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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`SANDOZ INC.,
`Petitioner,
`
`v.
`
`PHARMACYCLICS LLC,
`Patent Owner.
`
`__________________
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
`__________________
`
`DECLARATION OF DR. JOHN KORETH, M.B.B.S., D. Phil.
`
`
`
`

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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`C.
`
`D.
`
`TABLE OF CONTENTS
`
`I.
`INTRODUCTION ........................................................................................... 9
`PROFESSIONAL BACKGROUND AND QUALIFICATIONS .................. 9
`II.
`III. MATERIALS CONSIDERED ......................................................................13
`IV. BACKGROUND OF GRAFT VERSUS HOST DISEASE .........................14
`A.
`cGVHD Is a Major and Life-threatening Complication of HCT ........14
`B.
`cGVHD Is Distinct From and Treated Differently Than
`aGVHD ................................................................................................16
`The Pathogenesis of cGVHD Is Complex and Incompletely
`Understood ..........................................................................................18
`Treatment of cGVHD Is Difficult, Especially in Steroid-
`Dependent/Refractory, Steroid-Resistant, or Refractory cGVHD
`Patients ................................................................................................23
`Before 2013 There Were Many Treatment Failures and No
`FDA Approved Drugs for cGVHD .....................................................28
`THE ’604 PATENT .......................................................................................32
`A.
`The Specification .................................................................................32
`B.
`The Claims ..........................................................................................35
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................38
`VII. CLAIM CONSTRUCTION ..........................................................................39
`A.
`Legal Standards for Claim Construction .............................................39
`B.
`Claims 1 and 55: “method of treating chronic graft versus host
`disease (GVHD)” and “thereby treating the chronic GVHD in
`the patient” ..........................................................................................41
`Claims 6-8, 29-31, 44-46, and 51-53: the “wherein” efficacy
`limitations ............................................................................................44
`
`V.
`
`E.
`
`C.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`X.
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`D.
`E.
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`Claim 1: “therapeutically effective amount” .......................................46
`The clinical efficacy limitations are not inherent to the claimed
`methods................................................................................................46
`VIII. THE ASSERTED REFERENCES ................................................................47
`A.
`The ’085 Publication (Ex. 1002) .........................................................47
`B.
`Shimabukuro-Vornhagen (Ex. 1003) ..................................................51
`C.
`Herman (Ex. 1004) ..............................................................................54
`D. Uckun (Ex. 1005) ................................................................................55
`IX. LEGAL STANDARDS FOR PATENTABILITY ........................................56
`A. Anticipation .........................................................................................57
`B.
`Obviousness .........................................................................................58
`THE ’085 PUBLICATION DOES NOT DESCRIBE THE CLAIMED
`METHODS OF TREATING CHRONIC GVHD WITH IBRUTINIB
`(GROUND 1) .................................................................................................59
`A.
`The ’085 Publication Does Not Anticipate the Challenged
`Claims ..................................................................................................59
`The ’085 Publication Does Not Enable Treating cGVHD With
`Ibrutinib Without Undue Experimentation (Claims 1, 4, 6-10,
`13, 15, 24, 28-31, 35, 39, 43-46, 50-53, and 55) .................................60
`1.
`The Nature of the Invention / Relative Level of Skill ..............61
`2.
`The State and Unpredictability of the Prior Art ........................62
`3.
`The Quantity of Experimentation / The Lack of Direction
`or Guidance / The Absence of Working Examples ..................63
`The ’085 Publication Does Not Describe the Subject Matter of
`Claims 4, 13, and 15 and the Claims that Depend From Them
`(Claims 28-31, 43-46, and 50-53) .......................................................67
`
`B.
`
`C.
`
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`D.
`
`B.
`
`2.
`
`The ’085 Publication Does Not Disclose the Specific Efficacy
`Outcomes of Claims 6-8, 29-31, 44-46, and 51-53 .............................70
`XI. A POSA WOULD NOT HAVE BEEN MOTIVATED TO USE
`IBRUTINIB TO TREAT cGVHD, AND WOULD NOT HAVE
`REASONABLY EXPECTED SUCCESS IN TREATING, STEROID-
`DEPENDENT/REFRACTORY, STEROID-RESISTANT, AND
`REFRACTORY cGVHD ..............................................................................72
`A. Ground 2: The ’085 Publication and a POSA’s Knowledge Do
`Not Render Obvious Claims 4, 13, 15, 28-31, 43-46, and 50-53 .......72
`Ground 3: The Combination of the ’085 Publication,
`Shimabukuro-Vornhagen, and Herman Does Not Render
`Obvious Claims 4, 13, 15, 28-31, 43-46, and 50-53 ...........................77
`1.
`None of The Cited References Contain Any In Vitro,
`Preclinical, or Clinical Data for Ibrutinib in cGVHD ...............80
`Shimabukuro-Vornhagen’s Disclosures Regarding B-Cell
`Involvement and Rituximab Do Not Provide a Reason to
`Focus on Ibrutinib With a Reasonable Expectation of
`Success ......................................................................................81
`a.
`The role of B cells in cGVHD pathogenesis was
`complex and incompletely understood in 2013 ..............81
`Rituximab and ibrutinib are very different drugs ...........85
`Covalent BTK inhibitors and drugs targeting both
`B and T cells raised significant safety concerns in
`steroid-dependent/refractory, steroid-resistant, or
`refractory cGVHD patients .............................................88
`A POSA would have been skeptical of the
`rituximab studies referenced in Shimabukuro-
`Vornhagen .......................................................................91
`Herman’s Disclosures Regarding Cytokines Do Not Fill
`the Gaps in the Asserted References .........................................95
`
`b.
`c.
`
`d.
`
`3.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`
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`2.
`
`3.
`
`C.
`
`Ground 4: The Combination of the ’085 Publication,
`Shimabukuro-Vornhagen, and Uckun Does Not Render
`Obvious Claims 4, 13, 15, 28-31, 43-46, and 50-53 ...........................97
`1.
`Uckun, Like the ’085 Publication and Shimabukuro-
`Vornhagen, Does Not Contain Any In Vitro, Preclinical,
`or Clinical Data for Ibrutinib in cGVHD ..................................99
`Uckun Shows that LFM-A13 Alone Demonstrated
`Limited Efficacy in Preventing aGVHD ..................................99
`aGVHD Is Distinct From cGVHD and GVHD
`Prophylaxis Cannot be Conflated with GVHD Treatment .....101
`XII. GROUNDS 2-4 DO NOT PROVIDE MOTIVATION OR A
`REASONABLE EXPECTATION OF SUCCESS TO ACHIEVE THE
`METHODS OF CLAIM 1 ...........................................................................103
`XIII. CLAIMS 6-8, 29-31, 44-46, AND 51-53 ARE NOT OBVIOUS
`OVER ANY OF THE ASSERTED REFERENCES BECAUSE OF
`THEIR SPECIFIC CLINICAL EFFICACIES ............................................104
`XIV. THE COMBINED ASSERTED REFERENCES DO NOT PROVIDE
`ANY REASON TO TARGET A DAILY DOSE OF 420 MG/DAY
`AS CLAIMED IN CLAIMS 24, 28, 35, 39, 43, 50, AND 55 .....................107
`XV. ADDITIONAL OBJECTIVE EVIDENCE DEMONSTRATES THAT
`THE CLAIMED METHODS ARE NOT OBVIOUS .................................110
`A.
`Treatment of cGVHD Is Replete With Failures ................................111
`B.
`The Claimed Methods Fulfilled a Long-Felt But Unmet Need ........113
`C.
`The Claimed Methods Achieved Unexpected Results ......................118
`D.
`Praise and Industry Acclaim for Imbruvica® ....................................119
`E.
`There Is a Nexus Between the Claimed Invention and the
`Objective Evidence............................................................................123
`XVI. CONCLUSION ............................................................................................141
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`
`
`GLOSSARY
`
`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`’604 patent
`
`U.S. Patent No. 9,795,604
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`Patent Owner
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`AbbVie Inc; Pharmacyclics, LLC; and
`
`Pharmacyclics Inc.
`
`aGVHD
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`Acute graft versus host disease
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`BCR
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`BMT
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`BTK
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`B-cell receptor
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`Bone marrow transplant
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`Bruton’s tyrosine kinase
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`cGVHD
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`Chronic graft versus host disease
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`CLL
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`CR
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`Chronic lymphocytic leukemia
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`Complete response
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`DLBCL
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`Diffuse large B-cell lymphoma
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`FDA
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`HCT
`
`IFNγ
`
`IL-2
`
`IL-6
`
`IL-10
`
`Food and Drug Administration
`
`Hematopoietic cell transplantation
`
`Interferon gamma
`
`Interleukin-2
`
`Interleukin 6
`
`Interleukin 10
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`

`

`
`
`IL-6R
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`IPR
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`Interleukin 6 receptor
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`Inter partes review
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`U.S. Patent No. 9,795,604
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`Italicized text
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`Emphasis added unless otherwise indicated
`
`ITK
`
`JAK2
`
`kDa
`
`MCL
`
`MMF
`
`MoAbs
`
`MTX
`
`NIH
`
`NFκ-B
`
`NRM
`
`Interleukin-2-inducible T cell kinase
`
`Janus kinase 2
`
`Kilodalton
`
`Mantle cell lymphoma
`
`Mycophenolate mofetil
`
`Monoclonal antibodies
`
`Methotrexate
`
`National Institutes of Health
`
`Nuclear factor kappa-B
`
`Non-relapse mortality
`
`Office or USPTO United States Patent and Trademark Office
`
`Petitioner
`
`Sandoz Inc.
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`PLK
`
`POSA
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`PR
`
`SCT
`
`Polo-like kinase
`
`Person of ordinary skill in the art
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`Partial response
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`Stem cell transplant
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`

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`
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`SLL
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`TNFα
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`Case IPR2019-00865
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`Small lymphocytic lymphoma
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`Tumor necrosis factor alpha
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`
`I.
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`INTRODUCTION
`I, John Koreth, M.B.B.S., D. Phil., have been retained by Finnegan,
`1.
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`Henderson, Farabow, Garrett & Dunner, LLP on behalf of Patent Owner as an
`
`independent expert in the field of graft versus host disease (GVHD). My
`
`qualifications in this area are set forth in my curriculum vitae in Appendix A. I
`
`am being compensated for the time I spend on this matter, but no part of my
`
`compensation depends on the outcome of this proceeding.
`
`II.
`
`PROFESSIONAL BACKGROUND AND QUALIFICATIONS
`I have been practicing medicine for over two decades. I am
`2.
`
`currently a hematologist and oncologist at Brigham and Women’s Hospital and
`
`Dana-Farber Cancer Institute. I am also an associate professor at Harvard Medical
`
`School. In my clinical practice, I attend on the inpatient hematopoietic stem cell
`
`transplantation service for 8 weeks/year, and I am in clinic 2 days/week. I also
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`supervise and teach mid-level practitioners, house-staff and hematology/oncology
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`fellows during inpatient service (didactic 1-2 hour/week, daily bedside teaching
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`rounds) and ambulatory clinics. In my work, I seek to improve hematopoietic stem
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`cell transplantation outcomes by optimizing its use and improving its
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`toxicity/efficacy balance. I am licensed to practice by the state board in
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`Massachusetts.
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`9
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`

`3.
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`I obtained my M.B.B.S. from the University of Delhi, India, in 1993
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`and subsequently a D. Phil. from Oxford University, United Kingdom. After
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`receiving my D. Phil., I completed postgraduate training at Brigham and Women’s
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`Hospital in Boston, Massachusetts. I then completed fellowships in
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`hematology/oncology at Dana-Farber Cancer Institute, Brigham and Women’s
`
`Hospital, and Massachusetts General Hospital.
`
`4.
`
`In 2004, I started as an Associate Physician in the Department of
`
`Medicine at Brigham and Women’s Hospital and as a Physician in the Department
`
`of Medical Oncology (Hematologic Malignancies Division) at Dana-Farber Cancer
`
`Institute. I continue to hold these positions today. In addition, from 2004 to 2010,
`
`I served as an Instructor of Medicine at Harvard Medical School. In 2010, I was
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`promoted to Assistant Professor, and subsequently in 2014 to Associate Professor.
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`I continue to hold this teaching position today.
`
`5.
`
`As a professor and practicing physician, I have particular experience
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`conducting research in the area of bone marrow failure and blood and bone marrow
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`cancers, including transplantation and its complications, especially in the area of
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`GVHD. In particular, I have investigated multiple approaches for treating and
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`preventing GVHD. For example, in a phase II trial with the University of
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`Michigan, completed on October 26, 2018, we documented the safety and efficacy
`
`of alpha-1 antitrypsin as a therapy for steroid-refractory acute GVHD that is now
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`being evaluated in a national multicenter trial (BMT-CTN 1705). I am on the
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`U.S. Patent No. 9,795,604
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`protocol committee for this trial. I have extensive experience with novel therapies
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`for cGVHD and a member of the NIH Expert Consensus Panel that formulated the
`
`revised response criteria for cGVHD. As detailed in my curriculum vitae, much of
`
`my work is enhancing anti-inflammatory regulatory T cells for the treatment of
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`steroid refractory cGVHD.
`
`6.
`
`I have published numerous papers on GVHD and my work in this
`
`area. Specifically, I have authored over one hundred peer-reviewed articles in such
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`journals as Blood, Blood Advances, Biology of Blood and Marrow Transplantation,
`
`Bone Marrow Transplantation, Haematologica, Journal of Clinical Oncology,
`
`New England Journal of Medicine, Proceedings of the National Academy of
`
`Sciences of the United States of America, The Journal of the American Medical
`
`Association, The Lancet Haematology, and others. I have given numerous
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`presentations and invited lectures in my field at conferences and seminars, both in
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`the United States and abroad.
`
`7.
`
`I am internationally recognized as an expert in the field of
`
`hematopoietic cell transplantation (HCT) and blood and bone marrow cancers,
`
`specifically in the field of GVHD. I have served as ad hoc reviewer for various
`
`journals, including American Journal of Hematology, Annals of Oncology, Biology
`
`of Blood and Marrow Transplantation, Blood, Blood Advances, Bone Marrow
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`Transplantation, Clinical Cancer Research, Frontiers Immunology,
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`Haematologica, Journal of Clinical Oncology, Leukemia, The Journal of Clinical
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`Investigation, The Journal of Thrombosis and Haemostasis, and The Lancet
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`Diabetes & Endocrinology. I have served on and continue to serve on the editorial
`
`board of Haematologica, Blood Advances, and Biology of Blood and Marrow
`
`Transplantation.
`
`8.
`
`I have served on the selection committees of multiple professional
`
`organizations, including the American Society of Blood and Marrow
`
`Transplantation Committee on Aging and Transplantation, American Society of
`
`Blood and Marrow Transplantation New Investigator Award Committee, American
`
`Society of Blood and Marrow Transplantation/Center for International Blood and
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`Marrow Transplant Research 2012 Scientific Organizing Committee, The Blood
`
`and Marrow Transplant Clinical Trials Network Myeloma Committee, and the
`
`ASH Scholar Award Committee. I am also a member of the American Society of
`
`Hematology, the Massachusetts Medical Society, and the American Society of
`
`Transplantation and Cellular Therapy.
`
`9.
`
`I have received awards and recognition for my research and patient
`
`care, including the 2002 Partners in Excellence Award from Dana-Farber Cancer
`
`Institute, the New Investigator Award from the American Society of Blood and
`
`12
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`

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`Marrow Transplantation, and the Scholar in Clinical Research Award from the
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`Leukemia & Lymphoma Society.
`
`10. My professional qualifications are described in further detail in my
`
`curriculum vitae, which is attached as Appendix A.
`
`III. MATERIALS CONSIDERED
`I have been asked to consider U.S. Patent No. 9,795,604 (“the ’604
`11.
`
`patent”), the Declaration of Dr. James L. Ferrara, and certain documents raised in
`
`the Declaration.
`
`12.
`
`I understand that Petitioner has asserted that the claims of the ’604
`
`patent are either anticipated by or rendered obvious in view of the ’085 Publication
`
`(Ex. 1002), Shimabukuro-Vornhagen (Ex. 1003), Herman (Ex. 1004), and/or
`
`Uckun (Ex. 1005).
`
`13.
`
`I have been asked to offer my opinions in response. In forming my
`
`opinions, I have considered the materials cited in this declaration and in the
`
`attached Appendix B. I may consider additional documents and information in
`
`forming any supplemental opinions. To the extent I consider additional documents
`
`or information, including any expert declarations in this proceeding, I may offer
`
`further opinions.
`
`13
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`IV. BACKGROUND OF GRAFT VERSUS HOST DISEASE
`cGVHD Is a Major and Life-threatening Complication of
`A.
`HCT
`Chronic GVHD (“cGVHD”) is the most common and serious long-
`
`14.
`
`term complication following an allogenic hematopoietic cell transplant (HCT). Ex.
`
`1001, 1:28-31; Ex. 2002, 1, 12, 17; Ex. 2047, 946. It occurs when a donor’s
`
`immune cells (the “graft”) recognize the recipient as non-self and employ a wide
`
`range of immune mechanisms to attack the recipient’s tissues (the “host”). As
`
`discussed further below, this mode of immune inflammation is mediated by
`
`aberrant auto- or allo-reactive T cells, B cells, and other immune cells. See infra
`
`§ IV.C.
`
`15.
`
`cGVHD is a major cause of morbidity and mortality, affecting
`
`between 30-70% of patients who survive beyond the first 100 days post-transplant.
`
`Ex. 1001, 1:29-45; Ex. 2001, 2; Ex. 2002, 1, 12, 17; see also Ex. 1003, 7, 10.
`
`Symptoms usually present within three years after HCT. Ex. 2047, 946. It is a
`
`long-term illness that can last for years. Ex. 2059, 205. cGVHD and its associated
`
`complications are the leading cause of delayed non-relapse mortality in HCT
`
`patients. Ex. 1001, 1:32-36. For patients surviving beyond one-year post-
`
`transplant, about 50% develop cGVHD. Ex. 2059, 203.
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`14
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`16.
`
`cGVHD is a complex disease that can affect any organ system. Ex.
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`2001, 2, 3; Ex. 2005, 29-31, 33. It significantly harms tissue and organ function,
`
`leading to infection, end-stage lung disease, skin erythema, scarring, joint
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`contractures, and destruction of glands in the eyes, mouth, skin, and digestive tract.
`
`Ex. 2003, 2; Ex. 2006, 2; Ex. 1003, 10. If sclerotic changes develop, cGVHD may
`
`restrict mouth opening and cause joint stiffness or contractures. Ex. 2002, 15-16.
`
`Sclerodermatous cGVHD is one form of cGVHD that may involve the dermis
`
`and/or the subcutaneous facia. Ex. 2005, 29. cGVHD is also associated with
`
`visceral involvement, including liver and lung. Ex. 2002, 16; Ex. 2003, 2. For
`
`example, bronchiolitis obliterans, which significantly impacts normal lung
`
`function, can be fatal. Ex. 2002, 16; Ex. 2003, 2. Ultimately, cGVHD increases
`
`“mortality resulting from profound chronic immune suppression leading to
`
`recurrent or life-threatening infections.” Ex. 2047, 946. It is also a “major cause”
`
`of late treatment-related mortality. Ex. 2047, 954; Ex. 2059, 203.
`
`17.
`
`cGVHD is thus a serious and often life-threatening complication of
`
`HCT. Ex. 2059, 203. It is becoming more prevalent because more and more
`
`patients are both receiving HCT and surviving longer after transplant. Ex. 2059,
`
`203. Consequently, there has been “a significant increase in the number of
`
`transplant survivors living with, and in some cases dying from, CGVHD.” Ex.
`
`2003, 1. cGVHD is thus a serious and growing concern. Ex. 2059, 203. As Dr.
`
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`Ferrara noted in 2010, “[n]ovel approaches to GVHD are thus urgently needed.”
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`Case IPR2019-00865
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`Ex. 2002, 17.
`
`B.
`
`18.
`
`cGVHD Is Distinct From and Treated Differently Than
`aGVHD
`Historically, GVHD was classified based on the time of onset. Ex.
`
`2001, 2. Symptoms appearing within 100 days post-transplant were categorized as
`
`acute GVHD (aGVHD), whereas symptoms presenting after 100 days post-
`
`transplant were labeled as chronic GVHD. Ex. 2047, 946-47; Ex. 1003, 7; Ex.
`
`2001, 2; Ex. 2007, 2; Ex. 2059, 204. By 2013, however, aGVHD and cGVHD
`
`were understood to be distinct diseases involving unique pathophysiologies and
`
`cell types, and clinical manifestations, not time of onset, were used to categorize
`
`the disease as either acute or chronic. Ex. 2047, 947; Ex. 1003, 7; Ex. 2001, 2; Ex.
`
`2003, 2 (“Not surprisingly, the immune mechanisms implicated in the induction
`
`and propagation of CGVHD differ from those of acute GVHD.”); see also Ex.
`
`2005, 27, 31; Ex. 2059, 203 (“These data support the notion cGVHD is not merely
`
`a time-dependent expression of aGVHD.”), 204 (referring to Ex. 2047); Ex. 2001,
`
`2; Ex. 2004, 1-2 (citing Ex. 2047).
`
`19.
`
`Clinical aGVHD is characterized by selective epithelial damage of
`
`target organs, typically in gut or liver. Ex. 2005, 9. aGVHD may damage or even
`
`destroy the epidermis and hair follicles. Ex. 2005, 9. Small bile ducts and
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`intestinal crypt cells may also be profoundly affected. Ex. 2005, 9. Patients with
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`Case IPR2019-00865
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`aGVHD may exhibit maculopapular rash; nausea, vomiting, anorexia, profuse
`
`diarrhea, GI bleeding, or ileus (gut involvement); and cholestatic hepatitis or
`
`hepatic failure (liver involvement). Ex. 2047, 951.
`
`20. While some of these clinical manifestations may accompany
`
`cGVHD in the form of “overlap syndrome,” a diagnosis of cGVHD requires
`
`“[d]istinction from acute GVHD.” Ex. 2047, 946, 951. According to NIH
`
`diagnostic criteria, cGVHD must also include “at least 1 diagnostic clinical sign of
`
`chronic GVHD or presence of at least 1 distinctive manifestation confirmed by
`
`pertinent biopsy or other relevant tests.” Ex. 2047, 946; Ex. 2004, 1 (citing Ex.
`
`2047). cGVHD is much more commonly associated with fibrosis and scarring.
`
`Ex. 2069, 102; Ex. 2047, 949. Diagnostic clinical signs of cGVHD include,
`
`without limitation, poikiloderma, lichen planus-like eruption, deep sclerotic
`
`features, esophageal web, and fasciitis. Ex. 2047, 947-50. Distinctive signs and
`
`symptoms of cGVHD “refer to those manifestations that are not ordinarily found in
`
`acute GVHD but are not considered sufficient to establish an unequivocal
`
`diagnosis of chronic GVHD without further testing or additional organ
`
`involvement.” Ex. 2047, 947. Of course, to diagnose cGVHD, one must also rule
`
`out other possible diagnoses, such as infection or recurrence of malignancy. Ex.
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`17
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`2047, 946-47. Thus, by 2013, cGVHD was understood to be distinct from aGVHD
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`Case IPR2019-00865
`U.S. Patent No. 9,795,604
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`and was diagnosed and treated accordingly. Ex. 2059, 203-207.
`
`C. The Pathogenesis of cGVHD Is Complex and Incompletely
`Understood
`Although decades of work—both experimental studies and clinical
`
`21.
`
`observations—“have elucidated the pathophysiology of acute GVHD, []the biology
`
`of CGVHD has not been determined.” Ex. 2003, 1; Ex. 2005, 27-28 (“no singular
`
`pathologic feature of the former predicts the development of the latter”), 31 (“The
`
`pathophysiology of chronic GVHD is generally much less well understood than
`
`that of acute GVHD and has undergone less intensive experimental modeling.”);
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`Ex. 2059, abstract (“Pathophysiology of cGVHD is complex and poorly
`
`understood.”).
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`22.
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`Historically, the pathophysiology, prevention, and treatment of
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`cGVHD focused on donor T lymphocytes and strategies aimed at suppressing or
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`eliminating these cells. Ex. 2003, 4. For years, cGVHD had been thought of as a
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`predominantly T-cell condition. See also Ex. 2082, 1532. Specifically, cGVHD
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`had been attributed to the activation and overexpansion of pro-inflammatory
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`allo/autoreactive effector T-cells; the deficiency or dysfunction of anti-
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`inflammatory regulatory T-cells (Tregs); or both. Ex. 2082, 1532. Data from prior
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`art reports also “suggest[ed] that there are distinct T cell co-stimulatory
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`requirements in acute and chronic GVHD for various types of target organ
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`damage.” Ex. 2069, 107. While there was “conflicting data in humans concerning
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`the role of Tregs in the development of cGVHD” (Ex. 2059, 204), the prior art
`
`recognized “an intriguing possibility, given the negative impact of calcineurin
`
`inhibitors on Tregs, is that chronic GVHD results – or is exacerbated – as a
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`consequence of suppression of both the alloreactive donor cytopathic and the
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`regulatory T cells.” Ex. 2069, 109.
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`23.
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`By 2011, other theories about the pathophysiology of cGVHD were
`
`just starting to emerge. Some researchers reported that “[s]o far, at least 4 theories
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`have been generated to explain how CGVHD develops.” Ex. 2003, 2. Potential
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`involvement of B cells was but one of these theories (Ex. 2003, 4), that was poorly
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`developed as of 2013 (see generally Ex. 1003). For example, Shimabukuro-
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`Vornhagen states that “[t]he mechanisms by which B cells contribute to acute and
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`chronic GVHD currently are only incompletely understood.” Ex. 1003, 7. It
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`further states that “[o]ne of the major tasks of future research on the role of B cells
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`in GVHD will be to identify better markers for the pathogenic and protective B-
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`cell subsets and to dissect the relative contribution of antibody production, antigen-
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`presentation, and cytokine production by these B cells to the pathogenesis of
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`GVHD.” Ex. 1003, 12. In 2013, GVHD researchers reiterated that “[t]he
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`pathophysiology of cGVHD is poorly understood (to say the least) despite several
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`decades of research.” Ex. 2059, 204.
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`24.
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`Dr. Ferrara agrees that much was unknown. In 2009, he explained:
`
`By contrast with acute GVHD, the pathophysiology of
`chronic GVHD remains poorly understood . . . . The
`response of chronic GVHD to treatment is unpredictable,
`and mixed responses in different organs can take place in
`the same patient.
`
`Ex. 2007, 7.
`
`25.
`
`In 2012, he expanded on these concerns:
`
`It is important to understand that, given the myriad clinical
`presentation of chronic GVHD that tend to occur at
`variable time after HCT [transplant], it is possible that
`separate pathogenic mechanisms might be involved in
`causing distinct manifestations and that no single putative
`mechanism might be sufficient to cause chronic GVHD.
`
`Ex. 2005, 33.
`
`26.
`
`The art further taught that B cells represent only one part of the
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`complex milieu of immunomodulatory cells implicated in cGVHD. Ex. 2001, 1-
`
`11; Ex. 2003, 2-5; Ex. 2004, 9-10; Ex. 2017, 3; Ex. 2054, 8; Ex. 2059, 204; Ex.
`
`2069, 107-110. For example, Linhares and colleagues report that T cells and B
`
`cells appear to be involved in cGVHD pathogenesis. Ex. 2059, 204. They state
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`that “T- and B-cell pathways and others are potential targets for treating cGVHD”
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`but that to date “no immune parameter(s) is a reliable biomarker of diagnosis,
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`severity, prognosis or therapy outcome of cGVHD.” Ex. 2059, 204. Based on this
`
`understanding, Linhares states that “clinical trials, ideally randomized, blinded and
`
`placebo controlled, are the sole way to know whether a therap[eutic] intervention
`
`in cGVHD is safe and effective.” Ex. 2059, 204.
`
`27.
`
`The relative dearth of understanding about the pathogenesis and
`
`treatment of cGVHD was compounded by the absence of established animal
`
`models. Ex. 2003, abstract; Ex. 2006, 2. By 2013, no single animal model
`
`captured all of the features and kinetics of cGVHD. Ex. 2069, 103. Researchers
`
`explained that the lack of appropriate experimental models may be a result of
`
`differences between humans and experimental species. Ex. 2069, 103. For
`
`example, in contrast to murine models, the kinetics of clinical cGVHD in humans
`
`are slower and observed after administration of prophylaxis and/or treatment for
`
`aGVHD. Ex. 2069, 103. In animal models, the subject animals do not receive any
`
`prior treatment, whereas human cGVHD patients would have received other
`
`prophylaxis regimens. Ex. 2069, 103. And, even when clinical cGVHD arises de
`
`novo and in the absence of active immunosuppression, it was “not possible to
`
`definitively rule out the impact of either GVH prophylaxis and/or subclinical acute
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`GVHD on the subsequent development of chronic GVHD.” Ex. 2069, 103.
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`28.
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`Other researchers similarly noted the poor correlation between
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`
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`animal models and cGVHD in human patients. Ex. 2003, 5-6; Ex. 2005, 32; Ex.
`
`2008, 7; Ex. 2054, 2. For example, Min described various mouse models meant to
`
`permit study of the pathogenesis of cGVHD but identified multiple limitations.
`
`Ex. 2003, 5-6. In one instance, Min stated that “it is not clear whether the
`
`mechanisms revealed by this model reflect the pathogenesis of CGVHD in human
`
`transplant recipients receiving conditioning.” Ex. 2003, 5. In addition, Min stated:
`
`“the relevance of this model for human CGVHD is questionable because even
`
`though dsDNA-specific autoantibodies, immune complex glomerulonephritis, and
`
`proteinuria are characteristic of systemic lupus, they rarely occur in patients with
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`CGVHD.” Ex. 2003, 6. Thus, “[b]ecause models of CGVHD do not replicate
`
`human disease . . . it is difficult to determine whether these results can be
`
`applicable to clinical GVHD prevention and treatment.” Ex. 2008, 7. Dr. Ferrara
`
`acknowledged in 2012 that the hurdles to developing therapies for cGVHD were
`
`“due in part to the absence of appropriate animal models that can capture the
`
`kinetics and the protean manifestation of chronic GVHD.” Ex. 2005, 32; Ex. 2054,
`
`2 (“this paucity of appropriate mouse models for chronic GVHD has resulted in a
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`lack of significant understanding of the immunobiology of chronic GVHD when
`
`compared with acute GVHD”).
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`D. Treatment of cGVHD Is Difficult, Especially in Steroid-
`Dependent/Refractory, Steroid-Resistant, or Refractory
`cGVHD Patients
`29. While progress had been made in preventing and treating aGVHD,
`
`“[t]here has been little progress over the past 30 years in preventing and/or treating
`
`cGVHD.” Ex. 2059, 203. Indeed, there had been numerous notable failures. Infra
`
`§ IV.E.
`
`30.
`
`In 2012, a joint working group of British bone marrow specialists
`
`reported that “[a] clear diagnostic and management strategy for cGVHD had been
`
`difficult to achieve due to the polymorphic nature of the disorder and the paucity of
`
`evidence for the majority of treatment options.” Ex. 2001, 2; see also Ex. 2004, 6
`
`(“Due to a relatively limited understanding of cGVHD pathogenesis, developing
`
`preventative strategies specifically for this complication of allo-HCT has been
`
`more difficult.”).
`
`31.
`
`Corticosteroids, often simply referred to as steroids, have been and
`
`still are today, the first line therapy for cGVHD. Ex. 2001, 3; Ex. 2047, 954. Mild
`
`cGVHD “may often be treated with local therapies alone (e.g., topical steroids to
`
`the skin).” Ex. 2047, 954; see also Ex. 2001, 3. For more severe cGVHD where
`
`multiple organs are involved, “systemic immunosuppressive therapy may be
`
`considered.” Ex. 2047, 954. Corticosteroids have been used as first line treatment
`
`in cGVHD since the 1980s. Ex. 2001, 3; Ex. 2004, 8 (“The most widely used
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`initial systemic treatment of cGVHD relies on prednisone in conjunction with a
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`calcineurin inhibitor.”).
`
`32.
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`If a patient’s cGVHD improves with steroids plus/minus calcineurin
`
`treatment, a physician will attempt to taper the steroid dose. Ex. 2001, 3-4; Ex.
`
`2006, 2. There was no consistent tapering protocol emplo