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`SUPREME COURT OF THE STATE OF NEW YORK
`COUNTY OF NEW YORK
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`ERRANT GENE THERAPEUTICS, LLC,
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`Plaintiff,
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`– against –
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`SLOAN KETTERING INSTITUTE FOR
`CANCER RESEARCH and BLUEBIRD BIO
`INC.,
`
`Defendants.
`
`Index No. 150856/2017
`IAS Part 61
`Hon. Barry R. Ostrager, J.S.C.
`
`AFFIDAVIT OF MICHEL SADELAIN
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`AFFIDAVIT OF MICHEL SADELAIN
`
`STATE OF OHIO
`
`COUNTY OF
`MONTGOMERY
`
`)
`)
`)
`
`ss.:
`
`I, Michel Sadelain, MD, PhD, being duly sworn, state as follows:
`
`1.
`
`I am the founding director of the Center for Cell Engineering and head of the
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`Gene Transfer and Gene Expression Laboratory at Memorial Sloan Kettering Cancer Center
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`(“MSKCC”), where I hold the Stephen and Barbara Friedman Chair. I am also a member of the
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`departments of medicine at Memorial Hospital and the immunology program of the Sloan
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`Kettering Institute for Cancer Research (“Sloan Kettering”).
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`2.
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`The Center for Cell Engineering at MSKCC was established to foster research on
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`cellular therapies. The Center brings together researchers who investigate adoptive T-cell
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`therapies, bone marrow and cord blood transplantation, human stem cell biology, and the
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`transfer, regulation, and repair of genes in human cells. This unique physician-scientist
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`partnership comprises 28 faculty members from both Memorial Hospital and the Sloan Kettering
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`Institute who all have scientific or clinical interests in cancer or monogenic blood disorders and
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`strive to devise and implement breakthrough therapies for those diseases. As the director of the
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`Center, I provide scientific advice and organize meetings, annual retreats, and peer reviews of
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`scientific data. The Center has led to the establishment of two other entities that are critical for
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`the clinical implementation of cell therapies: (1) the Cell Therapy and Cell Engineering Facility
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`led by Dr. Isabelle Rivière and (2) the Cell Therapy Center led by Dr. Renier Brentjens.
`
`3.
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`The Gene Transfer and Gene Expression Laboratory, under my leadership,
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`investigates ways to insert genes into hematopoietic stem cells using viral vectors and to control
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`how those genes are expressed, as well as ways to improve immune responses against tumor
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`cells. The lab currently comprises 22 members who conduct research on T cell and stem cell
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`engineering. I am responsible for the scientific direction, experimental planning, review and
`
`analysis of data, publication, and funding of those research activities.
`
`I.
`
`Background and Experience
`
`4.
`
`I earned an M.D. degree from the University of Paris, France, in 1984 and a Ph.D.
`
`in immunology from the University of Alberta, Canada, in 1989. Following a clinical residency
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`at the Centre Hospitalier Universitaire Saint-Antoine in Paris, I completed a postdoctoral
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`fellowship at the Whitehead Institute for Biomedical Research, Massachusetts Institute of
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`Technology (“MIT”), before joining MSKCC in 1994 as an assistant member.
`
`5.
`
`I am a member of the American Society of Hematology, the American
`
`Association for Cancer Research, and the American Society of Cell and Gene Therapy, where I
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`served on the board of directors from 2004 to 2007 and as president from 2015 to 2016. I am an
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`elected member of the American Society for Clinical Investigation. I have authored more than
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`200 scientific papers and book chapters. Among other awards, I received the 2012 William B.
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`Coley Award for Distinguished Research in Tumor Immunology, the 2013 Sultan Bin Khalifa
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`International Thalassemia Award, the 2017 Passano Laureate and Physician Scientist Award, the
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`2018 Pasteur-Weizmann/Servier International Prize, the 2019 Jacob and Louise Gabbay Award
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`in Biotechnology and Medicine, the 2019 INSERM International Prize, and the 2020 Leopold
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`Griffuel Award.
`
`6.
`
`I have been working for almost three decades on a gene-therapy based treatment
`
`using stem cells for the blood disease beta-thalassemia. Beta-thalassemia is a genetic blood
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`disorder caused by mutations in or near the beta-globin gene, which provides instructions for
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`making the beta-chain of hemoglobin (also referred to as beta-globin), that is produced in red
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`blood cells and carries oxygen to cells throughout the body. In people with beta-thalassemia,
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`low levels of hemoglobin lead to a lack of oxygen in parts of the body. Patients with two
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`deficient beta-globin genes have a more severe form of the disease called beta-thalassemia
`
`major. Persons with beta-thalassemia major require regular blood transfusions. For most
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`patients, the disease is incurable because they lack matched donors for bone marrow or stem cell
`
`transplants to restore the production of red blood cells with a normal hemoglobin content. In
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`addition to the logistical difficulties associated with lifelong blood transfusions, a side-effect of
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`blood transfusions is a build-up of iron in the body of the transfusion recipient. Patients with
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`beta-thalassemia major experience this condition, known as iron-overload, as a result of
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`requiring regular blood transfusions. This side effect can lead to other health problems requiring
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`additional therapies.
`
`7.
`
`Whereas beta-thalassemia major affects only a few thousand people in the United
`
`States, beta-thalassemia (in all of its forms, not limited to major) is one of the two most common
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`monogenic blood disorders worldwide (the other being sickle cell anemia). It is in particular
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`found in people of Mediterranean origin. Worldwide, approximately 68,000 people are born
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`with beta-thalassemia each year.
`
`II. Discovery of the TNS9 Technology
`
`8.
`
`My work on gene therapy began in 1989. During my postdoctoral fellowship at
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`MIT, the head of the lab in which I was working suggested that I work on thalassemia (in
`
`addition to the work I was conducting on T-cells). My work on T-cells and thalassemia
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`continued after I joined MSK in September 1994. From 1989 to 1994, I had conducted the work
`
`myself while at MIT; then, from 1994 to 2000, I pursued this research in my laboratory with my
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`graduate students and postdoctoral fellows, devoting approximately 50% of my time to
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`thalassemia research and the other 50% to CAR-T cell research.
`
`9.
`
`In July 2000, my lab published a landmark paper in Nature describing the
`
`technology I had developed to introduce beta-globin genes into hematopoietic stem cells.
`
`10.
`
`As background, the body produces red blood cells through a complicated series of
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`events that begins with cells called hematopoietic (i.e., “blood producing”) stem cells, or HSCs.
`
`HSCs are normally found in the bone marrow. Our potentially curative treatment involves (1)
`
`extracting a patient’s hematopoietic stem cells (HSCs), (2) utilizing a genetically-modified virus,
`
`known as a lentiviral vector, to stably insert a functional beta-globin gene into the extracted
`
`HSCs—this process is called transduction, and then (3) infusing the patient with the “genetically
`
`restored” HSCs that should now be capable of producing beta-globin in the derivative red blood
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`cells.
`
`11.
`
`At a high level, the research that I published in Nature was a proof of concept for
`
`using gene-therapy techniques to modify a patient’s cells to produce therapeutic levels of
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`hemoglobin. The work was the result of a complex series of experiments, which I generally
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`describe in the following paragraphs.
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`12.
`
`The first step in this research—and the most innovative—was designing the
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`genetic material that would be inserted into the patient’s cells. The genetic material needed to
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`include a functional beta-globin gene, but the beta-globin gene alone was not enough to cause the
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`patient’s cells to produce enough beta-globin. Genes are typically accompanied by other DNA
`
`sequences that allow the cell to control when the gene is turned on or off. These DNA
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`sequences, called regulatory elements, are necessary for the cell to make beta-globin from the
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`beta-globin gene. In 2000, scientists were just beginning to understand the role that these
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`regulatory elements played in gene expression, both in general and in the specific case of
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`hemoglobin. I designed a sequence of genetic material that included both the beta-globin gene
`
`and the regulatory elements that were necessary for cells to express it (i.e., to make beta-globin
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`from the beta-globin gene).
`
`13.
`
`Designing this genetic material, however, was only the first step toward getting
`
`defective cells to make hemoglobin. The next challenge was getting this genetic material into
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`the DNA, or genome, of defective cells. Genetic material that is directly injected into a cell
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`typically is not incorporated into the cell’s genome, so this step required further experimentation.
`
`14.
`
`Certain viruses are known to infect cells by inserting their own genes (i.e., the
`
`viral genes) into the cell’s genome. They do this through a complicated series of biochemical
`
`processes. Beginning in the mid-1980s, scientists discovered that they could modify these
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`viruses to insert genetically engineered DNA into the genomes of living cells. These modified
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`viruses are called vectors.
`
`15.
`
`Early vectors could only hold short DNA sequences; however, by the mid- to late-
`
`1990s, certain viruses that could hold larger amounts of genetic material were discovered. These
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`are called lentiviruses, from which lentiviral vectors are derived. Lentiviruses are a type of
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`retrovirus.
`
`16.
`
`The genetic materials that I assembled to express the beta-globin gene was too
`
`large for early vectors, but they potentially could be used within a suitable lentiviral vector. To
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`make such a lentiviral vector, I combined the human genetic material that we had assembled to
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`control the beta-globin gene with the viral genetic material known to be necessary to produce
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`lentiviral vectors from so-called “packaging cells” (called a 293T cell). When these components
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`were combined, the 293T cell produced lentiviral vector particles containing the therapeutic
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`genetic material that we had designed. I called these particles the TNS9 vector.
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`17.
`
`In the late 1990s—the time that my lab did the work described in our Nature
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`paper—and in the 2000s, gene therapy was regarded as a nascent, cutting-edge, but potentially
`
`dangerous technique. Indeed, some well-publicized gene therapy failures during that time
`
`caused some scientists and others to be very wary of this field in general. For example, in 1999,
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`Jesse Gelsinger, a patient in a gene-therapy clinical trial for a liver disorder run by the University
`
`of Pennsylvania died from an adverse event. His death received widespread media coverage. In
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`addition, in 2000, gene therapy trials were conducted in France to treat children with Severe
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`Combined Immune Deficiency. The treatment in those trials, similar in concept to the treatment
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`we had invented for thalassemia, used retroviral vectors for inserting genes into HSCs. While
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`the results of this trial were initially promising, in the years following the application of the gene
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`therapy, several patients developed a leukemia-like cancer that was traced to the retroviral
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`vectors. That prompted researchers, institutions, and regulators to proceed very cautiously in the
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`gene-therapy area. Indeed, in 2003, in direct response to the trial in France, the Food and Drug
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`Administration (FDA) temporarily halted all trials that used retroviral vectors for inserting genes
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`into bone marrow stem cells.
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`18. My lab performed the first experiments with the TNS9 vector in mice. The first
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`step for these studies was to concentrate the TNS9 vector from the 293T cells. As of the late
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`1990s, there were methods for purifying vector on a small scale and to an acceptable level of
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`purity for animal studies; however, it was difficult to purify vectors on the scale or to the extent
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`necessary for human studies.
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`19.
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`For the TNS9 vector to have a therapeutic effect, it would need to cause a large
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`number of red blood cells in the patient or animal’s body to contain adequate amounts of normal
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`hemoglobin. It is not possible to achieve this effect by modifying red blood cells directly.
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`Instead, it is necessary to modify HSCs—i.e., the cells in the body that produce red blood cells.
`
`20.
`
`To treat the thalassemic mice in our study, we extracted their bone marrow,
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`isolated the HSCs, treated the HSCs with the TNS9 vector, and reinjected the treated HSCs into
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`the mice. We found that these treated mice expressed functional hemoglobin as the result of the
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`TNS9 vector treatment. In other words, we discovered that our technology could eventually
`
`work for treating human patients with beta thalassemia.
`
`21.
`
`Our Nature publication solved a conundrum of globin gene therapy that had
`
`previously been unsolved by other researchers in the field. A major challenge in designing an
`
`effective gene therapy for beta-thalassemia was to design a vector that could efficiently insert a
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`functional human beta-globin gene in patient cells. This required two things. First, it required
`
`high-efficiency transduction—i.e., gene transfer via a vector into the defective cell. Second,
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`uniquely for this disease, in order to be therapeutic, the vector would need to produce a very
`
`substantial amount of beta-globin—or, in scientific terms, express high levels of the encoded
`
`globin gene. For years, neither we nor any of the number of other research groups in the United
`
`States or in Europe conducting this research had succeeded in designing a vector that could both
`
`be transduced at high efficiency and express therapeutic levels of the beta-globin protein. Most
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`had concluded that retroviral vectors could not serve this purpose, and research teams other than
`
`us turned their efforts to alternative vector systems (adeno-associated virus, alpha-virus, etc.).
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`We, in contrast, perceived that some unique biological attributes of lentiviral vectors (a type of
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`retroviral vector) may allow us to assemble inside such a vector a set of elements that we had
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`carefully studied and reduced to a size compatible with genetic stability and efficient
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`transduction. It took me 11 years—from 1989 to 2000—to succeed in designing a vector
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`meeting those two fundamental criteria. That vector design—as published in Nature—became
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`the foundation for all present gene therapies for thalassemia and sickle cell disease (another
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`common genetic disorder that affects the same beta-globin gene).
`
`22. When my coworkers and I reported the results of our work in Nature, we noted
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`that our work was an “advancement towards the genetic treatment of severe
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`haemoglobinopathies” like thalassemia. But we also noted that it would only be “available for
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`therapeutic applications once safety concerns are fully addressed.” Our work was a major step
`
`toward a gene therapy to treat beta thalassemia, but much more remained to be done.
`
`23.
`
`I (and three co-inventors from my lab at MSKCC) filed for patent protection on
`
`the discoveries reported in my Nature article and ultimately were granted U.S. Patent No.
`
`7,541,179, entitled “Vector Encoding Human Globin Gene and Use Thereof in Treatment of
`
`Hemoglobinopathies.” A true and correct copy of the issued patent is marked as Exhibit JX3.
`
`III. Further Development of the TNS9 Technology
`
`24.
`
`As a result of the publication in Nature, my work received significant interest in
`
`both the academic community and general press. I received calls of interest from all over the
`
`world as soon as the article was published. I was also invited to speak at conferences around the
`
`world. During one such speaking engagement in Italy in spring of 2001, I first met Patrick
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`Girondi. Mr. Girondi, whose son Rocco suffers from thalassemia, is not a scientist or physician
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`but is a well-known patient advocate in the thalassemia community. I continued to encounter
`
`Mr. Girondi at other conferences and annual meetings related to thalassemia research in the early
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`2000s.
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`25.
`
`In December 2001, Dr. Philippe Leboulch, a founder of Genetix Pharmaceuticals,
`
`published a paper in Science disclosing research derivative of the research that I had published in
`
`Nature a year prior: Dr. Leboulch’s research—which of late had focused on alpha virus, and
`
`then turned to lentiviral vectors following our publication in Nature—likewise consisted in a
`
`lentiviral vector modeled on ours encoding a globin gene and the HS2, HS3, and HS4 control
`
`elements. The main distinction between my work and that of Dr. Leboulch was that Dr.
`
`Leboulch administered the therapy to three sickle-cell mice. I have known Dr. Leboulch for
`
`approximately 30 years and view him as both a personal acquaintance and a scientific
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`competitor.
`
`IV. SKI Sought a Commercial Partner to Develop to My Technology and Bring It to
`Patients.
`
`26.
`
`By 2005, I believed that, on the basis of the biological evidence we had obtained,
`
`we were scientifically ready to commence the process of preparing for and seeking regulatory
`
`approval to conduct human clinical trials. However, bringing the treatment to humans required
`
`several additional steps and faced hurdles, largely due to the novelty and highly innovative
`
`nature of this treatment. This was understood by both Sloan Kettering and EGT before the
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`parties entered into the 2005 Agreement.
`
`27.
`
`First, we needed to prepare and file an Investigational New Drug application
`
`(“IND”) (the regulatory filing required to commence human trials) with the FDA. Human
`
`clinical trials can commence only once an IND is accepted by the FDA. We could try to
`
`anticipate what the FDA would ask and could also seek a “pre-IND” meeting (a meeting with the
`
`FDA before an IND is submitted in which you can get a sense of what data the FDA expects to
`
`be provided in the IND). But because globin gene therapy was so novel, there was no
`
`comprehensive guideline to filing an IND or prior example to emulate. By 2005, there had been
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`very few clinical trials involving gene therapy, and as mentioned above, several had suffered
`
`serious setbacks. And as of this time there had been no clinical trial involving gene therapy for
`
`any type of hemoglobin disorder.
`
`28.
`
`Second, there were manufacturing issues that needed to be addressed with regard
`
`to the production of a lot of the vector that could be used in a Phase I clinical trial. The biggest
`
`unknown that would dictate our readiness to apply to the FDA was the quantity and quality of
`
`the vector that would be manufactured. Investigators are required to provide the data and results
`
`from validation or qualification runs or cross reference an already FDA approved manufacturing
`
`technique to get FDA approval to conduct a Phase I clinical trial. The results demonstrate to the
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`FDA that you can manufacture the therapeutic product—i.e., the transduced patient cells—in a
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`consistent way. The manufacture of the vector reagent in sufficient quantities to conduct clinical
`
`trials had to be contracted out. SKI did not have the facilities to manufacture vector in these
`
`quantities, so our ability to a conduct trial hinged on the timeline and quality of the vector stock
`
`we would be supplied with.
`
`29.
`
`Third, because this type of treatment had only been tested in mice, we needed to
`
`scale up the process for human treatment. We had worked out the transduction (i.e., gene
`
`transfer) of human stem cells (i.e., CD34+ progenitor cells) on a small scale (i.e., with small
`
`numbers of cells sufficient to conduct preclinical experiments) and now needed to perfect
`
`transduction conditions on the scale needed for infusion to a patient.
`
`30. MSKCC (specifically, the Office of Industrial Affairs, which was later called the
`
`Office of Technology Development) endeavored to obtain funding for further development of
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`my patented vector technology. Sloan Kettering is a non-profit research institution. It (along
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`with Memorial Hospital and MSKCC) relies on external sources to fund research, including
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`grants, contracts, and sponsored research projects, which may come from governmental,
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`industrial, philanthropic, or other sources. The majority of funding for research comes from
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`outside industry, and not from Sloan Kettering (or Memorial Hospital or MSKCC). Sloan
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`Kettering supported me (and supports its other researchers) by providing a laboratory and
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`facilities necessary to conduct research. But it is generally up to researchers to obtain external
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`funding to support their specific projects.
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`31.
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`To fund my thalassemia work, I was able to obtain grants from the National
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`Institutes of Health (“NIH”) and other foundations, but in amounts insufficient to cover the high
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`costs of human clinical trials. The NIH grant I received is known as an RO1 grant—it provides
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`funding for research but not for clinical trials.
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`32.
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`At some point in the early 2000s, Mr. Girondi proposed to fund the project
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`through his company, Errant Gene Therapeutics, LLC (“EGT”). At the time, Sloan Kettering
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`could not find other interested partners. Gene therapy was in its infancy, and, as explained
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`above, a significant amount of uncertainty existed over the entire field. In general, gene therapy
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`was seen as highly speculative and potentially dangerous. Also, it was well known that Dr.
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`Leboulch was already working on similar technology, had already conducted pre-clinical trials
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`(on mice) with his therapy, and was well funded by Genetix Pharmaceuticals (the predecessor to
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`Bluebird Bio Inc.).
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`V. Work Under the 2005 License Agreement
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`33.
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`I am generally familiar with the purpose of the 2005 License Agreement (the
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`“2005 Agreement”) that Sloan Kettering entered into with EGT, though I was not involved in the
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`negotiations or drafting of that Agreement.
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`34.
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`Though the 2005 Agreement granted a license to EGT, EGT did not have a lab
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`and had only had a few employees and, so all of the work to develop the licensed technology
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`needed to be performed at Sloan Kettering by Sloan Kettering staff. Among the Sloan Kettering
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`scientists with whom I worked on that project was Dr. Rivière, a scientist with extensive
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`experience in vector manufacturing (who later became my spouse).
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`35.
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`On January 30, 2006, January 8, 2007, and January 24, 2008, I signed Consulting
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`Agreements with EGT marked as DX175. Those Agreements provided, among other things (on
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`the second page), that “The Company [EGT] will have no rights by reason of the Agreement in
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`any document, material, invention, information, improvement, or other intellectual property
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`whatsoever, whether or not publishable, patentable or copyrightable which is or was generated as
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`a result of your activities as an employee of MSKCC or using the resources or proprietary
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`information of MSKCC.” The consulting agreements provided for EGT to pay me $3000 per
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`month for time spent on the project.
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`36.
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`During the period July 2006 through September 2008, Sloan Kettering entered
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`into several Industrial Research Agreements with EGT. See JX2. Dr. Rivière and I, and others
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`in our labs, performed research concerning the thalassemia gene therapy project pursuant to these
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`agreements.
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`37.
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`All of the scientific laboratory work conducted pursuant to the 2005 EGT license
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`agreement was performed by the researchers at Sloan Kettering. I do not recall any scientific
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`contributions or technological advancements to vector design by EGT. While EGT performed
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`certain paperwork relating to the IND submission and while I understand that Dr. Christopher
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`Ballas, an EGT consultant, had some interaction with third parties who manufactured the vector
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`that was used in the later clinical trial, EGT did not perform any scientific research patient cell
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`collection, transduction, or characterization and certainly provided no research results to me or,
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`to my knowledge, anyone else at Sloan Kettering.
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`38.
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`TNS9 suffered from a low “vector titer”—i.e., the amount of the vector that could
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`be produced by the 293T cells. After the Nature publication in 2000, my coworkers and I
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`continued to work to increase the vector titer in two ways: by improving the transduction method
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`and by modifying the vector. The vector titer problem was significant enough that we believed
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`that it was unlikely that improvements in transduction conditions would be sufficient on their
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`own. At one point, Dr. Ballas suggested experiments with chemical mediators to improve the
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`transduction method. We performed experiments using these mediators, but they did not
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`improve transduction to an acceptable level.
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`39. We therefore sought to systematically modify the vector generic material to
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`increase the titer. This work involved up to six Sloan Kettering researchers working in my lab
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`and in Dr. Rivière’s lab. The following figure, which is the color version of a figure in our IND
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`(JX 007.0196), illustrates the modifications to the TNS9 genetic material that led us to a vector
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`with significantly improved titer, which we called TNS9.3.55:
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`~
`
`+
`
`,p
`
`R
`
`RRE
`
`■
`
`-B-globin 3' enhancer
`
`exon3
`
`BssHII
`
`Mlel
`
`CMV11-HV-1 LTR
`
`cPPT
`
`exon3
`
`exon2 exon 1
`
`TNS9
`
`• ■ B,.globin promoter
`[8993bp) i
`
`I.
`
`exon2 exon 1
`
`HS2
`
`Hl;;i~
`
`B- globin LCR
`
`HS4
`
`~
`R
`
`HS2
`
`H
`
`HS4
`
`A
`
`B-globin 3' enhancer
`
`B-globin promoter
`
`B- globin LCA
`
`R
`
`CMV/HIV- 1 LTR
`
`)I!+
`
`RRE
`
`cPPT
`
`exon3
`
`C3T9.2
`
`(S946bp) i
`
`exon2 exon 1
`
`II.
`
`HS2
`
`H
`
`HS4
`
`A
`
`B-globin 3' enhancer
`
`B-globln promoter
`
`BspEI
`
`S,C,,I
`
`R
`
`TNS9.3
`(8946bp)
`
`III.
`
`B- globin LCR
`
`BspEI
`
`CMV/HIV-1 LTR
`
`'lp+
`
`ARE
`
`cPPT
`
`e)l;on3
`
`exon 2 exon 1
`
`HS2
`
`HS4
`
`WPRE BGH polyA
`
`R
`
`B- globin LCR
`
`A
`
`~ -B-globin 3' enhancer
`
`exon 3
`
`cPPT
`
`ARE
`
`■
`
`CMV/HIV-1 LTR
`
`-I
`
`\)J +
`II
`
`R
`
`TNS9.3.51
`(9719bp)
`
`IV.
`
`exon 2 exon 1
`
`HS2
`
`~ ii-
`■ I
`B-globin promo._"_' ________________ ___. R
`B- globin LCR
`
`HS3
`
`HS4
`
`WPRE BGH polyA
`
`TNS9.3.55
`(9635bp)
`
`
`Each box in these diagrams represents a different genetic element. For example, the boxes in red
`
`enable the vector to code for the human beta globin gene. The boxes to the right of all of the red
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`boxes represent what we call the “3’ LTR,” or long terminal repeat. The labels coming off of the
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`diagram on diagonal lines represent “restriction sites,” or places where the DNA can be cut so
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`new genetic material can be inserted.
`
`40.
`
`TNS9.3 (shown in the figure above) was our preferred vector around the time that
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`Sloan Kettering licensed the vector technology to EGT in 2005, and this is the vector that we
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`initially used when we tested Dr. Ballas’s process (transduction)-based suggestions to improve
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`the titer. The vector titer of TNS9.3 was still too low to be effective in clinical trials.
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