7681737
`
`June 06, 2018
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
`
`APPLICATION NUMBER: 10/438,213
`FILING DATE: May 15, 2003
`PATENT NUMBER: 7968569
`ISSUE DATE: June 28, 2011
`
`ALVOGEN, Exh. 1002, p. 0001
`
`

`

`- I
`
`‘
`
`
`
`METHODS AND COMPOSITIONS USING
`IMMUNOMODULATORY COMPOUNDS FOR TREATMENT
`AND MANAGEMENT OF CANCERS AND OTHER DISEASES
`
`This application claims the benefit of US. provisional application nos. 60/380,842,
`
`filed May 17, 2002, and 60/424,600, filed November 6, 2002, the entireties Of which are
`
`incorporated herein by reference.
`
`1.
`
`FIELD OF THE INVENTION
`
`This invention relates to methods of treating, preventing and/or managing specific
`
`cancers, and other diseases including, but not limited to, those associated with, or
`
`characterized by, undesired angio genesis, by the administration of onc or more
`
`immunomodulatory compounds alone or in combination with other therapeutics. In
`
`particular, the invention encompasses the use of specific combinations, or “cocktails,” of
`drugs and other therapy, e.g., radiation to treat these specific cancers, including those
`
`refractory to conventional therapy. The invention also relates to pharmaceutical
`
`compositions and dosing regimens.
`
`2.
`
`BACKGROUND OF THE INVENTION
`
`2.1
`
`PATHOBIOLOGY OF CANCER AND OTHER DISEASES
`
`Cancer is characterized primarily by an increase in the number of abnormal cells
`
`derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or
`
`lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant
`
`sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a
`
`multistep process that begins with minor preneoplastic changes, which may under certain
`
`conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an
`
`increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under
`
`conditions in which the neoplastic cells escape the host’s immune surveillance. Roitt, I.,
`
`Brostoff, J and Kale, D., Immunology, 17.1—17.12 (3rd ed., Mosby, St. Louis, MO., 1993).
`
`There is an enormous variety Of cancers which are described in detail in the medical
`
`literature. Examples includes cancer Of the lung, colon, rectum, prostate, breast, brain, and
`
`intestine. The incidence of cancer continues to climb as the general population ages, as new
`
`cancers develop, and as susceptible populations (e.g., people infected with AIDS or
`
`excessively exposed to sunlight) grow. A tremendous demand therefore exists for new
`
`methods and compositions that can be used to treat patients with cancer.
`
`10
`
`1'5
`
`20
`
`25
`
`30
`
`ALVOGEN, Exh. 1002, p. 0002
`
`ALVOGEN, Exh. 1002, p. 0002
`
`

`

`‘1
`
`
`
`Many types of cancers are associated with new blood vessel formation, a process
`
`known as angio genesis. Several of the mechanisms involved in tumor-induced
`
`angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by
`
`the tumor cells of cytokines with angiogenic properties. Examples of these cytokines
`
`include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular
`
`endothelial growth factor (VEGF), and TNF-a. Alternatively, tumor cells can release
`
`angiogenic peptides through the production of proteases and the subsequent breakdown of
`
`the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can
`
`also be induced indirectly through the recruitment of inflammatory cells (particularly
`
`macrophages) and their subsequent release of angiogenic cytokines (e. g., TNF-oz, bFGF).
`
`A variety of other diseases and disorders are also associated with, or characterized
`
`by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been
`
`implicated in a number of diseases and medical conditions including, but not limited to,
`ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases,
`
`rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory
`
`diseases, allergic diseases, and autoimmune diseases. Examples of such diseases and
`
`conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity;
`
`corneal graft rejection; neovascular glaucoma; retrolental fibrOplasia; and proliferative
`
`vitreoretinopathy.
`
`Accordingly, compounds that can control angiogenesis or inhibit the production of
`
`certain cytokines, including TNF-oz, may be useful in the treatment and prevention of
`
`various diseases and conditions.
`
`2.2 METHODS OF TREATING CANCER
`
`Current cancer therapy may involve surgery, chemotherapy, hormonal therapy
`
`and/or radiation treatment to eradicate neoplastic cells in a patient (see, for example,
`
`Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV).
`
`Recently, cancer therapy could also involve biological therapy or immunotherapy. All of
`
`these approaches pose significant drawbacks for the patient. Surgery, for example, may be
`
`contraindicated due to the health of a patient or may be unacceptable to the patient.
`
`Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is
`
`only effective when the neoplastic tissuc exhibits a higher sensitivity to radiation than
`
`normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal
`
`therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is
`
`often used to prevent or delay recurrence of cancer after other treatments have removed the
`
`-2-
`
`NYZ: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0003
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`ALVOGEN, Exh. 1002, p. 0003
`
`

`

`
`
`majority of cancer cells. Biological therapies and immunotherapies are limited in number
`
`and may produce side effects such as rashes or swellings, flu-like symptoms, including
`
`fever, chills and fatigue, digestive tract problems or allergic reactions.
`
`With respect to chemotherapy, there are a variety of chemotherapeutic agents
`
`available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting
`
`DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of
`
`deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant
`
`cell division. Gilman et al., Goodman and Gilman ’s: The Pharmacological Basis of
`
`Therapeutics, Tenth Ed. (McGraW Hill, New York).
`
`10
`
`Despite availability of a variety of chemotherapeutic agents, chemotherapy has
`
`many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect.
`
`10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes
`
`significant, and often dangerous side effects including severe nausea, bone marrow
`
`depression, and immunosuppression. Additionally, even with administration of
`
`15
`
`combinations of chemotherapeutic agents, many tumor cells are resistant or develop
`
`resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular
`
`chemotherapeutic agents used in the treatment protocol often prove to be resistant to other
`
`drugs, even if those agents act by different mechanism from those of the drugs used in the
`
`specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug
`
`resistance. Because of the drug resistance, many cancers prove refractory to standard
`
`chemotherapeutic treatment protocols.
`
`Other diseases or conditions associated with, or characterized by, undesired
`
`angiogenesis are also difficult to treat. However, some compounds such as protamine,
`
`hepain and steroids have been proposed to be useful in the treatment of certain specific
`
`diseases. Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221 :719 (1983); and
`
`US. Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives of it have also
`
`been proposed for the treatment of such diseases and conditions. US. patent nos.
`
`5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D’Amato.
`
`Still, there is a significant need for safe and effective methods of treating, preventing
`
`and managing cancer and other diseases and conditions, particularly for diseases that are
`
`refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and
`
`hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated
`
`20
`
`25
`
`30
`
`with the conventional therapies.
`
`NY2: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0004
`
`ALVOGEN, Exh. 1002, p. 0004
`
`

`

`
`
`2.3
`
`IMIDSTM
`
`A number of studies have been conducted with the aim of providing compounds that
`
`can safely and effectively be used to treat diseases associated with abnormal production of
`
`TNF-OL See, e.g., Marriott, J.B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G.W.
`
`Muller, et al., Journal of Medicinal Chemistry 39(17): 323 8—3240 (1996); and G.W. Muller,
`
`er al., Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998). Some studies have
`
`focused on a group of compounds selected for their capacity to potently inhibit TNF-a
`
`production by LPS stimulated PBMC. L.G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I)
`
`1107—1113 (1999). These compounds, which are referred to as IMiDsTM (Celgene
`
`Corporation) or Immunomodulatory Drugs, show not only potent inhibition of TNF-oz but 7
`
`also marked inhibition of LPS induced monocyte ILlB and 1L12 production. LPS induced
`
`1L6 is also inhibited by immunomodulatory compounds, albeit partially. These compounds
`
`are potent stimulators of LPS induced ILlO. Id. Particular examples of IMiDTMs include,
`
`but are not limited to, the substituted 2—(2,6—dioxopiperidin—3—yl) phthalimides and
`
`substituted 2—(2,6—dioxopiperidin-3-y1)—1-oxoisoindoles described in United States Patent
`
`Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al.
`
`3.
`
`SUMMARY OF THE INVENTION
`
`This invention encompasses methods of treating and preventing certain types of
`
`cancer, including primary and metastatic cancer, as well as cancers that are refractory or
`
`resistant to conventional chemotherapy. The methods comprise administering to a patient
`
`in need of such treatment or prevention a therapeutically or prophylactically effective
`
`amount of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate,
`
`hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses
`
`methods of managing certain cancers (e.g., preventing or prolonging their recurrence, or
`
`lengthening the time of remission) which comprise administering to a patient in need of
`
`such management a prophylactically effective amount of an immunomodulatory compound
`
`of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
`
`clathrate, or prodrug thereof.
`
`In particular methods of the invention, an immunomodulatory compound is
`
`administered in combination with a therapy conventionally used to treat, prevent or manage
`
`cancer. Examples of such conventional therapies include, but are not limited to, surgery,
`
`chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
`
`This invention also encompasses methods of treating, managing or preventing
`
`diseases and disorders other than cancer that are associated with, or characterized by,
`
`-4-
`
`NY2: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0005
`
`10
`
`15
`
`20
`
`25
`
`30
`
`ALVOGEN, Exh. 1002, p. 0005
`
`

`

`
`
`undesired angiogenesis, which comprise administering to a patient in need of such
`
`treatment, management or prevention a therapeutically or prophylactically effective amount
`
`of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate,
`
`hydrate, stereoisomer, clathrate, or prodrug thereof.
`
`In other methods of the invention, an immunomodulatory compound is administered
`
`in combination with a therapy conventionally used to treat, prevent or manage diseases or
`
`disorders associated with, or characterized by, undesired angiogenesis. Examples of such
`
`conventional therapies include, but are not limited to, surgery, chemotherapy, radiation
`
`therapy, hormonal therapy, biological therapy and immunotherapy.
`
`10
`
`This invention encompasses pharmaceutical compositions, single unit dosage forms,
`
`dosing regimens and kits which comprise an immunomodulatory compound, or a
`
`pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
`
`thereof, and a second, or additional, active agent. Second active agents include specific
`
`combinations, or “cocktails,” of drugs.
`
`15
`
`4.
`
`BRIEF DESCRIPTION OF FIGURE
`
`Figure 1 shows a comparison of the effects of 3—(4-amino-1-oxo—l,3-dihydro-
`
`isoindol-2-y1)-piperidine-2,6-dione (RevimidTM) and thalidomide in inhibiting the
`
`proliferation of multiple myeloma (MM) cell lines in an in vitro study. The uptake of [3H]-
`
`thymidine by different MM cell lines (MM. IS, Hs Sultan, U266 and RPMI—8226) was
`
`20
`
`measured as an indicator of the cell proliferation.
`
`5.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`30
`
`A first embodiment of the invention encompasses methods of treating, managing, or
`
`preventing cancer which comprises administering to a patient in need of such treatment or
`
`prevention a therapeutically or prophylactically effective amount of an immunomodulatory
`
`compound of the invention, or a pharmaceutically acceptable salt, solvate, hydrate,
`
`stereoisomer, clathrate, or prodrug thereof.
`
`In particular methods encompassed by this embodiment, the immunomodulatory
`
`compound is administered in combination with another drug (“second active agent”) or
`
`method of treating, managing, or preventing cancer. Second active agents include small
`
`molecules and large molecules (e.g., proteins and antibodies), examples of which are
`
`provided herein, as well as stem cells. Methods, or therapies, that can be used in
`
`combination with the administration of the immunomodulatory compomid include, but are
`
`not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation
`
`-5-
`
`NYZ: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0006
`
`ALVOGEN, Exh. 1002, p. 0006
`
`

`

`
`
`therapy, and other non-drug based therapies presently used to treat, prevent or manage
`cancer.
`
`Another embodiment of the invention encompasses methods of treating, managing
`
`or preventing diseases and disorders other than cancer that are characterized by undesired
`
`angiogenesis. These methods comprise the administration of a therapeutically or
`
`prophylactically effective amount of an immunomodulatory compound, or a
`
`pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
`
`thereof.
`
`Examples of diseases and disorders associated with, or characterized by, undesired
`
`angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases,
`
`viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular
`
`diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis
`
`(neovascularization of the angle).
`
`In particular methods encompassed by this embodiment, the immunomodulatory
`
`compound is administer in combination with a second active agent or method of treating,
`
`managing, or preventing the disease or condition. Second active agents include small
`
`molecules and large molecules (e.g., proteins and antibodies), examples of which are
`
`provided herein, as well as stem cells. Methods, or therapies, that can be used in
`
`combination with the administration of the immunomodulatory compound include, but are
`
`not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation
`
`therapy, and other non-drug based therapies presently used to treat, prevent or manage
`
`disease and conditions associated with, or characterized by, undesired angiogenesis.
`
`The invention also encompasses pharmaceutical compositions (e.g., single unit
`
`dosage forms) that can be used in methods disclosed herein. Particular pharmaceutical
`
`compositions comprise an immunomodulatory compound of the invention, or a
`
`pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodru g
`
`thereof, and a second active agent.
`
`5.1
`
`IMMUNOMODULATORY COMPOUNDS
`
`Compounds used in the invention include immunomodulatory compounds that are
`
`racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable
`
`salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred
`
`compounds used in the invention are small organic molecules having a molecular weight
`
`less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides,
`
`oligosaccharides or other macromolecules.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`NY2: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0007
`
`ALVOGEN, Exh. 1002, p. 0007
`
`

`

`
`
`As used herein and unless otherwise indicated, the terms “immunomodulatory
`
`compounds” and “llVIiDsTM” (Celgene Corporation) encompasses small organic molecules
`
`that markedly inhibit TNF-o; LPS induced monocyte ILl B and IL12, and partially inhibit
`
`1L6 production. Specific immunomodulatory compounds are discussed below.
`
`TNF—a is an inflammatory cytokine produced by macrophages and monocytes
`
`during acute inflammation. TNF—a is responsible for a diverse range of signaling events
`
`within cells. TNF-a may play a pathological role in cancer. Without being limited by
`
`theory, one of the biological effects exerted by the immunomodulatory compounds of the
`
`invention is the reduction of synthesis of TNF—Ot. Immunomodulatory compounds of the
`
`invention enhance the degradation of TNF—oz mRNA.
`
`Further, without being limited by theory, immunomodulatory compounds used in the
`
`invention may also be potent co—stimulators of T cells and increase cell proliferation
`
`dramatically in a dose dependent manner. Immunomodulatory compounds of the invention
`
`may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+
`
`T cell subset. In addition, the compounds preferably have anti—inflammatory properties, and
`
`efficiently co-stimulate T cells.
`
`Specific examples of immunomodulatory compounds of the invention, include, but
`
`are not limited to, cyano and carboxy derivatives of substituted styrenes such as those
`
`disclosed in U.S. patent no. 5,929,117; 1—oxo-2—(2,6-dioxo—3-fluoropiperidin-3y1)
`
`isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine—3—y1) isoindolines such as those
`
`described in U.S. patent no. 5,874,448; the tetra substituted 2—(2,6-dioxopiperdin-3-y1)—1-
`
`oxoisoindolines described in U.S. patent no. 5,798,368; l-oxo and 1,3-dioxo—2—(2,6—
`
`dioxopipcridin—3-yl) isoindolines (e. g., 4-methy1 derivatives of thalidomide and EM-12),
`
`including, but not limited to, those disclosed in U.S. patent no. 5,635,517; and a class of
`
`non—polypeptide cyclic amides disclosed in U.S. patent nos. 5,698,579 and 5,877,200;
`
`analogs and derivatives of thalidomide, including hydrolysis products, metabolites,
`
`derivatives and precursors of thalidomide, such as those described in U.S. patent nos.
`
`5,593,990, 5,629,327, and 6,071,948 to D’Amato; aminothalidomide, as well as analogs,
`
`hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and
`
`substituted 2-(2,6—dioxopiperidin—3—y1)phthalimides and substituted 2-(2,6-dioxopiperidin-
`
`3-y1)-1-oxoisoindoles such as those described in U.S. patent nos. 6,281,230 and 6,316,471;
`
`isoindole—imide compounds such as those described in U.S. patent application no.
`
`09/972,487 filed on October 5, 2001, U.S. patent application no. 10/032,286 filed on
`
`December 21, 2001, and International Application No. PCT/USOl/50401 (International
`
`Publication No. W0 02/059106). The entireties of each of the patents and patent
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`-7-
`
`NYZ: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0008
`
`ALVOGEN, Exh. 1002, p. 0008
`
`

`

`
`
`applications identified herein are incorporated herein by reference. Immunomodulatory
`
`compounds of the invention do not include thalidomide.
`
`Other specific immunomodulatory compounds of the invention include, but are not
`
`limited to, l—oxo—and 1,3 dioxo—2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with
`
`amino in the benzo ring as described in U.S. Patent no. 5,635,517 which is incorporated
`
`herein by reference. These compounds have the structure I:
`O2
`
`CEQX‘R
`
`/
`
`N
`
`Y
`
`H2N
`
`N’
`
`“
`
`‘
`
`o
`
`I
`
`in which one ofX and Y is C=O, the other ofX and Y is CZO or CH2 , and R2 is hydrogen
`
`or lower alkyl, in particular methyl. Specific immunomodulatory compounds include, but
`
`10
`
`are not limited to:
`
`1-oxo-2-(2,6-dioxopiperidin-3-y1)-4-aminoisoindoline;
`
`l —oxo—2—(2,6—dioxopiperidin-3—yl)—5—aminoisoindoline;
`
`1—oxo—2-(2,6—dioxopiperidin—3-yl)-6—aminoisoindoline;
`
`I l—oxo-2—(2,6—dioxopiperidin-3—yl)-7-aminoisoindoline;
`
`1,3-di0xo-2—(2,6—dioxopiperidin-3-y1)-4-aminoisoindoline; and
`
`1,3-dioxo-2-(2,6—dioxopiperidin—3—yl)—5—aminoisoindoline.
`
`Other specific immunomodulatory compounds of the invention belong to a class of
`
`substituted 2- (2, 6-dioxopiperidin-3 -yl) phthalimides and substituted 2—(2, 6— dioxopiperidin—
`
`3—yl)-l-oxoisoindoles, such as those described111 U.S. patent nos. 6,281,230; 6,316,471;
`
`6,335,349; and 6,476,052, and International Patent Application No. PCT/U897/ 13375
`
`(International Publication No. WO 98/03502), each of which is incorporated herein by
`
`reference. Compounds representative of this class are of the formulas:
`
`15
`
`20
`
`/7 l
`
`\
`
`H2N
`
`g
`o
`:NflH
`
`C
`II
`o
`
`o
`
`NYZ: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0009
`
`ALVOGEN, Exh. 1002, p. 0009
`
`

`

`
`
`wherein R1 is hydrogen or methyl. In a separate embodiment, the invention encompasses
`
`the use of enantiomerically pure forms (6.g. optically pure (R) or (S) enantiomers) of these
`
`compounds.
`
`Still other specific immunomodulatory compounds of the invention belong to a class
`
`of isoindole—imides disclosed in US. patent application nos. 10/032,286 and 09/972,487,
`
`and International Application No. PCT/USOl/50401 (International Publication No. WO
`
`02/059106), each of which are incorporated herein by reference. Representative compounds
`
`are of formula 11:
`
`O
`
`Y
`\
`/
`
`X
`
`N *
`
`R2
`
`NH
`
`O
`
`II
`
`1R
`
`\N )n
`H
`
`10
`
`and pharmaceutically acceptable salts, hydrates, solvates, elathrates, enantiomers,
`
`diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
`
`one of X and Y is C=O and the other is CH2 or C20;
`
`R1 is H, (C1—C3 )alkyl, (C3—C7)eycloalkyl, (Cg—Cg)alkenyl, (C2—C3)alkynyl, benzyl,
`
`aryl, (C0-C4)alky1—(C1—C6)heterocycloalkyl, (C0—C4)alkyl—(Cz—C5)heteroaryl, C(O)R3 ,
`
`15
`
`C(S)R3, C(O)OR4,
`
`(C1-C3)alky1—N(R6)2, (Cl-Cg)alkyl—OR5, (C1-C8)alky1—C(O)OR5,
`
`C(0)NHR3, C(S)NHR3, C(0)NR3R3’, C(S)NR3R3’ or (C1—C3)alkyliO(CO)R5;
`
`R2 is H, F, benzyl, (C1-C8)alkyl, (C2-C3)alkenyl, or (C2-C3)alkynyl;
`
`R3 and R3, are independently (Cl-Cg)alkyl, (C3—C7)cycloalkyl, (C2—C3)alkenyl, (C2—
`
`Cg)a1kyny1, benzyl, aryl, (Co—C4)alkyl—(C1-C6)heterocycloalkyl, (C0-C4)alkyl—(C2-
`
`20
`
`C5)heteroary1, (Co—Cg)alkyl—N(R6)2, (C1—C8)alky1—OR5, (C1—C8)alkyl—C(O)OR5, (c1—
`
`C8)alky1wO(CO)R5, or C(O)OR5;
`
`R4 is (Cl-Cg)alkyl, (C2-C8)alkenyl, (C2-C3)alkynyl, (C1—C4)alkylr 0R5, benzyl, aryl,
`
`(C0—C4)a1ky1—(C1—C6)heterocycloalkyl, or (Co-C4)alky1—(C2-C5)heteroaryl;
`
`_ 9 _
`
`NY2: 1425023.]
`
`ALVOGEN, Exh. 1002, p. 0010
`
`ALVOGEN, Exh. 1002, p. 0010
`
`

`

`
`
`R5 is (Cl-Cg)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, benzyl, aryl, or (C2—
`
`C5)heteroaryl;
`
`each occurrence of R6 is independently H, (Cl-Cg)alkyl, (C2—C8)alkenyl, (C2-
`
`Cg)alkynyl, benzyl, aryl, (C2—C5)heteroaryl, or (Co-Cg)alkyl—C(O)O—-R5 or the R6 groups can
`
`join to form a heterocycloalkyl group;
`
`n is 0 or 1; and
`
`* represents a chiral-carbon center.
`
`In specific compounds of formula II, when n is 0 then R1 is (C3-C7)cycloalkyl, (C2—
`
`Cg)alkenyl, (C2-C3)alkynyl, benzyl, aryl, (Co-C4)alkylA(C1—C6)heterocycloalkyl, (C0-
`
`10
`
`C4)a1ky1—(C2-C5)hctcroary1,C(O)R3, C(O)OR4, (C1—C3)alky1—N(R6)2, (C1—C3)alkyl~OR5,
`
`(C1-C3)alkyl—C(O)OR5, C(S)NHR3, or (C1-C3)alkyliO(CO)R5;
`
`R2 is H or (Cl-Cg)alkyl; and
`
`R3 is (C1-Cg)alkyl, (C3—C7)cycloalkyl, (C2-C8)alkenyl, (C2-C3)alkyny1, benzyl, aryl,
`
`(C0-C4)alkyl—(C1 —C6)heterocycloalkyl, (C0-C4)alkyl—(Cz—C5)heteroary1, (C5-C3)alkyl—
`
`15
`
`N(R“)2 ; (CO—Cg)alkyl#NH—C(O)O—R5; (C1-C3)alky1~OR5, (C1-C8)alky1—C(O)OR5, (C1-
`
`Cg)alkyl—O(CO)R5, or C(O)OR5; and the other variables have the same definitions.
`
`In other specific compounds of formula II, R2 is H or (C1—C4)alkyl.
`
`In other specific compounds of formula II, R1 is (C1-C8)alky1 or benzyl.
`
`In other specific compounds of formula II, R1 is H, (C1-C8)alkyl, benzyl, CH20CH3,
`
`20
`
`CH2CH20CH3, or
`
`I
`
`”CHzfl
`
`O
`
`In another embodiment of the compounds of formula II, R1 is
`
`WCHz‘Z/
`
`\> ’ mCHgl/S\>
`
`OI‘ WCIRl-iléiR-rs
`
`R7
`
`R7
`
`wherein Q is O or S, and each occurrence of R7 is independently H, (C1-C3)alkyl, benzyl,
`
`25
`
`CHZOCH3, or CH2CH20CH3.
`
`In other specific compounds of formula II, R1 is C(O)R3.
`
`In other specific compounds of formula II, R3 is (Co.C4)a1kyl—(C2.Cs)heteroaryl, (C1—
`
`Cs)alkyl, aryl, or (Co—C4)a1kyl—OR5.
`
`In other specific compounds of formula II, heteroaryl is pyridyl, fury], or thienyl.
`
`30
`
`In other specific compounds of formula II, R1 is C(O)OR4.
`
`In other specific compounds of formula II, the H of C(O)NHC(O) can be replaced
`
`with (C1—C4)alkyl, aryl, or benzyl.
`
`_ 10 -
`
`NY2: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0011
`
`ALVOGEN, Exh. 1002, p. 0011
`
`

`

`
`
`Still other specific immunomodulatory compounds of the invention belong to a class
`
`of isoindole—imides disclosed in US. patent application no. 09/781,179, International
`
`Publication No. WO 98/54170, and United States Patent No. 6,395,754, each of which are
`
`incorporated herein by reference. Representative compounds are of formula III:
`1
`
`R2
`
`R3
`
`R
`
`R4
`
`o
`
`Y
`\N *
`X, R6
`
`/R
`N
`
`0
`
`III
`
`and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers,
`
`diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
`
`one of X and Y is C=O and the other is CH2 or C=O;
`
`R is H or CHZOCOR’;
`
`10
`
`(i) each of R], R2, R3, or R4, independently of the others, is halo, alkyl of 1 to 4
`
`carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R1, R2, R3, or R4 is nitro
`
`or -NHR5 and the remaining of R1, R2, R3, or R4 are hydrogen;
`
`R5 is hydrogen or alkyl of 1 to 8 carbons
`
`R6 hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro;
`
`15
`
`R’ is R7—CHR‘O-N(R8R9);
`
`R7 is m—phcnylene or p—phenylene or —(Cn Hzn)- in which n has a value of 0 to 4;
`
`each of R8 and R9 taken independently of the other is hydrogen or alkyl of 1 to 8
`
`carbon atoms, or R8 and R9 taken together are tetramethylene, pentamethylene,
`
`hexamethylene, or —CH2CH2[X]X1CH2CH2— in which [X]X1 is —O-, -S-, or -NH-;
`
`20
`
`25
`
`R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and
`
`* represents a chiral-carbon center.
`
`The most preferred immunomodulatory compounds of the invention are 4—(amino)—
`
`2—(2,6-dioxo(3—piperidyl))—isoindoline—1,3—dione and 3-(4—amino-1-oxo~1,3-dihydro-
`
`isoindol-2-yl)-piperidine-2,6-dione. The compounds can be obtained via standard, synthetic
`
`methods (see e. g. , United States Patent No. 5,635,517, incorporated herein by reference).
`
`The compounds are available from Celgene Corporation, Warren, NJ. 4—(Amino)-2-(2,6-
`
`dioxo(3-piperidyl))-isoindoline-1,3-dione (ACTIMIDTM) has the following chemical
`
`structure:
`
`-11-
`
`NY2: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0012
`
`ALVOGEN, Exh. 1002, p. 0012
`
`

`

`
`
`NH2
`
`The compound 3-(4-amino- l -oxo— 1 ,3-dihydro—isoindol—2—yl)~piperidine—2,6-dione
`
`(REVIMIDTM) has the following chemical structure:
`
`0
`
`N
`
`NH2
`
`0
`
`o
`
`N\
`
`H
`
`Compounds of the invention can either be commercially purchased or prepared
`
`according to the methods described in the patents or patent publications disclosed herein.
`
`Further, optically pure compounds can be asymmetrically synthesized or resolved using
`
`known resolving agents or chiral columns as well as other standard synthetic organic
`
`chemistry techniques.
`
`As used herein and unless otherwise indicated, the term “pharmaceutically
`
`acceptable salt” encompasses non-toxic acid and base addition salts of the compound to
`
`which the term refers. Acceptable non-toxic acid addition salts include those derived from
`
`organic and inorganic acids or bases know in the art, which include, for example,
`
`hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid,
`
`acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic
`
`acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.
`
`Compounds that are acidic in nature are capable of forming salts with various
`
`pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically
`
`acceptable base addition salts of such acidic compounds are those that form non-toxic base
`
`addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not
`
`limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or
`
`potassium salts in partiCular. Suitable organic bases include, but are not limited to,
`
`N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine,
`
`meglumaine (N—methylglucamine), lysine, and procaine.
`
`As used herein and unless otherwise indicated, the term “prodrug” means a
`
`derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological
`
`conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but
`
`are not limited to, derivatives of immunomodulatory compounds of the invention that
`
`10
`
`15
`
`20
`
`-12-
`
`NYZ: l425028l1
`
`ALVOGEN, Exh. 1002, p. 0013
`
`ALVOGEN, Exh. 1002, p. 0013
`
`

`

`
`
`comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters,
`
`biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and
`
`biohydrolyzable phosphate analogues. Other examples of prodmgs include derivatives of
`
`immunomodulatory compounds of the invention that comprise -NO, -N02, -ONO,
`
`or -ON02 moieties. Prodrugs can typically be prepared using well—known methods, such as
`
`those described in 1 Burger ’s Medicinal Chemistry and Drug Discovery, 172-178, 949-982
`
`(Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier,
`
`New York 1985).
`
`As used herein and unless otherwise indicated, the terms “biohydrolyzable amide,”
`
`“biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzable carbonate,”
`
`“biohydrolyzable ureide,” “biohydrolyzable phosphate” mean an amide, ester, carbamate,
`
`carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not
`
`interfere with the biological activity of the compound but can confer upon that compound
`
`advantageous properties in viva, such as uptake, duration of action, or onset of action; or 2)
`
`is biologically inactive but is converted in vivo to the biologically active compound.
`
`Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower
`
`acyloxyalkyl esters (such as acetoxylmethyl,racetoxyethyl, aminocarbonyloxymethyl,
`
`pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and
`
`thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-
`
`oxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl
`
`esters, choline esters, and acylamino alkyl esters (such as acetamidomethyl esters).
`
`Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides,
`
`a—amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples
`
`of biohydrolyzable carbamates include, but are'not limited to, lower alkylamines,
`
`substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and
`
`heteroaromatic amines, and polyether amines.
`
`Various immunomodulatory compounds of the invention contain one or more chiral
`
`centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers.
`
`This invention encompasses the use of stereomerically pure forms of such compounds, as
`
`well as the use of mixtures of those forms. For example, mixtures comprising equal or
`
`unequal amounts of the enantiomers of a particular immunomodulatory compounds of the
`
`invention may be used in methods and compositions of the invention. These isomers may
`
`be asymmetrically synthesized or resolved using standard techniques such as chiral columns
`
`or chiral resolving agents. See, e. g., Jacques, J ., et al., Enantiomers, Racemates and
`
`Resolutions (Wiley—Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-13-
`
`NYZ: 1425028.]
`
`ALVOGEN, Exh. 1002, p. 0014
`
`ALVOGEN, Exh. 1002, p. 0014
`
`

`

`
`
`33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
`
`1962); and Wilen, S. H., Tables ofResolving Agents and Optical Resolution