Ultragenyx Pharmaceutical Inc. 10-K

Item 9A. Controls and Procedures Evaluation of Disclosure Controls and Procedures Management carried out an evaluation, under the supervision and with the participation of our Chief Executive Officer and our Chief Financial Officer, of the effectiveness of our “disclosure controls and procedures” as of the end of the period covered by this Annual Report, pursuant to Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, or the Exchange Act. In connection with that evaluation, our Chief Executive Officer and our Chief Financial Officer concluded that our disclosure controls and procedures were effective and designed to provide reasonable assurance that the information required to be disclosed is recorded, processed, summarized and reported within the time periods specified in the SEC rules and forms as of December 31, 2021. For the purpose of this review, disclosure controls and procedures means controls and procedures designed to ensure that information required to be disclosed by us in the reports that we file or submit is recorded, processed, summarized and reported within the time periods specified in the SEC’s rules and forms. These disclosure controls and procedures include, without limitation, controls and procedures designed to ensure that information required to be disclosed by us in the reports that we file or submit is accumulated and communicated to management, including our principal executive officer and principal financial officer, as appropriate to allow timely decisions regarding required disclosure. In designing and evaluating the disclosure controls and procedures, our management recognized that any controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving the desired control objectives, and our management necessarily was required to apply its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Management’s Annual Report on Internal Control Over Financial Reporting Management is responsible for establishing and maintaining adequate internal control over financial reporting as defined in Rules 13a-15(f) and 15d-15(f) of the Exchange Act. Our management used the Committee of Sponsoring Organizations of the Treadway Commission Internal Control - Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework), or the COSO framework, to evaluate the effectiveness of internal control over financial reporting. Management believes that the COSO framework is a suitable framework for its evaluation of financial reporting because it is free from bias, permits reasonably consistent qualitative and quantitative measurements of our internal control over financial reporting, is sufficiently complete so that those relevant factors that would alter a conclusion about the effectiveness of our internal control over financial reporting are not omitted and is relevant to an evaluation of internal control over financial reporting. Management has assessed the effectiveness of our internal control over financial reporting as of December 31, 2021 and has concluded that such internal control over financial reporting is effective. Our independent registered public accounting firm, Ernst & Young LLP, has audited the financial statements included in this Annual Report and has issued a report on the effectiveness of our internal control over financial reporting. The report of Ernst & Young LLP is included below. Changes in Internal Control over Financial Reporting There have been no changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) during our fourth quarter ended December 31, 2021, that have materially affected, or are reasonably likely to materially affect our internal control over financial reporting. 75 Report of Independent Registered Public Accounting Firm To the Stockholders and the Board of Directors of Ultragenyx Pharmaceutical Inc.: Opinion on Internal Control over Financial Reporting We have audited Ultragenyx Pharmaceutical Inc.’s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (the COSO criteria). In our opinion, Ultragenyx Pharmaceutical Inc. (the Company) maintained, in all material respects, effective internal control over financial reporting as of December 31, 2021, based on the COSO criteria. We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the consolidated balance sheets of Ultragenyx Pharmaceutical Inc. (the Company) as of December 31, 2021 and 2020, the related consolidated statements of operations, comprehensive loss, stockholders’ equity and cash flows for each of the three years in the period ended December 31, 2021, and our report dated February 15, 2022 expressed an unqualified opinion thereon. Basis for Opinion The Company’s management is responsible for maintaining effective internal control over financial reporting and for its assessment of the effectiveness of internal control over financial reporting included in the accompanying Management’s Annual Report on Internal Control over Financial Reporting. Our responsibility is to express an opinion on the Company’s internal control over financial reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB. We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects. Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our opinion. Definition and Limitations of Internal Control Over Financial Reporting A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control over financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial statements. Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate. /s/ Ernst & Young LLP Redwood City, California February 15, 2022 I tem 9B. Other Information None. Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections Not applicable 76 P ART III Item 10. Di rectors, Executive Officers and Corporate Governance The information required by this Item is incorporated herein by reference to information in the proxy statement for our 2022 Annual Meeting of Stockholders, which we will file with the SEC within 120 days of the end of the fiscal year to which this Annual Report relates (the “2022 Proxy Statement”), including under the headings “Proposal No. 1—Election of Class III Directors,” “Information About Our Executive Officers,” “Corporate Governance—Global Code of Conduct,” “Proposal No. 1—Election of Class III Directors—Nomination of Directors,” “Board of Directors and Committees,” and, as applicable, “Delinquent Section 16(a) Reports.” We have adopted a code of ethics that applies to all of our directors, officers and employees, including our principal executive, principal financial and principal accounting officers, or persons performing similar functions, or Code of Ethics. Our Code of Ethics is posted on our corporate governance website located at www.ultragenyx.com . We intend to disclose future amendments to certain provisions of the Code of Ethics, and waivers of the Code of Ethics granted to executive officers and directors, on the website within four business days following the date of the amendment or waiver. I tem 11. Executive Compensation The information required by this Item is incorporated herein by reference to information in the 2022 Proxy Statement, including under the headings “Executive Compensation,” “Director Compensation,” “Board of Directors and Committees—Compensation Committee Interlocks and Insider Participation,” “Executive Compensation—Risk Management and Mitigation,” and “Executive Compensation—Compensation Committee Report.” Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters The information required by this Item is incorporated herein by reference to information in the 2022 Proxy Statement, including under the headings “Security Ownership of Certain Beneficial Owners and Management” and “Equity Compensation Plan Information.” Item 13. Certain Relationships and Related Transactions, and Director Independence The information required by this Item is incorporated herein by reference to information in the 2022 Proxy Statement, including under the headings “Certain Relationships and Related-Person Transactions,” “Corporate Governance,” and “Board of Directors and Committees.” Item 14. Principal Accountant Fees and Services The information required by this Item is incorporated herein by reference to information in the 2022 Proxy Statement, including under the heading “Proposal No. 2—Ratification of the Selection of Independent Registered Public Accounting Firm.” 77 PA RT IV Item 15. Ex hibits and Financial Statement Schedules (a) The following documents are filed as part of this Annual Report. (1) Consolidated Financial Statements Consolidated Financial Statements—See Index to Consolidated Financial Statements at page F-1 of this Annual Report. (2) Consolidated Financial Statement Schedules Consolidated Financial Statement schedules have been omitted in this Annual Report because they are not applicable, not required under the instructions, or the information requested is set forth in the Consolidated Financial Statements or related notes thereto. (b) Exhibits Exhibit Incorporated by Reference Filed Number Exhibit Description Form Date Number Herewith 3.1 Amended and Restated Certificate of Incorporation 8-K 2/5/2014 3.1 3.2 Amended and Restated Bylaws 8-K 2/5/2014 3.2 4.1 Form of Common Stock Certificate S-1 11/8/2013 4.2 4.2 Form of Indenture 10-Q 5/5/2021 4.2 4.3 Description of Common Stock 10-K 2/14/2020 4.3 10.1 Open Market Sales Agreement, dated May 7, 2021, by and between Ultragenyx Pharmaceutical Inc. and Jefferies LLC 10-Q 8/3/2021 10.6 10.2† Collaboration and License Agreement, effective as of August 29, 2013, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. S-1/A 12/23/2013 10.1 10.3 Amendment No. 1 to Collaboration and License Agreement, effective as of August 24, 2015, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-Q 11/10/2015 10.2 10.4 Amendment No. 2 to Collaboration and License Agreement, effective as of November 28, 2016, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-K 2/21/2018 10.3 10.5† Amendment No. 3 to Collaboration and License Agreement, effective September 29, 2017, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-K 2/21/2018 10.4 10.6† Amendment No. 4 to Collaboration and License Agreement, effective as of January 29, 2018, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-K 2/21/2018 10.5 10.7† Amendment No. 5 to Collaboration and License Agreement, effective as of April 30, 2018, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-Q 8/3/2018 10.1 10.8* Amendment No. 6 to Collaboration and License Agreement, effective as of February 1, 2019, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-Q 5/7/2019 10.2 78 10.9* Amendment No. 7 to Collaboration and License Agreement, effective as of December 5, 2018, between Ultragenyx Pharmaceutical Inc. and Kyowa Hakko Kirin Co., Ltd. 10-Q 5/7/2019 10.3 10.10* Amendment No. 8 to Collaboration and License Agreement, effective as of July 4, 2019, between Ultragenyx Pharmaceutical Inc. and Kyowa Kirin Co., Ltd. (formerly, Kyowa Hakko Kirin Co., Ltd.) 10-Q 8/2/2019 10.1 10.11* Amendment No. 9 to Collaboration and License Agreement, effective December 23, 2019, between Ultragenyx Pharmaceutical Inc. and Kyowa Kirin Co., Ltd. 10-K 2/14/2020 10.10 10.12* Amendment No. 10 to Collaboration and License Agreement, effective as of April 1, 2020, between Ultragenyx Pharmaceutical Inc. and Kyowa Kirin Co., Ltd. 10-Q 5/7/2020 10.2 10.13* Amendment No. 11 to Collaboration and License Agreement, effective as of December 17, 2021 between Ultragenyx Pharmaceutical Inc. and Kyowa Kirin Co., Ltd. X 10.14* License Agreement, dated as of September 20, 2012, between Ultragenyx Pharmaceutical Inc. and Baylor Research Institute 10-K 2/12/2021 10.12 10.15* Amendment to the License Agreement, dated as of March 22, 2013, between Ultragenyx Pharmaceutical Inc. and Baylor Research Institute 10-K 2/12/2021 10.13 10.16† Exclusive License Agreement, dated as of November 22, 2010, between Ultragenyx Pharmaceutical Inc. and Saint Louis University S-1/A 12/23/2013 10.8 10.17† License Agreement, dated October 30, 2013, by and between Dimension Therapeutics, Inc. and REGENXBIO Inc. (f/k/a ReGenX Biosciences, LLC), as amended 10-K 2/21/2018 10.13 10.18† Option and License Agreement, dated March 10, 2015, by and between Dimension Therapeutics, Inc. and REGENXBIO Inc. 10-K 2/21/2018 10.14 10.19* First Amendment to Option and License Agreement, dated March 18, 2019, by and between REGENXBIO, Inc. and Ultragenyx Pharmaceutical Inc. (as assignee of Dimension Therapeutics, Inc.) 10-Q 5/7/2019 10.1 10.20* Second Amendment to Option and License Agreement, dated December 17, 2021, by and between REGENXBIO, Inc. and Ultragenyx Pharmaceutical Inc. X 10.21* Amended and Restated Collaboration Agreement and License Agreement, dated June 3, 2019, between Ultragenyx Pharmaceutical Inc. and Bayer Healthcare LLC 10-Q 8/2/2019 10.2 10.22† Research, Collaboration and License Agreement, dated as of May 5, 2016, by and between Dimension Therapeutics, Inc. and The Trustees of the University of Pennsylvania, as amended 10-K 2/21/2018 10.16 10.23† 3rd Amendment to Research, Collaboration and License Agreement, entered into as of October 30, 2017, by and between Dimension Therapeutics, Inc. and The Trustees of the University of Pennsylvania 10-K 2/21/2018 10.17 79 10.24† Commercial Supply and Services Agreement – Drug Substance, effective December 7, 2017, between Ultragenyx Europe GmbH and Rentschler Biopharma SE 10-K 2/21/2018 10.18 10.25† Commercial Supply and Services Agreement – Drug Product, effective January 31, 2018, between Ultragenyx Europe GmbH and Rentschler Biopharma SE 10-K 2/21/2018 10.19 10.26 Supply Agreement, dated as of November 19, 2012, between Ultragenyx Pharmaceutical Inc. and CREMER OLEO GmbH & Co KG 10-K 2/21/2018 10.11 10.27* Master Services Agreement, dated April 8, 2019, between Ultragenyx Pharmaceutical Inc. and Aenova Haupt Pharma Wolfratshausen GmbH 10-K 2/12/2021 10.24 10.28* Royalty Purchase Agreement, dated as of December 17, 2019, between Ultragenyx Pharmaceutical Inc. and RPI Finance Trust 10-K 2/14/2020 10.25 10.29# 2011 Equity Incentive Plan (including forms of Stock Option Grant Notice and Stock Option Agreement thereunder) S-1 11/8/2013 10.11 10.30# Amendment to the 2011 Equity Incentive Plan S-1 11/8/2013 10.12 10.31# 2014 Incentive Plan (as amended) 10-K 2/17/2017 10.20 10.32# Form of Incentive Stock Option Agreement S-1/A 1/17/2014 10.14 10.33# Form of Non Statutory Stock Option Agreement (Employees) S-1/A 1/17/2014 10.15 10.34# Form of Non Statutory Stock Option Agreement (Employees)(ex-U.S.) 10-Q 5/10/2016 10.3 10.35# Form of Restricted Stock Unit Agreement (Employees) 10-Q 5/10/2016 10.1 10.36# Form of Restricted Stock Unit Agreement (Employees)(ex-U.S.) 10-Q 5/10/2016 10.2 10.37# Form of Non-Statutory Stock Option Agreement (Directors) S-1/A 1/17/2014 10.16 10.38# Form of Restricted Stock Unit Agreement (Directors) S-1/A 1/17/2014 10.18 10.39# Form of Non-Statutory Stock Option Agreement (Annual Grant for Directors) 10-Q 8/3/2021 10.2 10.40# Form of Restricted Stock Unit Agreement (Annual Grant for Directors) 10-Q 8/3/2021 10.3 10.41# Form of Non-Statutory Stock Option Agreement (Grant for New Directors) 10-Q 8/3/2021 10.4 10.42# Form of Restricted Stock Unit Agreement (Grant for New Directors) 10-Q 8/3/2021 10.5 10.43# Form of Performance Stock Unit Agreement (2020) 10-Q 5/7/2020 10.3 10.44# Form of Performance Stock Unit Agreement (2021) 10-Q 5/5/2021 10.1 10.45# 2014 Employee Stock Purchase Plan (as amended) 10-K 2/17/2017 10.28 10.46# Corporate Bonus Plan S-1/A 1/17/2014 10.27 10.47# Employment Inducement Plan 10-K 2/12/2021 10.43 10.48# Form of Non Statutory Stock Option Agreement (Inducement Plan) 10-K 2/12/2021 10.44 10.49# Form of Non Statutory Stock Option Agreement (Inducement Plan) (ex-US) 10-K 2/12/2021 10.45 80 10.50# Form of Restricted Stock Unit Agreement (Inducement Plan) 10-K 2/12/2021 10.46 10.51# Form of Restricted Stock Unit Agreement (Inducement Plan)(ex-US) 10-K 2/12/2021 10.47 10.52# Ultragenyx Pharmaceutical Inc. Deferred Compensation Plan 10-Q 8/3/2021 10.1 10.53# Amendment No. 1 to the Ultragenyx Pharmaceutical Inc. Deferred Compensation Plan 10-Q 11/3/2021 10.1 10.54# Executive Employment Agreement, dated as of June 15, 2011, between Ultragenyx Pharmaceutical Inc. and Emil D. Kakkis, M.D., Ph.D. S-1 11/8/2013 10.18 10.55# Amendment No. 1 to Executive Employment Agreement, dated August 8, 2014, by and between Ultragenyx Pharmaceutical Inc. and Emil D. Kakkis, M.D., Ph.D. 10-Q 8/11/2014 10.2 10.56# Offer Letter, dated as of October 31, 2011, between Ultragenyx Pharmaceutical Inc. and Thomas Kassberg S-1 11/8/2013 10.19 10.57# Amendment No. 1 to Offer of Employment, dated as of August 8, 2014, by and between Ultragenyx Pharmaceutical Inc. and Thomas Kassberg 10-Q 8/11/2014 10.3 10.58# Offer Letter, dated as of August 28, 2020 between Ultragenyx Pharmaceutical Inc. and Mardi C. Dier. 8-K 9/2/2020 10.1 10.59# Amendment, dated as of, October 9, 2020 to the Offer Letter between Ultragenyx Pharmaceutical Inc. and Mardi C. Dier dated August 28, 2020 8-K 10/13/2020 10.1 10.60# Offer Letter, dated as of April 26, 2016, between Ultragenyx Pharmaceutical Inc. and Karah Parschauer 10-Q 8/9/2016 10.3 10.61# Offer Letter, dated as of February 20, 2015, between Ultragenyx Pharmaceutical Inc. and Dennis Huang 10-K 2/17/2017 10.36 10.62# Offer Letter, dated as of June 11, 2015, between Ultragenyx Pharmaceutical Inc. and John R. Pinion II 10-K 2/17/2017 10.37 10.63# Offer Letter, dated as of January 15, 2018, between Ultragenyx Pharmaceutical Inc. and Camille Bedrosian, M.D. 10-K 2/21/2018 10.46 10.64# Offer Letter, dated May 16, 2017, by and between Ultragenyx Pharmaceutical Inc. and Erik Harris 10-Q 8/2/2019 10.4 10.65# Addendum #1, dated August 8, 2017, to Offer Letter dated May 16, 2017 between Ultragenyx Pharmaceutical Inc. and Erik Harris 10-Q 8/2/2019 10.5 10.66# Addendum #2, dated June 19, 2019, to Offer Letter dated May 16, 2017 between Ultragenyx Pharmaceutical Inc. and Erik Harris 10-Q 8/2/2019 10.6 10.67# Form of Indemnification Agreement 10-K 3/24/2014 10.23 10.68 Standard Lease, dated as of July 5, 2011, between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. S-1 11/8/2013 10.22 10.69 Addendum One to Standard Lease, dated as of July 5, 2011, between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 10-K 2/26/2016 10.34 10.70 Addendum Two to Standard Lease, dated as of March 7, 2012, between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 10-K 2/26/2016 10.35 81 10.71 Addendum #3 to Standard Lease, effective as of February 12, 2014, by and between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 8-K 2/25/2014 10.1 10.72 Addendum #4 to Standard Lease, effective as of March 9, 2015, by and between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 8-K 3/13/2015 10.1 10.73 Addendum #5 to Standard Lease, effective as of April 7, 2015, by and between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 10-K 2/26/2016 10.38 10.74 Addendum #6 to Standard Lease, effective as of April 29, 2019, by and between Ultragenyx Pharmaceutical Inc. and Condiotti Enterprises, Inc. 10-Q 8/2/2019 10.3 10.75 Lease Agreement between Marina Boulevard Property, LLC and Ultragenyx Pharmaceutical Inc., dated as of December 8, 2015 10-K 2/26/2016 10.43 10.76 Indenture of Lease between Dimension Therapeutics, Inc. and Rivertech Associates II, LLC, dated March 11, 2014, as amended 10-K 2/21/2018 10.64 10.77 Second Lease Amendment to the Lease between Dimension Therapeutics, Inc. and Rivertech Associates II, LLC, dated April 28, 2017 10-K 2/21/2018 10.65 10.78 Third Lease Amendment to the Lease between Ultragenyx Pharmaceutical Inc. and Rivertech Associates II, LLC, effective December 31, 2018 10-K 2/20/2019 10.66 10.79 Lease Agreement, by and between Dimension Therapeutics, Inc. and ARE-MA Region No. 20, LLC, dated November 2, 2015, and Consent to Assignment to Ultragenyx Pharmaceutical Inc. 10-K 2/21/2018 10.66 10.80 First Amendment to Lease Agreement, dated March 20, 2018, between Ultragenyx Pharmaceutical Inc. and ARE-MA Region No. 20, LLC 10-Q 5/8/2018 10.6 10.81 Second Amendment to Lease Agreement, made July 1, 2018, between Ultragenyx Pharmaceutical Inc. and ARE-MA Region No. 20, LLC 10-Q 8/3/2018 10.3 10.82 Third Amendment, dated July 29, 2019, to the Lease Agreement dated October 30, 2015 by and between Ultragenyx Pharmaceutical Inc. and ARE-MA Region No., LLC. 10-Q 7/30/2020 10.2 10.83 Amended and Restated Fourth Amendment, dated August 4, 2020, to the Lease Agreement dated October 30, 2015 by and between Ultragenyx Pharmaceutical Inc. and ARE-MA Region No., LLC. 10-Q 10/27/2020 10.5 10.84 Lease Agreement, dated December 15, 2019, between Ultragenyx Pharmaceutical Inc. and ARE-San Francisco No. 17, LLC. 10-K 2/12/2021 10.81 10.85 First Amendment, dated September 20, 2020, to the Lease Agreement dated December 15, 2019 between Ultragenyx Pharmaceutical Inc. and ARE-San Francisco No. 17, LLC. 10-K 2/12/2021 10.82 10.86 Second Amendment, dated October 21, 2020, to the Lease Agreement dated December 15, 2019 between Ultragenyx Pharmaceutical Inc. and ARE-San Francisco No. 17, LLC. 10-K 2/12/2021 10.83 10.87 Office Lease, dated April 19, 2019, between Ultragenyx Pharmaceutical Inc. and Woburn MCB II, LLC 10-K 2/14/2020 10.70 82 10.88 Commercial Lease, dated July 2, 2018, between Ultragenyx Pharmaceutical Inc. and 32 Leveroni LLC 10-K 2/14/2020 10.71 21.1 Subsidiaries of Ultragenyx Pharmaceutical Inc. X 23.1 Consent of Independent Registered Public Accounting Firm X 24.1 Power of Attorney (included on the signature page of this report) 31.1 Certification of Chief Executive Officer of Ultragenyx Pharmaceutical Inc., as required by Rule 13a-14(a) or Rule 15d-14(a) of the Exchange Act as adopted pursuant to Section 302 of the Sarbanes-Oxley Act of 2002 X 31.2 Certification of Chief Financial Officer of Ultragenyx Pharmaceutical Inc., as required by Rule 13a-14(a) or Rule 15d-14(a) of the Exchange Act as adopted pursuant to Section 302 of the Sarbanes-Oxley Act of 2002 X 32.1§ Certification by the Chief Executive Officer and Chief Financial Officer, as required by Rule 13a-14(b) or Rule 15d-14(b) and Section 1350 of Chapter 36 of Title 18 of the United States Code (18 U.S.C. §1350) X 101.INS XBRL Instance Document, formatted in Inline XBRL X 101.SCH Inline XBRL Taxonomy Extension Schema Document X 101.CAL Inline XBRL Taxonomy Extension Calculation Linkbase Document X 101.DEF Inline XBRL Taxonomy Extension Definition Linkbase Document X 101.LAB Inline XBRL Taxonomy Extension Labels Linkbase Document X 101.PRE Inline XBRL Taxonomy Extension Presentation Linkbase Document X 104 The cover page from this Annual Report on Form 10-K, formatted in Inline XBRL † Confidential treatment has been granted with respect to certain portions (indicated by asterisks) of this exhibit. Omitted portions have been filed separately with the SEC. * Certain confidential portions of this exhibit were omitted by means of marking such portions with asterisks because the identified confidential portions (i) are not material and (ii) would be competitively harmful if publicly disclosed. # Indicates management contract or compensatory plan. § The certification attached as Exhibit 32.1 that accompanies this Annual Report is not deemed filed with the SEC and is not to be incorporated by reference into any filing of Ultragenyx Pharmaceutical Inc. under the Securities Act or the Exchange Act, whether made before or after the date of this Annual Report, irrespective of any general incorporation language contained in such filing. Item 16. Form 10-K Summary None. 83 SIGN ATURES Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized. U LTRAGENYX P HARMACEUTICAL I nc . By: /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D. President and Chief Executive Officer (Principal Executive Officer) Date: February 15, 2022 PO WER OF ATTORNEY KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Emil D. Kakkis, M.D., Ph.D. and Mardi C. Dier, and each of them, as his or her true and lawful attorneys-in-fact and agents, with full power of substitution for him or her, and in his or her name in any and all capacities, to sign any and all amendments to this Annual Report, and to file the same, with exhibits thereto and other documents in connection therewith, with the Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, and each of them, full power and authority to do and perform each and every act and thing requisite and necessary to be done therewith, as fully to all intents and purposes as he or she might or could do in person, hereby ratifying and confirming all that said attorneys-in-fact and agents, and any of them, his or her substitute or substitutes, may lawfully do or cause to be done by virtue hereof. Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the registrant and in the capacities and on the dates indicated. Signature Title Date /s/ Emil D. Kakkis Emil D. Kakkis, M.D., Ph.D President and Chief Executive Officer and Director (Principal Executive Officer) February 15, 2022 /s/ Mardi C. Dier Mardi C. Dier Executive Vice President and Chief Financial Officer (Principal Financial Officer) February 15, 2022 /s/ Theodore A. Huizenga Theodore A. Huizenga Senior Vice President, Corporate Controller (Principal Accounting Officer) February 15, 2022 /s/ Daniel G. Welch Daniel G. Welch Chairman of the Board February 15, 2022 /s/ William Aliski William Aliski Director February 15, 2022 /s/ Deborah Dunsire Deborah Dunsire, M.D. Director February 15, 2022 /s/ Lars Ekman Lars Ekman, M.D., Ph.D. Director February 15, 2022 /s/ Matthew K. Fust Matthew K. Fust Director February 15, 2022 /s/ Michael Narachi Michael Narachi Director February 15, 2022 /s/ Corsee D. Sanders Corsee D. Sanders, Ph.D. Director February 15, 2022 /s/ Shehnaaz Suliman Director February 15, 2022 Shehnaaz Suliman, M.D. 84 Ultragenyx Pharmaceutical Inc. INDEX TO FINANCIAL STATEMENTS Page Report of Independent Registered Public Accounting Firm (PCAOB ID: 42 ) F- 2 Consolidated Financial Statements: Consolidated Balance Sheets F- 4 Consolidated Statements of Operations F- 5 Consolidated Statements of Comprehensive Loss F- 5 Consolidated Statements of Stockholders’ Equity F- 6 Consolidated Statements of Cash Flows F- 7 Notes to Consolidated Financial Statements F- 9 F- 1 Report of Independent R egistered Public Accounting Firm To the Stockholders and the Board of Directors of Ultragenyx Pharmaceutical Inc.: Opinion on the Financial Statements We have audited the accompanying consolidated balance sheets of Ultragenyx Pharmaceutical Inc. (the Company) as of December 31, 2021 and 2020, the related consolidated statements of operations, comprehensive loss, stockholders' equity and cash flows for each of the three years in the period ended December 31, 2021, and the related notes (collectively referred to as the “consolidated financial statements”). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 2021 and 2020, and the results of its operations and its cash flows for each of the three years in the period ended December 31, 2021, in conformity with U.S. generally accepted accounting principles. We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the Company's internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control-Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) and our report dated February 15, 2022 expressed an unqualified opinion thereon. Basis for Opinion These financial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB. We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion. Critical Audit Matters The critical audit matters communicated below are matters arising from the current period audit of the financial statements that were communicated or required to be communicated to the audit committee and that: (1) relate to accounts or disclosures that are material to the financial statements and (2) involved our especially challenging, subjective or complex judgments. The communication of critical audit matters does not alter in any way our opinion on the Consolidated Financial Statements, taken as a whole, and we are not, by communicating the critical audit matters below, providing separate opinions on the critical audit matters or on the accounts or disclosures to which they relate. Net product sales Description of the Matter The Company sells approved products through a limited number of distributors. As discussed in Note 2, when recognizing revenue, the Company makes an estimate of the transaction price, including an assessment of whether to constrain any variable consideration. Product sales are recorded net of estimated government-mandated rebates and chargebacks, estimated product returns, and other deductions at the time revenue is recorded. Limited historical data is available for use in developing such estimates which are periodically reviewed and adjusted as necessary. Auditing the Company’s net product sales was complex due to the Company’s limited history of product sales and the growth of sales in international markets. The Company’s estimates of government mandated rebates, chargebacks and estimated product returns depend on the identification of key customer contract terms and conditions, as well as estimates of sales volumes to different classes of payors. The revenue recognition process can be complex and involves significant judgment to identify and assess the terms and conditions of customer agreements and related government regulations that could affect revenue recognition, as the Company’s revenue expands with new customers and new markets. F- 2 How We Addressed the Matter in Our Audit We obtained an understanding, evaluated the design and tested the operating effectiveness of controls over the Company’s process of recording product sales and related rebates, chargebacks and returns. We also tested management’s controls related to the identification and assessment of the terms and conditions of customer agreements and the completeness and accuracy of data utilized in the controls, and the calculations supporting management’s estimates. To test net product sales, our audit procedures included, among others, tracing a sample of revenue transactions recognized during the year to source documentation. We also confirmed a sample of outstanding receivable balances directly with the Company’s customers. To test management’s estimates of rebates, chargebacks and returns, we obtained management’s calculations for the respective estimates and performed one or more of the following procedures: tested management’s estimation process to assess whether the recorded reserve balances are within a reasonable range of estimate, performed retrospective reviews, assessed subsequent events, and tested a sample of credits issued throughout the year. Liability related to the sale of future royalties Description of the Matter As discussed in Note 9, the Company entered into a royalty purchase agreement in 2019, in which the Company sold its right to receive royalty payments arising from the net sales of Crysvita in the European market in exchange for $320 million. The proceeds from the transaction were recorded as a liability that is being amortized using the effective interest method over the estimated life of the arrangement. In order to determine the amortization of the liability, the Company is required to estimate the total amount of future royalty payments to be paid to the counterparty, subject to the capped amount, over the life of the arrangement. The Company estimates an imputed interest on the unamortized portion of the liability and records interest expense relating to the transaction. Auditing the Company’s liability related to the sale of future royalties was complex due to the subjective judgments required to forecast the expected royalty payments subject to the agreement. Specifically, the forecasted revenues of Crysvita in the European market involved significant estimation uncertainty. How We Addressed the Matter in Our Audit We obtained an understanding, evaluated the design and tested the operating effectiveness of controls over the Company’s process of accounting for the liability related to the sale of future royalties, including controls over the Company’s estimates of projected sales of Crysvita in the European market. To test management’s estimates of the future royalties and the imputed effective interest rate, we performed audit procedures that included, among others, evaluating the reasonableness of management’s assumptions related to the treatable patient population, estimated pricing and reimbursement, and the rate of adoption. We compared the significant assumptions with historical trends of actual sales, analyst expectations and performed sensitivity analyses of estimated future royalties to evaluate the impact of the changes in the future royalties on the implied effective interest rate. /s/ Ernst & Young LLP We have served as the Company’s auditor since 2010. Redwood City, California February 15, 2022 F- 3 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED BA LANCE SHEETS (In thousands, except share and per share amounts) December 31, 2021 2020 ASSETS Current assets: Cash and cash equivalents $ 307,584 $ 713,526 Marketable debt securities 432,612 488,007 Accounts receivable, net 28,432 23,093 Inventory 16,231 13,048 Prepaid expenses and other current assets 71,745 57,630 Total current assets 856,604 1,295,304 Property, plant, and equipment, net 141,247 73,515 Equity investments 34,925 155,375 Marketable debt securities 258,933 10,506 Right-of-use assets 34,936 40,524 Intangible assets, net 130,788 131,113 Goodwill 44,406 44,406 Other assets 20,558 8,812 Total assets $ 1,522,397 $ 1,759,555 LIABILITIES AND STOCKHOLDERS' EQUITY Current liabilities: Accounts payable $ 17,138 $ 12,923 Accrued liabilities 145,555 108,491 Contract liabilities 7,609 59,219 Lease liabilities 11,066 8,976 Total current liabilities 181,368 189,609 Contract liabilities 1,467 7,349 Lease liabilities 30,904 39,251 Deferred tax liabilities 33,306 33,306 Liability related to the sale of future royalties 351,786 335,665 Other liabilities 1,005 — Total liabilities 599,836 605,180 Commitments and contingencies (Notes 8 and 14) Stockholders’ equity: Preferred stock, par value of $ 0.001 per share— 25,000,000 shares authorized; nil outstanding as of December 31, 2021 and December 31, 2020 — — Common stock, par value of $ 0.001 per share— 250,000,000 shares authorized; 69,344,998 and 66,818,520 shares issued and outstanding as of December 31, 2021 and December 31,2020, respectively 69 67 Additional paid-in capital 2,997,497 2,773,195 Accumulated other comprehensive income (loss) ( 1,404 ) 689 Accumulated deficit ( 2,073,601 ) ( 1,619,576 ) Total stockholders’ equity 922,561 1,154,375 Total liabilities and stockholders’ equity $ 1,522,397 $ 1,759,555 See accompanying notes. F- 4 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED ST ATEMENTS OF OPERATIONS (In thousands, except share and per share amounts) Year Ended December 31, 2021 2020 2019 Revenues: Collaboration and license $ 256,438 $ 219,315 $ 83,493 Product sales 77,017 38,720 20,221 Non-cash collaboration royalty revenue 17,951 12,995 — Total revenues 351,406 271,030 103,714 Operating expenses: Cost of sales 16,008 6,129 9,008 Research and development 497,153 412,084 357,355 Selling, general and administrative 219,982 182,933 161,524 Total operating expenses 733,143 601,146 527,887 Loss from operations ( 381,737 ) ( 330,116 ) ( 424,173 ) Interest income 1,928 7,038 13,238 Change in fair value of equity investments ( 42,063 ) 170,403 13,413 Non-cash interest expense on liability related to the sale of future royalties ( 29,422 ) ( 33,291 ) ( 1,135 ) Other income (expense) ( 1,687 ) 607 ( 787 ) Loss before income taxes ( 452,981 ) ( 185,359 ) ( 399,444 ) Provision for income taxes ( 1,044 ) ( 1,207 ) ( 3,283 ) Net loss $ ( 454,025 ) $ ( 186,566 ) $ ( 402,727 ) Net loss per share, basic and diluted $ ( 6.70 ) $ ( 3.07 ) $ ( 7.12 ) Weighted-average shares used in computing net loss per share, basic and diluted 67,795,540 60,845,550 56,576,885 See accompanying notes. ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEM ENTS OF COMPREHENSIVE LOSS (In thousands) Year Ended December 31, 2021 2020 2019 Net loss $ ( 454,025 ) $ ( 186,566 ) $ ( 402,727 ) Other comprehensive income (loss): Foreign currency translation adjustments ( 550 ) 735 23 Unrealized gain (loss) on available-for-sale securities ( 1,543 ) 101 463 Other comprehensive income (loss): ( 2,093 ) 836 486 Total comprehensive loss $ ( 456,118 ) $ ( 185,730 ) $ ( 402,241 ) See accompanying notes. F- 5 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATE MENTS OF STOCKHOLDERS’ EQUITY (In thousands, except share amounts) Common Stock Additional Paid-In Accumulated Other Comprehensive Accumulated Total Stockholders' Shares Amount Capital Income (Loss) Deficit Equity Balance as of December 31, 2018 50,860,588 $ 51 $ 1,639,773 $ ( 633 ) $ ( 1,030,283 ) $ 608,908 Issuance of common stock in connection with underwritten public offering, net of issuance costs 5,833,333 6 330,409 — — 330,415 Issuance of common stock in connection with at-the-market offering, net of issuance costs 468,685 — 24,828 — — 24,828 Stock-based compensation — — 82,025 — — 82,025 Issuance of common stock under equity plan awards, net of tax 675,614 1 9,828 — — 9,829 Other comprehensive income — — — 486 — 486 Net loss — — — — ( 402,727 ) ( 402,727 ) Balance as of December 31, 2019 57,838,220 58 2,086,863 ( 147 ) ( 1,433,010 ) 653,764 Issuance of common stock in connection with underwritten public offering, net of issuance costs 5,111,110 5 435,551 — — 435,556 Issuance of common stock in connection with license agreement, net of issuance costs 1,243,913 1 55,267 — — 55,268 Issuance of common stock in connection with at-the-market offering, net of issuance costs 283,333 — 20,391 — — 20,391 Stock-based compensation — — 85,833 — — 85,833 Issuance of common stock upon exercise of warrants and under equity plan awards, net of tax 2,341,944 3 89,290 — — 89,293 Other comprehensive income — — — 836 — 836 Net loss — — — — ( 186,566 ) ( 186,566 ) Balance as of December 31, 2020 66,818,520 67 2,773,195 689 ( 1,619,576 ) 1,154,375 Issuance of common stock in connection with at-the-market offering, net of issuance costs 1,050,372 1 78,942 — — 78,943 Stock-based compensation — — 105,260 — — 105,260 Issuance of common stock under equity plan awards, net of tax 1,476,106 1 40,100 — — 40,101 Other comprehensive loss — — — ( 2,093 ) — ( 2,093 ) Net loss — — — — ( 454,025 ) ( 454,025 ) Balance as of December 31, 2021 69,344,998 $ 69 $ 2,997,497 $ ( 1,404 ) $ ( 2,073,601 ) $ 922,561 See accompanying notes. F- 6 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STA TEMENTS OF CASH FLOWS (In thousands) Year Ended December 31, 2021 2020 2019 Operating activities: Net loss $ ( 454,025 ) $ ( 186,566 ) $ ( 402,727 ) Adjustments to reconcile net loss to net cash used in operating activities: Stock-based compensation 104,952 85,735 81,995 Amortization of premium (discount) on marketable debt securities, net 6,606 848 ( 6,214 ) Depreciation and amortization 13,239 12,261 8,539 Change in fair value of equity investments 42,063 ( 170,403 ) ( 13,413 ) Non-cash collaboration royalty revenue ( 17,951 ) ( 12,995 ) — Non-cash interest expense on liability related to the sale of future royalties 29,422 33,291 1,135 Other 235 946 2,621 Changes in operating assets and liabilities: Accounts receivable ( 5,432 ) 9,840 ( 20,104 ) Inventory ( 3,117 ) ( 1,346 ) ( 4,451 ) Prepaid expenses and other assets ( 29,508 ) 2,748 ( 8,216 ) Accounts payable, accrued, and other liabilities 32,313 26,853 13,312 Contract liabilities, net ( 57,492 ) 66,568 — Deferred tax liabilities — — 2,140 Net cash used in operating activities ( 338,695 ) ( 132,220 ) ( 345,383 ) Investing activities: Purchase of property, plant, and equipment ( 73,093 ) ( 43,905 ) ( 24,832 ) Purchase of marketable debt securities ( 1,012,187 ) ( 813,237 ) ( 692,824 ) Purchase of equity investments — ( 37,062 ) ( 14,339 ) Proceeds from sale of marketable debt securities 92,896 50,990 42,718 Proceeds from sale of equity investments 79,843 79,842 — Proceeds from maturities of marketable debt securities 718,111 589,806 676,238 Other ( 942 ) ( 5,555 ) — Net cash used in investing activities ( 195,372 ) ( 179,121 ) ( 13,039 ) Financing activities: Proceeds from the sale of future royalties, net — — 314,234 Proceeds from the issuance of common stock in connection with underwritten public offerings, net — 435,556 330,415 Proceeds from the issuance of common stock in connection with the license agreement, net — 55,268 — Proceeds from the issuance of common stock in connection with at-the-market offering, net 78,943 20,391 24,828 Proceeds from the issuance of common stock from exercise of warrants and equity plan awards, net 40,101 89,293 9,829 Other ( 492 ) ( 236 ) — Net cash provided by financing activities 118,552 600,272 679,306 Effect of exchange rate changes on cash ( 1,194 ) 1,119 ( 165 ) Net (decrease) increase in cash, cash equivalents, and restricted cash ( 416,709 ) 290,050 320,719 Cash, cash equivalents, and restricted cash at beginning of year 726,294 436,244 115,525 Cash, cash equivalents, and restricted cash at end of year $ 309,585 $ 726,294 $ 436,244 See accompanying notes. F- 7 ULTRAGENYX PHARMACEUTICAL INC. CONSOLIDATED STATEMENTS OF CASH FLOWS (In thousands) Year Ended December 31, 2021 2020 2019 Supplemental disclosures of non-cash investing and financing information: Acquired lease liabilities arising from obtaining right-of-use assets $ 3,142 $ 18,775 $ 21,861 Stock-based compensation capitalized into ending inventory $ 1,453 $ 1,304 $ 1,206 Costs of property, plant and equipment included in accounts payable, accrued, and other liabilities $ 18,993 $ 8,515 $ 10,367 Non-cash interest expense on liability related to the sale of future royalties capitalized into ending property, plant and equipment $ 4,650 $ — $ — See accompanying notes. F- 8 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements 1. Organizat ion and Basis of Presentation Ultragenyx Pharmaceutical Inc. (the Company) is a biopharmaceutical company incorporated in Delaware. The Company is focused on the identification, acquisition, development, and commercialization of novel products for the treatment of serious rare and ultra-rare genetic diseases. The Company operates as one reportable segment. The Company has four commercially approved products. Crysvita® (burosumab) is approved in the United States (U.S.) by the U.S. Food and Drug Administration (FDA) and in Canada for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients one year of age and older, and is approved in the European Union (EU) and the United Kingdom, for the treatment of XLH with radiographic evidence of bone disease in children one year of age and older, adolescents, and adults. In Brazil, Colombia, and Mexico, Crysvita is approved for treatment of XLH in adult and pediatric patients one year of age and older. Crysvita is also approved in the U.S. by the FDA for the treatment of fibroblast growth factor 23 (FGF23)-related hypophosphatemia in tumor-induced osteomalacia (TIO), associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adults and pediatric patients 2 years of age and older. The Company has also received FDA approval for Mepsevii® (vestronidase alfa), the first medicine approved for the treatment of children and adults with mucopolysaccharidosis VII (MPS VII), also known as Sly syndrome. In the European Union and the United Kingdom, Mepsevii is approved under exceptional circumstances for patients of all ages for the treatment of non-neurological manifestations of MPS VII. In Brazil, Mepsevii is approved for the treatment of MPS VII for patients of all ages. Dojolvi®, formerly known as UX007, is approved in the U.S., Canada, and Brazil for the treatment of pediatric and adult patients severely affected by long-chain fatty acid oxidation disorders (LC-FAOD). On January 7, 2022, the Company announced a collaboration with Regeneron Pharmaceuticals (Regeneron) to commercialize Evkeeza® (evinacumab) outside of the U.S. Evkeeza is approved in the U.S. and the European Economic Area (EEA) for the treatment of homozygous familial hypercholesterolemia (HoFH). In addition to the approved products, the Company has the following ongoing clinical development programs: • DTX401 is an adeno-associated virus 8 (AAV8) gene therapy product candidate for the treatment of patients with glycogen storage disease type Ia (GSDIa); • DTX301 is an AAV8 gene therapy product candidate in development for the treatment of patients with ornithine transcarbamylase (OTC) deficiency, the most common urea cycle disorder; • UX143 (setrusumab), which is subject to the Company's collaboration agreement with Mereo BioPharma 3 (Mereo), is a fully human monoclonal antibody that inhibits sclerostin, a protein that acts on a key bone-signaling pathway and inhibits the activity of bone-forming cells for the treatment of patients with osteogenesis imperfect (OI); • GTX-102 is an antisense oligonucleotide (ASO), which the Company is collaborating on the development with GeneTx Biotherapeutics LLC (GeneTx) for the treatment of Angelman syndrome, a debilitating and rare neurogenetic disorder caused by loss-of-function of the maternally inherited allele of the UBE3A gene; • UX701 is an AAV type 9 gene therapy designed to deliver stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion to improve copper distribution and excretion from the body and reverse pathological findings of Wilson liver disease; and • UX053 is a messenger RNA (mRNA) product candidate designed for the treatment of patients with Glycogen Storage Disease Type III (GSDIII), a disease caused by a glycogen debranching enzyme (AGL) deficiency that results in glycogen accumulation in the liver and muscle. The Company has sustained operating losses and expects such annual losses to continue over the next several years. The Company’s ultimate success depends on the outcome of its research and development and commercialization activities, for which it expects to incur additional losses in the future. Management recognizes that the Company will likely need to raise additional capital to fully implement its business plans. Through December 31, 2021, the Company has relied primarily on its sale of equity securities, its revenue from commercial products, its sale of future royalties, and strategic collaboration arrangements, to finance its operations. The Company will likely raise additional capital through the issuance of equity, borrowings, or strategic alliances with partner companies. However, if such financing is not available at adequate levels, the Company would need to reevaluate its operating plans. 2. Summary of Significant Accounting Policies Basis of Consolidation The Consolidated Financial Statements include the accounts of Ultragenyx Pharmaceutical Inc. and its wholly owned subsidiaries. All intercompany balances and transactions have been eliminated. F- 9 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Use of Estimates The accompanying Consolidated Financial Statements have been prepared in accordance with U.S. generally accepted accounting principles (GAAP). The preparation of the Consolidated Financial Statements in conformity with GAAP requires management to make estimates and assumptions that affect the reported amounts of assets and liabilities, disclosure of contingent liabilities and the reported amounts of expenses in the Consolidated Financial Statements and the accompanying notes. On an ongoing basis, management evaluates its estimates, including those related to clinical trial accruals, fair value of assets and liabilities, income taxes, stock-based compensation, and the liability related to the sale of future royalties. Management bases its estimates on historical experience and on various other market-specific and relevant assumptions that management believes to be reasonable under the circumstances. Actual results could differ from those estimates. Cash, Cash Equivalents, and Restricted Cash The Company considers all highly liquid investments with original maturities of three months or less from the date of purchase to be cash equivalents. Cash equivalents consist primarily of amounts invested in money market accounts. Restricted cash primarily consists of money market accounts used as collateral for the Company’s obligations under its facility leases and the gene therapy building construction project. The following table provides a reconciliation of cash, cash equivalents, and restricted cash reported within the Consolidated Balance Sheets that sum to the total of the amounts shown in the Consolidated Statements of Cash Flows (in thousands): December 31, 2021 2020 2019 Cash and cash equivalents $ 307,584 $ 713,526 $ 433,584 Restricted cash included in prepaid expenses and other current assets — 10,847 161 Restricted cash included in other assets 2,001 1,921 2,499 Total cash, cash equivalents, and restricted cash shown in the statements of cash flows $ 309,585 $ 726,294 $ 436,244 Marketable Debt Securities All marketable debt securities have been classified as “available-for-sale” and are carried at estimated fair value as determined based upon quoted market prices or pricing models for similar securities. Management determines the appropriate classification of its investments at the time of purchase and reevaluates such designation as of each balance sheet date. Investments with a maturity of one year or less from the balance sheet date are reported as current marketable debt securities and investments with a maturity of greater than one year from the balance sheet date are reported as non-current marketable debt securities. Unrealized gains and losses are excluded from earnings and are reported as a component of comprehensive loss. Realized gains and losses and declines in fair value judged to be other than temporary, if any, on available-for-sale securities are included in other income (expense). The cost of securities sold is based on the specific-identification method. Interest on investments is included in interest income. Equity Investments In June 2019, the Company entered into an amendment to the Research Collaboration and License Agreement and an Equity Purchase Agreement with Arcturus Therapeutics Holdings Inc. (Arcturus). Pursuant to the Equity Purchase Agreement, the Company purchased 2,400,000 shares of Arcturus common stock and received an option to purchase an additional 600,000 shares of Arcturus common stock, which was exercised in May 2020. During the years ended December 31, 2021 and 2020 , the Company sold 1,700,000 shares and 800,000 shares, respectively, of Arcturus common stock . The Company elected to apply the fair value option to account for the equity investment in Arcturus. The option to purchase additional Arcturus stock was accounted for at fair value using the Black-Scholes option pricing method prior to the exercise of options. In October 2020, the Company entered into a Research Collaboration and License Agreement, Stock Purchase Agreement and Investor Agreement, with Solid Biosciences Inc. (Solid). Pursuant to the Stock Purchase Agreement, the Company purchased 7,825,797 shares of Solid’s common stock. The investment is being accounted at fair value based on quoted market prices. The changes in fair value of the equity investments are included in the Consolidated Statements of Operations. See “Note 7. License and Research Agreements” for additional details on the transaction. F- 10 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Concentration of Credit Risk, Credit Losses, and Other Risks and Uncertainties Financial instruments that potentially subject the Company to a concentration of credit risk consist of cash, cash equivalents, and investments. The Company’s cash, cash equivalents, and investments are held by financial institutions that management believes are of high credit quality. The Company’s investment policy limits investments to fixed income securities denominated and payable in U.S. dollars such as U.S. government obligations, money market instruments and funds, corporate bonds, commercial paper, and asset-backed securities and places restrictions on maturities and concentrations by type and issuer. Such deposits may, at times, exceed federally insured limits. The Company has not experienced any losses on its deposits of cash and cash equivalents and its accounts are monitored by management to mitigate risk. The Company is exposed to credit risk in the event of default by the financial institutions holding its cash and cash equivalents, corporate issuers, and other financial instruments, to the extent recorded in the Consolidated Balance Sheets. Effective January 1, 2020, the Company adopted Accounting Standards Update (ASU) 2016-13, Financial Instruments — Credit Losses, (Topic 326): Measurement of Credit Losses on Financial Instruments, which changed the impairment model for most financial assets and certain other instruments. For trade receivables and other instruments, the Company uses a new forward-looking expected loss model that generally results in the earlier recognition of allowances for losses. For available-for-sale debt securities with unrealized losses, the losses are recognized as allowances rather than as reductions in the amortized cost of the securities. The Company is exposed to credit losses primarily through receivables from customers and collaborators and through its available-for-sale debt securities. The Company’s expected loss allowance methodology for the receivables is developed using historical collection experience, current and future economic market conditions, a review of the current aging status and financial condition of the entities. Specific allowance amounts are established to record the appropriate allowance for customers that have a higher probability of default. Balances are written off when determined to be uncollectible. The Company’s expected loss allowance methodology for the debt securities is developed by reviewing the extent of the unrealized loss, the size, term, geographical location, and industry of the issuer, the issuers’ credit ratings and any changes in those ratings, as well as reviewing current and future economic market conditions and the issuers’ current status and financial condition. The Company considered the current and expected future economic and market conditions surrounding the novel coronavirus (COVID-19) pandemic and determined that the estimate of credit losses was not significantly impacted. The adoption of the guidance did not have a material impact on the Consolidated Financial Statements and related disclosures and there was no allowance for losses on available-for-sale debt securities which were attributable to credit risk for the years ended December 31, 2021 and 2020. The Company is dependent on third-party manufacturers to supply products for research and development activities in its programs. In particular, the Company relies and expects to continue to rely on a small number of manufacturers to supply it with its requirements for the active pharmaceutical ingredients and formulated drugs related to these programs. These programs could be adversely affected by a significant interruption in the supply of active pharmaceutical ingredients and formulated drugs. Inventory The Company values inventory at the lower of cost and net realizable value and determines the cost of inventory using the average-cost method. The Company expenses costs associated with the manufacture of product candidates prior to regulatory approval. Inventories consist of currently approved products. The Company periodically reviews its inventories for excess amounts or obsolescence and writes down obsolete or otherwise unmarketable inventory to its estimated net realizable value. Management determines excess inventory based on expected future demand. Estimates related to future demand are sensitive to significant inputs and assumptions such as acceptance by patients and physicians and the availability of formulary coverage and adequate reimbursement from private third-party payers for the product. Property, Plant, and Equipment Property, plant, and equipment are stated at cost, less accumulated depreciation and amortization. Depreciation and amortization is computed using the straight-line method over the estimated useful lives of the respective assets. Depreciation and amortization begins at the time the asset is placed in service. Interest costs incurred during the construction of major capital projects are capitalized until the underlying asset is ready to be placed in service, at which point the interest costs are amortized as depreciation expense over the life of the underlying asset. Maintenance and repairs are charged to operations as incurred. Upon sale or retirement of assets, the cost and related accumulated depreciation or amortization are removed from the balance sheet and the resulting gain or loss, if any, is reflected in operations. F- 11 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The useful lives of property, plant, and equipment are as follows: Research and development equipment 5 years Furniture and office equipment 5 years Computer equipment 3 years Software 3 - 5 years Land Not applicable Leasehold improvements Shorter of lease term or estimated useful life Intangible Assets The Company’s intangible assets consist of acquired in-process research and development (IPR&D) and contractual payments made for certain milestones achieved with collaboration partners. IPR&D assets represent capitalized incomplete research projects that the Company acquired through business combinations. Such assets are initially measured at their acquisition date fair values and are tested for impairment, until the completion or abandonment of the associated research and development efforts. When development of the project is complete, which generally occurs when regulatory approval to market a product is obtained, the associated assets will be deemed finite-lived and will be amortized over a period that best reflects the economic benefits provided by these assets. The contractual payments made for certain milestones achieved was recorded as an intangible and are amortized over its estimated useful life. The Company tests its definite and indefinite-lived intangible assets for impairment annually during the fourth quarter and more frequently if events or changes in circumstances indicate that it is more likely than not that the asset is impaired. If it is determined that the asset becomes impaired, the carrying value is written down to its fair value with the related impairment charge recognized in Consolidated Statements of Operations in the period in which the impairment occurs. The Company has not recorded any impairments of intangible assets. Goodwill Goodwill represents the excess of purchase price over fair value of net assets acquired in a business combination and is not amortized. Goodwill is subject to impairment testing at least annually during the fourth quarter or when a triggering event occurs that could indicate a potential impairment. If it is determined that the goodwill becomes impaired, the carrying value is written down to its fair value with the related impairment charge recognized in Consolidated Statements of Operations in the period in which the impairment occurs. The Company has not recorded any impairments of goodwill. Impairment of Long-Lived Assets The Company evaluates its long-lived assets, including property and equipment, for impairment whenever events or changes in circumstances indicate that the carrying value of these assets may not be recoverable. Recoverability of these assets is measured by comparison of the carrying amount of each asset to the future undiscounted cash flows expected to result from the use of the asset and its eventual disposition. If the asset is considered to be impaired, the amount of any impairment is measured as the difference between the carrying value and the fair value of the impaired asset. The Company has not recorded impairment of any long-lived assets. Accruals of Research and Development Costs The Company records accruals for estimated costs of research, preclinical and clinical studies and manufacturing development. These costs are a significant component of the Company’s research and development expenses. A substantial portion of the Company’s ongoing research and development activities are conducted by third-party service providers, including contract research organizations. The Company accrues the costs incurred under its agreements with these third parties based on actual work completed in accordance with agreements established with these third parties. The Company determines the actual costs through obtaining information from external service providers as to the progress or stage of completion of the services and the agreed-upon fee to be paid for such services. Revenue Recognition Collaboration and license revenue The Company has certain license and collaboration agreements that are within the scope of Accounting Standards Codification (ASC) 808, Collaborative Agreements , which provides guidance on the presentation and disclosure of collaborative arrangements. Generally, the classification of the transactions under the collaborative arrangements is determined based on the nature of contractual terms of the arrangement, along with the nature of the operations of the participants. The Company records its share of collaboration revenue, net of transfer pricing related to net sales in the period in which such sales occur, if the Company is considered as an agent in the arrangement. The Company is considered an agent when the collaboration partner controls the product before transfer to the F- 12 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) customers and has the ability to direct the use of and obtain substantially all of the remaining benefits from the product. Funding received related to research and development services and commercialization costs is generally classified as a reduction of research and development expenses and selling, general and administrative expenses, respectively, in the Consolidated Statements of Operations, because the provision of such services for collaborative partners are not considered to be part of the Company’s ongoing major or central operations. The Company also records royalty revenues under certain of the Company’s license or collaboration agreements in exchange for license of intellectual property. If the Company does not have any future performance obligations for these license or collaboration agreements, royalty revenue is recorded as the underlying sales occur. In order to record collaboration revenue, the Company utilizes certain information from its collaboration partners , including revenue from the sale of the product, associated reserves on revenue, and costs incurred for development and sales activities. For the periods covered in the financial statements presented, there have been no material changes to prior period estimates of revenues and expenses. The Company sold the right to receive certain royalty payments from net sales of Crysvita to RPI Finance Trust (RPI), an affiliate of Royalty Pharma, as further described in “Note 9. Liability Related to the Sale of Future Royalties”. The Company records the royalty revenue from the net sales of Crysvita in the applicable European territories on a prospective basis as non-cash royalty revenue in the Consolidated Statements of Operations over the term of the arrangement. The terms of the Company’s collaboration and license agreements may contain multiple performance obligations, which may include licenses and research and development activities. The Company evaluates these agreements under ASC 606, Revenue from Contracts with Customers (ASC 606), to determine the distinct performance obligations. The Company analogizes to ASC 606 for the accounting for distinct performance obligations for which there is a customer relationship. Prior to recognizing revenue, the Company makes estimates of the transaction price, including variable consideration that is subject to a constraint. Amounts of variable consideration are included in the transaction price to the extent that it is probable that a significant reversal in the amount of cumulative revenue recognized will not occur and when the uncertainty associated with the variable consideration is subsequently resolved. Total consideration may include nonrefundable upfront license fees, payments for research and development activities, reimbursement of certain third-party costs, payments based upon the achievement of specified milestones, and royalty payments based on product sales derived from the collaboration. If there are multiple distinct performance obligations, the Company allocates the transaction price to each distinct performance obligation based on its relative standalone selling price. The standalone selling price is generally determined based on the prices charged to customers or using expected cost-plus margin. The Company estimates the efforts needed to complete the performance obligations and recognizes revenue by measuring the progress towards complete satisfaction of the performance obligations using input measures. Product sales The Company sells its approved products through a limited number of distributors. Under ASC 606, revenue from product sales is recognized at the point in time when the delivery is made and when title and risk of loss transfers to these distributors. The Company also recognizes revenue from sales of certain products on a “named patient” basis, which are allowed in certain countries prior to the commercial approval of the product. Prior to recognizing revenue, the Company makes estimates of the transaction price, including any variable consideration that is subject to a constraint. Amounts of variable consideration are included in the transaction price to the extent that it is probable that a significant reversal in the amount of cumulative revenue recognized will not occur and when the uncertainty associated with the variable consideration is subsequently resolved. Product sales are recorded net of estimated government-mandated rebates and chargebacks, estimated product returns, and other deductions. Provisions for returns and other adjustments are provided for in the period the related revenue is recorded, as estimated by management. These reserves are based on estimates of the amounts earned or to be claimed on the related sales and are reviewed periodically and adjusted as necessary. The Company’s estimates of government mandated rebates, chargebacks, estimated product returns, and other deductions depends on the identification of key customer contract terms and conditions, as well as estimates of sales volumes to different classes of payors. If actual results vary, the Company may need to adjust these estimates, which could have a material effect on earnings in the period of the adjustment. Leases Lease agreements are evaluated to determine whether an arrangement is or contains a lease in accordance with ASC 842, Leases . The Company determines if an arrangement includes a lease at inception. Right-of-use lease assets and lease liabilities are recognized based on the present value of the future minimum lease payments over the lease term at the commencement date. The right-of-use lease asset includes any lease payments made and excludes lease incentives. Incremental borrowing rate is used in determining the present value of future payments. The Company applies a portfolio approach to the property leases to apply an incremental borrowing rate to leases with similar lease terms. The lease terms may include options to extend or terminate the lease. The Company recognizes the options to extend the lease as part of the right-of-use lease assets and lease liabilities only if it is F- 13 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) reasonably certain that the option would be exercised. Lease expense for minimum lease payments is recognized on a straight-line basis over the non-cancelable lease term. The Company has elected to not separate lease and non-lease components. See “Note 8. Leases” for further disclosure. Comprehensive Loss Comprehensive loss is the change in stockholders’ equity from transactions and other events and circumstances other than those resulting from investments by stockholders and distributions to stockholders. The Company’s other comprehensive loss is comprised of unrealized gains and losses on investments in available-for-sale securities and foreign currency translation adjustments. Research and Development Research and development costs are expensed as incurred and consist of salaries and benefits, stock-based compensation expense, lab supplies and facility costs, as well as fees paid to other nonemployees and entities that conduct certain research and development activities on the Company’s behalf. Amounts incurred in connection with license agreements are also included in research and development expense. Nonrefundable advance payments for goods or services to be received in the future for use in research and development activities are deferred. The deferred amounts are expensed as the related goods are delivered or the services are performed. Stock-Based Compensation Stock-based awards issued to employees, including stock options, restricted stock units (RSUs), and performance stock units (PSUs) are recorded at fair value as of the grant date and recognized as expense on a straight-line basis over the employee’s requisite service period (generally the vesting period). PSUs vest only if certain specified criteria are achieved and the employees’ continued service requirements are met; therefore, the expense recognition occurs when the likelihood of the PSUs being earned is deemed probable. Stock compensation expense on awards expected to vest are recognized net of estimated forfeitures. Income Taxes The Company uses the liability method of accounting for income taxes. Under this method, deferred tax assets and liabilities are determined based on the differences between the financial reporting and the tax bases of assets and liabilities and are measured using the enacted tax rates and laws that will be in effect when the differences are expected to reverse. The Company must then assess the likelihood that the resulting deferred tax assets will be realized. A valuation allowance is provided when it is more likely than not that some portion or all of a deferred tax asset will not be realized. Due to the Company’s lack of earnings history, the net deferred tax assets have been fully offset by a valuation allowance. In conjunction with Dimension acquisition, a deferred tax liability was recorded reflecting the tax impact of the difference between the book basis and tax basis of acquired IPR&D. Such deferred income tax liability is not used to offset deferred tax assets when analyzing the Company’s valuation allowance as the acquired IPR&D is considered to have an indefinite life until the Company completes or abandons development of the acquired IPR&D. The Company recognizes benefits of uncertain tax positions if it is more likely than not that such positions will be sustained upon examination based solely on their technical merits, as the largest amount of benefit that is more likely than not to be realized upon the ultimate settlement. The Company’s policy is to recognize interest and penalties related to the underpayment of income taxes as a component of income tax expense or benefit. To date, there have been no interest or penalties charged in relation to the unrecognized tax benefits. Foreign Currency Assets and liabilities of non-U.S. subsidiaries that operate in a local currency environment, where the local currency is the functional currency, are translated to U.S. dollars at exchange rates in effect at the balance sheet date, with the resulting translation adjustments directly recorded to a separate component of accumulated other comprehensive loss. Income and expense accounts are translated at average exchange rates for the period. Transactions which are not in the functional currency of the entity are remeasured into the functional currency and gains or losses resulting from the remeasurement recorded in other income (expense). Net Loss per Share Basic net loss per share is calculated by dividing the net loss by the weighted-average number of shares of common stock outstanding during the period, without consideration for common stock equivalents. Diluted net loss per share is the same as basic net loss per share, since the effects of potentially dilutive securities are antidilutive. In periods when we have incurred a net loss, options and warrants to purchase common stock are considered common stock equivalents, but have been excluded from the calculation of diluted net loss per share, as their effect is antidilutive. F- 14 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 3. Fair Value Measurements Financial assets and liabilities are recorded at fair value. The carrying amount of certain financial instruments, including cash and cash equivalents, accounts receivable, accounts payable and accrued liabilities approximate fair value due to their relatively short maturities. Assets and liabilities recorded at fair value on a recurring basis in the balance sheets are categorized based upon the level of judgment associated with the inputs used to measure their fair values. Fair value is defined as the exchange price that would be received for an asset or an exit price that would be paid to transfer a liability in the principal or most advantageous market for the asset or liability in an orderly transaction between market participants on the measurement date. The authoritative guidance on fair value measurements establishes a three-tier fair value hierarchy for disclosure of fair value measurements as follows: Level 1 —Inputs are unadjusted, quoted prices in active markets for identical assets or liabilities at the measurement date; Level 2 —Inputs are observable, unadjusted quoted prices in active markets for similar assets or liabilities, unadjusted quoted prices for identical or similar assets or liabilities in markets that are not active, or other inputs that are observable or can be corroborated by observable market data for substantially the full term of the related assets or liabilities; and Level 3 —Unobservable inputs that are significant to the measurement of the fair value of the assets or liabilities that are supported by little or no market data. The Company’s financial instruments consist of Level 1, Level 2, and Level 3 assets. Where quoted prices are available in an active market, securities are classified as Level 1. Money market funds and U.S. Government treasury bills are classified as Level 1. Level 2 assets consist primarily of corporate bonds, asset backed securities, commercial paper, U.S. Government Treasury and agency securities, and debt securities in government-sponsored entities based upon quoted market prices for similar movements in active markets, quoted prices for identical or similar instruments in markets that are not active and model-based valuation techniques for which all significant inputs are observable in the market or can be corroborated by observable market data for substantially the full term of the assets. Where applicable these models project future cash flows and discount the future amounts to a present value using market-based observable inputs obtained from various third party data providers, including but not limited to, benchmark yields, interest rate curves, reported trades, broker/dealer quotes and reference data. The Company determines the fair value of its equity investments in Arcturus and Solid by using the quoted market prices, which are Level 1 fair value measurements. The following table sets forth the fair value of the Company’s financial assets and liabilities remeasured on a recurring basis based on the three-tier fair value hierarchy (in thousands): December 31, 2021 Level 1 Level 2 Level 3 Total Financial Assets: Money market funds $ 266,765 $ — $ — $ 266,765 Certificates of deposits and time deposits — 16,000 — 16,000 Corporate bonds — 349,691 — 349,691 Commercial paper — 187,624 — 187,624 Asset-backed securities — 41,245 — 41,245 U.S. Government Treasury and agency securities — 87,435 — 87,435 Debt securities in government-sponsored entities — 19,549 — 19,549 Investments in Arcturus and Solid common stock 32,200 — — 32,200 Other — 942 — 942 Total $ 298,965 $ 702,486 $ — $ 1,001,451 December 31, 2020 Level 1 Level 2 Level 3 Total Financial Assets: Money market funds $ 598,392 $ — $ — $ 598,392 Time deposits — 10,000 — 10,000 Corporate bonds — 193,802 — 193,802 Commercial paper — 173,859 — 173,859 Asset-backed securities — 11,225 — 11,225 U.S. Government Treasury and agency securities 167,967 17,661 — 185,628 Investments in Arcturus and Solid common stock 154,756 — — 154,756 Total $ 921,115 $ 406,547 $ — $ 1,327,662 In July 2020, the Company invested $ 2.5 million in a private diagnostic company in the form of a convertible promissory note that matures in two years , if not converted earlier. The Company was also issued a warrant to purchase up to $ 1.0 million of the entity’s F- 15 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) preferred stock. The fair value of the warrant to purchase shares of the entity was based on unobservable inputs that are significant to the measurement of the fair value of the asset and is supported by little or no market data; accordingly, the warrant is considered a Level 3 financial asset and is remeasured on a nonrecurring basis using a Black-Scholes option pricing model. As of December 31, 2021 and 2020 , the balance of the convertible promissory note was $ 2.4 million and $ 2.1 million, respectively, including $ 0.5 million and $ 0.2 million, respectively, in interest receivable, and was recorded in other assets, and the allocated fair value of the warrant was $ 0.6 million and $ 0.6 million, respectively, and was recorded in equity investments. In December 2020, the Company invested $ 1.4 million in a private pharmaceutical company in the form of a convertible promissory note (Note). In October 2021, pursuant to a qualified financing event, the outstanding balance of the Note was fully converted into 606,506 shares of preferred stock. The equity investment is recorded at cost less impairment, if any, adjusted for observable price changes in orderly transactions for identical or similar investments. As of December 31, 2021, the carrying value of the investment was $ 2.1 million. 4. Balance Sheet Components Cash Equivalents and Marketable Debt Securities The fair values of cash equivalents and marketable debt securities classified as available-for-sale securities consisted of the following (in thousands): December 31, 2021 Gross Unrealized Amortized Cost Gains Losses Estimated Fair Value Money market funds $ 266,765 $ — $ — $ 266,765 Certificates of deposit and time deposits 16,000 — — 16,000 Corporate bonds 350,667 3 ( 979 ) 349,691 Commercial paper 187,624 — — 187,624 Asset-backed securities 41,282 1 ( 38 ) 41,245 U.S. Government Treasury and agency securities 87,642 1 ( 208 ) 87,435 Debt securities in government-sponsored entities 19,612 — ( 63 ) 19,549 Total $ 969,592 $ 5 $ ( 1,288 ) $ 968,309 December 31, 2020 Gross Unrealized Amortized Cost Gains Losses Estimated Fair Value Money market funds $ 598,392 $ — $ — $ 598,392 Time deposits 10,000 — — 10,000 Corporate bonds 193,610 209 ( 17 ) 193,802 Commercial paper 173,859 — — 173,859 Asset-backed securities 11,224 1 — 11,225 U.S. Government Treasury and agency securities 185,561 67 — 185,628 Total $ 1,172,646 $ 277 $ ( 17 ) $ 1,172,906 At December 31, 2021 , the remaining contractual maturities of available-for-sale securities were less than three years . There have been no significant realized gains or losses on available-for-sale securities for the periods presented. All marketable securities with unrealized losses at December 31, 2021 have been in a loss position for less than twelve months or the loss is not material and were temporary in nature. We do not intend to sell the investments that are in an unrealized loss position before recovery of their amortized cost basis. Inventory Inventory consists of the following (in thousands): F- 16 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) December 31, 2021 2020 Work-in-process $ 10,504 $ 7,184 Finished goods 5,727 5,864 Total $ 16,231 $ 13,048 Property, Plant, and Equipment, net Property, plant, and equipment, net consists of the following (in thousands): December 31, 2021 2020 Leasehold improvements $ 44,081 $ 39,356 Research and development equipment 38,661 28,394 Furniture and office equipment 5,413 5,051 Computer equipment and software 10,238 8,181 Land 15,487 11,722 Construction-in-progress 76,849 17,649 Other 556 554 Property, plant, and equipment, gross 191,285 110,907 Less accumulated depreciation ( 50,038 ) ( 37,392 ) Property, plant, and equipment, net $ 141,247 $ 73,515 Depreciation expense for the years ended December 31, 2021, 2020, and 2019 was $ 12.9 million, $ 12.1 million and $ 8.3 million respectively. Amortization of leasehold improvements and software is included in depreciation expense. The construction-in-progress balance primarily relates to the construction costs for the gene therapy manufacturing plant in Bedford, Massachusetts. Accrued Liabilities Accrued liabilities consists of the following (in thousands): December 31, 2021 2020 Research, clinical study, and manufacturing expenses $ 40,880 $ 25,875 Payroll and related expenses 62,591 58,176 Other 42,084 24,440 Total $ 145,555 $ 108,491 5. Intangible Assets, net The Company has IPR&D assets of $ 129.0 million and $ 129.0 million as of December 31, 2021 and 2020, respectively. IPR&D assets represent the fair value of acquired programs to develop an AAV gene therapy for OTC deficiency and to develop an AAV gene therapy for glycogen storage disease type Ia. The fair value of IPR&D assets acquired was determined based on the discounted present value of each research project’s projected cash flows using an income approach, including the application of probability factors related to the likelihood of success of the program reaching final development and commercialization. Additionally, the projections consider the relevant market sizes and growth factors, estimated future cash flows from product sales resulting from completed products and in-process projects and timing and costs to complete the in-process projects. The rates utilized to discount the net cash flows to their present value are commensurate with the stage of development of the projects and uncertainties in the economic estimates used in the projections. IPR&D assets are considered to be indefinite-life until the completion or abandonment of the associated research and development efforts. Subsequent to the FDA approval of Dojolvi for the treatment of LC-FAOD in June 2020, the Company recorded $ 2.3 million from contractual payments for the achievement of regulatory milestones to certain collaboration partners as intangible assets, which is being amortized over its useful life of seven years . The Company recorded research and development expense of $ 0.3 million, $ 0.2 million, and $ 0.2 million for the years ended December 31, 2021, 2020, and 2019, respectively, related to the amortization of the intangible assets. The Company tests the intangible assets for impairment annually during its fourth quarter. No impairment charges have been recognized on intangible assets. F- 17 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 6. Revenue The following table disaggregates total revenues from external customers by collaboration and license revenue and product sales (in thousands): Year Ended December 31, 2021 2020 2019 Collaboration and license revenue: Crysvita collaboration revenue in profit-share territory $ 171,198 $ 128,597 $ 74,869 Crysvita royalty revenue in European territory 244 1,498 8,120 Daiichi Sankyo 84,996 89,220 — Bayer — — 504 Total collaboration and license revenue 256,438 219,315 83,493 Product sales: Crysvita 21,422 10,350 4,286 Mepsevii 16,035 15,342 12,634 Dojolvi 39,560 13,028 3,301 Total product sales 77,017 38,720 20,221 Crysvita non-cash collaboration royalty revenue 17,951 12,995 — Total revenues $ 351,406 $ 271,030 $ 103,714 The following table disaggregates total revenues based on geographic location (in thousands): Year Ended December 31, 2021 2020 2019 North America $ 301,110 $ 237,666 $ 86,442 Europe 26,660 21,318 12,085 All other 23,636 12,046 5,187 Total revenues $ 351,406 $ 271,030 $ 103,714 The following table presents the activity and ending balances for sales-related accruals and allowances (in thousands): Year Ended December 31, 2021 2020 2019 Balance of product sales reserve at beginning of year $ 3,913 $ 1,818 $ 1,240 Provisions 9,586 5,763 3,846 Payments ( 6,120 ) ( 2,785 ) ( 2,739 ) Adjustments ( 198 ) ( 883 ) ( 529 ) Balance of product sales reserve at end of year $ 7,181 $ 3,913 $ 1,818 The following table presents changes in the contract assets (liabilities) for the years ended December 31, 2021 and 2020 (in thousands): December 31, 2021 2020 Balance of contract liabilities at beginning of period $ ( 66,568 ) $ — Additions ( 27,504 ) ( 155,788 ) Deductions 84,996 89,220 Balance of contract liabilities at end of period, net $ ( 9,076 ) $ ( 66,568 ) F- 18 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) See Note 7 for additional details on contract assets (liabilities) activities. The Company’s largest accounts receivable balance was from a collaboration partner and was 71 % and 71 % of the total accounts receivable balance as of December 31, 2021 and 2020 , respectively. 7. License and Research Agreements Kyowa Kirin Co., Ltd. Collaboration and License Agreement In August 2013, the Company entered into a collaboration and license agreement with Kyowa Kirin Co., Ltd. (KKC or formerly Kyowa Hakko Kirin Co., Ltd. or KHK). Under the terms of this collaboration and license agreement, as amended, the Company and KKC collaborate on the development and commercialization of Crysvita in the field of orphan diseases in the U.S. and Canada, or the profit-share territory, and in the European Union, United Kingdom, and Switzerland, or the European territory, and the Company has the right to develop and commercialize such products in the field of orphan diseases in Mexico and Central and South America, or Latin America. Development Activities In the field of orphan diseases, and except for ongoing studies being conducted by KKC, the Company is the lead party for development activities in the profit-share territory and in the European territory until the applicable transition date. The Company shares the costs for development activities in the profit-share territory and the European territory conducted pursuant to the development plan before the applicable transition date equally with KKC. In April 2023, which is the transition date for the profit-share territory, KKC will become the lead party and be responsible for the costs of the development activities. However, the Company will continue to share the costs of the studies commenced prior to the applicable transition date equally with KKC. The collaboration and license agreements are within the scope of ASC 808, which provides guidance on the presentation and disclosure of collaborative arrangements. Collaboration revenue related to sales in profit-share territory The Company and KKC share commercial responsibilities and profits in the profit-share territory until April 2023. Under the collaboration agreement, KKC manufactures and supplies Crysvita for commercial use in the profit-share territory and charges the Company the transfer price of 35 % of net sales through December 31, 2022, and 30 % thereafter. The remaining profit or loss after supply costs from commercializing products in the profit-share territory are shared between the Company and KKC on a 50 / 50 basis until April 2023. Thereafter, the Company will be entitled to receive a tiered double-digit revenue share in the mid-to-high 20 % range. As KKC is the principal in the sale transaction with the customer, the Company recognizes a pro-rata share of collaboration revenue, net of transfer pricing, in the period the sale occurs. The Company concluded that its portion of KKC’s sales in the profit-share territory is analogous to a royalty and therefore recorded its share as collaboration revenue, similar to a royalty. Royalty revenue related to sales in European territory KKC has the commercial responsibility for Crysvita in the European territory. In December 2019, the Company sold its right to receive royalty payments based on sales in the European territory to Royalty Pharma, effective January 1, 2020, as further described in “Note 9. Liability Related to the Sale of Future Royalties.” Prior to the Company’s sale of the royalty, the Company received a royalty of up to 10 % on net sales in the European territory, which was recognized as the underlying sales occur. Beginning in 2020, the Company records the royalty revenue as non-cash royalty revenues. During the years ended December 31, 2021 and 2020 , there was a change in estimate of the revenue reserves related to sales made prior to January 1, 2020, as a result of which, the Company recorded $ 0.2 million and $ 1.5 million, respectively, as royalty revenue in the European territory. The Company’s share of collaboration and royalty revenue related to Crysvita was as follows (in thousands): Year Ended December 31, 2021 2020 2019 Company's share of revenue in profit-share territory $ 171,198 $ 128,597 $ 74,869 Royalty revenue in European territory 244 1,498 8,120 Non-cash royalty revenue in European territory 17,951 12,995 — Total $ 189,393 $ 143,090 $ 82,989 Product revenue related to sales in other territories The Company is responsible for commercializing Crysvita in Latin America and Turkey. The Company is considered the principal in these territories as the Company controls the product before it is transferred to the customer. Accordingly, the Company records revenue on a gross basis related to the sale of Crysvita once the product is delivered and the risk and title of the product is transferred. The Company recorded product sales of $ 21.4 million, $ 10.4 million, and $ 4.3 million for the years ended December 31, F- 19 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 2021, 2020, and 2019, respectively, net of estimated product returns and other deductions. KKC has the option to assume responsibility for commercialization efforts in Turkey from the Company, after a certain minimum period. Under the collaboration agreement, KKC manufactures and supplies Crysvita, which is purchased by the Company for sales in Latin America based on 35 % of the net sales through December 31, 2022 and 30 % thereafter. The Company also pays to KKC a low single-digit royalty on net sales in Latin America. Cost sharing payments Under the collaboration agreement, KKC and the Company share certain development and commercialization costs. As a result, the Company was reimbursed for these costs and operating expenses were reduced as follows (in thousands): Year Ended December 31, 2021 2020 2019 Research and development $ 21,657 $ 21,476 $ 27,309 Selling, general and administrative 32,629 25,186 21,828 Total $ 54,286 $ 46,662 $ 49,137 Collaboration receivable and payable The Company had accounts receivable from KKC in the amount of $ 20.2 million and $ 16.4 million from profit-share revenue and royalties and other receivables recorded in prepaid and other current assets of $ 16.0 million and $ 9.6 million and accrued liabilities of $ 2.3 million and $ 2.4 million from commercial and development activity reimbursements, as of December 31, 2021 and 2020, respectively. Saint Louis University License Agreement In November 2010, the Company entered into a license agreement with Saint Louis University (SLU). Under the terms of this license agreement, SLU granted the Company an exclusive worldwide license to make, have made, use, import, offer for sale, and sell therapeutics related to SLU’s beta-glucuronidase product for use in the treatment of human diseases. The Company made a milestone payment of $ 0.1 million upon approval of Mepsevii for treatment of MPS 7. The Company is required to pay to SLU a low single-digit royalty on net sales of the licensed products in any country or region, upon reaching a certain level of cumulative worldwide sales of the product. Baylor Research Institute License Agreement In September 2012, the Company entered into a license agreement with Baylor Research Institute (BRI). Under the terms of this license agreement, as amended, BRI exclusively licensed to the Company its territories for certain intellectual property related to Dojolvi (triheptanoin) for the treatment of LC-FAOD. For the year ended December 31, 2020, the Company paid $ 2.0 million for the attainment of various development milestones related to the development of LC-FAOD. The Company may be obligated to make additional future payments of up to $ 2.5 million contingent upon attainment of various development milestones relating to the development of LC-FAOD and $ 7.5 million contingent upon attainment of various sales milestones. Additionally, the Company is paying BRI a mid-single-digit royalty on net sales of the licensed product in the licensed territories. REGENXBIO, Inc. The Company has a license agreement with REGENX, for an exclusive, sublicensable, worldwide commercial license under certain intellectual property for preclinical and clinical research and development, and commercialization of drug therapies using REGENX 's licensed patents for the treatment of hemophilia A, OTC deficiency, and GSD1a. The Company will pay an annual fee and certain milestone fees per disease indication, low to mid-single-digit royalty percentages on net sales of licensed products, and milestone and sublicense fees owed by REGENX to its licensors, contingent upon the attainment of certain development activities as outlined in the agreement. The Company also has an option and license agreement with REGENX under which the Company has an exclusive, sublicensable, worldwide license to make, have made, use, import, sell, and offer for sale licensed products to treat Wilson disease and CDKL5 deficiency. For each disease indication, the Company is obligated to pay an annual maintenance fee of $ 0.1 million and up to $ 9.0 million upon achievement of various milestones, as well as mid to high single-digit royalties on net sales of licensed products and mid-single-digit to low double-digit percentage sublicenses fees, if any. In March 2020, the Company entered into a license agreement with REGENX, for an exclusive, sublicensable, worldwide license to REGENX’s NAV AAV8 and AAV9 vectors for the development and commercialization of gene therapy treatments for a F- 20 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) rare metabolic disorder. In return for these rights, the Company made an upfront payment of $ 7.0 million, which was recorded as an in-process research and development expense during the year ended December 31, 2020. The Company will pay certain annual fees of $ 0.1 million, milestone payments of up to $ 14.0 million, and royalties on any net sales of products incorporating the licensed intellectual property that range from a high single-digit to low double-digit royalty . Bayer HealthCare LLC The Company has an agreement with Bayer Healthcare LLC (Bayer) to research, develop and commercialize AAV gene therapy products for the treatment of hemophilia A (DTX 201). Under this agreement, Bayer has been granted an exclusive license to develop and commercialize one or more novel gene therapies for hemophilia A. The agreement requires that Bayer use commercially reasonable efforts to conduct and fund a proof-of-concept (POC) clinical trial and any subsequent clinical trials and commercialization of gene therapy products for treatment of hemophilia A. Bayer will have worldwide rights to commercialize the potential future product. Bayer was responsible for funding certain research and development services performed by the Company in the performance of its obligations under the annual research plan and budget. Under the terms of the agreement with Bayer, the Company is eligible to receive development and commercialization milestone payments of up to $ 232.0 million, as well as, royalty payments ranging in the high single-digit to low double-digit percentages, not exceeding the mid-teens, of net sales of licensed products. The Company achieved the first milestone in December 2017, the second milestone in April 2018, and has received $ 15.0 million for such milestones to date. The Company has no further obligations under the contract. The Company may record future milestone payments as revenue if it becomes probable that a significant reversal in the amount of revenue recognized will not occur and when the uncertainty associated with the variable consideration is subsequently resolved. University of Pennsylvania The Company has a research, collaboration, and license agreement with University of Pennsylvania School of Medicine (Penn) which provides the terms for the Company and Penn to collaborate with respect to the pre-clinical development of gene therapy products for the treatment of certain indications. Under the agreement, Penn granted the Company an exclusive, worldwide license to certain patent rights arising out of the research program, subject to certain retained rights, and a non-exclusive, worldwide license to certain Penn intellectual property, in each case to research, develop, make, have made, use, sell, offer for sale, commercialize and import licensed products in each indication for the term of the agreement. The Company will fund the cost of the research program in accordance with a mutually agreed-upon research budget and will be responsible for clinical development, manufacturing and commercialization of each indication. The Company may be obligated to make milestone payments of up to $ 5.0 million for each indication, if certain development milestones are achieved over time. The Company may also be obligated to make milestone payments of up to $ 25.0 million per approved product if certain commercial milestones are achieved, as well as low to mid-single-digit royalties on net sales of each licensed product. Arcturus Research Collaboration and License Agreement In October 2015, the Company entered into a Research Collaboration and License Agreement with Arcturus Therapeutics Holdings Inc. (Arcturus) to collaborate on the research and development of therapies for select rare diseases. Arcturus was responsible for conducting certain research services, funded by the Company, and the Company was responsible for development and commercialization costs. On a product-by-product basis, the Company is obligated to make development and regulatory milestone payments of up to $ 24.5 million, and commercial milestone payments of up to $ 45.0 million, if certain milestones are achieved. For the year ended December 31, 2021, the Company achieved a $ 1.0 million development milestone related to UX053, which was paid with a corresponding credit received from Arcturus for prior research and collaboration activities. The Company is also obligated to pay Arcturus royalties on any net sales of products incorporating the licensed intellectual property that may range from a mid single-digit to low double-digit percentage. Pursuant to the agreement, the Company incurred nil , $ 0.4 million, and $ 0.8 million for the years ended December 31, 2021, 2020, and 2019, respectively, in research and development expense for the funding of certain research services received from Arcturus. In June 2019, the Company entered into an Equity Purchase Agreement and an amendment to the Research Collaboration and License Agreement (License Agreement) to expand the field of use and increase the number of disease targets to include mRNA, DNA and siRNA therapeutics for up to 12 rare diseases. Pursuant to the agreements, the Company paid $ 6.0 million in cash upfront to Arcturus and purchased 2,400,000 shares of Arcturus’ common stock at a stated value of $ 10.00 per share, resulting in a total of $ 30.0 million of consideration paid at the close of the transaction. As a result, the Company received expanded license rights under the License Agreement, Arcturus common stock, and an option to purchase an additional 600,000 shares of Arcturus’ common stock at $ 16.00 per share. In May 2020, the Company exercised its option to purchase 600,000 shares of Arcturus common stock for a total purchase price of $ 9.6 million. F- 21 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) During the years ended December 31, 2021 and 2020 , the Company sold 1,700,000 shares and 800,000 shares of Arcturus common stock, at a weighted-average price of $ 47.44 and $ 100.81 , respectively. As of December 31, 2021 and 2020 , the Company held 500,000 shares and 2,200,000 shares, respectively, of Arcturus common stock. Due to the decrease in ownership and in accordance with the terms of the Equity Purchase Agreement, the Company no longer had the right to have its director nominee included in the annual slate of Arcturus director nominees and as a result, the Company’s director designee resigned from the Arcturus board of directors effective August 25, 2021. The Company will continue to apply the fair value option to account for the equity investment. The changes in the fair value of the Company’s equity investment in Arcturus were as follows (in thousands): Arcturus common stock Option to purchase Arcturus common stock Total December 31, 2019 $ 26,088 $ 1,664 $ 27,752 Change in fair value 113,978 23,948 137,926 Transfer of value upon option exercise 35,212 ( 25,612 ) 9,600 Sale of shares ( 79,842 ) — ( 79,842 ) December 31, 2020 95,436 — 95,436 Change in fair value 2,912 — 2,912 Sale of shares ( 79,843 ) — ( 79,843 ) December 31, 2021 $ 18,505 $ — $ 18,505 GeneTx In August 2019, the Company entered into a Program Agreement and a Unitholder Option Agreement with GeneTx to collaborate on the development of GeneTx’s GTX-102, an ASO for the treatment of Angelman syndrome. Pursuant to the terms of the Unitholder Option Agreement, the Company made an upfront payment of $ 20.0 million for an exclusive option to acquire GeneTx, which was exercisable any time prior to 30 days following FDA acceptance of the IND for GTX-102. Pursuant to the agreement, upon acceptance of the IND, which occurred in January 2020, the Company elected to extend the option period by paying an option extension payment of $ 25.0 million (option extension premium) during the year ended December 31, 2020. The Company has a right to acquire GeneTx for a payment of $ 125.0 million, at any time, until the earlier of 30 months from the first dosing of a patient in a planned Phase 1/2 study (subject to extensions) or 90 days after results are available from that study. This exclusive option to acquire GeneTx can be extended under certain circumstances, by up to four additional three-month periods, by paying an additional extension fee for each three-month period. During the exclusive option period, GeneTx is responsible for conducting the program based on the development plan agreed between the parties and, subject to the terms in the Program Agreement, has the decision-making authority on all matters in connection with the research, development, manufacturing and regulatory activities with respect to the Program. The Company will provide support, at its discretion, including strategic guidance and clinical expertise. The Company and GeneTx will collaborate on the management of the Phase 1/2 study in patients with Angelman syndrome. If the Company acquires GeneTx, the Company will then be responsible for all development and commercialization activities from the date of acquisition. The Company would also be required to make payments upon achievement of certain development and commercial milestones, as well as royalties, depending upon the success of the program. Although GeneTx is a variable interest entity, the Company is not the primary beneficiary as it currently does not have the power to direct the activities that would most significantly impact the economic performance of GeneTx. Prior to product regulatory approval, all consideration paid to GeneTx represents rights to potential future benefits associated with GeneTx’s in-process research and development activities, which have not reached technological feasibility and have no alternative future use. Accordingly, for the years ended December 31, 2020 and 2019, the Company recorded the option extension payment of $ 25.0 million and a $ 20.0 million upfront payment as an in-process research and development expense, respectively. F- 22 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Daiichi Sankyo In March 2020, the Company entered into a License and Technology Access Agreement (the License Agreement) with Daiichi Sankyo Co., Ltd. (Daiichi Sankyo). Pursuant to the License Agreement, the Company granted Daiichi Sankyo a non-exclusive license to intellectual property, including know-how and patent applications, with respect to its P roducer Cell Line (PCL) and HEK293 transient transfection manufacturing technology platforms for AAV-based gene therapy products. The Company retains the exclusive right to use the manufacturing technology for its current target indications and additional indications identified now and in the future. The Company will provide certain technical assistance and technology transfer services during the technology transfer period of three years to enable Daiichi Sankyo to use the technologies for its internal gene therapy programs. Daiichi Sankyo has an option to extend the technology transfer period including know-how improvements by two additional one-year periods by paying a fixed amount for each additional year. Daiichi Sankyo will be responsible for the manufacturing, development, and commercialization of products manufactured with the licensed technology; however, the Company has the option to co-develop and co-commercialize rare disease products at the IND stage. The Company may also provide strategic consultation to Daiichi Sankyo on the development of both AAV-based gene therapy products and other products for rare diseases. Under the terms of the License Agreement, Daiichi Sankyo made an upfront payment of $ 125.0 million and an additional $ 25.0 million payment upon achievement of the milestones related to technology transfer of the PCL and HEK293 platforms in the fourth quarter of 2021. Daiichi Sankyo is also obligated to pay a single-digit royalties on net sales of products manufactured in the technology platforms. Daiichi Sankyo will reimburse the Company for all costs associated with the transfer of the manufacturing technology. In March 2020, the Company also entered into a Stock Purchase Agreement (SPA) with Daiichi Sankyo, pursuant to which Daiichi Sankyo purchased 1,243,913 shares of the Company’s common stock in exchange for $ 75.0 million in cash. The fair market value of the common stock issued to Daiichi Sankyo was $ 55.3 million based on the stock price of $ 44.43 per share on the date of issuance, resulting in a $ 19.7 million premium on the SPA. Daiichi Sankyo is also subject to a three-year standstill and restrictions on sale of the shares (subject to customary exceptions or release). In June 2020, the Company executed a subsequent license agreement (the Sublicense Agreement) with Daiichi Sankyo for transfer of certain technology in consideration for an upfront payment of $ 8.0 million and annual maintenance fees, milestone payments, and royalties on any net sales of products incorporating the licensed intellectual property. The License Agreement, the Sublicense Agreement, and the SPA are being accounted for as one arrangement because they were entered into at or near the same time and were negotiated in contemplation of one another. The Company evaluated the License Agreement and the Sublicense Agreement under ASC 606 and determined that the performance obligations under the agreements are (i) intellectual property with respect to its PCL and HEK293 transient transfection manufacturing technology platforms together with the initial technical assistance and technology transfer services, which were substantially completed in the fourth quarter of 2021, and (ii) the transfer of any know-how and improvements after the completion of the initial technology transfer. As of December 31, 2021, the Company has determined that the total transaction price of the License Agreement was $ 183.3 million which was comprised of the $ 19.7 million premium from the Stock Purchase Agreement, the $ 125.0 million upfront payment, the $ 25.0 million in unconstrained milestone payments, $ 8.0 million from the Sublicense Agreement, and the $ 5.6 million estimated reimbursement amount for delivering the license and technology services. Total revenue recognized under the license agreement through December 31, 2021 is $ 174.2 million. The Company allocated the total transaction price to the two performance obligations on a relative stand-alone selling price basis. Revenue allocated to the intellectual property and the technology transfer services is being recognized over an initial period which is substantially complete and was based on measuring the progress toward complete satisfaction of the individual performance obligation using an input measure. Revenue for know-how and improvements after the completion of technology transfer will be recognized on a straight-line basis over the remaining technology transfer period, which ends in March 2023, as it is expected that Daiichi Sankyo will receive and consume the benefits consistently throughout the period. Royalties from commercial sales will be accounted for as revenue upon achievement of such sales, assuming all other revenue recognition criteria are met. For the years ended December 31, 2021 and 2020 , the Company recognized $ 85.0 million and $ 89.2 million, respectively, in revenue related to this arrangement. The Company had recorded contract liabilities of $ 9.1 million and $ 66.6 million and an accounts receivable related to the above agreements of $ 0.1 million and $ 1.2 million, respectively, as of December 31, 2021 and 2020. F- 23 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Solid Biosciences, Inc. In October 2020, the Company entered into a strategic Collaboration and License Agreement with Solid Biosciences Inc. (Solid), and received an exclusive license for any pharmaceutical product that expresses Solid’s proprietary microdystrophin construct from AAV8 and variants thereof in clade E for use in the treatment of Duchenne muscular dystrophy and other diseases resulting from lack of functional dystrophin, including Becker muscular dystrophy. The Company is collaborating to develop products that combine Solid’s differentiated microdystrophin construct, the Company’s PCL manufacturing platform, and the Company’s AAV8 variants. Solid is providing development support and was granted an exclusive option to co-invest in products the Company develops for profit share participation in certain territories. On a product-by-product basis, the Company may be obligated to make development milestone payments of up to $ 25.0 million, regulatory milestone payments of up to $ 65.0 million, and commercial milestone payments of up to $ 165.0 million, if such milestones are achieved, as well as royalties on any net sales of products incorporating the licensed intellectual property that range from a low to mid-double-digit percentage. The royalty rate changes to mid to high double-digit percentage if Solid decides to co-invest in the product. The Company also entered into a Stock Purchase Agreement and the Investor Agreement with Solid, pursuant to which, the Company purchased 7,825,797 shares of Solid’s common stock for an aggregate purchase price of $ 40.0 million. Subject to the terms of the Investor Agreement, the Company is restricted from selling, transferring or otherwise disposing of the shares without the prior approval of Solid until the earlier of (i) 18 months following the closing of the transaction, (ii) the termination of the Collaboration and License Agreement and (iii) certain other specified events. The Company also agreed to customary standstill restrictions in accordance with the terms of the Investor Agreement until the earlier of (a) 24 months after the closing of the transaction and (b) certain specified events. The Company’s investment in Solid is being accounted at fair value, as the fair value is readily determinable. The Company recorded the common stock investment at $ 26.8 million on the transaction date, which was based on the quoted market price on the closing date. Although Solid is a variable interest entity, the Company is not the primary beneficiary as it does not have the power to direct the activities that would most significantly impact the economic performance of Solid. Prior to the achievement of certain development milestones, all consideration paid to Solid represents rights to potential future benefits associated with Solid’s in-process research and development activities, which have not reached technological feasibility and have no alternative future use. Accordingly, the remaining $ 13.2 million of the total $ 40.0 million paid as consideration was attributed to the license rights obtained and was recorded as in-process research and development expense during the year ended December 31, 2020. The changes in the fair value of the Company’s investment in Solid’s common stock were as follows (in thousands): Solid common stock Acquisition of investment in Solid common stock in October 2020 $ 26,843 Change in fair value 32,477 December 31, 2020 59,320 Change in fair value ( 45,625 ) December 31, 2021 $ 13,695 8. Leases The Company leases office space and research, testing and manufacturing laboratory space in various facilities in Novato and Brisbane, California, in Cambridge and Woburn, Massachusetts, and in certain foreign countries, under operating agreements expiring at various dates through 2028 . Certain lease agreements include options for the Company to extend the lease for multiple renewal periods and also provide for annual minimum increases in rent, usually based on a consumer price index or annual minimum increases. None of these optional periods have been considered in the determination of the right-of-use lease asset or the lease liability for the leases as the Company did not consider it reasonably certain that it would exercise any such options. The Company recognizes lease expense on a straight-line basis over the non-cancelable term of its operating leases. The variable lease expense primarily consists of common area maintenance and other operating costs. The components of lease expense were as follows (in thousands): F- 24 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Year Ended December 31, 2021 2020 Operating lease expense $ 11,209 $ 10,164 Variable lease expense 4,142 3,298 Financing: Amortization 310 158 Interest expense 58 40 Total $ 15,719 $ 13,660 Cash paid for amounts included in the measurement of operating lease liabilities for the year ended December 31, 2021 was $ 11.8 million and was included in net cash used in operating activities in the Consolidated Statements of Cash Flows. Future minimum lease payments under non-cancellable leases as of December 31, 2021 were as follows (in thousands): Year Ending December 31, Operating Financing Total 2022 $ 12,873 $ 606 $ 13,479 2023 13,072 349 13,421 2024 11,092 75 11,167 2025 6,247 — 6,247 2026 2,681 — 2,681 Thereafter 776 — 776 Total future lease payments 46,741 1,030 47,771 Less: Amount representing interest ( 5,749 ) ( 52 ) ( 5,801 ) Present value of future lease payments 40,992 978 41,970 Less: Lease liabilities, current ( 10,498 ) ( 568 ) ( 11,066 ) Lease liabilities , non-curre nt $ 30,494 $ 410 $ 30,904 Lease liabilities are based on the net present value of the remaining lease payments over the remaining lease term. As of December 31, 2021 , the weighted-average remaining operating and financing lease terms were 3.84 years and 3.88 years, respectively, and the weighted-average discount rates used to determine the lease liability for operating and financing leases were 6.64 % and 5.44 %, respectively. 9. Liability Related to the Sale of Future Royalties In December 2019, the Company entered into a Royalty Purchase Agreement with RPI. Pursuant to the agreement, RPI paid $ 320.0 million to the Company in consideration for the right to receive royalty payments effective January 1, 2020, arising from the net sales of Crysvita in the European Union, the United Kingdom, and Switzerland under the terms of the Company’s Collaboration and License Agreement with KKC dated August 29, 2013, as amended. The agreement with RPI will automatically terminate, and the payment of royalties to RPI will cease, in the event aggregate royalty payments received by RPI are equal to or greater than $ 608.0 million prior to December 31, 2030, or in the event aggregate royalty payments received by RPI are less than $ 608.0 million prior to December 31, 2030, when aggregate royalty payments received by RPI are equal to $ 800.0 million. Proceeds from the transaction were recorded as a liability (liability related to sale of future royalties on the Consolidated Balance Sheets). The Company amortizes $ 320.0 million, net of transaction cost of $ 5.8 million, using the effective interest method over the estimated life of the arrangement. In order to determine the amortization of the liability, the Company is required to estimate the total amount of future royalty payments to be received by the Company and paid to RPI, subject to the capped amount, over the life of the arrangement. The excess of future estimated royalty payments (subject to the capped amount), over the $ 314.2 million of net proceeds, is recorded as non-cash interest expense over the life of the arrangement. Consequently, the Company estimates an imputed interest on the unamortized portion of the liability and records interest expense relating to the transaction. The Company records the royalty revenue arising from the net sales of Crysvita in the applicable European territories as non-cash royalty revenue in the Consolidated Statements of Operations over the term of the arrangement. The Company periodically assesses the expected royalty payments using a combination of historical results, internal projections and forecasts from external sources. To the extent such payments are greater or less than the Company’s initial estimates or the timing of such payments is materially different than its original estimates, the Company will prospectively adjust the amortization of the liability and the effective interest rate. The Company's effective annual interest rate was approximately 9.6 % as of December 31, 2021. There are a number of factors that could materially affect the amount and timing of royalty payments from KKC in the applicable European territories, most of which are not within the Company’s control. Such factors include, but are not limited to, the success of KKC’s sales and promotion of Crysvita, changing standards of care, delays or disruptions related to the COVID-19 pandemic, the introduction of competing products, pricing for reimbursement in various European territories, manufacturing or other delays, intellectual property matters, adverse events that result in governmental health authority imposed restrictions on the use of Crysvita, significant changes in foreign exchange rates as the royalty payments are made in U.S. dollars (USD) while significant F- 25 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) portions of the underlying European sales of Crysvita are made in currencies other than USD, and other events or circumstances that could result in reduced royalty payments from European sales of Crysvita, all of which would result in a reduction of non-cash royalty revenue and the non-cash interest expense over the life of the arrangement. Conversely, if sales of Crysvita in Europe are more than expected, the non-cash royalty revenue and the non-cash interest expense recorded by the Company would be greater over the term of the arrangement. The following table shows the activity within the liability account (in thousands): Liability related to the sale of future royalties December 31, 2019 $ 315,369 Non-cash collaboration royalty revenue ( 12,995 ) Non-cash interest expense 33,291 December 31, 2020 335,665 Non-cash collaboration royalty revenue ( 17,951 ) Non-cash interest expense 34,072 December 31, 2021 $ 351,786 10. Equity At-the-Market Offerings In July 2017, the Company entered into an at-the-market (ATM) sales agreement with Cowen and Company, LLC (Cowen) whereby the Company could sell up to $ 150.0 million in aggregate proceeds of common stock from time to time, through Cowen as its sales agent. During the years ended December 31, 2020 and 2019, the Company sold 283,333 and 468,685 shares of common stock, respectively, resulting in net proceeds of approximately $ 20.4 million and $ 24.8 million, respectively, after commissions and other offering costs. T he Company has completed the sale of all available amounts under this ATM facility. In May 2021, the Company entered into an Open Market Sale Agreement with Jefferies LLC (Jefferies) pursuant to which the Company may offer and sell shares of the Company’s common stock having an aggregate offering proceeds up to $ 350.0 million, from time to time, in ATM offerings through Jefferies. For the year ended December 31, 2021 , the Company sold 1,050,372 shares under the arrangement resulting in net proceeds of approximately $ 78.9 million. Underwritten Public Offering In February 2019, the Company completed an underwritten public offering in which 5,833,333 shares of common stock were sold, which included 760,869 shares purchased by the underwriters pursuant to an option granted to them in connection with the offering, at a public offering price of $ 60.00 per share. The total proceeds that the Company received from the offering were approximately $ 330.4 million, net of underwriting discounts and commissions. In October 2020, the Company completed an underwritten public offering in which 5,111,110 shares of common stock were sold, which included 666,666 shares purchased by the underwriters pursuant to an option granted to them in connection with the offering, at a public offering price of $ 90.00 per share. The total proceeds that the Company received from the offering were approximately $ 435.6 million, net of underwriting discounts and commissions. Common Stock Warrants As of December 31, 2019, there was an aggregate of 149,700 of common stock warrants outstanding with exercise price of $ 3.01 and expiration dates in 2020 and 2021 . In March 2020, all of the outstanding common stock warrants were exercised. F- 26 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 11. Stock-Based Awards Equity Plan Awards In 2011, the Company adopted the 2011 Equity Incentive Plan (the 2011 Plan). The 2011 Plan provides for the granting of stock-based awards to employees, directors, and consultants under terms and provisions established by the board of directors. In 2014, the Company adopted the 2014 Incentive Plan (the 2014 Plan). The 2014 Plan had 2,250,000 shares of common stock available for future issuance at the time of its inception, which included 655,038 shares available under the 2011 Plan, which were transferred to the 2014 Plan upon adoption. No further grants subsequent to the IPO were made under the 2011 Plan. The 2014 Plan provides for automatic annual increases in shares available for grant, beginning on January 1, 2015 through January 1, 2024 . In February 2021, the Company adopted the Employment Inducement Plan (the Inducement Plan), with a maximum of 500,000 shares available for grant under the Inducement Plan. Under the terms of the 2014 Plan and Inducement Plan, awards may be granted at an exercise price not less than fair market value. For employees holding more than 10 % of the voting rights of all classes of stock, the exercise prices for awards must be at least 110 % of fair market of the common stock on the grant date, as determined by the board of directors. The term of an award granted under the 2014 Plan and Inducement Plan may not exceed ten years . Typically, the vesting schedule for option grants to the employees provides that 1/4 of the grant vests upon the first anniversary of the date of grant, with the remainder of the shares vesting monthly thereafter at a rate of 1/48 of the total shares subject to the option. Typically, the vesting schedule for RSU grants provides that 1/4 of the grant vests upon the annual anniversary of the date of grant over the period of four years . As of December 31, 2021 , an aggregate of 12,462,795 shares of common stock have been authorized for issuance under the 2011 Plan, the 2014 Plan, and the Inducement Plan. Stock Option Activity The following table summarizes activity under the Company’s stock option plans and related information: Options Outstanding Number of Options Weighted- Average Exercise Price Weighted-Average Remaining Contractual Term (Years) Aggregate Intrinsic Value (In thousands) Outstanding — December 31, 2018 5,353,124 $ 62.46 7.22 $ 23,243 Options granted 1,762,075 63.03 Options exercised ( 235,678 ) 32.87 Options cancelled ( 766,457 ) 72.48 Outstanding — December 31, 2019 6,113,064 $ 62.51 7.00 $ 18,989 Options granted 1,849,106 62.51 Options exercised ( 1,505,486 ) 58.51 Options cancelled ( 452,081 ) 69.38 Outstanding — December 31, 2020 6,004,603 $ 62.99 7.21 $ 453,253 Options granted 1,217,820 128.63 Options exercised ( 687,835 ) 53.14 Options cancelled ( 336,383 ) 81.78 Outstanding — December 31, 2021 6,198,205 $ 75.96 6.81 $ 112,242 Vested and exercisable — December 31, 2021 3,669,577 $ 64.93 5.66 $ 80,283 Vested and expected to vest — December 31, 2021 5,951,372 $ 75.09 6.73 $ 109,665 The aggregate intrinsic values of options outstanding, vested and exercisable, and vested and expected to vest were calculated as the difference between the exercise price of the options and the fair value of the Company’s common stock. The total intrinsic value of options exercised during the years ended December 31, 2021, 2020, and 2019 was $ 38.3 million, $ 56.9 million, and $ 6.5 million, respectively. Cash received from the exercise of options was $ 36.6 million, $ 88.1 million, and $ 7.7 million as of December 31, 2021, 2020, and 2019, respectively. The weighted-average estimated fair value of stock options granted was $ 70.84 , $ 35.22 , and $ 37.15 per share of the Company’s common stock during the years ended December 31, 2021, 2020, and 2019, respectively. The total estimated grant date fair value of options vested during the years ended December 31, 2021, 2020, and 2019 was $ 48.1 million, $ 45.4 million, and $ 45.3 million, respectively. F- 27 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Restricted Stock Units The following table summarizes activity under the Company’s Restricted Stock Units (RSU) plans and related information: RSUs Outstanding Number of Shares Weighted- Average Grant Date Fair Value Unvested — December 31, 2018 954,077 $ 63.12 RSUs granted 863,065 62.78 RSUs vested ( 313,682 ) 66.25 RSUs cancelled ( 205,310 ) 64.28 Unvested — December 31, 2019 1,298,150 $ 61.96 RSUs granted 967,310 64.36 RSUs vested ( 434,153 ) 62.65 RSUs cancelled ( 150,140 ) 61.42 Unvested — December 31, 2020 1,681,167 $ 63.21 RSUs granted 738,905 122.71 RSUs vested ( 559,595 ) 63.41 RSUs cancelled ( 187,852 ) 80.55 Unvested — December 31, 2021 1,672,625 $ 87.48 The fair value of the RSUs is determined on the grant date based on the fair value of the Company’s common stock. The fair value of the RSUs is recognized as expense ratably over the vesting period of one to four years . The total grant date fair value of the RSUs vested during the years ended December 31, 2021, 2020, and 2019 was $ 35.5 million, $ 27.2 million, and $ 20.8 million, respectively. The aggregate intrinsic value of the shares of the RSUs vested during the years ended December 31, 2021, 2020, and 2019 was $ 69.9 million, $ 29.5 million, and $ 18.4 million, respectively. Performance Stock Units The following table summarizes activity under the Company’s Performance Stock Units (PSUs) from the 2014 Plan and related information: PSUs Outstanding Number of Shares Weighted- Average Grant Date Fair Value Unvested — December 31, 2018 483,200 $ 49.65 PSUs granted 61,500 67.31 PSUs vested ( 65,643 ) 48.03 PSUs cancelled ( 79,517 ) 50.01 Unvested — December 31, 2019 399,540 $ 52.56 PSUs granted 47,600 56.08 PSUs vested ( 200,867 ) 51.21 PSUs cancelled ( 33,707 ) 52.48 Unvested — December 31, 2020 212,566 $ 54.64 PSUs granted 62,000 158.11 PSUs vested ( 168,274 ) 54.40 PSUs cancelled ( 12,400 ) 54.28 Unvested — December 31, 2021 93,892 $ 123.46 The fair value of the PSUs is determined on the grant date based on the fair value of the Company’s common stock, except for certain PSUs with a market vesting condition, for which fair value is estimated using a Monte Carlo simulation model. PSUs are subject to vest only if certain specified criteria are achieved and the employees’ continued service with the Company after achievement of the specified criteria. For certain PSUs, the number of PSUs that may vest are also subject to the achievement of certain specified criteria, including both performance conditions and market conditions. As of December 31, 2021, the specified criteria were deemed probable of achievement or already achieved. Stock-based compensation for PSUs is recognized over the service period beginning in the period the Company determines it is probable that the performance criteria will be achieved. The total grant date fair value of the PSUs vested during the years ended December 31, 2021, 2020, and 2019 was $ 9.2 million, $ 10.3 million, and $ 3.2 million, respectively, with an aggregate intrinsic value of the shares of $ 18.9 million, $ 14.4 million and $ 4.2 million, respectively. F- 28 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Employee Stock Purchase Plan In January 2014, the Company adopted the 2014 Employee Stock Purchase Plan (ESPP) and reserved a total of 600,000 shares of common stock for issuance under the ESPP. The ESPP provides for automatic annual increases in shares available for grant, beginning on January 1, 2015 through January 1, 2024 . Eligible employees may purchase common stock at 85 % of the lesser of the fair market value of common stock on the offering date or the purchase date with a six-month look-back feature. ESPP purchases are settled with common stock from the ESPP’s previously authorized and available pool of shares. During the year ended December 31, 2021 , the Company issued 69,738 shares of common stock under the ESPP. As of December 31, 2021 , an aggregate of 3,925,798 shares of common stock have been authorized for future issuance on the ESPP. Stock-Based Compensation Expense Total stock-based compensation recognized was as follows (in thousands): Year Ended December 31, 2021 2020 2019 Cost of sales $ 871 $ 827 $ 1,084 Research and development 59,097 47,949 44,205 Selling, general and administrative 45,011 36,959 36,706 Total stock-based compensation expense $ 104,979 $ 85,735 $ 81,995 Stock-based compensation of $ 1.7 million, $ 1.2 million, and $ 1.4 million was capitalized into inventory for the years ended December 31, 2021, 2020, and 2019, respectively. Capitalized stock-based compensation is recognized as cost of sales when the related product is sold. As of December 31, 2021 , the total unrecognized compensation expense related to unvested equity awards, net of estimated forfeitures, was $ 200.0 million, which the Company expects to recognize over an estimated weighted-average period of 2.33 years. In determining the estimated fair value of the stock options and ESPP, the Company uses the Black-Scholes option-pricing model and assumptions discussed below. Each of these inputs is subjective and generally requires significant judgment to determine. Expected Term —The Company’s expected term represents the period that the Company’s stock-based awards are expected to be outstanding and is determined using the simplified method (based on the mid-point between the vesting date and the end of the contractual term). Expected Volatility —The Company’s expected volatility is based on historical volatility over the look-back period corresponding to the expected term. Risk-Free Interest Rate —The risk-free interest rate is based on the U.S. Treasury zero coupon issues in effect at the time of grant for periods corresponding with the expected term of option. Expected Dividend —The Company has never paid dividends on its common stock and has no plans to pay dividends on its common stock. Therefore, the Company used an expected dividend yield of zero. The fair value of stock option awards granted was estimated at the date of grant using a Black-Scholes option-pricing model with the following weighted-average assumptions: Year Ended December 31, 2021 2020 2019 Expected term (years) 6.06 6.20 6.22 Expected volatility 60 % 61 % 61 % Risk-free interest rate 1.0 % 0.8 % 2.4 % Expected dividend rate 0.0 % 0.0 % 0.0 % 12. Defined Contribution Plan The Company sponsors a retirement plan in which substantially all of its full-time employees in the U.S. and certain other foreign countries are eligible to participate. Eligible participants may contribute a percentage of their annual compensation to this plan, subject to statutory limitations. The Company recorded $ 5.5 million, $ 4.3 million, and $ 3.6 million as contribution expenses for the years ended December 31, 2021, 2020, and 2019 , respectively. 13. Income Taxes The components of the Company’s loss before income taxes were as follows (in thousands): F- 29 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) Year Ended December 31, 2021 2020 2019 Domestic $ 455,314 $ 189,449 $ 399,709 Foreign ( 2,333 ) ( 4,090 ) ( 265 ) Total loss before income taxes $ 452,981 $ 185,359 $ 399,444 The components of the Company’s income tax provision were as follows (in thousands): Year Ended December 31, 2021 2020 2019 Current provision for income taxes: Federal $ — $ — $ — State ( 14 ) 15 51 International 1,058 1,192 1,092 Total current tax provision 1,044 1,207 1,143 Deferred tax provision: Federal — — — State — — 2,140 International — — — Total deferred tax provision — — 2,140 Total provision for income taxes $ 1,044 $ 1,207 $ 3,283 The Company has incurred net operating losses since inception. The Company has not reflected any benefit of such net operating loss carryforwards in the accompanying financial statements. The Company has established a full valuation allowance against its deferred tax assets due to the uncertainty surrounding the realization of such assets. The effective tax rate of our provision for income taxes differs from the federal statutory rate as follows: Year Ended December 31, 2021 2020 2019 Federal statutory income tax rate 21.0 % 21.0 % 21.0 % State income taxes, net of federal benefit — — ( 0.5 ) Federal tax credits 7.2 13.7 5.2 Other 0.5 ( 0.5 ) ( 0.2 ) Premium on equity issuance — 2.2 — Nondeductible permanent items ( 0.8 ) ( 0.9 ) ( 0.4 ) Stock-based compensation 1.3 0.9 ( 1.0 ) Uncertain tax positions ( 1.4 ) ( 2.7 ) ( 1.0 ) Change in valuation allowance ( 27.9 ) ( 33.9 ) ( 23.6 ) Foreign rate differential ( 0.1 ) ( 0.5 ) ( 0.3 ) Provision for income taxes ( 0.2 ) % ( 0.7 ) % ( 0.8 ) % F- 30 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The tax effect of temporary differences that give rise to significant portions of the deferred tax assets is presented below (in thousands): Year Ended December 31, 2021 2020 Deferred tax assets: Loss carryforwards $ 306,119 $ 222,902 Tax credits 218,131 184,961 Stock options 33,564 39,154 Accruals and reserves 25,735 24,922 Fixed assets and intangibles 18,263 7,242 Liability related to sale of future royalties 90,826 86,664 Basis difference in equity investments 3,912 — Other 13,060 28,642 Gross deferred tax assets 709,610 594,487 Valuation allowance ( 700,669 ) ( 561,139 ) Total deferred tax assets 8,941 33,348 Deferred tax liabilities: In-process research and development ( 33,306 ) ( 33,306 ) Basis difference in equity investments — ( 23,019 ) Right-of-use lease assets ( 8,941 ) ( 10,329 ) Gross deferred tax liabilities ( 42,247 ) ( 66,654 ) Net deferred tax liabilities $ ( 33,306 ) $ ( 33,306 ) As of December 31, 2021 and 2020 , the Company had approximately $ 1,085.4 million and $ 750.2 million, respectively, of federal net operating loss carryforwards available to reduce future taxable income that will begin to expire in 2031 . As of December 31, 2021 and 2020 , the Company had approximately $ 777.0 million and $ 616.8 million, respectively, of state net operating loss carryforwards available to reduce future taxable income that will begin to expire in 2031 . As of December 31, 2021 and 2020 , the Company had federal research tax credit carryforwards of $ 22.9 million and $ 17.7 million, respectively, available to reduce future tax liabilities that will begin to expire in 2030 . As of December 31, 2021 and 2020 , the Company had state research credit carryforwards of $ 44.6 million and $ 34.5 million, respectively, available to reduce future tax liabilities that will be carried forward indefinitely. As of December 31, 2021 and 2020 , the Company had federal Orphan Drug Credits of $ 208.1 million and $ 179.8 million available to reduce future tax liabilities that will begin to expire in 2031 . The Company’s ability to use net operating loss and tax credit carryforwards to reduce future taxable income and liabilities may be subject to annual limitations pursuant to Internal Revenue Code Sections 382 and 383 as a result of ownership changes in the past and future. As a result of ownership changes in 2012 and 2011, $ 3.6 million of federal net operating loss carryforwards, $ 3.6 million of state net operating loss carryforwards, and $ 0.2 million of federal tax credits are permanently limited. Deferred tax assets for net operating losses and tax credits have been reduced and a corresponding adjustment to the valuation allowance has been recorded. Based upon information available through the reporting date, the Company is not aware of any other changes in ownership that would result in material limitations under Section 382 as of December 31, 2021. The valuation allowance increased by $ 139.5 million and $ 74.3 million during the years ended December 31, 2021 and 2020, respectively. The Company recorded unrecognized tax benefits for uncertainties in income taxes. A reconciliation of the Company’s unrecognized tax benefits follows (in thousands): December 31, 2021 2020 2019 Balance at beginning of year $ 46,662 $ 39,954 $ 33,727 Additions based on tax positions related to current year 8,542 6,950 5,575 Additions for tax positions of prior years 356 382 652 Reductions for tax positions of prior years ( 200 ) ( 624 ) — Balance at end of year $ 55,360 $ 46,662 $ 39,954 F- 31 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) The entire amount of the unrecognized tax benefits would not impact the Company’s effective tax rate if recognized. The Company has elected to include interest and penalties as a component of tax expense. During the years ended December 31, 2021 and 2020 , the Company did no t recognize accrued interest and penalties related to unrecognized tax benefits. The Company does not anticipate that the amount of existing unrecognized tax benefits will significantly increase or decrease during the next year. It is the Company’s intention to reinvest the earnings of its non-U.S. subsidiaries in their operations. As of December 31, 2021 , the Company had not made a provision for any incremental foreign withholding taxes on approximately $ 4.1 million of the excess of the amount of net income for financial reporting over the tax basis of investments in foreign subsidiaries that are essentially permanent in duration. If these earnings were repatriated to the U.S., the deferred tax liability associated with these temporary differences would result in a nominal amount of withholding taxes. The Company files income tax returns in the U.S. federal, forty state tax jurisdictions, and ten foreign countries. The federal and state income tax returns from inception to December 31, 2021 remain subject to examination. 14. Commitments and Contingencies The Company has various manufacturing, clinical, research, and other contracts with vendors in the conduct of the normal course of its business. Other than as noted below, contracts are terminable, with varying provisions regarding termination. If a contract with a specific vendor were to be terminated, the Company would only be obligated for the products or services that the Company had received at the time the termination became effective. As of December 31, 2021, the aggregate payments under contractually binding manufacturing and service agreements are as follows (in thousands): Year Ended December 31, 2022 2023 Manufacturing and Services 19,225 774 The terms of certain of the Company’s licenses, royalties, development and collaboration agreements, as well as other research and development activities, require the Company to pay potential future milestone payments based on product development success. The amount and timing of such obligations are unknown or uncertain. These potential obligations are further described in “Note 7. License and Research Agreements”. See “Note 8. Leases” for lease commitments. Contingencies While there are no material legal proceedings the Company is aware of, the Company may become party to various claims and complaints arising in the ordinary course of business. Management does not believe that any ultimate liability resulting from any of these claims will have a material adverse effect on its results of operations, financial position, or liquidity. However, management cannot give any assurance regarding the ultimate outcome of these claims, and their resolution could be material to operating results for any particular period, depending upon the level of income for the period. Guarantees and Indemnifications The Company indemnifies each of its directors and officers for certain events or occurrences, subject to certain limits, while the director is or was serving at the Company’s request in such capacity, as permitted under Delaware law and in accordance with its certificate of incorporation and bylaws. The term of the indemnification period lasts as long as a director may be subject to any proceeding arising out of acts or omissions of such director in such capacity. The maximum amount of potential future indemnification is unlimited; however, the Company currently holds director liability insurance. This insurance allows the transfer of risk associated with the Company’s exposure and may enable it to recover a portion of any future amounts paid. The Company believes that the fair value of these indemnification obligations is minimal. Accordingly, it has not recognized any liabilities relating to these obligations for any period presented. F- 32 ULTRAGENYX PHARMACEUTICAL INC. Notes to Consolidated Financial Statements (continued) 15. Net Loss per Share The following table sets forth the computation of the basic and diluted net loss per share during the years ended December 31, 2021, 2020, and 2019 (in thousands, except share and per share data): Year Ended December 31, 2021 2020 2019 Numerator: Net loss $ ( 454,025 ) $ ( 186,566 ) $ ( 402,727 ) Denominator: Weighted-average shares used to compute net loss per share, basic and diluted 67,795,540 60,845,550 56,576,885 Net loss per share, basic and diluted $ ( 6.70 ) $ ( 3.07 ) $ ( 7.12 ) The following weighted-average outstanding common stock equivalents were excluded from the computation of diluted net loss per share for the periods presented because including them would have been antidilutive: Year Ended December 31, 2021 2020 2019 Options to purchase common stock, RSUs, and PSUs 8,214,063 8,532,236 7,978,666 Employee stock purchase plan 3,511 2,626 3,953 Common stock warrants — 29,449 149,700 8,217,574 8,564,311 8,132,319 16. Accumulated Other Comprehensive Income (Loss) Total accumulated other comprehensive income (loss) consisted of the following (in thousands): Year Ended December 31, 2021 2020 Cumulative foreign currency translation adjustment $ ( 121 ) $ 429 Unrealized gain (loss) on securities available-for-sale ( 1,283 ) 260 Total accumulated other comprehensive income (loss) $ ( 1,404 ) $ 689 17. Subsequent Events On January 7, 2022, the Company announced a collaboration with Regeneron to commercialize Evkeeza for HoFH outside of the U.S. Under the terms of the agreement, Regeneron received a $ 30.0 million upfront payment and is eligible to receive up to $ 63.0 million in future milestone payments, contingent upon the achievement of certain regulatory and sales milestones. Pursuant to the terms of the agreement, the Company received the rights to develop, commercialize and distribute the product in countries outside of the U.S. and will make payments to Regeneron based on net sales of the product. The Company will share in certain costs for global trials led by Regeneron and also have the right to opt into other potential indications. F- 33