UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`MILTENYI BIOMEDICINE GmbH and MILTENYI BIOTEC INC.
`Petitioners,
`
`v.
`
`THE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA
`Patent Owner.
`____________________
`
`IPR 2022-00852
`Patent 9,518,123
`____________________
`
`IPR 2022-00855
`Patent 9,540,445
`____________________
`
`EXPERT DECLARATION OF DR. ROBERT NEGRIN
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1 
`I. 
`QUALIFICATIONS ........................................................................................ 2 
`II. 
`III.  LEGAL STANDARDS ................................................................................... 7 
`IV.  THE ’123 AND ’445 PATENTS .................................................................... 9 
`  Overview ............................................................................................... 9 
`Claims .................................................................................................. 12 
` 
`The Time of the Invention or “Priority Date” ..................................... 14 
`The Person of Ordinary Skill In the Art .............................................. 14 
` 
`TECHNICAL BACKGROUND ................................................................... 17 
`T Cell Biology ..................................................................................... 17 
` 
`1. 
`T Cell Phenotypes ..................................................................... 17 
`
`V. 
`
` 
`
`2. 
`
`Graft-versus-Host Disease ........................................................ 23 
`
` 
`
` 
`
`NK Cells .............................................................................................. 24 
`CAR-Modified Immune Cells ............................................................. 27 
`1. 
`The CAR-T Field Prior to the Breakthroughs Achieved
`by the June Group at the University of Pennsylvania ............... 28 
`
`2. 
`
`The CAR NK Field ................................................................... 43 
`
`VI.  THE KEY REFERENCES RELIED ON BY DR. JUNGHANS .................. 45 
`Campana (Exhibit 1003) ..................................................................... 46 
` 
`1. 
`The Sequences of Campana’s CARs ........................................ 47 
`
`2. 
`
`3. 
`
`4. 
`
`Campana Prefers CAR Modified Natural Killer (NK)
`Cells and Teaches Away from Autologous CAR T Cells. ....... 51 
`
`Campana Emphasizes that 4-1BB CARs Have Been
`Much Less Studied than CD28 CARs ...................................... 57 
`
`Campana Used Jurkat Cells and Human Donor T Cells ........... 57 
`
`
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`5. 
`
`6. 
`
`7. 
`
`Campana Teaches that 1:1 Effector:Target Ratios Are
`Required .................................................................................... 60 
`
`Campana Does Not Suggest Autologous CAR T Cells
`Should be Used for the Patient Population CAR T Cells
`Were Being Tested For in 2011 ................................................ 63 
`
`Campana Pivots Away From T Cells and Toward CAR
`NK Cells .................................................................................... 68 
`
` 
`
` 
`
` 
`
`Nicholson (Ex. 1004) .......................................................................... 70 
`Jensen (Ex. 1007) ................................................................................ 71 
`ClinicalTrials.gov (Ex. 1006) .............................................................. 73 
`1. 
`This Study Was Designed to Compare Two Different
`CARs; It was Not Designed for Treatment ............................... 74 
`
`2. 
`
`Exhibit 1006 is Not the Study Described in Porter or in
`Example 1 of the Challenged Patents ....................................... 79 
`
`  Milone (Ex. 1008) ............................................................................... 79 
`1. 
`The Structure of the CAR Disclosed in Exhibit 1008 .............. 80 
`
`2. 
`
`3. 
`
`4. 
`
`The Animal Model .................................................................... 83 
`
`The Use of Donor T Cells ......................................................... 85 
`
`The Paper’s Conclusions ........................................................... 87 
`
` 
`
`Kokendorfer, Brentjens, and Davila. ................................................... 88 
` 
`VII.  THE CHALLENGED CLAIMS OF THE ’455 PATENT ............................ 91 
`Claim Construction of “Anti-Tumor Effective Amount” ................... 91 
` 
`The POSA’s Goal is to Treat Patients ................................................. 96 
`GROUND 1: Claims 1, 2, 4, 6, 8-9, 11, 16, 21-22, and 27-30
`Are Not Obvious Over Campana in View of Nicholson, Hosnik,
`and CART-19 Clinicaltrials.gov. ........................................................ 97 
`1. 
`The POSA Would Not Have Been Motivated to Make the
`Claimed Composition. .............................................................. 97 
`
` 
`
`ii
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`2. 
`
`The POSA Would Not Have Had A Reasonable
`Expectation of Success. .......................................................... 110 
`
`  Ground 2: Claims 1-6, 8-9, 11, 13, 16, 21-22 and 27-30 Are Not
`Obvious Over Campana in View of Jensen, Hosnik and CART-
`10 Clinicaltrials.gov .......................................................................... 116 
`1. 
`The POSA Would Not Have Been Motivated to Make the
`Claimed Composition. ............................................................ 116 
`
`2. 
`
`3. 
`
`The POSA Would Not Have Had A Reasonable
`Expectation for Success as to Any Claim. .............................. 121 
`
`The POSA Would Not Have Been Motivated to Make the
`Composition of Claim 3 and Would Not Have Had A
`Reasonable Expectation for Success as to Claim 3. ............... 122 
`
` 
`
`Ground 3: Claims 1-19 and 21-30 Are Not Obvious Over
`Campana in View of Milone, CART-19 ClinicalTrials.gov, the
`“Sequence Art” (Nicholson, Jensen, Littman, Sadelain), Hosnik
`and Riddell ........................................................................................ 130 
`1. 
`The POSA Would Not Have Been Motivated to Make the
`Claimed Composition. ............................................................ 130 
`
`2. 
`
`3. 
`
`The POSA Would Not Have Had A Reasonable
`Expectation for Success as to Any Claim. .............................. 131 
`
`The POSA Would Not Have Been Motivated to Make the
`Composition of Claim 3 and Would Not Have Had A
`Reasonable Expectation for Success as to Claim 3. ............... 133 
`
` 
`
`Ground 4: The Claims Would Not Have Been Obvious Over
`Porter ................................................................................................. 133 
`VIII.  THE CHALLENGED CLAIMS OF THE ʼ123 PATENT .......................... 135 
`IX.  OBJECTIVE INDICIA OF NON-OBVIOUSNESS FURTHER
`SUPPORT REJECTION OF DR. JUNGHANS’ OBVIOUSNESS
`OPINIONS ................................................................................................... 137 
`There Was Extensive Skepticism of CAR-T Compositions. ............ 137 
` 
`The Invention Garnered Significant Praise. ...................................... 138 
`
` 
`
`iii
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` 
`
`The Claimed Invention Has Unexpected and Desirable
`Properties. .......................................................................................... 141 
`CONCLUSION ............................................................................................ 142 
`
`X. 
`
`
`
`
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`
`I.
`
`I, Dr. Robert Negrin, declare and state as follows:
`
`INTRODUCTION
`
`I have been retained by counsel for The Trustees of the University of
`
`Pennsylvania (“Patent Owner”) in connection with the Petitions for Inter Partes
`
`Review filed by Petitioners Miltenyi Biomedicine GmbH and Miltenyi Biotec Inc.
`
`(“Miltenyi”). I have been asked to provide my opinions in this proceeding based
`
`on my qualifications as an expert in cellular therapies, immunology and
`
`hematology including CAR T cell therapy.
`
`
`
`The statements set forth in this declaration are based on my personal
`
`knowledge, experience, and study of the literature. I am being compensated at my
`
`usual rate of $750 per hour for the time spent preparing this declaration, and my
`
`compensation is not contingent on the outcome of any matter or any of the
`
`opinions provided below. I have no financial interest in this matter.
`
` My opinions are based on my academic training in hematology,
`
`immunology, and cellular therapies, and my many years of experience in treating
`
`patients with cancer with cellular therapies. My opinions are also based on my
`
`review of the materials cited in this declaration as well as my review of the
`
`Declarations of Dr. Richard P. Junghans submitted in IPR2022-852 and -855 and
`
`the materials cited therein. I have also reviewed and considered the transcript of
`
`the deposition of Dr. Junghans in IPR2022-852 and -855, and exhibits thereto.
`
`1
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`This declaration is based on the information currently available to me.
`
`I reserve the right to supplement my opinions in the event additional documents
`
`and information are produced. I also reserve the right to supplement my opinions
`
`to address any information obtained, or positions taken, based on any new
`
`information that comes to light throughout this proceeding, including in any
`
`depositions that have not yet been taken.
`
`II. QUALIFICATIONS
`
`I am a Professor of Medicine at Stanford University. I served as the
`
`Chief of the Division of Blood and Marrow Transplantation from 2000-2020.
`
`
`
`I received my undergraduate degree from the University of California
`
`at Berkeley and MD from Harvard University. I am certified by the American
`
`Board of Internal Medicine in Internal Medicine and Hematology. I have been re-
`
`certified in Hematology twice, most recently in 2019.
`
`
`
`I trained in medicine and hematology at Stanford University and
`
`joined the faculty in 1990. My research work has focused on cellular immunology,
`
`in particular developing a more fundamental understanding of complex biological
`
`reactions such as graft versus host and graft versus tumor reactions in animal
`
`models and in the clinic. I have authored over 270 original papers, 40 book
`
`chapters and a book on issues relating to the use of cellular therapies to treat
`
`2
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`cancers. A list of these publications and presentations is contained in my CV,
`
`which is attached as Exhibit 2066 to the Patent Owners’ Response.
`
`
`
`I have received a number of awards including fellowships from the
`
`Jose Carreras Foundation, the Damon Runyon-Walter Winchell Foundation and
`
`was a recipient of the Doris Duke Distinguished Clinical Scientist Award. I am an
`
`elected member of the Association of American Physicians. In 2022, the Stanford
`
`Cancer Cell Therapy and Blood and Marrow Transplant Symposium honored my
`
`contribution to the field and my service as the Chief of the Stanford Blood and
`
`Marrow Transplantation and Cellular Therapy Division. Many of the presentations
`
`at our symposium revolved around CAR T therapy.
`
`
`
`I was previously the President of the International Society of Cellular
`
`Therapy and the American Society of Blood and Marrow Transplantation
`
`(currently American Society of Transplantation and Cellular Therapy).
`
`
`
`I served as an Associate Editor of the journal Blood, and I am the
`
`founding editor of Blood Advances.
`
` At Stanford, I advise undergraduate, graduate and postdoctoral
`
`students and participate in multiple graduate and fellowship programs, including
`
`the PhD programs in cancer biology and immunology, and the master’s program in
`
`medicine. I teach in various courses as well as during clinical activities.
`
`3
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`
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`In addition to my work at Stanford, I am a frequent volunteer with the
`
`Cambodian Health Professional Society of America that runs an annual free clinic
`
`in rural Cambodia. I also volunteer at children’s organizations in that country.
`
`
`
`I have been involved in committee work more broadly in the field. I
`
`have served on numerous study sections through the National Institutes of Health
`
`and have chaired both NCI Committee D and the Clinical Oncology Study Section.
`
`This is relevant since these study sections fielded many of the early grant
`
`applications on cellular therapy and CAR T cells. I have also been involved in a
`
`number of committees through the American Society of Hematology, the
`
`American Board of Internal Medicine where I served on the Hematology Panel and
`
`other professional organizations.
`
`
`
`In recent years, I have engaged in several ongoing research projects
`
`relating to bone marrow and stem cell transplantation, which explores concerns
`
`relating to autologous and allogenic transplantation of cells highly relevant to the
`
`issues in this case. These issues include the role of T cells in transplantation,
`
`including graft versus host disease. Several of the concepts that have been studied
`
`in my laboratory have moved forward into clinical trials including the adoptive
`
`transfer of cytokine induced killer cells that has been pursued by a pharmaceutical
`
`company with CAR insertion. Another study involving the adoptive transfer of
`
`regulatory T cells has begun a phase III registration clinical trial. These concepts
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`4
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`developed in my laboratory have been pursued by pharmaceutical companies to
`
`execute these larger clinical trials.
`
` My current research focuses on clinical applications of cytotoxic and
`
`regulatory cells—like the T-cells involved in CAR-T therapy—for use in
`
`immunotherapy. I have developed animal models for transplantation of such cells
`
`and tumor response. Along with my colleague Christopher Contag, PhD. We
`
`developed the concept of bioluminescent imaging that has been widely utilized by
`
`numerous laboratories throughout the world to study the fate of the transferred
`
`cells including CAR T cells in experimental models. I also study the interaction
`
`between cytotoxic cells and specific tumor targets, as well as graft versus host and
`
`graft versus tumor reactions associated with these cells. I have also developed
`
`techniques to study the biological processes involved in therapies like CAR-T
`
`therapy, including by using bioluminescent markers that permit cells to be tracked
`
`non-invasively.
`
`
`
`I have extensive clinical trial experience, including experience
`
`relating to graft-vs-host disease and hematopoietic stem cell transplantation, as
`
`well as the study of autologous CAR T cells, a dual-targeted CD19 and CD22 CAR
`
`T therapy and allogeneic CAR T cells. These studies have led to a number of
`
`publications in the field of which I am a co-author. A number of projects in my
`
`research that have led to peer-reviewed publications relate specifically to CAR T
`
`5
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`therapy. For example, I have published regarding my work to develop CAR-
`
`engineered invariant natural killer T cells, which possess special potential due to
`
`reduced risk for graft versus host disease and their ability to stimulate a host
`
`directed immune response against the tumor.
`
` Over the past several years, I have been involved in the treatment of
`
`cancer patients using CAR T therapies. During that time, I estimate that I have
`
`been involved in treating over 500 patients using CAR T therapies. I remain active
`
`in clinical practice and continue to treat patients using CAR T therapies.
`
`
`
`I have been involved in CAR T cell therapy research and clinical
`
`applications since the late 2000s. As the Chair of two NIH Committees, I was
`
`involved in the review of many of the grants that were submitted evaluating the
`
`promise and challenges of CAR T cell therapy. Our Division began treating
`
`patients with CAR T cell therapies in February of 2016. I was the Chief of the
`
`Division at that time and was very involved in developing this therapy from the
`
`administrative, research and clinical perspectives. My leadership was instrumental
`
`in developing the resources for this important new therapy at Stanford, training of
`
`the staff, developing the laboratory needs through the Cellular Therapy Facility
`
`and Laboratory of Cell and Gene Medicine at Stanford that were instrumental in
`
`handling the CAR T cells and in some instances producing the cells onsite for
`
`clinical trials. I was involved in developing the correlative science programs to
`
`6
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`extensively study these patients to learn more about the successes and failures of
`
`CAR T cell therapy. I also have been studying CAR T cell therapies from the
`
`perspective of developing imaging strategies to study their migration through the
`
`body initially in experimental models and hopefully in patients in the future and
`
`through the development of novel cell products other than T cells for potential
`
`therapy.
`
`III. LEGAL STANDARDS
`
`In forming my opinions in this case, I have applied the following legal
`
`standards that were explained to me by counsel.
`
` Burden of proof. I understand that the Petitioner has the burden of
`
`proving a proposition of unpatentability by a preponderance of the evidence. I
`
`understand that to prove an element by a preponderance of the evidence means to
`
`prove that something is more likely than not.
`
` Obviousness. I understand that a claim is invalid for obviousness if
`
`the differences between it and the prior art are such that the claim’s subject matter
`
`would have been obvious to the “POSA” at the time of the claimed invention.
`
`(The instructions I received concerning the “POSA” are set forth below in Section
`
`IV.D.) I understand that obviousness is a question of law that requires underlying
`
`factual determinations of:
`
`a.
`
`The level of ordinary skill in the relevant art.
`
`7
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`b.
`
`The scope and content of the prior art. I understand that a reference
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`qualifies as prior art for obviousness when it is analogous to the
`
`claimed invention. A prior art reference is analogous if it either:
`
`i. is from the same field of the inventor’s endeavor, regardless of
`
`the problem addressed; or
`
`ii. is not from the same field of the inventor's endeavor, but is
`
`reasonably pertinent to the problem addressed by the claimed
`
`invention.
`
`c.
`
`The nature of the differences (if any) between the asserted claim and
`
`the prior art.
`
`d.
`
`Any secondary considerations of non-obviousness or obviousness,
`
`including:
`
`i. the claimed invention’s commercial success or lack thereof;
`
`ii. a long-felt need for the claimed invention that was not met by
`
`the prior art;
`
`iii. evidence that others tried but failed to develop the claimed
`
`invention;
`
`iv. initial skepticism or disbelief before industry acceptance;
`
`8
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`v. articles, awards, and other public statements praising the
`
`claimed invention's merits, as well as licenses showing industry
`
`respect;
`
`vi. evidence that the accused infringer or others copied the claimed
`
`invention;
`
`vii. evidence that a combination of known elements resulted in an
`
`effect or properties greater than what would have been
`
`predictable;
`
`viii. independent discovery of the claimed invention by others
`
`before or about the same time as the named inventor(s); and
`
`ix. other evidence tending to show obviousness.
`
`e.
`
`I further understand that there must be a nexus between the secondary
`
`consideration and the claimed invention’s novel features for the
`
`secondary consideration to have probative value.
`
`IV. THE ’123 AND ’445 PATENTS
` Overview
`
`I have reviewed US Patent Nos. 9,518,123 and 9,540,445, which I
`
`refer to as the ’123 and ’445 Patents. The two patents share substantially the same
`
`“specification,” that is, the patent’s drawings and text.
`
`9
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` The patents generally relate to the groundbreaking work of Dr. Carl
`
`June and his colleagues at the University of Pennsylvania and their success in
`
`treating humans with CAR-T cells. The patents’ specification teaches how Dr.
`
`June and his colleagues achieved these miraculous results. The specification
`
`explains how to collect a patient’s T cells and use them to create the cells used for
`
`therapy (see Figures 1A and 1B). Figures 2 through 7 report data from the
`
`treatment of these human patients. Figure 10 tabulates the clinical results and
`
`states how two patients achieved and maintained a complete remission for several
`
`months while one achieved and maintained a partial response. Taken as a whole,
`
`these patents provided an outline for treating actual cancer patients—from the
`
`design of the CAR, to the collection of the patient’s T cells, to the transfection and
`
`culturing of the CAR T cells, to the dosing and administration of the T cells,
`
`through to the management of the patient’s condition.
`
` Examples 1 and 2 of the patents’ specification then describe clinical
`
`results from using these techniques. Example 1 details a pilot study with three
`
`patients with advanced, chemotherapy-resistant CLL. -855, Ex. 1001 at 49:53-55.
`
` After treatment, testing found Patient UPN 01’s “[b]one marrow at 1,
`
`3, and 6 months after CART19 cell infusions show[ed] sustained absence of the
`
`lymphocytic infiltrate by morphology and flow cytometric analysis.” -855, Ex.
`
`1001 at 53:3-13. “Scans at 1 and 3 months after infusion show[ed] resolution of
`
`10
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`adenopathy” and “[c]omplete remission was sustained for 10+ months” as of the
`
`time the specification was written. -855, Ex. 1001 at 53:1313-16.
`
` After treatment, Patient UPN 02 had “rapid clearance of the p53-
`
`deficient CLL cells from peripheral blood” and a “partial reduction of
`
`adenopathy.” -855, Ex. 1001 at 53:17-30. The patient’s “bone marrow showed
`
`persistent extensive infiltration of CLL one month after therapy despite dramatic
`
`peripheral blood cytoreduction . . . . [and t]he patient remain[ed] asymptomatic.” -
`
`855, Ex. 1001 at 53:3030-33.
`
` Within one month of treatment, Patient UPN 03 had “clearance of
`
`circulating CLL from the blood and bone marrow by morphology, flow cytometry,
`
`cytogenetic, and FISH analysis. CT scans showed resolution of abnormal
`
`adenopathy” and “[c]omplete remission was sustained beyond 8 months from the
`
`initial CART19 cell infusion.” -855, Ex. 1001 at 53:34-53.
`
` Example 2 within the specification details the treatment of a patient
`
`first diagnosed with stage 1 CLL in 1996. -855, Ex. 1001 at 60:5-6. At three and
`
`six months after treatment, there was no palpable adenopathy, and CT scanning
`
`performed three months after CAR-T cell infusion showed sustained remission. -
`
`855, Ex. 1001 at 61:62-62:3. Bone marrow studies at three and six months also
`
`showed no evidence of CLL by means of morphologic analysis, karyotype
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`analysis, or flow-cytometric analysis. -855, Ex. 1001 at 61:62-62:3. “Remission
`
`had been sustained for at least 10 months.” -855, Ex. 1001 at 62:3.
`
` Claims
` Both patents end with numbered sentences that I understand are
`
`referred to as “claims.” The ’123 patent claims particular CAR-T cells, while the
`
`’445 Patent claims a pharmaceutical composition comprising particular amounts of
`
`those cells. The claims in both patents provide structural requirements for the
`
`CARs used in the CAR T cells, specifically, that the CARs “comprise” (which I
`
`have been instructed means “include”) an anti-CD19 antigen binding domain with
`
`particular amino acid sequences, a transmembrane domain, a 4-1BB costimulatory
`
`signaling region, and a CD3-ζ signaling domain.
`
`
`
`I understand that the following are the “Challenged Claims” of the
`
`’455 patent: 1-19 and 21-30. I have reproduced below for reference particular
`
`claims that I discuss throughout this declaration.
`
` Claim 1 of the ’445 patent reads:
`
`A pharmaceutical composition comprising an anti-tumor effective
`amount of a population of human T cells wherein the T cells comprise
`a nucleic acid sequence encoding a chimeric antigen receptor (CAR),
`wherein the CAR comprises a CD19 antigen binding domain
`comprising, from the ammo to the carboxy terminus, a light chain
`variable region and a heavy chain variable region of SEQ ID NO:20,
`wherein the CAR further comprises a transmembrane domain, a 4-1
`
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`BB costimulatory signaling region, and a CD3 zeta signaling domain,
`wherein the T cells are from a human having cancer.
`-855, Ex. 1001 at 91:10-20.
`
` Claim 2 of the ’445 patent reads:
`
`The composition of claim 1, wherein the anti-tumor effective amount
`of T cells is 104 to 109 cells per kg body weight of a human in need of
`such cells.
`-855, Ex. 1001 at 91:21-23.
`
` Claim 3 of the ’445 patent reads:
`
`The composition of claim 1, wherein the anti-tumor effective amount
`of T cells is 105 to 106 cells per kg body weight of a human in need of
`such cells.
`-855, Ex. 1001 at 91:23-25. I have been told that Claim 2 is referred to as a
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`“dependent claim” because it “depends from” claim 1 and incorporates all of claim
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`1’s requirements. Thus, claim 2 requires all of the limitations of claim 1 but also
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`requires an anti-tumor effective amount of T cells that is 104 to 109 cells per kg
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`body weight of a human in need of such cells. And claim 3 requires all of the
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`limitations of claims 1 and 2 but also requires an anti-tumor effective amount of T
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`cells that is 105 to 106 cells per kg body weight of a human in need of such cells.
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`
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`I understand that the following are the “Challenged Claims” of the
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`’123 patent: 1-17, 19-24, and 26. Claim 1 of the ’123 patent reads:
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`A human T cell comprising a nucleic acid sequence encoding a
`chimeric antigen receptor (CAR), wherein the CAR comprises a
`CD19 antigen binding domain comprising, from the amino to the
`carboxy terminus, a light chain variable region and a heavy chain
`variable region of SEQ ID NO:20, wherein the CAR further
`comprises a transmembrane domain, a 4-lBB costimulatory signaling
`region, and a CD3 zeta signaling domain, wherein the T cell is from a
`human having cancer.
`-852, Ex. 1001 at 91:16-24.
`
` The Time of the Invention or “Priority Date”
` As reflected in my instructions, various questions about the field must
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`be assessed as of the “time of the invention” or “priority date.” I have been told
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`that Petitioner contends that the applicable priority date for these patents is
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`December 9, 2011. I have been asked to apply that priority date in my analysis and
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`I have done so. When I refer to what was known or believed in the field in
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`December 2011, I am referring to this date.
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` The Person of Ordinary Skill In the Art
` As reflected in my instructions, various questions about the field must
`
`be assessed from the perspective of a hypothetical “person of ordinary skill in the
`
`art” or “POSA.” I have been told that Petitioner has defined the person of ordinary
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`skill in the art as:
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`[A] person skilled in the art of administering CAR T-cell therapies.
`The person would possess a relatively high level of skill and have at
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`least an MD, together with several years of experience in
`administering CAR T-cell therapies. The person would also have
`experience designing CARs. The POSA would have knowledge of
`the scientific literature pertaining to immunology, including CARs
`and methods for utilizing CARs before the priority date. A POSA
`would also be knowledgeable about laboratory techniques related to
`engineering and testing the function of CAR T cells. A POSA would
`also be knowledgeable about designing clinical trials, including
`selecting dose ranges, that evaluate CAR T-cell therapies.
`-855, Ex. 1002 at ¶48. I do not take issue with this definition, although, for clarity,
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`it is my opinion that the POSA would not have to have had personal experience
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`synthesizing the CARs. (In my experience, research teams often combine several
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`individuals that collectively have these skills and experience.) The POSA’s
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`experience designing CARs would include conceiving of and considering different
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`CAR constructs. And the POSA would be knowledgeable about designing CARs.
`
`
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`In this declaration and in analyzing the issues discussed below, I have
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`applied the definition set forth in the preceding paragraph. (And I note that the
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`opinions I express herein would not change if the definition were applied without
`
`my clarification.) I note that in his declaration concerning the ʼ123 cells patent,
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`Dr. Junghans proposed a definition with different but similar language. There, he
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`wrote that the POSA would have been:
`
`skilled in the art of constructing CAR T cells. The person would
`possess a relatively high level of skill, such as having an MD or a PhD
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`degree in the field of molecular or cellular biology, immunology, or a
`related discipline, together with several years of experience in
`evaluating CAR T cells. The POSA would have knowledge of the
`scientific literature pertaining to immunology, including CARs, before
`the priority date. A POSA would also have knowledge of laboratory
`techniques related to engineering CAR T cells.
`-852, Ex. 1002 at ¶ 48. Many aspects of this definition overlap with the definition
`
`proposed in connection with the ʼ445 patent, for example, the knowledge of
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`immunology and laboratory techniques and experience with CAR T cells. The
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`main point of difference I perceive relates to whether the POSA would have had
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`medical experience. I am familiar generally with the named inventors of these
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`patents, and Dr. Carl June had substantial medical experience. I therefore believe
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`that the first of these two definitions is more appropriate, especially as to the issue
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`of preparing pharmaceutical compositions. But as it pertains to the claimed
`
`inventions of the ʼ123 patent, my opinions would not change if one or the other
`
`definition were to be used.
`
` As of December 9, 2011, I worked in this field and I was familiar with
`
`those who practiced in it. I have an M.D., and I have been involved in the
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`administration of cellular therapies for decades. I had also been involved in years
`
`of research on the basic functioning of T cells and NK cells. I had the
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`qualifications of the POSA as of December 9, 2011.
`
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`V. TECHNICAL BACKGROUND
` T Cell Biology
` T cells are a naturally occurring type of cells in the human immune
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`system, one of a variety of cells referred to colloquially as “white blood cells.” In
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`nature, different subtypes of T cells play different roles in fighting off invaders
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`such as viruses and bacteria—and, in some instances, cancer cells.
`
` Dr. Junghans’ declaration provides a technology background
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`concerning T cells. -855, Ex. 1002 at ¶¶23-30. I provide below some additional
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`background information on T cell biology that I believe is pertinent to the issues in
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`this matter.
`
`1.
`T Cell Phenotypes
`“T cells” are not a