UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`SANDOZ INC.,
`Petitioners
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`v .
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`PHARMACYCLICS LLC,
`Patent Owner.
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`U.S. Patent No. 9,795,604 to Byrd et al.
`Issue Date: October 24, 2017
`Title: Methods of Treating and Preventing Graft Versus Host Disease
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`Inter Partes Review No.: IPR2019–00865
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`DECLARATION OF JAMES L. FERRARA, M.D.
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`SAN EX 1006, Page 1
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`I.
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`TABLE OF CONTENTS
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`Introduction ...................................................................................................... 1
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`II. My Background and Qualifications ................................................................. 2
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`III. List of Documents Considered ........................................................................ 4
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`IV. Background of the Technology ....................................................................... 4
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`A.
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`Ibrutinib ................................................................................................. 4
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`B.
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`Graft Versus Host Disease .................................................................... 8
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`1.
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`2.
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`Two Types of GVHD: Acute and Chronic ...............................10
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`Chronic GVHD .........................................................................13
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`V.
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`Claim Construction ........................................................................................15
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`A.
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`“Therapeutically Effective Amount” ..................................................16
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`B.
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`C.
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`“Thereby Treating the Chronic GVHD in the Patient” .......................17
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`Ibrutinib’s Chemical Structure ............................................................18
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`VI. Person of Ordinary Skill in the Art ................................................................20
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`VII. The Prior Art Pertinent to the Petition ...........................................................21
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`A.
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`The ’085 Publication ...........................................................................21
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`B.
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`C.
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`Shimabukuro-Vornhagen ....................................................................23
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`Herman ................................................................................................26
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`D. Uckun ..................................................................................................28
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`VIII. Ground 1: The Challenged Claims Are Anticipated by the ’085
`Publication .....................................................................................................30
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`A.
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`Legal Standard for Anticipation ..........................................................30
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`B.
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`The ’085 Publication Anticipates Independent Claim 1 of the
`’604 Patent ...........................................................................................30
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`1.
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`2.
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`“A method of treating chronic graft versus host disease
`(GVHD)” ...................................................................................31
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`“Administering to a patient having chronic GVHD a
`therapeutically effective amount of” ibrutinib ..........................32
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`3.
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`“thereby treating the chronic GVHD in the patient” ................34
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`The ’085 Publication Anticipates Dependent Claims 4, 13, and
`15 .........................................................................................................35
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`The ’085 Publication Anticipates Dependent Claims 6, 7, 8, 29,
`30, 31, 44, 45, 46, 51, 52, 53 ...............................................................36
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`The ’085 Publication Anticipates Dependent Claim 9 ........................37
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`The ’085 Publication Anticipates Dependent Claim 10 ......................39
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`The ’085 Publication Anticipates Dependent Claims 24, 28, 35,
`39, 43, 50 and Independent Claim 55 .................................................40
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`C.
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`D.
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`E.
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`F.
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`G.
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`IX. Ground 2: The Challenged Claims Would Have Been Obvious in
`View of the ’085 Publication .........................................................................42
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`A.
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`Legal Standard for Obviousness .........................................................42
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`B.
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`C.
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`Claim 1 Would Have Been Obvious in View of the ’085
`Publication ...........................................................................................43
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`Dependent Claims 4, 13, and 15 Would Have Been Obvious in
`View of the ’085 Publication ..............................................................44
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`D. Dependent Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, and 53
`Would Have Been Obvious in View of the ’085 Publication .............45
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`E.
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`F.
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`Dependent Claim 9 Would Have Been Obvious in View of the
`’085 Publication ..................................................................................45
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`Dependent Claim 10 Would Have Been Obvious in View of the
`’085 Publication ..................................................................................46
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`G. Dependent Claims 24, 28, 35, 39, 43, 50 and Independent
`Claim 55 Would Have Been Obvious in View of the ’085
`Publication ...........................................................................................47
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`H.
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`Secondary Considerations of Nonobviousness ...................................47
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`X. Ground 3: The Challenged Claims Would Have Been Obvious in
`View of the ’085 Publication Combined with Shimabukuro-
`Vornhagen and Herman .................................................................................47
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`A. Motivation to Combine the ’085 Publication, Shimabukuro-
`Vornhagen, and Herman .....................................................................48
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`B.
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`C.
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`The Combination of References Render Claim 1 Obvious to a
`POSA with a Reasonable Expectation of Success ..............................51
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`Dependent Claims 4, 13, and 15 Would Have Been Obvious in
`View of the ’085 Publication ..............................................................52
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`D. Dependent Claims 6, 7, 8, 29, 30, 31, 44, 45, 46, 51, 52, 53
`Would Have Been Obvious in View of the ’085 Publication .............53
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`E.
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`F.
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`Dependent Claim 9 Would Have Been Obvious in View of the
`’085 Publication ..................................................................................53
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`Dependent Claim 10 Would Have Been Obvious in View of the
`’085 Publication ..................................................................................54
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`G. Dependent Claims 24, 28, 35, 39, 43, 50 and Independent
`Claim 55 Would Have Been Obvious in View of the ’085
`Publication ...........................................................................................54
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`XI. Ground 4: The Challenged Claims Would Have Been Obvious Over
`the ’085 Publication in view of Shimabukuro-Vornhagen and Uckun .........55
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`A. Motivation to Combine the ’085 Publication, Shimabukuro-
`Vornhagen, and Uckun ........................................................................55
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`B.
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`The Combination of References Rendered the Challenged
`Claims Obvious to a POSA, with a Reasonable Expectation of
`Success ................................................................................................57
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`XII. Conclusion .....................................................................................................59
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`I.
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`Introduction
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`1.
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`I have been retained as an expert witness on behalf of Sandoz Inc.
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`(“Sandoz”) for the above-captioned inter partes review (“IPR”) proceeding. I am
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`over the age of eighteen (18) and otherwise competent to make the statements
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`contained in this Declaration, which I understand will be submitted in support of
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`Sandoz’s IPR petition. I am being compensated for my time in connection with this
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`IPR proceeding at my standard consulting rate, which is $500 per hour. My
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`compensation does not depend in any way on the outcome of this proceeding. I hold
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`no interest in Sandoz Inc. or Lek Pharmaceuticals D.D.
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`2.
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`I have been informed that the IPR proceeding involves the validity of
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`U.S. Patent No. 9,795,604 (the “’604 Patent”), EX1001. In analyzing the validity of
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`the ’604 Patent, I have been instructed to consider references published prior to
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`October 25, 2013. I have been informed that such references are referred to as “prior
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`art.”1 Thus, I will refer to these references as prior art in this Declaration. I confirm
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`1 While I am not an attorney, Sandoz’s counsel has explained certain aspects of
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`patent law to me that are relevant to the discussion in this Declaration. I state
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`throughout this Declaration where my understanding of an aspect of patent law has
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`been informed by counsel.
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`1
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`that the opinions expressed in this Declaration are my own and are based on my
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`independent review of the prior art.
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`II. My Background and Qualifications
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`3.
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`I have over 30 years of experience relating to the prevention, diagnosis,
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`and treatment of graft versus host disease (“GVHD”), which is a major complication
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`of allogeneic bone marrow transplantation. I received my M.D. from Georgetown
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`University in 1976, and completed my residency at Children’s Hospital in Boston,
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`Massachusetts. I then completed my fellowship in Pediatric Hematology/Oncology
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`at Children’s Hospital and
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`the Dana-Farber Cancer Institute
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`in Boston,
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`Massachusetts.
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`4.
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`I am currently employed by Icahn School of Medicine at Mount Sinai
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`as the Director of the Hematologic Malignancies Translational Research Center. I
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`have been with Mount Sinai since 2014.
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`5.
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`I have been employed as a Professor of Pediatrics and Internal Medicine
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`at Mount Sinai since 2014. Additionally, I am Professor of Cancer Medicine at
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`Mount Sinai. Prior to that, I was a Professor of Pediatrics and Internal Medicine at
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`the University of Michigan Medical School, a post I held from 1998–2014.
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`6. My current research interest focuses on treating, preventing, and
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`diagnosing GVHD. Clinically, my practice focuses on patients that undergo bone
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`marrow transplants as these patients are at risk of GVHD. I have treated hundreds of
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`patients with GVHD (both acute and chronic) over the past 30 years. I currently
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`monitor approximately 800 transplant patients per year from 24 different
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`hematopoietic cell transplant centers in the Mount Sinai Acute GVHD International
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`Consortium for the development of GVHD and the patients’ long-term outcomes. In
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`my clinical research capacity, I have served as chairman of the steering committee
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`of the Bone Marrow Transplant Clinical Trials Network.
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`7.
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`I have served as the principal investigator for a variety of research
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`grants and industry contracts.
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`8.
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`I have authored numerous articles and book chapters related to GVHD
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`as well as over 200 peer-reviewed articles in such journals as NEW ENGLAND
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`JOURNAL OF MEDICINE, THE JOURNAL OF CLINICAL INVESTIGATION, BLOOD, NATURE
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`MEDICINE, THE LANCET, AMERICAN JOURNAL OF HEMATOLOGY, INTERNATIONAL
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`JOURNAL OF HEMATOLOGY, and others.
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`9.
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`I have received numerous awards throughout my career such as election
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`to The American Society of Clinical Investigation and The American Association of
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`Physicians, and citations in “America’s Top Physicians Citation,” “America’s Top
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`Doctors Citation,” “Who’s Who in America,” and many others.
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`10.
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`I am considered an internationally recognized expert in the field of
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`hematology and specifically in the field of bone marrow transplantation and GVHD.
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`I have served on the editorial board of the JOURNAL OF IMMUNOLOGY, HEMATOLOGY
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`REVIEWS AND COMMUNICATIONS TRANSPLANTATION, and TRANSPLANTATION
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`IMMUNOLOGY AND BONE MARROW TRANSPLANTATION. I currently serve on the
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`editorial board of BIOLOGY OF BLOOD MARROW TRANSPLANTATION.
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`11. Additionally, I have held a variety of consulting roles, including being
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`the Scientific Director for the American Society of Blood and Marrow
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`Transplantation from 2002–2004.
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`12.
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`I provide additional details of my background and experience in my
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`curriculum vitae, attached as Exhibit A to this Declaration.
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`III. List of Documents Considered
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`13.
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`I have considered all of the documents I cite in this Declaration and all
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`of the documents cited in the Petition for Inter Partes Review of U.S. Patent No.
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`9,795,604 (the “Petition”) in forming my opinions. I refer to the prior art references
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`and other documents cited in this Declaration using the same exhibit numbers and
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`terminology as presented in the Petition.
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`IV. Background of the Technology
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`A.
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`Ibrutinib
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`14.
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`I am familiar with ibrutinib, its mechanism of action, and uses. As part
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`of my practice, I have prescribed ibrutinib to patients with chronic GVHD.
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`15. As I note above, I reviewed the ’604 Patent. The ’604 Patent provides
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`an image of ibrutinib’s molecular structure as follows:
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`(EX1001 at 53:25–45).
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`16.
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`In forming the opinions I discuss in this Declaration, I also reviewed
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`several prior art references that disclose information about ibrutinib. For example, I
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`reviewed U.S. Patent Application Publication No. 2015/0140085 A1 (the “’085
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`Publication”). The ’085 Publication discloses ibrutinib and explains that the drug
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`had been extensively studied in animals and humans due to its well-known ability to
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`irreversibly inhibit the Bruton’s tyrosine kinase (“BTK”) enzyme, which is located
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`in the cytoplasm of B cells. (EX1002 at ¶¶ [0002]–[0005]).
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`17. The ’085 Publication also discloses that Phase II human studies had
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`shown that ibrutinib has clinical effectiveness in treating B-cell malignancies CLL
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`and SLL and was showing promise in clinical trials for several other diseases.
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`(EX1002 at ¶ [0004]). Specifically, the studies demonstrated that oral administration
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`of 420 mg/day or 840 mg/day of ibrutinib provided desired therapeutic benefits to
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`patients with CLL and SLL. (EX1002 at ¶¶ [0004], [0005]).
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`18. Other prior art references I reviewed also disclose ibrutinib, its
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`chemical structure, and its effectiveness in treating various B-cell mediated diseases.
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`For example, U.S. Patent No. 7,514,444 (“the ’444 Patent”), discloses ibrutinib and
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`provides the following image of its chemical structure:
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` (EX1012 at Claim 8).
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`19. U.S. Patent No. 8,476,284 discusses using ibrutinib to treat lymphomas.
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`(EX1018 at claim 11). Likewise, U.S. Patent No. 8,497,277 B2 discusses using
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`ibrutinib to treat a number of B-cell-related diseases such as chronic lymphocytic
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`leukemia (“CLL”); Waldenström’s macroglobulinemia (“WM”); and non-Hodgkin
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`lymphomas such as diffuse large B cell lymphoma, follicular lymphoma, mantle cell
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`lymphoma, and Burkitt lymphoma. (EX1019 at claims 8, 9, and 18).
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`20. Several prior art journal articles I reviewed disclosed using ibrutinib to
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`treat a variety of diseases. For example, I reviewed an article by Honigberg et al.
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`explaining that, by 2010, ibrutinib was used in mice to successfully treat
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`autoimmune diseases such as arthritis and lupus-related kidney disease and in dogs
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`to treat the hematologic disease B-cell non-Hodgkin lymphoma. (EX1015 at 13075).
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`The Honigberg article also provides an image of ibrutinib’s chemical structure.
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`(EX1015 at 13076).
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`21.
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`I also reviewed an article by Advani et al. explaining that, in light of
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`the research conducted on ibrutinib, including the results of promising animal
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`studies, by 2010, Phase I studies of ibrutinib in humans were underway. These
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`clinical trials studied the use of ibrutinib in patients with hematologic B-cell
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`malignancies, including CLL, small lymphocytic lymphoma (“SLL”), diffuse large
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`B-cell lymphoma, follicular lymphoma, non-Hodgkin lymphoma, mantle-cell
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`lymphoma, and WM. (EX1016 at 89, 93).
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`22. An article in 2010 by Uckun et al. disclosed ibrutinib and its chemical
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`structure and explained that the drug was known to exhibit promising activity in
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`treating B-cell malignancies such as lymphoma. (EX1005 at 1464).
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`23.
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`In 2010 ibrutinib was known to have a few primary mechanisms of
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`action. First, as I mentioned above, ibrutinib was known to inhibit the BTK enzyme,
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`a fact that was discussed in several of the prior art references I reference above.
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`(EX1005 at 1464; EX1016 at 88; EX1016 at 13075; EX1002 at ¶¶ [0002]–[0005]).
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`By 2013, BTK inhibitors had been known for decades to successfully block B cells
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`from expressing cell-surface proteins, including CD80 and CD86. (See, e.g.,
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`EX1007 at 541 (discussing the role of BTK in the expression of CD80 and CD86)).
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`Both of these cell-surface proteins were known before 2013 to play a direct role in
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`antigen presentation and T cell activation—a key part of chronic GVHD’s
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`mechanism of action, as discussed in more detail below. (EX1003 at 4920–21).
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`Second, a 2011 article by Herman et al. (discussed further below) disclosed that
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`ibrutinib had a direct effect on T cells by inhibiting their production of inflammatory
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`cytokines that play an important role in chronic GVHD, such as IL-6 and TNF-α.
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`(EX1004 at 6291).
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`B. Graft Versus Host Disease
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`24. As I mentioned above, one of my primary research interests is the study
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`of GVHD. GVHD is a potentially serious complication of allogeneic hematopoietic
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`stem cell
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`transplantation, which
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`is commonly known as bone marrow
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`transplantation. During allogeneic hematopoietic stem cell transplantation, a patient
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`receives stem cells from a living donor or donated umbilical cord blood. The
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`donated stem cells contain T cells and B cells, which are types of white blood cell
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`that work together to help protect the body by recognizing foreign invaders (like
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`infections or bacteria) and then destroying them. T cells also attack cancer cells,
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`which is how allogeneic hematopoietic stem cell transplantation works to treat some
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`cancers.
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`25. However, after allogeneic hematopoietic stem cell transplantation,
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`donor T cells and B cells (the “graft”) may also work together to attack the patient’s
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`healthy tissues and organs (the “host”), which can harm tissue and organ function,
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`which—in some cases—may lead to patient death. This condition is called “graft
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`versus host disease” which is commonly abbreviated as GVHD. There are two types
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`of GVHD: acute GVHD and chronic GVHD, which I discuss in more detail below.
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`26. Allogeneic hematopoietic stem cell transplantation is used to treat
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`approximately a dozen diseases, including acute myeloid leukemia, chronic myeloid
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`leukemia, acute lymphoblastic leukemia, CLL, Hodgkin and Non-Hodgkin
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`lymphoma, myelodysplastic syndromes, severe combined immunodeficiency, and
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`aplastic anemia.
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`27.
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`In allogeneic hematopoietic stem cell transplantation, the patient will
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`be administered medication, typically chemotherapy, that kills the cells in the
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`patient’s bone marrow. (EX1003 at 4919). The goal is to eliminate the cells in the
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`patient’s bone marrow, thereby eliminating the patient’s underlying disease as well.
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`(EX1005 at 1461). After the patient’s bone marrow has been ablated, the patient will
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`receive transplanted bone marrow from a donor containing stem cells and white
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`blood cells (such as T cells and B cells). As noted above, in a successful allogeneic
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`hematopoietic stem cell transplantation, the transplanted stem cells and white blood
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`cells regenerate and function normally, without recurrence of the hematologic
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`disease that prompted the transplantation.
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`28. But as with other types of transplantation, allogeneic hematopoietic
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`stem cell transplantation often results in GVHD. In fact, GVHD is a major cause of
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`morbidity and mortality after allogeneic hematopoietic stem cell transplantation and
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`limits the use of the treatment. (EX1003 at 4919); (EX1005 at 1461). The vast
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`majority of GVHD cases (>95%) and virtually all chronic GVHD cases are caused
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`by allogeneic hematopoietic stem cell transplantation.
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`1.
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`Two Types of GVHD: Acute and Chronic
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`29. As noted above, GVHD is divided into two types: acute and chronic.
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`(EX1003 at 4919). Traditionally, acute GVHD was defined as disease occurring in
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`the first 100 days after transplantation, whereas chronic GVHD occurs after day 100.
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`(EX1003 at 4919). More recently, practitioners have moved away from the strict
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`over/under 100-day guideline for categorizing GVHD as acute or chronic and have
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`instead focused on the clinical characteristics of disease presentation. (EX1003 at
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`4919).
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`30. Chronic GVHD is a major cause of morbidity and mortality in long-
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`term survivors of hematopoietic stem cell transplantation. (EX1003 at 4922). Up to
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`70% of allogeneic hematopoietic stem cell transplantation patients experience
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`chronic GVHD. (EX1003 at 4922). Chronic GVHD affects a wide range of organs
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`and has features resembling autoimmune disorders. (EX1003 at 4922). Among the
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`most commonly affected organs are the skin, liver, gut, lung, and mucous
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`membranes. (EX1003 at 4922). Chronic GVHD can lead to debilitating
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`complications such as joint contractures, blindness, and end-stage lung disease.
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`(EX1003 at 4922).
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`31. Chronic GVHD may develop continuously from acute GVHD or occur
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`after resolution of acute GVHD. (EX1003 at 4922). Prior development of acute
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`GVHD is the primary risk factor for the development of chronic GVHD, although it
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`is possible to develop chronic GVHD without having first developed acute GVHD.
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`32. Acute GVHD and chronic GVHD are closely related. Physicians
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`commonly prescribe a number of the same drug treatments to patients with acute
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`GVHD and to patients with chronic GVHD. (See, e.g., EX1003 at 4922). For
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`example, glucocorticoids (a type of steroid), such as prednisone, with or without a
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`calcineurin inhibitor such as ciclosporin, are the standard regimen as primary
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`treatment for both acute and chronic GVHD. (EX1003 at 4922). Likewise, a number
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`of other promising acute GVHD treatments, such as statins, and extracorporeal
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`photopheresis (“ECP”) also appear useful in treating chronic GVHD. (EX1003 at
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`4919, 4922, 4924) (“ECP has been successfully used to treat acute and chronic
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`GVHD with substantial response rates. . . . Small studies in humans seem to confirm
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`the potential of statins as a GVHD-modifying drug in acute and chronic GVHD”).
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`Reports indicate rituximab has been used to treat both acute and chronic GVHD.
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`(EX1003 at 4922) (“[e]ncouraged by reports of the effectiveness of B-cell depletion
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`in the treatment of chronic GVHD, Kamble et al. treated patients with acute
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`GVHD”).
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`33. While steroids are the primary treatment for chronic GVHD, they are
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`often ineffective. For example, often systemic corticosteroids simply are not able to
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`inhibit inflammatory cytokine production to a large enough extent to treat chronic
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`GVHD. Other times, some patients become resistant to steroids’ ability to inhibit
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`inflammatory cytokine production. Also, in some patients, steroids are discontinued
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`as a treatment option or reduced in dosage because they significantly suppress the
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`immune system or cause other toxicities. In any of these patients a person of ordinary
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`skill in the art as of October 25, 2013 (“POSA”) would have used a second-line
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`treatment, including those that would have helped inhibit inflammatory cytokine
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`production, to help treat the patient’s chronic GVHD.
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`34. Chronic GVHD in patients for whom steroids are not effective is called
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`“refractory” chronic GVHD or “steroid resistant” chronic GVHD. Even when
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`steroids do work, some patients become “steroid-dependent,” meaning that their
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`chronic GVHD gets worse when treatment with steroids is discontinued.
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`35. Thus, researchers developed other drugs intended as second-line
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`treatments for chronic GVHD. Their research focused on the role of lymphocytes,
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`specifically T cells and B cells, in causing the disease. (EX1003 at 4919, 4920).
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`2.
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`Chronic GVHD
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`36. Chronic GVHD is an immune-mediated disease resulting from an
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`interaction between the lymphocytes (which are composed primarily of B cells and
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`T cells) in the donor bone marrow and cells in the recipient’s body. Until the early
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`2000s, T cells were considered to be the main effector cells mediating chronic
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`GVHD pathogenesis. (EX1003 at 4919) (“T cells have been identified as key players
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`in the graft-versus-host reaction and, therefore, most established drugs used against
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`GVHD target T cells.”). Thus, initial preventive and therapeutic treatment strategies
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`focused primarily on inhibiting T-cell function. (EX1003 at 4919). For example, it
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`has been known for decades that many inflammatory cytokines—which are proteins
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`created by a number of cells, including T cells—are produced in an abnormal fashion
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`in patients with chronic GVHD. (EX1010 at 169) (“Cytokines play a key role in the
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`pathogenesis of chronic Graft versus Host Disease (cGVHD) and various studies
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`have shown aberrant production of cytokines by immune cells from GVHD
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`patients.”). Two such cytokines known to be abnormally created in patients with
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`chronic GVHD are IL-6 and TNF-α. (EX1010 at 169) (“Many cytokines are
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`produced in an aberrant fashion in patients with cGVHD” including “Tumor
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`Necrosis Factor-alpha (TNF- α)” and “Interleukin-6 (IL-6).”). Indeed, one of the key
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`mechanisms of action of glucocorticoids is suppressing the secretion of
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`inflammatory cytokines such as IL-6 and TNF-α. (EX1022 at 286, 289).
`
`37. Subsequent studies showed that B cells also play an important role in
`
`chronic GVHD. (EX1003 at 4919). For example, activated B cells have been
`
`identified as having a key role in chronic GVHD by presenting antigens that bind to
`
`and activate T cells, which then attack healthy patient cells. (EX1003 at 4920–21).
`
`38. Specifically, it has been known for decades that inhibiting BTK—an
`
`enzyme that exists in the cytoplasm of B cells (but not T cells)—prevents expression
`
`of so-called “costimulatory” CD80 and CD86 proteins on activated B cells. (EX1007
`
`at 541). These “costimulatory” proteins play a key role in T-cell activation and
`
`survival. Without expression of these CD80 and CD86 proteins, B cells are unable
`
`to present antigens effectively to T cells and, thus, are unable to activate the T cells.
`
`(EX1003 at 4920–21).
`
`39. Due to this downstream effect that inhibiting BTK in B cells has on the
`
`activation of T cells, studies demonstrated that inhibiting BTK in B cells was
`
`effective in preventing acute GVHD in mice. (EX1005 at 1461); (EX1023 at 823)
`
`(“Targeting BTK
`
`.
`
`.
`
`. attenuates fatal acute GVHD across
`
`the major
`
`histocompatibility barrier in mice.”). Similarly, human clinical trials confirmed that
`
`rituximab, a drug that depletes B cells in the body and also down-regulates the
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`expression of important costimulatory molecules, including CD80, was known to
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`treat chronic GVHD effectively. (EX1003 at 4922–23).
`
`V. Claim Construction
`
`40.
`
`I have been instructed that I should read the Claims 1, 4, 6–10, 13, 15,
`
`24, 28–31, 35, 39, 43–46, 50–53, and 55 (the “Challenged Claims”) of the ’604
`
`Patent in accordance with the ordinary meaning that their terms would have as
`
`understood by a POSA unless that ordinary meaning is changed by the ’604 Patent’s
`
`specification or prosecution history. I understand this process of claim interpretation
`
`is known as “claim construction.”
`
`41.
`
`I have construed the terms used in the Challenged Claims as having
`
`their ordinary meaning other than the terms provided below in Table 1.
`
`Claim
`
`Term
`
`Construction
`
`Table 1
`
`1, 5
`
`“therapeutically
`effective amount”
`
`1
`
`“thereby treating
`the chronic GVHD
`in the patient”
`
`Plain and ordinary meaning, including dosages of at
`least about 40 mg/day, about 140 mg/day, about 280
`mg/day, about 420 mg/day, about 560 mg/day, and
`about 840 mg/day.
`
`The phrase includes therapeutic treatments that
`lessen the severity of chronic GVHD, cause
`regression of chronic GVHD, relieve a condition
`caused by chronic GVHD, and stop symptoms
`which result from chronic GVHD.
`
`
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`1, 55
`
`Ibrutinib (also known as PCI-32765).
`
`
`
`“Therapeutically Effective Amount”
`
`I have been instructed that an independent claim must be broader than
`
`A.
`
`42.
`
`and encompass the subject matter of its dependent claims. As an example, I have
`
`been instructed that in many instances, a dependent claim may refer to a term in an
`
`independent claim and provide examples of the subject matter that term
`
`encompasses. In those instances, I understand that the independent claim must
`
`include in its scope the examples provided in the dependent claim.
`
`43. Given this understanding, the phrase “therapeutically effective amount”
`
`should be construed as having its plain and ordinary meaning, including specifically
`
`the dosages of ibrutinib set forth in the dependent claims of the ’604 Patent. This is
`
`because dependent claim 5 recites: “The method of claim 1, wherein the
`
`therapeutically effective amount of the compound is about 40 mg/day, about 140
`
`mg/day, about 280 mg/day, about 420 mg/day, about 560 mg/day, or about 840
`
`mg/day.”
`
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`44. Accordingly, the Board should construe “therapeutically effective
`
`amount” to have its plain and ordinary meaning, encompassing dosages of at least
`
`about 40 mg/day, about 140 mg/day, about 280 mg/day, about 420 mg/day, about
`
`560 mg/day, and about 840 mg/day.
`
`B.
`
`45.
`
`“Thereby Treating the Chronic GVHD in the Patient”
`
`I have been instructed that where an explicit definition is provided in a
`
`patent, that definition generally provides the meaning for the claim term, but the
`
`prosecution history can alter the definition. I have also been instructed that the same
`
`claim terms are presumed to have the same meaning. Here, the phrase “thereby
`
`treating the chronic GVHD in the patient” (and likewise the word “treating” in claim
`
`1’s preamble) should be defined as stated in the ’604 Patent’s specification except
`
`as altered by the prosecution history.
`
`46. The specification explicitly defines the terms “treat,” “treating” and
`
`“treatment,” as follows:
`
`Certain Terminology
`
`. . . .
`
`
`The terms “treat,” “treating” or “treatment”, as used herein,
`include lessening of severity of GVHD, delay in onset of GVHD,
`causing regression of GVHD, relieving a condition caused by of
`GVHD, or stopping symptoms which result from GVHD. The terms
`“treat,” “treating” or “treatment”, include, but are not limited to,
`prophylactic and/or therapeutic treatments.
`
`
`(EX1001 at 25:33, 26:47–53).
`
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`47.
`
`In my opinion the prosecution history altered this definition by
`
`clarifying that “delay in onset of GVHD” and “prophylactic” treatment are not
`
`within the claimed scope. During prosecution, the Patent Owner changed the scope
`
`of claim 1 to exclude a “method of preventing the occurrence” of GVHD. (EX1009
`
`at 2, 6). In my opinion the phrases “delay in onset of GVHD” and “prophylactic”
`
`treatment are examples of a “method of preventing the occurrence.” Thus it should
`
`be excluded from the explicit definition of “treat,” “treating,” and “treatment” found
`
`in the patent.
`
`48. Accordingly, the clause “thereby treating the chronic GVHD in the
`
`patient” should be given the definition set forth in the ’604 Patent’s specification
`
`excluding the phrase “delay in onset of GVHD” as I provide above in Table 1.
`
`49.
`
`I also understand from counsel that there is a legal argument that
`
`“thereby treating the chronic GVHD in the patient” should not be given any weight
`
`in the claim. If that is the case, then I understand that the definition I provide above
`
`would not apply and the clause would be given no weight.
`
`C.
`
`50.
`
`Ibrutinib’s Chemical Structure
`
`I have been instructed that when claim terms are used interchangeably
`
`in the specification, they should be given the same meaning in the claims. The term
`
`ibrutinib and its associated chemical structure are set forth interchangeably in