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Dana-Farber Cancer Institute, Inc. v. Ono Pharmaceutical Co., Ltd.

United States District Court, D. Massachusetts

May 17, 2019

DANA-FARBER CANCER INSTITUTE, INC., Plaintiff,
v.
ONO PHARMACEUTICAL CO., LTD.; TASUKU HONJO; E.R. SQUIBB & SONS, L.L.C.; and BRISTOL-MYERS SQUIBB, CO., Defendants.

          FINDINGS OF FACT, CONCLUSIONS OF LAW, AND ORDER

          Hon. Patti B. Saris Chief United States District Judge.

         TABLE OF CONTENTS

         INTRODUCTION ................................................... 4

         FINDINGS OF FACT ............................................... 6

         I. Scientific Background ................................ 6

         A. The Immune System and Receptor-Ligand Signaling....6

         B. Experimental Methods ........................... 11

         II. Discoveries of PD-1 and 292 ......................... 14

         A. Dr. Honjo Discovers the PD-1 Receptor .......... 14

         B. Dr. Honjo Asks for Help Identifying the Ligand for PD-1 and Begins to Collaborate with Dr. Wood in September 1998 .............................. 17

         C. Dr. Freeman Discovers the 292 Ligand in July 1998 ............................................... 20

         D. Dr. Wood Connects the PD-1/PD-L1 Pathway in September 1999 ................................. 24

         III. October 25, 1999 Collaboration Meeting in Cambridge.

         27 IV. Developments Between the October 1999 and May 2000 Meetings ............................................ 29

         A. Dr. Freeman and Dr. Honjo Exchange Reagents, and Dr. Wood and Dr. Honjo Run Experiments Confirming the Inhibitory Effect of the PD-1/PD-L1 Pathway in November and December 1999 .................. 29

         B. Dr. Freeman and Dr. Wood File a Provisional Patent Application in November 1999 ............ 31

         C. Dr. Freeman, Dr. Wood, and Dr. Honjo Draft a Journal Article on the PD-1/PD-L1 Pathway in March and April 2000 ........................... 32

         D. Dr. Freeman Conducts Immunohistochemistry (“IHC”) Experiments in the Winter of 2000 .............. 34

         E. Dr. Freeman Discovers PD-L2 in the Fall of 1999 35

         F. Dr. Freeman, Dr. Wood, and Dr. Minato Independently Develop Antibodies Throughout 1999 and 2000 ....................................... 36

         G. Dr. Honjo and Dr. Wood's Meeting in March 2000. 37

         H. Dr. Iwai Begins In Vivo Tumor Model Studies in March 2000 ..................................... 38

         V. May 13, 2000 Collaboration Meeting in Seattle ....... 39

         VI. Developments During the Summer of 2000 .............. 39

         VII. September 8, 2000 Collaboration Meeting in Cambridge.. ................................................... 41

         VIII. Dr. Honjo and Dr. Iwai Conduct In Vivo Mouse Tumor Model Experiments and the Collaboration Ends ........ 43 IX. Dr. Honjo and Ono File Patent Application in July 2002 .................................................... 45

         X. BMS Develops Nivolumab with Exclusive License to the Honjo Patents ...................................... 47

         XI. Dana-Farber Initiates This Lawsuit .................. 48

         XII. Dr. Honjo Wins the Nobel Prize ...................... 50

         EXPERT OPINIONS ............................................... 51

         I. Dana-Farber's Expert: Dr. Kenneth Murphy ............ 51

         II. Defendants' Expert: Dr. Mark Greene ................. 54

         CONCLUSIONS OF LAW ............................................ 58

         I. Joint Inventorship .................................. 58

         A. Legal Standard ................................. 58

         B. Claim Construction ............................. 63

         C. Corroboration .................................. 64

         D. The Collaboration of Dr. Freeman, Dr. Wood, and Dr. Honjo ...................................... 70

         E. Conception of the Honjo Patents ................ 75

         F. Dr. Freeman's and Dr. Wood's Contributions to Conception ..................................... 78

         1. Dr. Freeman and Dr. Wood's Discovery of PD-L1 and Blocking Antibodies and Dr. Wood's Discovery of the Inhibitory Effect of the PD-1/PD-L1 Pathway ........................ 78

         2. Dr. Freeman's Discovery of the Expression of PD-L1 on Certain Tumors ................... 86

         3. Dr. Freeman and Dr. Wood's Discovery and Characterization of PD-L2 ................. 88

         4. Method of Treating Cancer ................. 89

         5. Dr. Freeman's and Dr. Wood's Provision of Reagents .................................. 91

         G. Significance of Dr. Freeman's and Dr. Wood's Contributions to the Claims in the Honjo Patents ............................................... 92

         1. Use of Anti-PD-1 or Anti-PD-L1 Antibodies to Treat Cancer .............................. 93

         2. Expression or Over-Expression of PD-L1 or PD-L2 ..................................... 99

         3. PD-L1 Expression by Specific Tumors ...... 102

         H. Conclusion .................................... 103

         II. Laches .............................................. 104

         A. Legal Standard ................................ 105

         B. Analysis ....................................... 107

         ORDER ........................................................ 110

         INTRODUCTION

         Plaintiff Dana-Farber Cancer Institute, Inc. (“Dana-Farber”) brings this civil action to correct inventorship of six disputed patents (“the Honjo patents”) against Defendants Ono Pharmaceuticals Co., Ltd. (“Ono”); Dr. Tasuku Honjo; E.R. Squibb & Sons, L.L.C.; and Bristol-Myers Squibb, Co. (“BMS”). The Honjo patents claim methods of cancer immunotherapy. Dr. Honjo is the named inventor on these patents together with two colleagues from Kyoto University and a researcher at Ono. Dana-Farber contends that Dr. Gordon Freeman, one of its professors, and Dr. Clive Wood, formerly of the Genetics Institute (“GI”), made significant contributions to the conception of the inventions in the Honjo patents through, among other things, the discovery and characterization of the PD-L1 and PD-L2 ligands, the discovery that the interaction between PD-1 and PD-L1 (“the PD-1/PD-L1 pathway”) is inhibitory and could be blocked by antibodies, and the discovery that PD-L1 is expressed in human tumors.[1] Dana-Farber seeks to add Dr. Freeman and Dr. Wood as joint inventors on the Honjo patents. Defendants argue that Dr. Freeman's and Dr. Wood's contributions to the inventions are not significant enough to make them joint inventors.

         After a bench trial, I find Dana-Farber has presented clear and convincing evidence that Dr. Freeman and Dr. Wood are joint inventors of the six Honjo patents. Dr. Honjo collaborated extensively with both Dr. Freeman and Dr. Wood from at least October 1999[2] until at least September 2000 through numerous meetings, joint authorship of scientific journal articles, written collaboration agreements, and sharing of experimental results and ideas. Indeed, Dr. Honjo himself referred to his work with Dr. Freeman and Dr. Wood as a collaboration on at least six occasions. While the relationship among these three brilliant scientists eventually soured, all three made significant contributions to the inventions. After a review of the extensive record and evaluation of the credibility of the witnesses, I conclude that both Dr. Freeman's and Dr. Wood's contributions were significant in light of the dimension of the full inventions claimed in the six Honjo patents, which are all premised on blocking the inhibitory interaction of the PD-1/PD-L1 pathway to treat tumors that express PD-L1 or PD-L2. Judgment shall enter for Dana-Farber.

         FINDINGS OF FACT

         I. Scientific Background [3]

         A. The Immune System and Receptor-Ligand Signaling

         The immune system is the body's defense against foreign invaders, such as viruses, bacteria, and other pathogens. The immune system works through a network of different types of cells, each with a specific function. Dendritic cells, for example, detect the presence of pathogens and alert the rest of immune system. B cells respond by producing proteins called antibodies that bind to pathogens and neutralize them. The most important immune cells for the purposes of this dispute are T cells. T cells either coordinate the immune system's response to pathogens (“helper” T cells) or eliminate infected or abnormal cells from the body (“killer” or “cytotoxic” T cells). Killer T cells can help prevent cancer from growing in the body. Once the immune system recognizes cancer cells as abnormal, T cells attack the cancer cells in the same way they attack cells infected with viruses and bacteria.

         In a healthy person, the immune system activates to fight pathogens and then deactivates to protect healthy cells from immune attack. Disorders of the immune system come in two forms. An individual with a suppressed immune response, such as someone with AIDS, is highly susceptible to infections and other diseases. An overactive immune response, on the other hand, can lead to autoimmune diseases in which the immune system attacks healthy cells.

         To maintain a healthy balance, the immune system relies on communication among immune cells and between immune cells and other cells found in the body. Cells can communicate through receptor-ligand interactions. A receptor is a protein located on the cellular membrane that allows the cell to detect and respond to its environment. The receptor receives a signal from outside the cell and then transmits the signal to the internal components of the cell to trigger a response. Ligands are proteins that bind to receptors to initiate signaling. Ligands can be secreted by cells (“cytokines”) or found on the cell surface. When a ligand binds to its receptor, it activates the intracellular signaling pathway that tells the cell with the receptor how to respond.

         Receptor-ligand interactions play a critical role in regulating the immune system. In the presence of pathogens, some receptors act as accelerators that “upregulate” or “stimulate” immune cells to increase the immune response. To prevent activated immune cells from damaging healthy cells, other receptors act as brakes to “downregulate” or “inhibit” the immune response. The immune system maintains a balance via the "on-off switches" of receptor-ligand signaling by upregulating when it detects infected or abnormal cells and downregulating once those cells are eliminated.

         (Image Omitted.)

         The primary receptor on a T cell is known as the T cell receptor ("TCR"). The TCR binds to foreign proteins known as antigens, which come from viruses, bacteria, or cancers. In combination with other signals, binding between the TCR and antigen activates the T cell to attack the pathogen.

         T cells also have other receptors on their surface. For example, a signal sent to the TCR does not activate a T cell unless a ligand binds to one of its co-stimulatory receptors. An important co-stimulatory receptor is called CD28. CD28's two ligands, B7-l and B7-2, are expressed on dendritic cells that have detected infection or cancer. In order for a T cell to activate, an antigen on the dendritic cell must bind to the TCR on the T cell and a B7 ligand on the dendritic cell must also bind to the CD28 receptor on the T cell. In the absence of an infection or cancer, the dendritic cell will not express a B7 ligand on its surface; if the TCR on the T cell interacts with the dendritic cell but does not receive a signal through CD28, the T cell will not activate. This requirement for co-stimulation ensures the immune system does not activate unless pathogens are present.

         The B7 ligands also bind to an inhibitory receptor called CTLA-4, which is only expressed on highly activated T cells. The B7 ligands bind more tightly to CTLA-4 than CD28. Thus, when a T cell expresses both CD28 and CTLA-4, CTLA-4 prevents the B7 ligands from activating the T cell through the CD28 receptor. CTLA-4 thereby ensures the immune system does not run out of control and harm healthy cells.

         The Honjo patents target another inhibitory receptor on T cells known as PD-1. When PD-1 binds to one of its ligands, PD-L1 or PD-L2, the T cell receives an inhibitory signal that prevents it from attacking the cell expressing PD-L1 or PD-L2. Expression of PD-L1 or PD-L2 on healthy cells protects the cells from immune attack. Some tumor cells also express PD-L1 or PD-L2, allowing them to masquerade as healthy cells by activating PD-1 to send an inhibitory signal to T cells.

         (Image Omitted.)

         Because of their importance in the immune system, receptor-ligand interactions are an attractive target for research and therapy. For example, scientists can develop monoclonal antibodies that bind to a specific receptor or ligand. Antibodies are named according to the target protein to which they bind (e.g., anti-PD-1 antibodies). A monoclonal antibody can be designed to trigger a receptor's signal (“agonist”) or block a signal either by binding to the ligand or the receptor (“antagonist”). If the receptor-ligand interaction stimulates immune cells, an antagonistic monoclonal antibody decreases the immune response by blocking the stimulation. This can be useful for treating autoimmune diseases. By contrast, if the receptor-ligand interaction inhibits immune cells, an antagonistic monoclonal antibody increases the immune response by blocking the inhibition. This can be useful for treating viruses or cancer.

         The Honjo patents claim methods of treating cancer by using the body's immune system to attack tumor cells, a type of treatment known as cancer immunotherapy. Specifically, the methods involve administering antagonistic monoclonal antibodies that bind to PD-1 or PD-L1 and block the inhibitory interaction between PD-1 and PD-L1/PD-L2. By blocking the signaling pathway, the methods aim to stimulate the immune system to attack the tumor cells.

         B. Experimental Methods

         This case also requires understanding how scientists study genes, proteins, and pathways. The Basic Local Alignment Search Tool (“BLAST”), a public database managed by the National Center for Biotechnology Information, contains millions of DNA sequences. Many of these sequences are short fragments of genetic material called “Expressed Sequence Tags” (“ESTs”) whose identity, complete sequence, and function are not known. A search through the BLAST database allows scientists to identify new DNA sequences and proteins to study. For example, a scientist can input a reference DNA sequence that encodes a known protein with a known function, and the BLAST search will show ESTs that share similar sequences with the reference DNA. After identifying the full-length sequences, she can then determine if they encode proteins with similar functions to the known proteins.

         Having identified a gene or protein of interest, she can use complementary DNA (“cDNA”) and “Fc-fusion proteins” to further study it. cDNA is a DNA sequence that contains only the parts of a gene necessary for encoding a protein. By inserting cDNA into a vector, scientists can cause a wide variety of cells to express a specific protein and then use those cells in experiments. An “Fc-fusion protein” contains a generic “handle” (the “Fc” region) that allows the protein to be easily manipulated and studied apart from the cell. The relevant portion of the amino acid sequence of the protein of interest is attached to the handle. For example, PD-1 fusion protein contains the binding portion of the PD-1 receptor attached to a generic protein handle. The fusion protein can then be used to test whether PD-1 binds to various molecules and whether the expression of PD-1 has an effect on the immune response.

         To explore the function and structure of proteins, scientists conduct both in vitro and in vivo experiments. In vitro experiments occur outside of a living organism in test tubes, flasks, and other controlled environments. They allow scientists to learn about a protein without worrying about confounding effects from other molecules within a living organism. For example, mixing T cells expressing a receptor with cells expressing the receptor's ligand and then observing the number of T cells shows whether the signaling pathway stimulates or inhibits the immune response. Another in vitro experiment, known as immunohistochemistry (“IHC”), involves administering a monoclonal antibody to thin sections of tissue to determine whether the molecule to which the antibody binds is present.

         In vivo experiments are conducted using living organisms. Scientists use in vivo experiments to study proteins in their biological context. “Knockout mouse” studies are one type of in vivo experiment. A “knockout mouse” is a mouse without the gene that encodes a particular protein and therefore is unable to make the protein. Observing the characteristics of the knockout mouse reveals the role the protein plays in the organism. For example, if knocking out a gene leads the mouse to have an abnormally active immune system, the protein encoded by that gene likely has an inhibitory effect on the immune system. Mouse tumor models are another type of in vivo experiment used to study cancer. In these experiments, mice are inoculated with tumor cells, and specific signaling pathways or proteins are then blocked in some of the mice. If the tumors grow more or less quickly in the altered mice than in normal mice, the tumor model suggests that the pathway or protein has an effect on tumor growth.

         II. Discoveries of PD-1 and 292

         A. Dr. Honjo Discovers the PD-1 Receptor

         Dr. Tasuku Honjo is a professor at the medical school at Kyoto University. T4-8:22-23, 12:24-25.[4] After receiving his medical degree and PhD in biochemistry in Japan, he came to the United States to work at the Carnegie Institution of Washington in Baltimore, Maryland where he began to study immunology. T4-10:6-24. He then worked at the National Institutes of Health before returning to Japan. T4-11:5-23. He has been a professor at Kyoto University since 1984. T4-12:16-25.

         In the early 1990s, Dr. Honjo discovered a new receptor expressed on certain mouse immune cells. T4-14:19-21, 19:10-15; JTX-0320.0001. He named the molecule “PD-1” because he believed the receptor was involved in programmed cell death, a process by which the body kills off old cells when new cells generate. T4-16:10-17:6. He published his discovery in 1992. T4-16:1-9; JTX-0320.0001. Dr. Honjo isolated the human DNA sequence for the gene that encodes PD-1 and, along with researchers from another Japanese University, developed antibodies against both mouse and human PD-1 to help study its function. T4-20:15-21:1, 22:2-23:5; Iwai Depo. 41:25-43:3; JTX-0272.0001; JTX-0373.0001; JTX-0429.0011. In 1996, he published another article describing the expression of PD-1 in mouse cells and the PD-1 fusion protein he was using to study the molecule. T4-22:2-11, 131:12-132:7; JTX-0272.0001-2. His early experiments demonstrated that PD-1 was not, in fact, involved in programmed cell death. T4-17:7-14.

         To learn more about PD-1's function, Dr. Honjo and Dr. Nagahiro Minato, a colleague studying tumor immunology, began experiments with PD-1 knockout mice. T4-14:1-18, 23:21-25, 29:3-7; T6-89:18-24; JTX-0354.0001. They discovered that mice without the gene encoding PD-1 showed symptoms typical of autoimmune disease, suggesting that PD-1 is involved in inhibiting the immune response. T4-26:11-16; T6-93:12-94:12; JTX-0354.0001. Dr. Honjo and Dr. Minato submitted these results on April 12, 1999. T2-136:18-137:8; JTX-0354.0010. Their article was published in Immunity in August 1999 and described PD-1 as “a negative regulator of immune responses.” JTX-0354.0001.

         Once Dr. Honjo and Dr. Minato discovered that PD-1 inhibited the immune system through their knockout mouse experiments, they discussed the possibility that altering the PD-1 signal could have therapeutic applications for autoimmune diseases, infectious diseases, organ transplantation, and cancer. T4-29:23-30:8; T6-129:19-25; Okazaki Depo. 50:25-51:13. They planned to conduct experiments involving tumors but did not do so at the time due to the limited manpower in their laboratories. T4-30:9-17; T6-98:22-99:8.

         Based on its structure, Dr. Honjo knew PD-1 was in the same family of proteins as CTLA-4, another inhibitory receptor. T4-31:6-9. But he did not fully understand the molecular mechanism through which PD-1 had its inhibitory effect because he had not identified its ligand. T4-28:3-24, 32:16-25, 141:12-142:6; JTX-0354.0008. Multiple students in his laboratory tried and failed to find PD-1's ligand. T4-143:8-13.

         In mid-1998, Dr. Honjo tasked a new graduate student, Dr. Yoshiko Iwai, with the ligand search. T4-38:8-24, 144:5-13; Iwai Depo. 12:2-25. At the May 21, 1999 meeting of Dr. Honjo's laboratory, Dr. Iwai reported her preliminary results. T4-42:23-43:3; JTX-0125.0021. She identified binding of various strengths with human and mouse PD-1 fusion protein in a number of mouse cells she had tested, including cells derived from mouse white blood cell tumor lines. T4-44:24-45:5, 147:8-149:4; Iwai Depo. 14:2-24; JTX-0125.0021. She also reported weak binding with PD-1 in one human B cell cancer line called Daudi. T4-47:17-48:1, 157:3-18; JTX-0125.0021.

         Although these results showed binding with the PD-1 fusion protein, they did not identify what molecule the protein was binding to. T4-146:10-147:7; Iwai Depo. 14:10-24, 15:5-12, 68:20-25, 70:9-17; Honjo Depo. 40:17-25. Dr. Iwai recognized that her experiment could have shown “false positives” because of the type of fusion protein she used. T4-48:2-19; JTX-0125.0022. About a month after disclosing her results, she reported at another laboratory meeting that PD-1's “[l]igand may express on B cell lines?!” JTX-0125.0024. She planned to conduct additional experiments using different fusion proteins to identify the ligand, but she had to take a leave of absence at the end of the summer due to illness. T4-49:2-8, 50:12-22, 51:11-18, 161:16-162:15; Iwai Depo. 13:13-14:5, 72:15-73:3, 82:7-19. The results of Dr. Iwai's experiments were never published. T4-51:1-9, 164:10-12.

         B. Dr. Honjo Asks for Help Identifying the Ligand for PD-1 and Begins to Collaborate with Dr. Wood in September 1998

         In September 1998, as Dr. Iwai was beginning her experiments to identify the ligand for PD-1, Dr. Honjo flew to Cambridge, Massachusetts for a meeting with representatives from Ono, a Japanese pharmaceutical company, and GI, a Cambridge biotechnology research and development company. T2-8:23-9:2, 20:3-6; T4-32:2-12; JTX-0432.0001. This meeting was part of a three-way research collaboration among GI, Dr. Honjo, and Ono that had been established in the mid-1990s. T2-18:6-19:7; JTX-0140; JTX-0142; Dkt. No. 314-1 ¶ 7 (“Stip.”). This “signal sequence trap” (“SST”) collaboration involved using yeast-based traps to identify signaling proteins secreted by cells that could then be studied as potential targets for new drug candidates. T2-17:1-18:5; JTX-0140.0001-2. The ultimate goal of the collaboration was “the discovery, development and commercialization of novel pharmaceutical products.” JTX-0142.0007. GI, Dr. Honjo, and Ono held core collaboration meetings biannually, which alternated between Cambridge and Japan. T2-19:13-21.

         While in Cambridge, Dr. Honjo asked Dr. Steve Clark, the coordinator at GI for the SST collaboration, if he had any ideas for how to identify the PD-1 ligand. T4-32:7-19. Dr. Clark proposed using GI's newly acquired Biacore machine, which would allow for quick screening of many ligand candidates. T4-34:4-12, 35:9-11. Because Dr. Honjo did not have access to a Biacore machine at Kyoto University, he agreed. T4-35:7-8.

         To facilitate this collaboration, Dr. Clark introduced Dr. Honjo to Dr. Clive Wood, the director of molecular immunology at GI, who also participated in the collaboration meeting that day. T2-13:13-15, 20:2-6; T4-36:18-22; JTX-0792.0004. Dr. Wood earned a PhD in biochemistry from Imperial College London. T2-8:2-6. He began working at GI in 1986 as a staff scientist. T2-8:19-22. In 1998, he was promoted to serve as the director of molecular immunology. JTX-0792.0004. He left GI in the early 2000s and now works as a corporate senior vice president responsible for global research activities for Boehringer Ingelheim. T2-7:10-14; JTX-0792.0004.

         Dr. Wood and Dr. Honjo had dinner the night of the September 1998 meeting and discussed Dr. Honjo's work on PD-1. T2-20:6-10; JTX-0432.0001. Dr. Honjo explained that he had discovered PD-1 and its inhibitory function but had not been able to find its ligand. T2-134:16-135:3. Dr. Wood agreed to collaborate with him to identify the ligand. T2-129:4-24.

         On September 22, about a week after the meeting, Dr. Honjo sent Dr. Wood a letter with more details about their collaboration. JTX-0432.0001. Dr. Wood responded on September 28 confirming his interest. T2-22:6-14; JTX-0436.0001. He also told Dr. Honjo that he thought the PD-1 receptor could be a candidate for a collaboration GI was establishing with Cambridge Antibody Technology (“CAT”) to develop antibodies as potential therapeutics. T2:22:21-23:6; JTX-0436.0001. The following day, Dr. Wood submitted a form to GI seeking approval for the PD-1 project and permission to exchange materials with Dr. Honjo. T2-23:14-24:6; JTX-0437.0001. Dr. Honjo sent PD-1 fusion proteins and cDNA developed in his laboratory to Dr. Wood to use in experiments to identify the ligand. T2-130:18-25; T4-36:23-37:2. Soon after their collaboration began, Dr. Honjo provided Dr. Wood with a confidential draft of his Immunity article that described his PD-1 knockout mouse experiments. T2-135:12-136:22; T4-191:9-192:8. As part of these preliminary discussions, Dr. Wood and Dr. Honjo decided to add the PD-1 project to the existing SST collaboration, which GI, Dr. Honjo, and Ono formally agreed to in March 1999. T2-21:9-13, 26:21-27:10; Shibayama Depo. 82:16-19, 84:18-85:8; JTX-0450.0003; JTX-0471.0001.

         When he started work on the project, Dr. Wood recognized that the PD-1 receptor looked like the CTLA-4 receptor found on T cells. T2-28:6-9. Accordingly, because B7-1 and B7-2 were ligands for CTLA-4, he hypothesized that the ligand for PD-1 would also be a member of the B7 family. T2-28:10-14, 29:11-12, 31:3-7, 69:8-16; JTX-0305.0002. And since the interaction between CTLA-4 and the B7 ligands inhibits T cells, he suspected that the interaction between PD-1 and its ligand would also be inhibitory. T2-29:12-14. However, his initial experiments failed to identify a B7 ligand that bound to PD-1. T2-35:14-17.

         C. Dr. Freeman Discovers the 292 Ligand in July 1998

         Dr. Gordon Freeman is a professor of medicine in the department of medical oncology at Dana-Farber and Harvard Medical School. T3:10:20-24, 11:18-22. Dana-Farber is a nonprofit cancer treatment and research center located in Boston, Massachusetts. Stip. ¶¶ 1, 26. Dr. Freeman earned a PhD from Harvard University in microbiology and molecular genetics in 1979. T3-9:8-13. He then began a postdoctoral fellowship at Dana-Farber working on tumor immunology. T3-9:14-17, 11:23-12:3. He became an assistant professor in 1994. T3-12:12-15.

         In July 1998, shortly before Dr. Honjo and Dr. Wood's meeting in Cambridge, Dr. Freeman began a search for novel B7 ligands. T3-22:14-23:1. Dr. Freeman's work had focused for almost fifteen years on B7 ligands, and he had discovered B7-2 and its role in immune regulation. T3-12:16-21, 17:21-18:11, 19:1-12, 20:22-21:1. Given the important interactions between the B7-1 and B7-2 ligands and the CD28 and CTLA-4 receptors, he suspected there might be similar ligands with immunological activity. T3-22:18-24. On July 27, 1998, Dr. Freeman ran a BLAST search with a sequence of 208 amino acids that forms part of binding portion of the B7-1 molecule. T3-25:25-26:18, 27:16-18, 150:13-21; JTX-0305.0002. The search produced a list of twelve ESTs that resembled the B7-1 sequence. T3-26:9-12, 151:11-14; JTX-0431.0001. Two of these twelve ESTs were part of the same sequence and came from a human ovarian tumor, which Dr. Freeman found interesting because the known B7 molecules were only expressed in immune cells, not in solid tumors. T3-28:9-24, 151:15-17; JTX-0431.0001. He decided to investigate this new sequence, which he called “292” after its label in the database. T3-28:24, 31:3-5. He generated the full human cDNA sequence for the 292 protein. T3-30:25-31:1. Through work on similar mouse DNA sequences found in the BLAST database, he also identified the full-length sequence for mouse 292. T3-33:23-34:7.

         In early 1999, Dr. Freeman investigated 292's expression and immunologic activity. T3-32:13-20. Although the ESTs came from a human ovarian tumor, his experiments showed that immune cells also express 292. T3-33:6-17. Given the similarities with B7-1 and B7-2, he thought 292 might affect the immune response. T3-33:18-22. When he exposed resting T cells to cells expressing the 292 protein, the T ...


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