UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`KITE PHARMA, INC.,
`Petitioner,
`
`v.
`
`
`
`
`
`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`___________________
`
`Case IPR2015-01719
`Patent No. 7,446,190
`___________________
`
`DECLARATION OF PROF. THOMAS BROCKER
`
`
`
`
`
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sloan-Kettering Ex 2022-1
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`

`
`I.
`
`II.
`
`INTRODUCTION .................................................................................. 2
`
`RESOURCES CONSULTED ................................................................ 2
`
`III. BACKGROUND, QUALIFICATIONS, AND
`COMPENSATION ................................................................................. 2
`
`IV. LEGAL STANDARDS .......................................................................... 2
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART .................................... 2
`
`VI. CLAIM CONSTRUCTION ................................................................... 2
`
`VII. SCIENTIFIC BACKGROUND ............................................................. 2
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`Cells of the Immune System ........................................................ 2
`
`Antibodies .................................................................................... 2
`
`T Cell Receptors and Co-Receptors ............................................. 2
`
`Structural and Corresponding Functional Characteristics
`of Antigen-Recognizing Receptors and Antibodies .................... 2
`
`Structural and Corresponding Functional Characteristics
`of T cell Surface Molecules ........................................................ 2
`
`T Cell Signaling ........................................................................... 2
`
`1.
`
`T Cell Receptors ................................................................ 2
`
`The Two-Signal Model of T Cell Activation ............................... 2
`
`CD28 Structure and Function ...................................................... 2
`
`VIII. THE ’190 PATENT ................................................................................ 2
`
`IX. STATE OF THE ART ............................................................................ 2
`
`A.
`
`CD28 Literature ........................................................................... 2
`
`1.
`
`Aruffo ................................................................................. 2
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`2.
`
`3.
`
`4.
`
`5.
`
`Peach .................................................................................. 2
`
`Kariv .................................................................................. 2
`
`Greenfield .......................................................................... 2
`
`Stein ................................................................................... 2
`
`B.
`
`CD28 Chimeric Constructs .......................................................... 2
`
`1.
`
`2.
`
`Krause ................................................................................ 2
`
`The ’783 Patent Publication ............................................... 2
`
`C.
`
`D.
`
`Surface Expression of the B7 Ligands ......................................... 2
`
`Chimeric TCRs ............................................................................. 2
`
`1.
`
`2.
`
`“First Generation” Chimeric TCRs with Signal 1
`Only .................................................................................... 2
`
`“Second Generation” Chimeric TCRs Combining
`Signal 1 and Signal 2 ......................................................... 2
`
`X. VALIDITY OF THE ’190 PATENT ..................................................... 2
`
`A. Ground 1: Claims 1-3, 6-9, 12 and 13 Are Not Obvious
`Under the Combination of Aruffo, Finney, and Krause .............. 2
`
`1.
`
`2.
`
`3.
`
`Kite’s Rationale 2: A Person of Ordinary Skill in
`the Art Would Not Have “Improved” Upon
`Finney’s Chimeric TCR By Replacing Finney’s
`CD28 Region With Krause’s CD28 Region ...................... 2
`
`Kite’s Rationale 1: A Person of Ordinary Skill in
`the Art Would Not Have Added a CD3ζ Domain to
`the Costimulatory Construct Referenced in Krause .......... 2
`
`Kite’s Rationale 3: A Person of Ordinary Skill in
`the Art Would Not Have Used Routine
`Optimization to Modify the Length of the CD28
`Extracellular Region of Finney .......................................... 2
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`B.
`
`C.
`
`Reasonable Expectation of Success ............................................. 2
`
`The ’190 Patent’s Dependent Claims .......................................... 2
`
`1.
`
`2.
`
`Ground 2: Claims 4 and 10 Are Not Obvious
`Under the Combination of Aruffo, Finney, Krause,
`and Gong ............................................................................ 2
`
`Ground 3: Claims 5 and 11 Are Not Obvious
`Under the Combination of Aruffo, Finney, Krause,
`and Bejcek .......................................................................... 2
`
`XI. OBJECTIVE INDICIA OF NONOBVIOUSNESS ............................... 2
`
`A.
`
`B.
`
`C.
`
`D.
`
`Skepticism of Experts .................................................................. 2
`
`Copying by Others ....................................................................... 2
`
`Unexpected Success ..................................................................... 2
`
`Failure of Others .......................................................................... 2
`
`XII. CONCLUSION ...................................................................................... 2
`
`
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`
`INTRODUCTION
`
`I.
`I, Dr. Thomas Brocker, declare as follows:
`
`1.
`
`I understand that in response to a Petition submitted by Kite
`
`Pharma, Inc. (“Kite”), an inter partes review (“IPR”) of claims 1-13 of U.S.
`
`Patent No. 7,446,190 (KIT1001, the “’190 Patent”) was instituted by the Patent
`
`Trial and Appeal Board (“PTAB”) on February 11, 2016.
`
`2.
`
`I have been retained as an independent expert witness on behalf of
`
`Patent Owner Sloan Kettering Institute for Cancer Research (“Sloan
`
`Kettering”) for this IPR proceeding. I understand that this Declaration is being
`
`submitted along with a Patent Owner’s Response to the Petition for IPR of the
`
`’190 Patent. I opine only with respect to certain issues that are discussed in this
`
`declaration. By doing so, however, I do not necessarily agree with other
`
`positions taken by Kite that I do not address here.
`
`II. RESOURCES CONSULTED
`I have reviewed the ’190 Patent, its file history, and Kite’s
`3.
`
`Petition for Inter Partes Review filed with the United States Patent and
`
`Trademark Office on August 13, 2015 (Paper No. 1). I have also reviewed the
`
`Declaration of Hinrich Abken (KIT1008), the transcript of the deposition of
`
`Dr. Abken (Ex. 2021), the exhibits listed on pages 5-7 of Dr. Abken’s
`
`declaration, including the Aruffo reference, the Finney reference, the Krause
`
`reference, the Gong reference and the Bejcek reference, and all references cited
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`in this declaration. I have also reviewed the Board’s decision to institute inter
`
`partes review in IPR2015-01719 (Paper No. 8, the “Institution Decision”).
`
`4.
`
`I understand that, in this proceeding, the Board instituted review
`
`of the ’190 Patent on the following grounds:
`
`(1) alleged obviousness of claims 1-3, 6-9, 12, and 13 over
`
`Krause, Finney, and Aruffo;
`
`(2) alleged obviousness of claims 4 and 10 over Krause, Finney,
`
`Aruffo, and Gong; and
`
`(3) alleged obviousness of claims 5 and 11 over Krause, Finney,
`
`Aruffo, and Bejcek.
`
`III. BACKGROUND, QUALIFICATIONS, AND COMPENSATION
`I currently serve, and have served since 2004, as the Director of
`5.
`
`the Institute for Immunology of the Ludwig Maximillian University Munich
`
`(LMU), Munich, Germany, where I also serve as a Full Professor of
`
`Immunology. From 2000-2004, I was an Associate Professor for Immunology
`
`at the LMU.
`
`6.
`
`Prior to my positions at LMU, I served as a scientist at the Max-
`
`Planck Institute for Immunobiology in Freiburg, Germany, and as a scientist at
`
`the University Clinic, Hematology/Oncology, at the University of Freiburg. I
`
`also previously served as a Scientific Member at the Basel Institute for
`
`Immunology.
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`7.
`
`I received my Ph.D. in 1992 from the University of Tübingen,
`
`and, in 1998, my Habilitation in Experimental Medicine from the University of
`
`Freiburg. I was also a Heisenburg Fellow of the German Research Foundation.
`
`8.
`
`I serve or have served as a reviewer for a number of scientific
`
`journals, including Science, Journal of Experimental Medicine, Cancer
`
`Research, Blood, Journal of Immunology, Immunology Today, Vaccine,
`
`Molecular Immunology, Frontiers in Immunology, European Journal of
`
`Immunology, International Immunology, International Journal of Cancer
`
`Immunology, Journal of General Virology, Gene Therapy¸ and EMBO Journal.
`
`9.
`
`I published my first paper on chimeric T cell receptors in 1992
`
`and my publications on chimeric T cell receptors have been continuously cited
`
`by those in the field for over twenty years, including by many of the
`
`publications introduced as exhibits in this IPR. I have extensive knowledge and
`
`experience in the field of chimeric receptors. In addition, I have substantial
`
`knowledge and experience in the fields of T cell function and signaling,
`
`costimulatory receptors, cell-cell interactions in immune responses, vaccine
`
`research, host-pathogen
`
`interactions, anti-tumor
`
`immunity and cancer
`
`immunotherapy.
`
`10.
`
`I am an expert in the fields of immunology, immunotherapy,
`
`cancer therapy, lymphocyte antigen and coreceptor signaling, T cell biology,
`
`and specifically, on chimeric T cell receptors. In total, I have over 26 years of
`
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`experience working and researching in these fields. Further details regarding
`
`my experience can be found in my curriculum vitae, attached as Ex. 2074. My
`
`CV also includes a list of publications.
`
`11.
`
`I am being compensated for my time at my standard hourly rate of
`
`350€ in connection with this proceeding. My compensation is in no way
`
`contingent upon my performance or outcome of this case.
`
`IV. LEGAL STANDARDS
`I have been advised and understand that a patent claim may not be
`12.
`
`found invalid under 35 U.S.C. § 103 unless it is demonstrated that the claimed
`
`invention would have been obvious to a person of ordinary skill in the art at the
`
`time of invention.
`
`13.
`
`I have been informed by counsel that a claim is invalid for
`
`obviousness under 35 U.S.C. § 103 if the differences between the claimed
`
`invention and the prior art are such that the claimed invention as a whole would
`
`have been obvious to a person of ordinary skill in the art at the time the
`
`invention was made. In determining whether or not a patented invention would
`
`have been obvious, certain factors should be considered, including: (1) the
`
`scope and content of the prior art; (2) the differences between the prior art and
`
`the claims at issue; (3) the level of ordinary skill in the art; and (4) objective
`
`indicia of nonobviousness. I am also informed that in conducting the
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`obviousness analysis, one should take into consideration the predictability of
`
`the relevant field.
`
`14.
`
`I understand that, while obviousness does not require that each of
`
`the claimed elements be found in a single prior art reference, a claimed
`
`invention is not proven obvious merely by demonstrating that each of its
`
`elements was independently known. I understand that I should consider
`
`whether Kite has demonstrated an “apparent reason” to modify or combine the
`
`prior art references or elements in a way that would have led to the claimed
`
`invention, and that a person of ordinary skill in the art (“POSA”) would have
`
`had a reasonable expectation of success in doing so.
`
`15. Requiring a showing of a reason for the proposed combination or
`
`modification protects against the distortion caused by hindsight-based
`
`assessment, which is impermissible. I have been advised that one cannot prove
`
`obviousness by using the ’190 Patent and its claims themselves as a blueprint
`
`to piece together particular components of the prior art, in just the right way so
`
`as to recreate the claimed invention.
`
`16. Accordingly, I understand that a claim is not rendered obvious by
`
`a combination of references if a POSA would not have combined the elements
`
`in a way that would have led to the claimed invention, such as when a POSA
`
`would not have had a reasonable expectation of success in doing so at the time
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`of the claimed invention, or when the references or the state of knowledge in
`
`the art taught away from the combination.
`
`17.
`
`I understand that to demonstrate that a POSA would have had a
`
`reasonable expectation of success, it must be shown that a POSA would have
`
`had a reasonable expectation that the prior art elements were capable of being
`
`physically combined, and that the combination would have worked for its
`
`intended purpose. For example, if an alleged reason is advanced that two
`
`components would have been combined to generate a construct intended to
`
`treat cancer in human patients, there should be shown that one of ordinary skill
`
`would have had a reasonable expectation that the resulting combination would
`
`work for this purpose.
`
`18. To determine whether there would have been an “apparent reason”
`
`for the person of ordinary skill to combine or modify the prior art references or
`
`elements so as to recreate the claimed invention, with a reasonable expectation
`
`of success, I have been advised it is appropriate to look at the teachings of the
`
`art as a whole. In this respect, it will often be necessary to look at the
`
`interrelated teachings of multiple pieces of prior art, the effects of market
`
`demands known to the persons of skill in the art, and the background
`
`knowledge possessed by a person having ordinary skill in the art.
`
`19. Conversely, I also understand that teachings within the references
`
`that would have dissuaded a POSA from making the proposed combination or
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`modification must be considered. In particular, an inference of nonobviousness
`
`is especially strong where teachings in the prior art undermine the very reason
`
`being proffered as to why a POSA allegedly would have combined the known
`
`elements. Thus, I understand that when the prior art “teaches away” from
`
`combining prior art references or certain known elements, a successful means
`
`of combining them is less likely to be obvious. A prior art reference may be
`
`said to “teach away” from a patent when a POSA, upon reading the reference,
`
`would have been discouraged from following the path that the challenger is
`
`alleging one would have taken to arrive at the claimed invention.
`
`20.
`
`I understand that an obviousness theory may be premised on a
`
`showing that one of ordinary skill would have found it “obvious to try” to
`
`modify the art by experimenting in a way that would have led to the invention,
`
`but only if there was a recognized problem or need in the prior art, and a finite
`
`number of identified, predictable potential solutions from which to choose, and
`
`a reasonable expectation of success by a POSA embarking on such an
`
`endeavor. I understand that a claim is not invalid as obvious if what was
`
`allegedly “obvious to try” was to explore a new technology or general
`
`approach that seemed to be a promising field of experimentation, where the
`
`prior art gave only general guidance as to the particular form of the claimed
`
`invention or how to achieve it. I also understand that a claim is not invalid as
`
`obvious if what was allegedly “obvious to try” was to vary all parameters or try
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`each of numerous possible choices until one possibly arrived at a successful
`
`result, where the prior art gave either no indication of which parameters were
`
`critical or direction as to which of many possible choices was likely to be
`
`successful.
`
`21.
`
`I understand that certain objective indicia of nonobviousness are
`
`also relevant in determining whether or not an invention would have been
`
`obvious, and that these objective indicia include evidence of (1) copying of the
`
`invention by others in the field; (2) unexpected results achieved by the
`
`invention; (3) skepticism of experts; (4) failure of others; (5) long-felt, unmet,
`
`need; (6) commercial success; (7) praise of the invention; and (8) the patentee
`
`proceeding contrary to the accepted wisdom of the prior art.
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`I understand
`that
`the nonobviousness analysis and claim
`22.
`
`construction are performed from the perspective of a person having ordinary
`
`skill in the art at the time of the invention. I also understand that factors to
`
`consider in determining the level of ordinary skill in the art may include the
`
`education level of the inventors, the type of problems encountered in the art,
`
`prior art solutions to those problems, rapidity with which innovations are made,
`
`sophistication of the technology, and education level of active workers in the
`
`field.
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`23. Based on the disclosure of the ’190 patent, a POSA would have
`
`had knowledge of the scientific literature relating to T cell biology, as well as
`
`laboratory techniques and strategy in designing recombinant DNA, and would
`
`have an advanced degree, such as an M.Sc., Ph.D., or M.D. in the field of
`
`immunology, biochemistry, cell biology, molecular biology, or a related
`
`discipline.
`
`24.
`
`I consider myself to be—and to have been at least as of the
`
`invention date of the ’190 Patent—of at least ordinary skill in the art.
`
`25.
`
`I understand that Dr. Abken contends that “a skilled person may
`
`have worked as part of a multidisciplinary team and drawn upon not only his or
`
`her own skills, but also taken advantage of certain specialized skills of others in
`
`the team, e.g., to solve a given problem. For example, an immunologist, a cell
`
`biologist, and a clinical oncologist may have been part of a team.” KIT1008,
`
`¶12. I do not disagree that such a POSA “may” have been a part of such a
`
`hypothetical team as Dr. Abken notes, but to the extent that Dr. Abken means
`
`to imply that the participation on such a team is a feature of a POSA, I
`
`disagree. This statement seems to improperly imply that a POSA would have
`
`participated in such a team, and, further, that he or she would have acquired the
`
`individual expertise of each of these hypothetical team members. Dr. Abken
`
`has provided no reason to assume that a POSA would have had the benefit of
`
`the combined expertise of each of these individuals. Id. Thus, such a
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`description of a skilled person is too broad, and does not represent the scientists
`
`who were actively contributing to the field at the time. Although I disagree
`
`with Dr. Abken’s contention, my conclusions regarding claim construction and
`
`validity would be the same regardless of which definition of the relevant level
`
`of ordinary skill is adopted.
`
`VI. CLAIM CONSTRUCTION
`I understand that, during an inter partes review, claims are to be
`26.
`
`given their broadest reasonable construction in light of the specification. My
`
`statements regarding claim construction, as well as the rest of my opinions set
`
`forth in this declaration, would also apply if the claim terms are construed as
`
`they would have been understood by a POSA as of the filing date of the patent.
`
`27.
`
`I understand that the Board has not provided express constructions
`
`of any claim terms. I understand that Kite has proposed a construction for “a
`
`costimulatory signaling region . . . wherein the costimulatory signaling region
`
`comprises the amino acid sequence encoded by SEQ ID NO:6.” Pet., 14-15.
`
`SEQ ID NO:6 sets forth the nucleotide sequence of the CD28 region, including
`
`a portion of the extracellular domain and the entire transmembrane and
`
`cytoplasmic domains of CD28. KIT1001, Cert. of Correction, 4:21-28. A
`
`POSA would understand that this claim term encompasses the amino acid
`
`sequence encoded by SEQ ID NO:6. I agree with Dr. Abken that the amino
`
`acid sequence could have been encoded by other nucleic acid sequences that
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`also encoded SEQ ID NO:6 (given the redundancy of the genetic code), and
`
`that there is no requirement in the claim that this portion of the claimed
`
`chimeric TCR necessarily be encoded by the precise same underlying
`
`nucleotide sequence. KIT1008, ¶23.
`
`VII. SCIENTIFIC BACKGROUND
`A. Cells of the Immune System
`28. The immune system is generally divided into two categories: the
`
`innate and adaptive immune systems. Innate immunity refers to nonspecific
`
`and specific defense mechanisms that are triggered very soon after the
`
`appearance of a pathogen in the body. The innate immune system consists of
`
`physical barriers such as the skin, cytokines and other chemicals in the blood,
`
`and certain cells that generally attack foreign cells in the body. Adaptive
`
`immunity, in contrast, refers to an antigen-specific immune response, which is
`
`much more complex and robust. In the adaptive immune response, once an
`
`antigen is recognized, the system creates an army of immune cells specifically
`
`designed to attack the antigen.
`
`29. The cells of
`
`the adaptive
`
`immune
`
`response are called
`
`lymphocytes. Ex. 1027, 2.1 They are divided into two main categories: B cells
`
`and T cells. Id. B cells, derived from bone marrow, become the cells that
`
`produce antibodies. Id. T cells, which mature in the thymus, differentiate into
`
`1 I cite to the internal page numbers for each of the exhibits.
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`cells that kill, or assist in killing, cells affected by pathogens or other harmful
`
`agents. Id., 10.
`
`30. T cells play a critical role in cell-mediated immunity. While there
`
`are various T cell types and subtypes, with different roles in immunity, a
`
`unifying feature that differentiates T cells from other types of immune cells is
`
`the presence of T-cell receptors (“TCRs”) on their surface, which are discussed
`
`in more detail below. See id., 10.
`
`31. There are several types and subtypes of T cells, each of which has
`
`a distinct function. The subset of T cells known as cytotoxic T lymphocytes or
`
`cytotoxic T cells express the CD8 co-receptor on their surface. The primary
`
`effect of activation of cytotoxic T cells is the selective killing of cells
`
`presenting a specific target antigen on their surface. Id., 14.
`
`32. Another subset, known as helper T cells, promotes the immune
`
`response by assisting other immune cells through, for example, the secretion of
`
`cytokines
`
`that promote
`
`the
`
`immune cells’ maturation, activation, or
`
`proliferation, also in response to surface-presented antigen. Helper T cells
`
`express the CD4 co-receptor on their surface. Id.,13-14.
`
`33. Both CD4 and CD8 can differentiate into memory T cells.
`
`Memory T cells promote a long-lasting immune response by persisting after
`
`the antigen triggering an immune reaction has been resolved. Memory T cells
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`quickly expand to large numbers of effector T cells when re-exposed to their
`
`cognate antigens. Id.,10
`
`B. Antibodies
`34. Antibodies are also known as immunoglobulins. They are large Y-
`
`shaped proteins produced by B cells that the immune system uses to identify
`
`and neutralize pathogens. Id., 3. Antibodies are not cells. Rather, they are
`
`molecules secreted by B cells that bind to antigens corresponding to harmful
`
`agents. Id., 2. In certain cases, the binding of the antibody alone can alone
`
`cause an effect on the cell or pathogen presenting the antigen. In other cases,
`
`the binding of the antibody serves to tag a cell for attack by the immune
`
`system, and the antibody thereby recruits other immune effectors to mount an
`
`immune response.
`
`C. T Cell Receptors and Co-Receptors
`35. TCRs recognize antigens that are presented in MHC complexes on
`
`target cells. Id., 11. TCRs are highly diverse and specific for antigens. As
`
`explained in more detail below, the TCR is a multi-protein complex. Id.,10-11.
`
`Activation of the T cell upon antigen binding by the TCR complex is the robust
`
`and specific cell-mediated immune response. Id., 12. The following figure,
`
`copied from Ex. 1027 at p. 11, depicts the general structure of a TCR complex.
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`36. T cells recognize antigens with a high degree of specificity and
`
`diversity through their TCRs. Id., 10. These receptors are specific for antigens
`
`derived from a particular infectious agent, pathogen, or harmful source. Id.
`
`While TCRs have a high degree of variability and confer antigen specificity to
`
`T cells, conserved accessory molecules facilitate their signaling. The TCR’s
`
`recognition of its antigen leads to highly specialized and robust effector
`
`functions by the T cells, prompting an immune response specifically directed at
`
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`IPR2015-1719
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`the cells displaying those antigens. Id. The result, for example, in cytotoxic T
`
`cells, is generally highly lethal to the cells displaying the antigens, and
`
`typically results in the killing of target cells and the recruitment of highly
`
`robust inflammatory factors. Id.,14. For this reason, erroneous triggering of T
`
`cells can be harmful, and in some cases can cause very serious conditions such
`
`as autoimmune diseases.
`
`D.
`
`Structural and Corresponding Functional Characteristics of
`Antigen-Recognizing Receptors and Antibodies
`
`37. Antigen-recognizing molecules, such as TCRs and antibodies,
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`generally include, among other things, a “variable” region, which confers the
`
`recognition function on the molecule, and a “constant” or “invariant” region,
`
`which performs structural, signaling and effector functions. Id., 467-69.
`
`38. The variable region of a TCR or antibody is distinct from the
`
`constant region. Id., 3. The variable regions are incredibly diverse and thus
`
`vary from one individual TCR or antibody to the next, providing highly
`
`selective recognition functions across a range of specificities. For example, the
`
`variable regions in TCRs can account for a huge amount (approximately 1018)
`
`of different specificities, i.e. antigens that can be recognized by different TCRs.
`
`Id., 2-4, 6. In contrast, the constant regions are much less diverse. Id. This is
`
`because structural, signaling or effector functions are invariant once the
`
`receptor or antibody recognizes its antigen. The combination of a diverse
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`IPR2015-1719
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`variable region and a more invariant constant region permits the receptor-
`
`bearing cell or antibody to carry out a similar protection response to a wide
`
`variety of different and diverse pathogens.
`
`39. Within variable regions of both TCRs and antibodies, the most
`
`highly variable portion—and those most important for binding—are the
`
`complementarity determining regions, or “CDRs.” Id., 6. Each variable region
`
`contains three CDRs, known as CDR1, CDR2, and CDR3. Of the CDRs,
`
`CDR3 is the most variable, and is most important for the recognition of and
`
`binding to an antigen. Id.
`
`40. Each CDR forms a loop structure that extends from the Ig fold
`
`structure on the extracellular region of the receptor or antibody. Id., 7. The
`
`CDR loops form the portion that contacts and recognize specific antigens, with
`
`the CDR3 loop generally playing the biggest role. Id., 6. The framework
`
`regions within the variable region, in contrast to the CDRs, are generally less
`
`variable and generally provide structural support
`
`that maintains
`
`the
`
`conformation of the CDRs. Id.
`
`41. The constant regions of TCRs include, among other things,
`
`domains that permit the receptor to associate with signaling chains to form a
`
`complex called the TCR/CD3 complex. Id., 10-11. Other molecules in the
`
`TCR/CD3 complex confer structural and effector functions, for example, to
`
`transmit the signal from the antigen-binding region into the cell.
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`42. The constant regions of antibodies include, among other things, in
`
`the heavy chain, CH1, hinge, CH2, and CH3 domain. Id., 2. The constant
`
`regions of TCRs and antibodies are considerably less varied than the variable
`
`regions, and are the portions responsible for exerting effector functions upon
`
`binding by the variable regions.
`
`E.
`
`Structural and Corresponding Functional Characteristics of
`T cell Surface Molecules
`
`43. Many other T cell surface molecules, such as CD28, CTLA4,
`
`CD4, CD8, and others, are referred to as Ig-like molecules because they share
`
`certain structural similarities with members of the immunoglobulin superfamily
`
`of proteins; they are not antigen receptors and do not embody the diversity or
`
`highly specified functions of TCRs or antibodies. Id., 474.
`
`44. Like Ig molecules, T cell surface molecules contain a region that
`
`recognizes a ligand. Id. While the ligand-recognizing regions of co-receptors
`
`share a functional resemblance to the variable regions of TCRs and antibodies
`
`in that they contain ligand-binding sites, the ligand-recognizing regions of co-
`
`receptors are not variable. Rather, every member of a co-receptor class
`
`recognizes the same family of ligand(s).
`
`45. Also like Ig molecules, some co-receptors, including CD28,
`
`contain constant-like domains, which, among other things, are responsible for
`
`inducing the appropriate signal upon ligand recognition. Id., 476.
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`IPR2015-1719
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`F.
`
`T Cell Signaling
`1.
`46. As explained above, the highly diverse and specific recognition
`
`T Cell Receptors
`
`function of a T cell is a function of its TCR, primarily through the variable
`
`antigen-recognition region. The effector function that results from specific
`
`recognition, however, is not as diverse and is provided by constant regions and
`
`invariant chains that are part of the TCR/CD3 complex. Depending on T cell
`
`type, the outcome of T cell activation can be proliferation, cytokine secretion,
`
`and/or cytotoxic function.
`
`47. The TCR/CD3 complex includes the TCR itself, along with
`
`several additional subunits, including those having the intracellular signaling
`
`(effector) domains that are triggered upon recognition by the antigen-binding
`
`component. Id., 468. The TCR portion of the complex is made up of two
`
`separate polypeptide chains encoded by the TCRα and TCRβ genes,
`
`respectively. Id. The complex also includes CD3 proteins, which are assembled
`
`as CD3εγ and CD3εδ heterodimers and CD3ζ, which predominantly exists as a
`
`homodimer. Id. The CD3ζ protein is involved in initiating signaling following
`
`antigen recognition by the TCR, which leads to T cell activation. Id., 468-469.
`
`Specifically, the CD3ζ chains within the complex contain immunoreceptor-
`
`based tyrosine activation motifs (“ITAMs”), which become phosphorylated as
`
`a result of binding of the TCR recognition domain to its specific antigen. Ex.
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`2004 at 217. The phosphorylated ITAMs recruit a number of second
`
`messengers, activating a complex signaling cascade. Id.
`
`48. TCRs recognize their antigens as processed peptides presented in
`
`the grooves of MHC molecules presented on the surface of a target cell.
`
`49. Normally, T cells develop in a manner that permits them to
`
`distinguish MHC molecules displaying peptide antigens from a foreign or
`
`dangerou