Annual Report 2007
`In Detail
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`Content
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`01 Marketed Products
`
`Summary of Achievements
`Tracleer®
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`Ventavis®
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`Zavesca®
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`02
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`Research & Development
`Drug Discovery
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`Drug Discovery Platforms
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`Therapeutic Areas
`
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`Clinical Development
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`03
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`Our Strategy
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`Business Development
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`
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`Financial Report
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`Corporate Governance
`Consolidated Financial Statements
`Holding Company Statements
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`04
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`05
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`04
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`05
`06
`08
`08
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`10
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`11
`11
`12
`18
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`27
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`29
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`32
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`37
`49
`78
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`01
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`Marketed Products
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`Summary of achievements
`
`Actelion continued its strong performance in 2007 and further
`built its leadership position in pulmonary arterial hypertension
`(PAH) with Tracleer® (bosentan) sales of CHF 1,18 billion, a
`growth of 31% compared to the previous year (+32% in lo-
`cal currencies). This strong performance was seen in all re-
`gions worldwide, including the United States, Europe, and
`Japan in particular. It was also the first full year of marketing
`Ventavis® (iloprost) after the acquisition of CoTherix in the
`United States. In an increasingly competitive PAH market,
`Ventavis® was able to contribute CHF 78.2 million to our PAH
`franchise revenues.
`
`These excellent results are particularly remarkable consider-
`ing that new competition entered the market in 2007 within
`the class of endothelin receptor antagonists (sitaxentan in
`the European Union and ambrisentan in the United States).
`Actelion’s in-depth knowledge of the PAH market, together
`with our highly professional and determined worldwide mar-
`keting and sales force, continued medical education activities,
`and further geographical expansion, were the basis for main-
`taining leadership and further growth.
`
`Actelion further strengthened the profile of its flagship brand,
`Tracleer®. In 2007, we submitted an application in the US and
`Europe to expand the indication of Tracleer® for patients with
`PAH in WHO Functional Class II* (FC II), based on the conclu-
`sive results of the EARLY study – the only study investigating
`the effects of a PAH therapy specifically in a FC II patient
`group. With EARLY, Tracleer® has shown a significant effect
`on delaying time to clinical worsening, a measure of disease
`progression, in three separate randomized controlled trials.
`
`The positive results of the double-blind, placebo-controlled,
`multi-national BENEFIT trial – which investigated the effects
`of Tracleer® in a patient population outside of WHO group
`I*, namely patients with chronic thromboembolic pulmo-
`nary hypertension (CTEPH) – further proved to the value of
`Tracleer® for patients. In June 2007, the EMEA granted ap-
`proval in the European Union for an expansion of the indi-
`cation of Tracleer® for reducing the number of new digital
`ulcers in patients suffering from systemic sclerosis and ongo-
`ing digital ulcer disease. Digital ulcers are a serious and very
`debilitating consequence of this disease.
`
`* WHO clinical classification of pulmonary hypertension group diseases sharing similarities.
`PAH is WHO group 1. Group 1 comprises the following classifications:
`
`I. Patients with pulmonary hypertension in whom there is no limitation of usual physical activity
`II. Patients with pulmonary hypertension who have mild limitation of physical activity
`III. Patients with pulmonary hypertension who have a marked limitation of physical activity
`IV. Patients with pulmonary hypertension who are unable to perform any physical activity at
`rest and who may have signs of right ventricular failure.
`
`Actelion’s strong commitment to expand Tracleer® into new
`indications is demonstrated by the comprehensive clini-
`cal trial program, including the COMPASS trials (combina-
`tion therapy), BUILD 3 (idiopathic pulmonary fibrosis) and
`FUTURE (pediatric indication).
`
`Several marketing and life cycle activities were initiated for
`Ventavis® in 2007 to enhance its profile and set it up for con-
`tinued success in 2008.
`
`Zavesca® (miglustat), Actelion’s second global brand, gener-
`ated sales of CHF 35.3 million, a growth of 39% compared
`to the previous year. Increased awareness and acceptance
`of the value of Zavesca® for patients suffering from Type 1
`Gaucher disease are the basis for future market share growth.
`New data published in 2007 confirmed the positive effects
`of Zavesca® on Gaucher disease related bone manifestations,
`and bone pain in particular, strengthening the competitive
`profile of the brand.
`
`The submission for an expansion of the indication to patients
`suffering from Niemann-Pick Type C disease is still under re-
`view by the European regulatory authorities.
`
`Actelion currently markets the following products:
`
`Product
`
`Indication(s)
`
`Status
`
`Commerciali-
`zation rights
`
`Tracleer®
`
`Pulmonary arterial hyper-
`tension
`
`marketed
`
`Actelion
`
`Prevention of digital
`ulcers in patients with
`systemic sclerosis
`
`Prevention of digital
`ulcers in patients with
`systemic sclerosis
`
`registered(1)
`
`Actelion
`
`in
`registration(2)
`
`Actelion
`
`Ventavis®
`
`Pulmonary arterial hyper-
`tension
`
`marketed
`
`Actelion(3)
`
`Zavesca®
`
`Type 1 Gaucher disease
`
`marketed
`
`Actelion(4)
`
`(1) Only in the EU
`(2) A product is said to be "in registration" when it has completed Phase III clinical trials and
`its developer is in discussion with the relevant regulatory authorities relating to the filing of
`a new drug application for the product.
`(3) Only in the USA.
`(4) Except Israel, the West Bank and Gaza Strip.
`
`
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`sels – makes the vessels stiffer and thicker, and some may
`become completely blocked. This increased stress causes
`the heart to enlarge and become less flexible. As the cycle
`continues, less and less blood is able to flow out of the heart,
`through the lungs and into the body, which causes additional
`severe symptoms to appear. Heart and lung functions are
`severely compromised in PAH patients, resulting in limited
`exercise capacity and, ultimately, a reduced life expectancy.
`
`The first signs of PAH – such as dyspnea (shortness of breath),
`fatigue and difficulty exercising – are subtle. As a result, the
`disease is often either misdiagnosed or not diagnosed at all
`until a patient's condition is advanced. According to a 1991
`study by D'Alonzo (et al) in the Annals of Internal Medicine, if
`the disease is left untreated, 45 to 60% of PAH patients die
`within two years of diagnosis.
`
`Prior to the availability of Tracleer®, the main treatment alter-
`natives for early-stage PAH were vasodilators – such as cal-
`cium channel blockers, which cause blood vessels to expand,
`and oral anti-coagulants, which reduce blood clotting. These
`therapies are able to relieve some of the symptoms of PAH,
`but do not work in all patients. As the disease progressed,
`many patients were forced to turn to prostacyclin therapy,
`which required a 24-hour infusion pump and an intravenous
`line implanted through the chest to deliver the drug directly
`into the patient's pulmonary vein.
`
`This treatment is associated with a number of quality-of-life
`and safety limitations. Ultimately, many patients would re-
`quire lung or heart-lung transplantation; this is costly and se-
`verely limited due to the lack of suitable donor organs.
`
`Tracleer® was approved on the basis of two Phase III clinical
`trials and is a twice-a-day oral formulation offering effective
`treatment for most moderate to severe PAH patients. It has
`been shown to significantly delay disease progression, im-
`prove exercise capacity and increases the patient's ability to
`perform daily activities without shortness of breath. It also
`improves quality of life, in some cases placing the patient
`in a less severe diagnostic class. In a number of patients,
`Tracleer® may stabilize the disease, and like any pharmaceuti-
`cal product, it may be ineffective for others.
`
`Tracleer®
`
`Actelion’s lead product is Tracleer®, the first and only dual en-
`dothelin receptor antagonist. Tracleer® was the first oral treat-
`ment approved for pulmonary arterial hypertension (PAH), a
`rare, chronic, life-threatening disorder that severely compro-
`mises the functions of the lungs and heart. Today, Tracleer®
`has been approved for the treatment of PAH in more than
`30 countries, including the United States in November 2001,
`the European Union in May 2002, and Japan in April 2005.
`We currently market Tracleer® in all major markets worldwide
`– including the United States, the European Union, Japan,
`Switzerland, Canada, Australia, and China.
`
`Actelion received an orphan drug designation for Tracleer® in
`PAH for jurisdictions including the European Union, the Unit-
`ed States, Japan, and Australia.
`
`In addition to the indication in PAH, based on compelling
`clinical data, Tracleer® received approval from the European
`regulatory authorities in 2007 for the reduction in the number
`of new digital ulcers in patients suffering from systemic scle-
`rosis and ongoing digital ulcer disease.
`
`Indications
`
`Tracleer® in pulmonary arterial hypertension
`Pulmonary hypertension, or high blood pressure in the cardio-
`pulmonary system, is a simplified name for a complex health
`problem. Pulmonary hypertension is a disease affecting peo-
`ple of all ages and ethnic background, seriously impacting
`the quality of life and life expectancy of patients. Pulmonary
`hypertension may result from any of a number of primary
`diseases. It can also arise idiopathically, that is, without a
`medically understood cause. The World Health Organization
`(WHO) classifies five different forms of pulmonary hyperten-
`sion. These five forms differ in both their causes and their
`precise effects. Tracleer® is currently indicated for the WHO
`group 1 classification of pulmonary arterial hypertension
`(PAH). An estimated 100,000 to 200,000 patients worldwide
`currently suffer from this disease.
`
`Chronic and life-threatening, PAH is characterized by abnor-
`mally high blood pressure in the arteries between the heart
`and lungs. It may arise in an idiopathic primary form or in
`secondary forms related to conditions or tissue disorders
`that affect the lungs, such as scleroderma, lupus, HIV/AIDS
`or congenital heart disease. PAH begins when small vessels
`that supply blood to the lungs constrict and make it more dif-
`ficult for blood to reach the lungs. As a result, the heart has to
`pump harder. Over time, fibrosis – the scarring of blood ves-
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`The COMPASS 2 study, which evaluates the effect of Tracleer®,
`when given in combination with sildenafil, on morbidity and
`mortality in a group of patients followed for up to three years.
`The results will be available sometime in 2010.
`
`Tracleer® in digital ulcers in scleroderma patients
`Systemic sclerosis (SSc) is a chronic autoimmune disease
`characterized by progressive fibrosis with deposition of colla-
`gen in the skin and internal organs. This uncontrolled fibrotic
`process leads to occlusion of the small vessels in the body
`which may result in the development of PAH as indicated
`above but also in the development of digital ulcers (DUs).
`DUs are very painful and result in difficult-to-heal open sores
`that occur on fingers and toes, leaving depressed scars.
`
`They also have a negative impact on the ability to work or per-
`form daily activities. In severe cases, infection can complicate
`the course of the ulcer, sometimes leading to bone infection
`and gangrene, where surgery and even amputation may be
`required. Endothelin is involved in this pathological process,
`and the evaluation of the benefit of Tracleer® as an endothelin
`receptor antagonist in this indication was granted.
`
`These potential benefits were tested in two placebo con-
`trolled trials (RAPIDS 1 and RAPIDS 2) in patients with
`systemic sclerosis and digital ulcers. In the two studies,
`Tracleer® prevented the occurrence of new digital ulcers and
`contributed to improving the patients’ quality of life. The two
`RAPIDS studies confirm the properties of Tracleer® as a dual
`endothelin receptor antagonist that prevents the remodeling
`of the vessels – the main and common pathological process
`leading to PAH and the formation of digital ulcers.
`
`In June 2007, the European Commission granted marketing
`approval for Tracleer® for the reduction of the number of new
`digital ulcers in patients with systemic sclerosis and ongoing
`digital ulcer disease.
`
`As of the end of 2007, regulatory proceedings to extend the
`label of Tracleer® to include digital ulcerations are ongoing
`worldwide.
`
`i. Additional clinical trials with Tracleer® in PAH
`
`Additional clinical trials have been conducted in PAH patients
`to increase the information about the use of Tracleer® in vari-
`ous conditions and help treating physicians to manage pa-
`tients appropriately. These trials are briefly summarized in the
`table below:
`
`Study name
`
`BREATHE 2
`
`Target patient
`population
`
`Patient at epopro-
`stenol initiation
`
`BREATHE 3
`
`Children
`
`BREATHE 4
`
`BREATHE 5
`
`EARLY
`
`PAH related to
`HIV in HIV positive
`patients
`
`PAH related to
`congenital heart
`defects with Eisen-
`menger syndrome
`
`PAH patients in
`WHO Functional
`Class II (early stage
`of the disease)
`
`Main result
`
`Tracleer® further improved cardiac
`hemodynamic when used in associ-
`ation with i.v. epoprostenol.
`
`This study has defined the pharma-
`cokinetics of bosentan in children.
`Tracleer® improved exercise capacity
`and cardiac hemodynamics.
`
`Tracleer® was shown to be safe in
`this population and improved both
`cardiac hemodynamics and exercise
`capacity.
`Tracleer® improved cardiac hemo-
`dynamics and delayed the time to
`clinical worsening. A trend towards
`an improvement in exercise capacity
`was also shown in this study.
`
`ii. Use of bosentan with sildenafil: the COMPASS clinical
`
`trial program
`
`Additional trials are currently being conducted with Tracleer®
`in the field of PAH to demonstrate that it needs to be part of
`all PAH treatment, either alone or in combination with other
`drugs. The COMPASS program evaluates specifically the ef-
`ficacy and safety of the use of bosentan in combination with
`sildenafil – an approved and effective treatment for PAH but
`one that addresses another pathological pathway of the dis-
`ease.
`
`The COMPASS program includes two main trials:
`
`The COMPASS 1 study completed in 2007, the results of
`which are summarized below:
`
`Study name
`
`Target patient
`population
`
`Main result
`
`COMPASS 1
`
`Patients on chronic
`bosentan for PAH
`
`Sildenafil showed a positive effect
`on cardiac hemodynamics when ad-
`ded to patients on chronic Tracleer®.
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`Tracleer® in the market
`
`Tracleer® continued strong growth in 2007, confirming its
`market leadership position in PAH. Its sales of CHF 1.18 bil-
`lion represent a growth of 31% over the previous year.
`
`This strong performance of our flagship product is attributed
`to two main factors:
`
`Actelion’s commitment to investigating the potential ben-
`efits of Tracleer® – in new disease conditions and indications
`where there is a high unmet medical need – continues to
`generate strong and unmatched clinical data that represent
`the fundamental position of Tracleer® as the undisputed cor-
`nerstone of therapy
`
`Our world class specialized and experienced marketing and
`sales force has been strengthened and expanded to deal
`with the increasing awareness and attention in the medical
`community and to ensure a continued leading share of voice
`in the market place. In addition, we are also creating the po-
`tential for future growth by expanding into new markets in
`Latin America, Eastern Europe and Asia.
`
`Ventavis®
`
`Ventavis® (iloprost) – the only inhalable PAH therapy on the
`market – was approved by the FDA in the United States at
`the end of 2004. Actelion gained the licensing rights to mar-
`ket Ventavis® in the United States through the acquisition
`of the US company, CoTherix Inc., at the end of 2006. 2007
`marks the first year of marketing Ventavis® and a strong per-
`formance with sales of CHF 78.2 million represent a substan-
`tial addition to our PAH franchise.
`
`Ventavis® is an inhaled formulation of iloprost, a synthetic
`compound that is structurally similar to prostacyclins – natu-
`rally occurring molecules that cause blood vessels to dilate.
`Iloprost is a synthetic analogue of prostacyclin PGI2 that di-
`lates systemic and pulmonary arterial vascular beds.
`
`It also affects platelet aggregation, although the relevance of
`this effect to the treatment of pulmonary hypertension is un-
`known. In controlled trials, Ventavis® improved a composite
`endpoint consisting of exercise tolerance, symptoms (NYHA
`Class), and lack of deterioration. In March 2005, top line data
`of the Phase II clinical trial, STEP – evaluating the safety and
`added benefit of using Ventavis® Inhalation Solution thera-
`py in patients with PAH already undergoing treatment with
`bosentan – were published.
`
`The analysis of this study showed that the combination of
`Ventavis® and bosentan therapy was well tolerated, was con-
`sistent with the safety profile observed in patients receiving
`only iloprost, and provided clinical benefit in patients with
`PAH. Ventavis® is indicated for the treatment of pulmonary
`arterial hypertension (WHO Group I) in patients with NYHA
`Class III or IV symptoms.
`
`Ventavis® is supported in the United States, as part of our
`PAH franchise by the marketing and sales force, for the treat-
`ment of patients suffering from this devastating disease.
`
`Parallel to our marketing and sales efforts, we are running
`several initiatives to further improve the convenience of us-
`ing Ventavis®, such as optimizing the cleaning protocol of the
`inhalation device and reducing inhalation time.
`
`Zavesca®
`
`Zavesca® (miglustat), currently the only approved oral treat-
`ment for Type 1 Gaucher disease – a rare and debilitating
`metabolic disorder – is used in patients for whom enzyme
`replacement therapy is unsuitable.
`
`In November 2002, Actelion in-licensed miglustat, the active
`ingredient of Zavesca®, from Oxford GlycoSciences (UK) Ltd.
`Market introduction in the European Union began in March
`2003, followed by the United States in January 2004. In No-
`vember 2005, we entered an agreement with UCB S.A., the
`legal successor to Oxford GlycoSciences.
`
`Under this agreement, Actelion is assigned all of UCB S.A’s
`rights and obligations regarding miglustat, including world-
`wide marketing rights, except in Israel, the West Bank and
`Gaza Strip. Geographical expansion to Australia, where we
`achieved marketing approval during the year is further in-
`creasing the commercial potential of Zavesca®.
`
`There are approximately 7,000 patients with Type 1 Gaucher
`disease in the EU and the USA, of whom about 3,000 receive
`enzyme replacement therapy.
`
`Based on clinical data with Zavesca® in another life threaten-
`ing lysosomal storage disease, Niemann-Pick Type C, Actelion
`filed for marketing authorization in the European Union for an
`expansion of the Zavesca® label. Assessment of the applica-
`tion by the European Regulatory Authority is ongoing. This is
`another area of high unmet medical need: there is currently
`no therapeutic option available for patients suffering from this
`debilitating condition, which often affects young children.
`
`
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`Indications
`
`Zavesca® in the market
`
`Zavesca® continues to grow steadily and achieved sales of
`CHF 35.3 million in 2007 – a growth of 39% compared to pre-
`vious year. In addition, we were able to significantly increase
`our share in several markets.
`
`Since the molecule appears to penetrate deep in tissues, it
`has been hypothezised to have a more significant effect on
`bone disease. Recently presented and published data have
`confirmed the positive effect of Zavesca® on Gaucher dis-
`ease related bone manifestations and bone pain, in particu-
`lar. This data confirms the beneficial effects of Zavesca® for
`Gaucher Type 1 patients and could help to further increase
`market share.
`
`Another key to future market penetration is the Zavesca®
`MAINTENANCE study. This evaluates whether patients with
`Type 1 Gaucher disease, who are treated with enzyme replace-
`ment therapy, remain stable after switching to Zavesca®.
`
`Zavesca® in Gaucher disease (Type 1)
`Gaucher disease is an inherited metabolic disorder caused by
`a genetic mutation. In Gaucher disease, the patient’s body is
`unable to produce sufficient amounts of glucocerebrosidase,
`an enzyme that metabolizes a lipid or fatty substance called
`glucosylceramide. Because the body cannot properly metab-
`olize this lipid, harmful quantities accumulate in the spleen,
`liver, lungs, bone marrow, and, in rare cases, the brain.
`
`Three phenotypes, or clinical forms, of Gaucher disease are
`commonly recognized. The first phenotype, Type 1, is non-
`neuronopathic, and by far the most common. Patients in this
`group usually bruise easily and experience fatigue due to
`anaemia and low blood platelet count. They also suffer from
`liver and spleen enlargement, bone disease manifestations
`and, in some instances, lung and kidney impairment.
`
`Before the introduction of Zavesca®, the only treatment for
`this debilitating disease was intravenous enzyme replace-
`ment therapy. With Zavesca®, patients with Gaucher disease
`have access to an additional treatment option. It has been
`shown to reduce the organomegaly induced by the accumu-
`lation of glycosylceramide.
`
`Zavesca® provides a therapeutic approach to controlling the
`overall level of glucosylceramide by reducing its generation.
`The goal of therapy with Zavesca® is to regulate the rate of
`synthesis of glucosylceramide to a level that allows its further
`degradation by the residual glucocerebrosidase activity.
`
`We received an orphan drug designation for Zavesca® in Type
`1 Gaucher disease in the European Union and the United
`States.
`
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`02
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`Research and
`Development
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`Drug Discovery
`
`Over the past 10 years, Actelion’s efforts in drug discovery
`have focused on developing platforms of expertise. This fo-
`cus allows high productivity in the generation of innovative
`compounds potentially addressing a wide range of highly un-
`met medical needs.
`
`The first focus is the design, synthesis and optimization of
`small molecular weight drug-like molecules. The productiv-
`ity of our endeavors is demonstrated with more than 1,000
`pending patent applications and/or granted patents currently
`in Actelion’s portfolio. In 2007, the company filed 28 priority
`patent applications.
`
`Actelion also focuses on the choice of its molecular target
`families. Initially, the company looked solely at G-protein cou-
`pled receptors (GPCR’s) and aspartic proteinases. In recent
`years, several other target areas have been progressively
`added. One example is the ion channel blocker platform. An-
`other is the anti-infective’s platform acquired after the integra-
`tion of a research group specialized in innovative anti-infective
`research.
`
`Actelion endeavors to follow innovation where it leads,
`as evidenced by the fact that from a few target platforms,
`Actelion’s compounds have found or might find applications
`in multiple disease areas, such as cardiovascular or immunol-
`ogy. In 2007, we expanded our research efforts by adding a
`dedicated oncology unit to evaluate all our ongoing efforts for
`further potential applications in the field of cancer.
`
`To maximize output from our focus on target families, we use
`the appropriate state-of-the-art technologies. We combine
`technology with human expertise on how to make the best
`use of our toolbox. We have over 100 medicinal and process
`chemists creating our low molecular weight compounds. For
`example, Actelion scientists have access to the rational input
`of computer-assisted molecular modeling. In 2007, we have
`solved 12 highly complex three-dimensional structures of
`proteins from different projects.
`
`This, in turn, has provided a basis for designing a multitude
`of molecules that our molecular biologists and biochemists
`then characterize in relation to the chosen targets, for which
`they develop a variety of assays and execute screens. In 2007,
`over one million assay results were generated, managed and
`analyzed by our Oracle-based data-warrior programs, built in-
`house.
`
`The lead is then passed to our pharmacologists, neurobi-
`ologists, immunologists and electro-physiologists to further
`characterize the compounds. These lead compounds are then
`passed back through this cycle until an optimized compound
`is available for pre-clinical development by our pharmacoki-
`neticists, galenicists and toxicologists.
`
`This platform approach, combined with our technologic capa-
`bilities and in-house expertise, has resulted in the selection
`of a number of valuable compounds for pre-clinical investi-
`gations. The final outcome is a robust clinical development
`pipeline filled with compounds discovered and optimized in
`Actelion’s laboratories.
`
`Drug discovery platforms
`
`New chemical entities (NCE)
`
`Our research focuses on the design and synthesis of novel
`low-molecular-weight, drug-like molecules. Experience has
`shown that small molecules generally lend themselves to
`easier formulation, have a broader array of dosage forms,
`have greater potential for bioavailability, in particular after oral
`administration, and are more efficiently manufactured. While
`our medicinal chemistry and parallel chemistry groups syn-
`thesize smaller quantities of structurally diverse molecules,
`our process research chemists prepare the quantities of se-
`lected compounds needed for further studies.
`
`G-Protein coupled receptors
`
`G-Protein coupled receptors (GPCR's), also described as
`seven transmembrane domain receptors (7TM's), are inte-
`gral membrane proteins. They can be activated by external
`signals, such as hormones, neurotransmitters or odors. This
`activation induces a conformational change of the receptor
`which in turn causes activation of G-proteins and the sub-
`sequent transmission of biochemical signals within the cell.
`There are more than 100 known GPCR's in humans and many
`of them are involved in a broad array of diseases. Some of
`these receptors are the subject of our development pro-
`grams, such as the endothelin receptors ETA and ETB, orexin
`receptors OX1 and OX2, or the sphingosine-1-phosphate re-
`ceptor S1P1.
`
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`Aspartic proteinases
`
`Aspartic proteinases are a class of enzymes that promote
`chemical reactions in and outside of cells. To perform their
`function, aspartic proteinases use an arrangement of two as-
`partic acids in order to activate a water molecule that acts as
`a chemical “scissor”.
`
`There are more than 50 known aspartic proteinases, of which
`at least nine are currently known to exist in humans. Al-
`though knowledge of their precise physiological roles is still
`emerging, they have been implicated in cancer, as well as in
`inflammatory, degenerative and cardiovascular diseases. In
`addition, aspartic proteinases play a vital role in organisms
`that cause infections, including parasites, fungi and retrovi-
`ruses such as HIV.
`
`Anti-infectives
`
`In early 2004, Actelion initiated a research program in the field
`of antibiotics. Due to the development of resistance to cur-
`rently available antibiotics and the emergence of new patho-
`gens, the medical need for new antibiotic compounds is high.
`Our program is focused on the discovery of novel classes
`of antibiotics that may offer improved properties, such as in-
`creased potency, coverage of multi-resistant infections and
`a decreased inherent liability for resistance development. A
`portfolio of projects has been established focusing on both
`antibiotics for intravenous treatment of severe hospital infec-
`tions and oral antibiotics for community acquired infections.
`We currently have one compound in full pre-clinical develop-
`ment and are in the optimization phase for several other com-
`pounds.
`
`
`Ion channels
`
`Ion channels are transmembrane pores that allow the pas-
`sage of ions (charged molecules) into or out of a cell. There
`are hundreds of different ion channels and they are distin-
`guished based upon ion selectivity, opening mechanism, and
`protein sequence. Ion channels can be opened by chemical
`ligands, voltage fluctuations, acidity changes, temperature
`variations, or mechanical stimuli (e.g. touch or sound).
`
`In mid-2004, Actelion established an in-house in-vitro electro-
`physiology group. This was primarily to provide internal sup-
`port for early pre-clinical evaluation of drug safety in the area
`of cardiac electrophysiology.
`
`However, since the scientific knowledge and technical capa-
`bilities required in this area are very similar to those in the
`area of cardiovascular ion channel therapies, research pro-
`grams were soon initiated looking for modulators of selected
`ion channels to treat cardiovascular diseases. In 2007, further
`development of the electrophysiology group led to the initia-
`tion of research projects targeting ion channels to treat neu-
`rological and immunological diseases.
`
`Therapeutic areas
`
`Cardiovascular disorders
`
`Cardiovascular disorders encompass all complaints where
`there is a disturbance in the function of the heart or blood
`vessels. Cardiovascular disease is one of the leading causes
`of death in industrialized countries, a fact which is also ex-
`pected to become the case in developing countries.
`
`Our focus
`
`i. Endothelial system
`
`The endothelium is an organ consisting of a single layer of
`cells between the blood stream and the blood vessel wall.
`
`The main functions of the endothelium include:
`
`- maintenance of blood vessel tone, which is critical for regu-
` lating blood pressure levels
` and
`- prevention of blood clots forming on the vessel wall by pro-
` viding a non-adhesive surface.
`
`The endothelium produces and secretes two important vaso-
`active molecules, endothelin and nitric oxide, that work in op-
`position. Nitric oxide dilates blood vessels, prevents platelet
`adhesion and inhibits cell proliferation.
`
`Endothelin, however, is a powerful blood vessel constric-
`tor that also promotes cell proliferation. In a normal, healthy
`state, the body maintains a balance between nitric oxide and
`endothelin. In contrast, in certain disease states endothelin is
`produced in excess. In addition to causing vasoconstriction –
`the narrowing of blood vessels – excessive endothelin can:
`
`- stiffen blood vessels and tissues by promoting fibrosis, the
` accumulation of connective tissue
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`- cause vascular remodeling, a change in the vessels' shape,
` vascular hypertrophy, an increase in the thickness of blood
` vessel walls and cardiac hypertrophy
` and
`- predispose the vessels to inflammation.
`
`Endothelin binds to two types of receptors found on the
`blood vessel walls and in tissues: ETA receptors, which are
`found predominantly in smooth muscle cells in the blood ves-
`sels, and ETB receptors, which are also found in connective
`tissue cells, neuronal cells, endothelial cells and hormone-
`producing cells.
`
`The activation of the endothelin system plays a critical role
`in chronic cardiovascular diseases, such as pulmonary hyper-
`tension, and in acute cardiovascular conditions, such as right
`heart failure and cerebral vasospasm – a constriction of blood
`vessels in the brain following subarachnoid hemorrhage.
`It is also implicated i