildenafil, vardenafil, tadalafil or udenafil. Claim 3 : the PDE5-I is tadalafil.

Claim 4 : the PDE5-I is sildenafil. Claim 5 : the disease wherein vasoconstriction is involved is hypertension, pulmonary hypertension, diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris. (

b) Claims 10-20 Claim 10 Parties’ proposed construction 10. A use of the compound of formula (

I) as defined in claim 1, or a pharmaceutically acceptable salt of said compound of formula (I), in combination with at least one compound having PDE5-inhibitory properties, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to treat a disease wherein vasoconstriction is involved.

a) use of macitentan (or its pharmaceutically acceptable salt) for the manufacture of a medicament;

b) in combination with at least one PDE5-I (or its pharmaceutically acceptable salt);

c) where the medicament is intended to treat a disease where vasoconstriction is involved. [ 125 ] As seen from the comparison, the parties’ proposed construction changes the order of the words in claim 10. Claim 10 reads (omitting the pharmaceutically acceptable salt for simplicity): a use of macitentan, in combination with at least one PDE5-I, for the manufacture of a medicament intended to treat a disease wherein vasoconstriction is involved.

The proposed construction of claim 10 is: a use of macitentan, for the manufacture of a medicament intended to treat a disease wherein vasoconstriction is involved, in combination with at least one PDE5-I. [ 126 ] Claim 10 is what is known as a " “Swiss-style” " claim, a recognized claim structure. As Justice Manson noted in Hoffman-La Roche , Swiss-style claims are not invariably construed in the same way and they do not " “automatically benefit from a literal construction” " : Hoffman-La Roche at para 102.

Recognizing the context-specific claims construction exercise, Justice Manson stated " “Swiss-style claims may be construed as use claims where the circumstances warrant.” " Justice Manson found that such a construction was warranted in that case.

He held that the Swiss-style structure of the claims at issue in that case could not be used to " “claim a novel product for use in a medicament when in fact that product used in a medicament is no longer novel” " : Hoffman-La Roche at para 102. [ 127 ] The plaintiffs argue that a purposive claim construction recognizes that a Swiss-style claim is a type of product claim. According to the plaintiffs, claim 10 has both a product element (a medicament) and a use element in that the medicament is used for treatment in combination with a PDE5-I.

Apotex argues that a purposive claim construction orients the analysis at what was invented. Claims 10-20 are fundamentally oriented at the use of macitentan, and in particular, how it is administered to patients. Apotex states this logic was applied in Hoffman-La Roche to reject the patentee’s attempt to enlarge the scope of use claims by recasting them as product claims. The plaintiffs counter that Apotex’s construction ignores the medicament element of 10. [ 128 ] As noted above, a purposive construction focuses on the language of the claims.

The words chosen by the patentee necessarily play a key role: ABB Technology AG v Hyundai Heavy Industries Co, Ltd , 2015 FCA 181 at paras 42-43 . In my view, the parties’ proposed construction strains the language of claim 10, rearranging the words of the claim to enlarge its scope. On a plain reading, claim 10 relates to a use for the manufacture of a medicament, and claim 10 ties " “in combination” " to that use. In other words, claim 10 claims the use of the combination—macitentan and a PDE5-I—for the manufacture of a medicament.

[ 129 ] Apotex’s concern, that the Swiss-style structure of claims 10-20 should not be used to claim a novel product for use in a medicament when the product is not novel, does not apply. This case does not raise the same concern as in Hoffman-La Roche , because claim 10 includes the element " “in combination” " , and the 770 Patent relates to a novel combination involving macitentan and a PDE5-I. [ 130 ] I find the elements of claim 10, which are all essential elements, to be: Claim 10

a) use of macitentan (or its ph

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