JANSSEN INC. v. ACTELION PHARMACEUTICALS LTD, 2022 FC 715

Date: 20220531 Docket: T-549-20 Citation: 2022 FC 715 Ottawa, Ontario, May 31, 2022 PRESENT: Madam Justice Pallotta BETWEEN: JANSSEN INC. AND ACTELION PHARMACEUTICALS LTD Plaintiffs and SANDOZ CANADA INC. Defendant PUBLIC JUDGMENT AND REASONS (Confidential Judgment and Reasons Issued May 12, 2022) Table of Contents I. Introduction 2 II. Background 2 A. The Parties and the Nature of this Proceeding 2 B. The 770 Patent 2 C. The Circulatory System and Diseases Involving Vasoconstriction 2 III. Issues and Relevant Dates 2 IV. Evidence 2 A. Dr. Zusman (Sandoz’s Expert Witness) 2 B. Dr.

Vachiery (Plaintiffs’ Expert Witness) 2 C. Dr. Chakinala (Plaintiffs’ Expert Witness) 2 D. Dr. Clozel (Plaintiffs’ Fact Witness) 2 V. The Skilled Person 2 VI. Claim Construction 2 VII. Validity 2 A. Obviousness 2

(1) The Test for Obviousness 2

(2) Introduction to Obviousness Analysis and Overview of the Parties’ Positions 2

(3) Step 1 : The Skilled Person and their Common General Knowledge (CGK) 2 (

a) PH/PAH and Biological Pathways 2 (

b) Treatment of PAH 2 (

c) CGK – Opinion of Sandoz’s Expert Witness (Dr. Zusman) 2 (

d) CGK – Opinions of Plaintiffs’ Expert Witnesses (Dr. Vachiery and Dr. Chakinala) 2 (

e) Analysis on CGK 2

(4) Step 2 : Identify the Inventive Concept 2

(5) Step 3 : Differences Between the State of the Art and the Inventive Concept 2 (

a) The Parties’ Submissions 2

(

b) Analysis 2

(6) Step 4: Was the Difference Obvious? 2 B. Utility 2

(1) The Experts’ Opinions 2

(2) Analysis 2 C. Overbreadth 2 D. Sufficiency of Disclosure 2 VIII. Conclusion 2

SCHEDULE A 2

SCHEDULE B 2

SCHEDULE C 2 I. Introduction [ 1 ] The plaintiffs, Janssen Inc. (Janssen) and Actelion Pharmaceuticals Ltd (Actelion), bring this patent action against Sandoz Canada Inc. (Sandoz) 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 the prescription medication OPSUMIT® in Canada. OPSUMIT® is a film-coated tablet containing 10mg of macitentan as the active ingredient, for the treatment of 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 disrupt 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 another biological pathway—the nitric oxide (NO) pathway. The vasorelaxation and anti-proliferative effects of the NO pathway are mediated by cyclic guanosine 3’,5’-monophosphate (cGMP). PDE5-Is work by blocking the effects of PDE5, an enzyme that breaks down cGMP. [ 5 ] Currently, Janssen is the only company authorized by Health Canada to sell macitentan as a prescription medication.

Sandoz seeks Health Canada’s approval to sell a generic prescription medication containing 10mg of macitentan as the active ingredient, for use alone or in combination with PDE5-Is. The plaintiffs allege Sandoz will infringe claims 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). [ 6 ] The 770 Patent relates to macitentan in combination with a PDE5-I to treat diseases wherein vasoconstriction is involved, including PAH.

Claim 21 is an independent claim of the 770 Patent that claims the use of macitentan in combination with a PDE5-I to treat a disease wherein vasoconstriction is involved. The other Asserted Claims depend directly or indirectly on claim 21 and they are narrower in scope. The dependent claims include limitations on the specific PDE5-I, the specific disease, or both. [ 7 ] For the purposes of this proceeding only, Sandoz concedes it would infringe the Asserted Claims if it is authorized to market macitentan tablets in Canada.

Sandoz defends the plaintiffs’ allegations on the basis that the Asserted Claims are invalid. [ 8 ] Sandoz advances four grounds of invalidity. Sandoz asserts that each Asserted Claim is invalid for one or more of the following reasons: (

i) the subject matter of the claim was obvious in view of what was already publicly known; (ii) the inventor had not demonstrated or soundly predicted the utility of the claimed invention; (iii) the claim is overly broad, claiming more than what the inventor actually made or disclosed; and (iv) the 770 Patent specification does not correctly and fully describe how macitentan in combination with a PDE5-I would be used to treat various diseases of vasoconstriction, failing to meet the sufficiency requirements of paragraphs 27(3) (

a) and (

b) of the Patent Act . [ 9 ] For the reasons below, Sandoz has not established that the Asserted Claims are invalid based on the alleged grounds of invalidity. The plaintiffs are entitled to a declaration that Sandoz would infringe the Asserted Claims by making, constructing, or using its macitentan tablets in Canada.

II. Background A. The Parties and the Nature of this Proceeding [ 10 ] 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 . [ 11 ] Sandoz is a pharmaceutical company with a head office in Boucherville, Quebec.

Sandoz is a " “second person” " within the meaning of subsections 5(1) and 6(1) of the PMNOC Regulations . [ 12 ] Sandoz filed an Abbreviated New Drug Submission (ANDS) with Health Canada, seeking authorization to market 10mg macitentan tablets based on their equivalent pharmaceutical and bioavailability characteristics, when compared to OPSUMIT®. [ 13 ] 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 Sandoz to address the patent list for OPSUMIT®. Sandoz served a Notice of Allegation on April 1, 2020 and the plaintiffs commenced this action in response. [ 14 ] 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. [ 15 ] By commencing this action, the plaintiffs triggered a stay that prevents the Minister of Health from issuing an NOC to Sandoz for up to 24 months, that is, before May 14, 2022, in order to allow time for the action to be heard and decided. B. The 770 Patent [ 16 ] 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: [ 17 ] 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. [ 18 ] 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. Some of the Asserted Claims do not include a limitation on the disease, while others are limited to: hypertension and pulmonary hypertension (PH), PH specifically, or PAH specifically. [ 19 ] 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.

Examples of such compounds are 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. The Circulatory System and Diseases Involving Vasoconstriction [ 20 ] Vasoconstriction is the constriction of the vasculature (arteries and veins) of the circulatory system. The vasculature can be divided into two circuits 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. [ 21 ] The 770 Patent specification lists particular diseases said to involve vasoconstriction: hypertension, PH (including PAH), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris.

The following provides a brief description of each disease of vasoconstriction listed in the 770 Patent. [ 22 ] Hypertension is a condition of persistently raised blood pressure in the systemic circulatory system (also known as systemic

hypertension and colloquially referred to as " “high blood pressure” " ). Long-term excessive force of the blood against the artery walls can damage the blood vessels and organs. [ 23 ] PH is a general term that describes abnormally high blood pressure in the pulmonary circulatory system. The blood pressure in the pulmonary circulation is far lower than in the systemic circulation. Abnormally high blood pressure in the pulmonary circulation is defined hemodynamically as a mean pulmonary arterial pressure of 25 mmHg or higher. [ 24 ] PAH is one subtype of PH.

As noted above, PAH is a progressive and incurable disease where the artery walls of 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. [ 25 ] Diabetic arteriopathy is a vascular disease caused by accelerated atherosclerosis, a condition in which plaque builds up and hardens in the arteries of diabetic patients. Over time this narrows the arteries, which limits the flow of oxygenated blood to the body. [ 26 ] Heart failure is a disorder of cardiac performance where the heart is unable to meet the blood supply needs of the body.

Patients with congestive heart failure may be breathless or fatigued during exertion, or even at rest. [ 27 ] Erectile dysfunction is an inability to obtain and maintain a penile erection sufficient for sexual intercourse. Penile erection is dependent upon a balance between vasoconstricting and vasorelaxing forces on cavernosal smooth muscle, which requires adequate levels of cGMP.

Inhibitors of enzymes that degrade cGMP, particularly PDE5-Is, aid in vasodilation and thus erection. [ 28 ] Angina pectoris is a disorder of vascular obstruction (a narrowing or blockage) of arteries that supply the heart muscle itself, which leads to chest pain or discomfort. III. Issues and Relevant Dates [ 29 ] The issues in this action relate to claim construction and validity of the Asserted Claims. Infringement of the Asserted Claims is not an issue that is before the Court.

Since Sandoz concedes that it would infringe the Asserted Claims for the purposes of this proceeding, the parties agree that the plaintiffs are not required to establish infringement of the essential elements of any Asserted Claims. [ 30 ] The 11 Asserted Claims of the 770 Patent must be construed—that is, interpreted—before there is an assessment of whether they are valid: 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 whom the patent is addressed (skilled person): Free World Trust v Électro Santé Inc , 2000 SCC 66 at para 44 [ Free World ]. [ 31 ] In this case, the parties and their expert witnesses disagree 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. [ 32 ] The parties’ disagreement on the skilled person affects their respective positions on issues of validity, but it does not affect their positions on claim construction. The parties and their experts agree on what the Asserted Claims mean. However, the Court is not required to accept the parties’ or the experts’ proposed construction. C laim 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. [ 33 ] Sandoz alleges that each of the Asserted Claims is invalid. The claims of a patent are presumed to be valid and Sandoz bears the burden of proving invalidity on a balance of probabilities. The parties’ joint statement of issues outlines the following validity issues in respect of the 770 Patent: (

i) Obviousness: Are any of the Asserted Claims invalid on the basis of obviousness? (ii) Utility: Are any of the Asserted Claims invalid for lack of utility (i.e. no demonstration of utility or sound prediction of utility)? (iii) Overbreadth: Are any of the Asserted Claims invalid for overbreadth (i.e. claiming more than what the inventor made or disclosed)? (iv) Sufficiency: Does the 770 Patent meet the sufficiency requirements of paragraphs 27(3) (

a) and (

b) of the Patent Act ? [ 34 ] The relevant date for construing the claims of a patent is the date the patent application was published. The application for the 770 Patent was published on March 6, 2008. [ 35 ] The same date, March 6, 2008, is the relevant date for determining whether the Asserted Claims are invalid for (iv) failing to meet the sufficiency requirements of paragraphs 27(3) (

a) and (

b) of the Patent Act . For simplicity, I will sometimes refer to the publication date as March 2008 or simply 2008. [ 36 ] The claim date (

section 28.1 of the Patent Act ) is the relevant date for determining whether the Asserted Claims are invalid for (

i) obviousness, (ii) lack of demonstrated or soundly predicted utility, and (iii) overbreadth. The application for the 770 Patent was filed in Canada on August 28, 2007, however, the application claimed the benefit of an earlier priority date based on applications that were filed on August 29, 2006 and October 19, 2006 (the October 19, 2006 application differs from the August 29, 2006 application in that it includes additional results from experimental testing on macitentan). [ 37 ] The parties do not allege any differences in the relevant prior art or the common general knowledge of the skilled person as of any of

these dates. Consequently, it makes no difference to the result if the earliest priority date is the claim date for the obviousness analysis, and the parties have addressed the question of obviousness as of August 29, 2006. For simplicity, I will sometimes refer to this date as August 2006 or simply 2006. [ 38 ] Similarly, the parties do not allege any material difference in assessing utility or overbreadth as of the priority date or the Canadian filing date. The parties have addressed those issues as of the Canadian filing date (August 28, 2007). For simplicity, I will sometimes refer to this date as 2007. IV.

Evidence [ 39 ] The parties agreed on a number of facts. They provided a joint scientific primer and a joint statement of facts. [ 40 ] The parties introduced expert evidence in support of their respective positions on claim construction and validity. Since Sandoz bears the burden on validity, the parties had agreed that Sandoz would serve its expert reports first and the plaintiffs would serve responding expert reports. Sandoz did not file a reply expert report. The trial evidence followed the same sequence, with Sandoz leading its evidence first. [ 41 ] Sandoz relied on the evidence of one expert witness, Dr.

Randall Zusman. The plaintiffs relied on the evidence of two expert witnesses, Dr. Jean-Luc Vachiery and Dr. Murali Chakinala. The plaintiffs also called Dr. Martine Clozel, the sole inventor named in the 770 Patent, as a fact witness. [ 42 ] The following summarizes each expert witness’ qualifications and provides an overview of the witnesses’ testimony. A. Dr. Zusman (Sandoz’s Expert Witness) [ 43 ] Dr. Zusman is a medical doctor specializing in cardiology at the Massachusetts General Hospital (MGH) in Boston, Massachusetts. Dr. Zusman received his M.D. from the Yale University School of Medicine in 1973.

He completed his internship, residencies, and chief residency at the MGH. Dr. Zusman has over 42 years of experience as a physician and clinical researcher. He was board certified in internal medicine in 1976 and cardiovascular diseases in 1983. Since 1982, Dr. Zusman has been the Director of Hypertension at the MGH Cardiac Unit. He is also an Associate Professor in Medicine at Harvard Medical School. [ 44 ] Dr. Zusman’s clinical activities include the care of patients with hypertension, PH, PAH, hyperlipidemia, cardiovascular risk factors, and other vascular diseases. Dr.

Zusman is active in professional societies including American College of Cardiology, American Heart Association, and American Society of Hypertension. He has been an editor and a member of the editorial board for several scientific journals on the topics of cardiology and hypertension. [ 45 ] At trial, the plaintiffs objected to the admissibility of Dr. Zusman’s report and his ability to testify. The plaintiffs first notified Sandoz and the Court that they intended to raise this objection during their opening statement at trial. The plaintiffs’ objection could have disqualified Dr.

Zusman from testifying at trial, and it should have been raised " “as early as possible in the proceeding” " , instead of the day of his scheduled testimony: Rule 52.5 of the Federal Courts Rules , SOR/98-106 . Nonetheless, I allowed the plaintiffs to argue their objection following their cross-examination on Dr. Zusman’s qualifications. The plaintiffs argued that Dr. Zusman is not properly qualified to provide expert evidence in respect of the issues in this action because he does not have the requisite expertise in PH and PAH, which they contend to be the focus of the 770 Patent.

While the plaintiffs presented a second argument, that the expertise as set out in Dr. Zusman’s proposed qualifications overreaches, it boiled down to the same concern: according to the plaintiffs, when Dr. Zusman’s evidence is properly narrowed to relate only to his actual expertise, there would be no purpose in having him testify because his opinion would only cover tangential issues. [ 46 ] Sandoz argued that while the commercial embodiment of macitentan is related to PAH, the 770 Patent is broader and does not exclude one disease condition over another.

The 770 Patent is about treatment of diseases of vasoconstriction, the skilled person does not change on a claim-by-claim basis, and Dr. Zusman is properly qualified to give expert evidence. He has experience treating patients with the diseases referred to in the 770 Patent, including seeing 300-400 patients a year with PH. While PAH is not the focus of his practice, it is also a rare disease: Hoffmann-La Roche Limited v Sandoz Canada Inc , 2021 FC 384 at para 139 . [ 47 ] The following morning I issued a ruling that I was satisfied Dr.

Zusman had the requisite expertise and qualifications to give expert opinion evidence on the material issues in dispute. I had not yet made any determinations regarding the focus of the 770 Patent and the characteristics of the skilled person to whom the patent is addressed. I stated that the importance of any specific expertise was a question that remained to be determined. I also noted that an expert witness may be in a position to opine on what the skilled person would know or understand, even if their qualifications do not mirror those of a skilled person: Halford v Seed Hawk Inc , 2006 FCA 275 at para 17 .

I held that Dr. Zusman’s evidence would be necessary to assist me in deciding material issues in this case and I was satisfied that Dr. Zusman had sufficient experience in the subject matter of his opinion to find that his report and testimony were admissible. [ 48 ] I noted that the extent of Dr. Zusman’s experience in the area of PH or PAH or the focus of his research or study were matters that could affect the weight that would be accorded to his evidence, or to parts of it. [ 49 ] Having reviewed the proposed qualifications put forward by Sandoz, I was satisfied that Dr.

Zusman was qualified to testify as an expert as follows: Dr. Randall M. Zusman is a practicing clinical cardiologist, researcher and professor in medicine with expertise in the diagnosis, management and treatment of hypertension, pulmonary hypertension (including pulmonary arterial hypertension), diabetic arteriopathy, heart failure, erectile dysfunction and angina pectoris, and other diseases wherein vasoconstriction is involved.

Dr. Zusman has expertise in the design, conduct and evaluation of clinical trials for therapies including in diseases wherein vasoconstriction is involved. Such expertise encompasses pre-clinical testing, including the use of animal models, and clinical trials of therapies of these diseases. [ 50 ] Dr. Zusman prepared an expert witness report dated July 29, 2021. The report sets out Dr.

Zusman’s opinions on a number of specific mandates related to the qualifications and knowledge of the skilled person, construction of the Asserted Claims, and the validity of the Asserted Claims. [ 51 ] The plaintiffs contend that a number of factors should negatively affect the weight accorded to Dr. Zusman’s opinions. According to the plaintiffs, Dr. Zusman is a relative stranger to ERAs, and has tangential knowledge of PH/PAH as a result of working with colleagues who are the true experts. They say he was evasive under cross-examination and revealed himself to be a professional witness (Dr.

Zusman has testified as an expert witness in a number of other cases) and an advocate for Sandoz. The plaintiffs further submit that Sandoz’s counsel provided the documents Dr. Zusman relied on, including 39 references cited as the prior art to support his opinion on obviousness. The plaintiffs allege that, as a physician who was not active in the PAH field at the relevant time, Dr. Zusman can only conduct the obviousness analysis with hindsight, and his opinions in this regard are therefore unreliable. I consider the weight that ought to be accorded to Dr. Zusman’s evidence in the context of my analysis below.

B. Dr. Vachiery (Plaintiffs’ Expert Witness) [ 52 ] Dr. Vachiery is a cardiologist, professor, and researcher. Dr. Vachiery received his M.D. from the Université Libre de Bruxelles in 1985 and became board certified in internal medicine in 1992 and cardiology in 1995. Dr. Vachiery has treated patients with various cardiovascular disorders since 1995 and he has specialized in PH and PAH. Currently, Dr. Vachiery is a Clinical Professor of Cardiology and Director of the Pulmonary Vascular Diseases and Heart Failure Clinic at the Hôpital Erasme – Cliniques Universitaires de Bruxelles, Belgium.

He is also a member of the pulmonary vascular disease interdisciplinary network at the International Society for Heart & Lung Transplant. [ 53 ] Dr.

Vachiery has been active on a number of councils and working groups related to PH, including by serving as co-chair of the Pulmonary Hypertension Council at the International Heart and Lung Society (2002-2005), chair of the Working Group on Pulmonary Circulation and Right Ventricular Function at the European Society of Cardiology (2006-2008), chair of the Working Group on Heart Failure at the Belgian Society of Cardiology (2008-2009), chair of the Pulmonary Hypertension Council at the International Society for Heart & Lung Transplantation (2018-2020), and Task Force member and

Section Editor of the European Guidelines on Pulmonary Hypertension (2009 and 2015). [ 54 ] Sandoz did not object to Dr. Vachiery’s proposed qualifications. I was satisfied Dr. Vachiery was qualified to provide expert opinion evidence according to the proposed qualifications that were put forward by the plaintiffs: Dr. Vachiery is a medical doctor, researcher, and clinical 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 analysis and

interpretation of data and results of pre-clinical experimentations, clinical drug trials, case reports and observational studies in the area of pulmonary medicine and cardiology, including the treatment of PAH. [ 55 ] Dr. Vachiery prepared an expert witness report dated October 29, 2021. The report responds to Dr. Zusman’s opinions on mandates related to the skilled person, construction of the Asserted Claims, and the validity of the Asserted Claims. [ 56 ] Sandoz contends that a number of factors should negatively impact the weight accorded to Dr. Vachiery’s opinion.

His assessment of the prior art was close-minded and he was quick to dismiss any teachings that were not backed by randomized, controlled clinical trials. Furthermore, Sandoz points to Dr. Vachiery’s ongoing relationship with the plaintiffs for more than 17 years, and states that his career has been and continues to be tied to and funded by the plaintiffs. I consider the weight accorded to Dr. Vachiery’s evidence in the context of my analysis below. C. Dr. Chakinala (Plaintiffs’ Expert Witness) [ 57 ] Dr. Chakinala is a pulmonologist (referred to as a respirologist in Canada), professor, and researcher.

He received his M.D. from Vanderbilt University in 1994 and completed his internship and residency at the University of Texas, Southwestern Medical Center between 1994 and 1997. In 2002, Dr. Chakinala completed fellowships at the Washington University School of Medicine, in Pulmonary and Critical Care Medicine, and General Medical Sciences. He is currently a professor of medicine at the Pulmonary and Critical Care Medicine Division of Washington University School of Medicine, where he is also the director of the Pulmonary Hypertension Care Center. [ 58 ] The focus of Dr.

Chakinala’s clinical practice and research as a clinician scientist is on pulmonary vascular disorders. He has been a staff physician and pulmonary consultant at Barnes-Jewish Hospital in Missouri since 2002. He is a pulmonary hypertension consultant at Washington University’s Pulmonary Fibrosis Foundation Care Center Network since 2016, and the Adult Congenital Heart Disease Center since 2017. [ 59 ] Dr. Chakinala is a member of the American College of Chest Physicians and Pulmonary Hypertension Association, among other professional societies.

He has also received awards for his work on pulmonary hypertension. [ 60 ] Sandoz did not object to Dr. Chakinala’s proposed qualifications as put forward by the plaintiffs. I was satisfied of Dr. Chakinala’s qualifications to testify as an expert as follows: Dr. Chakinala is a medical doctor, clinical researcher, and professor of pulmonary and critical care 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 analysis and

interpretation of data and results of pre-clinical experimentation, clinical drug trials, case reports and observational studies in the area of pulmonary medicine, including the treatment of PAH. [ 61 ] Dr. Chakinala prepared an expert witness report dated October 29, 2021. The report responds to Dr. Zusman’s opinions on mandates related to the skilled person, construction of the Asserted Claims, and the validity of the Asserted Claims. [ 62 ] Sandoz advances similar criticisms of Dr. Chakinala’s evidence as those advanced in respect of Dr.

Vachiery and argues that his evidence should be accorded less weight as a result. In addition, Sandoz argues that Dr. Chakinala made statements that were demonstrably false, gave opinions that were outside of his expertise, and opined on documents without reading them. I consider the weight accorded to Dr. Chakinala’s evidence in the analysis below. D. Dr. Clozel (Plaintiffs’ Fact Witness) [ 63 ] At the material times, Dr. Clozel was responsible for all pre-clinical drug development as Chief Scientific Officer, Head of Pharmacology, and Executive Vice President of Actelion.

She is the sole named inventor of the 770 Patent. [ 64 ] Dr. Clozel testified about her role in the conception of the invention of the 770 Patent and the experimental work that was conducted at Actelion prior to the filing date. [ 65 ] Dr. Clozel also testified about her role in the development of macitentan. Her work on ERAs started at Hoffmann-La Roche (Roche) where Dr. Clozel and her team conducted research that led to the discovery of ERAs, including a compound known as bosentan. In 1997, Dr.

Clozel and others left Roche to found Actelion and they continued their work in this area, including work on bosentan which was licensed from Roche. In November 2001, Actelion received regulatory approval from the U.S. Food and Drug Administration (FDA) to market bosentan (TRACLEER®) for the treatment of PAH. Bosentan was the first ERA to receive drug regulatory approval. [ 66 ] Actelion developed other compounds with ERA activity.

These included the compounds disclosed in now-expired Canadian Patent No. 2,437,675 titled, " “Novel Sulfamides and Their Use as Endothelin Receptor Antagonists” " , one of them being the compound now known as macitentan. V. The Skilled Person [ 67 ] The notional person of ordinary skill in the art or " “skilled person” " is a legal construct embodying a number of concepts that inform a proper approach to resolving issues in a patent action.

The concepts that are relevant to the claim construction and validity issues that arise in this action are set out below. [ 68 ] First, the skilled person possesses a level of skill and knowledge necessary to appreciate the nature and description of the invention at a technical level, and to put it into practice: Whirlpool at para 53 . This is the ordinary level of skill and knowledge of the particular art or science to which the patent relates: Free World at para 44 .

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).

The skilled person embodies the common general knowledge 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 . [ 69 ] Second, the skilled person adopts a fair and objective approach. They have a mind willing to understand and are trying to achieve success, not looking for difficulties or seeking failure: Les Laboratoires Servier v Apotex Inc , 2019 FC 616 at para 156 , citing Free World at para 44 .

They objectively apply the same standards to all issues, which relate to construction and validity in this case. [ 70 ] Third, the skilled person is not inventive. They pursue reasonable and logical enquiries, and can make deductions based on the information available, but they possess no imagination or inventiveness: Jay-Lor International Inc v Penta Farms Systems Ltd , 2007 FC 358 at para 75 , citing Beloit Canada Ltd v Valmet Oy , [1986] FCJ No 87, 8 CPR (3d) 289 at 294 (FCA) [ Beloit ] . [ 71 ] Fourth, the skilled person addresses each issue at the correct point in time.

They understand any differences in the relevant skills or knowledge as of each material date, and adopt the proper temporal frame of reference to analyze the issues, without hindsight. As noted above, in this case the parties do not identify any practical differences in the prior art or the relevant skills and knowledge of the skilled person at any material time between August 29, 2006 and March 6, 2008, which simplifies the analysis.

Nonetheless, the Court must guard against an ex post facto analysis and the dangers of a backward-looking perspective: Janssen Inc v Teva Canada Limited , 2020 FC 593 at para 169 . [ 72 ] Expert witnesses assist the Court by opining on the qualifications, relevant experience, and knowledge of the notional skilled person, and by providing expert evidence so as to put the Court in the position of the skilled person at the relevant time: Tetra Tech EBA Inc v Georgetown Rail Equipment Company , 2019 FCA 203 at para 88 , citing Free World at para 51 . [ 73 ] In this case, the parties and their experts disagree on how to define the skilled person in respect of the 770 Patent.

This disagreement only affects issues of validity, and particularly the

interpretation of the relevant prior art for assessing whether any of the Asserted Claims were obvious. As noted above, the parties agree on the construction of the Asserted Claims. [ 74 ] Sandoz’s expert witness, Dr. Zusman, opines that the 770 Patent relates to the use of macitentan administered to a patient in combination with at least one PDE5-I for the treatment of a disease wherein vasoconstriction is involved. Consequently, the skilled person is a clinician, that is, a specialist physician who would treat such diseases. Where the disease is one that involves the systemic

circulation, the specialist would be a cardiologist, endocrinologist, or nephrologist, with expertise in vascular medicine. Where the disease is one that involves the pulmonary circulation, the specialist would be a cardiologist, pulmonologist, or critical care physician. According to Dr. Zusman, pulmonologists focus on pulmonary circulation, but cardiology presents an overlap because cardiologists focus on both the systemic circulation and pulmonary circulation.

The clinician would have a good knowledge of the drugs and therapies to treat these diseases, including monotherapy and combination therapy, and would keep up to date with the research conducted in the field. [ 75 ] Since the 770 Patent describes tests for PDE5 inhibitory activity and experiments of the combined effects of macitentan and certain PDE5-Is in animal models, Dr.

Zusman further states that the skilled team would include a clinical or pre-clinical pharmacologist who might be a medical doctor and/or hold a Ph.D. in medicinal chemistry, pharmaceutics, or a related discipline, and have a few years of experience in the pharmaceutical industry. [ 76 ] The plaintiffs assert that Dr. Zusman’s opinion on the skilled person ignores the 770 Patent’s focus on the treatment of PH and PAH, and is belied by his own near-immediate focus on PH and PAH in his expert report. According to the plaintiffs, Dr.

Zusman broadly defines the skilled person as having expertise with diseases wherein vasoconstriction is involved because he lacks a sufficient level of expertise in PH and PAH, and his qualifications do not align with those of the skilled person. [ 77 ] The plaintiffs’ expert witnesses, Drs. Chakinala and Vachiery opine that the skilled person for the 770 Patent would have a narrower focus.

The skilled person would be a clinician—a cardiologist or pulmonologist—or a researcher who focuses their clinical and/or research interests on the treatment of patients with PH, and more specifically PAH, and who is knowledgeable about the treatment options. The skilled person would understand that the focus of the 770 Patent is on the use of an ERA (being macitentan) in combination with a PDE5-I for treating PAH.

The 770 Patent specification explicitly states that the disease intended to be treated according to the invention is " “more preferably” " selected from hypertension and PH, in particular PH, and notably PAH. [ 78 ] Drs. Vachiery and Chakinala state that a physician who does not have a particular focus on PH or PAH would not be a part of the skilled team because this would not be reflective of how PH or PAH is treated. In 2008 (and today) it was rare for a general cardiologist to treat PH or PAH patients—such patients were and still are referred to physicians who specialize in PH and PAH.

The PH/PAH specialist would be familiar with ERAs, and understand their role in treating PH, and particularly PAH, as of the relevant dates. [ 79 ] Also, Dr. Vachiery notes that the clinician would be part of a larger team that would include a pharmacologist, biologist or biochemist in the field of drug development who is interested in studying compounds in different animal models as part of pre-clinical development. [ 80 ] Sandoz asserts that Drs. Vachiery and Chakinala improperly adopted a claim-by-claim approach to defining the skilled person, rather than considering the 770 Patent as a whole. Dr.

Chakinala’s and Dr. Vachiery’s

definitions of the skilled person are problematic because they focus solely on PH/PAH and none of the other diseases to which the 770 Patent relates. [ 81 ] I find that the definition of the skilled person would not be limited to PH/PAH specialists. The 770 Patent is not limited to the treatment of PH and PAH. It describes the invention as being related to the treatment of a disease wherein vasoconstriction is involved. The experimental results included in the disclosure are not specific to PH/PAH.

While PH and particularly PAH are a focus of the patent, I disagree the skilled team consists solely of PH/PAH specialists. A number of claims are restricted to PAH, but as Sandoz correctly points out, the attributes of the skilled person do not change on a claim-by-claim basis. [ 82 ] Dr. Zusman acknowledges that the skilled person team includes a physician who would have a good knowledge of the drugs and therapies for treating PH and PAH, and would keep up to date with the research conducted in the field.

As a rare and potentially fatal disease largely treated by specialists, I find that a physician who treats patients with PH or PAH would have a fairly high level of knowledge of these conditions and their treatments. In my view, while the skilled team is not limited to those who focus on PH or PAH, the skilled person’s specialized knowledge in the area of PH and PAH is important to the issues in this action. ERAs were, at the material times, only being used to treat patients with PAH, and the majority of the prior art references relate to PH or PAH. [ 83 ] In

summary, I find the skilled person would be a specialist physician or researcher, who would have knowledge of systemic and pulmonary hypertension, the physiologic pathways involved in these diseases, and the drugs and therapies to treat them. The skilled person would have an understanding of the pre-clinical and clinical research and experiments used to develop drugs for systemic and pulmonary hypertension.

In my view, a specialist physician who treats systemic and pulmonary hypertension or researcher would have sufficient expertise in other diseases of vasoconstriction and the skilled person team does not need to include specialists for those diseases. VI. Claim Construction [ 84 ] An analysis of the skilled person’s common general knowledge (CGK) would normally precede claim construction; however, the parties agree on claim construction. Their disagreements on CGK do not affect their positions on claim construction, but they are central to the validity issues, and especially to obviousness.

My analysis of CGK is in the

section that addresses the issue of obviousness. [ 85 ] Claims are to be read in an informed and purposive way through the eyes of a skilled person, having regard to the CGK: Free World at para 44 . As noted above, the skilled person possesses the ordinary skill and knowledge of the art to which the patent relates, and approaches the construction of the patent claims with a mind willing to understand.

The application for the 770 Patent was published on March 6, 2008, which is the relevant date for construing the claims: Free World at paras 53-54 . [ 86 ] In actions where infringement is an issue, a purposive construction will determine whether claim elements are essential or non- essential: Free World at para 50 ; Tearlab Corporation v I-MED Pharma Inc , 2019 FCA 179 at para 31 [ Tearlab ]. There will be no infringement if an essential element of a claim is different or omitted: Free World at para 31 .

In view of Sandoz’s concession on infringement, the parties agree that the plaintiffs are not required to establish infringement of the essential elements for any of the

Asserted Claims. [ 87 ] The Asserted Claims read as follows: 21. A use of the compound of formula (

I) as defined in claim 1 [i.e., macitentan], 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. [ 88 ] The parties introduced a joint claim chart for the Asserted Claims that is attached as

Schedule A to these Reasons. As noted above, although the parties and their experts agree on the proper construction of the Asserted Claims, claim construction remains a question of law for the Court to decide: Whirlpool at para 61 ; Zero Spill at para 41 . [ 89 ] The construction of the Asserted Claims is straightforward based on the claim language, and I accept the construction proposed by the parties. For the purposes of determining the issues in this action, the following summarizes the key elements and

definitions: Claim 21 relates to the use of macitentan in combination with at least one PDE5-I for treating a disease wherein vasoconstriction is involved . • use means the administration of the compounds together, without limitation as to timing or route of administration; • PDE5-I is a compound that will inhibit the activity of the PDE5 enzyme by 50% at concentrations less than or equal to 1μM, measured according to the experimental protocol described in the 770 Patent; • disease wherein vasoconstriction is involved is a disorder of increased resistance to blood flow in the systemic or pulmonary circulation; the 770 Patent specification lists particular diseases said to involve vasoconstriction: hypertension, PH (including PAH), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris; the term disease wherein vasoconstriction is involved includes but is not limited to hypertension, PH (including PAH), diabetic arteriopathy, heart failure, erectile dysfunction or angina pectoris.

Claims 22-25 depend, directly or indirectly, on claim 21 and add limitations with respect to the specific PDE5-I: sildenafil, vardenafil, tadalafil or udenafil (claim 22); sildenafil or tadalafil (claim 23); sildenafil (claim 24); tadalafil (claim 25). Claims 26 depends on claim 21 and adds a limitation that the disease is hypertension or pulmonary hypertension . • hypertension is elevated blood pressure in the systemic circulation; • pulmonary hypertension (PH) is elevated blood pressure in the pulmonary circulation. Claim 27 depends on claim 26 and limits the disease to PH.

Claim 28 depends on claim 27 and limits the disease to pulmonary arterial hypertension . • pulmonary arterial hypertension (PAH) is a form of PH where the walls of the pulmonary arteries constrict and stiffen, straining the right side of the heart by requiring it to work harder to push blood through narrowed arteries. Claims 29-31 depend, directly or indirectly, on claim 28 and are limited specifically to the use of macitentan in combination with sildenafil (claim 30), tadalafil (claim 31), or both (claim 29) for treating PAH. VII. Validity [ 90 ] The 770 Patent is presumed to be valid: Patent Act , s 43(2).

Sandoz bears the onus of establishing invalidity on a balance of

probabilities. [ 91 ] Each claim is assessed independently for its validity: Patent Act , s 58. [ 92 ] Sandoz alleges that each of the Asserted Claims is invalid for obviousness, lack of utility, overbreadth, and insufficiency. [ 93 ] In the analysis of the validity issues, prior art references are identified using a short-form title.

Schedule B to these Reasons is a table that includes full titles of the prior art references referred to in the analysis. A. Obviousness

(1) The Test for Obviousness [ 94 ] The subject matter that is defined by a patent claim must be subject matter that would not have been obvious on the claim date to a person skilled in the art or science to which it pertains, having regard to the relevant prior art: Patent Act , s 28.3. [ 95 ] As the Federal Court of Appeal stated in Beloit (page 294), the test for obviousness is not to ask what competent inventors did or would have done. Inventors are by definition inventive.

The question to be asked is whether the skilled person, having no inventiveness, in light of the state of the art and the CGK as at the material date, would have come directly and without difficulty to the solution taught by the patent. [ 96 ] Sanofi-Synthelabo Canada Inc v Apotex Inc , 2008 SCC 61 (paragraph 67 ) [ Sanofi ] sets out a four-step framework for determining whether the subject matter of a claim is obvious: (1) (

a) Identify the notional “person skilled in the art”; (

b) Identify the relevant common general knowledge of that person;

(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3) Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept;

(4) Determine whether, when viewed without any knowledge of the alleged invention as claimed, those differences would have been obvious to the person skilled in the art, or whether they require any degree of invention. [ 97 ] This framework contemplates a flexible approach that must be applied contextually to the facts and circumstances of each claim: Allergan Inc v Sandoz Canada Inc , 2020 FC 1189 at para 154 [ Allergan ], citing Amgen Inc v Pfizer Canada ULC , 2020 FCA 188 at para 5 .

It is applied to the combination of the elements defining the invention, rather than to each of its discrete elements: Allergan at para 154 , citing Teva Canada Limited v Janssen Inc , 2018 FC 754 at para 86 . [ 98 ] Under step 4, it may be appropriate to consider whether the alleged invention would have been " “obvious to try” " in fields where advances often occur through experimentation. Relevant considerations for an " “obvious to try” " inquiry can include ( Sanofi at paras 67- 69):

(1) Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?

(2) What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?

(3) Is there a motive provided in the prior art to find the solution the patent addresses? [ 99 ] These considerations are not exhaustive. Other factors that might be considered include the actual course of conduct that culminated in the making of the invention: Sanofi at para 70. [ 100 ] Obvious to try does not mean " “worth a try” " ( Sanofi at para 65): Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions that were patentable.

The only research which would be worthwhile (because of the prospect of protection) would be into areas totally devoid of prospect. The “obvious to try” test really only works where it is more-or-less self-evident that what is being tested ought to work.

(2) Introduction to Obviousness Analysis and Overview of the Parties’ Positions [ 101 ] As part of his mandate, Dr. Zusman was asked to review 39 prior art documents provided by Sandoz’s counsel. Eight of the publications are patents or patent applications. Dr.

Zusman states that patent documents may not have been reviewed by a clinician of ordinary skill on a frequent basis, but advances in the field, including those described in patents and patent applications, formed part of poster presentations or publications and the skilled person would know how to find patent documents in a reasonably diligent online search. [ 102 ] In addition to these references, Dr. Zusman relies on review articles that relate to PAH or to ERAs as therapy in cardiovascular disease. One review

article was published in September 2006 and therefore post-dates the material claim date, but Dr. Zusman opines

that it reflects information that was known as of August 2006. Dr. Zusman also relies on references that are relevant to the experiments conducted at Actelion and described in the 770 Patent. [ 103 ] Sandoz takes the position that the prior art documents (including the patent references) would have formed part of the skilled person’s CGK; the skilled person knew how to find a patent. Alternatively, Sandoz states all of the prior art documents would have formed part of the state of the art. [ 104 ] The plaintiffs submit that by providing the prior art references to Dr.

Zusman, Sandoz created the danger of hindsight analysis— there was a " “selection” " of references without evidence that the skilled person would have focused on these references in particular. I do not see this criticism as important to this case. The plaintiffs had the opportunity to challenge Sandoz’s evidence on the basis that it does not reflect the state of the art, and their experts provided additional references, omitted by Dr. Zusman, that they allege to be relevant to a proper understanding of the state of the art and/or CGK.

The plaintiffs do not allege that any of Sandoz’s references are not " “citable” " as prior art, or that they would not have been located by a reasonably diligent search.

They do allege that not all the references would have formed part of the CGK, and a key difference between the parties and their experts in this case relates to how the skilled person would have interpreted and understood the information in the references at the relevant time. [ 105 ] Sandoz argues that the relevant prior art included numerous disclosures of the combination of an ERA with a PDE5-I to treat a disease involving vasoconstriction, including PH and PAH.

Accordingly, Sandoz asserts that the only difference between the CGK or state of the art and the subject matter of the Asserted Claims is that the Asserted Claims are limited to macitentan. This single difference applies equally to independent claim 21 and the dependent claims 22-31, because Sandoz asserts there was nothing inventive in limiting the disease or in limiting the PDE5-I. [ 106 ] The starting point for Sandoz’s obviousness allegation is that macitentan was not a new compound.

Sandoz states that Actelion admitted, on page 1 of the 770 Patent, that macitentan was disclosed in its earlier patent application WO 02/053557 (WO 557) that was published on July 11, 2002. WO 557 disclosed a group of compounds useful for treating diseases involving vasoconstriction due to their ERA activity. It also disclosed that the compounds could be used in combination with vasodilators or other therapeutics that treat high blood pressure or cardiac disorders, and macitentan is listed among 78 " “preferred compounds” " .

In Canada, WO 557 issued to Canadian Patent No. 2,431,675 (675 Patent). [ 107 ] Sandoz relies on Dr. Zusman’s opinion that all the Asserted Claims are obvious because it was already known by 2006 that the combination of an ERA and PDE5-I would be useful to treat a disease that involves vasoconstriction. Sandoz contends the skilled person would have expected, based on prior art disclosures of ERAs and PDE5-Is used in combination and the known " “class effects” " of ERA and PDE5-I drugs, that the combination of any ERA with a PDE5-I would be useful for treating diseases involving vasoconstriction, including PAH.

Sandoz maintains that the 770 Patent is not a " “selection patent” " in that it does not disclose or claim any particular advantage of macitentan as a selection over the ERAs that were disclosed in WO 557 and the 675 Patent. As such, advantages of macitentan itself, such as a level of safety or efficacy, must not inflate the claimed invention in order to widen the gap between the invention and the prior art. [ 108 ] Furthermore, Sandoz argues that it would have been obvious to try macitentan in combination with a PDE5-I.

The skilled person would be steered toward combining an ERA with a PDE5-I, which are orally administered medications, as opposed to combinations of compounds from other drug classes. For example, epoprostenol has a short half-life and requires continuous infusion into the pulmonary circulation by an intravenous catheter and pump, and so it was often reserved for patients with the most severe functional impairment. [ 109 ] The skilled person would also be steered toward macitentan as the particular ERA to combine with a PDE5-I.

Sandoz states there were a finite number of identified, predictable solutions because there were only three known pathways, a very limited number of PDE5- Is, a very limited number of ERAs, and macitentan was known to be the next generation ERA. The possible combinations of these therapies were " “incredibly limited” " , and the skilled person would have been led to macitentan.

Sandoz argues that in view of the CGK and the state of the art, it was self-evident to try the combination of macitentan and a PDE5-I to treat diseases involving vasoconstriction, and the skilled person would have expected that combination to be useful. [ 110 ] The plaintiffs argue that Sandoz’s position on obviousness is an exercise in hindsight.

The skilled person would not have expected that the combination of any ERA with a PDE5-I would be useful, and furthermore the skilled person would not have been led " “directly and without difficulty” " to the specific combination of macitentan with a PDE5-I: Beloit at 294. [ 111 ] In my view, there is a tension between Sandoz’s arguments that, on the one hand, the skilled person would expect any combination of an ERA and PDE5-I to be useful based on known class effects, and on the other hand, the combination of macitentan with a PDE5-I would have been obvious to try.

If the skilled person would expect any combination of an ERA and PDE5-I to work, there would be no need to identify macitentan from the numerous possible ERA candidates and test it in combination with a PDE5-I. According to this argument, specifying macitentan as the ERA to be combined with a PDE5-I can be thought of as an artificial limitation of the Asserted Claims because any ERA would be expected to work, and the Asserted Claims would be no more than an uninventive extension of Actelion’s monopoly under the 675 Patent (which included claims covering macitentan, among other compounds).

It seems to me that this argument and the obvious to try argument should have been presented as alternatives. As one aspect of my analysis, I have considered them as alternative arguments. [ 112 ] A large part of the evidence and argument was devoted to the CGK, the state of the art, and how the skilled person would have understood the relevant prior art references as of 2006. While I have considered all of the evidence and arguments in detail, I have focused on the key points in these Reasons. There is some repetition because of the overlapping nature of the parties’ arguments.

The parties did not clearly differentiate between CGK and the state of the art, which results in repetition in the analyses under steps 1 and 3 of the obviousness framework. The bulk of the analysis of the prior art references is found in the

section that addresses CGK, under step 1 of the obviousness framework. [ 113 ] I also note that, although claim 21 is not limited to any particular disease wherein vasoconstriction is involved, Sandoz’s obviousness argument and a majority of the prior art references in this case relate to PH, and particularly PAH. For this reason, my

analysis focuses on PAH and the CGK or state of the art in that field.

(3) Step 1 : The Skilled Person and their Common General Knowledge (CGK) [ 114 ] The first step in the obviousness analysis is to identify the skilled person and their CGK. [ 115 ] I have identified the skilled person above. The skilled person would be a specialist physician or researcher, who would have knowledge of systemic and pulmonary hypertension, the physiologic pathways involved in these diseases, and the drugs and therapies to treat them.

The skilled person would have an understanding of the pre-clinical and clinical research and experiments used to develop drugs for systemic and pulmonary hypertension. [ 116 ] The CGK consists of what the skilled person would generally know and accept at the relevant time, which is August 29, 2006 in this case: Sanofi at para 37; Mylan Pharmaceuticals ULC v Eli Lilly Canada Inc , 2016 FCA 119 at para 24 [ Mylan ]; Bell Helicopter Textron Canada Limitée v Eurocopter , 2013 FCA 219 at paras 64-65 [ Eurocopter ].

Information only migrates into the CGK if a skilled person would become aware of it and accept it as a good basis for further action: Mylan at para 24 . [ 117 ] As noted above, the CGK that is most relevant to the obviousness inquiry relates to the field of PH and notably PAH. I will begin with a

summary from the joint scientific primer provided by the parties. The parties agree that this information formed part of the skilled person’s CGK. I will then address aspects of the CGK where there is disagreement between the parties and the experts. (

a) PH/PAH and Biological Pathways [ 118 ] The disease: Pulmonary hypertension (PH) is a general term that describes abnormally high blood pressure in the pulmonary circulatory system. PAH is a subtype of PH where the constricted walls of the arteries of the lungs increase vascular resistance to blood flow.

If left untreated, the increased pressure strains the right side of the heart, which is responsible for pumping blood to the lungs, leading to heart failure. [ 119 ] There are three major biological pathways that affect blood pressure in the pulmonary vasculature, mainly by controlling the contraction and proliferation of smooth muscle cells in the pulmonary arteries. [ 120 ] Prostacyclin pathway : Prostacyclin released by endothelial cells in the pulmonary arteries acts as a potent vasodilator.

In patients with PAH, prostacyclin production is reduced and this contributes to vasoconstriction, blood clotting, and cell proliferation in the pulmonary arteries. Therapeutic use of prostacyclin analogues enables relaxation of the pulmonary arterial vasculature by targeting this pathway. [ 121 ] Nitric oxide (NO) pathway : NO is a potent vasodilator that relaxes vascular smooth muscle by stimulating the production of cGMP, which results in vasodilation. Phosphodiesterase (PDE) enzymes, particularly PDE5, break down cGMP.

In PH and PAH patients, NO levels are reduced and PDE5 levels are increased, which reduces cGMP levels and limits vasodilation in the pulmonary arteries. Therapeutic use of PDE5-Is targets the NO pathway by inhibiting PDE5, preventing the breakdown of intracellular cGMP and enhancing NO-mediated vasodilation. [ 122 ] Endothelin pathway : Endothelin is a potent vasoconstrictor synthesized and released by the endothelial cells lining the blood vessels. Vascular endothelial cells line the entire circulatory system.

There are three endothelin isoforms (variants) in humans, with ET-1 being the most important isoform in the cardiovascular system. ET-1 is a long-acting, potent vasoconstrictor that acts by binding to endothelin receptors. PAH patients have elevated levels of ET-1, which results in increased vasoconstriction and pulmonary arterial blood pressure. [ 123 ] There are two endothelin receptor subtypes, ET A and ET B . ET A receptors are relatively selective for ET-1 and mediate a vasoconstrictive effect. ET B receptors play a role in clearing circulating ET-1.

ET B receptors mediate local vasodilation by stimulating the release of NO and prostacyclin. [ 124 ] ERAs bind to and block ET A and/or ET B receptors, preventing them from being activated by ET-1. Two types of ERAs were known and either approved or under development for therapeutic use by 2006: (

i) dual ERAs that target both ET A and ET B receptors; and (ii) ERAs that preferentially or selectively bind to ET A . [ 125 ] The prostacyclin, NO, and endothelin pathways are illustrated in the diagram attached as

Schedule C to these Reasons. (

b) Treatment of PAH [ 126 ] WHO-FC : Physicians assess the severity of PAH by rating a patient’s degree of physical impairment, using a table developed by the New York Heart Association/World Health Organization that describes four functional classes. Class I reflects the lowest degree of impairment. Each class is described by functional limitations that reflect the severity of the disease.

The WHO-FC classes influence the choice of treatment, and help a physician to monitor disease progression. [ 127 ] The WHO-FC classes as they stood in August 2006 are set out in the table below: WHO-FC Description I Patients with pulmonary hypertension in whom there is no limitation of usual physical activity; ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain or pre-syncope.

II Patients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest, but normal physical activity causes increased dyspnoea, fatigue, chest pain or pre-syncope. III Patients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest, but less than ordinary activity causes increased dyspnoea, fatigue, chest pain or pre-syncope. IV Patients with pulmonary hypertension who are unable to perform any physical activity and who may have signs of right ventricular failure at rest.

Dyspnoea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity. WHO-FC Description [ 128 ] Approved drugs : As of 2006, drugs having a mechanism of action involving each of the three biological pathways had been approved. The prostacyclin analogues epoprostenol, treprostinil, and iloprost were approved in the mid-1990s, 2002, and 2004, respectively. One PDE5-I was approved to treat PAH (in 2005)—sildenafil. Tadalafil had been approved to treat erectile dysfunction and was sometimes prescribed " “off label” " for PAH.

Bosentan, a dual ERA, was the first ERA to be approved for PAH, in 2001. Sitaxsentan, a selective ET A inhibitor, was the second ERA to be approved. It was approved in Europe in 2006 but it was not approved in Canada until in May 2007. Ambrisentan was approved in the U.S. in 2007, and approved in Canada and Europe after March 2008. (

c) CGK – Opinion of Sandoz’s Expert Witness (Dr. Zusman) [ 129 ] Dr. Zusman describes the climate in the field as one that was focused on the three biological pathways noted above. He opines that in 2006, the skilled person was motivated to look for new drugs within the three known drug classes and furthermore, the concept of using combination therapy to target abnormalities in multiple pathways of a disease was well understood in medicine.

It was recognized that there may be important interactions between the NO, endothelin, and prostacyclin pathways—for example, prostanoids and NO had been shown to inhibit the release of endothelin—and as new therapies targeting each pathway emerged, there was a general interest in testing combinations of drugs for synergistic or additive effects. [ 130 ] In diseases wherein vasoconstriction is involved, combination therapy aimed at targeting multiple pathways that control vascular tone and growth had already been suggested as a means to improve patients’ functional capacity, and possibly survival.

The skilled person would, and did, test combinations of drugs from the different drug classes. According to Dr. Zusman, there was a preference to test combinations of orally administered ERAs and PDE5-Is, in view of their ease of administration, different mechanisms of action, and acceptable tolerability. [ 131 ] Dr. Zusman opines that the following formed part of the skilled person’s CGK as of August 2006 (and as of March 2008): a .

The prostacyclin pathway had been a focus of research for treating cardiovascular disease and was assumed to be useful in PAH very early.Epoprostenol was introduced as a PAH therapy in the early 1990s.While effective, epoprostenol has a short half-life at room temperature and must be continually administered using an intravenous catheter and pump.More stable prostacyclin analogues were developed; however, all forms of prostanoids were associated with similar limitations and side effects that restricted their use. b .

Researchers studied the potential for ERAs in vascular medicine throughout the 1990s and 2000s.In 2001, the FDA approved bosentan for the treatment of PAH in WHO-FC III or IV patients.Bosentan’s mechanism of action was well understood—it is a sulfonamide ERA that antagonizes both ET A and ET B receptors, with only slightly higher affinity for the ET A receptor.Bosentan was considered a significant addition to the treatment armamentarium against PAH as an orally active drug with a different mechanism of action than epoprostenol. c .

By the mid-2000s, several lines of evidence had demonstrated a strong relationship between endothelin system dysfunction and PAH, and antagonism of endothelin receptors was firmly established as a therapeutic target.Elucidation of the role of endothelin in the progression of pulmonary vascular disease, the demonstrated efficacy of ERAs, and long-term outcome data placed ERAs at the forefront of the treatment armamentarium against PAH, as a cornerstone therapy. d .

In 2004, the beneficial hemodynamic effects of combination therapy with bosentan and epoprostenol for PAH were shown in the BREATHE-2 clinical trial. e .

In the early 1990s, inhaled NO was viewed as one of the more effective therapies for treating PH and PAH, but it was inadequate as a long-term therapy due to its short half-life.It was known that: increased activity of cGMP-degrading PDEs in vascular smooth muscle cells causes vascular dysfunction, characterized by an increased vasoconstrictor response and reduced NO-dependant vasodilation; inhibiting PDE5 activity maintains high levels of cGMP, enhancing the relaxation cycle and vasodilating effects of endogenous NO; PDE5 is the main PDE expressed in the pulmonary vasculature. f .

Between the late-1990s and mid-2000s, three PDE5-Is—sildenafil, tadalafil, and vardenafil—were approved and shown to be highly effective for erectile dysfunction.It was known that they had similar affinities for PDE5 but varied in the pharmacokinetics and selectivity toward other PDEs.There was an expectation that PDE5-Is shared a common class effect on vasodilation due to their activity on PDE5 (Ghofrani et al (2004)).

Throughout the early to mid-2000s, researchers explored the use of different PDE5- Is to treat diseases wherein vasoconstriction is involved; their use to treat PAH became an area of research in the early 2000s (Ghofrani et al (2004)) and by 2006, sildenafil had been approved for PAH. g . By the mid-2000s, ERAs and prostanoids were used with PDE5-Is in combination therapies for patients with idiopathic PAH (IPAH), that is, where the underlying cause of PAH is unknown: (

i) even before sildenafil was approved for PAH, sildenafil and bosentan were used in clinical practice—a case series involving 9 patients with IPAH reported that the combination of bosentan

and sildenafil was well tolerated and highly efficient (Hoeper et al (2004)); (ii) in a separate study, the potential long term benefits of combination therapy with bosentan and sildenafil in 3 patients was reported in August 2006 (Minai & Arroliga (2006)); (iii) sildenafil exerted a marked synergistic effect when administered following an inhaled dose of iloprost; and (iv) sildenafil was being studied in combination with intravenous epoprostenol. (For points (iii) and (iv), Dr. Zusman relies on statements made by the authors of Minai & Arroliga (2006)). h .

Based on the redundant pathways that control vascular tone and cell proliferation, it was thought that endothelin receptor blockade would ultimately be used as part of a combined dose regimen.By 2005, if poor prognostic signs persisted after 3 months of bosentan, clinicians looked to add a prostanoid or sildenafil to the treatment regime, depending on the clinical circumstance.In doing so, physicians hoped to gain additional benefits from a class of medication that had a different mechanism of action than bosentan. i .

By 2004, data had emerged to support the particular combination approach with bosentan and sildenafil and/or prostanoid.The use of combination therapy was considered to have the potential to minimize dose-related side effects of bosentan.Further, dual ERAs were considered to share a common class effect in blocking both ET A and ET B receptors to prevent the pathological effects of endothelin conditions such as PH and other conditions related to pulmonary vasoconstriction. j .

Inhibition of ET A receptors was widely considered to be a target for alleviating vasoconstriction.Some studies suggested that in the pulmonary hypertensive state, blockade of both ET A and ET B is necessary to achieve maximal vasodilation and other studies suggested a protective role of ET B in PH.In 2005, it was unclear whether dual ET A /ET B receptor antagonism or selective ET A receptor antagonism would confer the most therapeutic benefit in cardiovascular disease or in PAH.As of August 2006, the general view was that dual receptor antagonism or selective ET A receptor antagonism could produce beneficial effects because no clear clinical use for selective ET B antagonists had yet been defined, and ET B receptor blockade alone impaired the clearance of endothelin and reduced NO-mediated vasodilation (Lee & Channick (2005); Lee & Rubin (2005)). k .

By the mid-2000s, other ERAs were in the research pipeline, including: (

i) the selective ET A antagonist sitaxsentan, which was approved for PAH in Canada and the US in 2006 and 2007, and the subject of investigational studies with a PDE5-I for hypertension and PH; sitaxsentan was subsequently withdrawn from the market due to liver toxicity; (ii) Actelion’s dual ET A /ET B antagonist tezosentan, which was being studied for acute and chronic heart failure; (iii) a selective ET A antagonist darusentan, which was being studied for heart failure; (iv) additional ERAs that were being studied in laboratory models, animal studies or Phase I (healthy human volunteer) clinical trials. (

d) CGK – Opinions of Plaintiffs’ Expert Witnesses (Dr. Vachiery and Dr. Chakinala) [ 132 ] Drs. Vachiery and Chakinala disagree with Dr. Zusman on the CGK. While they do not materially disagree with Dr. Zusman about a number of the underlying " “facts” " that were reported in the scientific literature, they strongly disagree with Dr. Zusman about the conclusions that he suggests the skilled person would draw from them. Drs.

Vachiery and Chakinala opine that the skilled person would recognize the hierarchies of scientific evidence, and that these hierarchies play a role in how the skilled person would have evaluated and understood the available information. PAH therapy was at an early stage in 2006. A number of the studies Dr. Zusman relied on to support his opinion of the skilled person’s CGK would not have been generally known and accepted in the way that Dr. Zusman presents. [ 133 ] Dr. Vachiery’s and Dr. Chakinala’s opinions of the CGK are as follows: a .

The first pharmaceutical intervention that was approved specifically for PAH was epoprostenol.It was approved in 1995.Before then physicians were forced to treat patients with drugs that do not address PAH directly, and often the only true treatment was lung or heart and lung transplantation.Epoprostenol was (and still is) an effective drug. b .

Bosentan was the second drug approved for PAH, and the first approved oral therapy.Since epoprostenol requires continuous, intravenous infusion, bosentan represented a sea-change in PAH treatment.It was approved in 2001 and essentially remained the only approved ERA up to August 2006.Two other ERAs had just been approved or were close to approval in certain countries at that time: ambrisentan (results of Phase 3 clinical trials in 2006, approved in the US in 2007 and approved in Europe after 2008) and sitaxsentan (approved in Europe as of August 2006, and approved later in Canada, but then withdrawn from the market worldwide). c .

Approved therapies were tied to the WHO-FC classes: (

i) as of 2006, and even as of 2008, there were no approved PAH-specific drugs for WHO-FC Class I patients; the primary goal of treating PAH was to slow disease progression, as opposed to what is now a more aggressive treatment goal of improving patient outcomes, and consequently, Class I patients were often monitored for clinical worsening and only started on treatment when their symptoms had progressed; (ii) as of 2008 there were relatively few treatment options for patients in Class II because the studies had focused on more seriously ill patients in Classes III/IV; patients in Class II would typically be started on sildenafil, or alternatively trepostinil, the only non-oral therapy that was approved for Class II patients; (iii) for patients in Class III, approved oral therapies included bosentan, and later sildenafil, ambrisentan, and sitaxsentan (precisely when each of these therapies were available depended on where the patient resided); the prostanoids trepostinil, iloprost, and epoprostenol were also approved for Class III; (iv) while bosentan was approved for Classes III and IV, patients in Class IV have difficultly breathing even at rest and the primary intervention for Class IV patients was epoprostenol by infusion due to its presumed superior efficacy; Class IV patients would also be considered for transplantation or palliative care. d .

Bosentan is a dual ERA that binds to both ET A and ET B receptors.Generally, these two receptors have opposing functions and it was believed that increased selectivity for ET A might provide greater efficacy and/or fewer side effects compared to dual ERAs.Interest in the field was somewhat moving away from dual ERAs, toward selective ET A antagonists.Sitaxsentan and

ambrisentan, the only other ERAs besides bosentan that were close to approval as of 2006, are both selective ET A antagonists. e . The skilled person would not agree that ERAs and PDE5-Is have a class effect just because they act on the same receptors.This was especially true for ERAs because it was unclear to the skilled person whether differences in ET A and ET B receptor activity would make a difference in treating PAH patients.And since only one dual ERA had been approved, there was also the potential for significant differences between dual ERAs. f .

ERAs were not without limitations, and they did not offer a cure for PAH (PAH remains incurable today); as of 2008, epoprostenol remained the preferred treatment for patients with severe PAH.

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