10-K 1 amgn-12312015x10k.htm 10-K 10-K


UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Form 10-K
(Mark One)
ý
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2015
OR
¨
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
Commission file number 000-12477
Amgen Inc.
(Exact name of registrant as specified in its charter)
Delaware
 
95-3540776
(State or other jurisdiction of
incorporation or organization)
 
(I.R.S. Employer
Identification No.)
One Amgen Center Drive,
 
91320-1799
Thousand Oaks, California
 
(Zip Code)
(Address of principal executive offices)
 
 
(805) 447-1000
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
Title of Each Class
 
Name of Each Exchange on Which Registered
Common stock, $0.0001 par value
 
The NASDAQ Global Select Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.    Yes  ý    No  ¨
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.    Yes  ¨    No  ý
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or Section 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.    Yes  ý    No  ¨
Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files).    Yes  ý    No  ¨
Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K.  ¨
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one):
Large accelerated filer x
Accelerated filer ¨
Non-accelerated filer ¨
Smaller reporting company ¨
 
 
(Do not check if a smaller reporting company)
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act)    Yes  ¨    No  ý
The approximate aggregate market value of voting and non-voting stock held by non-affiliates of the registrant was $102,117,764,803 as of June 30, 2015(A) 
 
(A)
Excludes 93,926,800 shares of common stock held by directors and executive officers, and any stockholders whose ownership exceeds ten percent of the shares outstanding, at June 30, 2015. Exclusion of shares held by any person should not be construed to indicate that such person possesses the power, directly or indirectly, to direct or cause the direction of the management or policies of the registrant, or that such person is controlled by or under common control with the registrant.
752,091,038
(Number of shares of common stock outstanding as of February 9, 2016)
DOCUMENTS INCORPORATED BY REFERENCE
Specified portions of the registrant’s Proxy Statement with respect to the 2016 Annual Meeting of stockholders to be held May 19, 2016, are incorporated by reference into Part III of this annual report.




INDEX
 
 
 
Page No.
 
Item 1.
 
 
 
 
 
 
 
 
 
 
 
Item 1A.
Item 1B.
Item 2.
Item 3.
Item 4.
 
Item 5.
Item 6.
Item 7.
Item 7A.
Item 8.
Item 9.
Item 9A.
Item 9B.
 
Item 10.
Item 11.
Item 12.
Item 13.
Item 14.
 
Item 15.
 
 

i



PART I

Item 1.
BUSINESS
Amgen Inc. (including its subsidiaries, referred to as “Amgen,” “the Company,” “we,” “our” or “us”) is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. A biotechnology pioneer, Amgen has grown to be one of the world’s leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
Amgen was incorporated in California in 1980 and became a Delaware corporation in 1987. Amgen operates in one business segment: human therapeutics.
Significant Developments
Following is a summary of significant developments affecting our business that have occurred since the filing of our Annual Report on Form 10-K for the year ended December 31, 2014, and in early 2016.
Products/Pipeline
Cardiovascular
Corlanor® (ivabradine)
In April 2015, we announced that the U.S. Food and Drug Administration (FDA) granted approval of Corlanor® to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35 percent, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta blockers or have a contraindication to beta blocker use.
Repatha® (evolocumab)
In July 2015, we announced that the European Commission (EC) granted marketing authorization for Repatha® for the treatment of high cholesterol, as an adjunct to diet:
In combination with statins or other lipid-lowering therapies in patients unable to control their low-density lipoprotein cholesterol (LDL-C) with maximum tolerated statin doses, or
Alone or in combination with other lipid-lowering therapies in patients who are statin intolerant or for whom a statin is contraindicated.
Repatha® is also approved in the European Union (EU) in combination with other lipid-lowering agents in patients with homozygous familial hypercholesterolemia (age 12 and over). The effect of Repatha® on cardiovascular morbidity and mortality has not been determined.
In August 2015, we announced that the FDA granted approval of Repatha® as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C; and as an adjunct to diet and other LDL-lowering therapies for the treatment of patients with homozygous familial hypercholesterolemia, who require additional lowering of LDL-C. The effect of Repatha® on cardiovascular morbidity and mortality has not been determined.
In September 2015, we announced that we submitted an application to the FDA for a single-dosing option for the monthly administration of Repatha®. The FDA has set a July 10, 2016, Prescription Drug User Fee Act (PDUFA) target action date as a goal for the completion of their review of our application.
In January 2016, we, together with our joint venture partner Astellas Pharma, Inc., announced that the Japanese Ministry of Health, Labour and Welfare approved Repatha® for the treatment of patients with familial hypercholesterolemia or hypercholesterolemia who have high risk of cardiovascular events and do not adequately respond to HMG-CoA reductase inhibitors (statins).
In February 2016, we announced that the phase 3 GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial evaluating Repatha® in patients with high cholesterol who cannot tolerate statins, met its co-primary endpoints.

1



Inflammation
Brodalumab
In August 2015, we terminated participation in the co-development and commercialization of brodalumab with AstraZeneca plc (AstraZeneca).
Nephrology
Aranesp® (darbepoetin alfa)
In February 2016, we announced that the randomized, double-blind, placebo-controlled phase 3 ARCADE trial met its primary endpoint of reducing the incidence of red blood cell transfusions in anemic patients with low and intermediate-1 risk myelodysplastic syndrome (MDS).
Parsabiv(etelcalcetide)*
In September 2015, we announced that we submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for Parsabiv, an intravenous calcimimetic agent, for the treatment of secondary hyperparathyroidism (SHPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.
In November 2015, we announced that the FDA accepted for review our New Drug Application (NDA) for Parsabiv for the treatment of SHPT in patients with CKD on hemodialysis. The FDA has set an August 24, 2016, PDUFA target action date.
Neuroscience
AMG 334
In July 2015, we announced that we initiated phase 3 studies in episodic migraine. AMG 334 is being jointly developed with Novartis AG (Novartis).
Oncology
BLINCYTO® (blinatumomab)
In November 2015, we announced that the EC granted conditional marketing authorization for BLINCYTO® for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).
In February 2016, we announced that the phase 3 TOWER study evaluating the efficacy of BLINCYTO® versus standard of care in adult patients with Ph- relapsed or refractory B-cell precursor ALL, met its primary endpoint of improved overall survival (OS) based on the results of a prespecified interim analysis.
IMLYGIC(talimogene laherparepvec)
In October 2015, we announced that the FDA granted approval of IMLYGICfor the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. IMLYGIC has not been shown to improve OS or have an effect on visceral metastases.
In December 2015, we announced that the EC approved the use of IMLYGICfor the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a), with no bone, brain, lung or other visceral disease.
Kyprolis® (carfilzomib)
In April 2015, we announced the initiation of a phase 3 study with weekly dosing in relapsed and refractory multiple myeloma.
In July 2015, we announced that the FDA approved the supplemental NDA (sNDA) for Kyprolis® in combination with Revlimid® (lenalidomide) and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy, based on the phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial.
In November 2015, we announced that the EC granted marketing authorization for Kyprolis® in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy, based on the phase 3 ASPIRE trial.

* FDA provisionally approved trade name

2



In December 2015, we announced that we submitted to the EMA a Variation to the MAA to expand the indication for Kyprolis® in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy based on the data from the ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial.
In January 2016, we announced that the FDA approved the sNDA of Kyprolis® in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The FDA also granted full approval for Kyprolis® as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. The combination with dexamethasone was approved based on the ENDEAVOR trial.
Neulasta® (pegfilgrastim)
In March 2015, we announced the Neulasta® Delivery kit, now known as the Neulasta® Onpro kit, was available in the United States. The Neulasta® Onpro kit includes a specially designed single-use prefilled syringe co-packaged with the new On-body Injector for Neulasta® that enables the healthcare provider to initiate administration of Neulasta® on the same day as chemotherapy—with delivery of the patient’s full dose of Neulasta® the day following chemotherapy administration, consistent with the Neulasta® prescribing information. This eliminates the need for patients to return to their healthcare provider the day after chemotherapy, which would otherwise be needed to receive the Neulasta® injection.
Trebananib
In April 2015, we announced that we stopped administration of blinded investigational product in the phase 3 study of trebananib in first-line ovarian cancer based on a recommendation by the Data Safety Monitoring Committee.
Vectibix® (panitumumab)
In April 2015, we announced that the EC approved a new use of Vectibix® as first-line treatment in combination with FOLFIRI for the treatment of adult patients with wild-type RAS metastatic colorectal cancer (mCRC).
In June 2015, we announced that the phase 3 study evaluating Vectibix® and best supportive care (BSC) compared to BSC alone in patients with chemorefractory wild-type KRAS (exon 2) mCRC, met its primary endpoint.
Bone health
Prolia® (denosumab)
In June 2015, we announced that the phase 3 study evaluating the treatment effect of adjuvant Prolia® therapy in postmenopausal women with early hormone receptor positive breast cancer receiving aromatase inhibitor therapy, met its primary endpoint.
Romosozumab  
In September 2015, we and UCB, our collaboration partner in the development of romosozumab, announced that the open label phase 3 STRUCTURE (STudy evaluating effect of RomosozUmab Compared with Teriparatide in postmenopaUsal women with osteoporosis at high risk for fracture pReviously treated with bisphosphonatE therapy) trial met its primary endpoint.
Biosimilars
In September 2015, we and Allergan plc (Allergan), our collaboration partner in the development and commercialization of biosimilar candidate ABP 215, announced that a phase 3 study of ABP 215 compared with Avastin® (bevacizumab) met its primary and secondary endpoints.
In January 2016, we announced that the FDA accepted for review our Biologics License Application (BLA) for ABP 501, a biosimilar candidate to Humira® (adalimumab). The FDA has set a September 25, 2016, Biosimilar User Fee Act target action date. In addition, in December 2015, we announced that we submitted an MAA to the EMA.

3


Marketing, Distribution and Selected Marketed Products
The largest concentration of our sales and marketing forces are based in the United States and Europe. Additionally, we continue to expand the commercialization and marketing of our products into new geographic territories, including parts of Latin America, the Middle East and Asia. This expansion can occur either via establishing our own affiliate, acquiring existing third party businesses or product rights, or in partnering with third parties. Use of our own sales and marketing forces versus a third-party varies across these markets. This typically depends on several factors including the nature of entry into the new market, the size of opportunity and the operational capabilities. Together with our partners, we market our products to healthcare providers, including physicians or their clinics, dialysis centers, hospitals and pharmacies.
In the United States, we sell primarily to pharmaceutical wholesale distributors who we utilize as the principal means of distributing our products to healthcare providers. We also market certain products directly to consumers through direct-to-consumer print and television advertising, as well as through multi-channel marketing. For further discussion, see Government Regulation—Regulation of Product Marketing and Promotion. Outside the United States, we sell principally to healthcare providers and/or pharmaceutical wholesale distributors depending on the distribution practice in each country.
Our product sales to three large wholesalers, AmerisourceBergen Corporation, McKesson Corporation and Cardinal Health, Inc., each accounted for more than 10% of total revenues for each of the years ended December 31, 2015, 2014 and 2013. On a combined basis, these wholesalers accounted for approximately 97%, 94% and 93% of our U.S. gross product sales, respectively, and approximately 81%, 77% and 75% of our worldwide gross revenues, respectively. We monitor the financial condition of our larger customers, and we limit our credit exposure by setting credit limits and, in certain circumstances, by requiring letters of credit.
For financial information related to our one business segment, see Part IV—Consolidated Statements of Income, Consolidated Balance Sheets and Note 19, Segment information, to the Consolidated Financial Statements.
Our products are marketed around the world with the United States being our largest market. The following chart shows our product sales by principal product and by geography for the years ended December 31, 2015, 2014 and 2013.

4


Enbrel® (etanercept)
We market ENBREL primarily in the United States. It was launched in 1998 and is used primarily in the indications for the treatment of adult patients with the following conditions:
moderately to severely active rheumatoid arthritis,
chronic moderate-to-severe plaque psoriasis patients who are candidates for systemic therapy or phototherapy, and
active psoriatic arthritis.
Pfizer Inc. (Pfizer) has the rights to market and sell ENBREL outside the United States and Canada.
Neulasta® (pegfilgrastim)
We market Neulasta®, a pegylated protein based on the filgrastim molecule, primarily in the United States and Europe. Neulasta® was launched in 2002, and is used primarily in the indication to help reduce the chance of infection due to a low white blood cell count, in people with certain types of cancer (non-myeloid) who receive anti-cancer medicines (chemotherapy) that can cause fever and a low blood cell count. In March 2015, the Neulasta® Onpro kit became available in the United States.
ESAs (erythropoiesis-stimulating agents)
Aranesp® (darbepoetin alfa)
We market Aranesp® primarily in Europe and in the United States. It was launched in 2001, and is indicated for the treatment of anemia caused by CKD (in both patients on dialysis and patients not on dialysis). Aranesp® is also indicated for the treatment of anemia due to concomitant myelosuppressive chemotherapy in patients with non-myeloid malignancies, and when chemotherapy will be used for at least two months after starting Aranesp®.
EPOGEN® (epoetin alfa)
We market EPOGEN® in the United States for dialysis patients. It was launched in 1989, and we market it for the indication to treat a lower-than-normal number of red blood cells (anemia) caused by CKD in patients on dialysis to lessen the need for red blood cell transfusions. The majority of our sales are to two large dialysis providers.
Aranesp® and EPOGEN® compete with each other in the United States, primarily in the dialysis setting.
Sensipar®/Mimpara® (cinacalcet)
We market cinacalcet as Sensipar® primarily in the United States and as Mimpara® primarily in Europe. It was launched in 2004 and is used primarily in the indication for the treatment of SHPT in adult patients with CKD on dialysis.
XGEVA® (denosumab)
We market XGEVA® primarily in the United States and Europe. XGEVA® was launched in the United States in 2010, and is used primarily in the indication for the prevention of skeletal-related events (SREs) (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in patients with bone metastases from solid tumors. It is not indicated for the prevention of SREs in patients with multiple myeloma. XGEVA® was launched in Europe in 2011, and is used primarily in the indication for the prevention of SREs in adults with bone metastases from solid tumors.
Prolia® (denosumab)
We market Prolia® primarily in the United States and Europe. It contains the same active ingredient as XGEVA® but is approved for different indications, patient populations, doses and frequencies of administration. Prolia® was launched in the United States and Europe in 2010. In the United States, it is used primarily in the indication for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In Europe, Prolia® is used primarily for the treatment of osteoporosis in postmenopausal women at increased risk of fractures.
NEUPOGEN® (filgrastim)
We market NEUPOGEN®, a recombinant-methionyl human granulocyte colony-stimulating factor (G-CSF), primarily in the United States, Canada and Europe. NEUPOGEN® was launched in 1991, and is used primarily in the indication to help reduce the chance of infection due to a low white blood cell count, in people with certain types of cancer (non-myeloid) who receive anti-cancer medicines (chemotherapy) that can cause fever and a low blood cell count.
Other Marketed Products
We market several other products including Vectibix® (panitumumab), Nplate® (romiplostim), Kyprolis® (carfilzomib), BLINCYTO® (blinatumomab), Repatha® (evolocumab), Corlanor® (ivabradine) and IMLYGIC(talimogene laherparepvec).

5


Patents
The following table describes our outstanding material patents for the indicated product by territory, general subject matter and latest expiry date. Certain of the European patents are the subject of supplemental protection certificates that provide additional protection for the product in certain European countries beyond the dates listed in the table (see footnotes).
One or more patents with the same or earlier expiry date may fall under the same “general subject matter” and are not separately listed.
Product
 
Territory
 
General Subject Matter
 
Expiration
Enbrel® 
(etanercept)
 
U.S.
 
Methods of treating psoriasis
 
8/13/2019
 
U.S.
 
Aqueous formulation and methods of treatment using the formulation
 
6/8/2023
 
U.S.
 
Fusion protein, and pharmaceutical compositions
 
11/22/2028
 
U.S.
 
DNA encoding fusion protein, and methods of making fusion protein
 
4/24/2029
Neulasta® 
(pegfilgrastim)
 
Europe
 
Pegylated G-CSF(1)
 
2/8/2015
Aranesp® (darbepoetin alfa)
 
U.S.
 
Glycosylation analogs of erythropoietin proteins
 
5/15/2024
 
Europe
 
Glycosylation analogs of erythropoietin proteins(1)
 
8/16/2014
Sensipar®/
Mimpara
® (cinacalcet)
 
U.S.
 
Methods of treatment
 
12/14/2016
 
U.S.
 
Calcium receptor-active molecules
 
3/8/2018
 
Europe
 
Calcium receptor-active molecules(1)
 
10/23/2015
Prolia®/
XGEVA
® (denosumab)
 
U.S.
 
RANKL antibodies; and methods of use(2)
 
12/22/2017
 
U.S.
 
Methods of treatment
 
6/25/2022
 
U.S.
 
Nucleic acids encoding RANKL antibodies, and methods of producing RANKL antibodies
 
11/30/2023
 
U.S.
 
RANKL antibodies including sequences
 
2/19/2025
 
Europe
 
RANKL antibodies(1)
 
12/22/2017
 
Europe
 
Medical use of RANKL antibodies(1)
 
4/15/2018
 
Europe
 
RANKL antibodies including epitope binding
 
2/23/2021
 
Europe
 
RANKL antibodies including sequences(1)
 
6/25/2022
Vectibix® (panitumumab)
 
U.S.
 
Human monoclonal antibodies to epidermal growth factor receptor (EGFr)
 
4/8/2020
 
Europe
 
Human monoclonal antibodies to EGFr(1)
 
5/5/2018
Nplate® (romiplostim)
 
U.S.
 
Thrombopoietic compounds
 
1/19/2022
 
Europe
 
Thrombopoietic compounds(1)
 
10/22/2019
Kyprolis® (carfilzomib)
 
U.S.
 
Compositions and compounds
 
12/7/2027
 
U.S.
 
Methods of treatment
 
4/14/2025
 
Europe
 
Compositions, compounds and methods of treatment
 
8/8/2025
BLINCYTO® (blinatumomab)
 
U.S.
 
Bifunctional polypeptides(3)
 
4/21/2019
 
U.S.
 
Method of administration
 
9/28/2027
 
Europe
 
Bifunctional polypeptides
 
11/26/2024
 
Europe
 
Method of administration
 
11/29/2026
Repatha®
(evolocumab)
 
U.S.
 
Antibodies(3)
 
10/25/2029
 
U.S.
 
Methods of treatment
 
10/8/2030
IMLYGIC
(talimogene laherparepvec)
 
U.S.
 
Compositions and method of treatment(3)
 
1/22/2021
 
Europe
 
Composition and uses
 
1/22/2021
(1) 
A European patent with this subject matter may also be entitled to supplemental protection in one or more countries in Europe and the length of any such extension will vary by country. For example, supplementary protection certificates have been issued related to the indicated products for patents in at least the following countries:
pegfilgrastim - France, Germany, Italy, Spain, and the United Kingdom, expiring in August 2017

6


darbepoetin alfa - France, Germany, Italy, Spain, and the United Kingdom, expiring in June 2016
denosumab - France, Italy, Spain and the United Kingdom, expiring in 2025
cinacalcet - France, Germany, Italy, Spain, and the United Kingdom, expiring in 2019
panitumumab - France, Germany, Italy, Spain, and the United Kingdom, expiring in 2022
romiplostim - France, Italy, Spain, and the United Kingdom, expiring in 2024
(2) 
The U.S. Patent and Trademark Office has issued a Notice of Final Determination that a patent with this subject matter is eligible for patent term extension with an expiry of September 17, 2021.
(3) 
A patent with this subject matter may be entitled to patent term extension in the United States.
Competition
We operate in a highly competitive environment. Our products compete with other products or treatments for diseases for which our products may be indicated. Our competitors market products or are actively engaged in research and development (R&D) in areas where we have products or where we are developing product candidates or new indications for existing products. Our competitive positions may be based on, among other things, safety, efficacy, reliability, availability, patient convenience/delivery devices, price, reimbursement, access and timing of market entry and patent position and expiration.
Certain of the existing patents on our principal products have recently expired and we face new and increasing competition, including from biosimilars. We may also compete against biosimilar or generic versions of our competitors’ products. A biosimilar is another version of a biological product for which marketing approval is sought or has been obtained based on a demonstration that it is “similar” to the original reference product. See Government Regulation. We expect the adverse impact from biosimilars to be more like branded biologics than generic small molecules. We expect patients, providers and payers to place a high value on the reputation, reliability and safety of biosimilars. Zarxio, a biosimilar version of NEUPOGEN® from Sandoz, a Novartis company (Sandoz), which launched in the United States on September 3, 2015, is the first biosimilar entrant into the U.S. market. Companies are developing biosimilar versions of EPOGEN® and Neulasta®, along with additional biosimilar versions of NEUPOGEN®. We expect our products to continue to generate substantial sales and cash flow for years to come even after competitors enter the market. We are prepared to compete and will leverage the experience that we have had in the United States versus branded competition as well as our considerable experience competing against epoetin alfa and filgrastim biosimilars in Europe.
The introduction of new products, the development of new processes or technologies by competitors or the emergence of new information about existing products may result in increased competition for our marketed products, even for those protected by patents, or in a reduction of the price that we receive from selling our products. In addition, the development of new treatment options or standards of care may reduce the use of our products or may limit the utility and application of ongoing clinical trials for our product candidates (as used in this document, clinical trials may include prospective clinical trials, observational studies, registries and other studies). For further discussion, see Item 1A. Risk Factors—Our products face substantial competition and Item 1A. Risk Factors—We currently face competition from biosimilars and expect to face increasing competition in the future.
The following table reflects our significant competitors and is not exhaustive.
Product
 
Territory
 
Competitor Marketed Product
 
Competitors
ENBREL
 
U.S. & Canada
 
REMICADE®
 
Janssen Biotech, Inc. (Janssen)(1)/Merck & Company, Inc. (Merck)
 
U.S. & Canada
 
HUMIRA®
 
AbbVie Inc.
 
U.S. & Canada
 
STELARA®(2)
 
Janssen(1)
Neulasta®
 
Europe
 
Lonquex®
 
Teva Pharmaceutical Industries Ltd. (Teva)
 
Europe
 
Filgrastim biosimilars(3)
 
Various
Aranesp®
 
U.S.
 
PROCRIT®(4)
 
Janssen(1)
 
Europe
 
EPREX®/ERYPO®
 
Janssen-Cilag(1)
 
Europe
 
Epoetin alfa biosimilars(3)
 
Various
 
U.S. & Europe
 
MIRCERA®(5)
 
Galenica Group (Galenica)/F. Hoffmann-La Roche Ltd. (Roche)
EPOGEN®
 
U.S.
 
MIRCERA®(5)
 
Galenica/Roche
Sensipar®(6)/
Mimpara®
 
U.S. & Europe
 
Active Vitamin D analogs
 
Various

7


Product
 
Territory
 
Competitor Marketed Product
 
Competitors
XGEVA®
 
U.S. & Europe
 
Zoledronate generics
 
Various
Prolia®
 
U.S. & Europe
 
Alendronate generics
 
Various
 
U.S. & Europe
 
Raloxifene generics
 
Various
 
U.S. & Europe
 
Zoledronate generics
 
Various
NEUPOGEN®
 
U.S.
 
Granix®
 
Teva
 
U.S.
 
Zarxio
 
Sandoz
 
Europe
 
Filgrastim biosimilars(3)
 
Various
Vectibix®
 
U.S. & Europe
 
Erbitux®
 
Eli Lilly/Bristol-Myers Squibb Company (BMS); Merck KGaA
 
U.S. & Europe
 
Avastin®
 
Genentech, Inc. (a Member of the Roche Group)
Nplate®
 
U.S. & Europe
 
Promacta®/Revolade®
 
Novartis

Kyprolis®(8)
 
U.S.
 
VELCADE®
 
Millennium Pharmaceuticals, Inc.(7)
 
U.S.
 
REVLIMID®
 
Celgene Corporation (Celgene)
 
U.S.
 
POMALYST®
 
Celgene
Repatha®
 
U.S. & Europe
 
PRALUENT®
 
Regeneron Pharmaceuticals, Inc.
(1) 
A subsidiary of Johnson & Johnson (J&J).
(2) 
Dermatology only.
(3) 
Approved via the EU biosimilar regulatory pathway.
(4) 
PROCRIT® competes with Aranesp® in the supportive cancer care and pre-dialysis settings.
(5) 
MIRCERA® competes with Aranesp® in the nephrology segment only.
(6) 
Teva and Barr Pharmaceuticals have received tentative approval from the FDA for generic versions of Sensipar® that could compete with Sensipar® in the future. There is an injunction prohibiting them from commercializing in the United States until expiration of the Sensipar® patents.
(7) 
A wholly-owned subsidiary of Takeda Pharmaceutical Company Limited.
(8) 
Kyprolis® operates in a rapidly growing market in a new therapeutic area where competition is changing rapidly.
Reimbursement
Sales of our principal products are dependent on the availability and extent of coverage and reimbursement from third-party payers. In many markets around the world, these payers, including government health systems, private health insurers and other organizations, continue to be focused on reducing the cost of healthcare. Their efforts have only intensified as a result of rising healthcare costs and economic challenges. Drugs, and specialty drugs, such as our products, remain a focus for cost containment by these parties. Government and private payers around the world are being more restrictive regarding the use of our and other biopharmaceutical products, while demanding a greater level of clinical evidence to support the benefit such products bring to patients and the broader healthcare system.
Recent developments have intensified scrutiny of biopharmaceutical companies in the United States. Pricing practices of a few biopharmaceutical companies have increased public media and government scrutiny of our entire industry. Such pricing practices provide greater incentive for government and private payers to limit or regulate the price of drug products and services. At the same time, value assessments of new technology, previously used predominantly outside the United States, are having an impact in the U.S. healthcare environment. Healthcare provider and independent organizations are creating their own value assessments of biopharmaceutical drugs for comparison to manufacturer pricing. While these organizations do not set drug prices, they seek to influence pricing and payer and provider decision-making by making their assessments public. These developments create greater pressure on the access, pricing and sales of our products.
In the United States, healthcare providers are reimbursed for covered services and products they deliver through Medicare, Medicaid and other government healthcare programs, as well as through private payers. Pharmacies are also reimbursed in a similar manner for drug products they dispense. We are required to provide specified rebates or discounts on the products we sell to certain government funded programs, including Medicare and Medicaid, which have increased over time. The Patient Protection and Affordable Care Act (ACA), enacted in 2010, increased many of the mandatory discounts and rebates required of us and

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imposed a new Branded Prescription Pharmaceutical Manufacturers and Importers (BPD) fee payable each year by us and other manufacturers. In addition, Medicare currently requires a 2% reduction to Medicare payment rates to providers due to federal budget cuts referred to as “sequestration”. Such changes have had, and are expected to continue to have, a material adverse impact on our business.
Further efforts to reduce government healthcare program costs could also affect us and our industry. Examples of proposals that have been discussed and debated but not yet enacted include state ballot initiatives designed to require pharmaceutical manufacturers to publicly report proprietary pricing information or state legislative efforts to place a maximum price ceiling, or cap, on pharmaceutical products purchased by state agencies. Other legislative and regulatory actions that would have a significant impact on Amgen include: changes to how the Medicare program covers and reimburses current and future drugs, including for patients with End-Stage Renal Disease; changes in the Federal payment rate or new rebate requirements for covered drugs and policies for payment; and coverage and payment for biosimilars, including the current Medicare biosimilar coverage and payment policies that enable greater utilization versus the branded originators, or other policies that provide easier substitution or reimbursement advantages.
In the U.S. private sector, healthcare providers and payers remain focused on reducing healthcare costs. They continue to institute various cost reduction and containment measures such as more limited benefit designs, tiering of co-pays, stricter usage requirements and higher deductible benefit plans that lower healthcare costs altogether or shift a greater proportion of costs to patients. In the retail pharmacy sector, where the majority of our sales for ENBREL, Sensipar® and Repatha® occur, pharmacy benefit managers (PBMs) and insurers are implementing more rigorous utilization and pricing tools that can reduce Amgen product usage or revenues. PBMs are third-party administrators of prescription drug programs for large employers, health plans and government programs. These customers, known as “plan sponsors,” increasingly rely on PBMs to help administer their plans in a cost effective manner and negotiate contracts on their behalf. Consolidation in the market has resulted in three PBMs overseeing approximately 75% and three insurers overseeing approximately 43%, respectively, of total covered lives in the United States. This has allowed each greater market power and negotiating leverage to influence or impact patient drug usage and price. In the case of PBMs, this can include mandating stricter utilization criteria or excluding drugs from their formulary altogether in favor of competitor drugs or alternative treatments. Formulary exclusion effectively encourages the patient and provider to seek alternative treatment or pay 100% of the cost of the drug.
Generally, in countries outside the United States, government-sponsored healthcare systems are the primary payers for drugs and biologics. With increased budgetary constraints, payers in many countries employ a variety of measures to exert downward price pressure. These measures can include mandatory price controls, price referencing, therapeutic reference pricing, increasing mandates or incentives for generic substitution and biosimilar usage, and government-mandated price cuts. In addition, healthcare reform and related legislative proposals have targeted the pharmaceutical sector with multiple mechanisms to reduce government healthcare expenditures. We expect that countries will continue to take aggressive actions to reduce expenditures on drugs and biologics. Similarly, fiscal constraints may also impact the extent to which countries are willing to approve new innovative therapies and/or allow access to new technologies. For example, many Health Technology Assessment (HTA) organizations use formal economic metrics such as cost-effectiveness to determine coverage and reimbursement of new therapies, and these organizations are proliferating in established and emerging markets.
These dynamics and recent developments serve to create pressure on the pricing and potential usage of our products, and the industry as a whole. We remain focused on addressing unmet medical needs. We believe the pricing of our medicines reflects the holistic value delivered to patients, providers and payers and is aligned with the investment and risk we undertake to develop medicines as well as fund future scientific innovation. We continue to adapt to these dynamics to successfully bring our medicines to patients. This includes working more closely with payers to address their concerns, delivering robust supporting data packages, and developing mutually beneficial contracting structures. As such, we believe we can successfully deliver the value of our medicines.
See Item 1A. Risk Factors—Our sales depend on coverage and reimbursement from third party payers, and pricing and reimbursement pressures may affect our profitability and Item 1A. Risk Factors—Guidelines and recommendations published by various organizations can reduce the use of our products.

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Manufacturing, Distribution and Raw Materials
Manufacturing
The products we manufacture include both biologics and small molecule drugs. The majority of our products are biologics which are produced in living cells and are inherently complex due to naturally-occurring molecular variations. Highly specialized knowledge and extensive process and product characterization are required to transform laboratory-scale processes into reproducible commercial manufacturing processes. For additional information regarding manufacturing facilities, see Item 2. Properties.
We perform most of our bulk manufacturing, formulation, fill and finish activities in our Puerto Rico facility and also conduct finish activities in the Netherlands. We also utilize third-party contract manufacturers to supplement the bulk, formulation, fill, and/or packaging of certain Amgen principal products, including ENBREL, Neulasta®, XGEVA®, Sensipar®/Mimpara®, Prolia®, as well as Kyprolis®.
Clinical bulk, formulation, fill and finish manufacturing facilities are operated primarily in our Thousand Oaks, California, and West Greenwich, Rhode Island locations. We also utilize third-party contract manufacturers for certain clinical products.
See Item 1A. Risk Factors for a discussion of the factors that could adversely impact our manufacturing operations and the global supply of our products.
Distribution
We operate distribution centers in the United States—principally in Kentucky and California—and the Netherlands for worldwide distribution of the majority of our commercial and clinical products. We also use third-party distributors to supplement distribution of our products worldwide.
Other
In addition to the manufacturing and distribution activities noted above, our operations in the United States, Puerto Rico and the Netherlands include key manufacturing support functions, including quality control, process development, procurement, production scheduling and warehousing. Certain of those manufacturing and distribution activities are highly regulated by the FDA as well as other international regulatory agencies. See Government Regulation—Regulation of Manufacturing Standards.
Manufacturing Initiatives
We believe we are a leader in manufacturing biologics and our manufacturing capabilities are a competitive advantage. We have multiple ongoing initiatives that are designed to extend this advantage by optimizing our manufacturing network and/or mitigating manufacturing risks while continuing to ensure adequate supply of our products. These initiatives include the licensure of a new formulation and fill facility at our Puerto Rico site; and as part of a risk mitigation strategy, full licensure of our formulation, fill and finish site in Ireland to manufacture our products. Both of these new facilities will require qualification and licensure by various regulatory authorities.
In 2015, we initiated the drug substance conformance campaign to facilitate licensure at our monoclonal antibody manufacturing facility in Singapore. Upon licensure, this facility will expand our capability to manufacture monoclonal antibodies utilizing new technology and innovation. The facility will be fully reconfigurable, providing efficient manufacturing capabilities to help ensure supply of our products worldwide. We have also begun construction on an additional new facility at the site in Singapore to enable the manufacture of the active pharmaceutical ingredient for Kyprolis®.
In addition to these initiatives, we have projects designed to optimize manufacturing asset utilization, to continue our use of third-party contract manufacturers and to maintain a state of regulatory compliance. This includes manufacturing network consolidation initiatives as well as process improvements surrounding manufacturing. See Item 1A. Risk Factors—Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.
Raw Materials and Medical Devices
Certain raw materials, medical devices and components necessary for the commercial and/or clinical manufacturing of our products are provided by and are the proprietary products of unaffiliated third-party suppliers, certain of which may be our only sources for such materials. We currently attempt to manage the risk associated with such suppliers by inventory management, relationship management and evaluation of alternative sources when feasible. We also monitor the financial condition of certain suppliers and their ability to supply our needs. See Item 1A. Risk Factors—We rely on third-party suppliers for certain of our raw materials, medical devices and components.

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We perform various procedures to assist in authenticating the source of raw materials, including intermediary materials used in the manufacture of our products, which include verification of the country of origin. These procedures are incorporated into the manufacturing processes we and our third-party contract manufacturers perform.
Government Regulation
Regulation by government authorities in the United States and other countries is a significant factor in the production and marketing of our products and our ongoing R&D activities. In order to clinically test, manufacture and market products for therapeutic use, we must satisfy mandatory procedures and safety and effectiveness standards established by various regulatory bodies. Compliance with these standards is complex and failure to comply with any of these standards can result in significant implications. See Item 1A. Risk Factors for a discussion of factors that can adversely impact our development and marketing of commercial products including global regulatory implications.
Regulation in the United States
In the United States, the Public Health Service Act, the Federal Food, Drug, and Cosmetic Act (FDCA) and the regulations promulgated thereunder, as well as other federal and state statutes and regulations govern, among other things, the production, research, development, testing, manufacture, quality control, labeling, storage, record keeping, approval, advertising and promotion, reporting of certain payments and other transfers of value, and distribution of our products.
Clinical Development and Product Approval. Drug development in our industry is complex, challenging and risky; and failure rates are high. Product development cycles are typically very long - approximately 10 to 15 years from discovery to market. A potential new medicine must undergo many years of preclinical and clinical testing to establish its safety and efficacy for use in humans at appropriate dosing levels and with an acceptable risk-benefit profile.
After laboratory analysis and preclinical testing in animals, we file an Investigational New Drug Application (IND) with the FDA to begin human testing. Typically, we undertake an FDA-designated three-phase human clinical testing program.
In phase 1, we conduct small clinical trials to investigate the safety and proper dose ranges of our product candidates in a small number of human subjects.
In phase 2, we conduct clinical trials to investigate side effect profiles and the efficacy of our product candidates in a large number of patients who have the disease or condition under study.
In phase 3, we conduct clinical trials to investigate the safety and efficacy of our product candidates in a large number of patients who have the disease or condition under study.
The FDA monitors the progress of each trial conducted under an IND and may, at its discretion, re-evaluate, alter, suspend or terminate the testing based on the data accumulated to that point and the FDA’s risk-benefit assessment with regard to the patients enrolled in the trial. The results of preclinical and clinical trials are submitted to the FDA in the form of a BLA for biologic products or an NDA for small molecule products. We cannot market or promote a new product until our marketing application has been approved by the FDA.
Approval of Biosimilars. The ACA authorized the FDA to approve biosimilars via a separate, abbreviated pathway. The pathway allows sponsors of a biosimilar to seek and obtain regulatory approval based in part on the non-clinical and clinical trial data of an originator product to which the biosimilar has been demonstrated to be “similar.” The relevance of demonstrating “similarity” is that in many cases, biosimilars can be brought to market without conducting the full suite of clinical trials typically required of originators, as risk-benefit has previously been established. In order to preserve incentives for future innovation, the law establishes a period of exclusivity for originators’ products, which prohibits biosimilars from gaining FDA approval based in part on reliance on or reference to the originator’s data in their application to the FDA for 12 years after FDA approval of the originator product. The law does not change the duration of patents granted on biologic products. The FDA has released seven guidance documents as part of the implementation of the abbreviated approval pathway for biosimilars and four of these have been finalized. The FDA has announced its planned publication of additional draft guidance documents relating to biosimilar interchangeability and biosimilars labeling. As of the end of 2015, one biosimilar application has been approved by the FDA, and a number of manufacturers have announced the filing of marketing applications to the FDA under the biosimilar pathway, some of which are for biosimilars of our products.
Regulation of Product Marketing and Promotion. The FDA regulates the marketing and promotion of products. Our product promotion for approved product indications must comply with the statutory standards of the FDCA, and the FDA’s implementing regulations and standards. The FDA’s review of marketing and promotional activities encompasses, but is not limited to, direct-to-consumer advertising, healthcare provider-directed advertising and promotion, sales representative communications to healthcare professionals, promotional programming and promotional activities involving the Internet. The FDA may also review industry-sponsored scientific and educational activities that make representations regarding product safety or efficacy in a

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promotional context. The FDA may take enforcement action against a company for promoting unapproved uses of a product or for other violations of its advertising and labeling laws and regulations. Enforcement action may include product seizures, injunctions, civil or criminal penalties or regulatory letters, which may require corrective advertising or other corrective communications to healthcare professionals. Failure to comply with the FDA’s regulations also can result in adverse publicity or increased scrutiny of company activities by the U.S. Congress or other legislators. Additionally, as described below, such failure may lead to additional liability under U.S. health care fraud and abuse laws.
Regulation of Manufacturing Standards. The FDA regulates and inspects equipment, facilities, laboratories and processes used in the manufacturing and testing of products prior to providing approval to market products. If after receiving approval from the FDA, we make a material change in manufacturing equipment, location or process, additional regulatory review may be required. We also must adhere to current Good Manufacturing Practice regulations and product-specific regulations enforced by the FDA through its facilities inspection program. The FDA conducts regular, periodic visits to re-inspect our equipment, facilities, laboratories and processes following an initial approval.
Regulation of Combination Products. Combination products are defined by the FDA to include products comprised of two or more regulated components (e.g., a biologic and/or drug and a device). Biologics/Drugs and devices each have their own regulatory requirements, and combination products may have additional requirements. A number of our marketed products meet this definition and are regulated under this framework, and we expect that a number of our pipeline product candidates will be evaluated for regulatory approval under this framework as well.
Regulation Outside the United States
In the EU countries, Switzerland, Canada, Australia and Japan, regulatory requirements and approval processes are similar in principle to those in the United States. In the EU, depending on the type of drug for which approval is sought, there are currently two potential tracks for marketing approval, a decentralized and centralized procedure. In the decentralized procedure, identical applications for marketing authorization are submitted simultaneously to the national regulatory agencies. The application is assessed by an initial national agency (Reference Member State) and the subsequent countries that the applicant chooses to seek approval (Concerned Member States). Regulatory review is led by the Reference Member State and acknowledged by the Concerned Member States leading to a single approval in all relevant countries. In the centralized procedure, which is required of all products derived from biotechnology, a company submits a single MAA to the EMA, which conducts a thorough product evaluation, drawing from its scientific resources across Europe. If the drug product is proven to fulfill the requirements for quality, safety and efficacy, the Committee for Medicinal Products for Human Use (CHMP) adopts a positive opinion, which is transmitted to the EC for final approval of the marketing authorization. While the EC generally follows the CHMPs opinion, it is not bound to do so. Subsequent commercialization is enabled by country-by-country reimbursement approval. In Japan, additional local clinical trials may be required as part of the drug registration process, which can add to the drug registration timelines.
In the EU, biosimilars have been approved under a specialized pathway of the centralized procedure. As with the U.S. pathway, sponsors of a biosimilar may seek and obtain regulatory approval based in part on the non-clinical and clinical trial data of an originator product to which the biosimilar has been demonstrated to be “similar.”
Other countries such as Russia, Turkey and those in Latin America and the Middle East have review processes and data requirements similar to those of the EU, and in some cases rely on prior marketing approval from U.S. or EU regulatory authorities. The regulatory process in these countries may include manufacturing/testing facility inspections, testing of drug product upon importation and other domestic requirements.
In Asia, a number of countries such as China, South Korea and Taiwan may require local clinical trials as part of the drug registration process in addition to the global clinical trials which can add to the drug registration timelines. In most Asian markets, registration timelines are dependent on marketing approval in the United States or EU. However, in some emerging markets in Asia, such as China, the regulatory landscape is evolving and the regulatory timelines can be less predictable.
Post-approval Phase
After approval, we continue to monitor adverse events reported following the use of our products through post marketing routine pharmacovigilance surveillance and studies when applicable. We report such events to the appropriate regulatory agencies, as required per local regulations for individual cases and aggregate reports. We proactively monitor (according to good pharmacovigilance practices) and ensure the implementation of signal detection, assessment and communication of adverse events that may be associated with the use of our products. We may also be required by regulatory agencies to conduct further clinical trials on our marketed products as a condition of their approval or to provide additional information on safety and efficacy. Health authorities, including the FDA, have authority to mandate labeling changes to products at any point in a product’s lifecycle based on new safety information or as part of an evolving label change to a particular class of products.

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Health authorities, including the FDA, also have the authority, before or after approval, to require companies to implement a risk management program for a product to ensure that the benefits of the drug outweigh the risks. Each risk management program is unique and varies depending on the specific factors required. In the United States, a risk management program is known as a risk evaluation and mitigation strategy (REMS) and we currently have REMS for our ESAs, Prolia®, Nplate® and BLINCYTO®.
Other Regulation
We are also subject to various laws pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal to solicit, offer, receive or pay any remuneration in exchange for or to induce the referral of business, including the purchase or prescription of a particular drug that is reimbursed by a state or federal program. False claims laws prohibit knowingly and willingly presenting, or causing to be presented for payment to third-party payers (including Medicare and Medicaid) any claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed or claims for medically unnecessary items or services. Violations of fraud and abuse laws may be punishable by criminal and/or civil sanctions, including fines and civil monetary penalties, as well as the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid). Liability under the false claims laws may also arise when a violation of certain laws or regulations related to the underlying products (for example, violations regarding improper promotional activity or unlawful payments) contributes to the submission of a false claim.
On December 19, 2012, Amgen announced that it had finalized a settlement agreement with the U.S. government and various other parties regarding allegations that Amgen’s promotional, contracting, sales and marketing activities and arrangements caused the submission of various false claims under the Federal Civil False Claims Act and various State False Claims Acts. In connection with entering into the settlement agreement, Amgen also entered into a corporate integrity agreement with the Office of Inspector General (OIG) of the U.S. Department of Health and Human Services that requires Amgen to maintain its corporate compliance program and to undertake a set of defined corporate integrity obligations for a period of five years. Due to the breadth of the statutory provisions and the absence of guidance in the form of regulations or court decisions addressing some of our practices, it is possible that in the future our practices might be further challenged under anti-kickback or similar laws.
Additionally, the U.S. Foreign Corrupt Practices Act (FCPA) prohibits U.S. corporations and their representatives from offering, promising, authorizing or making payments to any foreign government official, government staff member, political party or political candidate in an attempt to obtain or retain business abroad. The scope of the FCPA includes interactions with certain healthcare professionals in many countries. Other countries have enacted similar anti-corruption laws and/or regulations.
Our business has been and will continue to be subject to various other U.S. and foreign laws, rules and/or regulations.

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Research and Development and Selected Product Candidates
We focus our R&D on novel human therapeutics for the treatment of serious illness in the areas of oncology/hematology, cardiovascular disease, inflammation, bone health, nephrology and neuroscience. We take a modality-independent approach to R&D with a focus on biologics. Our discovery research programs may therefore yield targets that lead to the development of human therapeutics delivered as large molecules, small molecules, or other combination or new modalities. For the years ended December 31, 2015, 2014 and 2013, our R&D expenses were $4.1 billion, $4.3 billion and $4.1 billion, respectively.
We have major R&D centers in several locations throughout the United States (including Thousand Oaks and San Francisco, California and Cambridge, Massachusetts), Iceland and in the United Kingdom, as well as smaller research centers and development facilities globally. See Item 2. Properties.
We conduct clinical trial activities using both our internal staff and third-party contract clinical trial service providers. To increase the number of patients available for enrollment in our clinical trials, we have opened clinical sites and will continue to open clinical sites and to enroll patients in a number of geographic locations. See Government Regulation—Clinical Development and Product Approval for a discussion of government regulation over clinical development. Also see Item 1A. Risk Factors—We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.
Some of our competitors are actively engaged in R&D in areas where we have products or where we are developing product candidates or new indications for existing products. For example, we compete with other clinical trials for eligible patients, which may limit the number of available patients who meet the criteria for certain clinical trials. The competitive marketplace for our product candidates is significantly dependent on the timing of entry into the market. Early entry may have important advantages in gaining product acceptance, thereby contributing to the product’s eventual success and profitability. Accordingly, we expect that in some cases, the relative speed with which we can develop products, complete clinical testing, receive regulatory approval and supply commercial quantities of the product to the market will be important to our competitive position.
In addition to product candidates and marketed products generated from our internal R&D efforts, we acquire companies, acquire and license certain product and R&D technology rights and establish R&D arrangements with third parties to enhance our strategic position within our industry by strengthening and diversifying our R&D capabilities, product pipeline and marketed product base. In pursuing these R&D arrangements and licensing or acquisition activities, we face competition from other pharmaceutical and biotechnology companies that also seek to license or acquire technologies, product candidates or marketed products from those entities performing the R&D.
The following table is a selection of certain of our product candidates by phase of development in our therapeutic areas of focus as of February 15, 2016, unless otherwise indicated. Additional product candidate information can be found on our website at www.amgen.com. The website address is not intended to function as a hyperlink, and the information contained on our website is not intended to be a part of this filing. The information in this section does not include other, non-registrational clinical trials that we may conduct for purposes other than for submission to regulatory agencies for their approval of a new product indication. We may conduct non-registrational clinical trials for various reasons including to evaluate real-world outcomes or to collect additional safety information with the use of our products. In addition, the table does not include the biosimilar products we are developing, which are discussed later in this section.

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Molecule
 
Disease/Condition
Phase 3 Programs
 
 
AMG 334
 
Episodic migraine
Aranesp® 
 
Myelodysplastic syndromes
BLINCYTO®
 
ALL
ENBREL
 
Psoriatic arthritis;
Rheumatoid arthritis remission
IMLYGIC
 
Metastatic melanoma
Kyprolis®
 
Multiple myeloma
Parsabiv
 
SHPT in patients with CKD receiving dialysis
Prolia®
 
Glucocorticoid-induced osteoporosis
Repatha®
 
Hyperlipidemia
Romosozumab
 
Postmenopausal osteoporosis;
Male osteoporosis
Vectibix®
 
mCRC
XGEVA®
 
Delay or prevention of bone metastases in breast cancer;
Cancer-related bone damage in patients with multiple myeloma
Phase 2 Programs
 
 
AMG 157
 
Asthma;
Atopic dermatitis
AMG 181
 
Inflammatory bowel diseases
AMG 334
 
Chronic migraine
AMG 520
 
Alzheimer’s disease
AMG 899
 
Dyslipidemia

BLINCYTO®
 
Diffuse Large B-Cell Lymphoma (DLBCL)
Omecamtiv mecarbil
 
Heart failure
XGEVA®
 
Metastatic non-small cell lung cancer (NSCLC)
Phase 1 Programs
 
 
AMG 211
 
Various cancer types
AMG 224
 
Multiple myeloma
AMG 228
 
Solid tumors
AMG 232
 
Various cancer types
AMG 301
 
Migraine
AMG 319
 
Hematologic malignancies
AMG 330
 
Acute myeloid leukemia
AMG 357
 
Autoimmune diseases
AMG 557
 
Systemic lupus erythematosus
AMG 581
 
Schizophrenia
AMG 592
 
Inflammatory diseases
AMG 820
 
Various cancer types
Kyprolis®
 
Small-cell lung cancer
Oprozomib
 
Hematologic malignancies

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Phase 3
clinical trials investigate the safety and efficacy of a product candidate in a large number of patients who have the disease or condition under study; typically performed with registrational intent.
Phase 2
clinical trials investigate side effect profiles and efficacy of a product candidate in a large number of patients who have the disease or condition under study.
Phase 1
clinical trials investigate safety and proper dose ranges of a product candidate in a small number of human subjects.
Phase 3 Product Candidate Program Changes
As of February 12, 2015, we had 15 phase 3 programs. As of February 15, 2016, we had 15 phase 3 programs, as three programs initiated or advanced to phase 3 trials, and three programs were terminated or concluded. These changes are set forth in the following table:
Molecule
 
Disease / Condition
 
Program Change
AMG 334
 
Episodic migraine
 
Advanced to phase 3
Brodalumab
 
Psoriasis;
 
Terminated our participation
 
Psoriatic arthritis
 
Terminated our participation
ENBREL
 
Psoriatic arthritis;
 
Initiated phase 3 study
 
Rheumatoid arthritis remission
 
Initiated phase 3 study
Trebananib
 
First-line ovarian cancer
 
Terminated
Phase 3 Product Candidate Patent Information
The following table describes our outstanding composition of matter patents that have issued thus far for our product candidates in phase 3 development that have yet to be approved for any indication. Patents for products already approved for one or more indications but currently undergoing phase 3 clinical trials for additional indications are previously described. See Marketing, Distribution and Selected Marketed Products—Patents.
Molecule
 
Territory
 
General Subject Matter
 
Estimated Expiration*
AMG 334
 
U.S.
 
Polypeptides
 
2031
Parsabiv
 
U.S.
 
Compound
 
2030
Romosozumab
 
U.S.
 
Polypeptides
 
2026
 
 
Europe
 
Polypeptides
 
2026
*
Patent expiration estimates are based on issued patents, which may be challenged, invalidated, or circumvented by competitors. The patent expiration estimates do not include any term adjustments, extensions or supplemental protection certificates that may be obtained in the future and extend these dates. Corresponding patent applications are pending in other jurisdictions. Additional patents may be filed or issued and may provide additional exclusivity for the product candidate or its use.
Phase 3 and 2 Program Descriptions
The following text provides additional information about selected product candidates that have advanced into human clinical trials.
AMG 334
AMG 334 is a human monoclonal antibody that inhibits the receptor for calcitonin gene-related peptide. It is being evaluated for the prophylaxis of migraine. AMG 334 is being jointly developed with Novartis.
Phase 3 studies in episodic migraine are ongoing, and a phase 2 study in chronic migraine is ongoing.
Aranesp® 
Aranesp® is a recombinant human protein agonist of the erythropoietin receptor.
In February 2016, we announced that the randomized, double-blind, placebo-controlled phase 3 ARCADE trial met its primary endpoint of reducing the incidence of red blood cell transfusions in anemic patients with low and intermediate-1 risk MDS.


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BLINCYTO® 
BLINCYTO® is an anti-CD19 x anti-CD3 (BiTE®) bispecific antibody construct.
In February 2016, we announced that the phase 3 TOWER study evaluating the efficacy of BLINCYTO® versus standard of care in adult patients with Ph- relapsed or refractory B-cell precursor ALL, met its primary endpoint of improved OS based on the results of a prespecified interim analysis.
A phase 3 study in pediatric patients with high-risk first relapse B-precursor ALL is ongoing. Phase 2 studies in adult patients with relapsed/refractory Philadelphia chromosome-positive (Ph+) and minimal residual disease of ALL are ongoing. A phase 2 study in adult patients with DLBCL is ongoing.
Denosumab
Denosumab is a human monoclonal antibody that inhibits RANKL.
Prolia® 
A phase 3 study of Prolia® for the treatment of glucocorticoid-induced osteoporosis is ongoing.
XGEVA® 
Phase 3 studies for the delay or prevention of bone metastases in patients with adjuvant breast cancer and prevention of SREs in patients with multiple myeloma are ongoing. A phase 2 study in NSCLC is ongoing.
ENBREL
ENBREL is a fusion protein that inhibits tumor necrosis factor.
A phase 3 study to evaluate ENBREL as a monotherapy for psoriatic arthritis treatment is ongoing. A phase 3 study to evaluate ENBREL as a monotherapy in maintaining remission in rheumatoid arthritis is ongoing.
IMLYGIC 
IMLYGIC is an oncolytic immunotherapy derived from HSV-1.
A phase 1b/3 study to evaluate IMLYGIC in combination with Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab), in patients with mid- to late-stage metastatic melanoma is ongoing.
Kyprolis® 
Kyprolis® is a proteasome inhibitor.
In December 2015, we announced that we submitted to the EMA a Variation to the MAA to expand the indication for Kyprolis® in combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy based on the data from the ENDEAVOR trial.
A phase 3 study, CLARION, evaluating Kyprolis® in combination with melphalan and prednisone compared to bortezomib, melphalan and prednisone in newly diagnosed multiple myeloma is ongoing. A phase 3 study, ARROW (RAndomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing), with weekly dosing in relapsed and refractory multiple myeloma is also underway.
A phase 1b/2 study in small-cell lung cancer is ongoing.
Parsabiv 
Parsabiv is a peptide agonist of the human cell surface CaSR. It is being evaluated as an intravenously administered treatment of SHPT.
In September 2015, we announced that we submitted an MAA to the EMA for Parsabiv, for the treatment of SHPT in adult patients with CKD on hemodialysis.
In November 2015, we announced that the FDA has accepted for review our NDA for Parsabiv for the treatment of SHPT in adult patients with CKD on hemodialysis.

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Repatha® 
Repatha® is a human monoclonal antibody that inhibits PCSK9.
In September 2015, we announced that we submitted an application to the FDA for a single-dosing option for the monthly administration of Repatha®. The PDUFA target action date is July 10, 2016.
In February 2016, we announced that the phase 3 GAUSS-3 trial evaluating Repatha® in patients with high cholesterol who cannot tolerate statins, met its co-primary endpoints.
Additional phase 3 studies to evaluate Repatha® for cardiovascular outcomes, on cognitive function, in subjects with genetic LDL disorders, and with coronary imaging are ongoing.
Romosozumab
Romosozumab is a humanized monoclonal antibody that inhibits the action of sclerostin. It is being evaluated as a treatment for osteoporosis. Romosozumab is being developed in collaboration with UCB.
In September 2015, we and UCB announced that the open label phase 3 STRUCTURE trial met its primary endpoint.
Phase 3 studies for the treatment of postmenopausal women with osteoporosis and men with osteoporosis are ongoing.
Vectibix® 
Vectibix® is a human monoclonal antibody antagonist of the EGFr.
In June 2015, we announced that results of a phase 3 study evaluating Vectibix® and BSC met its primary endpoint, demonstrating a statistically significant improvement in OS in patients with chemorefractory wild-type KRAS (exon 2) mCRC compared to those patients treated with BSC alone.
AMG 157
AMG 157 is a human monoclonal antibody that inhibits the action of TSLP. It is being evaluated as a treatment for asthma and atopic dermatitis, with phase 2 studies ongoing. AMG 157 is being jointly developed in collaboration with AstraZeneca.
AMG 181
AMG 181 is a human monoclonal antibody that inhibits the action of alpha4/beta7. It is being evaluated as a treatment for ulcerative colitis and Crohn’s disease, with phase 2 studies ongoing. AMG 181 is being jointly developed in collaboration with AstraZeneca.
AMG 520
AMG 520 is a small molecule inhibitor of BACE. It is being evaluated for the prevention of Alzheimer’s disease, with phase 2 studies ongoing. AMG 520 is being jointly developed in collaboration with Novartis.
AMG 899
AMG 899 is a small molecule CETP inhibitor. It is being evaluated for the treatment of dyslipidemia and has completed certain phase 2 studies.
Omecamtiv mecarbil
Omecamtiv mecarbil is a small molecule activator of cardiac myosin. It is being evaluated for the treatment of heart failure. We are developing this product in collaboration with Cytokinetics, Inc. (Cytokinetics).
In October 2015, we announced that phase 2 data in patients with chronic heart failure showed statistically significant improvements in several measures of cardiac function.

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Amgen Development of Biosimilars
We continue to collaborate with Allergan to develop and commercialize, on a worldwide basis, four oncology antibody biosimilar medicines. The products our collaboration is pursuing include biosimilar versions of bevacizumab (Avastin®), trastuzumab (Herceptin®), rituximab (Rituxan® / Mabthera®) and cetuximab (Erbitux®).
We are also working to develop biosimilar versions of adalimumab (HUMIRA®) and infliximab (REMICADE®), in addition to three other biosimilar molecules. Our biosimilar product candidates are in varying stages of clinical development as described in the following table:
Biosimilar
 
Status
adalimumab (HUMIRA®)
 
BLA accepted by FDA for review
MAA submitted to EMA
bevacizumab (Avastin®)
 
Phase 3 NSCLC study met primary and key secondary endpoints
trastuzumab (Herceptin®)
 
Phase 3 breast cancer study ongoing
infliximab (REMICADE®)
 
Phase 1 completed
Business Relationships
From time to time, we enter into business relationships, including joint ventures and collaborative arrangements, for the R&D, manufacture and/or commercialization of products and/or product candidates. In addition, we also acquire product and R&D technology rights and establish R&D collaborations with third parties to enhance our strategic position within our industry by strengthening and diversifying our R&D capabilities, product pipeline and marketed product base. These arrangements generally provide for non-refundable, upfront license fees; development and commercial performance milestone payments; cost sharing; royalty payments and/or profit sharing. The activities under these collaboration agreements are performed with no guarantee of either technological or commercial success, and each is unique in nature.
Trade secret protection for our unpatented confidential and proprietary information is important to us. To protect our trade secrets, we generally require counterparties to execute confidentiality agreements upon the commencement of the business relationship with us. However, others could either develop independently the same or similar information or unlawfully obtain access to our information.
Kirin-Amgen, Inc.
Kirin-Amgen, Inc. (K-A) is a 50-50 joint venture with Kirin Holdings Company, Limited (Kirin). K-A develops and then out-licenses to third parties certain product rights which have been transferred to this joint venture from Amgen and Kirin.
K-A has given us exclusive licenses to manufacture and market: (i) G-CSF and pegfilgrastim in the United States, Europe, Canada, Australia, New Zealand, all Central American, South American, Middle Eastern and African countries and certain countries in Asia; (ii) darbepoetin alfa and romiplostim in the United States, Europe, Canada, Australia, New Zealand, Mexico, all Central and South American countries and certain countries in Central Asia, Africa and the Middle East; and (iii) recombinant human erythropoietin in the United States. We currently market pegfilgrastim, G-CSF, darbepoetin alfa, recombinant human erythropoietin and romiplostim under the brand names Neulasta®, NEUPOGEN®/GRANULOKINE®, Aranesp®, EPOGEN® and Nplate®, respectively. Under these agreements, we pay K-A royalties based on product sales. In addition, we also receive payments from K-A for milestones earned and for conducting certain R&D activities on its behalf. See Part IV—Note 8, Related party transactions, to the Consolidated Financial Statements.
K-A has also given Kirin exclusive licenses to manufacture and market: (i) G-CSF and pegfilgrastim in Japan, Taiwan and South Korea; (ii) darbepoetin alfa, romiplostim and brodalumab in Japan, China, Taiwan, South Korea and in certain other countries and/or regions in Asia; and (iii) recombinant human erythropoietin in Japan. K-A also gave Kirin and Amgen co-exclusive licenses to manufacture and market G-CSF, pegfilgrastim and recombinant human erythropoietin in China, which Amgen subsequently assigned to Kirin, and as a result, Kirin now exclusively manufactures and markets G-CSF and recombinant human erythropoietin in China. Kirin markets G-CSF, pegfilgrastim, darbepoetin alfa, romiplostim and recombinant human erythropoietin under the brand names GRAN®/Grasin®, Peglasta®/Neulasta®/G-Lasta®, NESP®/Aranesp®, ROMIPLATE® and ESPO®, respectively. Under these agreements, Kirin pays K-A royalties based on product sales. In addition, Kirin also receives payments from K-A for conducting certain R&D activities on its behalf.
K-A has also given J&J exclusive licenses to manufacture and market recombinant human erythropoietin for all geographic areas of the world outside the United States, China and Japan. Under this agreement, J&J pays royalties to K-A based on product sales.

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Pfizer Inc.
The co-promotion term of our ENBREL collaboration agreement with Pfizer in the United States and Canada expired on October 31, 2013, giving us full ownership of ENBREL promotional rights in the United States and Canada while the rights to market ENBREL outside the United States and Canada are reserved to Pfizer. Under the collaboration agreement, Amgen and Pfizer shared in the agreed-upon selling and marketing expenses approved by a joint committee. We paid Pfizer a percentage of annual gross profits on our ENBREL sales in the United States and Canada on a scale that increased with gross profits; however, we maintained a majority share of ENBREL profits. In 2016, we are required to pay Pfizer residual royalties of 10% of annual net ENBREL sales in the United States and Canada. The amounts of such payments are significantly less than what was owed based on the terms of the previous ENBREL profit share. Effective November 1, 2016, there will be no further royalty payments.
Bayer HealthCare Pharmaceuticals Inc.
As a result of our acquisition of Onyx Pharmaceuticals, Inc. (Onyx), we are party to a collaboration with Bayer HealthCare Pharmaceuticals Inc. (Bayer) to jointly develop and commercialize Nexavar® (sorafenib) worldwide, except in Japan. The rights to develop and market Nexavar® in Japan are reserved to Bayer.
In May 2015, we and Bayer amended the terms of the collaboration, which terminated the co-promotion agreement in the United States, and transferred all U.S. operational responsibilities to Bayer, including commercial and medical affairs activities. Prior to the termination of the co-promotion agreement, we co-promoted Nexavar® with Bayer and shared equally in the profits in the United States. In lieu of this profit share, Bayer now pays us a royalty on U.S. sales of Nexavar® at a percentage rate in the high 30s. Outside of the United States, excluding Japan, Bayer manages all commercialization activities and incurs all of the sales and marketing expenditures and mutually agreed R&D expenses, and we reimburse Bayer for half of those expenditures. In all countries outside of the United States, except Japan, we receive 50% of net profits on sales of Nexavar® after deducting certain Bayer-related costs.
UCB
We are in a collaboration with UCB for the development and commercialization of romosozumab. Under the agreement, we received the rights to commercialize romosozumab for all indications in the United States, Canada, Mexico and Japan. UCB has the rights for all EU members at the time of first regulatory approval, Australia and New Zealand. Prior to commercialization, countries that have not been initially designated will be designated to Amgen or UCB in accordance with the terms of the agreement.
Generally, development costs are shared equally and we will share equally in the worldwide commercialization profits and losses related to the collaboration after accounting for expenses.
DaVita Inc.
We are in a seven-year supply agreement with DaVita that commenced January 1, 2012. Pursuant to this agreement, we will supply EPOGEN® in amounts necessary to meet no less than 90% of DaVita’s and its affiliates’ requirements for ESAs used in providing dialysis services in the United States and Puerto Rico. The agreement may be terminated by either party before expiration of its term in the event of certain breaches of the agreement by the other party.
Human Resources
As of December 31, 2015, Amgen had approximately 17,900 staff members. We consider our staff relations to be good.

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Executive Officers of the Registrant
The executive officers of the Company as of February 9, 2016 are set forth below.
Mr. Robert A. Bradway, age 53, has served as a director of the Company since October 2011 and Chairman of the Board of Directors since January 1, 2013. Mr. Bradway has been the Company’s President since May 2010 and Chief Executive Officer since May 2012. From May 2010 to May 2012, Mr. Bradway served as the Company’s President and Chief Operating Officer. Mr. Bradway joined the Company in 2006 as Vice President, Operations Strategy and served as Executive Vice President and Chief Financial Officer from April 2007 to May 2010. Prior to joining the Company, he was a Managing Director at Morgan Stanley in London where, beginning in 2001, he had responsibility for the firm’s banking department and corporate finance activities in Europe.
Mr. Bradway has been a director of Norfolk Southern Corporation, a transportation company, since July 2011. He has served on the board of trustees of the University of Southern California since April 2014, and on the advisory board of the Leonard D. Schaeffer Center for Health Policy and Economics at that university since 2012.
Mr. Madhavan (“Madhu”) Balachandran, age 65, became Executive Vice President, Operations in August 2012. Mr. Balachandran joined the Company in 1997 and has held leadership positions in engineering, information systems and operations. From October 2007 to August 2012, Mr. Balachandran was Senior Vice President, Manufacturing. From February 2007 to October 2007, Mr. Balachandran was Vice President, Site Operations. From May 2002 to February 2007, Mr. Balachandran was Vice President, Puerto Rico Operations. Prior to 2002, Mr. Balachandran served as Associate Director Capital Projects before his promotion to Director Engineering and then to Vice President, Information Management. Previously, Mr. Balachandran served as Vice President, Engineering at Burroughs Wellcome & Company.
Mr. Jonathan P. Graham, age 55, became Senior Vice President, General Counsel and Secretary in July 2015. Prior to joining the Company, from July 2006 to May 2015, Mr. Graham was Senior Vice President and General Counsel at Danaher Corporation. From October 2004 to June 2006, Mr. Graham was Vice President, Litigation and Legal Policy at General Electric Company. Prior to General Electric Company, Mr. Graham was a partner at Williams & Connolly LLP.
Dr. Sean E. Harper, age 53, became Executive Vice President, Research and Development in February 2012. Dr. Harper joined the Company in 2002, and has held leadership roles in early development, medical sciences and global regulatory and safety. Dr. Harper served as Senior Vice President, Global Development and Corporate Chief Medical Officer from March 2007 to February 2012. Prior to joining the Company, Dr. Harper worked for five years at Merck Research Laboratories.
Mr. Anthony C. Hooper, age 61, became Executive Vice President, Global Commercial Operations in October 2011. From March 2010 to October 2011, Mr. Hooper was Senior Vice President, Commercial Operations and President, U.S., Japan and Intercontinental of BMS. From January 2009 to March 2010, Mr. Hooper was President, Americas of BMS. From January 2004 to January 2009, Mr. Hooper was President, U.S. Pharmaceuticals, Worldwide Pharmaceuticals Group, a division of BMS. Prior to this, Mr. Hooper held various senior leadership positions at BMS. Prior to joining BMS, Mr. Hooper was Assistant Vice President of Global Marketing for Wyeth Laboratories.
Mr. Brian McNamee, age 59, became Executive Vice President, Full Potential Initiatives in October 2013. Mr. McNamee joined the Company in June 2001 as Senior Vice President, Human Resources. From November 1999 to June 2001, Mr. McNamee served as Vice President of Human Resources at Dell Computer Corp. From 1998 to 1999, Mr. McNamee served as Senior Vice President, Human Resources for the National Broadcasting Corporation, a division of the General Electric Company. From July 1988 to November 1999, Mr. McNamee held human resources positions at General Electric.
Mr. David W. Meline, age 58, became Executive Vice President and Chief Financial Officer in July 2014. From April 2011 to July 2014, Mr. Meline served as Senior Vice President and Chief Financial Officer at 3M Company. From September 2008 to March 2011, Mr. Meline served as Vice President, Corporate Controller and Chief Accounting Officer of 3M. Prior to 2008, Mr. Meline served in a variety of senior leadership roles for General Motors Company for over 20 years, with his last position being Vice President and Chief Financial Officer, North America. Mr. Meline was a director of TRW Automotive Holdings, Corp., a supplier of automotive systems, modules and components, from February 2014 until its acquisition by ZF Friedrichshafen AG in May 2015.
Ms. Cynthia M. Patton, age 54, became Senior Vice President and Chief Compliance Officer in October 2012. Ms. Patton joined the Company in 2005. From July 2005 to September 2010, Ms. Patton was Associate General Counsel. From September 2010 to October 2012, Ms. Patton was Vice President, Law. Previously, Ms. Patton served as Senior Vice President, General Counsel and Secretary of SCAN Health Plan from 1999 to 2005.

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Mr. David A. Piacquad, age 59, became Senior Vice President, Business Development in March 2014. Mr. Piacquad joined the Company in June 2010. From June 2010 to January 2014, Mr. Piacquad served as Vice President, Strategy and Corporate Development. From January 2014 to March 2014, Mr. Piacquad served as Vice President, Business Development. Prior to joining the Company, from December 2009 to June 2010, Mr. Piacquad was Principal of David A. Piacquad Consulting LLC. From March 2006 to December 2009, Mr. Piacquad served as Senior Vice President, Business Development and Licensing for Schering-Plough Corporation. Prior to Schering-Plough, Mr. Piacquad served in a series of leadership roles in finance and business development at J&J, with his last position being Vice President, Ventures and Business Development.
Dr. Stuart A. Tross, age 49, became Senior Vice President, Human Resources in October 2013. Dr. Tross joined the Company in April 2006 as Vice President, Human Resources. Prior to joining Amgen, from November 1998 to April 2006, Dr. Tross served in a series of roles for BMS, with his last position being Vice President and Global Head of Human Resources of Mead Johnson Nutrition. Prior to joining BMS, Dr. Tross was a management consultant for Towers Perrin.
Geographic Area Financial Information
For financial information concerning the geographic areas in which we operate, see Part IV—Note 19, Segment information—Geographic information, to the Consolidated Financial Statements.
Investor Information
Financial and other information about us is available on our website at www.amgen.com. We make available on our website, free of charge, copies of our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after we electronically file such material with, or furnish it to, the U.S. Securities and Exchange Commission (SEC). In addition, we have previously filed registration statements and other documents with the SEC. Any document we file may be inspected, without charge, at the SEC’s public reference room at 100 F Street NE, Washington, DC 20549, or at the SEC’s internet address at www.sec.gov. These website addresses are not intended to function as hyperlinks, and the information contained in our website and in the SEC’s website is not intended to be a part of this filing. Information related to the operation of the SEC’s public reference room may be obtained by calling the SEC at 800-SEC-0330.
Item 1A.
RISK FACTORS
This report and other documents we file with the SEC contain forward-looking statements that are based on current expectations, estimates, forecasts and projections about us, our future performance, our business, our beliefs and our management’s assumptions. These statements are not guarantees of future performance and involve certain risks, uncertainties and assumptions that are difficult to predict. You should carefully consider the risks and uncertainties facing our business. The risks described below are not the only ones facing us. Our business is also subject to the risks that affect many other companies, such as employment relations, general economic conditions, geopolitical events and international operations. Further, additional risks not currently known to us or that we currently believe are immaterial may in the future materially and adversely affect our business, operations, liquidity and stock price.
Our sales depend on coverage and reimbursement from third-party payers, and pricing and reimbursement pressures may affect our profitability.
Sales of our principal products are dependent on the availability and extent of coverage and reimbursement from third-party payers, including government healthcare programs and private insurance plans. Governments and private payers continue to pursue aggressive initiatives to contain costs and manage drug utilization and are increasingly focused on the effectiveness, benefits and costs of similar treatments, which could result in lower reimbursement rates for our products or narrower populations for whom our products will be reimbursed by payers. Public scrutiny of the price of drugs and other healthcare costs is increasing and more control over pricing could hurt our ability to price our products based upon their value.
A substantial portion of our U.S. business relies on reimbursement from the U.S. federal government healthcare programs and private insurance plans regulated by the U.S. federal government. (See Item 1. Business—Reimbursement.) Changes to U.S. federal reimbursement policy may come through legislative actions such as the ACA or as a result of regulations implemented by the Centers for Medicare & Medicaid Services (CMS), the federal agency responsible for administering Medicare, Medicaid and the Health Insurance Marketplaces. CMS has substantial power to quickly implement policy changes that can significantly affect how our products are covered and reimbursed. Legislative or regulatory changes that decrease the coverage or reimbursement available for our products, require that we pay increased rebates, limit our ability to offer patient co-pay payment assistance or limit the pricing of pharmaceutical products could have a material adverse effect on our business and results of operations. Private payers, including healthcare insurers, PBMs and others, increasingly seek price discounts or rebates in connection with the placement of our products on their formularies or those they manage. Consolidation in the health insurance industry has resulted

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in a few large insurers and PBMs exerting greater pressure in pricing and usage negotiations with drug manufacturers. Insurers and others are adopting benefit plan changes that shift a greater portion of prescription costs to patients, and some payers may attempt to limit the use of patient co-pay payment assistance programs. Private payers also control costs by imposing restrictions on access to our products, such as requiring prior authorizations or step therapy, and may even choose to exclude coverage entirely. Such discounts, rebates, plan changes, restrictions or exclusions could have a material adverse effect on sales of our affected products.
We also face risks relating to the reporting of pricing data that affects the reimbursement of and discounts provided for our products to U.S. government healthcare programs. Pricing data that we submit impacts the payment rates for providers, rebates we pay, and discounts we are required to provide under Medicare, Medicaid and other government drug programs. Government price reporting regulations are complex and may require a manufacturer to update certain previously submitted data. Our price reporting data calculations are reviewed on a monthly and quarterly basis, and based on such reviews we have on occasion restated previously reported pricing data to reflect changes in calculation methodology, reasonable assumptions and/or underlying data. If our submitted pricing data are incorrect, we may become subject to substantial fines and penalties or other government enforcement actions, which could have a material adverse effect on our business and results of operations. In addition, as a result of restating previously reported price data we also may be required to pay additional rebates and provide additional discounts.
Outside the United States, we expect that countries will continue to take aggressive actions to reduce their healthcare expenditures. (See Item 1. Business—Reimbursement.) For example, international reference pricing (IRP) is widely used by a large number of countries to control costs based on an external benchmark of a product’s price in other countries. IRP policies can quickly and frequently change and may not reflect differences in the burden of disease, indications, market structures, or affordability differences across countries or regions. Any deterioration in the coverage and reimbursement available for our products or in the timeliness or certainty of payment by payers to physicians and other providers could negatively impact the ability or willingness of healthcare providers to prescribe our products for their patients or otherwise negatively affect the use of our products or the prices we receive for them. Such changes could have a material adverse effect on our product sales, business and results of operations.
Our products face substantial competition.
We operate in a highly competitive environment. (See Item 1. Business—Competition.) We expect that our products will compete with new drugs currently in development, drugs currently approved for other indications that may later be approved for the same indications as those of our products and drugs approved for other indications that are used off-label. Large pharmaceutical companies and generics manufacturers of pharmaceutical products are expanding into the biotechnology field, and some pharmaceutical companies and generics manufacturers have formed partnerships to pursue biosimilars. In addition, some of our competitors may have technical, competitive or other advantages over us for the development of technologies and processes or greater experience in particular therapeutic areas, and consolidation among pharmaceutical and biotechnology companies can enhance such advantages. These advantages may make it difficult for us to compete with them to successfully discover, develop and market new products and for our current products to compete with new products or new product indications that they may bring to market. As a result, our products may compete against products that have lower prices, equivalent or superior performance, better safety profiles, are easier to administer, reach the market before our products or that are otherwise competitive with our products. If we are unable to compete effectively, this could reduce sales, which could have a material adverse effect on our business and results of operations.
We currently face competition from biosimilars and expect to face increasing competition in the future.
We currently face competition from biosimilars in both Europe and the United States, and we expect to face increasing biosimilar competition in the future. To the extent that governments adopt more permissive approval frameworks and competitors are able to obtain broader or expedited marketing approval for biosimilars, the rate of increased competition for our products could accelerate. Expiration or successful challenge of applicable patent rights could trigger such competition, and we could face more litigation regarding the validity and/or scope of our patents. Our products may also experience greater competition from lower-cost biosimilars or generics that come to market when branded products that compete with our products lose their own patent protection.
In the EU, the EC has granted marketing authorizations for biosimilars pursuant to a set of general and product class-specific guidelines for biosimilar approvals issued in 2005. In addition, in an effort to spur biosimilar utilization and/or increase potential healthcare savings, some EU countries have adopted biosimilar uptake measures such as requiring physician prescribing quotas or promoting switching or pharmacy substitution of biosimilars for the corresponding reference products, and other countries may adopt similar measures. Some EU countries may impose automatic price reductions upon market entry of the second or third biosimilar competitor.

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In the United States, in 2010 the ACA authorized the FDA to approve biosimilars via a separate, abbreviated pathway. (See Item 1. Business—Government Regulation—Regulation in the United States—Approval of Biosimilars.) The first biosimilar entrant into the U.S. market, Zarxio, a biosimilar version of NEUPOGEN® from Sandoz, was launched in the United States in 2015. In addition, a growing number of companies have announced that they are in varying stages of development of biosimilar versions of existing biotechnology products, including biosimilars that would compete with our products. Some companies pursuing development of biosimilars versions of our products may challenge our patents well in advance of the expiration of our material patents. (See Our intellectual property positions may be challenged, invalidated or circumvented, or we may fail to prevail in present and future intellectual property litigation.) For example, in June 2013, Sandoz filed suit against us, seeking a declaratory judgment that the etanercept product it was developing as a biosimilar to ENBREL did not infringe certain of our patents, and that those patents were also invalid and unenforceable. While that suit was dismissed for lack of subject matter jurisdiction as Sandoz had not yet filed a marketing application with the FDA, Sandoz subsequently announced that its marketing application has now been accepted for review by the FDA. (For information related to our other biosimilars patent litigation, see Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.) The U.S. pathway includes the option for biosimilar products meeting certain criteria to be approved as interchangeable with their reference products. Some companies currently developing biosimilars may seek to register their products as interchangeable biologics, which could make it easier for prescribers or pharmacists to substitute those biosimilars for our products. In addition, critics of the 12-year exclusivity period in the biosimilar pathway law will likely continue to seek to shorten the data exclusivity period and/or to encourage the FDA to interpret narrowly the law’s provisions regarding which new products receive data exclusivity. While we are unable to predict the precise impact of biosimilars on our products, we expect in the future to face greater competition in the United States as a result of biosimilars and downward pressure on our product prices and sales. This additional competition could have a material adverse effect on our business and results of operations.
Our current products and products in development cannot be sold without regulatory approval.
Our business is subject to extensive regulation by numerous state and federal governmental authorities in the United States, including the FDA, and by foreign regulatory authorities, including the EMA. We are required in the United States and in foreign countries to obtain approval from regulatory authorities before we can manufacture, market and sell our products. Once approved, the FDA and other U.S. and foreign regulatory agencies have substantial authority to require additional testing and reporting, perform inspections, change product labeling or mandate withdrawals of our products. Failure to comply with applicable regulatory requirements may subject us to administrative and/or judicially imposed sanctions. The sanctions could include the FDA’s or foreign regulatory authorities’ refusal to approve pending applications, delay in obtaining or withdrawals of approvals, delay or suspension of clinical trials, warning letters, product recalls, product seizures, total or partial suspension of our operations, injunctions, fines, civil penalties and/or criminal prosecutions.
Obtaining and maintaining regulatory approval has been, and will continue to be, increasingly difficult, time-consuming and costly. Legislative bodies or regulatory agencies could enact new laws or regulations, change existing laws or regulations, or change their interpretations of laws or regulations at any time, which could affect our ability to obtain or maintain approval of our products or product candidates. The rate and degree of change in existing laws and regulations and regulatory expectations have accelerated in established markets, and regulatory expectations continue to evolve in emerging markets. Failure to comply with new laws, regulations or regulatory interpretations could result in significant monetary penalties as well as reputational and other harms. We are unable to predict when and whether any further changes to laws or regulatory policies affecting our business could occur, such as efforts to reform medical device regulation or the pedigree requirements for medical products or to implement new requirements for combination products, and whether such changes could have a material adverse effect on our business and results of operations.
Regulatory authorities may also question the sufficiency for approval of the endpoints we select for our clinical trials. A number of our products and product candidates have been evaluated in clinical trials using surrogate endpoints that measure an effect that is known to correlate with an ultimate clinical endpoint. For example, a therapeutic oncology product candidate may be evaluated for its ability to extend the length of time during and after the treatment that a patient lives without the disease worsening (progression-free survival, or PFS). Demonstrating that the product candidate produces a statistically significant improvement in PFS does not necessarily mean that the product candidate will show a statistically significant improvement in OS, the time that the patients remain alive. In the cardiovascular setting, a heart disease therapeutic candidate may be evaluated for its ability to reduce LDL-C levels, as elevated LDL-C level has been a surrogate endpoint for cardiovascular events such as death, heart attacks and stroke. The use of surrogate endpoints such as PFS and LDL-C reduction, in the absence of other measures of clinical benefit, may not be sufficient for broad usage or approval even when such results are statistically significant. Regulatory authorities could also add new requirements, such as the completion of enrollment in a confirmatory study or the completion of an outcomes study or a meaningful portion of an outcomes study, as conditions for obtaining approval or obtaining an indication. For example, our initial FDA application for Repatha® sought approval for a broader patient population based on data demonstrating that Repatha® reduced LDL-C levels. However, the FDA ultimately approved Repatha® only for a subset of those patients, citing among other things the absence of positive outcomes data showing that Repatha® prevents cardiovascular events. While our

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ongoing phase 3 study is evaluating the ability of Repatha® to prevent cardiovascular events, that study may fail to meet its clinical efficacy endpoints or may identify safety issues with the product. (See We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.) Even if the ongoing outcomes study meets its clinical endpoints, regulators may not approve Repatha® for use beyond the currently approved label indications. There may also be situations in which demonstrating the efficacy and safety of a product candidate may not be sufficient to gain regulatory approval unless superiority to comparative products can be shown. The imposition of additional requirements or our inability to meet them in a timely fashion or at all may delay our clinical development and regulatory filing efforts, delay or prevent us from obtaining regulatory approval for new product candidates or new indications for existing products, or prevent us from maintaining our current labels.
Some of our products have been approved by U.S. and foreign regulatory authorities on a conditional basis with full approval conditioned upon fulfilling the requirements of regulators. For example, in December 2014, we received accelerated approval for BLINCYTO® for the treatment of patients with Ph- relapsed or refractory B-cell precursor ALL in the United States, with continued approval contingent upon clinical benefit in subsequent trials. BLINCYTO® also received conditional marketing authorization for the treatment of patients with Ph- relapsed or refractory B-cell precursor ALL from the EC in November 2015. Regulatory authorities are placing greater focus on monitoring products originally approved on an accelerated or conditional basis and on whether the sponsors of such products have met the conditions of the accelerated or conditional approvals. If we are unable to fulfill the requirements of regulators that were conditions of a product’s accelerated or conditional approval and/or if regulators re-evaluate the data or risk-benefit profile of our product, our conditional approval may not result in full approval or may be revoked or not renewed. Alternatively, we may be required to change the products’ labeled indications or even withdraw the products from the market.
Safety problems or signals can arise as our products and product candidates are evaluated in clinical trials, including investigator sponsored studies, or as our marketed products are used in clinical practice. We are required to continuously collect and assess adverse events reported to us and to communicate to regulatory agencies these adverse events and safety signals regarding our products. Regulatory agencies periodically perform inspections of our pharmacovigilance processes, including our adverse event reporting. In 2012, pharmacovigilance legislation became effective in the EU that enhanced the authority of European regulators to require companies to conduct additional post-approval clinical efficacy and safety studies and increased the requirement on sponsor companies to analyze and evaluate the risk-benefit profiles of their products. Similarly, for our products with approved REMS (see Item 1. Business—Government Regulation—Post-Approval Phase) we are required to submit periodic assessment reports to the FDA to demonstrate that the goals of the REMS are being met. REMS and other risk management programs are designed to ensure that a drug’s benefits outweigh the risks, and vary in the elements they contain. For example, our ESA REMS requires applicable healthcare providers and institutions to enroll in the program, receive education about the product and the REMS and document and report certain information to us over time. We are responsible for tracking and documenting certain elements of healthcare provider and institution compliance with the ESA REMS, and we use third-party service providers to assist in the administration of certain portions of our REMS. If the FDA is not satisfied with the results of the periodic assessment reports we submit for any of our REMS, the FDA may also modify our REMS or take other regulatory actions, such as implementing revised or restrictive labeling. If regulatory agencies determine that we or other parties (including our clinical trial investigators, those operating our patient support programs or licensees of our products) have not complied with the applicable reporting or other pharmacovigilance requirements, we may become subject to additional inspections, warning letters or other enforcement actions, including monetary fines, marketing authorization withdrawal and other penalties. Our product candidates and marketed products can also be affected by safety problems or signals occurring with respect to products that are similar to ours and that implicate an entire class of products. Further, as a result of clinical trials, including sub-analyses or meta-analyses of earlier clinical trials (a meta-analysis involves the use of various statistical methods to combine results from previous separate but related studies) performed by us or others, concerns may arise about the sufficiency of the data or studies underlying a product’s approved label. Such actual or perceived safety problems or concerns can lead to:
revised or restrictive labeling for our products, or the potential for restrictive labeling that may result in our decision not to commercialize a product candidate;
requirement of risk management activities or other regulatory agency compliance actions related to the promotion and sale of our products;
mandated post-marketing commitments or pharmacovigilance programs for our approved products;
product recalls of our approved products;
revocation of approval for our products from the market completely, or within particular therapeutic areas or patient types;
increased timelines or delays in being approved by the FDA or other regulatory bodies; and/or
fewer treatments or product candidates being approved by regulatory bodies.

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For example, since 2006, when adverse safety results involving ESAs were observed, ESAs continue to be the subject of ongoing review and scrutiny. Reviews by regulatory authorities of the risk-benefit profile of ESAs has resulted in, and may continue to result in, changes to ESA labeling, our ESA REMS and usage in both the oncology and nephrology clinical settings.
In addition to our innovative products, we are working to develop and commercialize biosimilar versions of nine products currently manufactured, marketed and sold by other pharmaceutical companies. In many markets there is not yet a legislative or regulatory pathway for the approval of biosimilars. In the United States, the ACA provided for such a pathway; while the FDA continues to implement it, significant questions remain as to how products will be approved under the pathway. (See We currently face competition from biosimilars and expect to face increasing competition in the future.) Delays or uncertainties in the development of such pathways could result in delays or difficulties in getting our products approved by regulatory authorities, subject us to unanticipated development costs or otherwise reduce the value of the investments we have made in the biosimilars area.
We may not be able to develop commercial products despite significant investments in R&D.
Amgen invests heavily in R&D. Successful product development in the biotechnology industry is highly uncertain, and very few R&D projects produce a commercial product. Product candidates (including biosimilar product candidates) or new indications for existing products (collectively, “product candidates”) that appear promising in the early phases of development may fail to reach the market for a number of reasons, such as:
the product candidate did not demonstrate acceptable clinical trial results even though it demonstrated positive preclinical trial results, for reasons that could include changes in the standard of care of medicine;
the product candidate was not effective or more effective than currently available therapies in treating a specified condition or illness;
the product candidate is not cost effective in light of existing therapeutics;
the product candidate had harmful side effects in humans or animals;
the necessary regulatory bodies, such as the FDA or EMA, did not approve our product candidate for an intended use;
the product candidate was not economical for us to manufacture and commercialize;
the biosimilar product candidate fails to demonstrate the requisite biosimilarity to the applicable reference product, or is otherwise determined to be unacceptable for purposes of safety or efficacy, to gain approval;
other parties have or may have proprietary rights relating to our product candidate, such as patent rights, and will not let us sell it on reasonable terms, or at all;
we and certain of our licensees, partners or independent investigators may fail to effectively conduct clinical development or clinical manufacturing activities; and
the pathway to regulatory approval or reimbursement for product candidates is uncertain or not well-defined.
A number of our product candidates have failed or been discontinued at various stages in the product development process. For example, in May 2015, we terminated our participation in the co-development and commercialization of brodalumab with AstraZeneca. The decision was based on events of suicidal ideation and behavior in the brodalumab program, which we believe likely would necessitate restrictive labeling that would limit the appropriate patient population. Inability to bring a product to market or a significant delay in the expected approval and related launch date of a new product for any of the reasons discussed could potentially have a negative impact on our product sales and earnings and could result in a significant impairment of in-process research and development (IPR&D) or other intangible assets.
We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.
Before we can sell any products, we must conduct clinical trials to demonstrate that our product candidates are safe and effective for use in humans. The results of those clinical trials are used as the basis to obtain approval from regulatory authorities such as the FDA and EMA. (See Our current products and products in development cannot be sold without regulatory approval.) We are required to conduct clinical trials using an appropriate number of trial sites and patients to support the product label claims. The length of time, number of trial sites and patients required for clinical trials vary substantially and therefore, we may spend several years and incur substantial expense in completing certain clinical trials. In addition, we may have difficulty finding a sufficient number of clinical trial sites and subjects to participate in our clinical trials, particularly if competitors are conducting clinical trials in similar patient populations. Delays in planned clinical trials can result in increased development costs, associated delays in regulatory approvals and in product candidates reaching the market and revisions to existing product labels.

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Further, to increase the number of patients available for enrollment for our clinical trials, we have and will continue to open clinical sites and enroll patients in a number of locations where our experience conducting clinical trials is limited, including Russia, India, China, South Korea, the Philippines, Singapore and some Central and South American countries, either through utilization of third-party contract clinical trial providers entirely or in combination with local staff. Conducting clinical trials in locations where we have limited experience requires substantial time and resources to understand the unique regulatory environments of individual countries. Further, we must ensure the timely production, distribution and delivery of the clinical supply of our product candidates to numerous and varied clinical trial sites. If we fail to adequately manage the design, execution and diverse regulatory aspects of our large and complex clinical trials or to manage the production or distribution of our clinical supply, corresponding regulatory approvals may be delayed or we may fail to gain approval for our product candidates or could lose our ability to market existing products in certain therapeutic areas or altogether. If we are unable to market and sell our products or product candidates or to obtain approvals in the timeframe needed to execute our product strategies, our business and results of operations could be materially and adversely affected.
We rely on independent third-party clinical investigators to recruit subjects and conduct clinical trials on our behalf in accordance with the applicable study protocols and laws and regulations. Further, we rely on unaffiliated third-party vendors to perform certain aspects of our clinical trial operations. We also may acquire companies that have ongoing clinical trials. These trials may not be conducted to the same standards as ours; however, once an acquisition has been completed we assume responsibility for the conduct of the trial, including any potential risks and liabilities associated with the past and prospective conduct of those trials. If regulatory authorities determine that we or others, including our licensees or the independent investigators selected by us or by a company we have acquired, have not complied with regulations applicable to the clinical trials, those authorities may refuse or reject some or all of the clinical trial data or take other actions which could negatively impact our ability to obtain or maintain marketing approval of the product or indication. If we were unable to market and sell our products or product candidates, our business and results of operations could be materially and adversely affected.
In addition, some of our clinical trials involve drugs manufactured and marketed by other pharmaceutical companies. These drugs may be administered in a clinical trial in combination with one of our products or product candidates or in a head-to-head study comparing the products’ or product candidates’ relative efficacy and safety. In the event that any of these vendors or pharmaceutical companies have unforeseen issues that negatively impact the quality of their work or create a shortage of supply, or if we are otherwise unable to obtain an adequate supply of these other drugs, our ability to complete our applicable clinical trials and/or evaluate clinical results may also be negatively impacted. As a result, this could adversely affect our ability to timely file for, gain or maintain regulatory approvals worldwide.
Clinical trials must be designed based on the current standard of medical care. However in certain diseases, such as cancer, the standard of care is evolving rapidly. In these diseases, the duration of time needed to complete certain clinical trials may result in the design of such clinical trials being based on standards of medical care that are no longer the current standards by the time such trials are completed, limiting the utility and application of such trials. We may not obtain favorable clinical trial results and therefore may not be able to obtain regulatory approval for new product candidates, new indications for existing products or maintenance of our current product labels. Participants in clinical trials of our products and product candidates may also suffer adverse medical events or side effects that could, among other factors, delay or terminate the clinical trial program and/or require additional or longer trials to gain approval.
Even after a product is on the market, safety concerns may require additional or more extensive clinical trials as part of a risk management plan for our product or for approval of a new indication. For example, in connection with the June 2011 ESA label changes, we also agreed to conduct additional clinical trials examining the use of ESAs in CKD. Additional clinical trials we initiate, including those required by the FDA, could result in substantial additional expense and the outcomes could result in additional label restrictions or the loss of regulatory approval for an approved indication, each of which could have a material adverse effect on our business and results of operations. Additionally, any negative results from such trials could materially affect the extent of approvals, the use, reimbursement and sales of our products, our business and results of operations.
Some of our products are used with drug delivery or companion diagnostic devices which have their own regulatory, manufacturing and other risks.
Many of our products and product candidates may be used in combination with a drug delivery device, such as an injector or other delivery system. In addition, Vectibix® is used in combination with a test kit (which is a companion diagnostic device), and some of our product candidates may also be used in combination with a companion diagnostic device. Our product candidates or expanded indications of our products used with such devices may not be approved or may be substantially delayed in receiving regulatory approval if such devices do not gain or maintain regulatory approval or clearance. Where approval of the product and device is sought under a single marketing drug application, the increased complexity of the review process may also delay receipt of regulatory approval. In addition, some of these devices may be provided by single-source unaffiliated third-party companies. We are dependent on the sustained cooperation and effort of those third-party companies both to supply the devices and, in some cases, to conduct the studies required for approval or clearance by the applicable regulatory agencies. We are also dependent on

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those third-party companies continuing to meet applicable regulatory or other requirements. Failure to successfully develop or supply the devices, delays in or failure of the Amgen or third-party studies, or failure of Amgen or the third-party companies to obtain or maintain regulatory approval or clearance of the devices could result in increased development costs, delays in, or failure to obtain, regulatory approval and/or associated delays in a product candidate reaching the market or the addition of new indications for existing products. Loss of regulatory approval or clearance of a device that is used with our product may also result in the removal of our product from the market. Further, failure to successfully develop, supply, or gain or maintain approval for these devices could adversely affect sales of the related, approved products.
Our intellectual property positions may be challenged, invalidated or circumvented, or we may fail to prevail in present and future intellectual property litigation.
Our success depends in part on our ability to obtain and defend patent rights and other intellectual property rights that are important to the commercialization of our products and product candidates. The patent positions of pharmaceutical and biotechnology companies can be highly uncertain and often involve complex legal, scientific and factual questions. Third parties may challenge, invalidate or circumvent our patents and patent applications relating to our products, product candidates and technologies. Challenges to patents may come from potential competitors or from parties other than those who seek to market a potentially-infringing product. For example, a Texas hedge fund (acting with affiliated entities and individuals and proceeding under the name of the Coalition for Affordable Drugs) has sought to challenge dozens of patents held by pharmaceutical and biotechnology companies, including one of the patents we hold for ENBREL. In addition, our patent positions might not protect us against competitors with similar products or technologies because competing products or technologies may not infringe our patents. For certain of our product candidates, there are third parties who have patents or pending patent applications that they may claim necessitate payment of a royalty or prevent us from commercializing these product candidates in certain territories. Patent disputes are frequent, costly and can preclude, delay or increase the cost of commercialization of products. We have been in the past, and are currently and may be in the future, involved in patent litigation. These matters have included and may in the future include litigation with manufacturers of products that purport to be biosimilars of certain of our products for patent infringement and for failure to comply with certain provisions of the Biologics Price Competition and Innovation Act, including the requirement to provide 180 days’ notice in advance of commercial marketing. A determination made by a court, agency or tribunal concerning infringement, validity, enforceability, injunctive or economic remedy, or the right to patent protection, for example, are typically subject to appellate or administrative review. Upon review, such initial determinations may be afforded little or no deference by the reviewing tribunal and may be affirmed, reversed, or made the subject of reconsideration through further proceedings. A patent dispute or litigation may not discourage a potential violator from bringing the product that is alleged to infringe to market prior to a final resolution of the dispute or litigation. The period of time from inception until resolution of a patent dispute or litigation is subject to the availability and schedule of the court, agency or tribunal before which the dispute or litigation is pending. We may be subject to competition during this period and may not be able to fully recover for the losses, damages, and harms we incur from infringement by the competitor product even if we prevail. Moreover, if we lose or settle current or future litigations at certain stages or entirely, we could be subject to competition and/or significant liabilities, be required to enter into third-party licenses for the infringed product or technology or be required to cease using the technology or product in dispute. In addition, we cannot guarantee that such licenses will be available on terms acceptable to us, or at all.
Further, under the Hatch-Waxman Act, our products approved by the FDA under the FDCA may be the subject of patent litigation with generic competitors before expiry of the five-year period of data exclusivity provided for under the Hatch-Waxman Act and prior to the expiration of the patents listed for the product. Likewise, our innovative biologic products may be the subject of patent litigation prior to the expiration of our patents and, with respect to competitors seeking approval as a biosimilar or interchangeable version of our products, prior to the 12-year exclusivity period provided under the ACA. In addition, we may face additional patent litigation involving claims that the biosimilar product candidates we are working to develop infringe the patents of other companies that manufacture, market or sell the applicable reference products. While we may attempt to challenge such patents, our efforts may be unsuccessful.
Certain of the existing patents on our principal products have recently expired. (See Item 1. Business—Marketing, Distribution and Selected Marketed Products—Patents.) As our patents expire, competitors are able to legally produce and market similar products or technologies, including biosimilars, which may have a material adverse effect on our affected product sales, business and results of operations. In addition, competitors may be able to invalidate, design around or otherwise circumvent our patents and sell competing products.
Guidelines and recommendations published by various organizations can reduce the use of our products.
Government agencies promulgate regulations and guidelines directly applicable to us and to our products. However, professional societies, practice management groups, insurance carriers, physicians groups, private health/science foundations and organizations involved in various diseases also publish guidelines and recommendations to healthcare providers, administrators and payers, and patient communities. Recommendations by government agencies or other groups/organizations may relate to such matters as usage, dosage, route of administration and use of related therapies, and a growing number of organizations are providing

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assessments of the value and pricing of pharmaceutical products. These assessments may come from private organizations, such as the Institute for Clinical and Economic Review, who publish their findings and offer recommendations relating to the products’ reimbursement by government and private payers. In addition, government HTA organizations, such as the National Institute for Health and Clinical Excellence in the United Kingdom (UK) and the Canadian Agency for Drugs and Technologies in Health, make reimbursement recommendations to payers in their jurisdictions based on the clinical effectiveness, cost-effectiveness and service impact of new, emerging and existing medicines and treatments. Any recommendations or guidelines that result in decreased use, dosage or reimbursement of our products could have a material adverse effect on our product sales, business and results of operations. In addition, the perception by the investment community or stockholders that such recommendations or guidelines will result in decreased use and dosage of our products could adversely affect the market price for our common stock.
The adoption of new tax legislation or exposure to additional tax liabilities could affect our profitability.
We are subject to income and other taxes in the United States and other jurisdictions in which we do business. As a result, our provision for income taxes is derived from a combination of applicable tax rates in the various places we operate. Significant judgment is required for determining our provision for income tax and our tax returns are periodically examined by various tax authorities. We believe our accrual for income tax liabilities is appropriate based on past experience, interpretations of tax law, and judgments about potential actions by tax authorities; however, due to the complexity of the provision for income taxes, the ultimate resolution of any tax matters may result in payments greater or less than amounts accrued. Our provision for income taxes and results of operations in the future could be adversely affected by changes to our operating structure, changes in the mix of income and expenses in countries with differing tax rates, changes in the valuation of deferred tax assets and liabilities, and changes in applicable tax laws, regulations or administrative interpretations thereof. A change to the U.S. tax system, such as a change to the taxation of income earned outside the United States including credits allowed for foreign taxes, a change to the tax system in a jurisdiction where we have significant operations, such as Puerto Rico, or changes in tax law in the United States or other jurisdictions where we do business, could have a material and adverse effect on our business and on the results of our operations.
We rely on third-party suppliers for certain of our raw materials, medical devices and components.
We rely on unaffiliated third-party suppliers for certain raw materials, medical devices and components necessary for the manufacturing of our commercial and clinical products. Certain of those raw materials, medical devices and components are the proprietary products of those unaffiliated third-party suppliers and are specifically cited in our drug application with regulatory agencies so that they must be obtained from that specific sole source or sources and could not be obtained from another supplier unless and until the regulatory agency approved such supplier. For example, Insulet Corporation is our single source of the on-body injector for our Neulasta® Onprokit. Also, certain of the raw materials required in the commercial and clinical manufacturing of our products are sourced from other countries and/or derived from biological sources, including mammalian tissues, bovine serum and human serum albumin.
Among the reasons we may be unable to obtain these raw materials, medical devices and components include:
regulatory requirements or action by regulatory agencies or others;
adverse financial or other strategic developments at or affecting the supplier, including bankruptcy;
unexpected demand for or shortage of raw materials, medical devices or components;
failure to comply with our quality standards which results in quality and product failures, product contamination and/or recall;
a material shortage, contamination, recall and/or restrictions on the use of certain biologically derived substances or other raw materials;
discovery of previously unknown or undetected imperfections in raw materials, medical devices or components; and
labor disputes or shortages, including the effects of health emergencies, natural disasters, or otherwise.
These events could negatively impact our ability to satisfy demand for our products, which could have a material adverse effect on our product use and sales and our business and results of operations. For example, in prior years we have experienced shortages in certain components necessary for the formulation, fill and finish of certain of our products in our Puerto Rico facility. Further quality issues which result in unexpected additional demand for certain components may lead to shortages of required raw materials or components (such as we have experienced with EPOGEN® glass vials). We may experience or continue to experience these or other shortages in the future resulting in delayed shipments, supply constraints, contract disputes and/or stock-outs of our products.

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Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.
Manufacturing biologic human therapeutic products is difficult, complex and highly regulated. We currently are involved in the manufacture of many of our products and plan to manufacture many of our product candidates. In addition, we currently use third-party contract manufacturers to produce, or assist in the production of, a number of our products, and are using contract manufacturers to produce, or assist in the production of, a number of our late-stage product candidates and drug delivery devices. (See Item 1. Business—Manufacturing, Distribution and Raw Materials—Manufacturing.) Our ability to adequately and timely manufacture and supply our products and product candidates is dependent on the uninterrupted and efficient operation of our facilities and those of our third-party contract manufacturers, which may be impacted by:
capacity of manufacturing facilities;
contamination by microorganisms or viruses, or foreign particles from the manufacturing process;
natural or other disasters, including hurricanes, earthquakes, volcanoes or fires;
labor disputes or shortages, including the effects of health emergencies, natural disasters, or otherwise;
compliance with regulatory requirements;
changes in forecasts of future demand;
timing and actual number of production runs and production success rates and yields;
updates of manufacturing specifications;
contractual disputes with our suppliers and contract manufacturers;
timing and outcome of product quality testing;
power failures and/or other utility failures; and/or
breakdown, failure or substandard performance or improper installation or operation of equipment.
If the efficient manufacture and supply of our products or product candidates is interrupted, we may experience delayed shipments, delays in our clinical trials, supply constraints, stock-outs, adverse event trends, contract disputes and/or recalls of our products. From time to time we have initiated voluntary recalls of certain lots of our products. For example, in July 2014, we initiated a voluntary recall of an Aranesp® lot distributed in the EU after particles were detected in a quality control sample following distribution of that lot. If we are at any time unable to provide an uninterrupted supply of our products to patients, we may lose patients and physicians may elect to prescribe competing therapeutics instead of our products, which could have a material adverse effect on our product sales, business and results of operations.
Our manufacturing processes and those of our third-party contract manufacturers must undergo regulatory approval processes and are subject to continued review by the FDA and other regulatory authorities. It can take longer than five years to build, validate and license a new manufacturing plant and it can take longer than three years to qualify and license a new contract manufacturer. In 2015, we initiated the drug substance conformance campaign to facilitate licensure at our monoclonal antibody manufacturing facility in Singapore. This Singapore facility will utilize a novel manufacturing technology that has not been previously approved by the FDA or other regulatory authorities. We have also begun construction on an additional new facility at the site in Singapore to enable the manufacture of the active pharmaceutical ingredient for Kyprolis®. These facilities in Singapore will require licensure by various regulatory authorities. If we are unable to obtain needed licenses for either of these facilities on a timely basis, it could adversely affect our ability to achieve our planned risk mitigation and cost reductions which, as a result, could have a material adverse effect our product sales, business and results of operations.
If regulatory authorities determine that we or our third-party contract manufacturers or certain of our third-party service providers have violated regulations or if they restrict, suspend or revoke our prior approvals, they could prohibit us from manufacturing our products or conducting clinical trials or selling our marketed products until we or the affected third-party contract manufacturers or third-party service providers comply, or indefinitely. Such issues may also delay the approval of product candidates we have submitted for regulatory review, even if such product candidates are not directly related to the products, devices or processes at issue with regulators. Because our third-party contract manufacturers and certain of our third-party service providers are subject to the FDA and foreign regulatory authorities, alternative qualified third-party contract manufacturers and third-party service providers may not be available on a timely basis or at all. If we or our third-party contract manufacturers or third-party service providers cease or interrupt production or if our third-party contract manufacturers and third-party service providers fail to supply materials, products or services to us, we may experience delayed shipments, supply constraints, stock-outs and/or recalls of our products. Additionally, we distribute a substantial volume of our commercial products through our primary distribution centers in Louisville, Kentucky for the United States and in Breda, the Netherlands for Europe and much of the rest of the world. We also conduct all the labeling and packaging of our products distributed in Europe and much of the rest of the world in Breda.

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Our ability to timely supply products is dependent on the uninterrupted and efficient operations of our distribution and logistics centers, our third-party logistics providers and our labeling and packaging facility in Breda. Further, we rely on commercial transportation, including air freight, for the distribution of our products to our customers which may be negatively impacted by natural disasters or security threats.
We perform a substantial amount of our commercial manufacturing activities at our Puerto Rico manufacturing facility and a substantial amount of our clinical manufacturing activities at our Thousand Oaks, California manufacturing facility; if significant disruptions or production failures occur at the Puerto Rico facility, we may not be able to supply these products or, at the Thousand Oaks facility, we may not be able to continue our clinical trials.
We currently perform all of the formulation, fill and finish for NEUPOGEN®, Aranesp®, EPOGEN®, Prolia® and XGEVA® and substantially all of the formulation, fill and finish operations for Neulasta® and ENBREL at our manufacturing facility in Juncos, Puerto Rico. We also currently perform all of the bulk manufacturing for Neulasta®, NEUPOGEN® and Aranesp®, all of the purification of bulk EPOGEN® material and substantially all of the bulk manufacturing for Prolia® and XGEVA® at this facility. We perform substantially all of the bulk manufacturing and formulation, fill and finish, and packaging for product candidates to be used in clinical trials at our manufacturing facility in Thousand Oaks, California. The global supply of our products and product candidates is significantly dependent on the uninterrupted and efficient operation of these facilities. (See Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.) In June 2015, Puerto Rico’s Governor stated that the Puerto Rico government, which includes certain government entities, is unable to pay its roughly $72 billion in debt, and since that time, Puerto Rico failed to make certain debt payments. In September 2015, the Puerto Rico government released a Fiscal and Economic Growth Plan (FEGP), a proposal for economic growth and reform measures that also included recommendations for debt restructuring. Due to a deteriorating liquidity position, the Governor issued an executive order in December 2015, providing for certain extraordinary liquidity measures such as deferral of tax refunds, stretching of payments to suppliers and the implementation of a “clawback” of revenues assigned to certain government entities in order to make payments on general obligation bonds and provide essential government services. On January 18, 2016, the Puerto Rico government revised the FEGP to reflect larger government financing gaps in the near and long term as well as the government’s deteriorating liquidity position. The Puerto Rico government is currently in negotiations with creditors to restructure the government’s debt, and litigation has commenced with certain bond insurers over failure to make certain debt payments. If the Puerto Rico government is not able to restructure the debt obligations or get forbearance on debt payments, it could impact the territorial government’s provision of utilities or other services in Puerto Rico that we use in the operation of our business, create the potential for increased taxes or fees to operate in Puerto Rico, result in migration of workers from Puerto Rico to the mainland United States, and make it more expensive or difficult for us to operate in Puerto Rico.
Concentration of sales at certain of our wholesaler distributors and consolidation of free-standing dialysis clinic businesses may negatively impact our business.
The substantial majority of our U.S. product sales is made to three pharmaceutical product wholesaler distributors: AmerisourceBergen Corporation, Cardinal Health, Inc. and McKesson Corporation. These distributors, in turn, sell our products to their customers, which include physicians or their clinics, dialysis centers, hospitals and pharmacies. One of our products, EPOGEN®, is sold primarily to free-standing dialysis clinics, which have experienced significant consolidation. Two organizations, DaVita and Fresenius Medical Care North America (Fresenius), own or manage a large number of the outpatient dialysis facilities located in the United States and account for approximately 70% of all EPOGEN® sales. Due to this concentration, these entities have substantial purchasing leverage, which may put pressure on our pricing by their potential ability to extract price discounts on our products or fees for other services, correspondingly negatively impacting our bargaining position and profit margins. In addition, decisions by these entities to purchase less or none of our products in favor of competitive products can have a material adverse effect on our business and results of operations due to their purchasing volume.
We may not be able to access the capital and credit markets on terms that are favorable to us, or at all.
The capital and credit markets may experience extreme volatility and disruption which may lead to uncertainty and liquidity issues for both borrowers and investors. We expect to access the capital markets to supplement our existing funds and cash generated from operations in satisfying our needs for working capital; capital expenditure and debt service requirements; our plans to pay dividends and repurchase stock; and other business initiatives we plan to strategically pursue, including acquisitions and licensing activities. In the event of adverse capital and credit market conditions, we may be unable to obtain capital market financing on similar favorable terms, or at all, which could have a material adverse effect on our business and results of operations. Changes in credit ratings issued by nationally recognized credit rating agencies could adversely affect our ability to obtain capital market financing and the cost of such financing and have an adverse effect on the market price of our securities.

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Our efforts to acquire other companies or products and to integrate their operations may not be successful, and may result in costs, delays or failures to realize the benefits of the transactions.
We have an ongoing process of evaluating potential merger, acquisition, partnering and in-license opportunities that we expect will contribute to our future growth and expand our geographic footprint, product offerings and/or our R&D pipeline. Acquisitions may result in unanticipated costs, delays or other operational or financial problems related to integrating the acquired company and business with our company, which may result in the diversion of our management’s attention from other business issues and opportunities. Failures or difficulties in integrating or retaining new personnel or in integrating the operations of the businesses that we acquire (including their technology, compliance programs, distribution and general business operations and procedures), while preserving important R&D, distribution, marketing, promotion and other relationships, may affect our ability to grow and may result in us incurring asset impairment or restructuring charges. For example, on October 1, 2013, we acquired Onyx, a biopharmaceutical company with several currently marketed products as well as pipeline candidates progressing through the development process, and failures or difficulties in the integration of Onyx could result in a material adverse impact on our business and results of operations.
Our sales and operations are subject to the risks of doing business in emerging markets.
As we continue our expansion efforts in emerging markets around the world, through acquisitions and licensing transactions as well as through the development and introduction of our products into new markets, we face numerous risks to our business. There is no guarantee that our efforts and strategies to expand sales in emerging markets will succeed. Emerging market countries may be especially vulnerable to periods of global political, legal, regulatory and financial instability, including sovereign debt issues and/or the imposition of international sanctions in response to certain state actions. As we expand internationally, we are subject to fluctuations in foreign currency exchange rates relative to the U.S. dollar. While we have a program in place that is designed to reduce our exposure to foreign currency exchange rate fluctuations through foreign currency hedging arrangements, our hedging efforts do not completely offset the effect of these fluctuations on our revenues and earnings. We may also be required to increase our reliance on third-party agents and unfamiliar operations and arrangements previously utilized by companies that we partner with or acquire in emerging markets. (See We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.) Our international operations and business may also be subject to less protective intellectual property or other applicable laws, diverse data privacy and protection requirements, changing tax laws and tariffs, far-reaching anti-bribery and anti-corruption laws and regulations and/or an evolving legal and regulatory environment. These legal and operational challenges along with governmental controls, the challenges of attracting and retaining qualified personnel and obtaining and/or maintaining necessary regulatory or pricing approvals of our products may result in a material adverse impact on our international product sales, business and results of operations.
Our business may be affected by litigation and government investigations.
We and certain of our subsidiaries are involved in legal proceedings. (See Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.) Civil and criminal litigation is inherently unpredictable, and the outcome can result in costly verdicts, fines and penalties, exclusion from the federal healthcare programs and/or injunctive relief that affect how we operate our business. Defense of litigation claims can be expensive, time-consuming and distracting and it is possible that we could incur judgments or enter into settlements of claims for monetary damages or change the way we operate our business, which could have a material adverse effect on our business and results of operations. In addition, product liability is a major risk in testing and marketing biotechnology and pharmaceutical products. We may face substantial product liability exposure in human clinical trials and for products that we sell after regulatory approval. Product liability claims, regardless of their merits, could be costly and divert management’s attention and adversely affect our reputation and the demand for our products. We and certain of our subsidiaries have previously been named as defendants in product liability actions for certain of our products.
We are also involved in government investigations that arise in the ordinary course of our business. In recent years, there has been a trend of increasing government investigations and litigations against companies operating in our industry, both in the United States and around the world. Our business activities outside of the United States are subject to the FCPA and similar anti-bribery or anti-corruption laws, regulations or rules of other countries in which we operate, including the UK Bribery Act. As we announced on December 19, 2012, we finalized a settlement agreement with the U.S. government and various other parties to settle certain allegations regarding our sales and marketing practices. In connection with that settlement, we are now operating under a Corporate Integrity Agreement (CIA) with the OIG of the U.S. Department of Health and Human Services that requires us to maintain our corporate compliance program and to undertake a set of defined corporate integrity obligations until December 2017. The CIA also provides for an independent third-party review organization to assess and report on our compliance program. While we expect to fully comply with all of our obligations under the CIA, the failure to do so could result in substantial penalties and our being excluded from government healthcare programs. We may also be subject to actions by governmental entities, including those not participating in the settlement, and may in the future become subject to claims by other parties, in each case with respect to the alleged conduct which is the subject of the settlement. We may see new governmental investigations

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of or actions against us citing novel theories of recovery. Any of these results could have a material adverse effect on our business and results of operations.
We are increasingly dependent on information technology systems, infrastructure and data security.
We are increasingly dependent upon information technology systems, infrastructure and data security. The multitude and complexity of our computer systems and the potential value of our data make them inherently vulnerable to service interruption or destruction, malicious intrusion and random attack. Likewise, data privacy or security breaches by employees or others may pose a risk that sensitive data including intellectual property, trade secrets or personal information belonging to the Company, its patients, customers or other business partners may be exposed to unauthorized persons or to the public. As a global biotechnology company, our systems are subject to frequent cyber-attacks. These attacks are growing in their frequency, sophistication and intensity, and are becoming increasingly difficult to detect. They are often carried out by motivated, well-resourced, skilled and persistent actors including nation states, organized crime groups and “hacktivists.” Cyber-attacks could include the deployment of harmful malware and key loggers, a denial-of-service attack, a malicious website, the use of social engineering and other means to affect the confidentiality, integrity and availability of our information technology systems, infrastructure and data. Our key business partners face similar risks and any security breach of their systems could adversely affect our security posture. Although in the past we have experienced cyber-attacks and intrusions into our computer systems, we do not believe that such attacks have had a material adverse effect on our operations. While we continue to invest heavily in the protection of our critical or sensitive data and information technology, there can be no assurance that our efforts will prevent or detect service interruptions or breaches in our systems that could adversely affect our business and operations and/or result in the loss of critical or sensitive information, which could result in financial, legal, business or reputational harm to us.
Global economic conditions may negatively affect us and may magnify certain risks that affect our business.
Our operations and performance have been, and may continue to be, affected by global economic conditions. Financial pressures may cause government or other third-party payers to more aggressively seek cost containment measures. (See Our sales depend on coverage and reimbursement from third-party payers, and pricing and reimbursement pressures may affect our profitability.) As a result of global economic conditions, some third-party payers may delay or be unable to satisfy their reimbursement obligations. Job losses or other economic hardships may also affect patients’ ability to afford health care as a result of increased co-pay or deductible obligations, greater cost sensitivity to existing co-pay or deductible obligations, lost healthcare insurance coverage or for other reasons. We believe such conditions have led and could continue to lead to reduced demand for our products, which could have a material adverse effect on our product sales, business and results of operations. Economic conditions may also adversely affect the ability of our distributors, customers and suppliers to obtain the liquidity required to buy inventory or raw materials and to perform their obligations under agreements with us, which could disrupt our operations. Although we monitor our distributors’, customers’ and suppliers’ financial condition and their liquidity to mitigate our business risks, some of our distributors, customers and suppliers may become insolvent, which could have a material adverse effect on our product sales, business and results of operations.
We maintain a significant portfolio of investments disclosed as cash equivalents and marketable securities on our Consolidated Balance Sheet. The value of our investments may be adversely affected by interest rate fluctuations, downgrades in credit ratings, illiquidity in the capital markets and other factors that may result in other than temporary declines in the value of our investments. Any of those events could cause us to record impairment charges with respect to our investment portfolio or to realize losses on the sale of investments.
Our stock price is volatile.
Our stock price, like that of our peers in the biotechnology and pharmaceutical industries, is volatile. Our revenues and operating results may fluctuate from period to period for a number of reasons. Events such as a delay in product development or even a relatively small revenue shortfall may cause financial results for a period to be below our expectations or projections. As a result, our revenues and operating results and, in turn, our stock price may be subject to significant fluctuations. Announcements or discussions of possible restrictive actions by government or private payers that would impact our business or industry if ultimately enacted or adopted may also cause our stock price to fluctuate, whether or not such restrictive actions ever actually occur. Similarly, actual or perceived safety issues with our products or similar products can have an immediate and rapid impact on our stock price, whether or not our operating results are materially impacted.
Item 1B.
UNRESOLVED STAFF COMMENTS
None.

33



Item 2.
PROPERTIES
As of December 31, 2015, we owned or leased approximately 200 properties. The locations and primary functions of significant properties are summarized in the following table:
Excluded from the table above are undeveloped land and leased properties that have been abandoned and certain buildings that we still own but are no longer used in our business. There are no material encumbrances on our properties.
We believe that our facilities are suitable for their intended use and, in conjunction with our third-party contracting manufacturing agreements, provide adequate capacity and are sufficient to meet our expected needs. See Item 1A. Risk Factors for a discussion on the factors that could adversely impact our manufacturing operations and the global supply of our products.
See Item 1. Business—Manufacturing, Distribution and Raw Materials.
Item 3.
LEGAL PROCEEDINGS
Certain of the legal proceedings in which we are involved are discussed in Part IV—Note 18, Contingencies and commitments, to our Consolidated Financial Statements and are hereby incorporated by reference.
Item 4.
MINE SAFETY DISCLOSURES
Not applicable.

34



PART II
Item 5.
MARKET FOR REGISTRANT’S COMMON EQUITY, RELATED STOCKHOLDER MATTERS AND ISSUER PURCHASES OF EQUITY SECURITIES
Common stock
Our common stock trades on The NASDAQ Global Select Market under the symbol AMGN. As of February 9, 2016, there were approximately 6,809 holders of record of our common stock.
The following table sets forth, for the periods indicated, the range of high and low quarterly closing sales prices of the common stock as quoted on The NASDAQ Global Select Market:
Year ended December 31, 2015
 
High
 
Low
Fourth quarter
 
$
164.58

 
$
140.23

Third quarter
 
$
176.59

 
$
132.24

Second quarter
 
$
169.17

 
$
151.60

First quarter
 
$
170.10

 
$
150.01

Year ended December 31, 2014
 
 
 
 
Fourth quarter
 
$
171.64

 
$
130.45

Third quarter
 
$
144.01

 
$
115.39

Second quarter
 
$
126.07

 
$
110.29

First quarter
 
$
127.47

 
$
113.48


35



Performance graph
The following graph shows the value of an investment of $100 on December 31, 2010, in each of Amgen common stock, the Amex Biotech Index, the Amex Pharmaceutical Index and Standard & Poor’s 500 Index (S&P 500). All values assume reinvestment of the pretax value of dividends and are calculated as of December 31 of each year. The historical stock price performance of the Company’s common stock shown in the performance graph is not necessarily indicative of future stock price performance.
Amgen vs. Amex Biotech, Amex Pharmaceutical and S&P 500 Indices
Comparison of Five-Year Cumulative Total Return
Value of Investment of $100 on December 31, 2010
 
12/31/2010
 
12/31/2011
 
12/31/2012
 
12/31/2013
 
12/31/2014
 
12/31/2015
Amgen (AMGN)
100.00
 
118.23
 
161.10
 
216.72
 
308.43
 
320.68
Amex Biotech (BTK)
100.00
 
84.16
 
119.17
 
179.67
 
265.76
 
296.03
Amex Pharmaceutical (DRG)
100.00
 
112.91
 
129.74
 
170.24
 
198.46
 
206.75
S&P 500 (SPX)
100.00
 
102.10
 
118.23
 
156.11
 
177.46
 
179.90
The material in this performance graph is not soliciting material, is not deemed filed with the SEC, and is not incorporated by reference in any filing of the Company under the Securities Act or the Exchange Act, whether made on, before or after the date of this filing and irrespective of any general incorporation language in such filing.

36



Stock repurchase program
During the three months and year ended December 31, 2015, we had one outstanding stock repurchase program, under which the repurchasing activity was as follows:
 
 
Total
number of
shares
purchased
 
Average
price paid
per share(1)
 
Total number
of  shares
purchased as
part of
publicly
announced
program
 
Maximum dollar
value that may
yet be purchased
under the
program(2)
October 1 - October 31
 
709,600

 
$
140.92

 
709,600

 
$
5,000,000,000

November 1 - November 30
 
339,608

 
$
158.37

 
339,608

 
$
4,946,215,002

December 1 - December 31
 
188,807

 
$
158.38

 
188,807

 
$
4,916,311,000

 
 
1,238,015

 
$
148.37

 
1,238,015

 
 
January 1 - December 31
 
11,990,992

 
$
154.49

 
11,990,992

 
 
(1) 
Average price paid per share includes related expenses.
(2) 
In October 2015, our Board of Directors authorized an increase that resulted in a total of $5.0 billion available under the stock repurchase program.
Dividends
For the years ended December 31, 2015 and 2014, we paid quarterly dividends. We expect to continue to pay quarterly dividends, although the amount and timing of any future dividends are subject to approval by our Board of Directors. Additional information required by this item is incorporated herein by reference to Part IV—Note 15, Stockholders’ equity, to the Consolidated Financial Statements.
Securities Authorized for Issuance Under Existing Equity Compensation Plans
Information about securities authorized for issuance under existing equity compensation plans is incorporated by reference from Item 12—Securities Authorized for Issuance Under Existing Equity Compensation Plans.

37



Item 6.
SELECTED FINANCIAL DATA
 
Years ended December 31,
Consolidated Statement of Income Data:
2015
 
2014
 
2013
 
2012
 
2011
 
(In millions, except per share data)
Revenues:
 
 
 
 
 
 
 
 
 
Product sales
$
20,944

 
$
19,327

 
$
18,192

 
$
16,639

 
$
15,295

Other revenues
718

 
736

 
484

 
626

 
287

Total revenues
21,662

 
20,063

 
18,676

 
17,265

 
15,582

Operating expenses:
 
 
 
 
 
 
 
 
 
Cost of sales
4,227

 
4,422

 
3,346

 
3,199

 
2,708

Research and development
4,070

 
4,297

 
4,083

 
3,380

 
3,167

Selling, general and administrative
4,846

 
4,699

 
5,184

 
4,814

 
4,499

Other(1)
49

 
454

 
196

 
295

 
896

Net income
6,939

 
5,158

 
5,081

 
4,345

 
3,683

Diluted earnings per share
9.06

 
6.70

 
6.64

 
5.52

 
4.04

Dividends paid per share
3.16

 
2.44

 
1.88

 
1.44

 
0.56

 
As of December 31,
Consolidated Balance Sheet Data:
2015
 
2014
 
2013
 
2012
 
2011
 
(In millions)
Total assets
$
71,576

 
$
69,009

 
$
66,125

 
$
54,298

 
$
48,871

Total debt(2)
31,556

 
30,715

 
32,128

 
26,529

 
21,428

Total stockholders’ equity(3)
28,083

 
25,778

 
22,096

 
19,060

 
19,029

In addition to the following notes, see Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations and the Consolidated Financial Statements and accompanying notes and previously filed Annual Reports on Form 10-K for further information regarding our consolidated results of operations and financial position for periods reported therein and for known factors that will impact comparability of future results. Also, see Part IV—Note 15, Stockholders’ equity, to the Consolidated Financial Statements, for information regarding cash dividends declared per share of common stock.
(1) 
In 2011, we recorded a $780 million legal settlement charge ($705 million, net of tax) in connection with an agreement in principle to settle allegations related to our sales and marketing practices.
(2) 
See Part IV—Note 14, Financing arrangements, to the Consolidated Financial Statements for discussion of our financing arrangements. In addition, in 2012 and 2011, we issued $5.0 billion and $10.5 billion, respectively, aggregate principal amount of notes. In 2012, we repaid $123 million of Other notes. In 2011, we repaid our 0.125% Convertible Notes of $2.5 billion.
(3) 
Throughout the five years ended December 31, 2015, we had a stock repurchase program authorized by the Board of Directors through which we repurchased $1.9 billion, $0.2 billion, $0.8 billion, $4.7 billion and $8.3 billion, respectively, of Amgen common stock.

38



Item 7.
MANAGEMENT’S DISCUSSION AND ANALYSIS OF FINANCIAL CONDITION AND RESULTS OF OPERATIONS
The following management’s discussion and analysis (MD&A) is intended to assist the reader in understanding Amgen’s business. MD&A is provided as a supplement to, and should be read in conjunction with, our consolidated financial statements and accompanying notes. Our results of operations discussed in MD&A are presented in conformity with accounting principles generally accepted in the United States (GAAP). Amgen operates in one business segment: human therapeutics. Therefore, our results of operations are discussed on a consolidated basis.
Forward-looking statements
This report and other documents we file with the SEC contain forward-looking statements that are based on current expectations, estimates, forecasts and projections about us, our future performance, our business, our beliefs and our management’s assumptions. In addition, we, or others on our behalf, may make forward-looking statements in press releases or written statements, or in our communications and discussions with investors and analysts in the normal course of business through meetings, webcasts, phone calls and conference calls. Such words as “expect,” “anticipate,” “outlook,” “could,” “target,” “project,” “intend,” “plan,” “believe,” “seek,” “estimate,” “should,” “may,” “assume,” and “continue,” as well as variations of such words and similar expressions are intended to identify such forward-looking statements. These statements are not guarantees of future performance and they involve certain risks, uncertainties and assumptions that are difficult to predict. We describe our respective risks, uncertainties and assumptions that could affect the outcome or results of operations in Item 1A. Risk Factors. We have based our forward-looking statements on our management’s beliefs and assumptions based on information available to our management at the time the statements are made. We caution you that actual outcomes and results may differ materially from what is expressed, implied or forecast by our forward-looking statements. Reference is made in particular to forward-looking statements regarding product sales, regulatory activities, clinical trial results, reimbursement, expenses, earnings per share (EPS), liquidity and capital resources, trends and planned dividends, stock repurchases and restructuring plans. Except as required under the federal securities laws and the rules and regulations of the SEC, we do not have any intention or obligation to update publicly any forward-looking statements after the distribution of this report, whether as a result of new information, future events, changes in assumptions or otherwise.
Overview
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world’s leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
Our principal products include ENBREL, Neulasta®, Aranesp®, EPOGEN®, Sensipar®/Mimpara®, XGEVA®, Prolia® and NEUPOGEN®. For additional information about our products, see Part I, Item 1. Business—Marketing, Distribution and Selected Marketed Products.
In 2015, we advanced our strategy, by delivering strong financial performance across the business, advancing our innovative pipeline and branded biosimilar programs, developing improved biologic drug delivery systems, transforming our business to a more focused operating model and returning capital to shareholders.
Financial performance was strong, as total revenues and product sales increased 8% driven by strong performance across the portfolio except EPOGEN® and NEUPOGEN® which both decreased by 9%. Net income and diluted EPS increased by 35%, driven by higher total revenue and lower operating expenses. Cash flows from operating activities grew 6% to $9.1 billion, driven by higher operating income, enabling us to grow the business and invest for the future.
Our progress can also be seen in six innovative new launches - four in oncology and two in cardiovascular disease. For example, we continued to expand indications for our products, including for Kyprolis® , which is now the only approved therapy for relapsed or refractory multiple myeloma with proven efficacy as a single agent, doublet or triplet combination, that is offered in a variety of doses to meet individual patient needs.
Our pipeline continues to advance with the recent regulatory submissions for Parsabiv, positive phase 3 data for romosozumab (in collaboration with UCB), phase 2 data for AMG 334 (in collaboration with Novartis) and phase 2b data for omecamtiv mecarbil (in collaboration with Cytokinetics). In 2015, we also continued to advance our biosimilar program, including the filing for global regulatory approval for ABP 501, biosimilar adalimumab (HUMIRA®) and phase 3 data for ABP 215, biosimilar bevacizumab (Avastin®).

39



We continue to innovate with patient- and provider-friendly delivery systems to differentiate our products. The Neulasta® Onpro kit was approved by the FDA at the end of 2014 and now represents approximately one fourth of our U.S. Neulasta® business. We also submitted applications to regulators, including the FDA and EMA, for a single-dosing option for the monthly administration of Repatha®.
In 2015, we continued to execute the transformation and process improvement efforts announced in 2014. As part of these efforts, we committed to a more focused operating model. Our transformation and process improvement efforts across the Company have enabled us to reallocate resources to fund many of our innovative pipeline and growth opportunities to deliver value to patients and shareholders.
Finally, we continued returning capital to shareholders in 2015 through the payment of dividends and stock repurchases. We paid dividends of $0.79 per share of common stock in each of the four quarters of 2015, representing a 30% increase over the quarterly dividend paid in each of the four quarters of 2014. In December 2015, we declared a dividend of $1.00 per share of common stock for the first quarter of 2016, payable in March 2016, representing a 27% increase over the quarterly dividends paid in 2015. We also repurchased 12 million shares of our common stock throughout 2015 at an aggregate cost of $1.9 billion. As of December 31, 2015, $4.9 billion remained available under the Board of Directors-approved stock repurchase program.
We believe that we are uniquely positioned for the opportunities arising in biology and to deliver our strategy focusing on the areas of oncology/hematology, cardiovascular disease, inflammation, bone health, nephrology and neuroscience. We have near- and long-term opportunities ahead, including: (i) successfully executing on new product launches, (ii) advancing our robust pipeline with new innovative biologics and new delivery systems, (iii) the development, approval and launch of our biosimilars and (iv) advancing the next-generation manufacturing of high quality biologics. We expect our legacy products to continue to generate significant cash flows. In addition, we continue to focus on collaborating with innovators and value-creating business development activities to expand our approach to deliver significant impact for patients and advance programs where there remains high unmet medical need. Finally, we continue to expand into new geographic growth markets, enabling us to be present in over 100 countries.
Our business will continue to face various challenges. Certain of our products will face increasing competitive pressure as a result of competitive product launches, including from biosimilars. 2016 is the first full year we are competing without patent protection on several of our principal products in the United States. For additional information, including information on the expiration of patents for various products, see Part I, Item 1. Business-Marketing, Distribution and Selected Marketed Products-Patents and see Part I, Item 1. Business—Marketing, Distribution and Selected Marketed Products—Competition.
Current global economic conditions also pose challenges to our business, including continued pressure to reduce healthcare expenditures. Efforts to reduce healthcare costs are being made by third-party payers including governments and private payers. In the United States, various actions have been taken aimed at reducing healthcare spending. The continuing prominence of U.S. budget deficits increases the risk that taxes, fees, rebates, or other federal measures that would further reduce our revenues or increase our expenses may be enacted. As a result of global economic conditions, as well as public and private health care provider focus, the industry continues to experience significant pricing pressures and other cost containment measures.
Our long-term success depends to a great extent on our ability to continue to discover, develop and commercialize innovative products and acquire or collaborate on therapies currently in development by other companies. The discovery and development of safe and effective new products, as well as the development of additional indications for existing products, are necessary for the continued strength of our business. We must develop new products over time in order to offset revenue losses when products lose their exclusivity or competing products are launched, as well as in order to provide for revenue and earnings growth. We devote considerable resources to R&D activities. However, successful product development in the biotechnology industry is highly uncertain. We are also confronted by increasing regulatory scrutiny of safety and efficacy both before and after products launch.
Finally, our product sales can be affected by wholesaler and end-user buying patterns. These effects can cause fluctuations in quarterly product sales and have generally not been significant when comparing full-year product performance to the prior year.
See Part I, Item 1. Business—Marketing, Distribution and Selected Marketed Products and Part I, Item 1A. Risk Factors for further discussion of certain of the factors that could impact our future product sales.

40



Selected financial information
The following is an overview of our results of operations (in millions, except percentages and per share data):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
Product sales:
 
 
 
 
 
U.S.
$
16,523

 
12
 %
 
$
14,732

Rest of world (ROW)
4,421

 
(4
)%
 
4,595

Total product sales
20,944

 
8
 %
 
19,327

Other revenues
718

 
(2
)%
 
736

Total revenues
$
21,662

 
8
 %
 
$
20,063

Operating expenses
$
13,192

 
(5
)%
 
$
13,872

Operating income
$
8,470

 
37
 %
 
$
6,191

Net income
$
6,939

 
35
 %
 
$
5,158

Diluted EPS
$
9.06

 
35
 %
 
$
6.70

Diluted shares
766

 
(1
)%
 
770

In the following discussion of changes in product sales, any reference to unit demand growth or decline refers to changes in the purchases of our products by healthcare providers, such as physicians or their clinics, dialysis centers, hospitals and pharmacies.
U.S. product sales for 2015 increased across the portfolio except for EPOGEN® and NEUPOGEN®, which declined 9% and 5%, respectively. The U.S. increase was driven primarily by increases in net selling prices. The decrease in ROW product sales for 2015 reflects unfavorable changes in foreign exchange rates and declines in net selling prices, offset partially by unit demand growth.
The decrease in operating expenses for 2015 was driven primarily by savings from transformation and process improvement efforts, higher restructuring charges in the prior year and favorable changes in foreign currency exchange rates, offset partially by increased support for launch products.
Although changes in foreign currency exchange rates result in increases or decreases in our reported international product sales, the benefit or detriment that such movements have on our international product sales is offset partially by corresponding increases or decreases in our international operating expenses and our related foreign currency hedging activities. Our hedging activities seek to offset the impacts, both positive and negative, that foreign currency exchange rate changes may have on our net income by hedging our net foreign currency exposure, primarily with respect to product sales denominated in euros. The net impact from changes in foreign currency exchange rates was not material in 2015, 2014 or 2013.

41



Results of Operations
Product sales
Worldwide product sales were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
ENBREL
$
5,364

 
14
 %
 
$
4,688

 
3
 %
 
$
4,551

Neulasta®
4,715

 
3
 %
 
4,596

 
5
 %
 
4,392

Aranesp®
1,951

 
1
 %
 
1,930

 
1
 %
 
1,911

EPOGEN®
1,856

 
(9
)%
 
2,031

 
4
 %
 
1,953

Sensipar®/Mimpara®
1,415

 
22
 %
 
1,158

 
6
 %
 
1,089

XGEVA®
1,405

 
15
 %
 
1,221

 
20
 %
 
1,019

Prolia®
1,312

 
27
 %
 
1,030

 
38
 %
 
744

NEUPOGEN®
1,049

 
(9
)%
 
1,159

 
(17
)%
 
1,398

Other products
1,877

 
24
 %
 
1,514

 
33
 %
 
1,135

Total product sales
$
20,944

 
8
 %
 
$
19,327

 
6
 %
 
$
18,192

Total U.S.
$
16,523

 
12
 %
 
$
14,732

 
5
 %
 
$
14,045

Total ROW
4,421

 
(4
)%
 
4,595

 
11
 %
 
4,147

Total product sales
$
20,944

 
8
 %
 
$
19,327

 
6
 %
 
$
18,192

Future sales of our products will depend, in part, on the factors discussed in the Overview, Part 1—Item 1. Business—Marketing, Distribution and Selected Marketed Products—Competition, Part 1—Item 1A. Risk Factors and any additional factors discussed in the individual product sections below. In addition, for a list of our products’ significant competitors, see Part 1—Item 1. Business—Marketing, Distribution and Selected Marketed Products—Competition.
ENBREL
Total ENBREL sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
ENBREL — U.S.
$
5,099

 
16
 %
 
$
4,404

 
3
 %
 
$
4,256

ENBREL — Canada
265

 
(7
)%
 
284

 
(4
)%
 
295

Total ENBREL
$
5,364

 
14
 %

$
4,688

 
3
 %
 
$
4,551

The increase in ENBREL sales for 2015 was driven primarily by an increase in net selling price offset partially by the impact of competition.
The increase in ENBREL sales for 2014 was driven primarily by an increase in net selling price offset partially by unfavorable changes in wholesaler and, based on prescription data, end-user inventories.
Neulasta® 
Total Neulasta® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Neulasta®  —  U.S.
$
3,891

 
7
 %
 
$
3,649

 
4
%
 
$
3,499

Neulasta®  —  ROW
824

 
(13
)%
 
947

 
6
%
 
893

Total Neulasta®
$
4,715

 
3
 %

$
4,596

 
5
%
 
$
4,392


42



The increase in global Neulasta® sales for 2015 was driven primarily by an increase in net selling price in the United States, offset partially by unfavorable changes in foreign currency exchange rates. As of the end of December 2015, the Neulasta® Onpro kit represents approximately one fourth of our U.S. Neulasta® business.
In December 2014, the FDA granted approval of the Neulasta® Onpro kit which enables the healthcare provider to initiate administration of Neulasta® on the same day as chemotherapy—with delivery of the patient’s full dose of Neulasta® the day following chemotherapy administration, consistent with the Neulasta® prescribing information.
The increase in global Neulasta® sales for 2014 was driven primarily by an increase in net selling price in the United States.
Our final material U.S. patent for pegfilgrastim (Neulasta®) expired in October 2015. On December 17, 2014, Apotex, Inc. (Apotex) announced that the FDA accepted for filing its application, under the abbreviated pathway, for pegfilgrastim, a biosimilar version of Neulasta®. Therefore, we expect to face competition in the United States, which over time may have a material adverse impact on Neulasta® sales. For discussion of ongoing litigation between us and Apotex, see Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.
Future Neulasta® sales will also depend, in part, on the development of new protocols, tests and/or treatments for cancer and/or new chemotherapy treatments or alternatives to chemotherapy that may have reduced and may continue to reduce the use of chemotherapy in some patients.
Aranesp® 
Total Aranesp® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Aranesp® — U.S.
$
900

 
13
 %
 
$
794

 
6
 %
 
$
747

Aranesp® — ROW
1,051

 
(7
)%
 
1,136

 
(2
)%
 
1,164

Total Aranesp®
$
1,951

 
1
 %

$
1,930

 
1
 %
 
$
1,911

The increase in global Aranesp® sales for 2015 was driven by unit demand growth, including a shift from EPOGEN® in the United States, offset partially by unfavorable changes in foreign currency exchange rates and a decrease in net selling price.
The increase in U.S. Aranesp® sales for 2014 was driven by an increase in net selling price and, to a lesser extent, unit demand growth. The decrease in ROW Aranesp® sales for 2014 reflects a decrease in net selling price offset partially by unit demand growth in international markets.
Supplementary protection certificates issued by certain countries relating to our European patent for darbepoetin alfa (Aranesp®) expire in June 2016. See Part 1, Item 1. Business—Marketing, Distribution and Selected Marketed Products—Patents.
EPOGEN® 
Total EPOGEN® sales were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
EPOGEN® — U.S.
$
1,856

 
(9
)%
 
$
2,031

 
4
%
 
$
1,953

The decrease in EPOGEN® sales for 2015 was driven by a decline in unit demand resulting from competition and a shift in dialysis sales to Aranesp®, offset partially by an increase in net selling price. The decline in EPOGEN® sales accelerated in the second half of 2015 to 37% in the fourth quarter 2015 as compared to the fourth quarter in 2014.
The increase in EPOGEN® sales for 2014 was driven by an increase in net selling price offset partially by a decline in unit demand.
Our final material U.S. patent for EPOGEN® expired in May 2015. We face competition in the United States, which over time may have a material adverse impact on EPOGEN® sales. Currently, in the United States, EPOGEN® and Aranesp® compete with MIRCERA®, which Roche began selling in October 2014 and, as of May 2015, licensed commercialization rights in the United States to Galenica. Simultaneously, Galenica entered into an agreement to supply MIRCERA® to Fresenius, which provides treatment to a significant portion of U.S. dialysis patients. On December 16, 2014, Hospira, Inc. (Hospira), a subsidiary of Pfizer,

43



submitted a BLA to the FDA for Retacrit, a proposed biosimilar to EPOGEN®. For discussion of ongoing litigation between us and Hospira, see Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.
Sensipar®/Mimpara® 
Total Sensipar®/Mimpara® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Sensipar® — U.S.
$
1,069

 
34
 %
 
$
796

 
5
%
 
$
757

Sensipar®/Mimpara® — ROW
346

 
(4
)%
 
362

 
9
%
 
332

Total Sensipar®/Mimpara®
$
1,415

 
22
 %

$
1,158

 
6
%
 
$
1,089

The increase in global Sensipar®/Mimpara® sales for 2015 was driven primarily by unit demand growth and an increase in net selling price in the United States. ROW Sensipar®/Mimpara® sales were negatively impacted by changes in foreign currency exchange rates.
The increase in global Sensipar®/Mimpara® sales for 2014 was driven primarily by unit demand growth and an increase in net selling price in the United States, offset partially by unfavorable changes in U.S. wholesaler and, based on prescription data, end-user inventories.
XGEVA® 
Total XGEVA® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
XGEVA®  —  U.S.
$
1,006

 
17
%
 
$
857

 
12
%
 
$
764

XGEVA®  —  ROW
399

 
10
%
 
364

 
43
%
 
255

Total XGEVA®
$
1,405

 
15
%

$
1,221

 
20
%
 
$
1,019

The increases in global XGEVA® sales for 2015 and 2014 were driven primarily by unit demand growth.
Prolia®  
Total Prolia® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Prolia® — U.S.
$
837

 
34
%
 
$
625

 
35
%
 
$
462

Prolia® — ROW
475

 
17
%
 
405

 
44
%
 
282

Total Prolia®
$
1,312

 
27
%

$
1,030

 
38
%
 
$
744

The increases in global Prolia® sales for 2015 and 2014 were driven primarily by unit demand growth.
NEUPOGEN® 
Total NEUPOGEN® sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
NEUPOGEN® — U.S.
$
793

 
(5
)%
 
$
839

 
(28
)%
 
$
1,169

NEUPOGEN® — ROW
256

 
(20
)%
 
320

 
40
 %
 
229

Total NEUPOGEN®
$
1,049

 
(9
)%

$
1,159

 
(17
)%
 
$
1,398


44



The decrease in global NEUPOGEN® sales for 2015 was driven by a decline in unit demand due primarily to the impact of short-acting competition in the United States.
The decrease in global NEUPOGEN® sales for 2014 was driven by the $155-million order from the U.S. government in 2013. Excluding the special order, U.S. and global sales declined 17% and 7%, respectively, which reflected declines in unit demand in the United States, offset partially by the increased sales as a result of acquiring rights to filgrastim in certain international areas effective January 1, 2014.
There is competition in the United States, which we expect will have a material adverse impact on future sales of NEUPOGEN®. On September 3, 2015, Sandoz announced that they launched Zarxio, a biosimilar version of NEUPOGEN®, in the United States. On February 17, 2015, Apotex announced that the FDA accepted for filing its application, under the abbreviated pathway, for its biosimilar version of NEUPOGEN®. For discussion of ongoing litigation, see Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.
See Part 1, Item 1. Business—Marketing, Distribution and Selected Marketed Products—Competition and Part IV—Note 18, Contingencies and commitments, to the Consolidated Financial Statements.
Future NEUPOGEN® sales will also depend, in part, on the development of new protocols, tests and/or treatments for cancer and/or new chemotherapy treatments or alternatives to chemotherapy that may have reduced and may continue to reduce the use of chemotherapy in some patients.
Other products
Other product sales by geographic region were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Vectibix® — U.S.
$
204

 
21
%
 
$
168

 
33
 %
 
$
126

Vectibix® — ROW
345

 
2
%
 
337

 
28
 %
 
263

Nplate® — U.S.
317

 
22
%
 
260

 
8
 %
 
241

Nplate® — ROW
208

 
%
 
209

 
12
 %
 
186

Kyprolis® — U.S.
467

 
53
%
 
306

 
*

 
71

Kyprolis® — ROW
45

 
80
%
 
25

 
*

 
2

Other — U.S.
84

 
*

 
3

 
N/A

 

Other — ROW
207

 
%
 
206

 
(16
)%
 
246

Total other product sales
$
1,877

 
24
%
 
$
1,514

 
33
 %
 
$
1,135

Total U.S. — other products
$
1,072

 
45
%
 
$
737

 
68
 %
 
$
438

Total ROW — other products
805

 
4
%
 
777

 
11
 %
 
697

Total other product sales
$
1,877

 
24
%
 
$
1,514

 
33
 %
 
$
1,135

* Change in excess of 100%

45



Operating expenses
Operating expenses were as follows (dollar amounts in millions):
 
Year ended December 31,
 
 
 
Year ended December 31,
 
 
 
Year ended December 31,
 
2015
 
Change
 
2014
 
Change
 
2013
Operating expenses:
 
 
 
 
 
 
 
 
 
Cost of sales
$
4,227

 
(4
)%
 
$
4,422

 
32
 %
 
$
3,346

% of product sales
20.2
%
 
 
 
22.9
%
 
 
 
18.4
%
% of total revenues
19.5
%
 
 
 
22.0
%
 
 
 
17.9
%
Research and development
$
4,070

 
(5
)%
 
$
4,297

 
5
 %
 
$
4,083

% of product sales
19.4
%
 
 
 
22.2
%
 
 
 
22.4
%
% of total revenues
18.8
%
 
 
 
21.4
%
 
 
 
21.9
%
Selling, general and administrative
$
4,846

 
3
 %
 
$
4,699

 
(9
)%
 
$
5,184

% of product sales
23.1
%
 
 
 
24.3
%
 
 
 
28.5
%
% of total revenues
22.4
%
 
 
 
23.4
%
 
 
 
27.8
%
Other
$
49

 
(89
)%
 
$
454

 
*

 
$
196

* Change in excess of 100%
Transformation and process improvement
During the second half of 2014, we announced process improvement and transformation initiatives that are enabling us to invest in continuing innovation, expand into new countries and launch new products, while improving our cost structure. This plan includes a restructuring, which is delivering cost savings and funding investments. The restructuring includes reducing our geographic footprint, as well as reducing our staff by 3,500 to 4,000, both of which allow us to reinvest and hire in our strategic areas of focus.
We estimate that this restructuring plan will result in pre-tax accounting charges in the range of $800 million to $900 million, which is less than originally expected due to better than anticipated results from the exit of two of our closed facilities. Restructuring costs to date of $672 million were incurred as of December 31, 2015. During the years ended December 31, 2015 and 2014, we incurred restructuring costs of $114 million and $558 million, respectively. We expect that we will incur most of the remaining estimated costs in 2016 and 2017 in order to support our ongoing transformation and process improvement efforts. Net savings were not significant in 2015 and 2014 due to the investments in new product launch preparations, later stage clinical programs and external business development.
Additional information required for our restructuring plan is incorporated herein by reference to Part IV—Note 2, Restructuring and other cost savings initiatives, to the Consolidated Financial Statements.
Cost of sales
Cost of sales decreased to 19.5% of total revenues for 2015, driven primarily by lower royalties, higher net selling prices, manufacturing efficiencies and lower costs related to our restructuring plan. The year ended December 31, 2014, also had a $99-million charge related to the termination of the supply contract with Roche as a result of acquiring the licenses to filgrastim and pegfilgrastim effective January 1, 2014.
Cost of sales increased to 22.0% of total revenues for 2014, driven by acquisition-related expenses that included an increase of $642 million of non-cash amortization of intangible assets acquired in the Onyx acquisition. The year ended December 31, 2014, also included impairment and accelerated depreciation charges pursuant to our restructuring initiative of $104 million as well as the aforementioned $99-million charge related to the termination of the supply contract with Roche.
The excise tax imposed by Puerto Rico on the gross intercompany purchase price of goods and services from our manufacturer in Puerto Rico (Puerto Rico excise tax) is recorded as a cost of sales expense. Excluding the impact of the Puerto Rico excise tax, cost of sales would have been 17.8%, 20.1% and 16.0% of total revenues for 2015, 2014 and 2013, respectively. See Part IV—Note 5, Income taxes, to the Consolidated Financial Statements for further discussion of the Puerto Rico excise tax.

46



Research and development
The Company groups all of its R&D activities and related expenditures into three categories: (1) Discovery Research and Translational Sciences (DRTS), (2) later stage clinical programs and (3) marketed products. These categories include the Company’s R&D activities as set forth in the following table:
Category
 
Description
DRTS
 
R&D expenses incurred in activities substantially in support of early research through the completion of phase 1 clinical trials. These activities encompass our DRTS functions, including drug discovery, toxicology, pharmacokinetics and drug metabolism, and process development.
Later stage clinical programs
 
R&D expenses incurred in or related to phase 2 and phase 3 clinical programs intended to result in registration of a new product or a new indication for an existing product in the United States or the EU.
Marketed products
 
R&D expenses incurred in support of the Company’s marketed products that are authorized to be sold in the United States or the EU. Includes clinical trials designed to gather information on product safety (certain of which may be required by regulatory authorities) and their product characteristics after regulatory approval has been obtained, as well as the costs of obtaining regulatory approval of a product in a new market after approval in either the United States or the EU has been obtained.
R&D expense by category was as follows (in millions):
 
Years ended December 31,
 
2015
 
2014
 
2013
DRTS
$
997

 
$
1,212

 
$
1,233

Later stage clinical programs
1,876

 
2,287

 
1,950

Marketed products
1,197

 
798

 
900

Total R&D expense
$
4,070

 
$
4,297

 
$
4,083

The decrease in R&D expense for 2015 was driven by decreased costs associated with later stage clinical programs support of $411 million and DRTS of $215 million, offset partially by increased costs associated with marketed products support of $399 million. All categories of R&D spend benefited from savings from transformation and process improvement efforts under our restructuring plan, which were offset partially by increased launch related spend in marketed products, primarily Repatha®. Prior to approval, costs related to our launch products were largely categorized as later stage clinical programs. The 2015 DRTS expenses also included up-front milestone payments related to our collaborations with Xencor, Inc. and Novartis.
The increase in R&D expense for 2014 was driven primarily by increased costs of $326 million associated with Onyx across all categories of R&D spend, as well as increased costs associated with other later stage clinical program support. Overall, costs associated with later stage clinical programs support increased $337 million, offset partially by reduced expenses associated with marketed products support of $102 million and DRTS activities of $21 million. The 2014 DRTS expenses also included a $60 million upfront payment related to our cancer immunotherapy collaboration with Kite Pharma, Inc.
Selling, general and administrative
The increase in Selling, general and administrative (SG&A) expense for 2015 was driven primarily by new product launches offset partially by savings from transformation and process improvement efforts under our restructuring plan. 2014 also included an additional $129 million accrual for the BPD fee as the final regulations accelerated the expense recognition criteria for the fee obligation by one year.
The decrease in SG&A expense for 2014 was driven primarily by the expiration of the ENBREL profit share in October 2013, which reduced expenses by $818 million. That decline was offset partially by the addition of $183 million as a result of the Onyx acquisition, the aforementioned additional accrual for the BPD fee and increased commercial expenses of $109 million in preparation for new product launches.
Historically, under our ENBREL collaboration agreement, we paid Pfizer a percentage of annual gross profits on our ENBREL sales in the United States and Canada on a scale that increased with gross profits. The ENBREL co-promotion term expired on October 31, 2013, and we are required to pay Pfizer residual royalties on a declining percentage of net ENBREL sales in the United States and Canada. The royalty percentage was 12% through October 31, 2014, declining to 11% through October 31, 2015, and 10% through October 31, 2016. Effective November 1, 2016, there will be no further royalty payments.

47



Other
Other operating expenses for 2015 included $91 million of charges related to legal proceedings, certain charges related to our restructuring initiatives, primarily separation costs of $49 million, $31 million of write-offs of non-key assets acquired in a prior year business combination, and $111 million of gains from the sale of assets related to our site closures.
Other operating expenses for 2014 included certain charges related to our restructuring plan, primarily separation costs of $377 million. It also included a $46 million write-off of a non-key IPR&D program acquired in a prior year business combination.
Other operating expenses for 2013 included $113 million of adjustments to our estimated contingent consideration liability related to the BioVex Group, Inc. (BioVex) business combination, certain charges related to our other cost savings initiatives of $71 million, which included severance expenses, and $12 million of other charges related primarily to legal proceedings.
Non-operating expenses/income and provision for income taxes
Non-operating expenses/income and provision for income taxes were as follows (dollar amounts in millions):
 
Years ended December 31,
 
2015
 
2014
 
2013
Interest expense, net
$
1,095

 
$
1,071

 
$
1,022