7681737
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`June 06, 2018
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`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
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`APPLICATION NUMBER: 10/438,213
`FILING DATE: May 15, 2003
`PATENT NUMBER: 7968569
`ISSUE DATE: June 28, 2011
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`on
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`METHODS AND COMPOSITIONS USING
`IMMUNOMODULATORY COMPOUNDS FOR TREATMENT
`AND MANAGEMENTOF CANCERS AND OTHER DISEASES
`
`This application claims the benefit of U.S. provisional application nos. 60/380,842,
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`filed May 17, 2002, and 60/424,600, filed November6, 2002, the entireties of which are
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`incorporated herein by reference.
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`1.
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`FIELD OF THE INVENTION
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`This invention relates to methodsoftreating, preventing and/or managing specific
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`cancers, ‘and other diseases including, but not limited to, those associated with, or
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`characterized by, undesired angiogenesis, by the administration of onc or more
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`immunomodulatory compoundsalone 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
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`compositions and dosing regimens.
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`2.
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`BACKGROUNDOF THE INVENTION
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`2.1
`PATHOBIOLOGY OF CANCER AND OTHERDISEASES
`Canceris characterized primarily by an increase in the numberof abnormalcells
`derived froma given normaltissue, invasion of adjacent tissues by these abnormalcells, or
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`lymphatic or blood-borne spread of malignantcells to regional lymph nodes andto distant
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`sites (metastasis). Clinical data and molecular biologic studies indicate that canceris a
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`multistep process that begins with minor preneoplastic changes, which may undercertain
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`conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an
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`increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under
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`conditions in whichthe neoplastic cells escape the host’s immunesurveillance. Roitt, I,
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`Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
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`There is an enormousvariety of cancers which are described in detail in the medical
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`literature. Examples includes cancer ofthe lung, colon, rectum,prostate, breast, brain, and
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`intestine. The incidence of cancer continues to climb as the general population ages, as new
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`cancers develop, and as susceptible populations (e.g., people infected with AIDSor
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`excessively exposed to sunlight) grow. A tremendous demand therefore exists for new
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`methods and compositions that can be usedto treat patients with cancer.
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`Manytypesof cancers are associated with new blood vessel formation, a process
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`knownas angiogenesis. Several of the mechanisms involved in tumor-induced
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`angiogenesis have been elucidated. The most direct of these mechanismsis the secretion by
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`the tumor cells of cytokines with angiogenic properties. Examples of these cytokines
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`include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular
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`endothelial growth factor (VEGF), and TNF-a Altermatively, tumor cells can release
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`angiogenic peptides through the production of proteases and the subsequent breakdown of
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`the extracellular matrix where some cytokinesare stored (e.g., b-FGF). Angiogenesis can
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`also be inducedindirectly through the recruitment of inflammatorycells (particularly
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`macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-a, bFGF).
`A variety of other diseases and disorders are also associated with, or characterized
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`by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been
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`implicated in a numberof 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
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`diseases,allergic diseases, and autoimmunediseases. Examples of such diseases and
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`conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity;
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`corneal graft rejection; neovascular glaucoma;retrolental fibroplasia; and proliferative
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`vitreoretinopathy.
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`Accordingly, compounds that can control angiogenesis or inhibit the production of
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`certain cytokines, including TNF-c, may be useful in the treatment and prevention of
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`various diseases and conditions.
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`2.2 METHODS OF TREATING CANCER
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`Current cancer therapy may involve surgery, chemotherapy, hormonal therapy
`and/orradiation treatment to eradicate neoplastic cells in a patient (see, for example,
`Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section FV).
`Recently, cancer therapy could also involve biological therapy or immunotherapy. All of
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`these approachespose significant drawbacks for the patient. Surgery, for example, may be
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`contraindicated due to the health of a patient or may be unacceptable to the patient.
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`Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is
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`only effective when the neoplastic tissuc exhibits a higher sensitivity to radiation than
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`normaltissue. Radiation therapy can also often elicit serious side effects. Hormonal
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`therapyis rarely given as a single agent. Although hormonaltherapy can beeffective,it is
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`often used to prevent or delay recurrenceof cancerafter other treatments have removed the
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`majority of cancer cells. Biological therapies and immunotherapiesare limited in number
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`and mayproduceside effects such as rashes or swellings, flu-like symptoms,including
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`fever, chills and fatigue, digestive tract problemsor allergic reactions.
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`With respect to chemotherapy, there are a variety of chemotherapeutic agents
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`available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting
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`DNAsynthesis, either directly, or indirectly by inhibiting the biosynthesis of
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`deoxyribonucleotide triphosphate precursors, to prevent DNAreplication and concomitant
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`cell division. Gilmanet al., Goodman and Gilman’s: The Pharmacological Basis of
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`Therapeutics, Tenth Ed. (McGraw Hill, New York).
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`Despite availability of a vanety of chemotherapeutic agents, chemotherapy has
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`many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman,eds., ch. 12, sect.
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`10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes
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`significant, and often dangerous side effects including severe nausea, bone marrow
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`depression, and immunosuppression. Additionally, even with administration of
`combinations of chemotherapeutic agents, many tumorcells are resistant or develop
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`resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular
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`chemotherapeutic agents used in the treatment protocol often prove to be resistant to other
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`drugs, even if those agents act by different mechanism from those of the drugs used in the
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`specific treatment. This phenomenonis referred to as pleiotropic drug or multidrug
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`resistance. Because of the drug resistance, many cancers prove refractory to standard
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`chemotherapeutic treatment protocols.
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`Other diseases or conditions associated with, or characterized by, undesired
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`angiogenesisare also difficult to treat. However, some compoundssuchas protamine,
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`hepain and steroids have been proposedto be useful in the treatment of certain specific
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`diseases. Tayloret al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and
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`U.S. Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives of it have also
`
`been proposedfor the treatment of such diseases and conditions. U.S. patent nos.
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`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 methodsoftreating, preventing
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`and managing cancer and other diseases and conditions, particularly for diseases that are
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`refractory to standard treatments, such as surgery, radiation therapy, chemotherapy and
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`hormonal therapy, while reducing or avoiding the toxicities and/or side effects associated
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`with the conventional therapies.
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`2.3
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`IMIDS™
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`A numberofstudies have been conducted with the aim of providing compoundsthat
`can safely and effectively be used to treat diseases associated with abnormal production of
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`TNF-a. See, e.g., Marriott, J.B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G.W.
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`Muller, et al., Journal of Medicinal Chemistry 39(17): 3238-3240 (1996); and G.W. Muller,
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`et al., Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998). Some studies have
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`focused on a group of compoundsselected for their capacity to potently inhibit TNF-a
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`production by LPS stimulated PBMC. L.G.Corral, et al., Ann. Rheum. Dis. 58:(Suppl 1)
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`1107-1113 (1999). These compounds, whichare referred to as IMiDs™ (Celgene
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`Corporation) or Immunomodulatory Drugs, show notonly potent inhibition of TNF-a but.
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`also marked inhibition of LPS induced monocyte IL18 and TL12 production. LPS induced
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`IL6is also inhibited by immunomodulatory compounds,albeit partially. These compounds
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`are potent stimulators of LPS induced IL10.
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`/d. Particular examples of IMiD™sinclude,
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`but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and
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`substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in United States Patent
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`Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al.
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`3.
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`SUMMARY OF THE INVENTION
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`This invention encompasses methods oftreating and preventing certain types of
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`cancer, including primary and metastatic canccr, as well as cancersthat are refractory or
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`resistant to conventional chemotherapy. The methods comprise administering to a patient
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`in need of such treatment or prevention a therapeutically or prophylactically effective
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`amount of an immunomodulatory compound, or a pharmaccutically acceptable salt, solvate,
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`hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses
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`methods of managing certain cancers (e¢.g., preventing or prolonging their recurrence, or
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`Icngthening the time of remission) which comprise administering to a patient in need of
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`such managementa prophylactically effective amount of an immunomodulatory compound
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`of the invention, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
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`clathrate, or prodrug thercof.
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`In particular methods of the invention, an immunomodulatory compound is
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`administered in combination with a therapy conventionally used to treat, prevent or manage
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`cancer. Examples of such conventional therapies include, but are not limited to, surgery,
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`chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy.
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`This invention also encompasses methodsoftreating, managing or preventing
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`diseases and disorders other than cancer that are associated with, or characterized by,
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`undesired angiogenesis, which comprise administering to a patient in need of such
`treatment, managementor prevention a therapeutically or prophylactically effective amount
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`of an immunomodulatory compound,or a pharmaceutically acceptablesalt, solvate,
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`hydrate, stereoisomer, clathrate, or prodrug thereof.
`In other methodsof the invention, an immunomodulatory compound is administered
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`in combination with a therapy conventionally used to treat, prevent or manage diseases or
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`disorders associated with, or characterized by, undesired angiogenesis. Examples of such
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`conventional therapies include, but are not limited to, surgery, chemotherapy, radiation
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`therapy, hormonal therapy, biological therapy and immunotherapy.
`This invention encompasses pharmaceutical compositions, single unit dosage forms,
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`dosing regimens and kits which comprise an immunomodulatory compound,or a
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`pharmaccutically acceptable salt, solvate, hydrate, stereoisomer,clathrate, or prodrug
`thereof, and a second, or additional, active agent. Second active agents include specific
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`combinations,or “cocktails,” of drugs.
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`4.
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`BRIEF DESCRIPTION OF FIGURE
`
`Figure 1 shows a comparison ofthe effects of 3-(4-amino-1-oxo-1,3-dihydro-
`isoindol-2-yl)-piperidine-2,6-dione (Revimid™) and thalidomide in inhibiting the
`proliferation of multiple myeloma (MM)cell lines in an in vitro study. The uptake of CHI-
`thymidine by different MM cell lines (MM.1S, Hs Sultan, U266 and RPMI-8226) was
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`measured as an indicator of the cell proliferation.
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`5.
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`DETAILED DESCRIPTION OF THE INVENTION
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`A first embodiment of the invention encompasses methodsof treating, managing, or
`
`preventing cancer which comprises administering to a patient in need of such treatment or
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`prevention a therapeutically or prophylactically effective amount of an immunomodulatory
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`compoundof the invention, or a pharmaceutically acceptable salt, solvate, hydrate,
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`stcrcoisomer, clathrate, or prodrug thereof.
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`In particular methods encompassed by this embodiment, the immunomodulatory
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`compoundis administered in combination with another drug (“second active agent”) or
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`mcthodoftreating, managing, or preventing cancer. Second active agents include small
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`molecules and large molecules (¢.g., proteins and antibodies), examples of which are
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`provided herein, as well as stem cells. Methods,or therapies, that can be used in
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`combination with the administration of the immunomodulatory compoundinclude, but are
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`not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation
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`therapy, and other non-drug based therapies presently used to treat, prevent or manage
`cancer.
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`Another embodimentof the invention encompasses methodsoftreating, managing
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`or preventing diseases and disorders other than cancer that are characterized by undesired
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`angiogenesis. These methods comprise the administration of a therapeutically or
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`prophylactically effective amount of an immunomodulatory compound,or a
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`pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
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`thereof.
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`Examples of diseases and disorders associated with, or characterized by, undesired
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`angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases,
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`viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular
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`diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis
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`(neovascularization of the angle).
`
`In particular methods encompassed by this embodiment, the immunomodulatory
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`compoundis administer in combination with a second active agent or method oftreating,
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`managing, or preventing the disease or condition. Second active agents include small
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`molecules and large molecules (e.g., proteins and antibodies), examples of which are
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`provided herein, as well as stem cells. Methods, or therapies, that can be used in
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`combination with the administration of the immunomodulatory compoundinclude, but are
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`not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation
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`therapy, and other non-drug based therapies presently used to treat, prevent or manage
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`disease and conditions associated with, or characterized by, undesired angiogenesis.
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`The invention also encompasses pharmaceutical compositions(e.g., single unit
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`dosage forms) that can be used in methods disclosed herein. Particular pharmaceutical
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`compositions comprise an immunomodulatory compoundof the invention, or a
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`pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
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`thereof, and a secondactive agent.
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`5.1
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`IMMUNOMODULATORY COMPOUNDS
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`Compoundsused in the invention include immunomodulatory compoundsthat are
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`racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable
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`salts, solvates, hydrates, stereoisomers, clathrates, and prodrugs thereof. Preferred
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`compoundsusedin the invention are small organic molecules having a molecular weight
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`less than about 1,000 g/mol, and are not proteins, peptides, oligonucleotides,
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`oligosaccharides or other macromolecules.
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`Asused herein and unless otherwise indicated, the terms “immunomodulatory
`compounds”and “IMiDs™” (Celgene Corporation) encompasses small organic molecules
`that markedly inhibit TNF-c, LPS induced monocyte II.18 and IL12,and partially inhibit
`IL6 production. Specific immunomodulatory compoundsare 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 mayplay a pathological role in cancer. Without being limited by
`theory, one ofthe biological effects exerted by the immunomodulatory compoundsofthe
`invention is the reduction of synthesis of TNF-a. Immunomodulatory compoundsofthe
`
`invention enhance the degradation of TNF-a mRNA.
`Further, without being limited by theory, immunomodulatory compoundsusedin the
`invention may also be potent co-stimulators of T cells and increase cell proliferation
`dramatically in a dose dependent manner. Immunomodulatory compoundsofthe invention
`mayalso have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+
`T cell subset. In addition, the compoundspreferably have anti-inflammatory properties, and
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`efficiently co-stimulate T cells.
`Specific examples of immunomodulatory compoundsofthe 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-3yl)
`isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those
`described in U.S. patent no. 5,874,448; the tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-
`oxoisoindolines described in U.S. patent no. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-
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`dioxopipcridin-3-yl) isoindolines (e.g., 4-methy] 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.
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`5,593,990, 5,629,327, and 6,071,948 to D’ Amato; aminothalidomide, as well as analogs,
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`hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and
`substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-
`3-yl)-1-oxoisoindoles such as those described in U.S. patent nos. 6,281,230 and 6,316,471;
`isoindole-imide compoundssuchas 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
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`December21, 2001, and International Application No. PCT/US01/50401 (International
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`Publication No. WO 02/059106). The entireties of each of the patents and patent
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`applications identified herein are incorporated herein by reference. Immunomodulatory
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`compoundsofthe invention do not include thalidomide.
`
`Other specific immunomodulatory compoundsofthe invention include, but are not
`limited to, 1-oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with
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`amino in the benzo ring as described in U.S. Patent no. 5,635,517 which is incorporated
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`herein by reference. These compoundshavethe structure I:
`Oo
`
`2
`
`<
`
`Y
`
`N~
`
`Oo"N
`
`I
`oO
`|
`HoaN
`in which one of X and Y is C=O,the other of X and Y is C=O or CH), and R’is hydrogen
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`or loweralkyl, in particular methyl. Specific immunomodulatory compounds include,but
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`are not limited to:
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`1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline;
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`1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline;
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`1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline;
`-1-0xo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline;
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`1,3-dioxo0-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and
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`1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.
`
`Other specific immunomodulatory compoundsof the invention belong to a class of
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`substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-
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`3-yl)-1-oxoisoindoles, such as those described in U.S. patent nos. 6,281,230; 6,316,471;
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`6,335,349; and 6,476,052, and International Patent Application No. PCT/US97/13375
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`(International Publication No. WO 98/03502), each of which is incorporated herein by
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`reference. Compoundsrepresentative of this class are of the formulas:
`
`m
`Oo
`As | OYVe
`
`Iu
`
`O
`
`Ho2N
`
`Cc.oPorC
`
`O
`
`Oo
`
`|
`
`O
`
`ul
`Oo
`
`NH2
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`0
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`wherein R! is hydrogen or methyl. In a separate embodiment, the invention encompasses
`the use of enantiomerically pure forms(e.g. optically pure (R) or (S) enantiomers) of these
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`compounds.
`Still other specific immunomodulatory compoundsofthe invention belong to a class
`of isoindole-imides disclosed in U.S. patent application nos. 10/032,286 and 09/972,487,
`and International Application No. PCT/US01/50401 (International Publication No. WO
`02/059106), each of which are incorporated herein by reference. Represcntative compounds
`
`are of formula II:
`
`0.
`
`Y.
`\
`4
`xX
`
`N—-
`R?2
`
`NH
`
`Oo
`
`4R ™N ),
`
`H
`
`II
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`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;
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`R! is H, (C\-Cg)alkyl, (C3-C7)cycloalkyl, (Cz-Cg)alkenyl, (C2-Cg)alkynyl, benzyl,
`aryl, (Co-C4)alkyl{C |-C¢)heterocycloalkyl, (Co-C4)alkyl-(C2-Cs)heteroaryl, C(O)R?,
`C(S)R?, C(O)OR*, (C)-Cs)alkyl-N(R®), (Ci-Cg)alkyl-OR®, (Ci-Cg)alkyl-C(O)OR’,
`C(OYNHR?, C(S)NHR?’, C(O)NR?R?, C(S)NR?R®or (Ci-Cg)alkyl-O(CO)R?;
`R’is H,F, benzyl, (C1-Cg)alkyl, (C2-Cg)alkenyl, or (C2-Cg)alkynyl;
`R? and R®are independently (C;-Cs)alkyl, (C3-C7)cycloalkyl, (C2-Cg)alkenyl, (C2-
`Cg)alkynyl, benzyl, aryl, (Co-C4)alkyI(C\-Cs)heterocycloalkyl, (Co-Ca)alkyl-(Co-
` Cs)heteroaryl, (Co-Cg)alkyl-N(R)2, (Ci-Cg)alkyl-OR®, (Ci-Cs)alkyl-C(O)OR’, (Ci-
`Cs)alkyl-O(CO)R°®, or C(O)OR’;
`R‘ is (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, (C\-Ca)alkyl- OR®,benzyl,aryl,
`(Co-Ca)alkyl-(C}-C¢)heterocycloalkyl, or (Co-Ca)alkyl(C2-Csheteroaryl;
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`R° is (Cy-Cg)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, benzyl, aryl, or (C2-
`
`Cs)heteroaryl;
`each occurrence of R°is independently H, (C1-Cg)alkyl, (C2-Cs)alkenyl, (C2-
`Cs)alkynyl, benzyl, aryl, (C2-Cs)heteroaryl, or (Co-Cs)alkyl-C(O)O-R* or the R® groups can
`join to form a heterocycloalkyl group;
`
`nis 0 or 1; and
`
`10
`
`15
`
`* represents a chiral-carbon center.
`In specific compoundsof formula II, when n is 0 then R!is (C3-C7)cycloalkyl, (C2-
`Cg)alkenyl, (C2-Cg)alkynyl, benzyl, aryl, (Co-C4)alkyl-(C-Ce)heterocycloalkyl, (Co-
`C,4)alkyl-(Cy-Cs)hctcroaryl, C(O)R?, C(O)OR*, (Ci-Cs)alkyl-N(R°)2, (C1-Cs)alkyl-OR’,
`(C)-Cs)alkyl-C(O)OR>, C(S)NHR’, or (Ci-Cg)alkyl-O(CO)R’;
`R? is H or (C-Cg)alkyl; and
`R?is (Cy-Cg)alkyl, (C3-C7)cycloalkyl, (C2-Cg)alkenyl, (C2-Cs)alkynyl, benzyl, aryl,
`(Co-Ca)alkyl1{C, —Ce)heterocycloalkyl, (Co-C4)alkyl{(C2-Cs)heteroaryl, (Cs-Cg)alkyl—
`N(R°)2 ; (Co-Cg)alkyl-NH-C(O)O-R°; (C1-Cg)alkyl-OR®, (Ci-Cg)alkyl-C(O)OR®, (Ci-
`Cs)alkyl-O(CO)R°,or C(O)OR’; and the other variables have the samedefinitions.
`In other specific compoundsof formula II, R’ is H or (Cy-Ca)alkyl.
`In other specific compounds of formulaII, R' is (C\-Cs)alkyl or benzyl.
`In other specific compounds of formula I, R! is H, (C,-Cg)alkyl, benzyl, CH2OCH3,
`
`20
`
`CH»CH2,OCHs, or
`
`ctl\
`
`In another embodiment of the compoundsof formulaII, R!is
`R’
`RR’
`
`\\
`
`, “ctrl
`
`wocH,—ll
`
`or aa
`
`wherein Q is O or S, and each occurrence of R’is independently H, (C\-Cg)alkyl, benzyl,
`
`25
`
`30
`
`CH20CH3, or CH2CH20CH3.
`In other specific compoundsof formula I, R' is C(O)R’.
`In other specific compoundsof formula II, R? is (Co-Ca)alkyl-(C2-Cs)heteroaryl, (Ci
`Ca)alkyl, aryl, or (Co-Ca)alkyl-OR?.
`In other specific compoundsof formulaII, heteroarylis pyridyl, furyl, or thienyl.
`In other specific compoundsof formula II, R'is C(O)OR*.
`In other specific compoundsof formulaII, the H of C(Q)NHC(O)can be replaced
`
`with (C;-C,)alkyl, aryl, or benzyl.
`
`-10-
`
`NY2: 1425028.1
`
`ALVOGEN, Exh. 1002, p. 0011
`
`ALVOGEN, Exh. 1002, p. 0011
`
`

`

`
`
`Still other specific immunomodulatory compoundsofthe invention belongto a class
`of isoindole-imides disclosed in U.S. 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 compoundsare of formula I:
`1
`R
`Q
`R
`y
`N
`‘NN
`< RS
`
`O
`
`R2
`
`R3
`
`R4
`
`Ill
`
`and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers,
`diastereomers, racemates, and mixtures of stereoisomers thereof, wherein:
`
`one of X and Y is C=O andthe other is CHz or C=O;
`
`10
`
`15
`
`Ris H or CH2OCOR’;
`(i) each of R!, R2, R’, or RB’, independently of the others, is halo, alkyl of 1 to 4
`carbon atoms, or alkoxy of 1 to 4 carbon atomsor(ii) one of R', R’, R’, or R* is nitro
`or -NHR>and the remaining of R!, R2, R?, or R* are hydrogen;
`R° is hydrogen or alkyl of 1 to 8 carbons
`R® hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro,
`R’ is R’-CHR'°-N(RER’);
`R’ is m-phenylene or p-phenylene or -(Cy H2n)- in which n hasa value of 0 to 4;
`each of R® and R’ taken independently of the other is hydrogen or alkyl of 1 to 8
`carbon atoms, or R® and R” taken together are tetramethylene, pentamethylene,
`
`hexamethylene, or -CH2CH2[X]X,CH2CH2~— in which [X]X;is -O-, -S-, or -NH-;
`R!° is hydrogen,alkyl of to 8 carbon atoms, or phenyl; and
`
`20
`
`* represents a chiral-carbon center.
`
`The mostpreferred immunomodulatory compoundsofthe 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 compoundscan be obtained via standard, synthetic
`
`25
`
`methods (see e.g., United States Patent No. 5,635,517, incorporated herein by reference).
`
`The compoundsare available from Celgene Corporation, Warren, NJ. 4-(Amino)-2-(2,6-
`
`dioxo(3-piperidy]))-isoindoline-1,3-dione (ACTIMID™)hasthe following chemical
`
`structure:
`
`-1ll-
`
`NY2: 1425028.1
`
`ALVOGEN, Exh. 1002, p. 0012
`
`ALVOGEN, Exh. 1002, p. 0012
`
`

`

`
`
`O
`
`NH,
`
`© O
`
`N
`
`‘H
`
`The compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
`
`(REVIMID™)hasthe following chemical structure:
`
`o
`
`N
`
`NH2
`
`O
`
`N.
`
`U8
`
`o
`
`Compoundsofthe invention can either be commercially purchased or prepared
`
`according to the mcthods described in the patents or patent publications disclosed herein.
`
`Further, optically pure compounds can be asymmetrically synthesized or resolved using
`
`knownresolving agents or chiral columns as well as other standard synthetic organic
`
`chemistry techniques.
`
`Asused herein and unless otherwise indicated, the term “pharmaceutically
`
`acceptable salt” encompasses non-toxic acid and base addition salts of the compoundto
`
`whichthe term refers. Acceptable non-toxic acid addition salts include those derived from
`
`organic and inorganic acids or bases know intheart, which include, for example,
`
`10
`
`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, andthelike.
`
`Compoundsthat are acidic in nature are capable of forming salts with various
`
`pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically
`
`15
`
`acceptable basc addition salts of such acidic compoundsarc thosc that form non-toxic base
`
`addition salts, i.¢., 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,
`
`20
`
`meglumaine (N-methylglucamine), lysine, and procaine.
`
`As usedherein and unless otherwise indicated, the term “prodrug” means a
`
`derivative of a compoundthat can hydrolyze, oxidize, or otherwise react under biological
`
`conditions (in vitro or in vivo) to provide the compound. Examples of prodrugsinclude, but
`
`are not limited to, derivatives of immunomodulatory compoundsof the invention that
`
`-12-
`
`NY2: 1425028.1
`
`ALVOGEN, Exh. 1002, p. 0013
`
`ALVOGEN, Exh. 1002, p. 0013
`
`

`

`
`
`comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzableesters,
`biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and
`biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of
`immunomodulatory compoundsofthe invention that comprise -NO, -NOz2, -ONO,
`or -ONOQ; 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,”
`
`10
`
`“biohydrolyzable ester,” “biohydrolyzable carbamate,” “biohydrolyzable carbonate,”
`
`“biohydrolyzable ureide,” “biohydrolyzable phosphate” mean an amide,ester, carbamate,
`
`carbonate, ureide, or phosphate, respectively, of a compoundthat either: 1) does not
`
`interfere with the biological activity of the compoundbut can confer upon that compound
`
`advantageousproperties in vivo, such as uptake, duration of action, or onset of action; or 2)
`
`15
`
`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,:acetoxyethyl, aminocarbonyloxymethyl,
`
`pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and
`
`thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyl-
`
`20
`
`oxymethyl, ethoxycarbonyloxycthyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl
`
`esters, choline esters, and acylaminoalkyl esters (such as acetamidomethy]esters).
`
`Examples of biohydrolyzable amidesinclude, but are not limited to, lower alkyl amides,
`
`a-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples
`
`of biohydrolyzable carbamatesinclude, but arenot limited to, lower alkylamines,
`
`25
`
`substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and
`
`heteroaromatic amines, and polyether amines.
`
`Various immunomodulatory compoundsof the invention contain one or morechiral
`
`centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers.
`
`This invention encompassesthe use of stereomerically pure forms of such compounds,as
`
`30
`
`well as the use of mixtures of those forms. For example, mixtures comprising equal or
`
`unequal amounts of the enantiomers ofa particular immunomodulatory compoundsofthe
`
`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
`
`35
`
`Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron
`
`-13-
`
`NY2: 1425028.1
`
`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 Resolutions p. 268(E.L.
`Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
`As used herein and unless otherwise indicated, the term “stereomcrically pure”
`
`means a composition that comprises one stereoisomer of a compoundandis substantially
`free of other stereoisomers of that compound. For example, a stereomerically pure
`composition of a compound having onechiral cent