UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`
`HOLDINGS INC., and APOTEX HOLDINGS, INC.,
`
`Petitioners,
`V.
`
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`U.S. Patent No. 6,900,221
`
`Issue Date: May 31, 2005
`Title of Patent: Stable Polyrnorph on N-(3-ethylphenyl)-6,7-bis(2methoxyethoXy)-
`4-quinazolinamine hydrochloride, Methods of Production, and Pharmaceutical
`uses thereof
`
`Case No.: T.B.D.
`
`DECLARATION OF GIUSEPPE GIACCONE, M.D., Ph.D.
`
`APOTEX EX. 1002-001
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`APOTEX INC., APOTEX CORP., APOTEX PHARMACEUTICALS
`
`HOLDINGS INC., and APOTEX HOLDINGS, INC.,
`
`Petitioners,
`V.
`
`OSI PHARMACEUTICALS, INC.,
`Patent Owner.
`
`U.S. Patent No. 6,900,221
`
`Issue Date: May 31, 2005
`Title of Patent: Stable Polyrnorph on N-(3-ethylphenyl)-6,7-bis(2methoxyethoXy)-
`4-quinazolinamine hydrochloride, Methods of Production, and Pharmaceutical
`uses thereof
`
`Case No.: T.B.D.
`
`DECLARATION OF GIUSEPPE GIACCONE, M.D., Ph.D.
`
`APOTEX EX. 1002-001
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`I, Giuseppe Giaccone M.D. Ph.D, declare and state as follows:
`
`1.
`
`I have been retained by counsel for Petitioners Apotex Inc., Apotex
`
`Corp., Apotex Pharmaceuticals Holdings Inc., and Apotex Holdings, Inc.
`
`(collectively, “Petitioners”) to review and analyze certain facts concerning U.S.
`
`Patent No. 6,900,221 (“the ’221 patent”), and in particular, issued claims 44-47
`
`and 53 of the ’221 patent.
`
`2.
`
`The opinions and conclusions I express in this declaration are based
`
`on my education, my extensive experience in the diagnosis and treatment of
`
`various lung cancers, and my review of materials related to this matter.
`
`1.
`
`QUALIFICATIONS
`
`3.
`
`I am currently the Associate Director for Clinical Research and
`
`Professor of Medical Oncology and Pharmacology at the Lombardi
`
`Comprehensive Cancer Center, Georgetown University.
`
`I oversee clinical research
`
`in oncology at Georgetown University Medical Center as well as in the Medstar
`
`Cancer Network (which comprises several hospitals in Maryland and the District
`
`of Columbia). In particular, I am responsible for research on the treatment and
`
`diagnosis of thoracic malignancies, which include lung cancer.
`
`4.
`
`I earned my undergraduate degree in 1974 from Liceo Scientifico
`
`Galileo Ferrari, and my medical degree in 1980 from the University of Torino
`
`Medical School, both of which are located in Torino, Italy.
`
`APOTEX EX. 1002-002
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`5.
`
`After earning my medical degree, I completed an internship,
`
`residency, and fellowships in medical oncology. In particular, from 1988 to 1990,
`
`I was a visiting fellow at the National Cancer Institute Navy Medical Oncology
`
`Branch in Rockville, Maryland. After completing my fellowship at the National
`
`Cancer Institute, I continued my studies and research in medical oncology at the
`
`Vrije University in Amsterdam, Netherlands, where, in 1995, I eamed a doctorate
`
`from the Department of Medical Oncology. My thesis research concerned
`
`experimental and clinical research in lung cancer.
`
`6.
`
`While working towards my doctorate degree, I held an appointment as
`
`an Assistant Professor at Vrije University in the Department of Medical Oncology.
`
`I was later promoted to Associate (1998) and then Full Professor (2000).
`
`I became
`
`the Head of the Department of Medical Oncology at Vrije University in 2003.
`
`During my 16 years at Vrije University, I cared for patients suffering from various
`
`lung cancers, and also oversaw research in diagnosis and treatment of lung cancer,
`
`including the development ofnew medicines for treating lung cancer.
`
`7.
`
`In 2007, I returned to the National Cancer Institute in Bethesda,
`
`Maryland, as Chief of the Medical Oncology Branch.
`
`8.
`
`In 2013, Ijoined the Lombardi Comprehensive Cancer Center at
`
`Georgetown University as the Associate Director for Clinical Research and
`
`Professor of Medical Oncology and Pharmacology.
`
`APOTEX EX. 1002-003
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`9.
`
`During my 35—plus years in the field of medical oncology, I have
`
`authored over five hundred publications, many of which concern the diagnosis and
`
`treatment of various lung cancers.
`
`I have also authored many review articles
`
`concerning advances in the diagnosis and treatment of cancer, many of which dealt
`
`with advances in lung cancer therapy.
`
`10.
`
`I have been, and am currently, on the editorial board for multiple
`
`scientific and medical journals, including Clinical Lung Cancer (1990 to present),
`
`Clinical Cancer Research (2002 to present), and Frontiers in Oncology (Editor in
`
`Chief, 2010 to present).
`
`1 1.
`
`I have also presided over, been a board member, and been invited to
`
`speak at many symposia concerning lung cancer and oncology in general.
`
`12.
`
`A more detailed account of my work experience, professional
`
`services, publications, and other qualifications is listed in my Curriculum Vitae,
`
`which is attached here to as Appendix A.
`
`13.
`
`I have no financial interest in the outcome ofthis proceeding.
`
`I am
`
`being compensated at my standard hourly consulting rate for my time spent
`
`working on this matter, and my compensation is in no way contingent on the
`
`conclusions I reach herein, the specifics of my testimony, or the outcome of this
`
`proceeding.
`
`APOTEX EX. 1002-004
`
`
`
`U.S. Patent No. 6300,22 1—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, MD., Ph.D.
`
`11. MATERIALS REVIEWED
`
`14.
`
`In fonning my opinions, I have reviewed, among other things, the
`
`221 patent and papers filed in the U.S. Patent and Trademark Office (“PTO”) in
`
`connection with prosecution of the applications that led to the ’221 patent, which I
`
`understand constitute the prosecution history of the ’221 patent. A full list of
`
`materials I have considered can be found in Appendix B.
`
`111. TECHNICAL BACKGROUND
`
`A.
`
`Cancer and Epidermal Growth Factor Receptors
`
`15.
`
`Cancer is a group of diseases involving abnormal cell growth with the
`
`potential to invade or spread to other parts of the body. Cancer cells oftentimes
`
`proliferate more quickly than other cells in the body in response to growth factors.
`
`One such growth factor is epidemial growth factor (“EGF”), which promotes cell
`
`proliferation and is found in almost all body fluids under normal physiological
`
`conditions.
`
`(See, e.g., V. Rusch er a[., “The Epidermal Growth Factor Receptor
`
`and its Ligands as Therapeutic Targets in Human Tumors,” Ci/tokme & Growth
`
`Factor Reviews 7(2): 133-141 (1996) (EX. 1017).)
`
`16.
`
`Scientists have studied the role of EGF receptors in promoting tumor
`
`cell growth since at least the early 1980s. The receptor for EGF is a
`
`transmembrane glycoprotein found on the surface of many cells that includes: (1)
`
`an extracellular ligand-binding domain capable of binding a ligand such as EGF or
`
`APOTEX EX. 1002-005
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, MD., Ph.D.
`
`transforming growth factor-alpha (“TGF-or”); (2) a hydrophobic transmembrane
`
`region; and (3) an intracellular domain facing the cytoplasm. (See B.R. Voldborg
`
`et al., “Epidennal growth factor receptor (EGFR) and EGFR mutations, function
`
`and possible role in clinical trials,” Ann. Oncol. 8:1197-1206 (1997) (Ex. 1019) at
`
`1197-98.) The structure of the EGF receptor is summarized in the following
`
`schematic diagram:
`
`EGF Receptor
`
`3 Dcrmain 1
`J f)omai:n Ill
`
`'E)0mairi HI fiigarid h‘inding.§ dOf1‘13.lI1}
`
`] lffiomaizi IV
` ]'"E“y:*o:§i.t:re iszinasedomain
`
`3 C‘§a3'*' r‘egu§ato1‘yfinternaiisatiozi dcmiain
`] In.hibito1'y cicmiairi
`
`
`
`Extraw
`
`celluiar
`
`domain
`
`celluiar
`imam”
`
`(See id. at 1198.)
`
`17.
`
`Binding of a ligand (e. g., EGF or TGF—ci) at the extracellular ligand
`
`binding region transduces a signal across the cell membrane to the cytoplasm that
`
`results in intracellular phosphorylation of tyrosines, which subsequently leads to
`
`APOTEX EX. 1002-006
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`downstream signaling that promotes the growth and survival oftumor cells.
`
`(Id. at
`
`1197.)
`
`B.
`
`EGF Receptors and Lung Cancer
`
`18.
`
`Beginning in the early 1980s, extensive work began to examine the
`
`role of EGF receptors in promoting the growth of various lung cancers. It was
`
`recognized that lung cancers could be generally classified as either “small-cell”
`
`lung cancer (i.e., “SCLC”), which accounted for about 20% of cases, or “non—small
`
`cell lung cancer” (i.e., “NSCLC”) which accounted for about 80% of cases. In
`
`1999, and still today, the first step in the treatment of lung cancer by a person of
`
`ordinary skill in the art is a correct diagnosis of whether a patient suffers from
`
`NSCLC or SCLC.
`
`19. Whereas the EGF receptor is largely absent from the surface of SCLC
`
`cells, it was found that well over 80% of NSCLC cell lines contained elevated
`
`levels ofEGF receptors.
`
`(See, e. g., Veale et al., “The relationship of quantitative
`
`epidermal growth factor receptor expression in non—small cell cancer to long term
`
`survival,” Br. J. Cancer 68: 162-65 (1993) (Ex. 1024), Haeder et al., “Epidermal
`
`Growth Factor Receptor Expression in Human Lung Cancer Cell Lines,” Cancer
`
`Res. 48:1132-36 (1988) (Ex. 1025); Veale et al., “Epidermal growth factor
`
`receptors in non—small cell lung cancer,” Br. J. Cancer 55 :5 13-16 (1987)
`
`APOTEX EX. 1002-007
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`(Ex. 1026), T. Cerny, “Expression of epidermal growth factor receptor (EGF—R) in
`
`human lung tumours,” Br. J. Cancer 54 1265-69 (1986) (Ex. 1018).
`
`20.
`
`Thus, by 1999, a person of ordinary skill in the art would have known
`
`that NSCLC is one oftwo types of lung cancer. Additionally, persons of ordinary
`
`skill in the art would have known that high levels of EGF receptors present on lung
`
`cancer tumor cells would more likely be NSCLC, and that strategies aimed at
`
`inhibiting EGF receptor phosphorylation were meant for treating NSCLC. (See
`
`Ex. 1009, Ex. 1010, Ex. 1011; Ex. 1014; Ex. 1020.)
`
`C.
`
`EGF Receptor Variants
`
`21.
`
`Characterization of EGF receptors elucidated mutations that modify
`
`the extracellular domain.
`
`(See Ex. 1019 at 1198, col. 2.) By 1997, Variant Ill (Vlll
`
`or EGFRVHI), which included a deletion of a large portion of the EGFR gene, was
`
`the best understood of the Variants (and was also the most often overexpressed in
`
`human cancer cells).
`
`(See Ex. 1019 at 1198, col. 2.)
`
`22.
`
`It had been shown that the deletions resulted in dimerization of the
`
`extracellular ligand binding site which caused self-activation of EGFR leading to
`
`downstream tumor cell growth.
`
`(See Ex. 1019 at 1199, col. 1.) As a result,
`
`EGFRVIH was not affected by “indirect” inhibitors such as monoclonal antibodies,
`
`which acted on the ligand—binding domain.
`
`(See C.J. Wikstrand et al., “Cell
`
`Surface Localization and Density of the Tumor-associated Variant of the
`
`APOTEX EX. 1002-008
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`Epidermal Growth Factor Receptor, EGFRVHI,” Cancer Res. 5 7:41.30-40 (1997)
`
`(Ex. 1023).) Instead, inhibiting EGFRvllI at the intracellular tyrosine kinase
`
`domain demonstrated downstream antitumor effects. (DK. Moscatello et al.,
`
`“Constitutive Activation of Phophatidylinositol 3—Kinase by a Naturally Occurring
`
`Mutant Epidermal Growth Factor Receptor,” J. Biol. Chem. 273(1):200-206 (1998)
`
`(Ex. 1014).)
`
`23.
`
`By the late-1990s it was known that EGFRVHI was present in
`
`approximately 16% ofNSCLC cells.
`
`(See I.E. Garcia de Palazzo et al.,
`
`“Expression of Mutated Epidermal Growth Factor Receptor by Non—Small Cell
`
`Lung Carcinomas,” Cancer Res. 533217-20 (1993) (Ex. 1022).)
`
`D.
`
`The Development of Therapeutics Targeting EGF Receptors
`
`24.
`
`By the mid-1990’s, extensive research was underway to develop
`
`cancer treatments that stopped tumor cell growth by “indirect” or “direct”
`
`inhibition of tyrosine phosphorylation by EGF receptors. Because the EGF
`
`receptor was known to be over—expressed in NSCLC cells, NSCLC was viewed as
`
`a prime candidate for treatment using drugs that indirectly and/or directly block the
`
`phosphorylation of tyrosine kinase at EGF receptors.
`
`25. Monoclonal antibodies capable of blocking ligand-binding at the
`
`extracellular receptor domain were among the first therapies extensively studied in
`
`human NSCLC tumor cell lines.
`
`(See, e. g., J.B. Gibbs, “Anticancer drug targets:
`
`APOTEX EX. 1002-009
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`growth factors and growth factor signaling,” J. Clin. Invest. I 05(1):9—13 (Jan.
`
`2000) (“Gibbs”, EX. 1010) at 10, col. 1; M. Lee et al., “Epidermal Growth Factor
`
`Receptor Monoclonal Antibodies Inhibit the Growth of Lung Cancer Cell Lines,”
`
`J. Nat’! Cancer I. Monographs (13):1 17-123 (1992) (“Lee”, EX. 1020); H. Masui
`
`et al., “Growth Inhibition of Human Tumor Cells in Athymic Mice by Anti-
`
`Epidermal Growth Factor Receptor Monoclonal Antibodies,” Cancer Res.
`
`44: 1002-07 (1984) (“Maszu”, Ex. 1021).)
`
`26.
`
`The “direct” blocking strategy sought to identify ligands that would
`
`directly inhibit tyrosine phosphorylation of the EGFR at the intracellular tyrosine
`
`kinase domain.
`
`(See, e. EX. 1010 at 10, col. 1, U.S. Patent No. 5,747,498
`
`(“Scnnur”, Ex. 1009) at col. 1, 11. 45-53, JD. Moyer eta1., “Induction of Apoptosis
`
`and Cell Cycle Arrest by CP—3 58,774, an Inhibitor of Epidermal Growth Factor
`
`Receptor Tyrosine Kinase,” Cancer Res. 5714838-48 (1997) (EX. 1016), A.E.
`
`Wakeling er al., “Specific inhibition of epidermal growth factor receptor tyrosine
`
`kinase by 4-anilinoquinazolines,” Breast Cancer Res. Tr. 38:67-73 (1996) (EX.
`
`1013).) Of these early compounds, 4—anilinoquinazolines emerged as a leading
`
`class of compounds having potent antitumor properties.
`
`(EX. 1013.)
`
`10
`
`APOTEX EX. 1002-010
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`E.
`
`Erlotinib
`
`27.
`
`By 1999, erlotinib was developed as a leading 4—anilinoquinazoline
`
`compound that would directly inhibit phosphorylation at the intracellular tyrosine
`
`kinase domain.
`
`(EX. 1009; EX. 1010.)
`
`28.
`
`The drug erlotinib is described chemically as N—(3—ethynylphenyl)—
`
`6,7 -bis(2-methoxyethoxy)-4-quinazolinamine, or [6,7-Bis-(2-methoXyethoXy)-
`
`quinazolin-4-yl]-(3—ethynylphenyl)amine, and has the following chemical
`
`structure:
`
`CH
`
`(See, e.g., EX. 1016 at 4839, col. 1.)
`
`29. During joint clinical development of erlotinib between OSI and Pfizer,
`
`and then subsequently, only OSI, the hydrochloride salt of erlotinib was commonly
`
`referred by the identifier CP-35 8,774, which was prepared as set forth in PCT Pub.
`
`No. W0 96/30347. (See EX. 1016 at 4839, col. 1; See also VA. Pollack et al.,
`
`“Inhibition of Epidermal Growth Factor Receptor—Associated Tyrosine
`
`Phosphorylation in Human Carcinomas with CP-358,774: Dynamics of Receptor
`
`Inhibition In Situ and Antitumor Effects in Athymic Mice,” J. Pharmacol. Exp.
`
`ll
`
`APOTEX EX. 1002-011
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`Ther. 29I(2):739—748 (Nov. 1999) (“.P0llack,” Ex. 1015) at 740 (“CP-358,774 .
`
`.
`
`.
`
`a colorless, crystalline, anhydrous compound, was synthesized in our laboratories
`
`(Arnold and Schnur, 1998)).)
`
`30. As of 1999, Erlotinib was known to be a potent inhibitor of the EGF
`
`receptor tyrosine kinase domain.
`
`(See EX. 1015; Ex. 1009; Ex. 1010, Ex. 1011.)
`
`In various cultured human tumor cell lines that expressed EGF receptors, this small
`
`molecule prevented cancer cell proliferation and induced apoptosis of tumor cells.
`
`(See EX. 1015.)
`
`IV. U.S. PATENT NO. 6,900,221
`
`A.
`
`The ’221 Patent
`
`31.
`
`I have reviewed the 221 patent. In general, the ’221 patent discloses
`
`pharmaceutical compositions that contain specific polymorphic compositions of N-
`
`(3-ethynylphenyl)-6,7-bis(2-methoXyethoXy)-4-quinazolinamine (/'.e., erlotinib),
`
`methods of preparing the compositions, and methods of administering the
`
`compositions to treat various types of cancer.
`
`32.
`
`I have reviewed the claims of the ’221 patent. The vast majority of
`
`the claims of the ’22l patent require polymorph form B of erlotinib? However,
`
`1 This is true of claims 1-41, 43, and 55-79. Claims 1 and 5 of the ’221 patent, for
`example, require erlotinib hydrochloride to be present as “a homogeneous
`crystalline polymorph .
`.
`. designated the B polymorph,” or “a crystalline
`
`12
`
`APOTEX EX. 1002-012
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`claims 44-47 and 53 include no such limitation requiring a specific polymorphic
`
`form of erlotinib. Instead, claims 44-47 and 53 are directed to methods of treating
`
`various types of cancer using any polymorphic form of erlotinib. For example,
`
`claims 44-47 and 53 of the ’221 patent recite the following:
`
`44.A method for the treatment of NSCLC (non small cell
`lung cancer), pediatric malignancies, cervical and other
`tumors caused or promoted by human papilloma virus
`(HPV), Barrett’s esophagus (pre-malignant syndrome),
`or neoplastic
`cutaneous diseases
`in a mammal
`comprising
`administering
`to
`said mammal
`a
`therapeutically effective amount of a pharmaceutical
`composition comprised of at
`least one of N-(3-
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-
`quinazolinamine, or pharmaceutically acceptable salts
`thereof in anhydrous or hydrate forms, and a carrier.
`
`45 The method of claim 44, wherein the treatment further
`comprises
`a palliative
`or neo-adjuvant/adj uvant
`monotherapy.
`
`46.The method of claim 44, wherein the treatment further
`comprises blocking epidermal growth factor receptors
`(EGFR).
`
`47 .The method of claim 44, for use in treatment of tumors
`
`that express EGFRVIH.
`
`53.The method of claim 44 for the treatment of non-small
`
`cell cancer (NSCLC).
`
`(Ex. 1001 at col. 35,11. 26-65.)
`
`. designated the B polymorph .
`.
`polymorph .
`(See Ex. 1001, col. 31,11. 37-44; ll. 58-66.)
`
`.
`
`. which is free of the A polymorph.”
`
`13
`
`APOTEX EX. 1002-013
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`B.
`
`The PTO’s Reasons Why Claims 44-47 and 53 of the ’221 Patent
`Were Allowed to Issue
`
`33.
`
`I have reviewed portions of the prosecution history of the ’221 patent
`
`relevant to the entry, review, and allowance of the challenged claims. Issued
`
`claims 44-47 of the ’221 patent correspond to claims 64-67 that were pending
`
`during prosecution, and which were entered by way of an amendment dated June
`
`19, 2002. (See Ex. 1003 (Amendment dated June 19, 2002) at 28-29.) Issued
`
`claim 53 of the ’221 patent correspond to claims 88 of the ’272 application, and
`
`was entered by way of a subsequent amendment.
`
`(See Ex. 1005 (Amendment
`
`dated February 28, 2003) at 36-37.)
`
`34.
`
`The PTO initially rejected claim 64 (and dependent claims 65, 66, and
`
`67) as anticipated by U.S. Patent No. 5,747,498.
`
`(See Ex. 1004 (Office Action
`
`dated August 30, 2002) at 10-11 (citing EX. 1009 at col. 14, ll. 6-16, 28, col. 16,
`
`11. 46-51, claims 28 and 29).) In response, OSI amended claim 64 and argued that
`
`Sc/‘mur did not disclose the use of erlotinib to treat any of the conditions that were
`
`claimed.
`
`(See Ex. 1005 at 23, 35.) Specifically, OSI argued that, whereas Sc/mur
`
`discloses the use of erlotinib to treat lung cancer, the use of erlotinib to treat non-
`
`small cell lung cancer (NSCLC) is not mentioned. (See EX. 1005 at 23.)
`
`35.
`
`The PTO subsequently allowed pending claim 64 to issue as claim 44
`
`of the ’221 patent (and claims depending therefrom) based on a finding that this
`
`14
`
`APOTEX EX. 1002-014
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`claim “is drawn to treatment of specific cancers by any polymorph of the claimed
`
`compounds. These specific cancers are not found in Sc/mur (’498).” (See
`
`Ex. 1006 (Notice of Allowance dated June 18, 2003) at 6.)
`
`36.
`
`Thus, it is my understanding that the PTO’s sole reason for allowing
`
`claims 44-47 and 53 of the ’221 patent to issue was that Sc/mur did not disclose the
`
`use of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (z'.e.,
`
`erlotinib) to treat, inter alia, NSCLC (which is a subset of lung cancer). Instead,
`
`the PTO found that Sc/mur merely taught the use of erlotinib to treat “lung cancer.”
`
`(Ex. 1006.)
`
`C.
`
`Disclosure of Claims 44-47 and 53 of the ’221 Patent in U.S.
`
`Provisional Application No. 60/164,907 and U.S. Provisional
`Application No. 60/193,191
`
`37 .
`
`I have reviewed U.S. Provisional Application No. 60/164,907 and
`
`60/193,191. In my opinion the first express disclosure concerning the use of N-(3-
`
`ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (1'.e., erlotinib) to
`
`treat the conditions recited in claim 44, and in particular NSCLC, is in Provisional
`
`Appl. No. 60/ 193,191, which was filed March 30, 2000.
`
`(See Ex. 1008
`
`(Provisional Appl. No. 60/193,191) at 1, 11. 20-26, 2,1. 21-3, 1. 30, 4,11. 10-13, and
`
`7,1. 1)
`
`38.
`
`In contrast, Provisional Appl. No. 60/194,907, which was filed
`
`November 11, 1999, lacks express disclosure for the use of erlotinib to treat any of
`
`15
`
`APOTEX EX. 1002-015
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`the conditions recited in claim 44, including non-small cell lung cancer (NSCLC),
`
`pediatric malignancies, any tumors caused or promoted by human papilloma virus
`
`(HPV), Barrett's esophagus (pre-malignant syndrome), or neoplastic cutaneous
`
`diseases.
`
`(See Ex. 1007 (Provisional Appl. No. 60/ 194,907).) Instead, Provisional
`
`Appl. No. 60/194,907 discloses the use of erlotinib hydrochloride (z'.e., the
`
`hydrochloride salt of N-(3-ethynylphenyl)-6,7-bis(2-methoXyethoXy)-4-
`
`quinazolinamine) to treat conditions as described in Schnur. (See EX. 1007 at 6, 1.
`
`8 to 8,1. 8, and 10,1. 3 to 11,1. 24, compare Ex.1010 at col. 14,11. 1-30.)
`
`V.
`
`LEGAL STANDARDS
`
`39.
`
`I am not an attorney, and counsel for Petitioners informed of the
`
`following legal standards that are relevant to my opinions.
`
`40.
`
`I understand that an issued patent is presumed to be valid, and that the
`
`burden of establishing invalidity as to any claim of a patent rests upon the party
`
`asserting invalidity, here Petitioners.
`
`A.
`
`Anticipation
`
`41.
`
`I understand that a prior art reference “anticipates” a claim, and thus
`
`renders the claim unpatentable, if all elements of the claim are disclosed in that
`
`single prior art reference, either expressly or inherently.
`
`16
`
`APOTEX EX. 1002-016
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`42.
`
`Thus, I also understand that a prior art reference having an identical
`
`disclosure to that of the challenged claims would anticipate those claims to the
`
`extent that the claims are enabled and described.
`
`B.
`
`Obviousness
`
`43.
`
`I understand that an obviousness inquiry requires consideration of the
`
`following factors:
`
`(1) the scope and content of the prior art; (2) the differences
`
`between the claims and the prior art; (3) the level of ordinary skill in the pertinent
`
`art; and (4) any objective indicia of non-obviousness, such as commercial success,
`
`long—felt but unresolved need, failure of others, industry recognition, copying, and
`
`unexpected results.
`
`44.
`
`I further understand that a claim is invalid as obvious if the
`
`differences between the subject matter as claimed and the prior art would have
`
`been obvious to a person having ordinary skill in the art.
`
`45.
`
`It is my understanding that the analysis of all prior art references are
`
`to be looked at from the viewpoint of a person of ordinary skill in the art at the
`
`time the invention was made. Thus, the use of hindsight is not permitted.
`
`46.
`
`It is my understanding that differences between the claimed invention
`
`and the prior art can be deemed obviousness if the difference is simply within the
`
`common knowledge of a person of ordinary skill in the art.
`
`17
`
`APOTEX EX. 1002-017
`
`
`
`U.S. Patent No. 6,900,22 1—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`47.
`
`I also understand that obviousness may be based on a combination of
`
`references according to known methods to yield predictable results.
`
`I further
`
`understand that obviousness based on a. combination of references does not require
`
`an explicit suggestion in any of the references to combine them, if, as a matter of
`
`skill or practice in the field it would be known to do so.
`
`48.
`
`I also understand that in other circumstances, a claimed invention
`
`simply substitutes one known element for another to obtain predictable results.
`
`.
`
`C.
`
`The Field of the Invention and the Level of Ordinary Skill in
`the Art
`
`49.
`
`I was asked to consider the technical f1eld(s) relevant to the subject
`
`matter of the ’22l patent, as well as the level of skill that an ordinary person
`
`working in that technical field would have had in 1999 to 2000 (the earliest priority
`
`date of the ’22l patent). In my opinion, the technical field(s) relevant to the
`
`subject matter of the ’22l patent concern the diagnosis and treatment of various
`
`cancers, among them, lung cancer.
`
`50.
`
`I understand that factors such as the education level of those working
`
`in the field, the sophistication of the technology, the types of problems encountered
`
`in the art, the prior art solutions to those problems, and the speed at which
`
`innovations are made may help establish the level of ordinary skill in the art.
`
`I
`
`understand that a person of ordinary skill has the ability to understand the
`
`18
`
`APOTEX EX. 1002-018
`
`
`
`U.S. Patent No. 6,900,22 l—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`technology and make modest adaptions or advances, and that a person of ordinary
`
`skill in the art is also a person of ordinary creativity, not an automaton.
`
`51.
`
`Further, I understand that a person of skill in the art is not necessarily
`
`an individual, but instead could be a team of individuals. Thus, a person of
`
`ordinary skill in the art could involve a collaboration between a medical doctor
`
`and, for example, others having relevant expertise in pharmaceutical formulation
`
`development and pharmaceutical drug development.
`
`52.
`
`In my opinion, a person of ordinary skill in the art relevant to the ’22l
`
`patent would have a medical degree and at least some specialized training in
`
`oncology. More specifically, a person of ordinary skill in the art relevant to the
`
`221 patent would likely have at least some specialized training in thoracic
`
`oncology. Further, in my opinion a person of ordinary skill in the art would have
`
`several years of clinical experience, and a substantive understanding and
`
`experience using the medications and therapies effective for treating various lung
`
`cancers at the relevant time. A person of ordinary skill in the art would be aware
`
`of current advances at the time in the use of various medications and therapies to
`
`treat cancer.
`
`53. As of the earliest priority date of the ’22l patent, I was a person of at
`
`least ordinary skill in the medical arts relevant to the ’22l patent. My opinions
`
`l9
`
`APOTEX EX. 1002-019
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`provided herein are made through the lens of a person of ordinary skill in the art in
`
`the 1999 to 2000 time frame.
`
`D.
`
`Claim Construction
`
`54.
`
`I understand that in deciding whether to institute Petitioners’ request
`
`for Inter Partes Review, the first step in the PTO’s analysis will be to determine
`
`the scope of the claims of the ’22l patent.
`
`I understand that the PTO presumes that
`
`the words of a patent claim have their ordinary and customary meaning based on
`
`the broadest reasonable interpretation of the claim language.
`
`55.
`
`In my opinion, a person of ordinary skill in the art having reviewed
`
`the claims, the specification, and the prosecution history of the ‘Z21 patent would
`
`understand the words used in claims 44-47 and 53 of the ’221 patent to have their
`
`plain and ordinary meaning.
`
`E.
`
`Priority Date of the ’221 Patent
`
`56.
`
`I have been advised by counsel that:
`
`— A document that was made publicly available between March 30, 1999 and
`
`March 29, 2000 is prior art to claims 44-47 and 53 of the ’22l patent under
`
`pre-AIA 35 U.S.C. § l02(a),
`
`— A document that was made publicly available before March 30, 1999 is prior
`
`art to claims 44-47 and 53 of the 221 patent under pre—AlA 35 U.S.C.
`
`§ 102(b); and
`
`20
`
`APOTEX EX. 1002-020
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`— A patent filing made in the United States before March 30, 2000, and which
`
`became publicly available after March 30, 2000, is prior art to claims 44-47
`
`and 53 of the ’221 patent under pre-AIA 35 U.S.C. § l02(e).
`
`VI. DETAILED DESCRIPTION OF THE PRIOR ART
`
`57. As discussed below, the prior art discloses, teaches, or suggests every
`
`limitation of claims 44-47 and 53, including the subject matter the PTO found
`
`missing from the prior art in the Reason For Allowance.
`
`A.
`
`U.S. Patent No. 5,747,498 (EX. 1009)
`
`58.
`
`U.S. Patent No. 5,747,498 (“Schl/zur”, EX. 1009) was published on
`
`May 5, 1998, which is more than one year before the priority date of claims 44-47
`
`and 53 of the ’221 patent. As such, I understand that Schmzr is prior art to claims
`
`44-47 and 53 of the ’221 patent under 35 U.S.C. § 102(b) (pre-AIA).
`
`59.
`
`Schnur discloses a class of 4-anilinoquinazoline compounds that are
`
`“potent inhibitors of the erbB family of oncogenic and protooncogenic protein
`
`tyrosine kinases such as epidermal growth factor receptor (EGFR), erbB2, HER3,
`
`or HER4 and thus are all adapted to therapeutic use as antiproliferative agents
`
`(e.g., anticancer) in mammals, in particularly humans.” (EX. 1009 at col. 14, ll. 1-
`
`6.) Schnur recognizes that inhibiting phosphorylation of EGF receptors at the
`
`intracellular tyrosine kinase domain is the underlying mechanism to prevent tumor
`
`growth. (Ex. 1009 at col. 1, 11. 30-63; col. 14, 11. 35-41.) Further, Sc//mur discloses
`
`21
`
`APOTEX EX. 1002-021
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`that the compounds, including erlotinib, are suitable for use in the treatment of
`
`lung cancer.
`
`(See Ex. 1009 at col. 5, 11. 56-60; col. 14,11. 6-13.)
`
`60.
`
`Schnur discloses that the effective dosages are dependent on the
`
`subject being treated, on the severity of the affliction, on the manner of
`
`administration and on the judgment of the prescribing physician. (Ex. 1009 at col.
`
`15,11. 55-58.) Schnur further teaches that in general, the effective dosages are
`
`disclosed to be in the range of approximately 0.001-100 mg/kg and preferably 1 to
`
`35 mg/kg in single or divided doses.
`
`(EX. 1009 at col. 15, 11. 58-61.) For an
`
`Average 70 kg human, the taught amount would be from 0.05 to 7 g/day,
`
`preferably 0.2 to 2.5 g/day,
`
`(EX. 1009 at col. 15, 11. 61-62.)
`
`61.
`
`Sc//znur also teaches that a specific amount of active compound, for
`
`instance a therapeutically-effective amount of erlotinib, can be administered as part
`
`of a pharmaceutical composition. (Ex. 1009 at col. 15, l. 48 — col. 16, l. 19.)
`
`Schnur states that methods of preparing the various pharmaceutical compositions
`
`are taught to be routine to a person of ordinary skill in the art, and further cites a
`
`well-known reference titled Remington ’s ’Pnarmaceutieal Sciences, Mack
`
`Publishing Company, Easter, Pa., 15th Edition (1975).
`
`62.
`
`Scnnur further discloses that the compounds can be used to treat
`
`cancer as a sole therapy “or may involve, in addition to the active compound, one
`
`or more other antitumor substances” that can be simultaneously, sequentially,
`
`22
`
`APOTEX EX. 1002-022
`
`
`
`U.S. Patent No. 6,900,221—Petition for Inter Partes Review
`Declaration of Giuseppe Giaccone, M.D., Ph.D.
`
`cyclically, or separately.
`
`(See Ex. 1009 at col. 16,11. 46-51.) Thus, Sc//mur
`
`discloses the use of the disclosed compounds (including erlotinib) along with a
`
`neo-adjuvant/adjuvant monotherapy—that is, an additional anti-tumor treatment
`
`given along with (before or after) treatment with erlotinib.
`
`63.
`
`Schmzr discloses that the compounds can be prepared as
`
`pharmaceutically acceptable salts, such as an acid-addition salt, and “can exist in
`
`solvated, as well as unsolvated forms, such as the hydrated forms.” (Ex. 1009 at
`
`col. 13,11. 25-26,11. 30-36.)
`
`64.
`
`Sc/mur specifically discloses the synthesis of the freebase as well as
`
`the hydrochloride salt of erlotinib (1'.e., [6-,7-Bis-(2-methoxyethoxy)-quinazolin-4-
`
`yl]-(3—ethynylphenyl)amine hydrochloride).
`
`(See Ex. 1009 at col. 22, 11. 30-50
`
`(Example 20).) In discussing Schnur, the ’221 patent expressly admits that Schnur
`
`teaches an anhydrous
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