UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`BLUEBIRD BIO, INC.,
`Petitioner,
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`v.
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`SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH,
`Patent Owner.
`____________
`Case No. IPR2023-00074
`Patent No. 8,058,061
`____________
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`DECLARATION OF DR. LUCIO LUZZATTO
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
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`I, Lucio Luzzatto, declare as follows:
`1.
`I am over the age of 21 years and am fully competent to make this
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`Declaration. I make the following statements based on personal knowledge and,
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`if called to testify to them, could and would do so.
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`2.
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`I earned a Maturita Classica from Liceo D’Oria in Genova, Italy in
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`1953. In 1959, I received my M.D. from the University of Genova Medical
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`School, Genova, Italy. In 1968, I received my Ph.D. in Biochemistry from the
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`Ministry of Education, Italy. I am certified in Hematology in Italy and in UK
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`(FRCPath). I received my medical license from the State of New York in 1995. I
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`have been also licensed in Italy, Nigeria, the U.K., and Tanzania.
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`3.
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`After obtaining my M.D., I became a resident in infectious diseases
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`in Genova, Italy. In 1963, I became a fellow in Haematology at Columbia
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`Presbyterian Hospital’s Department of Medicine. In the period from 1964 to 1994
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`I was a lecturer and then professor of hematology first in Ibadan and later in
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`London, and I directed a Genetics Research Institute in Naples.
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`4.
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`From 1994 to 2000, I served as the Chairman of the Department of
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`Human Genetics and as Attending Physician in Genetics and Hematology at
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`Memorial Sloan Kettering Cancer Center. Thereafter, I served as the Scientific
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`Director for the National Institute for Cancer Research in Genova, Italy from
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`2000 to 2004. I also served as a Professor of Haematology at the University of
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`Genova from 2002 to 2006.
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`5.
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`From 2005 to 2015, I was the Scientific Director at the Istituto
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`Toscano Tumori in Florence Italy. I was also a Professor of Haematology
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`(Honorary since 2008) at the University of Florence in Italy.
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`6.
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`Until December 31, 2022, I have been a Professor of Haematology
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`at Muhimbili University College of Health and Allied Sciences in Dar-es-Salaam,
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`Tanzania.
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`7.
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`8.
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`Attached as Appendix A is my current CV.
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`As Chairman of the Department of Human Genetics at Memorial
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`Sloan-Kettering Cancer Center (MSKCC), I oversaw various research labs. One
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`of those labs was run by Dr. Michel Sadelain, whom I had recruited. I was aware
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`of the research that Dr. Sadelain and his team were conducting in the mid to late
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`1990s. Specifically, they were pursuing the idea of gene therapy, based on gene
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`transfer into hematopoietic stem cells, to treat hemoglobinopathies. Several
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`individuals worked in his lab, including Stefano Rivella and Chad May; and there
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`was collaboration with Joseph Bertino, who was chairman of the Department of
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`Pharmacology at MSKCC.
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`9.
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`Throughout the 1990s, there were several other labs working on
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`finding a vector capable of integrating into hematopoietic stem cells, that would
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`also result in adequate expression of the beta globin gene in vivo. One might say
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`there was a sort of race as to who would first find a solution.
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`10.
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`I remember Dr. Sadelain’s team was working on finding a solution
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`over my entire tenure at MSKCC, i.e., from 1994 to 2000. In fact, I had multiple
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`conversations with Dr. Sadelain over the years about his research, the challenges
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`he was facing, the progress his team had made, etc.
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`11.
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`In or around the 1996-1998 timeframe, Dr. Sadelain and his team
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`tested many vectors, and with a. vector they termed TNS9 they had a
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`breakthrough. They believed this vector was capable of successfully transferring
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`a globin gene into hematopoietic stem cells, and achieving a level of expression
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`that would be therapeutically-relevant.
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`12.
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`In or around 1999, the team initiated in vivo studies in mice. The
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`results of those studies were very encouraging. Not only was the beta-globin of
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`the TNS9 vector being expressed, but it was being expressed at therapeutic levels
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`that could be sustained over a period. I remember Dr Sadelan and all in his lab
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`being, understandably, very excited; and so was I by reflection.
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`13. The TNS9 vector and accompanying research became the subject of
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`U.S. Patent No. 7,541,179 (“the ‘179 Patent”) and U.S. Patent No. 8,058,061
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`(“the ‘061 Patent”). I am familiar with these patent applications.
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`14.
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`I understand the TNS9 vector is one embodiment of the vector
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`claimed in the ‘179 and ‘061 Patents. It utilized a lentiviral virus as the backbone
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`of the vector. It also included a human beta-globin gene, plus a 3.2 kb nucleotide
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`portion, which was taken from the human (cid:533)-globin locus control region (LCR).
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`The 3.2 kb nucleotide portion consisted of three fragments, each of which
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`encompassed one of the hypersensitive sites (HS) known to exist within the LCR.
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`I understand these fragments were created using restriction enzymes to cut the
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`DNA but other approaches would have been known and were regularly used,
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`including the polymerase chain reaction (PCR). The LCR was known to regulate
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`physiologically the expression of the globin genes, including the beta-globin gene
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`and the gamma-globin genes, It was and is my understanding that the different
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`globin genes share common characteristics and structures, making it possible for
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`their expression to come under the control of the same LCR.
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`15. While the TNS9 vector initially was tested for expression of a human
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`beta-globin gene, I remember recognizing that the vector design could be used
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`with other globin genes. This could be done by substituting the human beta-
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`globin gene with the nucleotide sequence of a different functional globin on the
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`TNS9 vector. I remember I had discussion with Dr. Sadelain and his team about
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`this.
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`16. On July 6, 2000, an article reporting some of Dr. Sadelain and his
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`team’s work was published in Nature (referred to as “the Nature Article”). I
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`understand this article is Exhibit 1005 in the IPR proceedings and is being
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`asserted by the Petitioner against the ‘179 and ‘061 Patents. This article was
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`entitled, “Therapeutic Haemoglobin Synthesis
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`in (cid:533)-Thalassaemic Mice
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`Expressing Lentivirus-Encoded Human (cid:533)-globin.” Chad May is one of the
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`authors and the first name on the article. I am one of the co-authors of that article
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`because of my counseling and advice to the team during their research, and
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`because I supervised some analytical procedures (Fig. 3e,f) and, as a
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`haematologist, I examined the blood slides (Fig. 5). In the authorship Michel
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`Sadelain was the last name, as is costumary for the person who has masterminded
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`and directed the work.
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`17.
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`I did not contribute to the new vector design. I am not an inventor of
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`the TNS9 vector or any subject matter claimed in the ‘179 and ‘061 Patents.
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`18. Even though the Nature Article did not provide detail regarding the
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`restriction enzymes used to create the fragments of the TNS9 vector, Dr Sadelain
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`and his lab at MSKCC were clearly aware of the restriction sites being used as
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`they had already constructed and tested the TNS9 vector prior to the publication
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`of the Nature Article. Logically, they would have had to have conceived of these
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`ideas and reduced them to practice prior to the Nature Article’s publication to
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`obtain the results of the tests that were included in the article.
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`I declare under penalty of perjury that the foregoingis true and correct.
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`Executed on January 21, 2023.
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`olsecbanalt
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`Dr. Lucio Luzzatto
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`é
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`CURRICULUM VITAE
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`
`
`NAME
`DATE OF BIRTH
`PLACE OF BIRTH
`NATIONALITY
`MARITAL STATUS
`ADDRESS
`
`e-mail:
`
`PRESENT POSITION
`Nov 2015
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`MEDICAL LICENCE
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`1963-64
`1964-67
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`Lucio Luzzatto
`September 28, 1936
`Genova, Italy
`Italian
`Married with Paola Caboara Luzzatto: children Stefano & Fatima
`Muhimbili Haematology Programme, Room Number 8, Ground Floor,
`1 Kipalapala street, Upanga; P. O. Box 65001, Dar-es-Sa;laam, Tanzania
`<lluzzatto@blood.ac.tz> <lucio.luzzatto@unifi.it>
`
`
`Professor of Haematology, Muhimbili University College of Health and
`Allied Sciences (MUHAS), Dar-es-Salaam, TANZANIA
`1960
`Italy
`1965 Nigeria
`1981 United Kingdom
`1995 New York State
`2016 Tanzania
`BOARD CERTIFICATION
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`1962 Hematology
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`
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`1982 FRCPath
`1983 FRCP
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`
`
`EDUCATION
`1953 Maturità Classica, Liceo D'Oria, Genova, Italy,
`1959 MD, University of Genova Medical School M.D., Genova, Italy,
`1968 Libera Docenza in Biochemistry (PhD), Ministry of Education, Italy,
`POSTGRADUATE CLINICAL AND RESEARCH TRAINING
`1959-62
`Resident, Department of Infectious Diseases, Ospedale S. Martino, Genova;
`Research Fellow (part-time), Department of Biochemistry (2 years), then
`Department of Biophysics (1 year), University of Genova, Genova, Italy
`Fellow in Haematology, Department of Medicine, College of Physicians & Surgeons,
`Columbia Presbyterian Hospital, New York, NY, USA.
`Lecturer in Haematology, in charge of Blood Transfusion Unit Department of
`Pathology, University of Ibadan, Ibadan, Nigeria.
`POSITIONS AND APPOINTMENTS
`1967-68
`Senior Lecturer in charge of Sub-Department of Haematology, University of Ibadan,
`Ibadan, Nigeria; Consultant Haematologist, UCH, Ibadan, Nigeria,
`1968-1974
`Professor of Haematology (from 1970 Head of Department) University of Ibadan,
`Ibadan, Nigeria.
`
`
`1974-1981
`Director, International Institute of Genetics and Biophysics, CNR, Napoli, Italy,
`1981-1994
`Professor of Haematology (University of London), and Director of Haematology
`Department, Royal Postgraduate Medical School (now Imperial College), London;
`Consultant Haematologist, Hammersmith Hospital,
`Chairman, Department of Human Genetics, Attending Physician in Genetics and
`Hematology, Memorial Hospital; Member of the Cell Biology and Genetics
`Programme, Sloan-Kettering Institute, Courtney Steel Chair, Memorial Sloan-
`Kettering Cancer Center; Professor of Medicine and Human Genetics, Cornell
`University Medical College, New York, NY, USA,
`Scientific Director, National Institute for Cancer Research, Genova, Italy,
`Professor of Haematology, DOBIG, University of Genova, Genova, Italy
`Scientific Director, Istituto Toscano Tumori, Florence, Italy
`Professor of Haematology (Honorary since 2008), University of Florence, Firenze,
`Italy.
`
`
`1994-2000
`
`2000-2004
`2002-2006
`2005-2015
`2006-
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`APPENDIX A
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`HONORARY DEGREES
`• Laurea ad honorem in Pharmacy, University of Urbino, Italy, 1990
`• DSc, University of Ibadan, Nigeria, 1998
`• Laurea ad honorem in Medicine, University of Patras, Greece, 2006.
`SCIENTIFIC AND MEDICAL SOCIETY MEMBERSHIPS (PARTIAL LIST)
`• International Society of Haematology, since 1972
`• University College Hospital Ibadan Medical Society, President-elect, 1968-70
`• Nigerian Society for Haematology and Blood Transfusion; Foundation President, 1968; now
`honorary member.
`• Expert Panel on Abnormal Haemoglobins and Thalassemia of the International Committee on
`Standardization in Haematology, 1972-81
`• Italian Association of Genetics: President 1979-81
`• Executive Council, Italian Society of Haematology, 1977-80
`• European Molecular Biology Organization (EMBO): Active Member since 1979
`• American Society of Haematology, Honorary member since 1981
`• Human Genome Organization (HUGO), Active member since 1993
`• American Association of Physicians, since 1995
`• Chairman, Ethics Committee, American Society for Gene Therapy (1997-2000)
`• President, Federazione Italiana Scienze della Vita, 2008-2010
`• Accademia dei Lincei, Elected Foreign Member, 2022.
`VISITING APPOINTMENTS AND NAMED LECTURES (PARTIAL LIST)
`• Visiting Scientist for one month at the Department of Human Genetics, University of Leiden,
`NL,1966
`• Visiting Scientist for seven months to the Department of Microbiology, Washington University
`Medical School, St. Louis, MO, USA, 1967
`• Visiting Professor for one month at the Department of Medicine, Makerere University,
`Kampala, Uganda, 1969
`• Visiting Professor for two weeks at the Department of Haematology, Mahidol University,
`Bangkok, Thailand, 1972
`• Visiting Professor for two weeks at the Faculty of Medicine, University of Nigeria, Enugu, 1974
`• Visiting Professor for three weeks at the Department of Medicine, Muhimbili University
`Hospital, University, Dar es Salaam, Tanzania, 1974.
`• Henry M. Stratton Lecture, XV International Congress of Haematology, 1974
`• Carl Harford Visiting Professor, Washington University Medical School, St. Louis, MO, USA,
`1983
`• British Exchange Professor, Department of Medicine, UCLA, Los Angeles, CA, USA, 1987
`• Ham-Wasserman Lecture, American Society of Haematology, San Francisco, CA, USA, 1988
`• Oliver-Sharpey Lecture, Royal College of Physicians, 1988
`• Visiting Professor, Department of Medicine, University of Michigan, Ann Arbor, MI, USA, 1989
`• Adolfo Ferrata Lecture, Italian Society of Haematology, Rome, Italy, 1989
`• Visiting Professor, Toronto General Hospital, Toronto, Canada, 1990
`• Visiting Professor, University of Modena, Italy, 1991
`• Visiting Professor, University of Naples, Italy, 1992
`• Visiting Professor, Department of Pathology, University of Alberta, Edmonton, Alberta,
`Canada, 1994
`• Fifth William C. Maloney Lecture Brigham and Women's Hospital, Boston, MA, 1998
`• Lilly Lectures - Royal College of Physicians London and Sheffield, UK, 1999
`• Josè Carreras Lecture - European Haematology Association, Firenze, 2002
`• Serafino Zappacosta Memorial Lecture, Napoli, 2012.
`• Address to International Leaders in Haematology, ASH, Orlando, FL, USA, 2015
`HONOURS AND AWARDS (PARTIAL LIST)
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`• Livierato Prize, University of Genova, 1957
`• Pasetto Prize, University of Genova, 1958
`• Istituto Nazionale Assistenza Infortuni sul Lavoro Prize, 1960
`• Ministero della Pubblica Istruzione Fellow, 1962
`• Fulbright Senior Fellow, 1967
`• Pius XI Medal, 1976
`• Sanremo International Prize for Human Genetics, 1982
`• International Chiron Award for Biomedical Research, 1995
`• Premio Napoli, 1995
`• Nigerian Society of Haematology and Blood Transfusion: 25thYear Jubilee Lecture, 1997
`• Premio Pier Camillo Beccaria, Associazione Angela Serra, Modena, Italy, 1999
`• Premio Liguria, 2000
`• James Blundell Award, British Society of Blood Transfusion, 2001
`• Foreign Member, American Academy of Arts and Sciences, 2004.
`• Montalenti Medal, University of Rome, 2007.
`• Premio Giovanni Maria Pace, Trieste, 2007.
`• Scientific Prize Accademia delle Scienze of Torino, 2011.
`• Accademia dei Lincei Annual Scientific Prize for Biology, 2015.
`• Environmental Mutagenesis and Genomics Society PIG-A Award, 2016
`OTHER
`• Director, WHO Regional Reference Centre (Africa) for glucose-6-phosphate dehydrogenase,
`1967-74
`• Chairman of the Organizing Committee for the first Advanced Seminar in Haematology for
`Africa, Ibadan Nigeria, 4-19 August, 1972
`• Director of WHO Collaborative Centre for human glucose-6-phosphate dehydrogenase, Naples,
`1976-1981
`• Member (Chairman from 1983) of Steering Committee of Scientific Working Group on
`Biomedical Sciences, Special Programme on Tropical Diseases, WHO, 1978-86
`• Chairman of the Ethics Committee of the American Scoiety of Gene Therapy, 1996-2000.
`• International Outreach ad hoc Committee, American Society of Hematology, 1999
`• Member National Cancer Advisory Board - Ministry of Health, Italy, 2000
`• Member National Advisory Board on Stem Cell Research - Ministry of Health, Italy, 2000
`• Member of Scientific Committee, Science Festival, Genova, 2003-2012
`• Member of Life Sciences Panel 7, European Research Council, Bruxelles, 2008-2014
`• Chairman, Scientific Advisory Committee, Italian Cystic Fibrosis Foundation, 2012-2015
`• Chairman, Scientific Advisory Committee, Josep Carreras Institute, Barcelona, 2013-
`• Chairman, WHO Evidence Review Group on Point of Care G6PD Testing to Support Safe Use
`of Primaquine for the Treatment of Vivax Malaria, Geneva, 2014
`• Chairman of the Italian Institute of Technology Genomi Valdostani Project, 2022-
`
`PUBLICATIONS
`435 scientific papers listed in PubMed.
`Many chapters in major textbooks.
` Book for general readership: CAPIRE IL CANCRO (UNDERSTANDING CANCER), Publ.
`Rizzoli, 2006; Paperback edition (BUR), 2009.
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