nova
`nordisk
`history
`
`1970
`
`1990
`
`1980
`
`2000
`
`changing
`diabetes·
`
`• ~ .
`
`nova nordisk
`
`Sanofi Exhibit 2137.001
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Preface
`
`Behind the Novo Nordisk we know today
`
`lies an exciting story that goes back more
`than 85 years. It began with two small
`
`Danish firms established in Copenhagen
`in the 1920s - Nordisk lnsulinlaboratorium
`
`and Novo Terapeutisk Laboratorium*
`- who under modest circumstances
`
`began manufacturing a revolutionary
`new medicine, insulin, that had just been
`
`discovered by two Canadian scientists.
`
`Competing intensely with one another, the
`companies developed into two of the best
`
`in their field. When at last they decided
`
`to merge in 1989, they created one of the
`world's largest biotechnology groups - a
`
`group that has been expanding rapidly ever
`
`since.
`
`This booklet tells in words and pictures
`of the many events that are the story of
`Novo Nordisk - a fascinating tale of one
`
`pioneering product after another, developed
`
`through the inspired thinking of talented
`and ambitious people.
`
`We hope you will enjoy the story!
`
`Novo Nordisk is a global
`healthcare company with more
`than 85 years of innovation
`and leadership in diabetes care.
`The company also has leading
`positions within haemophilia
`care, growth hormone therapy
`and hormone replacement
`therapy. Headquartered in
`Denmark, Novo Nordisk employs
`more than 30,000 employees
`in 76 countries, and markets its
`products in 179 countries. Novo
`Nordisk's B shares are listed on
`NASDAQ OMX Copenhagen
`(Novo-BJ. Its ADRs are listed on
`the New York Stock Exchange
`(NVO). For more information,
`visit novonordisk.com.
`
`* Both Nordisk lnsulinlaboratorium and Novo Terapeutisk Laboratorium changed their names several times over the
`years. To make things easier for our readers, we refer to the two companies as Nordisk and Novo respectively.
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.002
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Nordisk lnsulinlaboratorium
`is founded
`
`The story of Nordisk lnsulinlaboratorium
`
`who together with the pharmacist Norman
`
`began on an autumn day in 1922, when
`
`Jensen had developed a very precise
`
`August and Marie Krogh arrived in the United method of measuring blood sugar:
`
`States by sea. August Krogh was a professor
`
`at the University of Copenhagen and had
`
`"Since I believe that you ... will be interested
`
`received the Nobel Prize in physiology in
`
`in this preparation, I have persuaded my
`
`1920. The couple had been invited to the US
`
`husband to write Dr Macleod in Toronto and
`
`by researchers at Yale University, who had
`
`ask him if it would be possible to obtain its
`
`asked August Krogh to lecture throughout
`
`method of manufacture, making it possible
`
`the country on his medical research.
`
`for you to perform experiments with it in
`
`Marie Krogh's illness
`
`Denmark."
`
`On their tour of the US, the couple heard daily
`
`Both letters were well received, and after
`
`reports of people with diabetes being treated
`
`the meeting in Toronto, the couple returned
`
`with insulin -a hormone discovered in 1921 by
`
`to Copenhagen in December 1922 with
`
`two Canadian researchers, Banting and Best.
`
`permission to manufacture and sell the vital
`
`insulin in Scandinavia.
`
`Marie Krogh was particularly interested in the
`treatment. Herself a doctor, she had in 1914
`also become the fourth Danish woman to
`
`Back in Denmark
`
`The day after the couple's return to
`
`earn a doctorate in medicine. She was a
`
`Copenhagen, Krogh and Hagedorn decided
`
`researcher with her own medical practice and
`had several patients with type 1 diabetes .
`Marie Krogh herself had type 2 diabetes.
`
`The meeting in Toronto
`
`that some intensive research was required.
`
`Before they could begin, however, they had
`
`a problem to solve: research costs money.
`
`Krogh and Hagedorn sought help from the
`
`Danish pharmacist August Kongsted, who
`
`During their stay in the US, August Krogh
`
`owned the pharmaceutical company L0vens
`
`wrote to Professor Macleod, head of the
`
`kemiske Fabrik (Leo Pharmaceutical Products).
`
`institute in Toronto where the first insulin
`
`Kongsted offered to pay for the research
`
`extract had been produced. Meanwhile,
`
`and help start production, on condition that
`
`Marie Krogh wrote to her colleague in
`
`Krogh and Hagedorn called their first insulin
`
`Copenhagen, Dr Hans Christian Hagedorn,
`
`product 'Leo' - the Latin word for lion.
`
`In 1921, two Canadians, Charles Best (left)
`and Frederick Banting (right), became the
`first researchers in the world to produce
`an insulin extract from pancreases and
`treat a diabetic dog with it.
`
`2 The University of Toronto.
`
`3 August and Marie Krogh (1874-1949)
`(1874-1943). The photo was taken during
`their trip to the US and Canada in 1922.
`
`4 Excerpt from Marie Krog h's letter to Hans
`Christian Hagedorn about the revolutionary
`discovery of insulin for the treatment of
`diabetes.
`
`2
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.003
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`C,
`
`NOVO NORDISK HISTORY
`
`3
`
`Sanofi Exhibit 2137.004
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`The first insulin
`
`The first experiments took place at
`Hagedorn's house and at Krogh's institute,
`
`the Laboratory of Zoophysiology, and
`shortly afterwards - on 21 December 1922
`
`- the two men succeeded in extracting
`
`a small quantity of insulin from a bovine
`
`stopped practising medicine to become the
`head of the laboratory, which was given the
`name Nordisk lnsulinlaboratorium . At the
`
`same time, they began marketing Insulin
`Leo, which was the first Scandinavian insulin
`product.
`
`pancreas . Krogh and Hagedorn were thrilled
`- Krogh was, in fact, so excited that he said
`
`during a lecture on 2 January 1923: "I feel
`
`The company Nordisk lnsulinlaboratorium
`
`was thus a reality, and 1923 is today
`considered the year in which Novo Nordisk
`
`that it is right to set aside my own work,
`
`was established.
`
`at least for a time, and concentrate all my
`efforts on this matter ... "
`
`The first patients treated
`
`An independent institution
`
`In February 1924, Nordisk became
`
`an independent institution under the
`
`In March 1923, the first patients were treated
`with insulin manufactured by Krogh and
`
`management of Krogh, Hagedorn and
`Kongsted. The three men decided that any
`
`Hagedorn. The treatment was not always
`
`profits should be used for scientific and
`
`successful, but Hagedorn wrote the following
`about a nine-year-old girl: " ... this child, who
`was previously very quiet, has become lively
`and alert, almost uncontrollable." In the
`
`spring of 1923, Krogh and Hagedorn moved
`
`to new and larger premises. Hagedorn
`
`humanitarian purposes. Insulin production
`in Denmark was in full swing.
`
`1 Hans Christian Hagedorn (1888-1971).
`
`2 In 1923, Nordisk produced Insulin Leo,
`the first insulin product in Scandinavia .
`
`3 In 1927, Nordisk established its first factory
`buildings in Gentofte.
`
`4 Labelling of insulin vials.
`
`4
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.005
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`NOVO NORDISK HISTORY
`
`5
`
`Sanofi Exhibit 2137.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Novo Terapeutisk Laboratorium
`is founded
`
`0
`
`When Krogh and Hagedorn began to
`
`manufacture insulin at Nordisk in 1923, they
`agreed that Harald Pedersen was the right
`
`spring of 1924 they succeeded in producing
`a stable liquid insulin product which they
`called Insulin Novo. At the same time,
`
`man to build the machines they needed for
`insulin production. Harald Pedersen was
`
`Harald Pedersen designed a special syringe
`- the Novo Syringe - that ensured that
`
`an unusually talented inventor who had
`worked for Krogh for a number of years as
`
`patients could comfortably inject themselves
`with correctly dosed insulin. The brothers
`
`manager of the mechanical workshop at the
`Zoophysiology Laboratory. Harald's brother,
`
`Thorvald Pedersen, was a pharmacist who
`
`was later hired by Nordisk to analyse the
`
`chemical processes involved in insulin
`production.
`
`were ready to place their products on the
`
`market, but doubted whether they could
`cope with the marketing themselves.
`Therefore they contacted Nordisk to offer
`
`some form of cooperation. Krogh and
`
`Hagedorn turned the offer down, however,
`
`and the brothers decided to go it alone.
`
`Cooperation problems
`The two brothers' work for Nordisk did not
`
`last very long, however. Thorvald Pedersen
`
`did not get on with Hagedorn, and in April
`
`1924 things came to a head and Hagedorn
`fired him. Out of loyalty to his brother,
`Harald Pedersen decided to hand in his
`
`notice to Krogh, even though he enjoyed
`
`1 Harald Pedersen (1878-1966).
`
`working for him.
`
`The brothers set up on their own
`
`The two brothers decided to try to
`
`manufacture insulin themselves. The
`brothers made a good team, and in the
`
`2 Thorvald Pedersen (1887-1961).
`
`3 Insulin Novo and the Novo Syringe, marketed
`in 1925.
`
`4 The Apis bull became Novo's logo in 1926.
`The A pis bu II was one of the ancient Egyptians'
`sacred animals and was worshipped as the
`incarnation of the god Ptah.
`
`6
`
`NOVO NORDISK HISTORY
`
`\
`
`Sanofi Exhibit 2137.007
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`
`
`Sanofi Exhibit 2137 .008
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`The firm is named
`
`good as possible. In his New Year's speech
`
`to his staff, Thorvald Pedersen said for
`The brothers named their firm Novo
`Terapeutisk Laboratorium, and on 16 February many years: "If Novo does well, we all do
`
`1925 they sent a letter of introduction to
`Danish pharmacists, informing them that
`
`well." Novo's employees had good working
`conditions compared to other workplaces at
`
`Insulin Novo and the Novo Syringe were now
`on sale. That date is regarded as the date on
`
`the time. Even in the first decades, benefits
`included a salary increment for employees
`
`which Novo was founded.
`
`with dependents, a modern, well-appointed
`
`A family firm
`
`Right from the beginning, Novo was a
`
`family firm. The two brothers received
`financial assistance from their sister, Thora
`Pedersen, and from Harald Pedersen's
`
`wife, Mine Pedersen. Thora Pedersen was
`
`a teacher and women's rights activist who
`lent her brothers a monetary gift she had
`
`received as thanks for her efforts to secure
`
`equal pay for teachers of both sexes. Mine
`Pedersen's inheritance and savings were
`used to purchase the house called 'Rolighed',
`
`where there was room for the family and
`
`factory with an excellent staff canteen and
`a yearly company picnic for all employees .
`
`Harald Pedersen, the other co-founder of
`
`Novo, has been quoted as having a favourite
`
`saying of the company's daily work: "We
`must be able to do better". By the same
`
`token, employees strove to improve both
`
`research and production, benefiting the
`company's products and turnover. The sense
`of community within the company developed
`over time into a mutual loyalty - a loyalty that
`
`came to be known as the Novo spirit.
`
`manufacturing insulin .
`
`Two companies
`
`The Novo spirit
`
`The entire family took an active part in the
`
`manufacture of Novo's products. Soon
`they began to hire other employees, but
`the sense of family and community at Novo
`
`remained. Having grown up with very modest
`
`means, the brothers found it important that
`conditions for Novo's employees were as
`
`Nordisk's earlier start had enabled it to get
`
`established before Novo in the Scandinavian
`countries, so Novo sought growth in other
`markets. But both companies grew rapidly.
`By 1936, Novo had 56 employees, and 90%
`
`of its production was exported. Denmark
`
`now had two companies that in the years
`to come would develop into the world's
`leading manufacturers of insulin.
`
`The villa 'Rolighed', where the Petersen
`brothers developed Novo's first insulin .
`
`2 The letter to Danish pharmacists dated
`16 February 1925 is Novo's birth certificate.
`
`3 Device used in Novo's test production for
`the comminution of glands.
`
`4 Working with the filling and sealing machine
`constructed by Harald Pedersen .
`
`5 In 1932, Novo moved to new premises,
`and two years later a new factory plant was
`built on the neighbouring property. It was
`designed by the architect Arne Jacobsen .
`
`8
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.009
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`1
`
`NOVO NORDISK HISTORY
`
`9
`
`Sanofi Exhibit 2137.010
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`New insulin products
`
`0
`
`At the beginning of the 1930s, insulin
`
`new, long-acting insulin product. This was
`
`researchers recognised that the effect of
`the existing insulin products was too short
`- a serious disadvantage because patients
`had to inject themselves with insulin several
`
`of great benefit to patients, who now
`needed fewer daily injections.
`
`News from Canada
`
`times a day. Therefore, Nordisk and Novo
`turned their attention to developing a
`
`The new product had a disadvantage,
`however: patients had to add a neutralising
`
`longer-acting type of insulin .
`
`liquid before use. So it was good news later
`
`I z -
`
`In 1935, Thorvald and Harald Pedersen
`marketed an insulin with adrenaline - a
`
`substance which had been shown to
`prolong the effect of insulin. However, it
`
`soon disappeared from the market because
`
`it turned out not to have the desired
`
`effect. Attention was instead focused on
`a sensational discovery made at Nordisk.
`
`"The most important advance"
`
`In 1936, Hagedorn and his colleague
`Norman Jensen discovered that the effect of
`
`insulin could be prolonged by adding to it
`
`a protein called protamine, developed from
`
`the milt of river trout. The discovery was
`hailed worldwide as a breakthrough, and in
`
`1937, the American nestor of diabetology,
`E P Joslin, wrote: "Protamine is the most
`
`important advance in the treatment of
`diabetes since the discovery of insulin in
`
`1921." In 1936, on the basis of Hagedorn
`and Norman Jensen's scientific work,
`
`Nordisk was able to introduce a completely
`
`that year when two Canadian researchers,
`DA Scott and AM Fisher, developed a long(cid:173)
`acting product - zinc-protamine-insulin (ZPI)
`
`- that only had to be shaken before injection .
`
`Novo marketed the new product in 1938,
`
`and this triggered a lawsuit that attracted
`a great deal of media attention in Denmark.
`
`In court
`Hagedorn claimed that Novo was making
`ZPI insulin using a method patented by
`Nordisk. Harald and Thorvald Pedersen
`
`denied the allegation and the case ended up
`
`in court. The brothers won the first round,
`but Hagedorn appealed to the Supreme
`
`Court and won his case by a majority of
`
`one. The ruling meant that Nordisk was
`entitled to a share of the money earned by
`Novo from sales of ZPI.
`
`Two hospitals
`
`In 1932, Nordisk inaugurated Steno
`Memorial Hospital. Hagedorn and Krogh
`chose this name in honour of one of
`
`1 Long-acting zink-protamine-insulin, marketed
`by Novo in 1938.
`
`2 Photo collage illustrating the manufacture of
`insulin at Novo in the 1930s.
`
`10
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137 .011
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`
`
`Sanofi Exhibit 2137.012
`Sanofi Exhibit 2137.012
`Mylan v. Sanofi
`Mylan v. Sanofi
`IPR2018-01675
`lPR2018-01675
`
`

`

`0
`
`NPH insulin (Neutral Protamine Hagedorn).
`
`2 Steno Memorial Hospital, which Nordisk
`opened in 1932. The hospital was designed
`by the architect Ivar Bentsen.
`
`3 The beautiful Hvid0re Palace, inaugurated
`by Novo in 1938 as the Hvid0re Diabetes
`Sanatorium .
`
`4 Knud Hallas-M0ller (1914-1984) working
`in the laboratory in the late 1930s.
`
`12
`
`NOVO NORDISK HISTORY
`
`Denmark's pioneers in the field of science,
`
`was to find an alternative to ZPI, the action
`
`Niels Steensen, who lived in the 17th
`
`century. This luxuriously equipped hospital
`
`treated diabetes patients and conducted
`research into the causes and development
`
`of diabetes . The results of the research
`
`were so good that Steno Memorial Hospital
`
`became the largest and most important
`diabetes centre in Scandinavia. In 1957, a
`
`profile of which was not optimal. In 1944
`he developed a number of insulin products
`
`with both rapid and slow action. While
`
`these products were widely used in many
`
`countries, ZPI remained popular among
`patients and continued to account for a
`
`substantial part of Novo's insulin sales .
`
`research laboratory was attached to the
`
`hospital, and in 1978 it was named the
`
`News from Nordisk
`The main event in diabetes treatment in
`
`Hagedorn Research Laboratory. Its purpose
`was basic research. In 1938, Novo founded
`
`the 1940s took place at Nordisk. In 1946,
`
`two of its researchers, C Krayenbuhl and
`
`Hvid0re Diabetes Sanatorium, the name of
`
`which was changed to Hvid0re Hospital in
`
`Th Rosenberg, succeeded in producing
`crystalline protamine insulin. The crystalline
`
`1949. At Hvid0re, the treatment received by
`patients at public hospitals was checked and
`
`form meant that it was now possible to
`
`mix protamine insulin with rapid-acting
`
`adjusted. For many people with diabetes,
`
`a stay at Hvid0re enabled them to live an
`
`insulin without any loss or change of effect
`in either product. This unique product was
`
`almost normal life when they returned
`home. Hvid0re also became a centre for
`
`research and clinical testing of Novo's new
`
`insulin products. In 1992, Steno Memorial
`
`Hospital and Hvid0re Hospital merged to
`
`launched on the US market in 1950 under
`the name NPH - short for Neutral Protamine
`Hagedorn. NPH was a great success and
`soon accounted for a large part of the
`western world's consumption of longer(cid:173)
`
`form the Steno Diabetes Center.
`
`acting insulin.
`
`New man at Novo
`
`In 1937, a pharmacist, Knud Hallas-M0ller,
`joined Novo. He had an extraordinary
`
`talent for research and management, and
`
`over the next decades he became a central
`
`figure in the firm. His first task at Novo
`
`Sanofi Exhibit 2137.013
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`· o
`
`NOVO NORDISK HISTORY
`
`13
`
`Sanofi Exhibit 2137.014
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`The search for purer insulin
`
`Following the introduction of the successful
`NPH insulin by Nordisk, a research team was
`gathered together at Novo with the aim of
`
`developing an insulin product that would be
`just as good as NPH insulin or perhaps even
`better.
`
`The research team achieved its aim. In
`1953, Novo was able to present the
`Lente® products, which for several years
`
`larger and larger doses to keep their disease
`under control. There were also still cases of
`
`patients becoming allergic to insulin.
`
`To find the reason for these effects,
`insulin was studied with the help of new
`
`and very sensitive methods. This revealed
`
`'impurities', ie small quantities of substances
`
`originating in the basic material for insulin
`production. Researchers at both Novo and
`
`covered nearly a third of the world's insulin
`consumption. The Lente® series consisted of
`
`Nordisk now concentrated on purifying the
`
`insulin products to reduce or perhaps even
`
`avoid 'impurities' and the development of
`antibodies.
`
`three medications, each with its own degree
`
`of prolonged action, achieved through a
`
`chemical combination of insulin and zinc.
`
`This enabled doctors to prescribe a dosage
`regimen suited to the needs of the individual.
`
`At the same time, the prolonged action was
`achieved without use of non-insulin-related
`
`agents. For patients, this had the added
`benefit of fewer allergic reactions.
`
`Insulin and antibodies
`
`Although insulin products had become
`much purer than in the 1920s, there were
`
`still many problems to be solved. In 1960, US
`
`studies showed that all people with diabetes
`
`formed antibodies against insulin. This meant
`that the effect of the insulin was somewhat
`
`weakened and that patients would need
`
`The three inventors of the Lente® products,
`(from left) Knud Hallas-M0ller, J0rgen
`Schlichtkrull and Karl Pedersen.
`
`2 In 1952, the first 200 Arne Jacobsen 'Ant'
`chairs were produced for Novo's new
`canteen.
`
`3 For a time, the Lente ® products covered up
`to a third of the world's insulin consumption.
`
`4 A consultation at Hvid0re Hospital in the
`1950s, when Novo launched the Lente®
`products.
`
`14
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.015
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`
`
`Sanofi Exhibit 2137.016
`Sanofi Exhibit 2137.016
`Mylan v. Sanofi
`Mylan v. Sanofi
`IPR2018-01675
`lPR2018-01675
`
`

`

`New, highly purified products
`
`In 1973, the research on antibody
`reactions led to the introduction by Novo
`of Monocomponent insulin (MC insulin).
`The name refers to the product's unusual
`
`purity, in that it consisted largely of just one
`component: the insulin itself. In 1977, Novo
`
`was able to market a complete range of
`insulin products of MC standard.
`
`Nordisk also developed improved
`
`purification methods, and in 1974 it
`launched a highly purified porcine insulin.
`
`Nordisk made only porcine insulin after
`
`1967, when US studies revealed that bovine
`
`insulin produced more antibody reactions
`than porcine insulin.
`
`Clinical tests showed that people with
`diabetes formed far fewer antibodies when
`treated with highly purified insulin from
`
`Novo and Nordisk. Doctors therefore felt
`
`safe in prescribing the new products for
`
`patients who had previously developed
`insulin allergies.
`
`It was also found that with highly purified
`insulin, the dosage needed to control the
`disease could be reduced.
`
`1 By 1977, Novo's entire portfolio of insulins
`was of Monocomponent quality.
`
`2 In 1974, Novo's kindergarten opened in
`Bagsvaerd . It was one of the first company
`childcare facilities in Denmark.
`
`3 Highly purified insulin from Nordisk.
`
`16
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.017
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

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`Sanofi Exhibit 2137.018
`Sanofi Exhibit 2137.018
`Mylan v. Sanofi
`Mylan v. Sanofi
`IPR2018-01675
`lPR2018-01675
`
`

`

`International growth
`
`At the beginning of the 1970s, Novo and
`
`of the 1960s, creating a dynamic, product(cid:173)
`
`Nordisk could look back on 50 years in
`
`oriented organisation that generated
`
`which they both had developed insulin
`
`further growth for Novo in the ensuing
`
`products that had improved the quality
`
`decades. In 1974, this continuous growth
`
`of life of people with diabetes. Novo was
`
`culminated in the introduction of Novo's B
`
`the larger company, having gained an
`
`shares on the Copenhagen Stock Exchange.
`
`impressive worldwide market share. The
`
`Pedersen brothers began exporting to the
`
`Two years earlier, in 1972, a young lawyer
`
`rest of Scandinavia and Germany as early
`
`was hired for a one-year project aimed
`
`as 1926, later expanding into other European
`
`primarily at introducing the company on
`
`markets, the Middle East and Latin America.
`
`the stock exchange. The lawyer's name was
`
`By 1936 Novo was supplying insulin to no
`
`Mads 0vlisen, and he had just returned
`
`less than 40 countries.
`
`to Denmark with an MBA from Stanford
`
`New markets
`
`University in California. As secretary to
`
`the Board of Directors, it was his job to
`
`The Lente® insulins made Novo one of
`
`facilitate the public offering by going
`
`the world's leading insulin manufacturers.
`
`through the company structure.
`
`In 1959, Novo built its first laboratories
`
`in Bagsvaerd, and in the 1960s, this city
`
`What began as a temporary assignment
`
`became the headquarters of the company's
`
`turned into more than three decades of
`
`activities. Subsidiaries had been established
`
`service to the company, during which he as
`
`a few years earlier in Germany, France and
`South Africa, and by 1975 Novo had 14
`subsidiaries.
`
`CEO from 1981 to 2000 exerted a decisive
`
`influence on some of the most important
`
`events in the history of the company. With
`
`his special talent for commitment, Mads
`
`Continuity and innovation
`
`0vlisen also brought an exceptional quality
`
`Knud Hallas-M0ller played a crucial role in
`
`to Novo Nordisk. Based on ideas that reach
`
`the development of Novo, first as a scientist
`and later as CEO from 1961 to 1981. To
`cope with the growing sales, Hallas-M0ller
`
`back to the founders of the company, he
`
`developed, defined and implemented the
`
`fundamental values that still characterise
`
`restructured the company at the beginning
`
`the Novo Nordisk of today.
`
`Knud Hallas-Moller, Novo's CEO from 1961
`to 1981, and Mads 0vlisen, CEO at Novo
`from 1981 to 1989 and Novo Nordisk CEO
`from 1989 to 2000.
`
`2 A 1935 export advertisement for Insulin
`Novo.
`
`3 In 1958, Novo established its first subsidiary
`in Mainz, Germany. The building was
`constructed a decade later.
`
`4 In the 1960s, Novo moved to a 122,000
`square metre site in Bagsvcerd, north of
`Copenhagen.
`
`18
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.019
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`NOVO NORDISK HISTORY
`
`19
`
`Sanofi Exhibit 2137.020
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Sales in the US
`
`In 1979, Novo's subsidiary in the US began
`
`that the management, led by Hagedorn,
`did not want increased marketing of the
`
`marketing the company's MC insulins. This
`
`company's products. What mattered most,
`
`was difficult initially, because Novo was
`not allowed to mention the advantages of
`
`the new products until American clinical
`
`the management felt, was research and the
`
`treatment of diabetes.
`
`studies had confirmed the results of the
`
`Changing times
`
`European tests.
`
`However, by collaborating with the US
`
`During the 1970s, however, the new
`
`management pursued an intensive
`marketing policy which resulted in
`
`pharmaceutical company Squibb, which
`
`Nordisk gaining a share of export markets
`
`had an extensive sales organisation and
`a nationwide distribution system, the US
`
`became in 1982 Novo's largest market for
`
`including the US, particularly with its highly
`
`purified porcine insulin. The management
`restructured the company in 1980, spinning
`
`insulin and other pharmaceutical products.
`
`off production, sales and applied research
`
`into a separate unit under the name of
`
`In 1980, Novo established its own sales
`
`organisation in Japan. This resulted in
`
`Nordisk Gentofte. In 1984, Nordisk Gentofte
`was transformed into a public limited
`
`explosive sales growth, and Japan quickly
`
`company, and in 1986 its shares were
`
`became Novo's largest pharmaceutical
`market, closely followed by the US .
`
`listed on the Copenhagen Stock Exchange.
`With this, the company - like Novo - had a
`
`corporate structure that was well prepared
`
`Problems at Nordisk
`
`for continued international growth.
`
`At the beginning of the 1970s, the situation
`at Nordisk was critical . The company had
`
`almost no exports. The reason for this was
`
`In July 1981, Novo became the first
`Scandinavian company to introduce its
`shares on the New York Stock Exchange.
`
`2 A restructuring in 1980 created Nordisk
`Gentofte. The company's shares were listed
`on the Copenhagen Stock Exchange in 1986.
`
`3 Novo's B shares were quoted on the
`Copenhagen Stock Exchange for the
`first time on 17 May 1974.
`
`20
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.021
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`
`
`mum I.-
`1-. Nova 3
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`
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`v
`
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`
`h.
`
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`y
`
`.
`
`lPR2018-01675
`
`Sanofi Exhibit 2137.022
`Sanofi Exhibit 2137.022
`Mylan v. Sanofi
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`\ I
`
`'
`
`Human insulin
`
`' o
`
`Following the introduction of highly purified
`
`insulin in the 1970s, both companies set
`their sights on a new goal: to produce
`human insulin - insulin that was exactly like
`the insulin produced by the human body.
`
`Tests showed that patients developed even
`fewer antibodies when treated with human
`insulin, and that those who suffered allergic
`
`reactions to highly purified porcine insulin
`could benefit from the new human insulin.
`
`Many difficulties had to be overcome, but
`
`Genetic engineering
`
`in 1982 Novo succeeded in its endeavours,
`becoming the first company in the world to
`
`convert porcine insulin into human insulin by
`
`In 1987, Novo began industrial production
`
`of human insulin on the basis of genetically
`engineered yeast cells . This meant that
`
`replacing a single amino acid in the porcine
`
`Novo was no longer dependent on animal
`
`insulin molecule. This produced an insulin
`with the same molecular structure and
`
`properties as the insulin produced by the
`
`pancreases and could therefore produce
`
`almost unlimited quantities of insulin. Nordisk
`also developed a method of making human
`
`human body. Nordisk took up the gauntlet,
`
`insulin by means of genetic engineering, but
`
`and was able to introduce human insulin
`just two years later.
`
`did not manage to get the product to market
`
`before the merger in 1989.
`
`Jan Markussen was a research chemist at
`Novo. In 1979, he suggested a method of
`converting porcine insulin into human insulin.
`
`2 Human insulin from Novo.
`
`3 Novo's presentation of the world's first
`human insulin in 1982 was a big event.
`
`4 Human insulin from Nordisk.
`
`22
`
`NOVO NORDISK HISTORY
`
`Sanofi Exhibit 2137.023
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`NOVO NORDISK HISTORY
`
`23
`
`Sanofi Exhibit 2137.024
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Nordisk Infuser and NovoPen®
`
`delighted with the convenient NovoPen®
`
`In the 1980s, doctors became aware that
`
`device, and before long it was selling all
`
`long-term diabetic complications such as
`
`over the world.
`
`kidney failure and blindness could be delayed
`or avoided with better control of patients'
`
`blood sugar. In 1983, Nordisk therefore
`
`Nordisk decided to develop an insulin pen as
`well, and in 1986 it introduced its lnsuject®
`
`marketed an insulin pump called Nordisk
`
`device to the market. Three years later, Novo
`
`Infuser. Just like the pancreas of healthy
`people, this pump constantly released small
`
`presented the world's first disposable insulin
`syringe, Novolet®. Because it was prefilled
`
`quantities of insulin to the body, giving the
`
`patient an almost normal blood sugar level.
`
`with insulin, it was the simplest way of taking
`an insulin injection - Novolet® was always
`
`Novo chose a different solution, introducing
`in 1985 the elegant NovoPen® device.
`
`The pen gave people with diabetes a
`simple means of injecting themselves with
`
`precisely the right dose of insulin several
`
`at hand, easy to operate and offered high
`
`dosage accuracy. With their highly purified
`
`insulin products, human insulin, elegant
`
`pen devices and mastery of the new genetic
`
`engineering techniques, the two Danish
`companies were now in a strong position as
`
`times a day. This meant better control of
`
`international competition increased. Before
`
`their blood sugar level and a reduced risk
`of developing the unpleasant long-term
`
`diabetic complications . Patients were
`
`long, however, they had to admit that
`
`they could achieve even better results by
`combining their efforts .
`
`• ;·
`
`Sanofi Exhibit 2137.025
`Mylan v. Sanofi
`IPR2018-01675
`
`1 Nordisk Infuser.
`
`2 The first Novo Pen® device.
`
`3 lnsuject®.
`
`4 Patient injecting himself using a Novolet®
`device.
`
`5 Novo Let® - the world's first disposable
`insulin syringe.
`
`6 Training in the kitchen at Steno Memorial
`Hospital, ca. 1990.
`
`24
`
`NOVO NORDISK HISTORY
`
`

`

`NOVO NORDISK HISTORY
`
`25
`
`Sanofi Exhibit 2137.026
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`More than insulin
`
`During World War II, rumours of the
`incredible properties of penicillin reached
`
`Denmark. The Pedersen brothers and
`
`Hallas-M0ller immediately realised the
`potential of this new drug, and in 1943
`
`tanning industry to soften leather. They
`
`assumed, however, that the process of
`extracting insulin destroyed the trypsin.
`But during World War II there was such a
`shortage of pancreases that Novo decided
`
`they started a series of experiments with
`
`fermentation of penicillin. The experiments
`
`presented many problems, but in 1947
`Novo was able to introduce Penicillin Novo,
`
`to look for a method of extracting insulin
`and enzymes from the same gland. The
`
`effort succeeded, and in 1941 Novo was
`
`able to introduce its first enzyme product
`
`the company's first product to be made by
`
`for industrial use