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)  
Page: 2  
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  
Page: 3  
VIII. Conclusion......................................................................................................................... 103  
SCHEDULE A........................................................................................................................... 106  
SCHEDULE B........................................................................................................................... 113  
SCHEDULE C........................................................................................................................... 115  
Page: 4  
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  
 
Page: 5  
pressure, but they do so by enhancing the vasorelaxation and anti-proliferative effects of another  
biological pathwaythe 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.  
Page: 6  
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.  
   
Page: 7  
[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.  
Page: 8  
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  
 
Page: 9  
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.  
 
Page: 10  
[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.  
Page: 11  
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 construedthat 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.  
 
Page: 12  
[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.  
Page: 13  
[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.  
Page: 14  
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  
   
Page: 15  
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  
Page: 16  
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.  
Page: 17  
[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  
Page: 18  
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.  
Page: 20  
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  
 
Page: 23  
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,  
Page: 24  
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  
Page: 25  
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  
cliniciana cardiologist or pulmonologistor a researcher who focuses their clinical and/or  
research interests on the treatment of patients with PH, and more specifically PAH, and who is  
Page: 26  
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 patientssuch 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.  
Page: 27  
[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  
 
Page: 29  
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  
   
Page: 33  
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.  
 
Page: 35  
[104] The plaintiffs submit that by providing the prior art references to Dr. Zusman, Sandoz  
created the danger of hindsight analysisthere 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  
Page: 36  
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  
Page: 37  
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  
Page: 38  
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  
 
Page: 40  
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  
Page: 41  
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, ETA and ETB. ETA receptors are relatively  
selective for ET-1 and mediate a vasoconstrictive effect. ETB receptors play a role in clearing  
circulating ET-1. ETB receptors mediate local vasodilation by stimulating the release of NO and  
prostacyclin.  
[124] ERAs bind to and block ETA and/or ETB receptors, preventing them from being activated  
by ET-1. Two types of ERAs were known and either approved or under development for  
therapeutic use by 2006: (i) dual ERAs that target both ETA and ETB receptors; and (ii) ERAs  
that preferentially or selectively bind to ETA.  
[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 ETA inhibitor, was  
the second ERA to be approved. It was approved in Europe in 2006 but it was not approved in  
Canada until in May 2007. Ambrisentan was approved in the U.S. in 2007, and approved in  
Canada and Europe after March 2008.  
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(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 pathwaysfor example, prostanoids and NO had been shown  
to inhibit the release of endothelinand 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  
understoodit is a sulfonamide ERA that antagonizes both ETA and ETB  
receptors, with only slightly higher affinity for the ETA receptor. Bosentan was  
considered a significant addition to the treatment armamentarium against PAH as  
an orally active drug with a different mechanism of action than epoprostenol.  
c. By the mid-2000s, several lines of evidence had demonstrated a strong  
relationship between endothelin system dysfunction and PAH, and antagonism of  
endothelin receptors was firmly established as a therapeutic target. Elucidation of  
the role of endothelin in the progression of pulmonary vascular disease, the  
demonstrated efficacy of ERAs, and long-term outcome data placed ERAs at the  
forefront of the treatment armamentarium against PAH, as a cornerstone therapy.  
d. In 2004, the beneficial hemodynamic effects of combination therapy with  
bosentan and epoprostenol for PAH were shown in the BREATHE-2 clinical trial.  
e. In the early 1990s, inhaled NO was viewed as one of the more effective therapies  
for treating PH and PAH, but it was inadequate as a long-term therapy due to its  
short half-life. It was known that: increased activity of cGMP-degrading PDEs in  
vascular smooth muscle cells causes vascular dysfunction, characterized by an  
increased vasoconstrictor response and reduced NO-dependant vasodilation;  
inhibiting PDE5 activity maintains high levels of cGMP, enhancing the relaxation  
cycle and vasodilating effects of endogenous NO; PDE5 is the main PDE  
expressed in the pulmonary vasculature.  
f. Between the late-1990s and mid-2000s, three PDE5-Issildenafil, tadalafil, and  
vardenafilwere 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-  
Page: 45  
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 practicea 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 ETA and ETB receptors to prevent the pathological effects of endothelin  
conditions such as PH and other conditions related to pulmonary vasoconstriction.  
j. Inhibition of ETA receptors was widely considered to be a target for alleviating  
vasoconstriction. Some studies suggested that in the pulmonary hypertensive  
Page: 46  
state, blockade of both ETA and ETB is necessary to achieve maximal vasodilation  
and other studies suggested a protective role of ETB in PH. In 2005, it was  
unclear whether dual ETA/ETB receptor antagonism or selective ETA receptor  
antagonism would confer the most therapeutic benefit in cardiovascular disease or  
in PAH. As of August 2006, the general view was that dual receptor antagonism  
or selective ETA receptor antagonism could produce beneficial effects because no  
clear clinical use for selective ETB antagonists had yet been defined, and ETB  
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 ETA antagonist sitaxsentan, which was approved for PAH in Canada and  
the US in 2006 and 2007, and the subject of investigational studies with a PDE5-I  
for hypertension and PH; sitaxsentan was subsequently withdrawn from the  
market due to liver toxicity; (ii) Actelion’s dual ETA/ETB antagonist tezosentan,  
which was being studied for acute and chronic heart failure; (iii) a selective ETA  
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 ETA and ETB receptors. Generally,  
these two receptors have opposing functions and it was believed that increased  
selectivity for ETA might provide greater efficacy and/or fewer side effects  
compared to dual ERAs. Interest in the field was somewhat moving away from  
dual ERAs, toward selective ETA antagonists. Sitaxsentan and ambrisentan, the  
only other ERAs besides bosentan that were close to approval as of 2006, are both  
selective ETA antagonists.  
e. The skilled person would not agree that ERAs and PDE5-Is have a class effect  
just because they act on the same receptors. This was especially true for ERAs  
because it was unclear to the skilled person whether differences in ETA and ETB  
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  
Page: 49  
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  
Page: 50  
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 evidenceit 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 circulationa 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 ETA-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 ETA antagonist) and published on March 9, 2006; WO  
395 describes combination therapies comprising at least one ETA antagonist 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 ETA antagonist 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  
Page: 54  
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  
considerationit 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  
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tenor of these articles was that multiple avenues were being explored and the reported results—  
both positive and negativewere of interest. Lee & Rubin (2005) notes the lack of direct,  
prospective comparisons between different PAH medications to guide decisions to use one  
treatment over another. This article also states that the expert consensus statement on primary  
pulmonary hypertension (now referred to as PAH) published in 1993 by the ACCP was a 14-  
page document, and had “evolved into a 92-page, updated evidence-based monograph”,  
reflecting the expansion in treatment decisions. The authors did include comments on  
combination therapy, but in this regard, they wrote that the addition of a second PAH drug may  
be reasonable for patients who deteriorate or have a suboptimal response to monotherapy, and  
“[a] handful of case series and observational cohort studies preliminarily have shown promising  
results using various combinations of sequential add-on therapy”. Dr. Zusman pointed to the  
statement that “there may be important interactions between the NO, [endothelin], and  
prostacyclin pathways” to support his opinion that there was a focus on targeting the interactions  
between the pathways. However, this statement (made in Lee & Channick (2005) and Lee &  
Rubin (2005)) was an acknowledgement that interactions between the pathways were not fully  
understood.  
[163] In addition to the NO, endothelin, and prostacyclin pathways, McLaughlin & McGoon  
(2006) describe other mechanisms implicated in PAH. When discussing combination therapy in  
particular, McLaughlin & McGoon (2006) note that the evidence on combination therapy with  
bosentan included a study with epoprostenol that failed to demonstrate benefits, that other study  
results were expected imminently, and more studies were underway.