Janssen Inc. v. Sandoz Canada Inc.

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)

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Table of Contents

I.

Introduction ........................................................................................................................... 4

II. Background............................................................................................................................ 6

A. The Parties and the Nature of this Proceeding............................................................. 6

B. The 770 Patent ............................................................................................................. 8

C. The Circulatory System and Diseases Involving Vasoconstriction............................. 9

III. Issues and Relevant Dates ................................................................................................... 11

IV. Evidence .............................................................................................................................. 14

A. Dr. Zusman (Sandoz’s Expert Witness)..................................................................... 14

B. Dr. Vachiery (Plaintiffs’ Expert Witness).................................................................. 18

C. Dr. Chakinala (Plaintiffs’ Expert Witness)................................................................ 20

D. Dr. Clozel (Plaintiffs’ Fact Witness).......................................................................... 21

V. The Skilled Person............................................................................................................... 22

VI. Claim Construction.............................................................................................................. 28

VII. Validity................................................................................................................................ 31

A. Obviousness ............................................................................................................... 32

(1) The Test for Obviousness................................................................................. 32

(2) Introduction to Obviousness Analysis and Overview of the Parties’ Positions34

(3) Step 1: The Skilled Person and their Common General Knowledge (CGK) ... 38

(a) PH/PAH and Biological Pathways.......................................................... 39

(b) Treatment of PAH................................................................................... 41

(c) CGK – Opinion of Sandoz’s Expert Witness (Dr. Zusman)................... 43

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

Dr. Chakinala)......................................................................................... 46

(e) Analysis on CGK .................................................................................... 50

(4) Step 2: Identify the Inventive Concept ............................................................. 64

(5) Step 3: Differences Between the State of the Art and the Inventive Concept.. 67

(a) The Parties’ Submissions........................................................................ 67

(b) Analysis................................................................................................... 71

(6) Step 4: Was the Difference Obvious?............................................................... 74

B. Utility ......................................................................................................................... 82

(1) The Experts’ Opinions...................................................................................... 84

(2) Analysis ............................................................................................................ 87

C. Overbreadth................................................................................................................ 99

D. Sufficiency of Disclosure......................................................................................... 101

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VIII. Conclusion......................................................................................................................... 103

SCHEDULE A........................................................................................................................... 106

SCHEDULE B........................................................................................................................... 113

SCHEDULE C........................................................................................................................... 115

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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

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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.

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Sandoz advances four grounds of invalidity. Sandoz asserts that each Asserted Claim is

[8]

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.

A.

Background

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.

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[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.

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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

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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.

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[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.

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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.

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[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. 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.

[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.

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[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.

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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

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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

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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.

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[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

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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

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(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.

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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:

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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.

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[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

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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,

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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

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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

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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.

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[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

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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

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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.

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[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,

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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.

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[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

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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

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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.

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[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

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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

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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

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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.

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[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

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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

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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_Aand ET_B. ET_Areceptors are relatively

selective for ET-1 and mediate a vasoconstrictive effect. ET_Breceptors play a role in clearing

circulating ET-1. ET_Breceptors mediate local vasodilation by stimulating the release of NO and

prostacyclin.

[124] ERAs bind to and block ET_Aand/or ET_Breceptors, 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_Aand ET_Breceptors; 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

Page: 42

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

IV

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.

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.

[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_Ainhibitor, 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.

Page: 43

(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

Page: 44

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_Aand ET_B

receptors, with only slightly higher affinity for the ET_Areceptor. 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-

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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_Aand ET_Breceptors to prevent the pathological effects of endothelin

conditions such as PH and other conditions related to pulmonary vasoconstriction.

j. Inhibition of ET_Areceptors was widely considered to be a target for alleviating

vasoconstriction. Some studies suggested that in the pulmonary hypertensive

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state, blockade of both ET_Aand ET_Bis necessary to achieve maximal vasodilation

and other studies suggested a protective role of ET_Bin PH. In 2005, it was

unclear whether dual ET_A/ET_Breceptor antagonism or selective ET_Areceptor

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_Areceptor antagonism could produce beneficial effects because no

clear clinical use for selective ET_Bantagonists 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_Aantagonist 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_Bantagonist 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

Page: 47

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

Page: 48

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_Aand ET_Breceptors. Generally,

these two receptors have opposing functions and it was believed that increased

selectivity for ET_Amight 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_Aantagonists. Sitaxsentan and ambrisentan, the

only other ERAs besides bosentan that were close to approval as of 2006, are both

selective ET_Aantagonists.

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_Aand 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.

g. While sildenafil and other PDE5-Is were approved for erectile dysfunction, as of

2008, only sildenafil had been approved for PAH.

h. As of 2006, PAH therapies had only been studied and used for a short time.

There was a considerable knowledge gap regarding the best use of PAH

medications, including whether it was safe and effective to combine them.

Combination treatment would not have been the standard of care, given the lack

of evidence supporting this approach.

i. Even as of 2008, the standard of care for PAH treatment was monotherapy, for

several reasons: (i) the clinical trials conducted to that time had compared the

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treatments to placebo; (ii) the trials were relatively short (around 12 weeks) and

measured outcomes such as the 6-minute walking score, which was not

necessarily indicative of clinical outcome; (iii) most PAH treatments had only

recently become available and they were costly, which created hurdles to

prescribing more than one treatment at a time. If the disease was not being

managed effectively with one therapy, that therapy would be stopped and the

patient would be switched to another treatment option (sequential monotherapy).

j. The American College of Chest Physicians (ACCP) 2007 treatment guidelines for

PAH stated that combination treatments for PAH were being investigated but at

the time, there was no consensus evidence available on combination treatment.

The ACCP guidelines do not mention combination therapy with bosentan and

sildenafil, or with other ERAs and PDE5-Is. Similarly, the 2004 European

Society of Cardiology (ESC) guidelines do not mention combination therapy

using ERAs and PDE5-Is (sildenafil had not been approved for PAH when these

guidelines were published). The ESC guidelines do mention combination therapy

generally, but gave it the lowest level of evidence for efficacy (C) and the lowest

grade of recommendation short of being discouraged (Class IIb).

k. As of 2006, one clinical trial, STEP-1, showed that adding inhaled iloprost to

bosentan was safe and efficacious, although these results were limited by a

relatively small sample size (67 patients).

l. With the exception of STEP-1, trials investigating combination treatment were

either ongoing or inconclusive: (i) COMPASS-1 investigating bosentan and

sildenafil, and PACES investigating sildenafil and IV epoprostenol, were ongoing

and the results were not available; (ii) COMPASS-2, a large-scale, international

randomized controlled trial investigating bosentan and sildenafil, was still

enrolling patients as of March 2008; (iii) BREATHE-2 investigating bosentan and

epoprostenol did not meet its primary endpoints and the results were inconclusive;

(iv) COMBI investigating the addition of inhaled iloprost to bosentan was

terminated early after a futility analysis failed to show a positive effect; (v)

bosentan significantly decreased the plasma concentration of sildenafil when

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administered in combination (Paul et al (2005)), this would cause the skilled

person to have reservations on the potential benefits of combination treatment.

m. The papers cited by Dr. Zusman that discussed the idea of combination treatments

(Channick et al (2004); Lee & Channick (2005)) acknowledged that a

considerable amount of additional research was needed. The case studies he

relied on, including Hoeper et al (2004) and Minai & Arroliga (2006), were small,

retrospective case series/reports that did not provide sufficient evidence to

conclude that the combination of bosentan and sildenafil would work in PAH

patients. These case series did not reflect the standard of care and they were

meant to be hypothesis-generating. The skilled person would require more

information on whether bosentan could be combined with other PAH treatments,

let alone whether other ERAs could be combined.

n. As of 2006, some PAH patients received an additional treatment to their pre-

existing treatments; this was not common practice and the decision was based on

a hypothesis and limited, anecdotal evidence—it was not “evidence-based

medicine”. Generally, patients who received an additional treatment would have

been in circumstances where the treating physician had no other option for that

patient other than transplant or palliative care (salvage therapy).

(e)

Analysis on CGK

[134] As noted above, Sandoz takes the position that all of the prior art documents referred to

in Dr. Zusman’s report (including the patent references) would have formed part of the skilled

person’s CGK. Alternatively, Sandoz states all of the prior art documents would have formed

part of the state of the art.

[135] With some exceptions (such as the ACCP and ESC treatment guidelines), the parties’

experts do not provide a definitive opinion on whether a particular reference was or was not

generally known and accepted, so as to become part of the CGK. Instead, the experts’ opinions

Page: 51

of CGK focus on specific information referred to in the prior art references and how the skilled

person would have understood it.

[136] However, CGK and state of the art are distinct concepts with different roles in the

analyses of the issues at play. Identifying the CGK is the first step of the obviousness inquiry,

whereas a comparison of the inventive concept to the state of the art is the third. The state of the

art is the cumulative effect of the relevant prior art, and is understood by reading the prior art in

light of the CGK of the skilled person: Tearlab at para 81; Beloit at 294; Bourns Inc v Raychem

Corp (1997), [1998] RPC 31 at 40.

[137] In some cases, there may be little practical difference between CGK and the state of the

art, but in this case, Sandoz’s position is inconsistent with Dr. Zusman’s evidence.

[138] Dr. Zusman’s report states he was instructed about the differences between CGK and the

public knowledge known as “state of the art”. He notes the following instructions: public

knowledge includes any public disclosure before August 29, 2006, while CGK is derived from a

common sense approach to what would in fact be known to a skilled person who is good at their

job; in some industries, CGK may include patent specifications that are well known amongst

those versed in the art; CGK does not necessarily include scientific papers, no matter how wide

the circulation—a disclosure in a paper only becomes CGK when it is generally known and

accepted without question by the bulk of those engaged in the particular art.

Page: 52

[139] According to Dr. Zusman, only the information included in paragraphs 44-104 and 124-

125 of his report formed part of the CGK. Dr. Zusman does not mention many of the prior art

references in those paragraphs.

[140] Turning to the patent references in particular, Dr. Zusman only considers these references

in the section of his report that describes the state of the art. He does not opine that any of the

patent references formed part of the CGK. Certain patent references are said to be relevant

because they would have led the skilled person to test the combination of ERAs and PDE5-Is, or

they would have led the skilled person to combine macitentan with a PDE5-I. The following are

patent references from Dr. Zusman’s report:

a. US 2004/0063731 (US 731) published April 1, 2004, describes the use of PDE5-

Is in combination with at least one ERA;

b. US 5,250,534, published October 5, 1993, describes a class of PDE5-Is, including

sildenafil, for treating conditions that include angina, hypertension, and heart

failure;

c. US 5,859,006, published January 12, 1999, describes a class of PDE5-Is,

including tadalafil, for treating conditions that include hypertension, PH, angina,

and congestive heart failure;

d. WO 99/64004 (WO 004), published December 16, 1999, describes a class of

PDE5-Is said to be useful for the treatment of a wide range of “cGMP-associated”

conditions including hypertension, angina, heart failure, and erectile dysfunction;

the disclosure refers to classes of therapeutic agents that can be administered with

the PDE5-Is including, for endothelin antagonists, “bosentan, ABT-627, and those

described in U.S. Patent No. 5,612,359 and U.S. Patent Application Serial No.

601035,832”;

e. WO 00/27848, published May 18, 2000, describes PDE5-Is, including udenafil,

for treating erectile dysfunction;

Page: 53

f. WO 02/053557 (WO 557) is an Actelion patent application published July 11,

2002 and referenced at page 1 of the 770 Patent; WO 557 describes substituted

pyrimidine-sulfamides useful as ERAs, including ET_A-selective and dual acting; a

diagram of macitentan’s chemical structure is depicted among diagrams of

chemical structures said to be “another group of preferred compounds”, and

macitentan falls within claim 11, which lists 72 compounds by their chemical

names;

g. WO 2006/026395 (WO 395) is a patent application filed by the developer of

sitaxsentan (a selective ET_Aantagonist) and published on March 9, 2006; WO

395 describes combination therapies comprising at least one ET_Aantagonist and a

PDE5 inhibitor; it states that embodiments of the invention would be useful to

treat a number of vascular disorders, including erectile dysfunction, hypertension,

heart failure, complications of diabetes, and PAH; it includes claims to the

combination of an ET_Aantagonist and a PDE5 inhibitor for the treatment of a

number of conditions; although WO 395 states that non-selective ERAs would not

function as effectively, the skilled person having knowledge of the efficacy of

bosentan and sildenafil would not be dissuaded from studying combinations of

dual ERAs with PDE5-Is. WO 395 describes testing of sildenafil and sitaxsentan

in human subjects in pharmacokinetic drug interaction and efficacy studies and

states minimal drug interactions and side effects were observed in treatments with

the combination, while maintaining a successful therapeutic effect.

[141] I am aware that Dr. Zusman supported some statements within his CGK discussion by

citing to passages from three patent references (WO 004, WO 557, and WO 395); however, it is

unclear why he did so. The passages often referred to basic “textbook” information (such as the

definitions for hypertension and erectile dysfunction). While patent references often include

CGK as background information, Dr. Zusman does not indicate that these patent references in

particular would have been generally known and accepted in the field as of 2006 or explain why

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they would be. Sandoz has not established that WO 004, WO 557, WO 395, or the other patent

references relied on as prior art would have formed part of the skilled person’s CGK as of 2006.

[142] Sandoz argues that the reference to WO 557 in the 770 Patent constitutes an admission

that macitentan was disclosed (Shire Biochem Inc v Canada (Minister of Health), 2008 FC 538 at

para 25); however, the plaintiffs do not dispute that macitentan was disclosed in WO 557 or that

WO 557 is citable prior art. There is no admission that WO 557 was CGK, and the evidence

fails to establish that WO 557 was CGK.

[143] I will address the patent references under step 3 of the obviousness framework. I will

now turn to the substance of the parties’ submissions about CGK.

[144] Sandoz submits that much was known and generally accepted in the field, and the skilled

person would have expected that the combination of macitentan (an ERA) with a PDE5-I would

be useful for treating a disease involving vasoconstriction. As discussed above, it was known

that there were three classes of PAH-specific drugs, grouped according to their mechanism of

action as prostanoids, ERAs, and PDE5-Is. In addition, Sandoz submits it was CGK that: (i)

monotherapies were associated with short-term benefits and a proportion of patients would

deteriorate after initial improvement on monotherapy; (ii) the class effects of known drugs

extended beyond a shared mechanism of action, and included shared side effects, among other

shared effects; (iii) combination therapies (including an ERA and a PDE5-I) were known and

being used in the treatment of PAH in clinical practice, the scientific basis for combination

therapy was known and understood, and patients receiving combination therapy had a safe and

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effective response; and (iv) the specific combination of bosentan and sildenafil was used in

clinical practice.

[145] The plaintiffs paint a different picture of the CGK. They say there were only hypotheses

about class effects and about combination therapy, but the evidence supporting combination

therapy was not established to an acceptable level of confidence. The plaintiffs note that PAH

treatments had only recently become available and the clinical experience with them as of 2006

was limited. Only two ERAs (bosentan and sitaxsentan) and one PDE5-I (sildenafil) were

approved in at least one country for PAH. The best uses of the available medicines, including

whether or how to combine them, was unknown as of August 29, 2006.

[146] The plaintiffs state the standard of care for PAH in 2006 was monotherapy, due in large

part to the lack of scientific evidence relating to combinations. Only one randomized, controlled

clinical trial (BREATHE-2) had been published for any combination therapy, and it investigated

the combination of bosentan and the prostanoid epoprostenol in 33 patients but failed to meet its

clinical endpoint. The authors of BREATHE-2 cautioned against the use of its results, noting

that larger trials designed to assess the long-term safety and efficacy of this combination were

required. No clinical trial had been conducted or published on the combination of an ERA and

PDE5-I. Treatment guidelines from professional organizations, such as the ACCP and the ESC,

did not recommend any combination treatments for PAH, which reflects this lack of knowledge.

Dr. Vachiery opined that the ACCP guidelines stated that combination treatment was being

investigated, but there was no consensus evidence available at the time. He stated that there may

have been some patients who received an added treatment to their pre-existing treatment, this

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would have been a last resort by the physician (other than organ transplant or palliative care),

and it was not evidence-based medicine.

[147] The plaintiffs argue that Dr. Zusman is an expert “hired for the purpose of testifying”

(Beloit at 295; Bayer AG v Apotex Inc, 2007 FCA 243 at paras 24-25) who was not active in the

field at the relevant time and could only conduct his obviousness review with hindsight. The

Courts have repeatedly cautioned against a hindsight analysis in the obviousness inquiry:

Janssen Inc v Teva Canada Limited, 2020 FC 593 at para 169; Valeant Canada LP/Valeant

Canada SEC v Generic Partners Canada Inc, 2019 FC 253 at para 76; Bridgeview

Manufacturing Inc v 931409 Alberta Ltd, 2010 FCA 188 at para 50; Beloit at 295. The plaintiffs

say Drs. Vachiery and Chakinala, in contrast, are recognized experts who were active in the field

at all relevant times, and they can situate their analyses from the point of view of the skilled

person.

[148] Sandoz submits that the plaintiffs’ experts were overly dismissive of the prior art and

skeptical of any teachings that were not backed up by clinical trials. They adopted a pessimistic

and failure-seeking interpretation of the prior art. This is antithetical to the skilled person: Free

World at para 44; Arctic Cat Inc v Bombardier Recreational Products Inc, 2016 FC 1047 at para

164, aff’d 2018 FCA 125; Shire Biochem Inc v Canada (Minister of Health), 2008 FC 538 at

paras 64-65; Apotex Inc v Sanofi-Syntholabo Canada Inc, 2008 SCC 61 at para 25. According to

Sandoz, the plaintiffs’ experts elevated CGK to something accepted as a standard treatment

(which would require evidence from clinical trials), when CGK only needs to be a good basis for

further action. Dr. Zusman took a much more fair and reasonable approach, recognizing the

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skilled person would and did apply their knowledge to the care of an individual patient, even

knowing that some things had not yet been proven.

[149] Sandoz states Dr. Vachiery was dismissive of the case studies reported by Hoeper et al

(2004) and Minai & Arroliga (2006), failing to recognize that the skilled person would have been

aware of the prior art teachings and would have accepted these teachings as a good basis for

further action: Eli Lilly Canada Inc v Apotex Inc, 2020 FC 814 at para 130. Hoeper et al (2004)

reported on the long-term use of bosentan and sildenafil, stating “combining bosentan and

sildenaﬁl might be feasible in patients with IPAH. This combination was well tolerated by all

patients and proved to be highly efﬁcient.” Sandoz states that Dr. Vachiery admitted on cross-

examination that Hoeper et al (2004) reports on real patients and he admitted that some respected

physicians treating PAH patients were using this combination of therapies. According to

Sandoz, this case report provided a key teaching to the skilled person that bosentan in

combination with sildenafil was safe and effective. Sandoz states a number of later publications

relied on the Hoeper et al (2004) case report, including articles authored by Drs. Clozel,

Chakinala, and Vachiery. Additionally, Sandoz notes that in an editorial by McLaughlin &

Hoeper (2005), the authors stated, “[t]o us the question is not bosentan or sildenafil, but bosentan

and sildenafil?”

[150] As noted in the section outlining the evidence, Sandoz also points to Dr. Vachiery’s and

Dr. Chakinala’s ongoing relationships with the plaintiffs. I have been mindful of this criticism,

particularly since the relationships extended to projects for macitentan in particular, and Drs.

Vachiery and Chakinala did not disclose the details and extent of their involvement with the

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plaintiffs in their expert reports. I was attentive to possible bias and did not perceive any. Both

experts provided reasoned opinions and explained why their opinions diverged from those of Dr.

Zusman. They did not take unreasonable positions under cross-examination.

[151] Drs. Vachiery and Chakinala sometimes pointed to a lack of evidence in the prior art to

establish the safety and efficacy of combination treatments for PAH. This is not an irrelevant

consideration—it is tied to whether the skilled person would be led in a particular direction.

However, the 770 Patent does not disclose an advantage of the claimed combination in terms of

its safety or efficacy and I was mindful of this point in considering the difference between the

inventive concept and the state of the art, discussed under step 4.

[152] I agree with Sandoz that the plaintiffs’ experts were sometimes overly critical of

teachings in the prior art that were not backed up by controlled clinical trials. The plaintiffs’

experts state that case series/reports such as those published by Hoeper et al (2004) and Minai &

Arroliga (2006) were merely “hypothesis-generating”. In my view, however, the hypotheses had

already been generated and the results of retrospective case studies that reported on the co-

administration of two or more PAH drugs to patients would have been noteworthy because they

presented some evidence in support of this alternative therapy that was based on a combination

of two drugs.

[153] However, the skilled person would evaluate and take into account the quality of the

evidence. In this regard, I accept the opinions of Drs. Vachiery and Chakinala that the case

reports of bosentan and sildenafil administered to patients did not demonstrate that ERAs and

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PDE5-Is could be combined to treat PAH. Even for the particular combination of bosentan and

sildenafil, they provided preliminary rather than definitive evidence that this combination

worked for the patients who participated in the study. This was the authors’ conclusion in

Hoeper et al (2004): “the data presented provide preliminary evidence that the combination of

bosentan and sildenaﬁl may be safe and effective in selected patients with idiopathic PAH;

theoretical reasoning favours an effect of the combination, however switching to sildenaﬁl may

have been equally effective as combining bosentan and sildenaﬁl”. The acknowledgement that

the effect in these patients could have been due to sildenafil alone, rather than the combination of

bosentan and sildenafil is an important one.

[154] This question had not been resolved by the time the findings in Minai & Arroliga (2006)

were published, in August 2006. The authors reported observations in three patients who

received the addition of sildenafil as “rescue therapy”. In the first patient, sildenafil was added

as rescue therapy for worsening symptoms despite bosentan therapy, and in the other two

patients, sildenafil was used as rescue therapy to allow successful discontinuation of IV

epoprostenol or subcutaneous treprostinil sodium. The authors noted a “paucity of objective

evidence” and stated that in spite of preliminary reports, it remained unclear whether

combination therapy is truly superior to monotherapy.

[155] Also, Dr. Chakinala opined that the lack of scientific evidence regarding combination

therapy was reflected in the treatment guidelines. The ACCP treatment guidelines published in

2007 (based a review of the evidence up to September 1, 2006) treated combination therapy as

an open question. The ACCP 2007 treatment guidelines noted that trials were underway, and

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stated that until additional evidence becomes available, “add-on or combination therapy might be

considered in the context of enrollment into clinical trials”. Dr. Chakinala characterized the

recommendations for combination therapy in the ESC treatment guidelines as being “the lowest

level of evidence for efficacy” and “the lowest grade of recommendation short of being

discouraged”.

[156] Sandoz argues that Dr. Chakinala’s characterization is misleading. The ESC treatment

guidelines were admitted to be part of the CGK, and combination therapy were endorsed with the

same level of recommendation as anticoagulants, oxygen, calcium channel blockers and other

therapies that, despite a “low” level of evidence, were all being used to treat PAH patients.

Combination therapies that had not been the subject of randomized, controlled drug trials were

nonetheless endorsed in the treatment guidelines, rather than discouraged (which would have

been identified as a Class III recommendation).

[157] I disagree that Dr. Chakinala’s characterization is misleading. Combination therapy was

not specifically discouraged but the guidelines reflect a field that had not reached a consensus

about combination therapy and its role in treatment. Those in the field were watching the

developments, but they acknowledged that important questions had not been answered.

[158] Sandoz also points to statements in Channick et al (2004), Lee & Channick (2005), and

Lee & Rubin (2005). In Channick et al (2004), the authors stated that “bosentan may have a role

as part of a combination of drugs such as a prostanoid or sildenafil.” In Lee & Rubin (2005), the

authors included combination therapy in their recommended therapies for PAH and in Lee &

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Channick (2005), the authors confirmed that “the combination of bosentan and sildenafil is

already being used in clinical practice.” Dr. Chakinala testified that Channick et al (2004)

reiterated a hope in the field of using combination therapies, and admitted that the reference in

Lee & Channick (2005) about adding sildenafil to existing bosentan treatment was a type of

salvage treatment being used. Sandoz points out that despite claiming that nobody knows which

compounds to combine or the safety of combinations, Dr. Vachiery conceded that the

combination of bosentan and sildenafil had been used in clinical practice.

[159] I accept the opinions of Drs. Vachiery and Chakinala that the skilled person would not

have expected the combination of any ERA with a PDE5-I to be useful for treating diseases

involving vasoconstriction, including PAH. I find the skilled person would consider that there

was not an acceptable level of confidence that bosentan and sildenafil were effective as a

combination therapy. There was some positive and encouraging evidence in this regard;

however, the data were limited. The skilled person would have considered the evidence

insufficient to extrapolate the teachings about bosentan and sildenafil to a combination of any

ERA and a PDE5-I, based on shared mechanisms of action.

[160] In Channick et al (2004), the authors referred to a study of combined epoprostenol and

bosentan, and considered combination therapy of bosentan with other therapeutic agents as a

question that “remains to be answered”. Similarly, Lee & Rubin (2005) included combination

therapy as a possible consideration for patients who saw no improvement or deterioration on

monotherapy, but within the treatment algorithm, the authors added a question mark next to

“combination therapy” and a footnote indicating that trials studying add-on combination

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treatment regimens were underway. The statement in Lee & Channick (2005) about the

combination of bosentan and sildenafil in clinical practice is a reference to the Hoeper et al

(2004) case report, and for the reasons I noted above, this case report did not establish that

bosentan and sildenafil worked as a combination therapy.

[161] Furthermore, I disagree with Sandoz that the skilled person was steered toward the

combination of an ERA and PDE5-I in particular, or even steered toward combination therapy. I

find that the prior art references relied on by Dr. Zusman do not support a focus in the field on

therapy using an ERA and PDE5-I in combination, nor do they reflect a field that was moving in

that direction. Consistent with the expert opinions of Drs. Vachiery and Chakinala, these

references report on numerous, incremental advances without a discernable direction toward

ERAs used in combination, or even a direction toward combination therapy generally as of 2006.

I prefer the evidence of Drs. Vachiery and Chakinala as they were experts in the field at the time

and as a result, in a better position to opine on how the skilled person would have viewed the

body of research generally. In addition, I find that their opinions more closely reflect the

meaning of the prior art passages when read in context. The references Dr. Zusman relied on did

not focus on combination therapies, or on combination therapy using an ERA and PDE5-I in the

way that he did. The direction that Dr. Zusman discerns from his selection of passages from the

prior art references is not apparent from reading those passages in the context of the references

themselves, or in the context of the prior art references when considered together.

[162] Dr. Zusman refers to three review articles published close to August 2006: Lee &

Channick (2005), Lee & Rubin (2005), and McLaughlin & McGoon (September 2006). The