What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2022-03-01 compared with 2021-02-23 · 584 added, 421 removed, 541 unchanged (65% of the section changed)

Jazz Pharmaceuticals plc is an innovative global biopharmaceutical company dedicated to developing and commercializing life-changing medicines that transform the lives of patients with serious diseases – often with limited or no options.

We have a diverse portfolio of marketed medicines and novel product candidates, in early- to late-stage development, across key therapeutic areas.

Our focus is in neuroscience, including sleep and movement disorders, and in oncology, including hematologic malignancies and solid tumors.

We actively explore new options for patients including novel compounds, small molecule advancements, biologics and innovative delivery technologies.

Jazz Pharmaceuticals plc is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families.

We are dedicated to developing life-changing medicines for people with serious diseases - often with limited or no therapeutic options.

We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology.

Within these therapeutic areas, we strive to identify new options for patients by actively exploring small molecules and biologics, and through innovative delivery technologies and cannabinoid science.

Our strategy for growth is rooted in executing commercial launches and ongoing commercialization initiatives;

advancing robust research and development, or R&D, programs and delivering impactful clinical results;

effectively deploying capital to strengthen the prospects of achieving our short- and long-term goals through strategic corporate development;

and delivering strong financial performance.

We focus on patient populations with high unmet needs.

We identify and develop differentiated therapies for these patients that we expect will be long-lived assets and that we can support with an efficient commercialization model.

In addition, we leverage our efficient, scalable operating model and integrated capabilities across our global infrastructure to effectively reach patients around the world.

At the 40th Annual J.P.

Morgan Healthcare Conference in January 2022, we announced our Vision 2025, which aims to deliver sustainable growth and enhanced value, driving our continued transformation to an innovative, high-growth global pharmaceutical leader.

The three core components of our Vision 2025 focus on commercial execution, pipeline productivity and operational excellence.

Our lead marketed products are:

• Xyrem ® (sodium oxybate) oral solution , a product approved by the U.S.

Food and Drug Administration, or FDA, and marketed in the U.S.

for the treatment of both cataplexy and excessive daytime sleepiness, or EDS, in narcolepsy patients seven years of age and older;

• Xywav™ (calcium, magnesium, potassium, and sodium oxybates) oral solution , a product that contains 92% less sodium than Xyrem, approved by FDA and launched in the U.S.

in November 2020 for the treatment of cataplexy or EDS in narcolepsy patients seven years of age and older;

• Sunosi ® (solriamfetol) , a product approved by FDA and the European Commission, or the EC, and marketed in the U.S.

and in Europe to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea, or OSA;

• Defitelio ® (defibrotide sodium) , a product approved in the U.S.

for the treatment of adult and pediatric patients with hepatic veno-occlusive disease, or VOD, also known as sinusoidal obstruction syndrome, or SOS, with renal or pulmonary dysfunction following hematopoietic stem cell transplantation, or HSCT, and in Europe (where it is marketed as Defitelio ® (defibrotide)) for the treatment of severe VOD in adults and children undergoing HSCT therapy;

• Erwinaze ® (asparaginase Erwinia chrysanthemi ) , a product approved in the U.S.

and in certain markets in Europe (where it is marketed as Erwinase ® ) for patients with acute lymphoblastic leukemia, or ALL, who have developed hypersensitivity to E.

• Xywav® (calcium, magnesium, potassium, and sodium oxybates) oral solution , a product approved by the U.S.

Food and Drug Administration, or FDA, in July 2020 and launched in the U.S.

in November 2020 for the treatment of cataplexy or excessive daytime sleepiness, or EDS, in patients with narcolepsy aged seven years of age and older, and also approved by FDA in August 2021 for the treatment of idiopathic hypersomnia, or IH, in adults and launched in the U.S.

in November 2021.

Xywav contains 92% less sodium than Xyrem®;

• Xyrem (sodium oxybate) oral solution , a product approved by FDA and distributed in the U.S.

for the treatment of both cataplexy and EDS in patients seven years of age and older with narcolepsy;

Jazz also markets Xyrem in Canada for the treatment of cataplexy in patients with narcolepsy.

Xyrem is also approved and distributed in Europe, Great Britain and other markets through a licensing agreement;

• Epidiolex® (cannabidiol) oral solution , a product approved by FDA and launched in the U.S.

in 2018 by GW Pharmaceuticals plc, or GW, and currently indicated for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex, or TSC, in patients one year of age or older;

in Europe (where it is marketed as Epidyolex®) and other markets, it is approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, in conjunction with clobazam (EU and Great Britain only), in patients 2 years of age and older and for adjunctive treatment of seizures associated with TSC in patients 2 years of age and older;

• Sunosi® (solriamfetol) , a product approved by FDA and marketed in the U.S., Canada, Europe and Great Britain to improve wakefulness in adult patients with EDS associated with narcolepsy or obstructive sleep apnea, or OSA;

• Sativex® (nabiximols) oral solution , a product approved and marketed in the U.K., Canada and other markets as treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis, or MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

• Zepzelca® (lurbinectedin) , a product approved by FDA in June 2020 and launched in the U.S.

in July 2020 for the treatment of adult patients with metastatic small cell lung cancer, or SCLC, with disease progression on or after platinum-based chemotherapy;

i n Canada, Zepzelca was approved in September 2021 for the treatment of adults with Stage III or metastatic SCLC, who have progressed on or after platinum-containing therapy;

• Rylaze™ (recombinant Erwinia asparaginase), a product approved by FDA in June 2021 and launched in the U.S.

in July 2021 for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia, or ALL, or lymphoblastic lymphoma, or LBL, in adults and pediatric patients who have developed hypersensitivity to E.

coli -derived asparaginase;

• Vyxeos ® (daunorubicin and cytarabine) liposome for injection , a product approved in the U.S.

and in Europe (where it is marketed as Vyxeos ® liposomal 44 mg/100 mg powder for concentrate for solution for infusion) for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia, or t-AML, or AML with myelodysplasia-related changes, or AML-MRC;

• Zepzelca ™ (lurbinectedin) , a product approved by FDA and launched in July 2020 in the U.S.

for the treatment of adult patients with metastatic small cell lung cancer, or SCLC, with disease progression on or after platinum-based chemotherapy.

Our strategy to create sustainable shareholder value is focused on:

• Strong commercial execution to drive diversified revenue growth and address unmet medical needs of our patients across our product portfolio including with rapid adoption of Xywav in the U.S., Sunosi growth globally and establishing Zepzelca as a treatment of choice for second line SCLC patients;

• Expanding and advancing our pipeline with internal and external patient-centric innovation to achieve a valuable product portfolio of durable, highly differentiated programs;

• Continuing to build a flexible, efficient, and productive development engine for targeted therapeutic conditions to identify and progress early- and mid-stage assets;

• Investing in an efficient, scalable operating model and differentiated capabilities to enable growth;

and unlock further value through indication expansion and global markets.

In 2020, consistent with our strategy, we continued to focus on research and development activities within our neuroscience and oncology therapeutic areas, such as our expansion into movement disorders and solid tumors, and exploring and investing in adjacent therapeutic areas that could further diversify our portfolio, such as post-traumatic stress disorders through our acquisition of SpringWorks Therapeutics, Inc.’s, fatty acid amide hydrolase, or FAAH, inhibitor program.

• Vyxeos® (daunorubicin and cytarabine) liposome for injection , a product approved in the U.S., Canada, Europe and Great Britain (marketed as Vyxeos® liposomal in Europe and Great Britain) for the treatment of adults with newly-diagnosed therapy-related acute myeloid leukemia, or t-AML, or AML with myelodysplasia-related changes (AML-MRC).

An expanded indication was granted in the U.S.

for the treatment of newly diagnosed t-AML or AML-MRC in pediatric patients aged 1 year and older;

• Defitelio® (defibrotide sodium) , is a product approved in the U.S.

and Brazil for the treatment of hepatic veno-occlusive disease, or VOD, with renal or pulmonary dysfunction following hematopoietic stem cell transplantation, or HSCT, and in Japan for the treatment of hepatic sinusoidal obstruction syndrome (hepatic-veno occlusive disease).

It is currently approved in the EU, Great Britain, Canada, Israel, South Korea, Australia and Switzerland for the treatment of severe hepatic VOD, also known as sinusoidal obstructive syndrome, or SOS, in HSCT therapy.

It is indicated in adults and pediatric patients over 1 month of age.

In 2021, consistent with our strategy, we continued to focus on research and development activities within our neuroscience and oncology therapeutic areas.

For a summary of our ongoing research and development activities, see “Business—Research and Development” in this Part I, Item 1.

Proposed Acquisition of GW Pharmaceuticals

On February 3, 2021, we announced that we have entered into a definitive transaction agreement, or the GW Transaction Agreement, with GW Pharmaceuticals plc, or GW, under which a wholly-owned subsidiary of ours, Jazz Pharmaceuticals UK Holdings Limited, or Acquisition Sub, agreed to acquire GW.

The GW Transaction Agreement provides, among other things, that, subject to the satisfaction or waiver of the conditions set forth in the GW Transaction Agreement, we (through Acquisition Sub) will acquire the entire issued share capital of GW, which we refer to in this report as the GW Acquisition.

Under the GW Transaction Agreement, the consideration to be paid by us in the GW Acquisition consists of $220.00 per American Depositary Share in GW, to be paid in the form of $200 in cash and $20 in our ordinary shares, for total consideration of approximately $7.2 billion.

The GW Acquisition is expected to close in the second quarter of 2021, subject to the satisfaction or waiver of the

conditions set forth in the GW Transaction Agreement, including applicable regulatory approvals and the approval of GW shareholders.

Acquisition of GW Pharmaceuticals

In May 2021, we acquired GW Pharmaceuticals plc, or GW.

The total consideration paid by us for the entire issued share capital of GW was $7.2 billion.

The acquisition, which we refer to as the GW Acquisition, closed on May 5, 2021.

We acquired GW with the objective of broadening our neuroscience portfolio, further diversifying our revenue and driving sustainable, long-term value creation opportunities.

GW was a global leader in discovering, developing, manufacturing and commercializing novel, regulatory approved therapeutics from its proprietary cannabinoid research platform to address a broad range of diseases.

For further information regarding the GW Acquisition, please see Note 3 Business Combinations, Asset Acquisitions and Collaborations of the Notes to Consolidated Financial Statements, included in Part IV of this Annual Report on Form 10‑K .

Our Commercialized Products

Xyrem is a product approved by FDA and marketed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy.

Sodium oxybate, the active pharmaceutical ingredient, or API, in Xyrem, is a formulation of the sodium salt of gamma-hydroxybutyrate, an endogenous neurotransmitter and metabolite of gamma-aminobutyric acid.

Xywav is a product approved by FDA for the treatment of cataplexy or EDS in both adult and pediatric patients aged seven years of age and older with narcolepsy and for the treatment of adults with IH.

Xywav is an oxybate product that contains 92% less sodium than Xyrem.

In July 2020, FDA approved Xywav for the treatment of both cataplexy and EDS in patients with narcolepsy.

We commenced the U.S.

launch in November 2020.

We met our goal to obtain broad payor coverage of Xywav within six months of launch.

To date, we have entered into agreements with various entities and have achieved benefit coverage for Xywav for approximately 90% of commercial lives.

Narcolepsy is a chronic, debilitating neurological disorder characterized by EDS and the inability to regulate sleep-wake cycles normally.

10 unchanged sentences

Cataplexy can severely impair a patient’s quality of life and ability to function.

Narcolepsy patients, by virtue of their diagnosis, are at increased risk of cardiovascular events and disease, and the impact of sodium on cardiovascular health is well established.

There is also extensive scientific evidence that reducing sodium

consumption, which is a modifiable risk factor, is associated with clinically meaningful reductions in blood pressure and cardiovascular disease risk.

Therefore, we believe that reducing sodium intake compared to the standard of care by 92% each and every day is a significant advancement for these patients.

The 92% reduction of sodium translates into a reduction of approximately 1,000 to 1,500 milligrams per day for a patient prescribed Xyrem, depending on the dose.

When patients transition from Xyrem to Xywav, Xywav treatment is initiated at the same dose and regimen (gram for gram) and titrated as needed based on efficacy and tolerability.

The label for Xywav, unlike Xyrem, does not include a warning to prescribers to monitor patients sensitive to sodium intake, including patients with heart failure, hypertension or renal impairment.

Our internal market research finds that health care providers and patients who understand the increased risk of cardiovascular disease faced by narcolepsy patients and who have been educated on the meaningful reduction in sodium from Xyrem to Xywav cite that meaningful reduction as a key reason for prescribing or starting on Xywav.

In June 2021, FDA recognized seven years of Orphan Drug Exclusivity, or ODE, for Xywav in narcolepsy through July 21, 2027, stating that Xywav is clinically superior to Xyrem by means of greater safety due to reduced chronic sodium burden.

In approving Xywav, FDA approved a REMS to cover both Xywav and Xyrem.

The Xywav and Xyrem REMS has the same requirements for both products and both products are also distributed by the central pharmacy through exclusive agreements described more fully below.

On August 12, 2021, FDA approved Xywav for the treatment of IH in adults.

Xywav is the first and only FDA-approved therapy to treat IH.

We initiated the U.S.

commercial launch of Xywav for the treatment of IH in adults on November 1, 2021.

IH is a debilitating neurologic sleep disorder characterized by chronic EDS (the inability to stay awake and alert during the day resulting in the irrepressible need to sleep or unplanned lapses into sleep or drowsiness), severe sleep inertia, and prolonged and non-restorative nighttime sleep.

Although there are overlapping clinical features with other conditions, including narcolepsy, IH has its own specific diagnostic criteria.

IH can significantly affect social, educational and occupational functioning.

An estimated 37,000 people in the U.S.

have been diagnosed with IH and are actively seeking healthcare.

In January 2022, FDA recognized seven years of ODE for Xywav in IH through August 12, 2028.

In 2021, net product sales of Xywav were $535.3 million, which represented 17% of our total net product sales.

There were approximately 6,900 active patients on Xywav exiting the fourth quarter of 2021, including approximately 6,650 active patients with narcolepsy and approximately 250 active patients with IH.

With respect to Xywav and Xyrem in the aggregate, the average number of active oxybate patients on therapy was approximately 16,200 in the fourth quarter of 2021.

Xyrem is a product approved by FDA and distributed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy.

Xyrem was approved in the U.S.

2 unchanged sentences

for the treatment of cataplexy or EDS in pediatric narcolepsy patients ages seven and older.

The American Academy of Sleep Medicine recommends Xyrem as a standard of care for the treatment of both cataplexy and EDS associated with narcolepsy.

In an effort to reach more patients who might benefit from our oxybate products, we continue to implement initiatives such as outreach to prescribers who treat narcolepsy, physician/healthcare provider education, enhanced patient and physician support services and unbranded disease awareness programs for the public.

Our marketing, sales and distribution of Xyrem in the U.S.

are subject to a risk evaluation and mitigation strategy, or REMS, which is required by FDA to mitigate the risks of serious adverse outcomes resulting from inappropriate prescribing, abuse, misuse and diversion of Xyrem.

Under this REMS, all of the Xyrem sold in the U.S.

In its updated 2021 treatment guidelines, the American Academy of Sleep Medicine gives sodium oxybate a strong recommendation for the treatment of narcolepsy in adults.

To support the development and commercialization of Xyrem internationally, we have license and distribution agreement with UCB Pharma Limited, or UCB, across other countries.

This agreement provides UCB and its affiliates with the sole right to commercialize Xyrem in exclusive territories for all indications.

In 2021, net product sales of Xyrem were $1.3 billion, which represented 41% of our total net product sales.

Xywav and Xyrem REMS .

Our marketing, sales and distribution of Xywav and Xyrem in the U.S.

are subject to a REMS, which is required by FDA to mitigate the risks of serious adverse outcomes resulting from inappropriate prescribing, abuse, misuse and diversion of Xywav and Xyrem.

Under this REMS, all of the Xywav and Xyrem sold in the U.S.

must be dispensed and shipped directly to patients or caregivers through a central pharmacy.

Xyrem may not be stocked in retail pharmacies.

Physicians and patients must complete an enrollment process prior to fulfillment of Xyrem prescriptions, and each physician and patient must receive materials concerning the serious risks associated with Xyrem before the physician can prescribe, or a patient can receive, the product.

The central certified pharmacy must monitor and report instances of patient or prescriber behavior giving rise to a reasonable suspicion of abuse, misuse or diversion of Xyrem, and maintains enrollment and prescription monitoring information in a central database.

Xywav and Xyrem may not be stocked in retail pharmacies.

Physicians and patients must complete an enrollment process prior to fulfillment of Xywav and Xyrem prescriptions, and each physician and patient must receive materials concerning the serious risks associated with Xywav and Xyrem before the physician can prescribe, or a patient can receive, the product.

The central certified pharmacy must monitor and report instances of patient or prescriber behavior giving rise to a reasonable suspicion of abuse, misuse or diversion of Xywav and Xyrem, and maintains enrollment and prescription monitoring information in a central database.

The central pharmacy ships the product directly to the patient (or caregiver) by a courier service.

We have had exclusive agreements with Express Scripts Specialty Distribution Services, Inc., or ESSDS, the central pharmacy for Xyrem, to distribute Xyrem in the U.S.

We have had exclusive agreements with Express Scripts Specialty Distribution Services, Inc., or ESSDS, the central pharmacy for Xywav and Xyrem, to distribute Xywav and Xyrem in the U.S.

and provide patient support services related to Xyrem since 2002.

1 unchanged sentence

Our current agreements with ESSDS, which expire on July 1, 2022, may be terminated by either party at any time without cause on 180 days’ prior written notice to the other party.

In 2020, net product sales of Xyrem were $1.7 billion, which represented 74% of our total net product sales.

Xywav (formerly JZP-258) is a product approved by FDA for the treatment of cataplexy or EDS in both adult and pediatric patients with narcolepsy.

Xywav is an oxybate product that contains 92% less sodium than Xyrem.

In January 2020, we submitted a new drug application, or NDA, for Xywav for the treatment of both cataplexy and EDS in patients with narcolepsy and in connection with this submission, redeemed the priority review voucher, or PRV, we acquired in May 2018.

FDA approved Xywav for this indication in July 2020 and we commenced the U.S.

launch of Xywav in November 2020.

The 92% reduction of sodium translates into a reduction of approximately 1,000 to 1,500 milligrams per day for a patient prescribed an oxybate product, depending on the dose.

When patients start Xywav after a sodium oxybate product, Xywav treatment is

initiated at the same dose and regimen as the sodium oxybate product (gram for gram) and titrated as needed based on efficacy and tolerability.

The label for Xywav, unlike Xyrem, does not include a warning to prescribers to monitor patients sensitive to sodium intake, including patients with heart failure, hypertension or renal impairment.

Narcolepsy is a chronic condition where patients, by virtue of their diagnosis, are at increased risk of cardiovascular events and disease, and the impact of sodium on cardiovascular health is well established.

There is also broad scientific consensus that reducing sodium consumption, which is a modifiable risk factor, is associated with clinically-meaningful reductions in blood pressure and cardiovascular disease risk.

Given that narcolepsy is a life-long condition, we therefore believe that reducing sodium intake vs.

the standard of care by 92% each and every day is a significant advancement for these patients.

Health care providers and patients who understand the increased risk of cardiovascular disease faced by narcolepsy patients and who have been educated on the meaningful reduction in sodium from Xyrem to Xywav cite that meaningful reduction as a key reason for prescribing or starting on Xywav.

In approving Xywav, FDA approved a REMS to cover both Xywav and Xyrem.

The Xywav and Xyrem REMS have the same requirements for both products and is also distributed by the central pharmacy through exclusive agreements with ESSDS.

In 2020, net product sales of Xywav were $15.3 million, which represented 1% of our total net product sales.

Following the U.S.

launch of Xywav in November 2020, approximately 1,900 patients were taking Xywav by the end of 2020.

With respect to Xyrem and Xywav in the aggregate, average active oxybate patients on therapy was approximately 15,300 in the fourth quarter of 2020.

Total net product sales of Xywav were offset by the cost of launch related co-pay coupons and a free product program for certain qualified patients.

We expect to have broad commercial payor coverage within the first 6 to 9 months following launch.

To date, we have entered into agreements with various entities and have achieved coverage for Xywav for over 60% of commercial lives.

We acquired Epidiolex (Epidyolex outside the U.S.) in May 2021 as part of the GW Acquisition, which expands our growing neuroscience business with a global, high-growth childhood-onset epilepsy franchise.

Epidiolex is a pharmaceutical formulation comprising highly purified plant-derived cannabidiol, or CBD, for which we retain global commercial rights.

Epidiolex was approved in the U.S.

in June 2018 for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome, or LGS, and Dravet syndrome, or DS, in patients two years of age and older, and subsequently approved in July 2020 for the treatment of seizures associated with tuberous sclerosis complex, or TSC, in patients one year of age and older.

FDA also approved the expansion of the prior approved indications, LGS and DS, to patients one year of age and older.

The rolling European launch of Epidyolex is also underway following European Commission, or EC, approval in September 2019 for use as adjunctive therapy of seizures associated with LGS or DS, in conjunction with clobazam, for patients two years of age and older.

The clobazam restriction is limited to EU and Great Britain.

Outside the U.S.

and Europe, Epidiolex/Epidyolex is approved in Israel and Australia.

See “Research and Development” below for a discussion of clinical development activities for Epidiolex.

LGS and DS are severe childhood-onset, drug-resistant epilepsy syndromes.

LGS and DS affect approximately 35,000-50,000 and approximately 10,000 individuals in the U.S., respectively.

TSC is a rare genetic disorder that causes non-malignant tumors to form in many different organs and is a leading cause of genetic epilepsy.

TSC affects approximately 50,000 individuals in the U.S.

Epidiolex has received ODE to treat seizures associated with LGS and DS through 2025 and TSC through 2027.

Net product sales of Epidiolex/Epidyolex in 2021, beginning from the closing of the GW Acquisition on May 5, 2021 were $463.6 million , w hich represented 15% of our total net product sales.

On a pro forma basis, assuming the GW Acquisition had closed on January 1, 2021, Epidiolex/Epidyolex net product sales in 2021 were $658.3 million.

For a detailed discussion of the GW Acquisition, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in Part II, Item 7 of this Annual Report on Form 10-K.

Sunosi received FDA approval in March 2019 and was launched in the U.S.

1 unchanged sentence

Sunosi was also approved in January 2020 by the EC to improve wakefulness and reduce EDS in adults with narcolepsy (with or without cataplexy) or OSA.

We launched Sunosi in Germany for the treatment of narcolepsy in May 2020 and in Denmark in October 2020.

We launched Sunosi in Germany for the treatment of narcolepsy in May 2020 followed by OSA in July 2021 and for the treatment of both indications in Denmark in October 2020, in France in March 2021, and in Italy in April 2021.

We expect to continue the rolling launch in Europe as we secure pricing and reimbursement approvals in more European countries.

Sunosi was approved in Canada in May 2021 for the treatment of EDS associated with narcolepsy or OSA in adult patients.

OSA, commonly referred to as sleep apnea, is a highly prevalent disease, and EDS, a major symptom of OSA, is characterized by the inability to stay awake and alert during the day resulting in unplanned lapses into sleep or drowsiness.

2 unchanged sentences

In 2021, net product sales of Sunosi were $57.9 million, which represented 2% of our total net product sales.

We acquired Sativex (nabiximols) in May 2021 as part of the GW Acquisition.

Sativex is approved in the U.K.

and certain other countries outside the U.S.

as treatment for symptom improvement in adult patients with moderate to severe spasticity due to MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy.

Nabiximols is a complex botanical mixture formulated from extracts of the cannabis sativa plant that contains the principal cannabinoids delta-9-tetrahydrocannabinol, or THC, and CBD as well as specific minor cannabinoids and other non-cannabinoid components.

We developed nabiximols to be administered as an oromucosal spray, whereby the active ingredients are absorbed in part in the lining of the mouth, either under the tongue or inside the cheek.

Nabiximols is already approved in more than 25 countries outside the U.S.

for the treatment of spasticity due to multiple sclerosis under the brand name Sativex.

We market Sativex directly in the U.K.

To support the development and commercialization of Sativex internationally, we have license and development agreements with commercial partners across other countries.

These agreements provide our collaborators with the sole right to commercialize Sativex in exclusive territories for all indications.

See “Research and Development” below for a discussion of clinical development activities for nabiximols.

Net product sales of Sativex in 2021, beginning from the closing of the GW Acquisition on May 5, 2021 were $12.7 million , w hich represented less than 1% of our total net product sales.

On a pro forma basis, assuming the GW Acquisition had closed on January 1, 2021, Sativex net product sales in 2021 were $18.5 million.

In December 2019, we entered into an exclusive license agreement with Pharma Mar, S.A., or PharmaMar, pursuant to which we obtained exclusive U.S.

development and commercialization rights to Zepzelca.

In October 2020, we entered into an amendment to the license agreement with PharmaMar to expand our exclusive license to include rights to develop and commercialize Zepzelca in Canada.

The term of the amended license agreement extends on a licensed product-by-licensed product and country-by-country basis until the latest of:

(i) expiration of the last PharmaMar patent covering Zepzelca in that country (subject to certain exclusions), (ii) expiration of regulatory exclusivity for Zepzelca in that country and (iii) 12 years after the first commercial sale of Zepzelca in that country.

We have the right to terminate the amended license agreement at will upon a specified notice period, and either party can terminate the amended license agreement for the other party’s uncured material breach or bankruptcy.

For a description of additional terms of the amended license agreement, including financial terms, see Note 3, Business Combinations, Asset Acquisitions and Collaborations—License Agreement of the Notes to Consolidated Financial Statements included in Part IV of this Annual Report on Form 10‑K.

Zepzelca for injection (4 mg) is approved by FDA to treat adults with metastatic SCLC, with disease progression on or after platinum-based chemotherapy.

Zepzelca is an alkylating drug that binds guanine residues within DNA.

This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.

Zepzelca was granted Orphan Drug Designation for SCLC by FDA in August 2018.

In December 2019, PharmaMar submitted a New Drug Application, or NDA, to FDA for accelerated approval of Zepzelca for relapsed SCLC based on data from a Phase 2 trial, and in February 2020, FDA accepted the NDA for filing with priority review.

In June 2020, FDA granted accelerated approval of Zepzelca for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.

Zepzelca is approved based on response rate and duration of response.

After discussion with FDA, PharmaMar initiated a confirmatory trial in second-line SCLC in December 2021.

This is a three-arm trial comparing Zepzelca as either monotherapy or in combination with irinotecan to investigator's choice of irinotecan or topotecan.

Data from this trial, if positive, will serve as the confirmatory trial for Zepzelca to secure full approval in the U.S.

See “Research and Development” below for a discussion of clinical development activities for Zepzelca.

In 2021, net product sales of Zepzelca were $246.8 million, which represented 8% of our total net product sales.

Rylaze was approved by FDA in June 2021 under the Real-Time Oncology Review (RTOR) program, and was launched in the U.S.

in July 2021, for use as a component of a multi-agent chemotherapeutic regimen for the treatment of ALL or LBL in pediatric and adult patients one month and older who have developed hypersensitivity to E.

coli -derived asparaginase.

Rylaze is the only recombinant erwinia asparaginase manufactured product that maintains a clinically meaningful level of serum asparaginase activity throughout the entire intended duration of treatment.

We developed Rylaze with the goal of addressing the needs of patients and health care providers for an innovative, high-quality erwinia asparaginase with reliable supply.

Rylaze has been granted Orphan Drug Designation for the treatment of patients with ALL or LBL.

See “Research and Development” below for a discussion of clinical development activities for Rylaze.

In 2021, net product sales of Rylaze were $85.6 million, which represented 3% of our total net product sales.

Vyxeos is a liposomal formulation of a fixed ratio combination of daunorubicin and cytarabine for intravenous infusion that is indicated for the treatment of adults with newly-diagnosed t-AML or AML-MRC and has been shown to have synergistic effects at killing leukemia cells in vitro and in animal models.

Vyxeos is the first drug delivery combination product based on our CombiPlex ® technology platform to be approved by FDA and the EC.

AML is a rapidly progressing and life-threatening blood cancer that begins in the bone marrow, which produces most of the body's new blood cells.

AML cells crowd out healthy cells and move aggressively into the bloodstream to spread cancer to other parts of the body.

AML is a relatively rare disease representing about 1% of all new cancer cases and has the lowest survival rate of any form of leukemia.

Patients with newly diagnosed t-AML or AML-MRC may have a particularly poor prognosis.

In 2017, we launched Vyxeos in the U.S.

after FDA approved our NDA for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In August 2018, the EC granted marketing authorization for Vyxeos and, as part of our rolling launch of Vyxeos in Europe, we are continuing to make pricing and reimbursement submissions in European countries.

In March 2021, FDA approved a revised label to include a new indication to treat newly-diagnosed t-AML or AML with myelodysplasia-related changes in pediatric patients aged one year and older.

We have a number of ongoing development activities and continue to expand into new markets internationally.

See “Research and Development” below for a discussion of clinical development activities for Vyxeos.

In 2021, Vyxeos product sales were $134.1 million, which represented 4% of our total net product sales.

Defibrotide, the API in Defitelio, is approved for the treatment of VOD, a potentially life-threatening complication of HSCT, and is in development for other complications following anti-cancer treatment.

13 unchanged sentences

In June 2019, Nippon Shinyaku Co., Ltd., the partner to whom we have granted exclusive rights to develop and commercialize defibrotide in Japan, received marketing authorization from Japan’s Ministry of Health, Labour and Welfare and launched defibrotide in Japan in September 2019.

Further geographic expansion occurred in July 2020 and

September 2020, as Defitelio was approved by the Australian Therapeutic Goods Administration and Swissmedic in Switzerland, respectively, for the treatment of VOD.

Further geographic expansion occurred in July 2020 and September 2020, as Defitelio was approved by the Australian Therapeutic Goods Administration and Swissmedic in Switzerland, respectively, for the treatment of VOD.

In 2021, Defitelio/defibrotide product sales were $197.9 million, which represented 6% of our total net product sales.

Erwinaze (called Erwinase in markets outside the U.S.) is a biologic product used in conjunction with chemotherapy to treat patients with ALL who have developed hypersensitivity to E.

Revenue Diversification

As part of our objective to reduce business risk by diversifying our revenue sources, we have been actively seeking to expand our commercial portfolio thorough a combination of launching internally developed therapies and corporate development.

In 2018, 75% of net product sales were generated by one product, Xyrem.

In the fourth quarter of 2021, 59% of net product sales were generated from products that we launched or acquired since 2019, including Xywav, Zepzelca, Epidiolex, Sunosi, Sativex and Rylaze.

Product Indication(s) Initial Approval Date Market(s)

Xywav ® (calcium, magnesium, potassium, and sodium oxybates)

Treatment of cataplexy or EDS in patients seven years of age and older with narcolepsy.

Treatment of IH in adults.

Xyrem ® (sodium oxybate)

Treatment of cataplexy or EDS in patients seven years of age and older with narcolepsy.

For the treatment of cataplexy in patients with narcolepsy.

Treatment of narcolepsy with cataplexy in adult patients, adolescents and children from age of 7 years.

October 2005 U.S.

EU, Great Britain, other markets (through licensing agreement)

Epidiolex ® (cannabidiol)

Epidyolex ® (cannabidiol)

Treatment of seizures associated with LGS, DS or TSC, in patients 1 year of age and older.

For adjunctive therapy of seizures associated with LGS or DS, in conjunction with clobazam, for patients 2 years of age and older.*

For adjunctive therapy of seizures associated with TSC for patients 2 years of age and older.** June 2018

September 2019

April 2021 U.S.

EU, Great Britain, other markets

Sunosi ® (solriamfetol)

Improve wakefulness in adult patients with EDS associated with narcolepsy or OSA.

Improve wakefulness and reduce EDS in adult patients with narcolepsy (with or without cataplexy) or adult patients with OSA whose EDS has not been satisfactorily treated by primary OSA therapy, such as CPAP.

Treatment of EDS in adult patients with narcolepsy or OSA.

May 2021 U.S.

EU, Great Britain

Sativex ® (nabiximols)

Treatment for adult patients with moderate to severe spasticity due to MS, who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy.

June 2010 U.K.

and Canada (other markets through licensing agreements with partners)

Zepzelca ® (lurbinectedin)

Treatment of adult patients with metastatic SCLC, with disease progression on or after platinum-based chemotherapy.

Treatment of adults with Stage III or metastatic SCLC who have progressed on or after platinum-containing therapy.

September 2021 U.S.

(licensed from PharmaMar)

Canada (licensed from PharmaMar)

Rylaze™ (asparaginase erwinia chrysanthemi (recombinant)-

rywn) A component of a multi-agent chemotherapeutic regimen for the treatment of ALL, and LBL, in adult and pediatric patients 1 month or older who have developed hypersensitivity to E.

coli -derived asparaginase.

Originally developed by Public Health England, a national executive agency of the United Kingdom, or UK, Erwinaze is an asparaginase, a type of enzyme that can deprive leukemic cells of an amino acid essential for their growth.

It is derived from a rare bacterium ( Erwinia chrysanthemi ) and is immunologically distinct from E.

coli -derived asparaginase and suitable for patients with hypersensitivity to E.

coli -derived treatments.

For ALL patients with hypersensitivity to E.

coli -derived asparaginase, Erwinaze can be a crucial component of their therapeutic regimen.

Current treatment guidelines and protocols recommend switching a patient receiving E.

coli- derived asparaginase to treatment with Erwinaze if the patient’s hypersensitivity reaction to the E.

coli -derived asparaginase is clinically meaningful, indicating that the hypersensitivity reaction has resulted in an intervention or interruption in infusion occurring in the patient’s treatment regimen.

While treatment protocols for pediatric, adolescent and young adult (up to age 39) patients commonly include asparaginase, adult protocols do not.

First approved by FDA under a biologics license application, or BLA, for administration via intramuscular injection in conjunction with chemotherapy, Erwinaze was launched in the U.S.

In 2014, FDA approved a supplemental BLA for administration of Erwinaze via intravenous infusion in conjunction with chemotherapy.

Erwinaze was exclusively licensed to us for worldwide marketing, sales and distribution by Porton Biopharma Limited, or PBL, a company that is wholly owned by the UK Department of Health and Social Care.

Our license and supply agreement with PBL, which includes our license to Erwinaze trademarks and manufacturing know-how, expired on December 31, 2020.

Under our agreement with PBL, we have the right to sell certain Erwinaze inventory for a post-termination sales period of 12 months and retain ownership of certain data, know-how and other rights, including the BLA for Erwinaze in the U.S.

and marketing authorizations for Erwinase in several other countries.

During this post-termination period, PBL also manufactures the product for us and is our sole supplier for Erwinaze.

We are obligated to make tiered royalty payments to PBL based on worldwide net sales of Erwinaze.

Subject to successful receipt, release and FDA approval for the batches from PBL, we expect to distribute available Erwinaze supply during the first half of 2021.

In 2020, net product sales of Erwinaze were $147.1 million, which represented 6% of our total net product sales.

Vyxeos is the first drug delivery combination product based on our CombiPlex technology platform to be approved by FDA and the EC.

AML is a rapidly progressing and life-threatening blood cancer that begins in the bone marrow, which produces most of the body's new blood cells.

AML cells crowd out healthy cells and move aggressively into the bloodstream to spread cancer to other parts of the body.

AML is a relatively rare disease representing about 1% of all new cancer cases and has the lowest survival rate of any form of leukemia.

Patients with newly diagnosed t-AML or AML-MRC may have a particularly poor prognosis.

In 2017, we launched Vyxeos in the U.S.

after FDA approved our NDA for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In 2020, Vyxeos product sales were $121.1 million, which represented 5% of our total net product sales.

In furtherance of our interest in and efforts to expand our oncology therapeutic area, in December 2019, we entered into an exclusive license agreement with Pharma Mar, S.A., or PharmaMar, pursuant to which we obtained exclusive U.S.

development and commercialization rights to Zepzelca.

Zepzelca for injection (4 mg) is approved by FDA to treat adults with metastatic small cell lung cancer, or SCLC, with disease progression on or after platinum-based chemotherapy.

Zepzelca is approved based on response rate and how long the response lasted.

Additional studies will further evaluate the benefit of Zepzelca for this use.

Zepzelca was granted orphan drug designation for SCLC by FDA in August 2018.

In December 2019, PharmaMar submitted an NDA to FDA for accelerated approval of Zepzelca for relapsed SCLC based on data from a Phase 2 trial, and in February 2020, FDA accepted the NDA for filing with priority review.

In June 2020, FDA granted accelerated approval of Zepzelca for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.

In October 2020, we entered into an amendment to the license agreement with PharmaMar to expand our

exclusive license to include rights to develop and commercialize Zepzelca in Canada.

The term of the amended license agreement extends on a licensed product-by-licensed product and country-by-country basis until the latest of:

For a description of additional terms of the amended license agreement, including financial terms, see Note 3, Asset Acquisitions, Collaborations and Disposition—License Agreement of the Notes to Consolidated Financial Statements included in this Annual Report on Form 10‑K.

In December 2020 we, in conjunction with PharmaMar, announced results from the ATLANTIS Phase 3 study evaluating Zepzelca in combination with doxorubicin for adult patients with SCLC whose disease progressed following one prior platinum-containing line.

The study did not meet the pre-specified criteria of significance for its primary endpoint.

Key secondary and subgroup analyses favored the lurbinectedin combination arm.

Patients received lurbinectedin at 2.0mg/m 2 in the combination arm, which is lower than the FDA approved dose of Zepzelca at 3.2mg/m 2 .

Lurbinectedin monotherapy was not tested in ATLANTIS.

We anticipate initiating the Phase 4 study for the Zepzelca program, with an objective to provide critical data to complement the findings from the Basket trial, which supported the accelerated approval of Zepzelca.

In 2020, Zepzelca product sales were $90.4 million, which represented 4% of our total net product sales.

June 2021 U.S.

Vyxeos ® (daunorubicin and cytarabine) liposome for injection

Vyxeos ® liposomal 44 mg/100 mg powder for concentrate for solution for infusion

Vyxeos ® Daunorubicin and cytarabine liposome for injection Powder, 44 mg daunorubicin and 100 mg cytarabine per vial, intravenous infusion

Treatment of newly-diagnosed therapy-related t-AML or AML-MRC in adults and pediatric patients one year and older.

Treatment of adults with newly-diagnosed t-AML or AML-MRC.

Treatment of adults with newly diagnosed therapy-related t-AML or AML with AML-MRC.

EU, Great Britain

Defitelio ® (defibrotide sodium)

Defitelio ® (defibrotide)

Treatment of adult and pediatric patients with hepatic VOD, also known as SOS, with renal or pulmonary dysfunction following HSCT.

Treatment of severe hepatic VOD, also known as SOS, following HSCT therapy.

October 2013 U.S.

EU, Great Britain, other markets

*The Clobazam restriction limited to EU and Great Britain

**TSC approval pending in certain markets

Research and Development

A key aspect of our growth strategy is our continued investment in our evolving and expanding research and development activities.

A key aspect of our strategy is our continued investment in expanding our research and development organization and initiatives.

We actively explore new options for patients including novel compounds, small molecule advancements, biologics and innovative delivery technologies.

We are focused on research and development activities within our neuroscience and oncology therapeutic areas, such as our expansion into movement disorders and solid tumors, and exploring and investing in adjacent therapeutic areas that could further diversify our portfolio.

We are focused on research and development activities within our neuroscience and oncology therapeutic areas, such as our expansion into movement disorders and solid tumors, and exploring and potentially investing in adjacent therapeutic areas.

Our development activities encompass all stages of development and currently include clinical testing of new product candidates and activities related to clinical improvements of, or additional indications or new clinical data for, our existing marketed products.

We have also expanded into preclinical exploration of novel therapies primarily through external research collaborations, including precision medicines in hematology and oncology.

We are increasingly leveraging our growing research and development function, and have supported additional investigator-sponsored trials that will generate additional data related to our products.

We also have active preclinical programs for novel therapies, including precision medicines in hematology and oncology and the GW cannabinoid platform.

We are increasingly leveraging our growing internal research and development function, and we have also entered into collaborations with third parties for the research and development of innovative early-stage product candidates and have supported additional investigator-sponsored trials, or ISTs, that are anticipated to generate additional data related to our products.

We also seek out investment opportunities in support of development of early- and mid-stage technologies in our therapeutic areas and adjacencies.

We have a number of licensing and collaboration agreements with third parties, including biotechnology companies, academic institutions and research-based companies and institutions, related to preclinical and clinical research and development activities in hematology and in precision oncology, as well as in neuroscience.

Our current and planned development activities in our neuroscience therapeutic area are focused on JZP-258 for the treatment of idiopathic hypersomnia, JZP-385, JZP-150 and JZP-324, as well as exploring additional indications for Sunosi.

JZP-258 for the treatment of idiopathic hypersomnia .

In October 2020, we announced positive top-line results from a Phase 3 clinical trial evaluating JZP-258 in adult patients with idiopathic hypersomnia, a chronic, neurological disorder that is primarily characterized by EDS and that currently has no approved therapies in the U.S.

We completed the rolling submission of a supplemental new drug application, or sNDA, in February 2021, and if approved by FDA in a timely manner, we expect a potential launch of JZP-258 in the fourth quarter of 2021.

FDA granted Fast Track designation for JZP-258 for the treatment of idiopathic hypersomnia in September 2020.

JZP-385 is a T-type calcium channel modulator that is a small molecule currently in development for the treatment of essential tremor.

We acquired JZP-385 in our acquisition of Cavion, Inc., or Cavion, a clinical-stage biotechnology company, in August 2019.

We expect to initiate a Phase 2b study of JZP-385 in mid-year 2021.

JZP-150 is a FAAH inhibitor program for the potential treatment of post-traumatic stress disorder and associated symptoms.

Our current and planned development activities in our neuroscience therapeutic area are focused on an additional indication for Epidiolex, and advancing novel therapies, including nabiximols, suvecaltamide (JZP385) and JZP150.

We anticipate the initiation of a pivotal Phase 3 clinical trial of Epidiolex for the treatment of Epilepsy with Myoclonic-Atonic Seizures, or EMAS, also known as Doose syndrome, in the first half of 2022.

This trial is designed to evaluate Epidiolex in a fourth childhood-onset epileptic encephalopathy with high unmet need.

EMAS is characterized by generalized myoclonic-atonic seizures, and this trial is designed to provide the first randomized, controlled clinical data with Epidiolex in this syndrome type.

Seizure types including atonic, tonic, clonic, tonic-clonic, and partial onset seizures are seen in LGS, DS and TSC.

We have three ongoing Phase 3 clinical trials in multiple sclerosis (MS)-related spasticity.

Collectively these trials will expand the body of evidence on the safety and efficacy of nabiximols in addressing spasticity in MS patients, and either individually or jointly may support an NDA submission to FDA.

Spasticity occurs in up to 84% of MS patients, and approximately one-third of those who experience spasticity live with uncontrolled symptoms.

The first trial is a smaller, shorter trial relative to the other two.

The first trial is assessing changes in muscle tone using elements of the Modified Ashworth scale.

If results from this first trial are positive, there is the potential for an NDA submission to FDA by the end of 2022.

The two additional trials have larger sample sizes.

Suvecaltamide .

Suvecaltamide (JZP385) is a highly selective modulator of T-type calcium channels currently in development for the treatment of essential tremor, or ET.

ET is the most common pathological movement disorder, and there have been no new approved therapies in more than 50 years.

We acquired suvecaltamide in our acquisition of Cavion, Inc., or Cavion, a clinical-stage biotechnology company, in August 2019.

We initiated a Phase 2b clinical trial of suvecaltamide in December 2021.

In this multicenter, double-blind, randomized, placebo-controlled trial, we are evaluating the safety and efficacy of suvecaltamide in the treatment of adults with moderate to severe ET.

The primary efficacy outcome measure is the change from baseline to Week 12 on the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) composite outcome score, which represents items from the TETRAS-Activities of Daily Living and TETRAS-Performance Subscale, and measures the functional impact due to tremor.

JZP150 is a fatty acid amide hydrolase, or FAAH, inhibitor program for the potential treatment of post-traumatic stress disorder, or PTSD, and associated symptoms.

PTSD affects up to 8% of adults during their lifetime, and there are limited treatment options available.

In October 2020, we entered into an asset purchase and exclusive license agreement with SpringWorks, under which we acquired SpringWorks’ FAAH inhibitor program, including an assignment of SpringWorks’ proprietary FAAH inhibitor PF-04457845, or PF-’845, now named JZP150.

We expect to initiate a Phase 2 study of JZP-150 in late 2021.

We are also pursuing early-stage activities related to the development of JZP-324, an extended-release low sodium, oxybate formulation that we believe could provide a clinically meaningful option for narcolepsy patients.

Our current and planned research and development activities in our oncology therapeutic area are focused on JZP-458, exploring additional indications for Defitelio and Vyxeos, generating additional clinical data for Zepzelca and Vyxeos, including in combination with other therapeutic agents, and the research and development of new product candidates through our external collaborations.

JZP-458 is a recombinant Erwinia asparaginase that uses a novel Pseudomonas fluorescens expression platform, which is being developed for use as a component of a multi-agent chemotherapeutic regimen in the treatment of pediatric and adult patients with ALL or lymphoblastic lymphoma, or LBL, who are hypersensitive to E.

coli -derived asparaginase products.

JZP-458 was granted Fast Track designation by FDA in October 2019 for the treatment of this patient population, and in December 2019, the first patient was enrolled in the pivotal Phase 2/3 clinical study for JZP-458 conducted in collaboration with the Children’s Oncology Group.

In December 2020, we initiated the submission of a BLA to FDA for JZP-458 under Real-Time Oncology Review, or RTOR, pilot program, with the potential approval and launch in the U.S.

in mid-year of 2021.

Our Defitelio clinical development strategy generally focuses on the prevention and treatment of serious diseases associated with stem cell transplantation and endothelial cell damage.

We initiated a Phase 2 clinical trial of JZP150 for PTSD in December 2021.

In this trial, we are evaluating the safety and efficacy of JZP150 in the treatment of adults with PTSD as measured by improvement in the Clinician Administered Post Traumatic Stress Disorder (PTSD) Scale (CAPS-5) Total Symptom Severity Score, a validated clinical instrument for assessing the severity of PTSD symptoms.

Our current and planned research and development activities in our oncology therapeutic area are focused on Rylaze and Zepzelca, including in combination with other therapeutic agents, exploring additional indications for Vyxeos, and the research and development of new product candidates through our external collaborations.

In collaboration with F.

Hoffmann-La Roche Ltd, or Roche, we have initiated a Phase 3 pivotal clinical trial in first-line extensive stage SCLC of Zepzelca in combination with Tecentriq ® (atezolizumab).

After discussion with FDA, our licensor PharmaMar initiated a confirmatory trial in second-line SCLC in December 2021.

This is a three-arm trial comparing Zepzelca as either monotherapy or in combination with irinotecan to investigator's choice of irinotecan or topotecan.

Data from this trial, if positive, would serve as the confirmatory trial for Zepzelca to secure full approval in the U.S.

We initiated a Phase 2 basket trial in the first quarter of 2022 to explore Zepzelca monotherapy in patients with select advanced or metastatic solid tumors.

Cohorts will include advanced urothelial cancer, large cell neuroendocrine tumor of the lung, and homologous recombinant deficient positive (HRD+) cancers.

In addition, we have initiated a Phase 4 observational study to collect real world safety and outcome data in adult Zepzelca monotherapy patients with SCLC who progress on or after prior platinum-containing chemotherapy.

The current approved recommended dosage of Rylaze is for an intramuscular, or IM, administration of 25 mg/m 2 every 48 hours.

In February 2022, we announced the submission of a supplemental Biologics License Application, or sBLA, to FDA with data to support a Monday/Wednesday/Friday (M/W/F) IM dosing schedule, which has also been granted review under the RTOR program.

An additional part of the ongoing Rylaze study has evaluated intravenous, or IV, administration and, if the data are supportive, we expect to submit an additional sBLA to FDA in 2022 in support of IV administration.

We also are planning a regulatory submission in Europe for IM and IV administration in mid-2022.

Our Vyxeos clinical development strategy is designed to target potential new patient segments across the AML landscape and to generate clinical data on Vyxeos when used in combination with other therapeutic agents.

1 unchanged sentence

In August 2018, we announced a five-year collaboration with MD Anderson to evaluate potential treatment options for hematologic malignancies, with a near-term focus on Vyxeos, and shortly thereafter, commenced development activities under this collaboration.

In addition, there are multiple ongoing investigator-sponsored trials studying Vyxeos.

We anticipate the initiation in 2021 of a Phase 3 study evaluating Zepzelca in combination with immunotherapy versus immunotherapy alone in patients with extensive-stage SCLC after induction chemotherapy.

In addition, there are multiple ongoing ISTs studying Vyxeos.

CombiPlex Platform.

We are also evaluating the use of our CombiPlex delivery technology platform in a number of therapeutic combinations in oncology as part of our internal oncology research and development activities.

We are also evaluating the use of our CombiPlex delivery technology platform in a number of therapeutic formulations and combinations in oncology as part of our internal oncology research and development activities.

CombiPlex enables the design and rapid evaluation of various combinations of therapies to deliver enhanced anti-cancer activity by identifying an optimal synergistic ratio of drugs in vitro and fixing this ratio in a nanoscale delivery complex that maintains and then coordinates the release of the synergistic combination after administration.

2 unchanged sentences

Through third parties, we are also pursuing preclinical and clinical research and development activities in hematology and in precision oncology under a number of licensing and collaboration agreements, including with:

• Codiak BioSciences, Inc., or Codiak, for an exclusive, worldwide, royalty-bearing license to develop, manufacture and commercialize potential therapeutic candidates directed at five targets to be developed using Codiak's engEx™ precision engineering platform for exosome therapeutics;

• Pfenex, Inc., which was acquired by Ligand Pharmaceuticals Incorporated, or Ligand, for rights to an early-stage long-acting Erwinia asparaginase and an option to negotiate a license for a recombinant pegaspargase product candidate;

• Codiak BioSciences, Inc., or Codiak, for an exclusive, worldwide, royalty-bearing license to develop, manufacture and commercialize potential therapeutic candidates directed at up to four targets to be developed using Codiak's engEx™ precision engineering platform for exosome therapeutics;

• Pfenex, Inc., which was acquired by Ligand Pharmaceuticals Incorporated, or Ligand, for rights to JZP341, an early-stage long-acting Erwinia asparaginase;

• XL-protein GmbH, or XLp, for rights to use XLp’s PASylation ® technology to extend the plasma half-life of selected asparaginase product candidates;

2 unchanged sentences

Product Candidates Description

JZP-258 (oxybate;

92% sodium reduction) Idiopathic hypersomnia

JZP-385 Essential tremor (planned study)

Post-traumatic stress disorder (planned study)

JZP-324 Oxybate extended-release formulation

Epidiolex EMAS, also known as Doose syndrome (planned study)

Nabiximols MS Spasticity (multiple studies ongoing)

Spinal cord injury spasticity (planned study)

Suvecaltamide (JZP385)

ET (ongoing study)

PTSD (ongoing study)

Additional cannabinoids Schizophrenia (ongoing study)

Autism spectrum disorders (ongoing study)

JZP324 Oxybate extended-release formulation (planned study)

Additional cannabinoids Neonatal hypoxic-ischemic encephalopathy (ongoing study)

Neuropsychiatry targets (ongoing study)

Undisclosed targets Neuroscience

Product Candidates Description

JZP-458 (recombinant Erwinia asparaginase) (pivotal Phase 2/3)

Vyxeos AML or high-risk Myelodysplastic Syndrome, or MDS (AML18 and AML19) (cooperative group studies)

Newly diagnosed adults with standard- and high-risk AML (AML Study Group cooperative group study)

Newly diagnosed pediatric patients with AML (Children’s Oncology Group cooperative group study)

Vyxeos High-risk MDS (European Myelodysplastic Syndromes Cooperative Group cooperative group study)

Newly diagnosed older adults with high-risk AML (planned cooperative group study)

Vyxeos + venetoclax De novo or relapsed/refractory, or R/R, AML (MD Anderson collaboration study)

Vyxeos Low intensity dosing for higher risk MDS (MD Anderson collaboration study)

Vyxeos + other approved therapies R/R AML or hypomethylating agent failure MDS (MD Anderson collaboration study)

First-line, fit AML (Phase 1b study)

Low intensity therapy for first-line, unfit AML (Phase 1b study)

CombiPlex Hematology/oncology exploratory activities

Regulatory Review

Rylaze ALL/LBL

FDA approval in June 2021;

announced completion of sBLA submission to FDA in January seeking approval for Monday/Wednesday/Friday intramuscular dosing schedule;

regulatory submission planned for Europe in mid-2022

Zepzelca First-line extensive stage SCLC in combination with Tecentriq (collaboration with Roche) (ongoing study)

Confirmatory Study (Pharma Mar study) (ongoing study)

Vyxeos AML or high-risk Myelodysplastic Syndrome, or MDS (AML18) (cooperative group studies) (ongoing study) Newly diagnosed adults with standard- and high-risk AML (AML Study Group cooperative group study) (ongoing study) Newly diagnosed pediatric patients with AML (Children’s Oncology Group cooperative group study) (ongoing study)

Zepzelca Basket trial including urothelial cancer, large cell neuroendocrine tumor of the lung, and HRD+ (homologous recombinant deficient) cancers (ongoing study)

Vyxeos High-risk MDS (European Myelodysplastic Syndromes Cooperative Group cooperative group study) (ongoing study)

Newly diagnosed older adults with high-risk AML (cooperative group study) (planned study)

Vyxeos + venetoclax De novo or relapsed/refractory, or R/R, AML (MD Anderson collaboration study) (ongoing study)

Vyxeos Low intensity dosing for higher risk MDS (MD Anderson collaboration study) (ongoing study)

Vyxeos + other approved therapies R/R AML or hypomethylating agent failure MDS (MD Anderson collaboration study) (ongoing study)

First-line, fit AML (Phase 1b study) (ongoing study)

Low intensity therapy for first-line, unfit AML (Phase 1b study) (ongoing study)

Hematology/oncology exploratory activities

JZP341 (long-acting Erwinia asparaginase)

ALL and other hematological malignancies (collaboration with Ligand)

Recombinant pegaspargase Hematological malignancies (Jazz opt-in opportunity with Ligand)

Pan-Raf inhibitor program Raf and Ras mutant tumors (acquired from Redx, which is continuing development)

Undisclosed targets Ras/Raf/MAP kinase pathway (collaboration with Redx)

Exosome targets (NRAS, STAT3 and 3 others) Hematological malignancies/solid tumors (collaboration with Codiak)

Defitelio Exploratory activities

Exosome targets (up to 4) Hematological malignancies/solid tumors (collaboration with Codiak BioSciences, Inc., or Codiak)

Undisclosed targets Oncology

As a result of the effects of the COVID-19 pandemic, we have taken measures to implement remote and virtual approaches, including remote data monitoring where possible, to maintain patient safety and trial continuity and to preserve study integrity.

Although we have seen limited COVID-19-related impact to our mid- and late-stage clinical trial activity, despite delays in initiating trial sites, if the effects of the COVID-19 pandemic become more severe, we could experience significant disruptions to our clinical development timelines, which would adversely affect our business, financial condition, results of operations and growth prospects.

For a more detailed discussion of the impact of the COVID-19 pandemic on our clinical trial activities, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Overview—COVID-19 Business Update” in Part II, Item 7 of this Annual Report on Form 10‑K.

For 2021 and beyond, we expect that our research and development expenses will continue to increase from previous levels, particularly as we prepare for anticipated regulatory submissions and data read-outs from clinical trials, initiate and undertake additional clinical trials and related development work and potentially acquire rights to additional product candidates.

Subsequent Events

GW Transaction Agreement

On February 3, 2021, we announced that we have entered into the GW Transaction Agreement with GW, under which a wholly-owned subsidiary of ours, Acquisition Sub, agreed to acquire GW.

The GW Transaction Agreement provides, among other things, that subject to the satisfaction or waiver of the conditions set forth in the GW Transaction Agreement, Acquisition Sub will acquire the entire issued share capital of GW pursuant to a scheme of arrangement under Part 26 of the United Kingdom Companies Act 2006, or Scheme of Arrangement, which we refer to as the GW Acquisition.

Under the GW Transaction Agreement, at the effective time of the Scheme of Arrangement, all GW ordinary shares issued and outstanding will be transferred to Acquisition Sub, and the holders of GW ordinary shares will have the right to receive, for each such share, (a) $16.66 2 ⁄ 3 in cash and (b) an amount of our ordinary shares determined based on the exchange ratio, which exchange ratio will be determined as follows:

• If the volume-weighted average sales price of our ordinary shares, as determined in accordance with the GW Transaction Agreement, or the Defined VWAP, is greater than $139.72 but less than $170.76, the exchange ratio will be an amount equal to the quotient obtained by dividing (x) $1.66 2 ⁄ 3 by (y) the Defined VWAP;

• If the Defined VWAP is equal to or less than $139.72, the exchange ratio will be 0.011929;

• If the Defined VWAP is an amount equal to or greater than $170.76, the exchange ratio will be 0.009760.

Because each American Depositary Share in GW, or GW ADSs, represents a beneficial interest in 12 GW ordinary shares, holders of GW ADSs will be entitled to receive 12 times the foregoing cash and share amounts, or (1) $200 in cash and (2) $20 in the form of our ordinary shares with the actual number of our ordinary shares being determined based on the exchange ratio set out above.

The total consideration to be paid by us for the entire issued share capital of GW is approximately $7.2 billion.

The respective obligations of GW and us to consummate the GW Acquisition are subject to the satisfaction or waiver of a number of customary conditions, including the approval by GW’s shareholders of the Scheme of Arrangement, obtaining certain regulatory approvals, including expiration of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, and obtaining sanction of the Scheme of Arrangement by the High Court of Justice of England and Wales.

The GW Acquisition is not subject to approval by our shareholders, nor is the GW Acquisition subject to a financing contingency.

The GW Acquisition is expected to close in the second quarter of 2021, subject to the satisfaction or waiver of the conditions set forth in the GW Transaction Agreement.

The GW Transaction Agreement contains customary representations and warranties given by GW and us , covenants regarding the conduct of GW ’s business prior to the consummation of the GW Acquisition, termination rights and other customary provisions.

Financing Commitment

On February 3, 2021, in connection with the execution of the GW Transaction Agreement, we entered into a commitment letter with BofA Securities, Inc., Bank of America, N.A.

and JPMorgan Chase Bank, N.A.

pursuant to which these commitment parties have committed to provide us with a senior secured revolving credit facility in an aggregate principal amount of up to $500.0 million, a senior secured term loan B facility in an aggregate principal amount of up to $3,150.0 million and a senior secured bridge loan facility in an aggregate principal amount of up to $2,200.0 million to, among other things, finance our obligations in respect of the GW Acquisition.

The effectiveness of such credit facilities is subject to the occurrence of customary closing conditions, including the consummation of the GW Acquisition.

Commercialization Activities

We have commercial operations primarily in the U.S., Europe and Canada.

In the U.S., our products are commercialized through a number of teams, including a team of experienced, trained sales professionals who provide education and promote

Xyrem, Xywav, Sunosi, Defitelio, Erwinaze, Vyxeos and Zepzelca to healthcare providers in the appropriate specialties for each product, a team that interacts with payors and institutions to ensure access and coverage for the products, and a team that distributes the products throughout the U.S.

In the U.S., our products are commercialized through a number of teams, including a team of experienced, trained sales professionals who provide education and promote Xywav, Xyrem, Epidiolex, Sunosi, Zepzelca, Rylaze, Vyxeos and Defitelio to healthcare providers in the appropriate specialties for each product, a team that interacts with payors and institutions to ensure access and coverage for the products, and a team that distributes the products throughout the U.S.

healthcare system (wholesalers, pharmacies, hospitals, and community and academic institutions) and provides patient services.

In Canada and in approved markets in Europe where we commercialize Defitelio, Erwinase and Vyxeos, we have a field force of hematology sales specialists.

In Canada and in approved markets in Europe where we commercialize Defitelio and Vyxeos, we have a field force of hematology sales specialists.

In markets where these products either are not approved or are unable to be promoted under local regulation, we have medical affairs personnel responsible for responding to medical information requests and for providing information consistent with local treatment protocols with respect to such products.

In certain European markets, we have a sales team and a team of medical science liaisons supporting our rolling launch of Sunosi in Europe.

Outside the U.S., we directly market Xyrem in Canada for the treatment of cataplexy in patients with narcolepsy.

In certain European markets, we have a sales team and a team of medical science liaisons supporting our rolling launches of Epidyolex and Sunosi.

Outside the U.S., we directly market Xyrem, Sunosi and Zepzelca in Canada.

We also utilize distributors in certain markets outside the U.S.

where we do not market our products directly.

Our commercial activities include marketing related services, distribution services and commercial support services.

Other commercial activities include marketing related services, industry analytics and insights, distribution services and commercial support services.

We employ third party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with our commercial activities.

1 unchanged sentence

We intend to scale the size of our sales force as appropriate to effectively reach our target audience in the specialty markets in which we currently operate.

We promote Defitelio, Erwinaze, Vyxeos and Zepzelca to many hematology and oncology specialists who operate in the same hospitals, and we believe that we benefit from operational synergies from this overlap.

We expect that a potential launch of JZP-458 in the U.S.

or Europe would require minimal additional support.

Continued growth of our current marketed products and the launch of any future products may require further expansion of our field force and support organization in and outside the U.S.

We promote Zepzelca, Rylaze, Vyxeos and Defitelio to many hematology and oncology specialists who operate in the same hospitals and outpatient clinical sites, and we believe that we benefit from operational synergies from this overlap.

We expect that a potential launch of Rylaze in Europe would require minimal additional support.

Continued growth of our current marketed products and the launch of any future products may require a

reevaluation of our field force and support organization in and outside the U.S.

In addition, beginning in March 2020, we transitioned our field-based sales, market access, reimbursement and medical employees out of the field and suspended work-related travel and in-person customer interactions as a result of the COVID-19 pandemic.

1 unchanged sentence

In late June 2020, as clinics and institutions began to allow in-person interactions pursuant to local health authority and government guidelines, our field teams resumed in-person interactions with healthcare professionals and clinics combined with virtual engagement.

The level of renewed engagement varies by account, region and country and may be adversely impacted in the future as a result of the continuing impact of the COVID-19 pandemic.

The level of renewed engagement varies by account, region and country.

There continues to be some negative impact on demand, new patient starts and treatments for our products arising from the pandemic, primarily due to the inherent limitations of telemedicine and a reprioritization of healthcare resources toward COVID-19.

As healthcare systems have adapted to cope with the ongoing situation, we have seen improvements.

The lack of access to health care providers has caused, and may continue to cause, delays in appropriate diagnosis, treatment and ongoing care for some patients, which could subsequently impact prescribing and use of our products.

For a more detailed discussion of the impact of the COVID-19 pandemic on our commercialization activities, see “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Overview—COVID-19 Business Update” in Part II, Item 7 of this Annual Report on Form 10‑K.

6 unchanged sentences

and approximately 50% were outside the U.S.

in the UK, Ireland and across the European Union, or EU.

primarily in the U.K., Ireland and across the European Union, or EU.

As an innovative biopharmaceutical company, we have over 700 full-time employees — greater than 22% of our global workforce — supporting our research and development activities.

We consider our employee relations to be very good.

Diversity, Equity and Inclusion.

We make diversity, equity and inclusion, or DEI, a priority because it is a key to unlocking the potential of our people and living our core values.

We strive to create a workplace culture that fosters the ability to be your authentic self and contribute boldly.

Diversity, Equity, Inclusion and Belonging.

We make diversity, equity, inclusion and belonging, or DEIB, a priority because it is a key to unlocking the potential of our people and living our core values.

We strive to create a workplace culture that fosters the ability of our employees to be their authentic selves and contribute boldly.

We aspire to have multi-dimensional diversity through our entire Jazz workforce.

We seek to surround underrepresented groups with allies to enable all employees to thrive equitably.

Our Board and management team are committed to fostering DEI in all parts of our business.

Our DEI strategy includes:

Our Board and management team are committed to fostering DEIB in all parts of our business.

Our DEIB strategy includes:

(1) building a more diverse workforce in terms of gender identity, race, ethnicity and sexual orientation and that represent unique backgrounds, experiences, thoughts and talents;

1 unchanged sentence

and (3) and creating a culture of inclusion and belonging.

We designed our Employee DEI program to empower employees to guide and support our strategy and programs related to hiring diverse talent and using education and communication to continue fostering an inclusive environment.

We also have a DEI Delegation, a committee of employees focused on helping to embed DEI into all we do.

We designed our Employee DEIB program to empower employees to guide and support our strategy and programs related to hiring diverse talent and using education and communication to continue fostering an inclusive environment.

We also have a DEIB Delegation, a committee of employees focused on helping to embed DEIB into all we do.

Jazz ConcERTos, our employee resource teams, are self-led teams of employee volunteers with diverse backgrounds who come together to promote innovation through inclusion and to increase awareness of all dimensions of diversity.

We believe that these groups will contribute positively to Jazz’s culture and business success by working cross-functionally to drive

innovation, helping to decrease unconscious bias, and encouraging employees to be their whole selves so they can perform at their best.

We believe that these groups will contribute positively to Jazz’s culture and business success by working cross-functionally to drive innovation, helping to decrease unconscious bias, and encouraging employees to be their whole selves so they can perform at their best.

We have established goals related to increasing all dimensions of diversity, including representation of females and people of color, particularly at the leadership level (i.e., employees at executive director and above).

In this regard, we have made some meaningful progress, as demonstrated by the following, as of February 9, 2022:

• Approximately 40% of our board of directors is diverse in terms of gender and ethnicity.

• 45% of our Executive Committee are women.

• 50% of each of our board of directors and Executive Committee is diverse in terms of gender, ethnicity and sexual orientation.

• Females represent 55% of our global workforce and 43% at the leadership level (employees at executive director and above).

8 unchanged sentences

We have transparent and regular communication channels with our employees consisting of many forms – including all employee meetings, regular communication messages from executive leadership, top leadership forums, pulse check feedback mechanisms and engagement surveys.

Our employee feedback surveys are designed to help us measure overall employee engagement and we consistently achieve participation rates between 80 to 90%.

Our employee feedback surveys are designed to help us measure overall employee engagement and we consistently achieve participation rates between 80 to 90% in our annual engagement survey.

We consistently have high levels of engagement measured by feelings of connection to our mission, Jazz as a great place to work where their well-being is supported and they feel valued and included.

4 unchanged sentences

Growth, Development and Total Rewards .

We understand that empowering people to find new and better ways of doing things, to gain new experiences and to development new capabilities can also support our growth and achievements as a company.

The exciting opportunities within our business provide rich and ample learning opportunities and experiences for career growth.

Our talent strategy focuses on attracting the best talent, recognizing and rewarding the performance of our employees as defined by both what they accomplished and how they accomplished it, and continually developing our talent through new experiences and learning opportunities.

We recently launched a new performance management system to support our culture of learning, feedback, and continual growth.

We believe there is ample opportunity for growth and development at Jazz and there is not a one size fits all approach to growing our talent.

We strive to create the best career experience for all of our employees.

We work with each employee to chart their own course that matches their career ambitions and strengths with customized development.

Our performance management process supports our culture of continual feedback and coaching, and ongoing growth and development through new experiences and learning.

We encourage all employees to have an individual development plan to outline learning and growth interests and focus areas.

We invest in manager and leadership development that emphasizes the important behaviors and values to successfully lead others and promote our culture.

We leverage several digital learning platforms to provide on demand bite sized learning to all employees that can be accessed 24/7 on a range of topics from leadership, personal effectiveness and well-being.

We deliver our “Harmonize” program to all managers to ensure they are grounded in our core Leadership Behaviors we expect all leaders to demonstrate (Instills Trust, Values Differences, Executes through Teams, Develops Talent, Drives Accountability and Provides and Receives Feedback).

In 2021, we targeted a development effort towards our Global Leadership Team (top 70 leaders) and created a 9-month learning journey to build leadership excellence, strengthen relationships, and encourage cross functional collaboration in pursuit of our enterprise strategic goals.

Additionally, we focused on diverse early career talent by piloting an executive coaching program to support their development.

We offer tuition reimbursement in our major markets aimed at growth and career development.

5 unchanged sentences

In addition to traditional employee benefits, Jazz supports employees and their families through access to a suite of innovative programs that are designed to enhance their physical, financial, emotional and social well-being.

For 2022, we are introducing an enhanced suite of differentiated global leave and time-off polices to address the needs of our diverse employee population through varying stages of life, including minimum standards for new parent leave (irrespective of gender or how a family is created), family caregiver leave, and bereavement leave.

Additionally, in 2022, we are launching a new global volunteer day, which will provide employees time off with full pay to give back to their communities.

Workplace Safety & Employee Care During COVID-19 .

1 unchanged sentence

To create and sustain a safe and healthy workplace, we have implemented initiatives designed to address risk evaluation, education and training of employees, use of appropriate personal protective equipment, and compliance with relevant national and international health and safety standards.

In response to COVID-19, we launched a new employee support framework focused on Care, Connection, Continuity and Consciousness (our “4Cs”) to enable our employees to live into our values and support one another while doing everything we can to deliver on our patient mission.

In response to COVID-19, we launched an employee support framework focused on Care, Connection, Continuity and Consciousness (our “4Cs”) to enable our employees to live into our values and support one another while doing everything we can to deliver on our patient mission.

Important to this framework were new leader expectations and tools given the rise and complexity of emerging employee demands and needs – including more flexibility to address personal needs, a greater connection to understand the whole person and their lives, and more active support surrounding social injustice.

4 unchanged sentences

Environment, Health and Safety .

Our operations are subject to complex and increasingly stringent environmental, health and safety laws and regulations in the countries where we operate and, in particular, in Italy and Ireland where we have manufacturing facilities.

Our operations are subject to complex and increasingly stringent environmental, health and safety laws and regulations in the countries where we operate and, in particular, in Ireland, the U.K.

and Italy where we have manufacturing facilities.

Our manufacturing activities involve the controlled storage, use and disposal of chemicals and solvents.

Environmental and health and safety authorities in Italy and Ireland administer laws governing, among other matters, the emission of pollutants into the air (including the workplace), the discharge of pollutants into bodies of water, the storage, use, handling and disposal of hazardous substances, the exposure of persons to hazardous substances, and the general health, safety and welfare of employees and members of the public.

Environmental and health and safety authorities in Ireland, the U.K.

and Italy administer laws governing, among other matters, the emission of pollutants into the air (including the workplace), the discharge of pollutants into bodies of water, the storage, use, handling and disposal of hazardous substances, the exposure of persons to hazardous substances, and the general health, safety and welfare of employees and members of the public.

In certain cases, such laws, directives and regulations may impose strict liability for pollution of the environment and contamination resulting from spills, disposals or other releases of hazardous substances or waste.

4 unchanged sentences

Our environmental policies and management systems include procedures for assessing compliance with applicable environmental laws and regulations and reporting incidents of non-compliance to applicable governmental authorities.

For example, we have environmental policies governing both of our manufacturing facilities in Athlone, Ireland and Villa Guardia (Como), Italy, which demonstrate our commitment to environmental sustainability and require us to minimize resource use (e.g., energy and water) and waste generation, optimize the use of raw materials, and undertake continuous improvement in environmental performance, with an emphasis on pollution prevention.

For example, we have environmental policies governing our manufacturing facilities in Ireland, the U.K.

and Italy, which demonstrate our commitment to environmental sustainability and require us to minimize resource use (e.g., energy and water) and waste generation, optimize the use of raw materials, and undertake continuous improvement in environmental performance, with an emphasis on pollution prevention.

The biopharmaceutical industry is highly competitive.

4 unchanged sentences

Generic competition often results in decreases in the prices at which branded products can be sold.

We are aware of:

exploratory research into the effects of THC and CBD drug formulations;

discovery research within the pharmaceutical industry into synthetic agonists and antagonists of CB1 and CB2 receptors;

companies that supply synthetic cannabinoids and cannabis extracts to researchers for pre-clinical and clinical investigation;

and various companies that cultivate cannabis plants with a view to supplying herbal cannabis or nonpharmaceutical cannabis-based formulations to patients.

These activities have not been approved by the FDA but may in the future compete with our products.

In particular, our products and most advanced product candidates face or may face competition as described below:

• Xyrem and Xywav .

While Xyrem and Xywav are currently the only products approved by FDA and marketed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy, we and others

have launched products to treat EDS in narcolepsy and may in the future launch products to treat cataplexy in narcolepsy that are competitive with or disrupt the market.

In the future, we expect to face competition from authorized generic and generic versions of sodium oxybate.

For a description of generic versions of sodium oxybate and/or new products for treatment of cataplexy and/or EDS that could compete with, or otherwise disrupt the market for, Xyrem and Xywav, as well as a description of our settlement agreements with abbreviated new drug application, or ANDA, filers, see the risk factor under the heading “ The introduction of new products in the U.S.

• Xywav and Xyrem .

While Xywav and Xyrem are currently the only products approved by FDA and marketed in the U.S.

for the treatment of both cataplexy and EDS in both adult and pediatric patients with narcolepsy, we and others have launched products to treat EDS in narcolepsy and may in the future launch products to treat cataplexy in narcolepsy that are competitive with or disrupt the market.

We expect to face competition from authorized generic and generic versions of sodium oxybate.

For a description of generic versions of sodium oxybate and/or new products for the treatment of cataplexy and/or EDS that could compete with, or otherwise disrupt the market for, Xywav and Xyrem, as well as a description of our settlement agreements with abbreviated new drug application, or ANDA, filers, see the risk factor under the heading “ The introduction of new products in the U.S.

market that compete with, or otherwise disrupt the market for, our oxybate products and product candidates would adversely affect sales of our oxybate products and product candidates” in Part I, Item 1A of this Annual Report on Form 10‑K.

In addition to generic competition, Xyrem and Xywav may face competition in the future from other new sodium oxybate formulations for treatment of narcolepsy.

In December 2020, Avadel Pharmaceuticals plc, or Avadel, announced the filing of a NDA for an extended-release formulation of sodium oxybate which uses its proprietary technology for the treatment of EDS and cataplexy in patients with narcolepsy.

Avadel has also announced that it has obtained an orphan drug designation from FDA for its extended-release sodium oxybate formulation.

To obtain approval with orphan drug exclusivity, Avadel will have to show clinical superiority to Xyrem and Xywav.

In addition to generic competition, Xywav and Xyrem may face competition in the future from other new sodium oxybate formulations for treatment of narcolepsy.

In February 2021, FDA accepted for filing an NDA submitted by Avadel Pharmaceuticals plc, or Avadel, for an extended-release formulation of sodium oxybate which uses its proprietary technology for the treatment of EDS and cataplexy in patients with narcolepsy with a Prescription Drug User Fee Act, or PDUFA, target action date of October 15, 2021.

On October 15, 2021, Avadel announced that FDA review is ongoing and FDA will likely not take action in October 2021 and will provide a new target action date.

To obtain approval with ODE, Avadel will have to show clinical superiority to Xywav and Xyrem.

We cannot predict the timing or approvability of Avadel’s sodium oxybate product candidate or how FDA will evaluate any clinical superiority arguments that either we or Avadel may make, but in any event, we expect to face competition from Avadel, if its product candidate is approved.

Xyrem and Xywav may also face increased competition from new branded entrants to treat EDS in narcolepsy such as pitolisant, which has been approved by FDA for the treatment of both cataplexy and EDS in adult patients with narcolepsy.

Xywav and Xyrem may also face increased competition from new branded entrants to treat EDS or cataplexy in narcolepsy such as pitolisant, which has been approved by FDA for the treatment of both cataplexy and EDS in adult patients with narcolepsy.

Other companies have announced that they have product candidates in various phases of development to treat the symptoms of narcolepsy, such as Axsome Therapeutics, Inc.’s reboxetine, and various companies are performing research on orexin agonists for the treatment of sleep disorders.

In addition, we are also aware that prescribers often prescribe branded or generic medications for cataplexy before prescribing or instead of prescribing oxybate therapy in Xyrem or Xywav, and that payors often require patients to try such medications before they will cover Xyrem or Xywav, even if they are not approved for this use.

In addition, we are also aware that prescribers often prescribe branded or generic medications for cataplexy before prescribing or instead of prescribing oxybate therapy in Xywav or Xyrem, and that payors often require patients to try such medications before they will cover Xywav or Xyrem, even if they are not approved for this use.

For example, prescribers often treat mild cataplexy with drugs that have not been approved by FDA for this indication, including tricyclic antidepressants and selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors.

We are also aware that branded or generic stimulants may be prescribed off-label for treatment of EDS in narcolepsy.

Wake-promoting agents modafinil and armodafinil, including both branded and generic equivalents, are approved for the treatment of EDS in narcolepsy and other conditions, and may be used in conjunction with or instead of Xyrem or Xywav.

Patients in the U.S.

suffering from seizures associated with Dravet or LGS are treated with a variety of FDA-approved products, including clobazam, clonazepam, valproate, lamotrigine, levetiracetam, rufinamide, topiramate, ethosuximide, and zonisamide.

FDA approved Zogenix, Inc.'s low-dose fenfluramine, or Fintepla, in DS in June 2020, and Zogenix submitted its supplemental NDA for LGS in 2021.

In January 2022, Zogenix announced that it entered into a definitive agreement with UCB S.A.

for the acquisition of Zogenix by UCB.

Ovid Therapeutics Inc./Takeda Pharmaceutical Company Limited and Marinus Pharmaceuticals, Inc.

are developing therapies for treating Developmental and Epileptic Encephalopathies (includes Dravet and LGS).

Stiripentol has been approved in Europe for several years to treat DS and was approved in 2018 by the FDA.

Zynerba Pharmaceuticals, Inc.

is developing a topical formulation of CBD, for which it is working with FDA on a path forward on CONNECT-FX data for Zygel in Fragile X syndrome.

There are a number of public and private companies in the early stages of developing genetic therapies for DS, including Stoke Therapeutics, Inc., which has an antisense oligonucleotide, STK-001, in early clinical trials.

Sunosi faces competition from existing branded and generic products that treat EDS or improve wakefulness in adult patients with narcolepsy or OSA in a competitive retail pharmacy market.

1 unchanged sentence

We are also aware that stimulants are prescribed off-label for patients to treat excessive sleepiness in OSA.

Sunosi may face competition from new branded entrants such as pitolisant, a drug that was approved by FDA in August 2019 for the treatment of EDS in adult patients with narcolepsy and in October 2020 for the treatment of cataplexy in adult patients with narcolepsy.

Sunosi faces competition from new branded entrants such as pitolisant, a drug that was approved by FDA in August 2019 for the treatment of EDS in adult patients with narcolepsy and in October 2020 for the treatment of cataplexy in adult patients with narcolepsy.

Pitolisant became commercially available in the U.S.

in the fourth quarter of 2019, and has also been approved and marketed in Europe to treat adult patients with narcolepsy with or without cataplexy.

in the fourth quarter of 2019, and has also been approved and marketed in Europe to treat adult patients with narcolepsy,

with or without cataplexy, and OSA.

Sunosi may also face competition from other products in development as potential treatments for EDS in patients with narcolepsy or OSA.

• Defitelio .

While there is currently no direct competition to Defitelio to treat severe VOD, changes in the types of conditioning regimens used as part of HSCT may affect the incidence of VOD diagnosis and demand for Defitelio.

While there is currently no direct competition to Erwinaze to treat ALL patients with hypersensitivity to E.

coli -derived asparaginase, we and other companies have developed or are developing new treatments for ALL.

For example, we initiated the submission of a BLA to FDA for JZP-458 (recombinant Erwinia asparaginase) in December 2020.

Some new asparaginase treatments could reduce the rate of hypersensitivity in patients with ALL, and new treatment protocols are being developed and approved for ALL that may not include asparaginase-containing regimens, including some for the treatment of relapsed or refractory ALL patients.

We have experienced frequent intermittent shortages of the product that have impacted prescribing habits for Erwinaze, including prescribers’ use of alternate methods to address hypersensitivity reactions.

As a biologic product, Erwinaze also faces potential competition from biosimilar products.

In April 2020, PBL announced that it had entered into an agreement with a new partner to commercialize and distribute Erwinaze after our license and supply agreement expired in December

Subject to successful receipt, release and FDA approval for the batches from PBL, we expect to distribute available Erwinaze supply during the first half of 2021.

• Nabiximols.

Nabiximols aims to treat adult patients with MS-related spasticity.

Patients in the U.S.

suffering from MS-related spasticity are currently treated with a variety of FDA-approved therapies such as baclofen, tizanidine, gabapentin, dantrolene and various botulinum toxin products.

Bionorica SE is in late stage development of an oral solution containing dronabinol for spasticity due to MS.

Ipsen and Echo pharmaceuticals are in the early stages of development with various oral products aimed to treat MS-related spasticity.

Zepzelca faces competition from topotecan, which is also an approved treatment in second line SCLC in the U.S., as well as other regimens for relapsed SCLC currently recommended in compendia guidelines.

There are also a number of products and immunotherapies for the treatment of second line SCLC in various phases of development.

Rylaze may face competition from Erwinase, which was previously approved and commercialized by Jazz as a treatment for ALL patients with hypersensitivity to E.

coli -derived asparaginase.

In April 2020, Porton Biopharma Limited, or PBL, granted Clinigen Group plc, or Clinigen, a global license for Erwinase.

However, in December 2021, Clinigen announced that FDA has issued a Complete Response Letter to PBL’s BLA for Erwinaze, indicating that the BLA cannot be approved in its current form.

Rylaze may also face competition from other companies who have developed or are developing new treatments for ALL, including an L-asparaginase product candidate that is in development for the treatment of ALL patients.

In addition, some new asparaginase treatments could reduce the rate of hypersensitivity in patients with ALL, and new treatment protocols are being developed and approved for ALL that may not include asparaginase-containing regimens, including some for the treatment of relapsed or refractory ALL patients.

As a biologic product, Rylaze also faces potential competition from biosimilar products.

With respect to Vyxeos, there are a number of alternative established therapies in AML.

5 unchanged sentences

We are also aware of the increasing use of venetoclax combined with either a hypomethylating agent or low-dose cytarabine, a treatment approved by FDA in newly diagnosed AML patients who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

There are also a number of products and immunotherapies for the treatment of second line SCLC in various phases of development.

• Defitelio .

An important part of our corporate strategy is to build a diversified product pipeline, including by acquiring or in-licensing and developing, or partnering to license and develop, additional products and product candidates that we believe are highly differentiated and have significant commercial potential.

Our ability to continue to grow our product portfolio requires that we compete successfully with other pharmaceutical companies, many of which may have substantially greater financial sales and marketing resources, to acquire or in-license products and product candidates.

In the U.S., Xyrem and Xywav are sold to one specialty pharmacy, ESSDS, that ships Xyrem and Xywav directly to patients.

Also in the U.S., Sunosi is distributed through a retail channel consisting of numerous distributors who sell Sunosi to retail pharmacies.

Defitelio and Erwinaze are sold to hospital customers through subsidiary specialty distributors of McKesson Corporation, or McKesson.

Zepzelca and Vyxeos are sold to customers through subsidiary specialty distributors of McKesson, AmerisourceBergen Corporation, or ABC, and Cardinal Health, Inc., or Cardinal.

We have distribution services agreements made in the ordinary course of business with McKesson, ABC and Cardinal and a pharmacy services agreement with ESSDS that provides for the distribution of Xyrem and Xywav to patients.

In the U.S., Xywav and Xyrem are sold to one certified specialty pharmacy, ESSDS, that ships Xywav and Xyrem directly to patients.

Also in the U.S., Epidiolex is sold to specialty pharmacies, wholesalers and specialty distributors.

Sunosi is distributed through a retail channel consisting of numerous distributors who sell Sunosi to retail pharmacies.

Defitelio is sold to hospital customers through subsidiary specialty distributors of McKesson Corporation, or McKesson.

Zepzelca, Rylaze and Vyxeos are sold to customers through subsidiary specialty distributors of McKesson, AmerisourceBergen Corporation, or ABC, and Cardinal Health, Inc., or Cardinal.

For more information regarding our relationship with ESSDS, see “Business—Our Commercialized Products—Xyrem” in this Part I, Item 1.

Purchases are made on a purchase order basis.

In certain countries in Europe, Sunosi, Defitelio, Erwinase and Vyxeos are sold pursuant to marketing authorizations.

We distribute these products through Durbin PLC, a UK-based wholesaler and distributor, and O&M Movianto Nederland BV, our centralized European logistics services provider, to hospitals and local wholesalers in Europe where we market these products directly and, in other markets in Europe and elsewhere where we do not market these products directly, to local distributors and wholesalers.

In countries where there is no marketing authorization, Defitelio, Erwinase and Vyxeos are sold pursuant to named patient programs, temporary use authorizations or similar authorizations.

In certain countries in Europe, Sunosi, Defitelio and Vyxeos are sold pursuant to marketing authorizations.

We distribute these products through Durbin PLC, a U.K.-based wholesaler and distributor, and O&M Movianto Nederland BV, our centralized European logistics services provider, to hospitals and local wholesalers in Europe where we market these products

directly and, in other markets in Europe and elsewhere where we do not market these products directly, to local distributors and wholesalers.

In certain countries in Europe, Epidyolex is sold pursuant to marketing authorizations.

We distribute Epidyolex through a variety of wholesalers and distributors.

Sativex is sold outside of the United States for the treatment of spasticity due to MS, pursuant to license agreements with commercial partners and directly to customers in the U.K.

In countries where there is no marketing authorization, Defitelio, Vyxeos, Epidyolex and Sativex are sold pursuant to named patient programs, temporary use authorizations or similar authorizations.

We directly market Xyrem in Canada for the treatment of cataplexy in patients with narcolepsy.

Xyrem is also sold in 20 countries by UCB Pharma Limited, or UCB (which has rights to market Xyrem in 54 countries).

Xyrem is also sold in 21 countries by UCB (which has rights to market Xyrem in 54 countries).

Manufacturing

We have a manufacturing and development facility in Athlone, Ireland where we manufacture Xyrem and Xywav, and a manufacturing plant in Villa Guardia, Italy where we produce the defibrotide drug substance.

We have a manufacturing and development facility in Athlone, Ireland where we manufacture Xywav and Xyrem, a manufacturing and development facility in the U.K.

in Kent Science Park, where we produce Epidiolex/Epidyolex and Sativex, and a manufacturing plant in Villa Guardia, Italy where we produce the defibrotide drug substance.

We currently do not have our own commercial manufacturing or packaging capability for our other products, product candidates or their APIs.

As a result, our ability to develop and supply products in a timely and competitive manner depends primarily on third party suppliers being able to meet our ongoing commercial and clinical trial needs for API, other raw materials, packaging materials and finished products.

Our manufacturing facility in Athlone, Ireland currently continues to be operational with essential staff onsite and office-based staff working remotely.

In March 2020, we temporarily ceased operations at our Villa Guardia, Italy manufacturing facility, which produces defibrotide, to ensure the safety of our employees and communities in northern Italy.

We reopened the facility in the second quarter of 2020 taking into account applicable public health authority and local government guidelines as well as employee safety, and the facility has now resumed operations with essential staff onsite and office-based staff working remotely.

However, the effects of the COVID-19 pandemic continue to rapidly evolve and even if our employees more broadly return to work in our global offices, the field and our manufacturing facilities, we may

nevertheless have to resume a remote work model, whether as a result of spikes or surges in COVID-19 infection or hospitalization rates or otherwise.

Our manufacturing facilities currently continue to be operational with essential staff onsite and office-based staff working onsite and remotely as business needs require.

Lead Marketed Products

Xywav is manufactured at our Athlone facility.

Xywav, like Xyrem, is a Schedule III controlled substance in the U.S.

The API of Xywav are the calcium, magnesium, potassium and sodium salts of gamma-hydroxybutyric acid (as gamma-hydroxybutyric acid is the API for Xyrem), which are Schedule I controlled substances in the U.S.

As a result, Xywav and Xyrem are subject to regulation by the U.S.

Drug Enforcement Administration, or DEA, under the Federal Controlled Substances Act, or CSA, and its manufacturing and distribution are highly restricted.

Quotas from the DEA are required in order to manufacture and package calcium, magnesium, potassium and sodium oxybate, Xywav and Xyrem in the U.S.

For information related to DEA quota requirements, see “Business—Government Regulation—Other Post-Approval Pharmaceutical Product Regulation—Controlled Substance Regulations” in this Part I, Item 1.

Xyrem is manufactured by us in our Athlone facility and by Patheon Pharmaceuticals Inc., which we refer to together with its affiliates as Patheon, under a Master Manufacturing Services Agreement, or the Patheon Agreement, entered into with Patheon in 2015.

7 unchanged sentences

During the term of the agreement and, under certain circumstances for 18 months after the agreement terminates, Siegfried is not permitted to manufacture sodium oxybate for any other company.

Xyrem is a Schedule III controlled substance in the U.S., and the API of Xyrem is the sodium salt of gamma-hydroxybutyric acid, which is a Schedule I controlled substance in the U.S.

As a result, Xyrem is subject to regulation by the U.S.

Drug Enforcement Administration, or DEA, under the Controlled Substances Act, or CSA, and its manufacturing and distribution are highly restricted.

Quotas from the DEA are required in order to manufacture and package sodium oxybate and Xyrem in the U.S.

Xywav is manufactured at our Athlone facility.

Xywav is a Schedule III controlled substance in the U.S., and the API of Xywav are the calcium, magnesium, potassium and sodium salts of gamma-hydroxybutyric acid, which is a Schedule I controlled substance in the U.S.

As a result, Xywav is subject to regulation by the DEA under the CSA, and its manufacturing and distribution are highly restricted.

Quotas from the DEA are required in order to manufacture and package calcium, magnesium, potassium and sodium oxybate and Xywav in the U.S.

Epidiolex/Epidyolex is manufactured by us in our Kent Science Park facility in the U.K.

Epidiolex is a pharmaceutical formulation comprising highly purified plant-derived CBD.

We cultivate our cannabinoid plants in the U.K.

under highly controlled and standardized conditions.

Siegfried AG is our sole supplier of both the API and finished product for Sunosi for both commercial sale as well as development activities.

3 unchanged sentences

Solriamfetol, the API of Sunosi, and Sunosi were designated Schedule IV controlled substances by the DEA under the CSA.

Sativex is manufactured by us in our Kent Science Park facility in the U.K.

Sativex (nabiximols) is a complex botanical mixture formulated from extracts of the cannabis sativa plant that contains the principal cannabinoids THC and CBD as well as specific minor cannabinoids and other non-cannabinoid components.

We cultivate our cannabinoid plants in the U.K.

under highly controlled and standardized conditions.

Zepzelca is manufactured by Baxter.

The initial term of the agreement with Baxter will expire in December 2023 and will then be subject to automatic two-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

PharmaMar retains manufacturing rights for the API for U.S.

and Canadian commercial supply of Zepzelca.

We also entered into a manufacturing agreement for ongoing commercial supply of the drug product Zepzelca with GP Pharm S.A.

Rylaze is currently manufactured by Patheon, and the API of Rylaze is manufactured by AGC Biologics A/S.

The initial term of the agreement with Patheon will expire in December 2025 and will then be subject to automatic two-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

The initial term of the agreement with AGC Biologics A/S will expire in October 2026 and will then be subject to automatic three-year extensions, unless either party provides advance notice of its intent to terminate the agreement.

Vyxeos is manufactured by Baxter Oncology GmbH, or Baxter, which is a sole source supplier from a single site location, using our CombiPlex technology platform.

CombiPlex products represent formulations with increased manufacturing complexities associated with producing drug delivery vehicles encapsulating two or more drugs that are maintained at a fixed ratio and, in the case of Vyxeos, two drugs that are co-encapsulated in a freeze-dried liposomal format.

Our manufacturing agreement with Baxter expires in August 2025, subject to automatic three-year renewal terms, unless either party provides advance notice of its intent to terminate the agreement.

While other contract manufacturers may be able to produce Vyxeos, the proprietary technology that supports the manufacture of Vyxeos is not easily transferable.

The marketing authorization in the EU for Vyxeos also requires us to comply with certain manufacturing-related post-approval commitments.

We are our own sole supplier of, and we believe that we are currently the sole worldwide producer of, the defibrotide API.

4 unchanged sentences

If Patheon does not or is not able to supply us with Defitelio for any reason, it may take time and resources to implement and execute the necessary technology transfer to another processor, and such delay could negatively impact our anticipated revenues from Defitelio and could potentially cause us to breach contractual obligations with customers or to violate local laws requiring us to deliver the product to those in need.

PBL is our sole supplier of Erwinaze.

Our license and supply agreement with PBL, which includes an exclusive right to market, sell or distribute Erwinaze, expired on December 31, 2020.

Under our agreement with PBL, we have the right to sell certain Erwinaze inventory for a post-termination sales period of 12 months.

Subject to successful receipt, release and FDA approval for the batches from PBL, we expect to distribute available Erwinaze supply during the first half of 2021.

For information related to our expired agreement with PBL, see “Business—Our Commercialized Products—Erwinaze” in this Part I, Item 1.

Vyxeos is manufactured by Baxter Oncology GmbH, or Baxter, which is a sole source supplier from a single site location, using our CombiPlex technology platform.

Our manufacturing

agreement with Baxter expires in August 2025, subject to automatic three-year renewal terms, unless either party provides advance notice of its intent to terminate the agreement.

While other contract manufacturers may be able to produce Vyxeos, the proprietary technology that supports the manufacture of Vyxeos is not easily transferable.

The marketing authorization in the EU for Vyxeos also requires us to comply with certain manufacturing-related post-approval commitments.

Zepzelca is manufactured by Baxter.

PharmaMar retains manufacturing rights for the API for U.S.

and Canadian commercial supply of Zepzelca.

We also entered into a manufacturing agreement for ongoing commercial supply of the drug product Zepzelca with GP Pharm S.A.

Product Candidates

JZP-458 is currently manufactured by Patheon, and the API of JZP-458 is manufactured by AGC Biologics A/S.

JZP-258 for idiopathic hypersomnia is currently manufactured at our Athlone facility, and we expect to manufacture this product commercially at our Athlone facility should this candidate receive regulatory approval.

For discussion of the challenges we face with respect to supply of our products and product candidates, see the risk factor under the heading “ Delays or problems in the supply of our products for sale or for use in clinical trials, loss of our single source suppliers or failure to comply with manufacturing regulations could materially and adversely affect our business, financial condition, results of operations and growth prospects” in Part I, Item 1A of this Annual Report on Form 10‑K.

1 unchanged sentence

We actively seek to patent, or to acquire or obtain licenses to third party patents, to protect our products and product candidates and related inventions and improvements that we consider important to our business.

We own a portfolio of U.S and non-U.S.

We own a portfolio of U.S.

patents and patent applications and have licensed rights to a number of issued patents and patent applications.

7 unchanged sentences

The patents, patent applications and regulatory exclusivities that relate to our marketed products include:

We have 12 U.S.

patents that relate to Xywav.

These patents expire from 2023 to 2033.

In addition, we have patent applications that relate to Xywav for use in additional indications that would, if issued, expire between 2040 and 2041.

Xywav has been granted ODE by FDA to treat narcolepsy through 2027 and to treat IH through 2028.

We currently have six issued, unexpired patents in the U.S.

3 unchanged sentences

In October 2018, as a result of FDA’s grant of pediatric exclusivity, an additional six months was added to the original expiration dates of all of our Orange Book-listed patents that existed at that time.

As a result, our Orange Book-listed patents have periods of exclusivity between December 2022 and September 2033.

our Orange Book-listed patents have periods of exclusivity between December 2022 and September 2033.

Some of our Xyrem patents have been subject to patent litigation with the companies who filed ANDAs seeking to market a generic version of Xyrem, including challenge through the inter partes review, or IPR, procedures of the Patent Trial and Appeal Board, or PTAB, of the U.S.

8 unchanged sentences

A Xyrem formulation patent that had issued in multiple non-U.S.

countries expired in December 2019.

The European Patent Office has issued a method of administration patent relating to the DDI between Xyrem and divalproex sodium that will expire in February 2034.

countries expired in 2019.

The European Patent Office has issued a method of administration patent relating to the DDI between Xyrem and divalproex sodium that will expire in 2034.

That patent is licensed to UCB as the marketing authorization holder outside of the U.S.

2 unchanged sentences

and other countries.

patents and patent applications that relate to Xywav.

Some of these patents expire in early 2033.

In addition, we have patent applications that relate to Xywav for use in additional indications that would, if issued, expire between 2040 and 2041.

Our patent portfolio relating to the use of CBD in the treatment of epileptic encephalopathies includes 90 distinct patent families that are either granted or filed.

Most of the patent families in this portfolio claim the use of CBD in the treatment of particular childhood epilepsy syndromes, seizure sub-types and interactions with other concomitantly dosed anti-seizure drugs.

To date, we have obtained 21 issued U.S.

patents, including patents with claims for the use of CBD for the treatment of convulsive, drop and atonic seizures associated with both LGS and DS, an oral composition of CBD, as well as the use of CBD with clobazam, and the teaching that dose adjustment may be needed when concomitantly prescribed.

These issued patents are directly aligned with the Epidiolex label, and we have listed them in the Orange Book.

These patents have expiry between 2022 and 2041.

We have filed corresponding patent applications in many jurisdictions worldwide, including Europe, UK, Canada, Japan, Mexico, Australia and New Zealand.

The USPTO has granted a patent based on data that demonstrates that Epidiolex provides a benefit over synthetic CBD in an animal model of epilepsy, which has an expiry date of 2039 and we have listed it in the Orange Book.

Epidiolex has received ODE to treat seizures associated with LGS and DS through 2025 and TSC through 2027.

We acquired worldwide development, manufacturing and commercial rights to solriamfetol from Aerial BioPharma LLC, or Aerial, in 2014, including Aerial’s patent rights relating to solriamfetol, other than in certain jurisdictions in Asia where SK Biopharmaceuticals Co., Ltd.

3 unchanged sentences

Four of our U.S.

patents are method of use patents covering treatment of sleep-related conditions expiring between June 2026 and August 2027 and another U.S.

patent is directed to dose escalation regimens expiring in June 2038.

patents are method of use patents covering treatment of sleep-related conditions expiring between 2026 and 2027 and another U.S.

patent is directed to dose escalation regimens expiring in 2038.

Two other U.S.

patents cover, respectively, the formulation of solriamfetol and the method of treating select conditions with formulations of solriamfetol (both expiring in September 2037).

patents cover, respectively, the formulation of solriamfetol and the method of treating select conditions with formulations of solriamfetol (both expiring in 2037).

A request for a patent term extension for one of the above method of use patents has been filed.

Requests for Supplementary Protection Certificate in certain European validation countries for a related European patent have been granted in Austria, Ireland, Italy, Netherlands, and Sweden (expiring in June 2031) and remain pending in the others.

Sunosi has also been granted orphan drug exclusivity for narcolepsy and new chemical entity exclusivity in the U.S.

• Defitelio .

The unique process of deriving defibrotide from porcine DNA is extensive and uses both chemical and biological processes that rely on complex characterization methods.

patents and patent applications relating to various compositions, methods of use and methods of characterization, with the issued patents expiring at various times between April 2021 and November 2035.

None of these patents are listed in the Orange Book.

Defibrotide has been granted orphan drug exclusivity by FDA to treat and prevent VOD until March 2023.

Defibrotide has also been granted orphan drug designation by the EC and the Korean Ministry of Food and Drug Safety to treat and prevent VOD, by the Commonwealth of Australia-Department of Health for the treatment of VOD and by the EC for the prevention of acute Graft-versus-Host Disease, or aGvHD.

We acquired the rights to defibrotide for the treatment and prevention of VOD in North America, Central America and South America from Sigma-Tau Pharmaceuticals, Inc.

Erwinaze has no patent protection.

It had been granted orphan drug exclusivity by FDA for the treatment of ALL in the U.S.

until November 2018, and as a biological product approved under a BLA, we believe that it is protected by exclusivity that prevents approval of a biosimilar in the U.S.

through late 2023 under the U.S.

Biologics Price Competition and Innovation Act, or BPCIA.

In the EU, the regulatory data protection that provides an exclusivity period for Erwinase has lapsed.

We have a portfolio of U.S.

patents and patent applications for Vyxeos and the CombiPlex technology platform relating to various compositions and methods of making and use.

These include seven U.S.

patents covering Vyxeos compositions and methods of use expiring between April 2025 and September 2034 and two U.S.

patents covering CombiPlex (which also cover Vyxeos) expiring in January 2027.

These patents are listed in the Orange Book.

Vyxeos has been granted orphan drug exclusivity by FDA until August 2024, seven years from its FDA approval, for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In addition, Vyxeos has been granted orphan drug designation by the EC until August 2028, ten years from its EC approval for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

Requests for Supplementary Protection Certificate in certain European validation countries for a related European patent have been granted in Austria, Denmark, France, Ireland, Italy, Netherlands, Spain and Sweden (expiring in 2031) and remain pending in the others.

Sunosi has also been granted ODE for narcolepsy and new chemical entity exclusivity in the U.S.

In the U.S., our patents (and our pending applications if they issue) relating to nabiximols would expire on various dates between 2022 and 2029, excluding possible patent term extensions.

We have at least seven different patent families containing one or more pending and/or issued patents directed to the nabiximols formulation, the medical use of nabiximols, the extracts from which nabiximols is composed, the extraction technique used to produce the extracts and the therapeutic use of nabiximols.

Due to the product’s significant complexity, we believe that nabiximols will benefit from strong long-term market regulatory protection.

In December 2019, we entered into an exclusive license agreement with PharmaMar pursuant to which we obtained exclusive U.S.

6 unchanged sentences

A request for a patent term extension for this U.S.

patent has been filed.

Zepzelca has also been granted orphan drug exclusivity for the treatment of adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy until 2027 and new chemical entity exclusivity until 2025 in the U.S.

patent has been filed and, if granted, would extend to 2029.

A request for extension (CSP) has also been filed in Canada.

Zepzelca has also been granted orphan drug exclusivity for the treatment of adults with metastatic

SCLC with disease progression on or after platinum-based chemotherapy until 2027 and new chemical entity exclusivity until 2025 in the U.S.

In 2016, we obtained worldwide rights from Pfenex, Inc., including Pfenex’s patent rights relating to Rylaze, to develop and commercialize multiple early-stage hematology product candidates, including a license to two U.S.

process patents relating to Rylaze, with respective expirations in 2026 and 2038.

Pfenex has been acquired by Ligand Pharmaceuticals Incorporated.

Rylaze has been granted ODE for the treatment of patients with ALL or LBL until 2028.

We have two patent application families relating to dosing regimens.

One covers the current dosing regimen (25mg/m2 intramuscularly every 48 hours), while the other covers various dosing regimens of interest.

If issued, these would expire in 2040 and 2042, respectively.

Another application relating to formulations of asparaginase would expire in 2042 if issued.

We have a portfolio of U.S.

patents and patent applications for Vyxeos and the CombiPlex technology platform relating to various compositions and methods of making and use.

These include seven U.S.

patents covering Vyxeos compositions and methods of use expiring between 2025 and 2034 and two U.S.

patents covering CombiPlex (which also cover Vyxeos) expiring in January 2027.

These patents are listed in the Orange Book.

Vyxeos has been granted ODE by FDA until August 2024, seven years from its FDA approval, for the treatment of adults with newly-diagnosed t-AML or AML-MRC.

In March 2021, FDA approved an expanded label for Vyxeos for the treatment of t-AML or AML-MRC in pediatric patients 1 year and older.

In addition, Vyxeos has been granted orphan drug designation by the EC until August 2028, ten years from its EC approval for the treatment of adults with newly-diagnosed t-AML or AML-MRC and was approved by Health Canada for treatment of adults with newly diagnosed t-AML or AML-MRC in April 2021.

• Defitelio .

The unique process of deriving defibrotide from porcine DNA is extensive and uses both chemical and biological processes that rely on complex characterization methods.

patents and patent applications relating to various compositions, methods of use and methods of characterization, with the issued patents expiring at various times between 2021 and 2035.

patent is listed in the Orange Book and an additional allowed patent is expected to be Orange Book listed in 2022.

Defibrotide has been granted ODE by FDA to treat and prevent VOD until March 2023.

We acquired the rights to defibrotide for the treatment and prevention of VOD in North America, Central America and South America from Sigma-Tau Pharmaceuticals, Inc.

The patents and/or patent applications that relate to our product candidates include:

• Suvecaltamide (JZP385) .

Through the acquisition of Cavion in 2019, we obtained a portfolio of U.S.

patents and patent applications, including rights relating to compositions and methods of using JZP-385.

patents and patent applications, including rights relating to compositions and methods of using suvecaltamide.

The portfolio includes a U.S.

composition of matter patent relating to JZP-385, which expires in 2027.

composition of matter patent relating to suvecaltamide, which expires in 2027, but which can be extended to 2032 depending on regulatory approval.

Two further U.S.

patents to the treatment of specific conditions (Angelman Syndrome and memory and cognitive disorders) provide supplemental protection to 2038.

Through the asset purchase and exclusive license agreement with SpringWorks in 2020, we obtained a license to a portfolio of U.S.

patents and patent applications, including rights relating to compositions

and methods of using JZP-150.

patents and patent applications, including rights relating to compositions and methods of using JZP150.

The portfolio includes a U.S.

composition of matter patent relating to JZP150, which expires in 2029.

In 2016, we obtained worldwide rights from Pfenex, Inc., including Pfenex’s patent rights relating to JZP-458, to develop and commercialize multiple early-stage hematology product candidates, including a license to two U.S.

process patents relating to JZP-458, with respective expirations in 2026 and 2038.

Pfenex has been acquired by Ligand Pharmaceuticals Incorporated.

In addition, we have rights to a number of trademarks and service marks, and pending trademark and service mark applications, in the U.S.

17 unchanged sentences

Human clinical trials conducted before approval of a product generally proceed in three sequential phases, although the phases may overlap.

In Phase 1, the initial introduction of the product candidate in humans, the product candidate is typically tested to assess metabolism, pharmacokinetics, pharmacological actions and side effects associated with increasing doses.

Phase 2 usually involves clinical trials in a limited patient population to determine the effectiveness of the product candidate for a particular indication or indications, dosage tolerance and optimum dosage and to identify common adverse effects and safety risks.

5 unchanged sentences

Once accepted for filing, FDA begins an in-depth review of the application.

Under the current goals and policies agreed to by FDA under the Prescription Drug User Fee Act, or PDUFA, for a new molecular entity, FDA has ten months from the filing decision in which to complete its initial review of a standard application and respond to the applicant, and eight months for a priority application.

Under the current goals and policies agreed to by FDA under the PDUFA for a new molecular entity, FDA has ten months from the filing decision in which to complete its initial review of a standard application and respond to the applicant, and six months from the filing decision for a priority application.

FDA does not always meet its PDUFA goal dates, and in certain circumstances, the PDUFA goal date may be extended.

1 unchanged sentence

Generally, products may be eligible for one or more of these programs if they are intended for serious or life-threatening diseases or conditions, have potential to address unmet medical needs, or may provide meaningful benefit over existing treatments.

For example, FDA granted Vyxeos Breakthrough Therapy and Fast Track designations and also granted Priority Review with respect to our NDA for Vyxeos for the treatment of t-AML and AML-MRC that was approved in August 2017.

In addition, a PRV may be used to obtain priority review by FDA for one of our future regulatory submissions.

We used the PRV we acquired in May 2018 to obtain priority review for our JZP-258 for the treatment of idiopathic hypersomnia sNDA, which is under review by FDA.

For example, FDA granted Vyxeos Breakthrough Therapy and Fast Track designations and granted Priority Review with respect to our NDA for Vyxeos for the treatment of t-AML and AML-MRC that was approved in August 2017.

In addition, a priority review voucher, or PRV, may be used to obtain priority review by FDA for one of our future regulatory submissions.

We used the PRV we acquired in May 2018 to obtain priority review for our Xywav for the treatment of IH sNDA, which was approved by FDA in August 2021.

In June 2020, FDA granted Accelerated Approval to Zepzelca for relapsed SCLC.

In December 2020, we initiated the submission of a BLA for JZP-458 for ALL under the RTOR pilot program.

During its review of an application, FDA evaluates whether the product demonstrates the required level of safety and efficacy for the indication for which approval is sought and also conducts the inspections and audits described above.

In December 2020, we initiated the submission of a BLA for Rylaze for ALL under the RTOR pilot program, which was approved by FDA in June 2021.

During its review of an application, FDA evaluates whether the product demonstrates the required level of safety and efficacy for the indication for which approval is sought and conducts the inspections and audits described above.

FDA may also refer an application to an advisory committee, typically a panel of clinicians, for review, evaluation and a non-binding recommendation as to whether the application should be approved.

When FDA completes its evaluation, it issues either an approval letter or a complete response letter.

A complete response letter generally outlines what FDA considers to be the deficiencies in the application and may indicate that substantial additional testing or information is required in order for FDA to approve the product.

If and when identified deficiencies have been addressed to FDA’s satisfaction after a review of the resubmission of the application, or if the decision is reversed through an administrative appeal, FDA will issue an approval letter.

If and when identified deficiencies have been addressed to FDA’s satisfaction after a review of the resubmission of the application FDA will issue an approval letter.

Even if a product is approved, the approval may be subject to limitations based on FDA’s interpretation of the data submitted in the application.

For example, as a condition of approval, FDA may require the sponsor to agree to certain post-marketing requirements, such as conducting Phase 4, or post-approval, clinical trials to gain additional safety data or to document a clinical benefit in the case of products approved under Accelerated Approval regulations.

FDA’s approval of the BLA for Erwinaze includes a number of post-marketing commitments and requirements.

Several post-marketing commitments and requirements were also mandated by FDA in connection with its approval of Defitelio, including the requirement that we conduct a clinical trial to analyze the safety of defibrotide versus best supportive care in the prevention of VOD in adult and pediatric patients, and its approval of Vyxeos, including the requirement that we conduct a safety study to characterize infusion-related reactions in patients treated with Vyxeos and a clinical trial to determine dosing to minimize toxicity in patients with moderate and severe renal impairment.

For example, FDA granted Accelerated Approval to Zepzelca for relapsed SCLC based on data from a Phase 2 trial, which approval is contingent upon verification and description of clinical benefit in a post-marketing clinical trial.

FDA’s approval of the NDA for Defitelio included a number of post-marketing commitments and requirements, including the requirement that we conduct a clinical trial to analyze the safety of defibrotide versus best supportive care in the prevention of VOD in adult and pediatric patients.

For its approval of Vyxeos, FDA required that we conduct a safety study to characterize infusion-related reactions in patients treated with Vyxeos and a clinical trial to determine dosing to minimize toxicity in patients with moderate and severe renal impairment.

Further, FDA granted Accelerated Approval to Zepzelca for relapsed SCLC based on data from a Phase 2 trial, which approval is contingent upon verification and description of clinical benefit in a post-marketing clinical trial.

In addition, if FDA determines that a REMS is necessary to ensure that the benefits of the product outweigh the risks, a sponsor may be required to include a proposed REMS (either as part of the application or after approval), which may include a patient package insert or a medication guide to provide information to consumers about the product’s risks and benefits;

1 unchanged sentence

or conditions on the product’s prescribing or distribution referred to as elements to assure safe use.

Xyrem and Xywav are required to have a REMS.

For more discussion regarding the Xyrem and Xywav REMS, see the risk factors under the headings “ The distribution and sale of our oxybate products are subject to significant regulatory restrictions, including the requirements of a REMS, and these regulatory requirements subject us to risks and uncertainties, any of which could negatively impact sales of Xyrem and Xywav ” and “Risks Related to Our Intellectual Property” in Part I, Item 1A of this Annual Report on Form 10‑K.

Xywav and Xyrem are required to have a REMS.

For more discussion regarding the Xywav and Xyrem REMS, see the risk factors under the headings “ The distribution and sale of our oxybate products are subject to significant regulatory restrictions, including the requirements of a REMS, and these regulatory requirements subject us to risks and uncertainties, any of which could negatively impact sales of Xywav and Xyrem ” and “Risks Related to Our Intellectual Property” in Part I, Item 1A of this Annual Report on Form 10‑K.

The EU and many individual countries have regulatory structures similar to the U.S.

for conducting preclinical and clinical testing and applying for marketing approval or authorization, although specifics may vary widely from country to country.

Clinical trials in the EU must be conducted in accordance with the requirements of the EU Clinical Trials Directive, which may be replaced with the new EU Clinical Trials Regulation in 2022, and applicable good clinical practice standards.

Clinical trials in the EU must be conducted in accordance with the requirements of the EU Clinical Trials Regulation and applicable good clinical practice standards.

In the EU, there are several procedures for requesting marketing authorization which can be more efficient than applying for authorization on a country-by-country basis.

3 unchanged sentences

There is also a “decentralized” procedure allowing companies to file identical applications to several EU member states simultaneously for product candidates that have not yet been authorized in any EU member state and a “mutual recognition” procedure allowing companies that have a product already authorized in one EU member state to apply for that authorization to be recognized by the competent authorities in other EU member states.

The UK’s withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has, however, created significant uncertainty concerning the future relationship between the UK and the EU.

The impact of Brexit on the on-going validity in the UK of current EU authorizations for medicinal products,

whether granted through the centralized procedure, decentralized procedure, or mutual recognition, and on the future process for obtaining marketing authorization for pharmaceutical products manufactured or sold in the UK remains uncertain.

In December 2020, the EU and UK reached an agreement in principle on the framework for their future relationship, the EU-UK Trade and Cooperation Agreement, or TCA.

The TCA primarily focuses on ensuring free trade between the EU and the UK in relation to goods, including medicinal products.

Although the body of the TCA includes general terms which apply to medicinal products, greater detail on sector-specific issues is provided in an Annex to the TCA.

The Annex provides a framework for the recognition of Good Manufacturing Practice, or GMP, inspections and for the exchange and acceptance of official GMP documents.

The regime does not, however, extend to procedures such as batch release certification.

Among the changes that will now occur are that Great Britain (England, Scotland and Wales) will be treated as a third country.

Northern Ireland will, with regard to EU regulations, continue to follow the EU regulatory rules.

As part of the TCA, the EU and the UK will recognize GMP inspections carried out by the other party and the acceptance of official GMP documents issued by the other party.

The U.K.’s withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has created uncertainty concerning the future relationship between the U.K.

Among the changes that have had a direct impact are that Great Britain (England, Scotland and Wales) is now treated as a third country.

To mitigate the immediate impact of this in December 2020, the EU and U.K.

reached an agreement in principle on the framework for their future relationship, the EU-U.K.

Trade and Cooperation Agreement, or TCA.

With regard to EU regulations, Northern Ireland continues to follow the EU regulatory rules.

As part of the TCA, the EU and the U.K.

recognize Good Manufacturing Practice, or GMP, inspections carried out by the other party and the acceptance of official GMP documents issued by the other party.

The TCA also encourages, although it does not oblige, the parties to consult one another on proposals to introduce significant changes to technical regulations or inspection procedures.

Among the areas of absence of mutual recognition are batch testing and batch release.

The UK has unilaterally agreed to accept EU batch testing and batch release for a period of at least 2 years until January 1, 2023.

has unilaterally agreed to accept EU batch testing and batch release for a period of at least 2 years until January 1, 2023.

However, the EU continues to apply EU laws that require batch testing and batch release to take place in the EU territory.

This means that medicinal products that are tested and released in the UK must be retested and re-released when entering the EU market for commercial use.

As regards marketing authorizations, Great Britain will have a separate regulatory submission process, approval process and a separate national marketing authorization.

Northern Ireland will, however, continue to be covered by the marketing authorizations granted by the EC.

This means that medicinal products that are tested and released in the U.K.

must be retested and re-released when entering the EU market for commercial use.

As regards marketing authorizations, Great Britain has introduced a separate regulatory submission process, approval process and a separate national marketing authorization.

Northern Ireland, however, continues to be covered by the marketing authorizations granted by the EC.

The maximum timeframe for the evaluation of an application in the EU under the centralized procedure is 210 days, subject to certain exceptions and clock stops.

2 unchanged sentences

In the EU, if an applicant can demonstrate that comprehensive data on the efficacy and safety of the product under normal conditions of use cannot be provided due to certain specified objective and verifiable reasons, products may be granted marketing authorization “under exceptional circumstances.” A marketing authorization granted under exceptional circumstances is valid for five years, subject to an annual reassessment of conditions imposed by the EC.

The marketing authorization in the EU for Defitelio was granted under exceptional circumstances because it was not possible to obtain complete information about the product due to the rarity of the disease and because ethical considerations prevented conducting a study directly comparing Defitelio with best supportive care or a placebo.

The marketing authorization in the EU for Defitelio was granted under exceptional circumstances because it was not possible to obtain

complete information about the product due to the rarity of the disease and because ethical considerations prevented conducting a study directly comparing Defitelio with best supportive care or a placebo.

As a result, the marketing authorization requires us to comply with a number of post-marketing obligations, including obligations relating to the manufacture of the drug substance and finished product, the submission of data concerning patients treated with the product collected through a third-party patient registry and the establishment of a multi-center, multinational and prospective observational patient registry to investigate the long-term safety, health outcomes and patterns of utilization of Defitelio during normal use.

1 unchanged sentence

Similar to the use of REMS in the U.S.

to ensure that the benefits of a product outweigh its risks, in the EU and other countries we are required and may, in the future in relation to new products, be required to agree to post-marketing obligations in the marketing authorization for our products, to include a patient package insert or a medication guide to provide information to consumers about the product’s risks and benefits, to implement a plan for communication to healthcare providers, and to impose restrictions on the product’s distribution.

to ensure that the benefits of a product outweigh its risks, in the EU and other countries we are required and may, in the future in relation to new products, be required to agree to post-marketing obligations or conditions in the marketing authorization for our products, to include a patient package insert or a medication guide to provide information to consumers about the product’s risks and benefits, to implement a plan for communication to healthcare providers, and to impose restrictions on the product’s distribution.

For example, the marketing authorization in the EU for Vyxeos requires us to comply with certain manufacturing-related post-approval commitments.

6 unchanged sentences

FDA also periodically inspects manufacturing facilities and the sponsor’s and manufacturer’s records related to manufacturing, and assesses compliance with cGMP.

Following such inspections, FDA may issue notices on Form FDA 483 and warning

For example, FDA issued a warning letter to PBL, the Erwinaze manufacturer, in January 2017 indicating that it was not satisfied with PBL’s responses to a Form 483 issued to PBL and citing significant violations of cGMP for finished pharmaceuticals and significant deviations from cGMP for APIs.

As recently as August 2018, FDA conducted an inspection of the PBL manufacturing facility and issued an FDA Form 483 to PBL citing observations related to items referenced in the existing warning letter as well as other manufacturing practices, including data and records management.

Following such inspections, FDA may issue notices on Form FDA 483 and warning letters.

In addition to Form FDA 483 notices and warning letters, failure to comply with the statutory and regulatory requirements may result in suspension of manufacturing, product seizure, withdrawal of the product from the market, administrative, civil and criminal penalties, among other enforcement remedies both in the U.S.

13 unchanged sentences

Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU.

Other applicable laws at the EU level and in the individual EU member states also apply to the advertising and promotion of medicinal products, including laws that prohibit the direct-to-consumer advertising of prescription-only medicinal products and further limit or restrict the advertising and promotion of our products to the general public and to health care professionals.

further limit or restrict the advertising and promotion of our products to the general public and to health care professionals.

Violations of the rules governing the promotion of medicinal products in the EU could be penalized by administrative measures, fines and imprisonment.

13 unchanged sentences

repeat attendees or attendees without a legitimate business interest;

marketing influence on speaker selection;

sales or marketing influence on speaker selection;

and excessive speaker compensation.

14 unchanged sentences

If, upon review, an authority determines that any events and/or reports indicate a trend or signal, they can require a change in a product label, restrict sales and marketing, require post-approval safety studies, require a labor intensive collection of data regarding the risks and benefits of marketed products and ongoing assessments of those risks and benefits and/or require or conduct other actions, potentially including withdrawal or suspension of the product from the market.

For example, if the EMA has concerns that the risk-benefit profile of a product has changed, it can, following an investigation procedure, adopt an opinion advising that the existing marketing authorization for the product be varied or suspended and requiring the marketing authorization holder to conduct post-authorization safety studies.

For example, if the EMA has concerns that the risk-benefit profile of a product has changed, it can, following an investigation

procedure, adopt an opinion advising that the existing marketing authorization for the product be varied or suspended and requiring the marketing authorization holder to conduct post-authorization safety studies.

The opinion is then submitted for approval by the EC.

24 unchanged sentences

may be listed as Schedule II, III, IV or V, with Schedule II substances considered to present the highest potential for abuse or dependence and Schedule V substances the lowest relative risk of abuse.

The API of Xyrem and Xywav, oxybate salts, are regulated by the DEA as Schedule I controlled substances, and Xyrem and Xywav are regulated as Schedule III controlled substances.

The API of Xywav and Xyrem, oxybate salts, are regulated by the DEA as Schedule I controlled substances, and Xywav and Xyrem are regulated as Schedule III controlled substances.

The API of Sunosi, solriamfetol, and Sunosi are regulated as Schedule IV controlled substances.

Individual countries also impose similar requirements for controlled substances.

Nabiximols and certain other product candidates we are developing contain controlled substances as defined in the CSA.

Drug products approved by FDA that contain cannabis or cannabis extracts may be controlled substances and will be rescheduled to Schedules II-V after approval, or, like Epidiolex, removed completely from the schedules by operation of other laws.

The DEA limits the quantity of certain Schedule I controlled substances that may be manufactured and procured in the U.S.

in any given calendar year through a quota system and, as a result, quotas from the DEA are required in order to manufacture and package sodium oxybate and Xyrem in the U.S.

Accordingly, we require DEA quotas for Siegfried, our U.S.‑based sodium oxybate supplier, to procure sodium oxybate and for Patheon, our U.S.-based Xyrem supplier, to obtain the sodium oxybate from Siegfried in order to manufacture and supply us with Xyrem.

Xyrem and Xywav manufactured at our plant in Ireland enters the U.S.

Accordingly, we require DEA quotas for Siegfried, our U.S.

based sodium oxybate supplier, to procure sodium oxybate and for Patheon, our U.S.-based Xyrem supplier, to obtain the sodium oxybate from Siegfried in order to manufacture and supply us with Xyrem.

Xywav and Xyrem manufactured at our plant in Ireland enters the U.S.

as a Schedule III drug and thus does not require a manufacturing quota.

As Schedule III drugs, Xyrem and Xywav are also subject to DEA import volume limits and state regulations relating to manufacturing, storage, distribution and physician prescription procedures, including limitations on prescription refills.

In addition, the third parties who perform our clinical and commercial manufacturing, distribution, dispensing and clinical studies for Xyrem and Xywav are required to maintain necessary DEA registrations and state licenses.

As Schedule III drugs, Xywav and Xyrem are also subject to DEA import volume limits and state regulations relating to manufacturing, storage, distribution and physician prescription procedures, including limitations on prescription refills.

In addition, the third parties who perform our clinical and commercial manufacturing, distribution, dispensing and clinical studies

for Xywav and Xyrem are required to maintain necessary DEA registrations and state licenses.

The DEA periodically inspects facilities for compliance with its rules and regulations.

6 unchanged sentences

are subject to the U.S.

Foreign Corrupt Practices Act, or FCPA, and similar anti-bribery or anti-corruption laws, regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct or rules of other countries in which we operate, including the UK Bribery Act of 2010, or the UK Bribery Act.

Bribery Act of 2010, or the U.K.

The FCPA and similar anti-corruption laws in other countries generally prohibit the offering, promising, giving, or authorizing others to give anything of value, either directly or indirectly, to U.S.

1 unchanged sentence

The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect the transactions of the company and to devise and maintain an adequate system of internal accounting controls.

The UK Bribery Act prohibits giving, offering, or promising bribes to any person, including UK and non-UK government officials and private persons, as well as requesting, agreeing to receive, or accepting bribes from any person.

In addition, under the UK Bribery Act, companies that carry on a business or part of a business in the UK may be held liable for bribes given, offered or promised to any person, including UK and non-UK government officials and private persons in any country, by employees and persons associated with the company in order to obtain or retain business or a business advantage for the company.

Bribery Act prohibits giving, offering, or promising bribes to any person, including U.K.

government officials and private persons, as well as requesting, agreeing to receive, or accepting bribes from any person.

In addition, under the U.K.

Bribery Act, companies that carry on a business or part of a business in the U.K.

may be held liable for bribes given, offered or promised to any person, including U.K.

government officials and private persons in any country, by employees and persons associated with the company in order to obtain or retain business or a business advantage for the company.

Liability is strict, with no element of a corrupt state of mind, but a defense of having in place adequate procedures designed to prevent bribery is available.

As described above, our business

is heavily regulated and therefore involves significant interaction with government officials in many countries.

As described above, our business is heavily regulated and therefore involves significant interaction with government officials in many countries.

Additionally, in certain countries, the health care providers who prescribe pharmaceuticals are employed by their government, and the purchasers of pharmaceuticals are government entities;

therefore, our dealings with these prescribers and purchasers may be subject to the FCPA, the UK Bribery Act and similar laws.

therefore, our dealings with these prescribers and purchasers may be subject to the FCPA, the U.K.

Bribery Act and similar laws.

Recently the Securities and Exchange Commission, or SEC, and the DOJ have increased their FCPA enforcement activities with respect to pharmaceutical companies.

7 unchanged sentences

The legislative and regulatory landscape for privacy and data security continues to evolve with an increased attention in countries globally that could potentially affect our business.

In particular, we are subject to the EU General Data Protection Regulation, which became effective on May 25, 2018 and imposes penalties up to 4% of annual global turnover and the California Consumer Privacy Act of 2018, which became effective on January 1, 2020.

In particular, we are subject to the EU General Data Protection Regulation, which imposes penalties up to 4% of annual global revenue, and the California Consumer Privacy Act of 2018.

These laws and regulations applicable to our business, increase potential enforcement and litigation activity.

19 unchanged sentences

The NDA and patent holders then have 45 days to initiate a patent infringement lawsuit.

Filing the lawsuit triggers an automatic stay on FDA’s approval of the ANDA or the Section 505(b)(2) NDA until the earliest of 30 months after the NDA

holder’s receipt of the notice of Paragraph IV Certification, expiration of the patent, certain settlements of the lawsuit, or a decision in the infringement case that is favorable to the applicant.

Filing the lawsuit triggers an automatic stay on FDA’s approval of the ANDA or the Section 505(b)(2) NDA until the earliest of 30 months after the NDA holder’s receipt of the notice of Paragraph IV Certification, expiration of the patent, certain settlements of the lawsuit, or a decision in the infringement case that is favorable to the applicant.

FDA may issue tentative approval of an application if the application meets all conditions for approval but cannot receive effective approval because the 30-month stay or another period of regulatory exclusivity has not expired.

11 unchanged sentences

Data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar marketing authorization application can be submitted, and the innovator’s data may be referenced.

However, the generic product or biosimilar products cannot be marketed in the EU for a further two years thereafter.

However, the generic

product or biosimilar products cannot be marketed in the EU for a further two years thereafter.

The overall ten-year period may be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

5 unchanged sentences

Orphan drug designation does not shorten the duration of the regulatory review process or lower the approval standards, but can provide important benefits, including consultation with FDA.

If a product is approved for its orphan designated use, it may be entitled to orphan drug exclusivity, which blocks FDA from approving for seven years any other application for a product that is the same drug for the same indication.

If there is a previously-approved product that is the same drug for the same indication, orphan drug designation requires the sponsor to provide a plausible hypothesis of clinical superiority over the approved product, whereas orphan drug exclusivity requires the sponsor to actually demonstrate clinical superiority.

If a product is approved for its orphan designated use, it may be entitled to ODE, which blocks FDA from approving for seven years any other application for a product that is the same drug for the same indication.

If there is a previously-approved product that is the same drug for the same indication, orphan drug designation requires the sponsor to provide a plausible hypothesis of clinical superiority over the approved product, whereas ODE requires the sponsor to actually demonstrate clinical superiority.

Clinical superiority can be established by way of greater efficacy, greater safety, or making a major contribution to patient care.

Additionally, a later product can be approved if the sponsor holding orphan drug exclusivity consents, or cannot adequately supply the market.

Orphan drug exclusivity does not prevent approval of another sponsor’s application for different indications or uses of the same drug, or for different drugs for the same indication.

Defibrotide has been granted orphan drug exclusivity by FDA to treat and prevent VOD until March 2023.

Vyxeos has been granted orphan drug exclusivity by FDA for the treatment of AML until August 2024.

Biologic products approved under a BLA are subject to the BPCIA, which authorizes an abbreviated approval pathway for a biological product that is “biosimilar” to an already approved biologic, or reference product.

Additionally, a later product can be approved if the sponsor holding ODE consents, or cannot adequately supply the market.

ODE does not prevent approval of another sponsor’s application for different indications or uses of the same drug, or for different drugs for the same indication.

Defibrotide has been granted ODE by FDA to treat and prevent VOD until March 2023.

Vyxeos has been granted ODE by FDA for the treatment of AML until August 2024.

Epidiolex has received ODE to treat seizures associated with LGS and DS through 2025 and TSC through 2027.

In June 2021, FDA, recognized seven years of ODE for Xywav stating that Xywav is clinically superior to Xyrem by means of greater safety due to reduced chronic sodium burden.

Xywav has been granted ODE by FDA to treat narcolepsy through 2027 and to treat IH through 2028.

Rylaze has been granted ODE for the treatment of patients with ALL or LBL until 2028.

Biologic products approved under a BLA are subject to the Biologics Price Competition and Innovation Act, or BPCIA, which authorizes an abbreviated approval pathway for a biological product that is “biosimilar” to an already approved biologic, or reference product.

The BPCIA provides periods of exclusivity that protect a reference product from competition by biosimilars.

FDA may not accept a biosimilar application for review until four years after the date of first licensure of the reference product, and the biosimilar cannot be licensed until 12

years after the reference product was first licensed.

We believe that Erwinaze, which was approved under a BLA in November 2011, is subject to an exclusivity period that will prevent approval of a biosimilar in the U.S.

into November 2023.

FDA may not accept a biosimilar application for review until four years after the date of first licensure of the reference product, and the biosimilar cannot be licensed until 12 years after the reference product was first licensed.

Under certain circumstances, the exclusivity periods applicable to drugs and biologics and the patent-related protections applicable to drugs may be eligible for a six-month extension if the sponsor submits pediatric data that fairly respond to a written request from FDA for such data.

8 unchanged sentences

The period of market exclusivity granted in relation to the original orphan medicinal product may, in addition, be reduced to six years if it can be demonstrated, on the basis of available evidence, that the original orphan medicinal product is sufficiently profitable not to justify maintenance of market exclusivity.

Defibrotide has been granted orphan drug designation by the EC and the Korean Ministry of Food and Drug Safety to treat and prevent VOD, by the Commonwealth of Australia-Department of Health for the treatment of VOD and by the EC for the prevention of aGvHD.

Defibrotide has been granted orphan drug designation by the EC for the treatment of VOD and prevention of GvHD until October 2023, by the Korean Ministry of Food and Drug Safety to treat and prevent VOD, and by the Commonwealth of Australia-Department of Health for the treatment of VOD.

Vyxeos has been granted orphan drug designation by the EC until August 2028.

We also received Orphan Designation from EMA’s Committee for Orphan Medicinal Products, or COMP, for Epidyolex for DS, LGS and TSC, and the COMP reconfirmed the designation for DS, LGS and TSC upon EC’s approval.

Pharmaceutical Pricing, Reimbursement by Government and Private Payors and Patient Access

9 unchanged sentences

Beginning in the third quarter of 2019, we have been entering into agreements with certain PBMs to provide rebates for our products where coverage was provided and products were listed in certain formulary positions, among other conditions.

We expect to enter into additional agreements in 2021.

Medicaid is a joint federal and state program that is administered by the states for low‑income and disabled beneficiaries.

6 unchanged sentences

in any pricing structure, calculated to include all applicable sales and associated rebates, discounts and other price concessions.

If we become aware that our reporting for a prior quarter was incorrect, or has changed as a result of

recalculation of the pricing data, we are obligated to resubmit the corrected data for up to three years after those data originally were due.

If we become aware that our reporting for a prior quarter was incorrect, or has changed as a result of recalculation of the pricing data, we are obligated to resubmit the corrected data for up to three years after those data originally were due.

We are required to provide average sales price, or ASP, information for certain of our products to CMS on a quarterly basis.

3 unchanged sentences

The 340B program, which is administered by the Health Resources and Services Administration, or HRSA, requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B “ceiling price” for the manufacturer’s covered drugs used in an outpatient setting.

These 340B covered entities include a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as hospitals that serve a disproportionate share of low-income patients.

These 340B covered entities include certain qualifying community health clinics, a variety of entities that receive health services grants from the Public Health Service, and multiple categories of hospitals, including children’s hospitals, critical access hospitals, free standing cancer hospitals and hospitals that serve a disproportionate share of low-income patients.

The 340B ceiling price is calculated using a statutory formula, which is based on the average manufacturer price and rebate amount for the covered outpatient drug as calculated under the Medicaid Drug Rebate Program, and in general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement.

2 unchanged sentences

In addition, legislation may be introduced that, if passed, would further expand the 340B program to additional covered entities or would require participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.

A provision in The American Rescue Plan Act of 2021 eliminates, effective January 2024, the statutory cap on rebates drug manufacturers are required to pay under the Medicaid Drug Rebate Program.

Since 2010, the total Medicaid rebate amount a drug manufacturer is required to pay under the Medicaid Drug Rebate Program has been capped at 100 percent of the Average Manufacturer Price.

The elimination of the cap on rebates means that manufacturer discounts to Medicaid may rise beginning in 2024 and, in certain circumstances, rebates could exceed the amount that state Medicaid programs pay for the

This policy change will have the greatest impact on drugs whose prices have reached the 100 percent Average Manufacturer Price rebate cap.

Effective January 2023, a provision of the Infrastructure Investment and Jobs Act requires a manufacturer of single source drugs or biologicals in single-use packages or single dose containers to pay a refund on discarded amounts of drug under Medicare Part B where the discarded amount exceeds an applicable threshold.

In order to be eligible to have our products paid for with federal funds under the Medicaid and Medicare Part B programs and purchased by certain federal agencies and grantees, we also participate in the U.S.

18 unchanged sentences

The outcome of HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU member states.

On January 31, 2018, the EC adopted a proposal for an HTA regulation intended to boost cooperation among EU member states in assessing health technologies, including new medicinal products.

The proposal, which currently continues its progress through the EU adoption process, provides that EU member states will be able to use common HTA tools, methodologies, and procedures across the EU.

Individual EU member states will continue to be responsible for assessing non-clinical (e.g., economic, social and ethical) aspects of health technologies, and making decisions on pricing and reimbursement.

In December 2021, the EC adopted a HTA regulation intended to boost cooperation among EU member states in assessing health technologies, including new medicinal products.

The regulation will apply to all EU member states from January 2025 provides that EU member states will be able to use common HTA tools, methodologies, and procedures across the EU.

Individual EU member states will continue to be responsible for drawing conclusions on the overall value of a new health technology for their healthcare system, and pricing and reimbursement decisions.

In the EU, our products are marketed through various channels and within different legal frameworks.

5 unchanged sentences

In the EU, prices can be reduced further by parallel distribution and parallel trade, or arbitrage between low-priced and high-priced EU member states.

For more information, including with respect to recent legal developments regarding the Medicaid Drug Rebate program, Medicare Part B, and the 340B program, see the risk factors under the headings “ Adequate coverage and reimbursement from third party payors may not be available for our products and we may be unable to successfully contract for coverage from pharmacy benefit managers and group purchasing organizations, which could diminish our sales or affect our ability to sell our products profitably;

For more information, including with respect to recent legal developments regarding the Medicaid Drug Rebate Program, Medicare Part B, and the 340B program, see the risk factors under the headings “ Adequate coverage and reimbursement from

third party payors may not be available for our products and we may be unable to successfully contract for coverage from pharmacy benefit managers and group purchasing organizations, which could diminish our sales or affect our ability to sell our products profitably;

conversely, to secure coverage from these organizations, we may be required to pay rebates or other discounts or other restrictions to reimbursement that could diminish our sales,” “ The pricing of pharmaceutical products has come under increasing scrutiny as part of a global trend toward healthcare cost containment and resulting changes in healthcare law and policy may impact our business in ways that we cannot currently predict, which could have a material adverse effect on our business and financial condition” and “If we fail to comply with our reporting and payment obligations under the Medicaid Drug Rebate Program or other governmental pricing programs, we could be subject to additional reimbursement requirements, penalties, sanctions and fines, which could have a material adverse effect on our business, financial condition, results of operations and growth prospects” in Part I, Item 1A of this Annual Report on Form 10‑K.

8 unchanged sentences

In April 2019, we finalized our civil settlement agreement with the DOJ and OIG, and entered into a corporate integrity agreement requiring us to maintain our ongoing corporate compliance program and obligating us to implement or continue, as applicable, a set of defined corporate integrity activities to ensure compliance with OIG’s policies around charitable contributions for a period of five years from the effective date of the corporate integrity agreement.

Healthcare Reform

The Patient Protection and Affordable Care Act, as amended by the Healthcare and Education Reconciliation Act of 2010, which we refer to together as the Healthcare Reform Act, was intended to expand healthcare coverage within the U.S., primarily through the imposition of health insurance mandates on employers and individuals, the provision of subsidies to eligible individuals enrolled in plans offered on the health insurance exchanges, and the expansion of the Medicaid program.

This law has substantially changed the way healthcare is financed by both governmental and private insurers and significantly impacts the pharmaceutical industry.

Changes that may affect our business include those governing enrollment in federal healthcare programs, reimbursement changes, benefits for patients within a coverage gap in the Medicare Part D prescription drug program (commonly known as the “donut hole”), rules regarding prescription drug benefits under the health insurance exchanges, changes to the Medicaid Drug Rebate program, expansion of the 340B program, and fraud and abuse and enforcement.

These changes have impacted previously existing government healthcare programs and have resulted in the development of new programs, including Medicare payment for performance initiatives.

Certain provisions of the Healthcare Reform Act have been subject to judicial challenges, as well as efforts to repeal or replace them or to alter their interpretation or implementation.

For example, the U.S.

Tax Cuts and Jobs Act of 2017, signed

into law in December 2017, includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment, commonly referred to as the “individual mandate,” imposed by the Healthcare Reform Act on certain individuals who fail to maintain qualifying health coverage for all or part of a year.

Additional legislative changes, regulatory changes, and judicial challenges related to the Healthcare Reform Act remain possible.

The nature and extent of any additional legislative changes, regulatory changes, or judicial challenges to the Healthcare Reform Act are uncertain at this time.

About Jazz Pharmaceuticals plc

10 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business