BeiGene USA, Inc. et al. vs Pharmacyclics LLC

Order Denying Director Review of Final Written Decision

Authorized Response to Director Review Request (6.6.25)

Ex. 3100 Counsel email for Authorized Response

Updated Mandatory Notice (5.29.25)

Patent Owner's Request for Director Review

Corrected Final Written Decision Determining All Challenged Claims Unpatentable

E-mail regarding Final Written Decision

EXPUNGED

Updated Mandatory Notice (3.20.25)

Ex. 2124 Supervisory Patent Examiner Response - Return for Certificate of Correction

Patent Owner's Updated Exhibit List

Other: Hearing transcript

Patent Owner's Demonstratives part 1 of 2

Patent Owner's Demonstratives part 2 of 2

Petitioners' Demonstrative Exhibits

ORDER Granting Petitioner’s Motion for Admission Pro Hac Vice of Kevin Hoagland-Hanson 37 C.F.R. § 42.10

LEAP Practitioner Request and Verification Form (Petitioner)

Motion for PHV Admission (Kevin Hoagland-Hanson)

Joint Stipulation to Extend Service Date of Demonstrative Exhibits

ORDER Setting Oral Argument 37 C.F.R. § 42.70

Petitioners' Request for Oral Argument

Patent Owner's Request for Oral Argument

Declaration ISO Motion for PHV Admission (Kevin Hoagland-Hanson)

Patent Owner's Sur-Reply

Ex. 2118 Showalter Dep. (11.08.2024)

Ex. 2119 Veal Dep. (11.22.2024)

Ex. 2120 Veal, ch. 16 in Kinase Inhibitor Drugs (Veal Dep. Ex. 1)

Ex. 2121 Adams et al., ch. 2 in Protein Crystallography (2004) (Veal Dep. Ex. 2)

Ex. 2122 Eck Deposition Errata

Ex. 2123 Scott Deposition Errata

Amended POA

Updated Mandatory Notice

Petitioners' Updated Exhibit List

Patent Owner's Objections to Petitioner's Evidence

Patent Owner's Notice of Deposition of James Veal

Petitioners' Updated Exhibit List

Petitioner's Reply to Patent Owner's Response

Reply Declaration of Dr. Hollis D. Showalter, Ph.D.

Reply Declaration of James M. Veal, Ph.D.

Curriculum Vitae of James M. Veal, Ph.D.

WIPO Publication No. WO 2014/173289A1

WIPO Publication No. WO 2016/007185A1

Deposition Transcript of Michael J. Eck, M.D., Ph.D,

Eck Deposition Exhibit 1

Eck Deposition Exhibit 2

Eck Deposition Exhibit 3

Eck Deposition Exhibit 4

Eck Deposition Exhibit 5

Eck Deposition Exhibit 6

Deposition Transcript of David A. Scott

Scott Deposition Exhibit 1

Deposition Transcript of Stephen E. Spurgeon

Spurgeon Deposition Exhibit 1

Spurgeon Deposition Exhibit 2

Syed Awais Attique, et. al. “A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension"

Ahmed H.H. Bakheit, et. al., Chapter 1. Azithromycin, “Profiles of Drug Substances, Excipients, and Related Methodology”

Miklos Feher and Christopher I. Williams, “Numerical Errors and Chaotic Behavior in Docking Simulations”

Supplementary Material for the manuscript “Numerical Errors and Chaotic Behavior in Docking Simulations”

Kun-Yi Hsin, et. al., “Combining Machine Learning Systems and Multiple Docking Simulation Packages to Improve Docking Prediction Reliability for Network Pharmacology”

Dian Jiao, et. al. “Calculation of protein-ligand binding free energy by using a polarizable potential”

Xuan-Yu Meng, et. al., “Molecular Docking: A powerful approach for structure-based drug discovery”

Dariusz Plewczynski, et. al., “Can We Trust Docking Results? Evaluation of Seven Commonly Used Programs on PDBbind Database”

David Ramirez and Julio Caballero, “Is it Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?”

Robert Roskoski, Jr., “Rule of five violations among the FDA-approved small molecule protein kinase inhibitors”

“What is the difference between GlideScore and Emodel, and which should I use for ranking poses?”

“Dramatically improving hit rates with a modern virtual screening workflow”

“Docking and Scoring”, Schrödinger, Inc.

Sara Shamsian, et. al., “Bencchmarking different docking protocols for predicting the binding poses of ligands complexed with cyclooxygenase enzymes and screening chemical libraries”

Ermias Mergia Terefe and Arabinda Ghosh, “Molecular Docking, Validation, Dynamics Simulations, and Pharmacokinetic Prediction of Phytochemicals Isolated From Croton dichogamus Against the HIV-1 Reverse Transcriptase”

Vincente Zoete, et. al. “Docking, virtual high throughput screening and in silico fragment-based drug design”

Ibrutinib (Glide Modeling)

Zanubrutinib (Glide Modeling)

Compound 81, WO’289 (Glide Modeling)

Compound 9, WO’185 (Glide Modeling)

Compound 30, 446 Patent (Glide Modeling)

Compound 122, 446 Patent (Glide Modeling)

Compounds with Reported IC50 Values (Glide Modeling)

Structure E2, 803 Patent (Glide Modeling)

Structure E3, 803 Patent (Glide Modeling)

Structure E4, 803 Patent (Glide Modeling)

Formula I, 820 Patent (Glide Modeling)

PDB - 2QD9 (Glide Modeling)

PDB - 5TR6 and 5TT7 (Glide Modeling)

RCSB PDB - 2QD9_ P38 Alpha Map Kinase inhibitor based on heterobicyclic scaffolds

RCSB PDB - 5TR6_ Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)

RCSB PDB - 5TT7_ Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)

Zanubrutinib and Compound 81, WO’289 (Glide Modeling)

Elizabeth H. Krenske et. al., “Transition States and Energetics of Nucleophilic Additions of Thiols to Substituted a,β-Unsaturated Ketones: Substituent Effects Involve Enone Stabilization, Product Branching, and Solvation”

Supplementary Material for “Transition States and Energetics of Nucleophilic Additions of Thiols to Substituted a,β-Unsaturated Ketones: Substituent Effects Involve Enone Stabilization, Product Branching, and Solvation”

Patent Owner's Notice of Deposition of Hollis Showalter

PETITIONERS' NOTICE OF DEPOSITION OF DAVID A. SCOTT, PH.D.

PETITIONERS' NOTICE OF DEPOSITION OF STEPHEN E. SPURGEON, M.D.

PETITIONERS' NOTICE OF DEPOSITION OF MICHAEL J. ECK, M.D., PH.D.

Petitioners’ Objections to Admissibility of Evidence Submitted by Patent Owner

Ex. 2011 Eck CV

Ex. 2013 Scott CV

Ex. 2015 Spurgeon CV

Ex. 2017 Hsieh-Yee CV

Ex. 2018 Showalter Dep. (7.18.2024)

Ex. 2019 USP 6,150,359 (Showalter Dep. Ex. 1)

Ex. 2020 Guo et al. (2023) (Showalter Dep. Ex. 2)

Ex. 2021 Rosen Dep. (6.17.2024)

Ex. 2022 Ma & Rosen (Rosen Dep. Ex. 1)

Ex. 2023 USP 7,435,820

Ex. 2024 USP 10,358,446

Ex. 2025 USP Appl. Publ. 2008-0108636

Ex. 2026 USP Appl. Publ. 2010-0160303

Ex. 2027 Intl Pat. Publ. WO2010-126960

Ex. 2028 Akritopoulou-Zanze & Hajduk (2009)

Ex. 2029 Attwood et al. (2021)

Ex. 2030 Bernstein et al. (1977)

Ex. 2031 Bissantz et al. (2010)

Ex. 2034 De Cesco et al. (2017)

Ex. 2035 Friesner et al. (2004)

Ex. 2036 Friesner et al. (2006)

Ex. 2037 Glide 5.5 User Manual (2009)

Ex. 2038 Gracias et al. (2008)

Ex. 2039 Guo et al. (2019) (Supporting Info to. Ex. 1053)

Ex. 2040 Hafenbradl et al. ch.1 in Protein Kinases as Drug Targets (2011)

Ex. 2041 Halgren et al. (2004)

Ex. 2042 Honigberg et al. (2010) (Supporting Info to Ex. 1055)

Ex. 2043 Johnson (2009)

Ex. 2045 Kumalo et al. (2015)

Ex. 2046 Lam et al. (2016)

Ex. 2047 Laskowski & Swindells (2011)

Ex. 2048 Le Corre et al. (2010)

Ex. 2049 Lin et al. (2012)

Ex. 2050 Liu et al. (2015)

Ex. 2052 Lovering et al. (2009)

Ex. 2053 Mohammadi et al. (1997)

Ex. 2054 Morris et al. (2009)

Ex. 2055 Murali Dhar et al. (2007)

Ex. 2056 Pierce et al. (2008)

Ex. 2057 Ravindranathan et al. (2010)

Ex. 2058 Roskoski (2021)

Ex. 2059 Singh et al. (2011)

Ex. 2060 Waring (2010)

Ex. 2061 Watterson et al. (2016)

Ex. 2033 Cohen (2002)

Ex. 2063 Zhang et al. (2020)

Ex. 2065 Badoux et al. (2011)

Ex. 2066 Broekman et al. (2011)

Ex. 2067 Brukinsa (Zanubrutinib) Prescribing Information (revised June 2024)

Ex. 2068 Brunetto et al. (2010)

Ex. 2069 Bryan & Borthakur (2011)

Ex. 2070 Cheson et al. (2012)

Ex. 2073 Fischer et al. (2016)

Ex. 2074 Gribben (Blood 2010)

Ex. 2075 Gribben (Expert Revs. 2010)

Ex. 2077 Grimminger et al. (2010)

Ex. 2078 Herman et al. (2010)

Ex. 2079 Imbruvica (Ibrutinib) Prescribing Information (revised May 2024)

Ex. 2080 Keating et al. (2002)

Ex. 2081 Le Tourneau et al. (2009)

Ex. 2082 LoRusso et al. (2010)

Ex. 2083 Morrison (2010)

Ex. 2084 Narang et al. (2021)

Ex. 2085 Natoli et al. (2010)

Ex. 2086 Zelenetz et al. (2010)

Ex. 2087 Natl Comp. Cancer Network CLL Patient Guidelines (3.16.2021)

Ex. 2088 NIH Tirabrutinib Clinical Trial (NCT01659255) (last updated 3.16.2021)

Ex. 2089 NIH Zanubrutinib v Ibrutinib Clinical Trial (NCT03734016) (last updated 4.1.2024)

Ex. 2090 NIH Zanubrutinib Clinical Trial (NCT03206918) (last updated 10.4.2021)

Ex. 2091 Ponader et al. (2012)

Ex. 2092 Raedler (2015)

Ex. 2094 Smolej (2010)

Ex. 2095 Smyth & Collins (2009)

Ex. 2096 Stilgenbauer & Zenz (2010)

Ex. 2097 Tamdor et al. (2024)

Ex. 2098 Timar & Dome (2008)

Ex. 2099 Walter et al. (2016)

Ex. 2100 Walter et al. (2017)

Ex. 2101 Xu et al. (2020)

Ex. 2102 Understanding MARC Bibliographic, pts VII-X

Ex. 2103 Marcotte et al. (2010) (Publisher copy)

Ex. 2104 Marcotte et al. (2010) (Natl Library of Med copy)

Ex. 2105 Protein Science, Bibliographic & MARC recs

Ex. 2106 LocatorPlus (May 2009 archival)

Ex. 2107 Marcotte et al. (2010) (PubMed record)

Ex. 2108 PubMed (May 2010 archivals)

Ex. 2109 References citing Marcotte et al. (2010)

Ex. 2110 Frank-White Decl. (Internet Archives Recs Processor)

Ex. 2111 Intl Pat. Publ. WO2008-121742

Ex. 2010 Eck Declaration

Ex. 2012 Scott Declaration

Ex. 2014 Spurgeon Declaration

Ex. 2016 Hsieh-Yee Declaration

Patent Owner's Response

Ex. 2009 Certificate of Correction Patent No. 11672803

Patent Owner's Updated Exhibit List

Order: Granting Patent Owner’s Motion for Leave to Request a Certificate of Correction

Exhibit 3002

Patent Owner's Motion for Leave to Request Certificate of Correction

Ex. 2008 Request for Correction of Inventorship in Patent No. 11672803

Order: Granting Petitioner's Unopposed Motion to Submit Supplemental Information - 37 CFR 42.223(a)

Ex. 3001

Patent Owner's Objections to Petitioner's Evidence

Petitioners' Unopposed Motion to Submit Supplemental Information

Affidavit of Nathaniel E Frank-White (Byrd Protocol (Ex. 1011))

Affidavit of Nathaniel E Frank-White (IMBRUVICA Label (Ex. 1058))

Affidavit of Nathaniel E Frank-White (2013 New England Journal of Medicine website, with links to the Byrd reference (Ex. 1009) and its Supplementary Material (Ex. 1010))

Patent Owner's Notice of Deposition of Steven Rosen

Patent Owner's Notice of Deposition of Hollis Showalter

Joint Stipulation to Extend Due Dates 1 - 3

Patent Owner's Objections to Petitioner's Evidence

Petitioners' Objections to Admissibility of Evidence Submitted by Patent Owner

Granting Institution of Post-Grant Review 35 U.S.C. § 324

EXPUNGED

SCHEDULING ORDER

Patent Owner's Sur-Reply in Support of Patent Owner's Preliminary Response

Petitioner's Reply to Patent Owner's Preliminary Response

January 9, 2024 office action rejection in U.S. Patent Application 18/180,064

November 21, 2023 Information Disclosure Statement in U.S. Patent Application 18/180,064

Patent Owner's Preliminary Response

Ex. 2001 Marcotte 2010

Ex 2002 Hallek 2008 [2008 CLL Guideline]

Ex 2003 Hallek 2018 [2018 CLL Guideline]

Ex. 2004 Press Release, AbbVie IMBRUVICA

Ex. 2005 Non-Final Rejection Issued in USP Appl. No. 18180064

Ex. 2006 USP 10,570,139

Ex. 2007 USP 11,142,528

Patent Owner's Mandatory Notices

Patent Owner's Power of Attorney

Notice: Notice filing date accorded

Notice : Power of Attorney

U.S. Patent No. 11,672,803

Prosecution File History of U.S. Patent No. 11,672,803

Petition : as filed

Declaration of Hollis D. Showalter, Ph.D.

Curriculum Vitae of Hollis D. Showalter, Ph.D.

Declaration of Steven T. Rosen, M.D., F.A.C.P., FASCO, FAIMBE

Curriculum Vitae of Steven T. Rosen, M.D., F.A.C.P., FASCO, FAIMBE

Declaration of Sylvia D. Hall-Ellis, Ph.D.

Curriculum Vitae of Sylvia D. Hall-Ellis, Ph.D.

Byrd, Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

Supplementary Appendix to John C. Byrd, et. al.

Protocol for John C. Byrd, et. al

BRUKINSA Prescribing Information (Revised April 2023)

BRUKINSA Prescribing Information (Revised Nov. 2019)

IMBRUVICA Prescribing Information (Revised May 2023)

IMBRUVICA Prescribing Information (Revised Aug. 2022)

Prosecution File History of U.S. Provisional Application No. 61/351,130

Prosecution File History of U.S. Provisional Application No. 61/351,655

Prosecution File History of U.S. Provisional Application No. 61/351,762

Prosecution File History of U.S. Provisional Application No. 61/351,793

Prosecution File History of U.S. Provisional Application No. 61/419,764

Prosecution File History of U.S. Provisional Application No. 61/472,138

1/2 Prosecution File History of U.S. Patent Application No. 13/153,317

2/2 Prosecution File History of U.S. Patent Application No. 13/153,317

1/2 Prosecution File History of U.S. Patent Application No. 13/869,700

2/2 Prosecution File History of U.S. Patent Application No. 13/869,700

U.S. Patent No. 9,801,881

1/2 Prosecution File History of U.S. Patent No. 9,801,881

2/2 Prosecution File History of U.S. Patent No. 9,801,881

U.S. Patent No. 10,016,435

1/3 Prosecution File History of U.S. Patent No. 10,016,435

2/3 Prosecution File History of U.S. Patent No. 10,016,435

3/3 Prosecution File History of U.S. Patent No. 10,016,435

U.S. Patent No. 10,478,439

1/2 Prosecution File History of U.S. Patent No. 10,478,439

2/2 Prosecution File History of U.S. Patent No. 10,478,439

U.S. Patent No. 10,653,696

1/2 Prosecution File History of U.S. Patent No. 10,653,696

2/2 Prosecution File History of U.S. Patent No. 10,653,696

U.S. Patent No. 10,751,342

1/2 Prosecution File History of U.S. Patent No. 10,751,342

2/2 Prosecution File History of U.S. Patent No. 10,751,342

U.S. Patent Publication No. 2015/0259354

U.S. Patent Publication No. 2019/0275037

U.S. Patent Publication No. 2020/0140432

PCT Patent Publication No. WO 2009/158571

John C. Alexander, et. al. “Modern Drug Discovery & Development,”

Alpert, Prevalence of Cytopenia in the Gen. Population

Bender, A practical guide to large-scale docking

Bhalani, Bioavailability Enhancement Techniques

Brown, Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia

Brullo, Btk Inhibitors: A Medicinal Chemistry & Drug Delivery Perspective

D.S. Chabot-Richards and T.I. George, Leukocytosis

Currie, Pharmacology Part 1 Introduction to Pharmacology & Pharmacodynamics

D'Cruz, Novel Bruton’s tyrosine kinase inhibitors currently in development

Estupiñán, Comparative Analysis of BTK Inhibitors

Garuti, Irreversible Protein Kinase Inhibitors

Ge, Discovery of Novel Bruton’s Tyrosine Kinase (BTK) Inhibitors

Gennari, Thiol-based michael-type addition. A systematic evaluation

Ghose, Knowledge Based Prediction of Ligand Binding Modes

Guo, Discovery of Zanubrutinib (BGB-3111)

Herman, Bruton tyrosine kinase represents a promising therapeutic target

Honigberg Bruton tyrosine kinase inhibitor PCI32765 blocks Bcell activation

Jorda, Scaffold hopping of the SYK inhibitor entospletinib

Liclican, Biochemical characterization of tirabrutinib

IMBRUVICA Prescribing Information (Revised June 2016)

Nadhan and Rosen, Chronic Lymphocytic Leukemia: A Clinical Review

Pan, Discovery of Selective Irreversible Inhibitors for BTK

Roeker, Real-world comparative effectiveness of acalabrutinib and ibrutinib

Sabat, Discovery of the Bruton’s Tyrosine Kinase Inhibitor

Seymour, Detailed safety profile of acalabrutinib vs ibrutinib

Singh, Targeted covalent drugs of the kinase family

Singh, Role of Bruton’s tyrosine kinase in B cells and malignancies

St-Pierre and Ma, Use of BTK Inhibitors in Chronic Lymphocytic Leukemia

Sun, Why 90% of clinical drug development fails and how to improve it?

Tam, Phase 1 study of the selective BTK inhibitors in B-cell malign

Tam, Clinical pharmacology and PK/PD translation of the second-generation

Tang, Cell-active irreversible covalent inhibitors

Tasso, The Development of BTK Inhibitors: A Five-Year Update

Uckun, Clinical Potential of Targeting Bruton’s Tyrosine Kinase

Uckun and Qazi, Bruton’s tyrosine kinase as a molecular target in treatment

Xu, Treatment of relapsed/refractory chronic lymphocytic leukemia

Zain, Structure Relationships of Covalent and Non-Covalent BTK Inhibitor

Zhang, Recent Advances in BTK Inhibitors for the Treatment of Inflammatory

Zhang, Targeting cancer with small molecule kinase inhibitors

Plaintiffs’ Post-Trial Proposed Findings of Fact

Brief of Plaintiffs-Appellees Pharmacyclics LLC & Janssen Biotech, Inc.

IMBRUVICA Prescribing Information (Revised May 2016)

IMBRUVICA Prescribing Information (Revised November 2013)

FDA approves zanubrutinib for chronic lymphocytic leukemia

BRUKINSA Prescribing Information (Revised January 2023)

FDA letter to Pharmacyclics, Inc. re NDA application for Imbruvica

Leukemia information

Non-Hodgkin Lymphoma information

NCCN Revamps Treatment Preferences in CLL / SLL

Project Orbis: FDA approves acalabrutinib for CLL and SLL

Brukinsa FDA Approval History

Imbruvica FDA Approval History

Update on Withdrawal of Ibrutinib Accelerated Approvals for MCL and MZL

Update Patient enrollment of phase III tolebrutinib trials paused in US

A Study of Zanubrutinib (BGB-3111) Versus Ibrutinib

Safety of PCI-32765 in Chronic Lymphocytic Leukemia

Study of the Safety and Tolerability of PCI-32765

2011-2020 Clinical Development Success Rates and Contributing Factors

Selected chapters from Comprehensive Heterocyclic Chemistry III

U.S. Patent No. 11,672,803 Claim Listing

Swami, Impact of physiochemical properties on pharmacokinetics