UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ROXANE LABORATORIES., INC.,
`Petitioner
`
`V.
`
`NOVARTIS AG,
`Patent Owner
`
`Case Not Yet Assigned
`Patent 9,006,224
`
`DECLARATION OF KENNETH HO—MING YU, M.D., M.SC., IN
`SUPPORT OF THE PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 9,006,224
`
`Roxane Labs., Inc.
`Exhibit 1003
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`Page 001
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 001
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ROXANE LABORATORIES., INC.,
`Petitioner
`
`V.
`
`NOVARTIS AG,
`Patent Owner
`
`Case Not Yet Assigned
`Patent 9,006,224
`
`DECLARATION OF KENNETH HO—MING YU, M.D., M.SC., IN
`SUPPORT OF THE PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 9,006,224
`
`Roxane Labs., Inc.
`Exhibit 1003
`
`Page 001
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`Roxane Labs., Inc.
`Exhibit 1003
`Page 001
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`TABLE OF CONTENTS
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`INTRODUCTION ................................................................................. .. ...... ..3
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`QUALIFICATIONS AND EXPERIENCE ................................................... ..3
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`III.
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`IV.
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`SIHVIMARY OF OPINIONS ........................................................ .._ ............... ..5
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`PERSON OF ORDINARY SKILL IN THE ART .................................... ..6
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`LEGAL STANDARDS ................................................................................. ..7
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`VI.
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`TECHNICAL BACKGROUND AND STATE OF THE ART .................... ..8
`
`A.
`
`B.
`
`C.
`
`The Biology Of Pancreatic Neuroendocrine Tumors ......................... ..8
`
`Everolimus As A Treatment For PNET .............................................. ..9
`
`The Prior Art Taught That Everolimus Has Enhanced Solubility
`And Improved Pharmacokinetics Compared To Rapamycin ........... .. 12
`
`VII.
`
`OPINIONS .........................................................................
`
`........................ ..13
`
`A.
`
`I B.
`
`Claims 1 And 2 Of The ’224 Patent Are Obvious Over The
`’54l Publication In View Of Tabernero ........
`.................................. .. l 3
`
`Claims 1 And 2 Of The ’224 Patent Are Obvious Over von
`Wichert In View Of Dutcher, The ‘772 Patent And Tabernero ........ .. 15
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`Page 2 of 18
`Roxane Labs., Inc.
`Exhibit 1003
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`Page 002
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`Roxane Labs., Inc.
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`Page 002
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`I.
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`INTRODUCTION
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`1.
`
`I, Kenneth Ho-ming Yu, M.D., M.Sc., have personal knowledge of the
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`facts set forth in this Declaration and am competent to testify to the same.
`
`2.
`
`I have been retained by counsel for Roxane (Roxane Laboratories,
`
`Inc.) in this proceeding regarding US Patent No. 9,006,224 (“the ’224 patent”).
`
`3.
`
`I hereby offer this Declaration in support of the petition for inter
`
`partes review of the ’224 patent.
`
`4.
`
`A list of materials that I have reviewed is attached hereto as
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`Attachment A.
`
`II.
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`QUALIFICATIONS AND EXPERIENCE
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`5.
`
`I have been a licensed medical doctor since 1999 and am board
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`certified in Medical Oncology.
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`I currently serve as an Assistant Attending
`
`Physician at Memorial Hospital for Cancer & Allied Diseases in the Department of
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`Medicine, NY, and Assistant Member of Memorial Sloan Kettering Cancer Center,
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`NY.
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`I also serve as an Assistant Professor at Weill Cornell Medical College, NY;
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`Adjunct Assistant Professor at the Universityof Pennsylvania, Philadelphia; and
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`Clinical Fellow at Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
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`6.
`
`t I graduated from Harvard University, Cambridge in 1995 and
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`completed my M.D. at John Hopkins University, Baltimore in 1999.
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`I completed
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`an M.Sc. qualification at the University of Pennsylvania, Philadelphia in 2009.
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`Roxane Labs., Inc.
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`7.
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`I was a Medical Intern at the Hospital of the University of
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`Pennsylvania between 1999-2000, before becoming a Medical Resident at the
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`Hospital of the University of Pennsylvania from 2000-2002.
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`I was a Fellow of
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`Hematology and Oncology at the Hospital of the University of Pennsylvania
`
`between 2002-2005.
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`8.
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`I was an Attending Physician at Abramson Cancer Center in the
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`Division of Hematology—Oncology at the Hospital of the University of
`
`Pennsylvania between 2005-2010.
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`I am currently an Assistant Attending Physician
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`at Memorial Hospital for Cancer & Allied Diseases at the Department of Medicine
`
`in NYC.
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`. 9.
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`I hold several other professional memberships.
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`I am currently a
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`member of the American Society of Clinical Oncology. I have previously been a
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`member of the American Association of Cancer Research’, the American
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`Gastroenterology Association and the American Society for Mass Spectroscopy.
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`10.
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`I have been awarded several honors over my career to date.
`
`I was
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`designated magna cum laude with highest honors in 1995 at Harvard University.
`
`I
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`was also a Research Scholar at the Institute for Translational Medicine and
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`Therapeutics, University of Pennsylvania in 2005, and received the Bernard L.
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`Schwartz Designated Research Award in Pancreatic Cancer, AGA Foundation for
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`Digestive Health and Nutrition in 2006.
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`Roxane Labs., Inc.
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`11.
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`I hold various editorial responsibilities in several academic journals
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`including, for example, Gastroenterology, Journal of Gastrointestinal Cancer,
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`Pancreatology, Oncogene, Journal of Surgical Oncology and Cancer
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`Chemotherapy and Pharmacology.
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`12.
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`I have authored more than 40 journal articles, abstracts, and other
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`presented lectures relating primarily to the diagnosis and treatment of pancreatic
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`cancers and other advanced solid tumors.
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`13. My research has been directed to various facets of pancreatic cancers,
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`including the development of novel therapeutics and biomarkers in pancreatic
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`ductal adenocarcinoma (PDAC).
`
`I am also the principal investigator or co-
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`investigator on a number of clinical trials focused on pancreatic cancer and PNET.
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`14. My complete Curriculum Vitae is attached as Attachment B.
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`III.
`
`SUMMARY OF OPINIONS
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`15.
`
`It is my opinion for the reasons described below that claims 1 and 2 of
`
`the ‘Z24 patent would have been obvious to a person of ordinary skill in the art in
`
`View of the prior art disclosing at least the following: (1) that everolimus is
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`effective against CAZO9-48 pancreatic cell line which is a rat cell line which can be
`
`used as a model for pancreatic neuroendocrine tumors; (2) that 10 mg everolimus
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`is safe and effective against advanced solid tumors; (3) that rapamycin inhibits
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`proliferation in BON cells, a cell line established from human PNET; (4) that
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`everolimus has antitumor properties and mechanisms of action similar to those of
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`rapamycin; and (5) that everolimus has increased solubility and improved
`
`pharmacokinetic properties compared to rapamycin.
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`16.
`
`I have reviewed pancreatic neuroendocrine tumor and mTOR inhibitor
`
`prior art. Based on my review of the prior art, my opinion is that one of ordinary
`
`skill in the art would have understood that the ’541 publication (Exhibit 1005) and
`
`Tabernero (Exhibit 1006) render obvious the challenged claims of the ’224 patent.
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`17.
`
`It is also my opinion that one of ordinary skill in the art would have
`
`understood that von Wichert (Exhibit 1007), Dutcher (Exhibit 1008), the ’772
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`patent (Exhibit 1009) and Tabemero (Exhibit 1006) would render obvious the
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`challenged claims of the ’224 patent.
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`IV.
`
`PERSON OF ORDINARY SKILL IN THE ART
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`18.
`
`The purported inventions of the ’224 patent involve an understanding
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`of the principles of the treatment of advanced tumors in patients suffering from a
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`tumor such as pancreatic neuroendocrine tumor (“PNET”). It is my opinion that a
`
`person of ordinary skill in the art (“POSA”) pertaining to the subject matter of the
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`’224 patent as of November 21, 2005 would have had: (1) a Ph.D. in biology,
`
`biochemistry, pharmaceutical sciences, molecular biology, cancer biology, or other
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`biological sciences, and/or (2) a medical degree. The POSA would have
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`experience conducting preclinical, clinical, and/or laboratory research relating,
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`Page 006
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`inter alia, to rapamycin and its analogs, cancers of the pancreas or neuroendocrine
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`system, and/or intracellular pathways. The POSA would also have collaborated
`
`with others having skills and expertise in areas pertinent to the above subject
`
`matter, including, for example, pharmacologists, formulators, and biochemists.
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`V.
`
`LEGAL STANDARDS
`
`19.
`
`I have been informed regarding the legal principle of obviousness and
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`have used my understanding of that principle in forming my opinions.
`
`20.
`
`I have been informed by counsel for Roxane that the first three factors
`
`to be considered in an obviousness inquiry are: (l) the scope and content of the
`
`prior art; (2) the differences between the prior art and the claims; and (3) the level
`
`of ordinary skill in the pertinent art.
`
`21.
`
`I am also informed by counsel for Roxane that certain factors,
`
`sometimes known as “secondary considerations,” must be considered, if present,
`
`when making obviousness determination. These secondary considerations include:
`
`(i) long-felt need, (ii) unexpected results, (iii) skepticism of the invention, (iv)
`
`teaching away from the invention, (v) commercial success, (vi) praise by others for
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`' the invention, and (vii) copying by other companies.
`
`22.
`
`I am also informed by counsel for Roxane that the earliest U.S. patent
`
`application leading to the ’224 Patent was filed on November 20, 2006.
`
`I have
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`therefore analyzed obviousness as of that day or somewhat before, understanding
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`Roxane Labs., Inc.
`Exhibit 1003
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`Page 007
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`Roxane Labs., Inc.
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`Page 007
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`that as time passes, the knowledge of a person of ordinary skill in the art will
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`increase.
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`VI. TECHNICAL BACKGROUND AND STATE OF THE ART
`
`A.
`
`The Biology Of Pancreatic Neuroendocrine Tumors
`
`23.
`
`The prior art teaches that PNETS are rare neoplastic growths that
`
`derive from endocrine pancreatic tissue. See, e.g. , Doran Exhibit 1010 at 5; Guo
`
`Exhibit 1011 at 73. The prior art further teaches that when PNETS can be resected
`
`or surgically removed, this can lead to rapid regression of clinical symptoms
`
`(WHO Exhibit 1012 at 175), but that antitumor treatments are necessary to treat
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`poorly defined or metastasized tumors (McStay Exhibit 1013 at 47). Such
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`antitumor treatments include, inter alia, chemotherapy, such as a combination of
`
`streptozocin, 5—fluorouracil (“SFU”) and Adriamycin (doxorubicin), which was
`
`reported to significantly prolong survival, inhibit tumor progression, and produce
`major shrinkage ofwell-differentiated tumors in up to two—thirds of cases. Id.
`3
`
`24.
`
`It was understood by 2000 that the molecular biology of PNETS
`
`would render them susceptible to treatment with mTOR inhibitors such as
`
`everolimus. It was known that PNETS are associated with mutations to the MEN-
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`1, VHL, NF1 , TSC1 or TSC2 genes, (Doran Exhibit 1010 at 10-12), and that
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`dysfunctional VHL gene product would lead to increase HIF—1 activity and
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`overexpression of growth factors (VEGF) associated with tumor growth and
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`Page 008
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`Roxane Labs., Inc.
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`metastasis. See, e. g., Harris Exhibit 1014 at 32-33; Calender Exhibit 1015 at 8-9;
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`Maxwell Exhibit 1016 at 271; and Semenza, Exhibit 1017 at 86-87. It was further
`
`known that dysfunctional TSC1 or TSC2 genes products would result in activation
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`of the PI3K/Akt/mTOR signaling pathway, HIF—1 activation, and cell growth. See,
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`e. g., Figure 3 of Kwiatkowski Exhibit 1018 and 473-474;. Brugarolas Exhibit 1019
`
`at 2894. A POSA also would have known that the tumor suppressor PTEN may
`
`function abnormally in PNETS. Perren Exhibit 1020 at 1097. Moreover, a POSA
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`would have known that PTEN acts upstream of the PI3K/Akt/mTOR pathway and
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`that loss or mutation of PTEN results in the stimulation of the PI3K/Akt/mTOR
`
`pathway. See, e. g., Seku1ic' Exhibit 1021 at 3505; Podsypanina Exhibit 1027 at
`
`1 03 24.
`
`25.
`
`By the early 2000s, it was known that the involvement of mTOR is
`
`common to each of these tumor growth pathways. Based on that knowledge, a
`
`POSA would have recognized that the use of mTOR inhibitors, such as rapamycin
`
`and everolimus, provide an opportunity to shut down these pathways. See, e. g.,
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`Brugarolas Exhibit 1019; Sekulié Exhibit 1021; Dutcher Exhibit 1008 at 112; Yee
`
`Exhibit 1022; Vara Exhibit 1023 at 201; and Vignot Exhibit 1024 at 531.
`
`B.
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`Everolimus As A Treatment For PNET
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`26.
`
`The prior art teaches that the mTOR signaling pathway impacts
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`cellular functions, including those important for growth and proliferation of
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`Page 009
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`various tumor types. As of 2004, researchers had developed and tested specific
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`inhibitors of mTOR, like rapamycin and its derivatives everolimus and CCI—779
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`(temsirolimus), that target the PI3K/Akt pathway for use as antitumor agents. See,
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`e.g., Boulay, Exhibit 1025 at 252; and Carraway, Exhibit 1026 at 222.
`
`27.
`
`In preclinical and clinical studies, everolimus and CCI—779 were
`
`demonstrated to be tolerable, and to have a broad range of activity against human
`
`cancers, such as breast cancer, hematologic malignancies, prostate cancer,
`
`leukemia, melanoma, renal cell cancer, glioblastoma, and pancreatic cancer (see,
`
`e.g., Yee Exhibit 1022, Dutcher Exhibit 1008, Yu Exhibit 1035, Carraway Exhibit
`
`1026, Vara Exhibit 1023, Boulay Exhibit 1025, ’54l Publication Exhibit 1005,
`
`Tabernero Exhibit 1006,), and even against cancers that were advanced, refractory,
`
`and/or resistant to other anticancer treatments (see, e.g., Hidalgo Exhibit 1028 at
`
`187a).
`
`28.
`
`For instance, the ’541 Publication teaches that everolimus
`
`monotherapy can treat human advanced solid tumors, including those of the
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`pancreas. ’54l Publication at [0009—00l8], [0099—0l05]. The ’54l Publication
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`further states that everolimus’s efficacy in treating solid tumors may be
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`demonstrated in animal studies. Id. at [0009], [0074].
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`In one such study, a mouse
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`study, tumors were established by injection of the CA20948 pancreatic cell line. In
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`that study, everolimus, when administered as a monotherapy by mouth at a daily
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`dose of 0.5 to 2.5 mg/kg resulted in a mean increase in tumor volume that was only
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`23% of the increase in tumor volume when control was administered. Id. at
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`[0088]. In addition, the ’541 Publication states that everolimus “significantly and
`
`consistently decreases in these assays the rate of CA20948 pancreatic tumor
`
`growth when compared to vehicle controls.” Id.
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`29.
`
`A POSA would have understood that the CA20948 pancreatic cell line
`
`was used as a model for evaluating PNETs.i See De Jong 1999 at 356 (using
`
`CA20948 as a model for somatostatin positive neuroendocrine tumors.) Breeman
`1993 at 1089. Boulay teaches that everolimus has antitumor efficacy against the
`
`CA20948 cell line. Boulay Exhibit 1025, at 252. Boulay demonstrated
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`everolimus’s activity against PNET as a monotherapy, and also tied such activity
`
`to everolimus’s ability to inhibit mTOR, teaching a role of the mTOR pathway in
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`PNETS.
`
`30.
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`The prior art taught that everolimus is a rapamycin derivative that has
`
`antineoplastic activity and that everolimus, like rapamycin, blocks mTOR and
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`P705“ activity. See, e.g., Dutcher Exhibit 1008, at 112; Yee Exhibit 1022; vata
`
`Exhibit 1023, at 201; Sekulié Exhibit 1021 at 3504; see also Vignot Exhibit 1024,
`
`at531.
`
`31.
`
`The prior art taught that everolimus would be efficacious against
`
`PNET. von Wichert Exhibit 1007, for example, teaches that rapamycin inhibits
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`growth of BON cells, a human pancreatic endocrine cancer cell line, “by a pathway
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`that involves PI3 -kinase, [mTOR]/p7056k, and mitogen—activated protein kinase
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`kinase 1 activity.” von Wichert Exhibit 1007, at 4573; see also Evers, Exhibit
`
`1030 (disclosing that the BON cell line is derived from a metastatic human
`
`carcinoid tumor of the pancreas or PNET); Ahnert—Hi1ger, Exhibit 1036 at 1601
`
`(describing BON as a PNET cell line); Lemmer, Exhibit 1037 at 667 (describing
`BON as a pancreatic neuroendocrine cell line); Jonas, Exhibit 1038 at 91, 92
`
`(describing human neuroendocrine pancreatic cell line BON); Detjen, Exhibit 1039
`
`at 736 (disclosing BON as a neuroendocrine pancreatic cell line); John, Exhibit
`
`1040 at 791, 796 (disclosing BON as a pancreatic cell line derived from a human
`
`neuroendocrine tumor).
`
`C.
`
`The Prior Art Taught That Everolimus Has Enhanced Solubility
`And Improved Pharmacokinetics Compared To Rapamycin
`
`32. A POSA would have been motivated to use everolimus rather than
`
`rapamycin to treat PNET for the following reasons. First, a POSA would have
`
`known that rapamycin had poor pharmaceutical properties that precluded its
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`development as an anticancer agent. See, e.g., Houghton Exhibit 1034, at 352
`
`(teaching that Ayerst Research Laboratories, which first isolated and characterized
`
`rapamycin, failed to develop a satisfactory IV formulation of rapamycin); see also
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`Hidalgo Exhibit 1028 at 6680 (“the poor aqueous solubility and chemical stability
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`of rapamycin precluded its development as an anti-cancer agent”); ’772 at 1:34-40
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`(describing rapamycin, in comparison to everolimus, as having antitumor activity,
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`but having low solubility and very low and variable bioavailability which restricts
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`itsutility as a pharmaceutical). Second, compared to rapamycin, everolimus was
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`known to have a better pharmacological profile. See Crowe Exhibit 1032 at 630
`
`(teaching that everolimus has 60% greater absolute oral bioavailability than
`
`rapamycin); see also ’772 Patent Exhibit 1009 at 1:41-45, 2:55-60 (describing
`
`everolimus as having an improved pharmacologic profile, greater stability and
`
`bioavailability, and greater ease in producing galenic formulations).
`
`33. Moreover, a POSA would have known that everolimus could be
`
`conveniently administered orally in View of its improved bioavailability compared
`
`to rapamycin and CCI-779. See e.g., ’772 Patent Exhibit 1009 at 1:41-45, 2:20,
`
`2:30; see also id. at 22:28-29; see also Boulay Exhibit 1025, Tabernero Exhibit
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`1006. Everolimus was also given as a monotherapy. See, e.g., Yee Exhibit 1022;
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`’772 Patent Exhibit 1009 at 728-16; see also id. at 4:56-57; seealso Boulay Exhibit
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`1025; Tabernero Exhibit 1006,.
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`VII. OPINIONS
`
`A.
`
`Claims 1 And 2 Of The ’224 Patent Are Obvious Over The ’541
`Publication In View Of Tabernero
`
`34.
`
`As discussed in more detail below, in my opinion, claim 1 and claim 2
`
`of the ’224 Patent are obvious over the ’541 Publication in view of Tabernero.
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`35.
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`The efficacy of everolimus in a preclinical rat model for PNET is
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`described in the ’541 Publication. The ’54l Publication describes orally
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`administering everolimus to CA20948 tumor bearing mice. A POSA would have
`
`understood that CA20948 pancreatic cell line was used to screen compounds for
`
`efficacy against PNET. See e. g. , Boulay Exhibit 1025, Abstract; De Jong Exhibit
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`1033 at 356; Breeman Exhibit 1029 at 1089.
`
`36.
`
`The prior art ’541 Publication describes administering daily doses of
`
`0.5 mg/kg to 2.5 mg/kg of everolimus “p.o.”, 1'. e., the doses were orally
`
`administered. Exhibit 1005 at [0088]. In addition, the ’54l Publication states that
`
`everolimus “significantly and consistently decreases in these assays the rate of
`
`CA20948 pancreatic tumor growth when compared to vehicle controls.” Ia’. A
`
`POSA readingthe ’54l Publication would have understood that everolimus had
`
`been shown to inhibit growth of tumors of the CA20948 cell line, a model for
`
`evaluating PNET as an anticancer monotherapy, which would have given the
`
`POSA a reasonable expectation that everolimus would be active against PNET.
`
`37.
`
`It was also known from Phase I clinical trials that everolimus was safe
`
`and efficacious against advanced solid tumors in humans. Tabernero describes a
`
`Phase I trial in which everolimus, a known mTOR inhibitor, was orally
`
`administered as a monotherapy at 10 mg daily to human patients suffering from
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`advanced solid tumors. More specifically, Tabernero reports that administration of
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`everolimus at 10 mg daily results in intratumoral inhibition of mTOR signaling and
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`recommends further phase lI—III development of everolimus monotherapy at a
`
`dosage of 10 mg daily. Typically, patients who present with advanced solid
`
`tumors have tumors which are surgically refractory and which have not responded
`
`to cytotoxic chemotherapy. A POSA reading Tabernero would understand that
`
`everolimus is a safe and effective therapy for treatment of advanced solid tumors.
`
`38.
`
`A POSA reading the ’541 Publication would have known that
`
`everolimus is active against the C/X20948 pancreatic cell line, which is a model for
`
`PNET. In View of Tabernero, a POSA would have known that everolimus is
`
`nontoxic and effective at a dose of 10 mg daily. In view of the combined teachings
`
`ofthe ’541 Publication and Tabernero, a POSA would have been motivated to
`
`orally administer everolimus, which is nontoxic, as a monotherapy antitumor agent
`
`to a human patient with advanced PNET after failure of cytotoxic chemotherapy
`
`with a reasonable expectation of success.
`
`B.
`
`Claims 1 And 2 Of The ’224 Patent Are Obvious Over von
`
`Wichert In View Of Dutcher, The ’772 Patent And Tabernero
`
`39. As discussed in more detail below, in my opinion, claim 1 and claim 2
`
`of the ’224 patent are obvious over von Wichert in view of Dutcher, the ’772
`
`patent and Tabernero.
`
`40.
`
`Von Wichert describes the use of rapamycin, in vitro, to inhibit
`
`proliferation of BON cells, which are cells established from human PNET. Exhibit
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`1007, at 4578; see also Evers, Exhibit 1030 (disclosing that the BON cell line is
`
`derived from a metastatic human carcinoid tumor of the pancreas or PNET);
`
`Ahnert—Hilger, Exhibit 1036 at 1601 (describing BON as a PNET cell line);
`
`Lemmer, Exhibit 1037 at 667 (describing BON as a pancreatic neuroendocrine cell
`
`line); Jonas, Exhibit 1038 at 91, 92 (describing human neuroendocrine pancreatic
`
`cell line BON); Detjen, Exhibit 1039 at 736 (disclosing BON as a neuroendocrine
`
`pancreatic cell line); John, Exhibit 1040 at 791, 796 (disclosing BON as a
`
`pancreatic cell line derived from a human neuroendocrine tumor). A POSA
`
`reading von Wichert would understand that BON cells are a useful model to study
`
`the biology of PNET in vitro. Id. at 45 73. von Wichert reports that incubation of
`
`BON cells with rapamycin inhibited proliferation of BON cells by about 70%. Id.
`
`A POSA reading Von Wichert would have reasonably expected that rapamycin,
`
`which was found to inhibit BON cells, should also inhibit proliferation of PNET
`cells, from which BON cells are established.
`
`41.
`
`As discussed above, a POSA would have known that rapamycin and
`
`everolimus are both mTOR inhibitors and inhibit tumor proliferation through the
`
`same mechanism of action. Dutcher Exhibit 1008 at 112. Because everolimus and
`
`rapamycin inhibit tumor proliferation through the same mechanism of action, a
`
`POSA would have reasonably expected that like rapamycin, everolimus, by
`
`targeting mTOR, would be effective against tumors, such as PNET tumors.
`
`Page 16 of 18
`Roxane Labs., Inc.
`Exhibit 1003
`
`Page 016
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 016
`
`
`
`42.
`
`A POSA also would have known that in comparison to rapamycin,
`
`everolimus exhibits improved solubility, has an improved pharmacologic profile,
`
`exhibits greater stability and bioavailability, and allows for greater ease in
`
`producing galenic formulations.
`
`’772 patent Exhibit 1009 at 1:34-45.
`
`43.
`
`In View of rapamycin’s efficacy with respect to BON cells, the similar
`
`antitumor action of everolimus and rapamycin, and the superior solubility and
`
`pharmacokinetic properties of everolimus, a POSA would have been motivated to
`
`g develop a treatment for PNET using everolimus as a monotherapy and would have
`
`reasonably expected that everolimus would be active against PNET.
`
`44.
`
`As discussed above, a POSA reading Tabernero would have
`
`understood that 10 mg daily of everolimus is a safe and effective therapy for
`
`treatment of advanced solid tumors.
`
`45.
`
`A POSA reading von Wichert and Dutcher would have expected that
`
`everolimus was active against the BON cell line, which is a model for PNET. In
`
`view of the ’772 patent and Tabernero, a POSA would have been motivated to
`
`orally administer 10 mg everolimus as a monotherapy agent to a human patient
`
`with advanced PNET after failure of cytotoxic chemotherapy with a reasonable
`
`expectation of success.
`
`46.
`
`I am unaware of any secondary considerations which would overcome
`
`obviousness of claim l and claim 2 of the ’224 patent. In view of the above prior
`
`Page 17 ofl8
`Roxane Labs., Inc.
`Exhibit 1003
`
`Page 017
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 017
`
`
`
`art, the efficacy of everolimus to treat PNET is not surprising, and certainly is not
`
`unexpected. In addition, other therapies for PNET, such as a combination
`
`chemotherapeutic regimen of streptozocin, 5—fluorouracil (“5FU”) and Adriamycin
`
`’ (doxorubicin), had been reported to significantly prolong survival, inhibit tumor
`
`progression, and produce major shrinkage of well—differentiated tumors in up to
`
`two-thirds of cases. McStay Exhibit 1013 at 47.
`
`I hereby declare that all statements made herein of my own knowledge are true and
`
`that all statements made on information and belief are believed to be true; and
`
`further that these statements were made with the knowledge that willful false
`
`statements and the like so made are punishable by fine or imprisonment, or both,
`
`under Section 1001 of Title 18 of the United States Code.
`
`Dated:
`
`7/18/16
`
`Kenneth
`Yu
`
`Digitally signed by Kenneth Yu
`DN: cn=Kenneth Yu, o=MSKCC,
`CIU, emai|=yuki@mskccrorg,
`c=US
`Date: 2016.07.18 09:07:37
`~o4'oo'
`
`By:
`Kenneth Ho—Ming Yu, M.D., M.Sc.,
`
`Page 18 of 18
`Roxane Labs., Inc.
`Exhibit 1003
`
`Page 018
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 018
`
`
`
`Declaration of Kenneth Ho-ming Yu, M.D., M.Sc. in Support of Petition
`
`Attachment A: Materials Considered
`
`Petition for inter partes Review of U.S. Patent No. 9,006,224.
`
`Exhibit No.
`
`Description
`
`1001
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`U.S. Patent No. 9,006,224 (“the ’224 Patent”)
`
`U.S. Patent Application Publication No. 2004/0147,541 A1 (“’541
`Publication”)
`
`Tabernero et al., A phase I study with tumor molecular
`pharmacodynamics (MPD) evaluation of dose and schedule of the
`oral mTOR-inhibitor Everolimus (RAD001) in patients (pts) with
`advanced solid tumors, DEVELOPMENTAL THERAPEUTICS:
`MOLECULAR THERAPEUTICS, Abstract 3007, 193s (2005)
`(“Tabernero”)
`
`von Wichert et al., Insulin-like Growth Factor-I is an Autocrine
`Regulator of Chromogranin A Secretion and Growth in Human
`Neuroendocrine Tumor Cells, CANCER RESEARCH, 60: 4573-4581
`(August 15, 2000) (“von Wichert”)
`
`Dutcher, Mammalian Target of Rapamycin (mTOR) Inhibitors,
`CURRENT ONCOLOGY REPORTS, 6: 111-115 (2004) (“Dutcher”)
`
`U.S. Patent No. 5,665,772 (“the ’772 Patent”)
`
`Doran et al., Epidemiology of Pancreatic Neuroendocrine
`Tumours, in PANCREATIC DISEASE: BASIC SCIENCE AND CLINICAL
`MANAGEMENT 5 (Johnson et al., eds., 2004) (“Doran”)
`
`Guo et al., Frequent overexpression of cyclin D1 in sporadic
`pancreatic endocrine tumours, JOURNAL OF ENDOCRINOLOGY, 179:
`73-79 (2003) (“Guo”)
`
`World Health Organization Classification of Tumours, Pathology
`& Genetics | Tumours of Endocrine Organs, (DeLellis et al., eds.)
`175-261 (April 23-26, 2003) (“WHO”)
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 019
`
`
`
`Exhibit No.
`
`Description
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`McStay & Caplin, GI Hormone Producing Tumours: Syndromes
`and Treatment Options, in PANCREATIC DISEASE: BASIC SCIENCE
`AND CLINICAL MANAGEMENT 31 (Johnson et al. eds., 2004)
`(“McStay”)
`
`Harris, von Hippel-Lindau Syndrome: Target for Anti-Vascular
`Endothelial Growth Factor (VEGF) Receptor Therapy, THE
`ONCOLOGIST, 5(suppl. 1): 32-36 (2000) (“Harris”)
`
`Calender, Molecular Genetics of Neuroendocrine Tumors,
`DIGESTION, 62(suppl. 1): 3-18 (2000) (“Calender”)
`
`Maxwell et al., The tumour suppressor protein VHL targets
`hupoxia-inducible factors for oxygen-dependent proteolysis,
`NATURE, 399: 271-275 (1999) (“Maxwell”)
`
`Semenza, Hypoxia, Clonal Selection, and the Role of HIF-1 in
`Tumor Progression, CRITICAL REVIEWS IN BIOCHEMISTRY &
`MOLECULAR BIOLOGY, 35(2): 71-103 (2000) (“Semenza-II”)
`
`Kwiatkowski, Rhebbing up mTOR, CANCER BIOLOGY & THERAPY,
`2(5): 471-76 (2003) (“Kwiatkowski”)
`
`Brugarolas et al., Regulation of mTOR function in response to
`hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex,
`GENES & DEVELOPMENT, 18: 2893–2904 (2004) (“Brugarolas”)
`
`Perren et al., Mutation and Expression Analyses Reveal Differential
`Subcellular Compartmentalization of PTEN in Endocrine
`Pancreatic Tumors Compared to Normal Islet Cells, AMERICAN
`JOURNAL OF PATHOLOGY, 157(4): 1097-1103 (October 2000)
`(“Perren”)
`
`Sekulić et al., A Direct Linkage between the Phosphoinositide 3-
`Kinase-AKT Signaling Pathway and the Mammalian Target of
`Rapamycin in Mitogen-stimulated and Transformed Cells, CANCER
`RESEARCH, 60: 3504-3513 (July 1, 2000) (“Sekulić”)
`
`
`
`2
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 020
`
`
`
`Exhibit No.
`
`Description
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`
`
`Yee et al., A Phase I/II Study of the Oral mTOR Inhibitor RAD001
`in Patients with Advanced Hematologic Malignancies, JOURNAL OF
`IMMUNOTHERAPY, 27(6): S35, Abstract (November/December
`2004) (“Yee”)
`
`Vara et al., PI3K/Akt signalling pathway and cancer, CANCER
`TREATMENT REVIEWS, 30: 193-204 (2004) (“Vara”)
`
`Vignot et al., mTOR-targeted therapy of cancer with rapamycin
`derivatives, ANNALS OF ONCOLOGY, 16: 525-537 (February 22,
`2005) (“Vignot”)
`
`Boulay et al., Antitumor Efficacy of Intermittent Treatment
`Schedules with the Rapamycin Derivative RAD001 Correlates with
`Prolonged Inactivation of Ribosomal Protein S6 Kinase 1 in
`PERIPHERAL BLOOD MONONUCLEAR CELLS, CANCER RESEARCH, 64:
`252-261 (2004) (“Boulay”)
`
`Carraway & Hidalgo, New targets for therapy in breast cancer:
`Mammalian target of rapamycin (mTOR) antagonists, BREAST
`CANCER RESEARCH, 6: 219-224 (2004) (“Carraway”)
`
`Podsypanina et al., An Inhibitor of mTOR Reduces Neoplasia and
`Normalizes p70/S6 Kinase Activity in Pten+/- Mice, PNAS, 98(18):
`10320-10325 (2001) (“Podsypanina”)
`
`Hidalgo & Rowinsky, The rapamycin-sensitive signal transduction
`pathway as a target for cancer therapy, ONCOGENE 19: 6680-6686
`(2000) (“Hidalgo”)
`
`Breeman et al., Radioiodinated Somatostatin Analogue RC-160:
`Preparation, Biological Activity, in Vivo Application in Rats and
`Comparison with [123I-Tyr3]Octreotide, EUROPEAN JOURNAL OF
`NUCLEAR MEDICINE, 20: 1089-1094 (1993) (“Breeman”)
`
`Evers et al., Establishment and Characterization of a Human
`Carcinoid in Nude Mice and Effect of Various Agents on Tumor
`Growth, GASTROENTEROLOGY, 101(2): 303-11 (1991) (“Evers”)
`
`3
`
`Roxane Labs., Inc.
`Exhibit 1003
`Page 021
`
`
`
`Exhibit No.
`
`Description
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`
`
`
`
`Crowe et al., Absorption and Intestinal Metabolism of SDZ-RAD
`and Rapamycin in Rats, DRUG METABOLISM & DISPOSITION, 27(5):
`627-32 (1999) (“Crowe”)
`
`De Jong et al., Therapy of neuroendocrine tumors with
`radiolabeled somatostatin analogues, THE QUATERLY JOURNAL OF
`NUCLEAR MEDICINE, 43: 356-66 (1999) ("De Jong")
`
`Houghton & Huang, mTOR as a Target for Cancer Therapy in
`TOR TARGET OF RAPAMYCIN, G. Thomas et al. (eds.) 339-359
`(2004) (“Houghton”)
`
`Yu et al., mTOR, a novel target in breast cancer: the effect of CCI-
`779, an mTOR inhibitor, in preclinical models of breast cancer,
`ENDOCRINE-RELATED CANCER, 8: 249-258 (2001) (“Yu”)
`
`Ahnert-Hilger et al, γ-Aminobutyric Acid Secretion From
`Pancreatic Neuroendocrine Cells, GASTROENTEROLOGY, 110:
`1595–1604 (1996) (“Ahnert-Hilger”)
`
`Lemmer et al., Expression of dopamine receptors and transporter
`in neuroendocrine gastrointestinal tumor cells, LIFE SCIENCES, 71:
`667–678 (2002) (“Lemmer”)
`
`Jonas et al., Somatostatin receptor subtypes in neuroendocrine
`tumor cell lines and tumor tissues, LANGENBECKS ARCHIVES OF
`SURGERY, 380: 90–95 (1995) (“Jonas”)
`
`Detjen et al., Molecular Mechanism of Interferon Alfa–Mediated
`Growth Inhibition in Human Neuroendocrine Tumor Cell
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