-~
`
` WIPO
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`WORLD
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`ORGANIZATION
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`DOCUMENT MADE AVAILABLE UNDER THE
`PATENT COOPERATION TREATY (PCT)
`PCT /I B2015/000645
`International application number:
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`International filing date:
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`21 January 2015 (21.01.2015)
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`Certified copy of priority document
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`61/974,665
`03 April 2014 (03.04.2014)
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`Remark: Priority document submitted or transmitted to the International Bureau in compliance with Rule
`17.1(a),(b) or (b-bis)
`
`34, chemin des Colombettes
`1 2 I I Geneva 20, Switze1·1and
`
`www.wipo.int
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 1 of 143
`
`

`

`Patent 1111:d Tn1.dcm:1rk Offkc
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 2 of 143
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/31/2015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
`
`lnventor(s)
`
`Inventor 1
`
`Given Name
`
`Middle Name
`
`Family Name
`
`City
`
`State
`
`Ahmed
`
`HAMDY
`
`San Carlos
`
`CA
`
`All Inventors Must Be Listed -Additional Inventor Information blocks may be
`generated within this form by selecting the Add button.
`
`Im R~ovij ti
`Country 1
`
`us
`
`I ?Ada
`
`]
`
`Title of Invention
`
`Therapeutic Combination of a Pl3K Inhibitor and a BTK Inhibitor
`
`Attorney Docket Number (if applicable)
`
`055112-5002-PR1
`
`Correspondence Address
`
`Direct all correspondence to (select one):
`
`@ The address corresponding to Customer Number 0 Firm or Individual Name
`
`Customer Number
`
`28977
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`
`@ No.
`0 Yes, the invention was made by an agency of the United States Government. The U.S. Government agency name is:
`O Yes, the invention was under a contract with an agency of the United States Government. The name of the U.S.
`Government agency and Government contract number are:
`
`EFS - Web 1.0.1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 3 of 143
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 05/31/2015. 0MB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995. no persons are required to respond to a collection of information unless it displays a valid 0MB control number
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`Entity Status
`Applicant asserts small entity status under 37 CFR 1.27 or applicant certifies micro entity status under 37 CFR 1.29
`
`0 Applicant asserts small entity status under 37 CFR 1.27
`0 Applicant certifies micro entity status under 37 CFR 1.29. Applicant must attach form PTO/SB/15A or B or equivalent.
`@ No
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`Signature
`
`Please see 37 CFR 1.4(d) for the form of the signature.
`
`Signature
`
`/Frederick G. Vogl/
`
`Date (YYYY-MM-DD)
`
`2014-04-03
`
`First Name
`
`Frederick G.
`
`Last Name
`
`Vogt
`
`Registration Number
`(If appropriate)
`
`70115
`
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`the provisional application.
`
`EFS - Web 1.0.1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 4 of 143
`
`

`

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`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 5 of 143
`
`

`

`120
`
`100
`
`C 80
`0
`.:; 60
`:0
`.c
`C
`
`40
`
`~ 0
`
`20
`
`0
`
`-20
`
`1/4
`
`~ Tested Btk inhibitor
`"'~'" Tested Pl3K inhibitor
`Btki + Pl3Ki (1 000nM)
`Btki + Pl3Ki (300nM)
`"&l" Btki + Pl3Ki (1 00nM)
`+ Btki + Pl3Ki (30nM)
`_.. Btki + Pl3Ki (1 0nM)
`"~" Btki + Pl3Ki (3nM)
`
`-10
`
`-8
`Log M compound
`
`-6
`
`FIG. 1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 6 of 143
`
`

`

`2/4
`
`~ Tested Btk inhibitor
`"~"' Tested Pl3K inhibitor
`Btki + Pl3Ki (1 000OnM)
`Btki + Pl3Ki (3000nM)
`·'~" Btki + Pl3Ki (1 000nM)
`+ Btki + Pl3Ki (300nM)
`+ Btki + Pl3Ki (1 00nM)
`-~, Btki + Pl3Ki (30nM)
`
`-4
`
`.
`
`§...
`
`·~,t~~~~~~
`-8
`Log M lont"l>ound
`
`120
`
`100
`
`C: 80
`0
`+:. 60
`:0
`.c:
`C:
`
`40
`
`~ 0
`
`20
`
`0
`
`-20
`
`FIG. 2
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 7 of 143
`
`

`

`3/4
`
`~ ---~-,.C
`ro: ·~ >
`
`~
`
`[Tested Btk inhibitor]
`
`,,,-.~ Tested Pt3Ki
`
`"'"~'" (10 µM)Tested P!3Ki
`
`FIG. 3
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 8 of 143
`
`

`

`M/A
`4/4
`
`T
`
`4l&.
`
`T
`
`ioiD—“~o
`
`•
`
`UOHORJAzU|
`XapUl
`
`,t-t-f#.·
`.
`. ~
`•
`0~0"""'-----------~-
`~ " ~
`¼")
`~
`~ ~ .r:t
`*
`j
`j
`~
`
`Ct
`Cf
`~ ~
`
`f
`
`FIG. 4
`FIG. 4
`
`SANDOZINC.
`
`IPR2023-00478
`
`Ex. 1012, p. 9 of 143
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 9 of 143
`
`

`

`Electronic Acknowledgement Receipt
`
`EFS ID:
`
`Application Number:
`
`18659888
`
`61974665
`
`International Application Number:
`
`Confirmation Number:
`
`8182
`
`Title of Invention:
`
`Therapeutic Combination of a Pl3K Inhibitor and a BTK Inhibitor
`
`First Named Inventor/Applicant Name:
`
`Ahmed Hamdy
`
`Customer Number:
`
`28977
`
`Filer:
`
`Frederick Vogt
`
`Filer Authorized By:
`
`Attorney Docket Number:
`
`055112-5002-PRl
`
`Receipt Date:
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`03-APR-2014
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`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 10 of 143
`
`

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`1
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`Provisional Cover Sheet (SBl 6)
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`20140403PROVTRANS.PDF
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`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 11 of 143
`
`

`

`Attorney Docket No.: 055112-5002-PR-01
`
`THERAPEUTIC COMBINATION OF A PI3K INHIBITOR AND A BTK INHIBITOR
`
`FIELD OF THE INVENTION
`
`[001]
`
`A therapeutic combination of a phosphoinositide 3-kinase (PI3K) inhibitor and a
`
`Bruton's Tyrosine Kinase (BTK) inhibitor and uses of the therapeutic combination are disclosed
`
`herein.
`
`BACKGROUND OF THE INVENTION
`
`[002]
`
`PI3K inhibitors are members of a unique and conserved family of intracellular lipid
`
`kinases that phosphorylate the 3'-OH group on phosphatidylinositols or phosphoinositides. PI3K
`
`inhibitors are key signaling enzymes that relay signals from cell surface receptors to downstream
`
`effectors. The PI3K family comprises 15 kinases with distinct substrate specificities, expression
`
`patterns, and modes ofregulation. The class I PI3K inhibitors (pl lOa, pl 10~, pl 108, and pl l0y)
`
`are typically activated by tyrosine kinases or G-protein coupled receptors to generate PIP3,
`
`which engages downstream effectors such as those in the Akt/PDKI pathway, mTOR, the Tee
`
`family kinases, and the Rho family GTPases.
`
`[003]
`
`The PI3K signaling pathway is known to be one of the most highly mutated in human
`
`cancers. PI3K signaling is also a key factor in disease states including hematologic
`
`malignancies, non-Hodgkin lymphoma (such as diffuse large B-cell lymphoma), allergic contact
`
`dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel diseases, chronic obstructive
`
`pulmonary disorder, psoriasis, multiple sclerosis, asthma, disorders related to diabetic
`
`complications, and inflammatory complications of the cardiovascular system such as acute
`
`coronary syndrome. The role of PI3K in cancer has been discussed, for example, in J. A.
`
`Engleman, Nat. Rev. Cancer 2009, 9, 550-562. The PBK-8 and PI3K-y isoforms are
`
`preferentially expressed in normal and malignant leukocytes.
`
`[004]
`
`The delta (8) isoform of class I PI3K (PBK-8) is involved in mammalian immune
`
`system functions such as T-cell function, B-cell activation, mast cell activation, dendritic cell
`
`function, and neutrophil activity. Due to its role in immune system function, PBK-8 is also
`
`involved in a number of diseases related to undesirable immune response such as allergic
`
`reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis,
`
`DBl/ 78131794.5
`DRAFT 04/03/14
`
`1
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 12 of 143
`
`

`

`Attorney Docket No.: 055112-5002-PR-01
`
`auto-immune diseases such as lupus, asthma, emphysema and other respiratory diseases. The
`
`gamma (y) isoform of class I PI3K (PI3K-y) is also involved in immune system functions and
`
`plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis,
`
`and autoimmune diseases such as lupus.
`
`[005]
`
`Downstream mediators of the PI3K signal transduction pathway include Akt and
`
`mammalian target of rapamycin (mTOR). One important function of Akt is to augment the
`
`activity of mTOR, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine(cid:173)
`
`threonine kinase related to the lipid kinases of the PI3K family and has been implicated in a wide
`
`range of biological processes including cell growth, cell proliferation, cell motility and survival.
`
`Disregulation of the mTOR pathway has been reported in various types of cancer.
`
`[006]
`
`In view of the above, PI3K inhibitors are prime targets for drug development, as
`
`described in J.E. Kurt and I. Ray-Coquard, Anticancer Res. 2012, 32, 2463-70. Several PI3K
`
`inhibitors are known, including those those that are PBK-8 inhbitors, PI3K-y inhibitors and those
`
`that are PBK-8,y inhibitors.
`
`[007]
`
`Bruton's Tyrosine Kinase (BTK) is a Tee family non-receptor protein kinase expressed
`
`in B cells and myeloid cells. The function of BTK in signaling pathways activated by the
`
`engagement of the B cell receptor (BCR) and FCERl on mast cells is well established.
`
`Functional mutations in BTK in humans result in a primary immunodeficiency disease
`
`characterized by a defect in B cell development with a block between pro- and pre-B cell stages.
`
`The result is an almost complete absence of B lymphocytes, causing a pronounced reduction of
`
`serum immunoglobulin of all classes. These findings support a key role for BTK in the
`
`regulation of the production of auto-antibodies in autoimmune diseases.
`
`[008]
`
`Other diseases with an important role for dysfunctional B cells are B cell malignancies.
`
`The reported role for BTK in the regulation of proliferation and apoptosis ofB cells indicates the
`
`potential for BTK inhibitors in the treatment of B cell lymphomas. BTK inhibitors have thus
`
`been developed as potential therapies, as described in 0. Cruz et al., OncoTargets and Therapy
`
`2013, 6, 161-176.
`
`DBl/ 78131794.5
`DRAFT 04/03/14
`
`2
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 13 of 143
`
`

`

`Attorney Docket No.: 055112-5002-PR-01
`
`[009]
`
`The present invention includes the unexpected discovery that the combination of a
`
`PI3K inhibitor with a BTK inhibitor is effective in the treatment of any of several types of
`
`cancers such as leukemia, lymphoma and solid tumor cancers.
`
`SUMMARY OF THE INVENTION
`
`[0010]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K inhibitor and a BTK inhibitor.
`
`[0011]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K-y inhibitor and a BTK inhibitor.
`
`[0012]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PBK-8 inhibitor and a BTK inhibitor.
`
`[0013]
`
`In an embodiment, the invention includes a method of treating leukemia, lymphoma or
`
`a solid tumor cancer in a subject, comprising co-administering to a mammal in need thereof a
`
`therapeutically effective amount of a PI3K-y,8 inhibitor and a BTK inhibitor.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0014] The foregoing summary, as well as the following detailed description of the invention,
`
`will be better understood when read in conjunction with the appended drawings.
`
`[0015] FIG. 1 illustrates the sensitivity of the TMD8 diffuse large B cell lymphoma (DLBCL)
`
`cell line to individual treatment with the BTK inhibitor of Formula XVIII ("Tested Btk
`
`Inhibitor") and the PI3K inhibitor of Formula IX ("Tested PI3K Inhibitor") and combined
`treatment with Formula XVIII and Formula IX ("Btki + PI3Ki") at different concentrations. The
`
`concentration of the first agent in the combination (the BTK inhibitor) and the concentration of
`
`the individual agents is given on the x-axis, and the concentration of the added PI3K inhibitor in
`
`combination with the BTK inhibitor is given in the legend.
`
`DBl/ 78131794.5
`DRAFT 04/03/14
`
`3
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1012, p. 14 of 143
`
`

`

`Attorney Docket No.: 055112-5002-PR-01
`
`[0016] FIG. 2 illustrates the sensitivity of the MINO mantle cell lymphoma cell to individual
`
`treatment with the BTK inhibitor of Formula XVIII ("Tested Btk Inhibitor") and the PI3K
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`inhibitor of Formula IX ("Tested PI3K Inhibitor") and combined treatment with Formula XVIII
`and Formula IX ("Btki + PI3Ki") at different concentrations. The concentration of the first agent
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`in the combination (the BTK inhibitor) and the concentration of the individual agents is given on
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`the x-axis, and the concentration of the added PI3K inhibitor in combination with the BTK
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`inhibitor is given in the legend.
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`[0017] FIG. 3 illustrates the proprofliferative activity in primary mantle cell lymphoma cells of
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`Formula XVIII ("Tested Btki") and Formula IX ("Tested PI3Ki"). The percentage viability of
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`cells ("%viability", y-axis) is plotted versus the concentration of the Formula XVIII ("[Tested
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`Btk Inhibitor]", x-axis). The concentration of the individual BTK and PI3K inhibitors (i.e. not in
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`combination) are also given on the x-axis.
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`[0018] FIG. 4 illustrates the interaction index of the combination of the BTK inhibitor of
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`Formula XVIII and the PI3K inhibitor of Formula IX in primary mantle cell lymphoma cells.
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`DETAILED DESCRIPTION OF THE INVENTION
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`[0019] While preferred embodiments of the invention are shown and described herein, such
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`embodiments are provided by way of example only and are not intended to otherwise limit the
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`scope of the invention. Various alternatives to the described embodiments of the invention may
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`be employed in practicing the invention.
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`f 0020] Unless defined otherwise, all technical and scientific terms used herein have the same
`meaning as is commonly understood by one of skill in the art to which this invention belongs.
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`All patents and publications referred to herein are incorporated by reference in their entireties.
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`[0021] The terms "co-administration" and "administered in combination with" as used herein,
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`encompass administration of two or more agents to a subject so that both agents and/or their
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`metabolites are present in the subject at the same time. Co-administration includes simultaneous
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`administration in separate compositions, administration at different times in separate
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`compositions, or administration in a composition in which both agents are present.
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`IPR2023-00478
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`Ex. 1012, p. 15 of 143
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`[0022] The term "effective amount" or "therapeutically effective amount" refers to that amount
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`of a compound or combination of compounds as described herein that is sufficient to effect the
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`intended application including, but not limited to, disease treatment. A therapeutically effective
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`amount may vary depending upon the intended application (in vitro or in vivo), or the subject and
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`disease condition being treated (e.g., the weight, age and gender of the subject), the severity of
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`the disease condition, the manner of administration, etc. which can readily be determined by one
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`of ordinary skill in the art. The term also applies to a dose that will induce a particular response
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`in target cells, (e.g., the reduction of platelet adhesion and/or cell migration). The specific dose
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`will vary depending on the particular compounds chosen, the dosing regimen to be followed,
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`whether the compound is administered in combination with other compounds, timing of
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`administration, the tissue to which it is administered, and the physical delivery system in which
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`the compound is carried.
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`[0023] A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit
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`and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or
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`eliminating the appearance of a disease or condition, delaying or eliminating the onset of
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`symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or
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`condition, or any combination thereof.
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`[0024] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of
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`organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition
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`salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can
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`be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid
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`and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic
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`acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic
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`acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
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`methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
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`Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
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`Inorganic bases from which salts can be derived include, for example, sodium, potassium,
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`lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic
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`bases from which salts can be derived include, for example, primary, secondary, and tertiary
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`amines, substituted amines including naturally occurring substituted amines, cyclic amines and
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`basic ion exchange resins. Specific examples include isopropylamine, trimethylamine,
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`diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the
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`pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium,
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`calcium, and magnesium salts.
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`[0025]
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`"Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is
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`intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal
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`agents, isotonic and absorption delaying agents. The use of such media and agents for
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`pharmaceutically active substances is well known in the art. Except insofar as any conventional
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`media or agent is incompatible with the active ingredient, its use in the therapeutic compositions
`
`of the invention is contemplated. Supplementary active ingredients can also be incorporated into
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`the described compositions.
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`[0026]
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`"Prodrug" is intended to describe a compound that may be converted under
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`physiological conditions or by solvolysis to a biologically active compound described herein.
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`Thus, the term "prodrug" refers to a precursor of a biologically active compound that is
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`pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is
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`converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound
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`often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian
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`organism (see, e.g., Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam). The term
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`"prodrug" is also intended to include any covalently bonded carriers, which release the active
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`compound in vivo when administered to a subject. Prodrugs of an active compound, as described
`
`herein, may be prepared by modifying functional groups present in the active compound in such
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`a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the
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`active parent compound. Prodrugs include, for example, compounds wherein a hydroxy, amino
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`or mercapto group is bonded to any group that, when the prodrug of the active compound is
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`administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free
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`mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetates,
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`formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or
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`acetamide, formamide and benzamide derivatives of an amine functional group in the active
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`compound.
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`[0027] The term "in vivo" refers to an event that takes place in a subject's body.
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`Ex. 1012, p. 17 of 143
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`Attorney Docket No.: 055112-5002-PR-01
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`[0028] The term "in vitro" refers to an event that takes places outside of a subject's body. In
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`vitro assays encompass cell-based assays in which cells alive or dead are employed and may also
`
`encompass a cell-free assay in which no intact cells are employed.
`
`[0029] Unless otherwise stated, the chemical structures depicted herein are intended to include
`
`compounds which differ only in the presence of one or more isotopically enriched atoms. For
`
`example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or
`wherein one or more carbon atoms is replaced by 13C- or 14C-enriched carbons, are within the
`
`scope of this invention.
`
`[0030] When ranges are used herein to describe, for example, physical or chemical properties
`
`such as molecular weight or chemical formulae, all combinations and subcombinations of ranges
`
`and specific embodiments therein are intended to be included. Use of the term "about" when
`
`referring to a number or a numerical range means that the number or numerical range referred to
`
`is an approximation within experimental variability (or within statistical experimental error), and
`
`thus the number or numerical range may vary from, for example, between 1 % and 15% of the
`
`stated number or numerical range. The term "comprising" (and related terms such as "comprise"
`
`or "comprises" or "having" or "including") includes those embodiments such as, for example, an
`
`embodiment of any composition of matter, method or process that "consist of' or "consist
`
`essentially of' the described features.
`
`[0031]
`
`"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of
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`carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms
`
`(e.g., C1-C10 alkyl). Whenever it appears herein, a numerical range such as" l to 10" refers to
`
`each integer in the given range - e.g., "I to 10 carbon atoms" means that the alkyl group may
`
`consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon
`
`atoms, although the definition is also intended to cover the occurrence of the term "alkyl" where
`
`no numerical range is specifically designated. Typical alkyl groups include, but are in no way
`
`limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl,
`
`pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The