1
`
`Grun. Exh. 1050
`PGR for U.S. Patent No. 9,867,839
`
`Grün. Exh. 1011
`PGR for U.S. Patent No. 10,052,338
`
`Grün. Exh. 1012
`PGR for U.S. Patent No. 10,052,338
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Amendments to the Claims:
`
`Patent
`195860300025 CIP
`
`This listing of claims will replace all prior versions, and listings, of claims in the
`
`application:
`
`1-166. (Canceled)
`
`167.
`
`(New)
`
`A method of enhancing the oral bioavailability of zoledronic acid
`
`comprising orally administering a dosage form containing zoledronic acid in
`
`the
`
`disodium salt form.
`
`168.
`
`(New) The method of claim 167, wherein the zoledronic acid in the disodium salt
`
`form provides an enhancement to bioavailability, as compared to zoledronic acid in the
`
`diacid form, which adds to any enhancement
`
`to bioavailability provided by any
`
`bioavailability-enhancing agents in the dosage form.
`
`169.
`
`(New) The method of claim 167, wherein the zoledronic acid in the disodium salt
`
`form is administered to a mammal in an amount that provides an area under the plasma
`
`concentration curve of zoledronic acid of about 4 ng‘h/mL to about 2000 ng.h/mL to the
`
`mammal each time the zoledronic acid in the disodium salt form is administered.
`
`170.
`
`(New) The method of claim 169, wherein the zoledronic acid in the disodium salt
`
`form is administered at an interval of about 3 to about 4 weeks in an amount that
`
`provides an area under the plasma concentration curve of zoledronic acid of about 100
`
`ng-h/mL to about 2000 ng-h/mL to the mammal each time the zoledronic acid in the
`
`disodium salt form is administered.
`
`171.
`
`(New) The method of claim 169, wherein the zoledronic acid in the disodium salt
`
`form is administered weekly, or 3 to 5 times in a month, in an amount that provides an
`
`area under the plasma concentration curve of zoledronic acid of about 20 ng-h/mL to
`
`about 700 ng-h/mL to the mammal each time the zoledronic acid in the disodium salt
`
`form is administered.
`
`172.
`
`(New) The method of claim 169, wherein the zoledronic acid in the disodium salt
`
`form is administered daily in an amount
`
`that provides an area under the plasma
`
`concentration curve of zoledronic acid of about 4 ng-h/mL to about 100 ng-h/mL to the
`
`mammal each time the zoledronic acid in the disodium salt form is administered.
`
`173.
`
`(New) The method of claim 167, wherein the dosage form is a solid.
`
`2
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Patent
`195860300025 CIP
`
`174.
`
`(New) The method of claim 167, wherein the bioavailability of zoledronic acid is
`
`improved by at least about 20% as compared to administration of zoledronic acid in the
`
`diacid form.
`
`175.
`
`(New) The method of claim 167, further comprising administering, on a molar
`
`basis, less of the zoledronic acid in the disodium salt form than would be administered
`
`of zoledronic acid in the diacid form in order to achieve the same plasma levels of
`
`zoledronic acid.
`
`176.
`
`(New) The method of claim 175, wherein at least about 10 mole% less of the
`
`disodium salt form is administered as compared to the amount of zoledronic acid in the
`
`diacid form that would be administered in order to achieve the same plasma levels of
`
`zoledronic acid.
`
`177.
`
`(New) The method of claim 175, wherein the disodium salt form is administered
`
`in an amount, on a molar basis, that has a value of about 0.8ndto about 12nd, wherein:
`
`nd = (ba/bd)(na)
`
`wherein ba is the bioavailability of the diacid form, bd is the bioavailability of the
`
`disodium salt form, and n2! is the number of moles of zoledronic acid in the diacid form
`
`that would be administered in order to achieve the same plasma levels of zoledronic
`
`acid.
`
`178.
`
`(New) The method of claim 167, wherein the zoledronic acid is used to treat an
`
`inflammatory condition.
`
`179.
`
`(New) The method of claim 167, wherein the zoledronic acid is used to treat
`
`arthritis or complex regional pain syndrome.
`
`180.
`
`(New) The method of claim 167, wherein the zoledronic acid is for the treatment
`
`of an inflammatory condition, arthritis, or complex regional pain syndrome, and wherein:
`
`a first oral dosage form is administered; and
`
`a second oral dosage form is administered;
`
`3
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Patent
`195860300025 CIP
`
`wherein, with respect to the first oral dosage form, the second oral dosage form
`
`is administered at 10 x Tmax or greater, wherein Tmax is the time of maximum plasma
`
`concentration for the first oral dosage form.
`
`181.
`
`(New) An oral dosage form comprising zoledronic acid in the disodium salt form,
`
`wherein the bioavailability,
`
`in a mammal, of zoledronic acid in the disodium salt form is
`
`greater than the bioavailability of zoledronic acid in the diacid form would be in the same
`
`dosage form.
`
`182.
`
`(New) The oral dosage form of claim 181, wherein the dosage form contains an
`
`amount of zoledronic acid in the disodium salt form that provides an area under the
`
`plasma concentration curve of zoledronic acid of about 100 ng‘h/mL to about 2000
`
`ng-h/mL to a human being to which the dosage form is administered.
`
`183.
`
`(New) The oral dosage form of claim 181, wherein the dosage form contains an
`
`amount of zoledronic acid in the disodium salt form that provides an area under the
`
`plasma concentration curve of zoledronic acid of about 20 ng-h/mL to about 700
`
`ng-h/mL to a human being to which the dosage form is administered.
`
`184.
`
`(New) The oral dosage form of claim 181, wherein the dosage form contains an
`
`amount of zoledronic acid in the disodium salt form that provides an area under the
`
`plasma concentration curve of zoledronic acid of about 4 ng-h/mL to about 100 ng-h/mL
`
`to a human being to which the dosage form is administered.
`
`185.
`
`(New) The oral dosage form of claim 181, wherein the disodium salt form is
`
`present in a lower molar amount than would be present if the zoledronic acid were in the
`
`diacid form; and wherein the zoledronic acid in the disodium salt form has an improved
`
`bioavailability as compared to the zoledronic acid in the diacid form to the extent that
`
`the lower molar amount of the disodium salt in the dosage form does not reduce the
`
`amount of zoledronic acid delivered to the plasma of a mammal.
`
`186.
`
`(New) The oral dosage form of claim 185, containing at least about 20 mole%
`
`less of the disodium salt form as compared to the amount of the zoledronic acid in the
`
`diacid form that would be present if the zoledronic acid were in the diacid form.
`
`4
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Patent
`195860300025 CIP
`
`187.
`
`(New) The oral dosage form of claim 185, wherein the disodium salt form is
`
`present in an amount, on a molar basis, that has a value of about 0.9nd to about 1.1nd,
`
`wherein:
`
`nd = (ba/bd)(na)
`
`wherein ba is the bioavailability of the diacid form, bd is the bioavailability of the
`
`disodium salt form, and n8 is the number of moles of the diacid form that would be
`
`present if the zoledronic acid were in the diacid form.
`
`188.
`
`(New)
`
`The oral dosage form of claim 187, wherein the disodium salt
`
`is
`
`administered in an amount that has a value of about nd.
`
`189.
`
`(New) The oral dosage form of claim 181, wherein the dosage form is a solid.
`
`190.
`
`(New)
`
`The oral dosage form of claim 181, wherein the bioavailability of
`
`zoledronic acid in the disodium salt form is
`
`improved by at
`
`least about 10% as
`
`compared to an othen/vise identical dosage form containing zoledronic acid in the diacid
`
`form.
`
`191.
`
`(New) The method of claim 167, wherein the zoledronic acid is for the treatment
`
`of an inflammatory condition, arthritis, or complex regional pain syndrome, and wherein:
`
`only a single oral dosage form is administered; or
`
`a first oral dosage form is administered, and a second oral dosage form is
`
`administered after the first oral dosage form;
`
`wherein the second oral dosage form is administered before the maximum
`
`pain relieving effect of the first oral dosage form is achieved, or the second oral
`
`dosage form is administered before an observable pain relieving effect
`
`is
`
`achieved.
`
`192.
`
`(New) The method of claim 191 wherein the second oral dosage form is
`
`administered before an observable pain relieving effect is achieved.
`
`193.
`
`(New) The method of claim 167, wherein the zoledronic acid is for the treatment
`
`of an inflammatory condition, arthritis, or complex regional pain syndrome, and
`
`5
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Patent
`195860300025 CIP
`
`wherein a first oral dosage form is administered, followed by administration of a
`
`second oral dosage form;
`
`wherein the second oral dosage form is administered after the maximum pain
`
`relieving effect of the first oral dosage form is achieved; and
`
`the second oral dosage form is administered while a pain relieving effect from the
`
`first oral dosage form is observable.
`
`194.
`
`(New) The method of claim 193, wherein the second oral dosage form is
`
`administered about 24 hours to about 28 days after the first oral dosage form is
`
`administered.
`
`195.
`
`(New) The oral dosage form of claim 181, wherein the zoledronic acid in the oral
`
`dosage form has a 24 hour sustained plasma level factor of about 1 or higher.
`
`196.
`
`(New) The oral dosage form of claim 181, wherein the zoledronic acid in the
`
`oral dosage form has a 24 hour sustained plasma level factor that is higher than that of
`
`intravenously administered zoledronic acid.
`
`6
`
`

`

`Appl. No.:
`Preliminary Amendment
`
`Patent
`195860300025 CIP
`
`REMARKS/ARGUMENTS
`
`Claims 1-166 have been cancelled in this application. Claims 167-196 have
`
`been added as new.
`
`Applicants respectfully assert that the pending claims are in condition for
`
`allowance and request that a timely Notice of Allowance be issued in this case.
`
`The Commissioner is authorized to charge any fee which may be required in
`
`connection with this Amendment to deposit account No. 50-3207.
`
`Respectfully submitted,
`
`Dated: 25 October 2013
`
`/Brent A. Johnson/
`
`Brent A. Johnson, Ph.D.
`
`Registration No. 51851
`CUSTOMER NUMBER: 45,200
`
`K&L GATES LLP
`1 Park Plaza, 12th Floor
`Irvine, California 92614
`
`(949) 253-0900
`Telephone:
`Facsimile: (949) 253-0902
`
`7
`
`

`

`COMPOSITIONS FOR ORAL ADMINISTRATION OF ZOLEDRONIC ACID OR
`RELATED COMPOUNDS FOR TREATING DISEASE
`
`Patent Application
`195860300025
`
`inventor: Herriot Tabuteau
`
`CROSS—REFERENCE TO RELATED APPLICATIONS
`
`[001]
`
`This application is a continuation-in-part of United States Patent
`
`Application No. 13/894,274, filed May 14, 2013, which claims the benefit of
`
`United States Provisional Applications 61/646,538,
`
`filed May 14, 2012;
`
`61/647,478, filed May 15, 2012; 61/654,292, filed June 1, 2012; 61/654,383, filed
`
`June 1, 2012; 61/655,527, filed June 5, 2012; 61/655,541, filed June 5, 2012;
`
`61/764,563,
`
`filed February 14, 2013; 61/762,225,
`
`filed February 7, 2013;
`
`61/767,647, filed February 21, 2013; 61/767,676, filed February 21, 2013; and
`
`61/803,721, filed March 20, 2013, all of which are incorporated by reference in
`
`their entirety herein.
`
`BACKGROUND
`
`[002]
`
`Bisphosphonate compounds are potent inhibitors of osteoclast
`
`activity, and are used clinically to treat bone-related conditions such as
`
`osteoporosis and Paget’s disease of bone; and cancer-related conditions
`
`including multiple myeloma, and bone metastases from solid tumors. They
`
`generally have low oral bioavailability.
`
`SUMMARY
`
`[003]
`
`It
`
`has
`
`been
`
`discovered
`
`that
`
`oral
`
`dosage
`
`forms
`
`of
`
`bisphosphonate compounds, such as zoledronic acid, can be used to treat or
`
`alleviate pain or related conditions.
`
`[004]
`
`Some embodiments include a method of enhancing the oral
`
`bioavailability of zoledronic acid comprising orally administering a dosage form
`
`containing zoledronic acid in the disodium salt form.
`
`[005]
`
`Some
`
`embodiments
`
`include
`
`a dosage form comprising
`
`zoledronic acid in the disodium salt
`
`form, wherein the bioavailability,
`
`in a
`
`8
`
`

`

`Patent Application
`195860300025
`
`mammal, of zoledronic acid in the disodium salt
`
`form is greater than the
`
`bioavailability of zoledronic acid in the diacid form would be in the same dosage
`
`form.
`
`[006]
`
`Some
`
`embodiments
`
`include
`
`a dosage form comprising
`
`zoledronic acid in the disodium salt form, wherein the dosage form contains an
`
`amount of zoledronic acid in the disodium salt form that provides an area under
`
`the plasma concentration curve of zoledronic acid of about 4 ng‘h/mL to about
`
`2000 ng-h/mL to a human being to which the dosage form is administered.
`
`[007]
`
`Some
`
`embodiments
`
`include
`
`a dosage form comprising
`
`zoledronic acid in the disodium salt form, wherein the disodium salt form is
`
`present in a lower molar amount than would be present if the zoledronic acid
`
`were in the diacid form; and wherein the zoledronic acid in the disodium salt form
`
`has an improved bioavailability as compared to the zoledronic acid in the diacid
`
`form to the extent that the lower molar amount of the disodium salt in the dosage
`
`form does not reduce the amount of zoledronic acid delivered to the plasma of a
`
`mammal.
`
`[008]
`
`Although an oral dosage form with enhanced bioavailability with
`
`respect to the bisphosphonate compound can be used, the treatment can also be
`
`effective using an oral dosage form that includes a bisphosphonate compound,
`
`such as zoledronic acid, wherein the bioavailability of the bisphosphonate is
`
`unenhanced, or is substantially unenhanced.
`
`[009]
`
`Some embodiments include a method of relieving inflammatory
`
`pain comprising administering an oral dosage form containing zoledronic acid to
`
`a mammal
`
`in need thereof, wherein the mammal experiences significant pain
`
`relief more than 3 hours after administration of the dosage form.
`
`[010]
`
`Some
`
`embodiments
`
`include
`
`a method of
`
`relieving
`
`pain
`
`associated with an arthritis comprising administering an oral dosage form
`
`containing zoledronic acid to a human being in need thereof.
`
`9
`
`

`

`Patent Application
`195860300025
`
`[011]
`
`Some embodiments include a method of treating complex
`
`regional pain syndrome comprising administering an oral dosage form containing
`
`zoledronic acid to a mammal in need thereof.
`
`[012]
`
`Some embodiments include an oral dosage form comprising
`
`zoledronic acid, wherein the oral bioavailability of zoledronic acid is substantially
`
`unenhanced. For example, in some embodiments, the oral bioavailability in the
`
`dosage form is about 0.01% to about 4%.
`
`[013]
`
`Some
`
`embodiments
`
`include
`
`a
`
`pharmaceutical
`
`product
`
`comprising more than one unit of an oral dosage form described herein.
`
`In some
`
`embodiments, each unit of the oral dosage form contains about 1 mg to about 50
`
`mg of zoledronic acid.
`
`[014]
`
`Some embodiments include a method of relieving inflammatory
`
`pain comprising administering an oral dosage form containing zoledronic acid to
`
`a mammal in need thereof.
`
`[015]
`
`In some embodiments,
`
`the mammal receives a total monthly
`
`dose of zoledronic acid that is about 800 mg/m2 or less.
`
`[016]
`
`In some embodiments,
`
`the dosage form contains about 10
`
`mg/m2 to about 20 mg/m2 based upon the body surface area of the mammal.
`
`[017]
`
`Some embodiments include a method of relieving inflammatory
`
`pain comprising orally administering zoledronic acid to a mammal
`
`in need
`
`thereof.
`
`[018]
`
`In some embodiments, about 300 mg/m2 to about 600 mg/m2 of
`
`zoledronic acid is administered per month, based upon the body surface area of
`
`the mammal.
`
`[019]
`
`In some embodiments, about 50 mg/m2 to about 600 mg/m2 of
`
`zoledronic acid is administered per month, based upon the body surface area of
`
`the mammal.
`
`10
`
`10
`
`

`

`BRIEF DESCRIPTION OF DRAWINGS
`
`Patent Application
`195860300025
`
`[020]
`
`FIG. 1
`
`is a plot of pain compression thresholds in a rat model of
`
`inflammatory pain using three different doses of zoledronic acid. Measurements
`
`were taken at baseline (BL) and at various time points after dosing on the days
`
`indicated.
`
`[021]
`
`FIG. 2A is a graph depicting reversal of arthritis pain for two
`
`different doses of zoledronic acid in a rat model of arthritis pain.
`
`[022]
`
`FIG. 28 is a graph depicting pain thresholds for two different
`
`doses of zoledronic acid in a rat model of arthritis pain.
`
`[023]
`
`FIG. 3 is a graph summarizing the results for vehicle and
`
`zoledronic acid treated rats in a rat model of complex regional pain syndrome.
`
`[024]
`
`FIG. 4 depicts hindpaw pain thresholds for vehicle and
`
`zoledronic acid treated rats in a rat model of complex regional pain syndrome.
`
`[025]
`
`FIG. 5 depicts weight bearing for vehicle and zoledronic acid
`
`treated rats in a rat model of complex regional pain syndrome.
`
`[026]
`
`FIG. 6 depicts paw thickness change for vehicle and zoledronic
`
`acid treated rats in a rat model of complex regional pain syndrome.
`
`[027]
`
`FIG. 7 depicts the aqueous solubility of disodium zoledronate
`
`tetrahydrate as compared to the diacid form of zoledronic acid.
`
`[028]
`
`FIG. 8 depicts the plasma concentration of zoledronic acid in
`
`dogs over time after administration of 150 mg of the disodium salt form of
`
`zoledronic acid and the diacid form of zoledronic acid.
`
`[029]
`
`FIG. 9 depicts the compressibility of dosage forms containing
`
`zoledronic acid in the disodium salt form as compared to the diacid form.
`
`DETAILED DESCRIPTIQN
`
`[030]
`
`Bisphosphonate
`
`compounds
`
`such
`
`as
`
`pamidronate
`
`or
`
`pamidronic acid, neridronate or neridronic acid, olpadronate or olpadronic acid,
`
`alendronate or alendronic acid,
`
`incadronate or incadronic acid,
`
`ibandronate or
`
`11
`
`11
`
`

`

`Patent Application
`195860300025
`
`ibandronic acid, risedronate or risedronic acid, zoledronate or zoledronic acid,
`
`etidronate or etidronic acid, clodronate or clodronic acid, tiludronate or tiludronic
`
`acid, etc., may be used for a number of medical purposes, such as treatment of
`
`undesirable conditions or diseases,
`
`including pain relief.
`
`This may be
`
`accomplished in many instances by administration of oral dosage forms.
`
`Generally, an oral dosage form comprising a bisphosphonate such as zoledronic
`
`acid is administered orally to a mammal, such as a human being, at least once,
`
`to treat a disease or condition, or to relieve pain.
`
`[031]
`
`The term “treating” or “treatment” broadly includes any kind of
`
`treatment activity,
`
`including the diagnosis, cure, mitigation, or prevention of
`
`disease in man or other animals, or any activity that otherwise affects the
`
`structure or any function of the body of man or other animals.
`
`[032]
`
`An oral dosage form of a bisphosphonate such as zoledronic
`
`acid may be used to treat, or provide relief of, any type of pain including, but not
`
`limited to,
`
`inflammatory pain, arthritis pain, complex regional pain syndrome,
`
`lumbosacral pain, musculoskeletal pain, neuropathic pain, chronic pain, cancer-
`
`related pain, acute pain, postoperative pain, etc.
`
`In some instances, pain relief
`
`may be palliative, or pain relief may be provided independent of improvement of
`
`the disease or condition or the underlying cause of the disease or condition. For
`
`example, although the underlying disease may not improve, or may continue to
`
`progress, an individual suffering from the disease may experience pain relief.
`
`In
`
`some embodiments, enhanced bioavailability of the zoledronic acid may be
`
`achieved in treating one of these conditions by administering a dosage form
`
`comprising zoledronic acid in the form of a disodium salt. This may allow a
`
`reduced molar amount of the disodium salt to be used as compared to what
`
`would be used with the diacid form.
`
`[033]
`
`In some embodiments,
`
`the mammal being treated is not
`
`suffering from bone metastasis.
`
`In some embodiments,
`
`the mammal being
`
`treated is not suffering from cancer.
`
`In some embodiments, the mammal being
`
`treated is not suffering from osteoporosis.
`
`12
`
`12
`
`

`

`Patent Application
`195860300025
`
`[034]
`
`For example, zoledronic acid or another bisphosphonate may
`
`be administered orally to relieve musculoskeletal pain including low back pain,
`
`and pain associated with rheumatoid arthritis,
`
`juvenile rheumatoid arthritis,
`
`osteoarthritis,
`
`erosive
`
`osteoarthritis,
`
`sero-negative
`
`(non-rheumatoid)
`
`arthropathies,
`
`non—articular
`
`rheumatism,
`
`peri—articular
`
`disorders,
`
`axial
`
`spondyloarthritis
`
`including ankylosing spondylitis, Paget’s disease,
`
`fibrous
`
`dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush
`
`fractures, osteoporosis, etc.
`
`In some embodiments, enhanced bioavailability of
`
`the zoledronic acid may be achieved in treating one of these conditions by
`
`administering a dosage form comprising zoledronic acid in the form of a disodium
`
`salt. This may allow a reduced molar amount of the disodium salt to be used as
`
`compared to what would be used with the diacid form.
`
`[035]
`
`In
`
`some
`
`embodiments,
`
`zoledronic
`
`acid
`
`or
`
`another
`
`bisphosphonate may also be administered orally to relieve neuropathic pain,
`
`including diabetic peripheral neuropathy, post—herpetic neuralgia,
`
`trigeminal
`
`neuralgia, monoradiculopathies, phantom limb pain, and central pain. Other
`
`causes of neuropathic pain include cancer-related pain,
`
`lumbar nerve root
`
`compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain,
`
`HIV-associated neuropathy, and radio-therapy or chemo-therapy associated
`
`neuropathy.
`
`In some embodiments, enhanced bioavailability of the zoledronic
`
`acid may be achieved in treating one of these conditions by administering a
`
`dosage form comprising zoledronic acid in the form of a disodium salt. This may
`
`allow a reduced molar amount of the disodium salt to be used as compared to
`
`what would be used with the diacid form.
`
`[036]
`
`In
`
`some
`
`embodiments,
`
`zoledronic
`
`acid
`
`or
`
`another
`
`bisphosphonate may be administered orally to relieve inflammatory pain
`
`including musculoskeletal pain, arthritis pain, and complex regional pain
`
`syndrome.
`
`In some embodiments, enhanced bioavailability of the zoledronic acid
`
`may be achieved in treating one of these conditions by administering a dosage
`
`form comprising zoledronic acid in the form of a disodium salt. This may allow a
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`Patent Application
`195860300025
`
`reduced molar amount of the disodium salt to be used as compared to what
`
`would be used with the diacid form.
`
`[037]
`
`Examples of musculoskeletal pain include low back pain; and
`
`pain associated with vertebral crush fractures, fibrous dysplasia, osteogenesis
`
`imperfecta, Paget’s disease of bone,
`
`transient osteoporosis, and transient
`
`osteoporosis of the hip.
`
`[038]
`
`Arthritis
`
`refers to inflammatory joint diseases that can be
`
`associated with pain. Examples of arthritis pain include pain associated with
`
`osteoarthritis, erosive osteoarthritis,
`
`rheumatoid arthritis,
`
`juvenile rheumatoid
`
`arthritis, sero—negative (non—rheumatoid) arthropathies, non—articular rheumatism,
`
`peri-articular disorders, neuropathic arthropaties including Charcot’s foot, axial
`
`spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.
`
`[039]
`
`In some embodiments, a human being that is treated for arthritis
`
`by an oral dosage form of zoledronic acid has an age of about 10 years to about
`
`90 years, about 20 years to about 80 years, about 30 years to about 75 years
`
`old, about 40 years to about 70 years, about 1 year to about 16 years, or about
`
`80 years to about 95 years.
`
`[040]
`
`In some embodiments, a human being that is treated for arthritis
`
`by an oral dosage form of zoledronic acid has suffered from the arthritis for at
`
`least 1 month, at least 2 months, at least 6 months, or at least 1 year.
`
`[041]
`
`In some embodiments, the arthritis affects, a knee, an elbow, a
`
`wrist, a shoulder, or a hip.
`
`[042]
`
`In
`
`some
`
`embodiments,
`
`zoledronic
`
`acid
`
`or
`
`another
`
`bisphosphonate may be administered orally to relieve complex regional pain
`
`syndrome, such as complex regional pain syndrome type I
`
`(CRPS—I), complex
`
`regional pain syndrome type II (CRPS—II), CRPS-NOS, or another type of CRPS.
`
`CRPS is a type of inflammatory pain. CRPS can also have a neuropathic
`
`component.
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`Patent Application
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`[043]
`
`Complex regional
`
`pain
`
`syndrome
`
`is
`
`a
`
`debilitating
`
`pain
`
`syndrome.
`
`It
`
`is characterized by severe pain in a limb accompanied by edema,
`
`and autonomic, motor and sensory changes.
`
`[044]
`
`With respect to use of oral zoledronic acid for relieving pain
`
`associated with an inflammatory condition, relief of pain can be short-term, e.g.
`
`for a period of hours after administration of the dosage form, and/or relief of pain
`
`can be long—term, e.g.
`
`lasting for days, weeks, or even months after oral
`
`administration of zoledronic acid.
`
`In some embodiments, a mammal, such as a
`
`human being, experiences significant pain relief at least about 3 hours, at least
`
`about 6 hours, at least about 12 hours, at least about 24 hours, at least about 48
`
`hours, at least about one week, at least about 2 weeks, or at least about 3 weeks
`
`after administration of an oral dosage form comprising zoledronic acid.
`
`In some
`
`embodiments, a mammal, such as a human being, experiences significant pain
`
`relief during at least part of the time from about 3 hours to about 2 weeks, about
`
`3 hours to about 3 weeks, about 3 hours to about 24 hours, about 6 hours to
`
`about 2 weeks, or about 6 hours to about 24 hours, about 3 days to about 2
`
`weeks, about 6 days to about 2 weeks, after administration of an oral dosage
`
`form comprising zoledronic acid.
`
`[045]
`
`With respect to the treatment of any condition recited herein, in
`
`some embodiments a first oral dosage form comprising zoledronic acid is
`
`administered and a second oral dosage form comprising oral zoledronic acid is
`
`administered. The timing of the administration of the two dosage forms may be
`
`such that, with respect to the first oral dosage form, the second oral dosage with
`
`respect to the first oral dosage form, the second oral dosage form is administered
`
`at 5 x Tmax or greater (e.g., if Tmax is 1 hour, at 5 hours or later), at least 10 x Tmax
`
`or greater, at least about 15 x Tmax or greater, at least about 20 x Tmax or greater,
`
`at least about 50 X Tmax or greater, or at least about 200 X Tmax or greater,
`
`wherein Tmax is the time of maximum plasma concentration for the first oral
`
`dosage
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`Patent Application
`195860300025
`
`[046]
`
`Some embodiments include treatment of a condition recited
`
`herein, such as inflammatory pain, arthritis, or complex regional pain syndrome,
`
`wherein the treatment comprises either: administering only one dosage form to a
`
`mammal
`
`to treat
`
`the condition, or administering a first dosage form to the
`
`mammal, followed by administering a second dosage form to the mammal.
`
`If two
`
`or more dosage forms are administered,
`
`the second oral dosage form is
`
`administered before the maximum pain relieving effect of the first oral dosage
`
`form is achieved, or before a peak in the pain relieving effect of the first oral
`
`dosage form is experienced by a mammal, receiving the dosage form.
`
`In some
`
`embodiments, the second oral dosage form is administered before an observable
`
`pain relieving effect is achieved.
`
`In some embodiments, the second dosage form
`
`is administered about 12 hours to about 60 days, about 24 hours to about 28
`
`days, about 24 hours to about 7 days, about 24 hours to about 14 days, or about
`
`24 hours to about 21 days, after the first dosage form is administered.
`
`[047]
`
`Some embodiments include treatment of a condition recited
`
`herein, such as inflammatory pain, arthritis, or complex regional pain syndrome,
`
`wherein the treatment comprises administering a first dosage form to the
`
`mammal, followed by administering a second dosage form to the mammal,
`
`wherein the second dosage form is administered after the maximum pain
`
`relieving effect of the first oral dosage form is achieved, and the second oral
`
`dosage form is administered while the mammal
`
`is still experiencing pain relief
`
`from the first oral dosage form, or while the pain relieving effect from the first oral
`
`dosage form is observable.
`
`In some embodiments, the second dosage form is
`
`administered about 12 hours to about 60 days, about 24 hours to about 28 days,
`
`about 24 hours to about 7 days, about 24 hours to about 14 days, or about 24
`
`hours to about 21 days, after the first dosage form is administered.
`
`[048]
`
`Zoledronic acid or another bisphosphonate may also be
`
`administered orally to relieve cancer-related pain, including pain associated with
`
`multiple myeloma
`
`and bone metastases
`
`from solid tumors.
`
`In
`
`some
`
`embodiments, zoledronic acid is used to treat pain that is not cancer-related pain.
`
`For example, zoledronic acid may be used to treat pain that is not associated
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`Patent Application
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`with multiple myeloma, bone metastasis from solid tumors, hypercalcemia of
`
`malignancy, giant cell tumor of bone, blood cancers or Ieukemias, or solid tumors
`
`or cancers.
`
`In some embodiments, enhanced bioavailability of the zoledronic
`
`acid may be achieved in treating one of these conditions by administering a
`
`dosage form comprising zoledronic acid in the form of a disodium salt. This may
`
`allow a reduced molar amount of the disodium salt to be used as compared to
`
`what would be used with the diacid form.
`
`[049]
`
`In addition to relieving pain, oral administration of zoledronic
`
`acid or another bisphosphonate may also be useful
`
`to treat diseases or
`
`conditions that may or may not
`
`include a pain component.
`
`For example,
`
`zoledronic acid or another bisphosphonate may be useful to treat any of the pain
`
`conditions or types of conditions listed above, including treatment that does not
`
`simply relieve the pain of those conditions, and treatment that is carried out in
`
`such a way that the condition is treated without pain relief occurring.
`
`In addition
`
`to any pain relief zoledronic acid or another bisphosphonate may or may not
`
`provide, zoledronic acid or another bisphosphonates may be used to treat a
`
`disease or condition such as a metabolic disease or condition; an inflammatory
`
`disease or condition,
`
`including an inflammatory disease or condition that is not
`
`associated with pain; a cancer disease or condition; a neurological disease or
`
`condition; etc.
`
`In some embodiments, enhanced bioavailability of the zoledronic
`
`acid may be achieved in treating one of these conditions by administering a
`
`dosage form comprising zoledronic acid in the form of a disodium salt. This may
`
`allow a reduced molar amount of the disodium salt to be used as compared to
`
`what would be used with the diacid form.
`
`[050]
`
`In some embodiments, oral administration of zoledronic acid or
`
`another bisphosphonate may also be useful
`
`to treat complex regional pain
`
`syndrome,
`
`rheumatoid arthritis, osteoarthritis,
`
`erosive osteoarthritis,
`
`axial
`
`spondyloarthritis including ankylosing spondylitis, acute vertebral crush fracture,
`
`fibrous dysplasia, SAPHO syndrome, osteoporosis,
`
`transient osteoporosis, or
`
`transient osteoporosis
`
`of
`
`the
`
`hip.
`
`In
`
`some
`
`embodiments,
`
`enhanced
`
`bioavailability of the zoledronic acid may be achieved in treating one of these
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`

`Patent Application
`195860300025
`
`conditions by administering a dosage form comprising zoledronic acid in the form
`
`of a disodium salt. This may allow a reduced molar amount of the disodium salt
`
`to be used as compared to what would be used with the diacid form.
`
`[051]
`
`In some embodiments, oral administration of zoledronic acid or
`
`another bisphosphonate may also be useful
`
`to treat hypercalcemia of
`
`malignancy, multiple myeloma, bone metastases from solid tumors, Paget’s
`
`disease of bone, giant cell tumor of bone, blood cancers or leukemias, or solid
`
`tumors or cancers.
`
`In some embodiments, enhanced bioavailability of the
`
`zoledronic acid may be achieved in
`
`treating one of
`
`these conditions by
`
`administering a dosage form comprising zoledronic acid in the form of a disodium
`
`salt. This may allow a reduced molar amount of the disodium salt to be used as
`
`compared to what would be used with the diacid form.
`
`[052]
`
`Zoledronic acid has the structure shown below, and is also
`
`referred to as zoledronate.
`
`{1‘
`
`‘3
`
`Zoledronic acid
`
`[053]
`
`Unless otherwise indicated, any reference to a compound
`
`herein, such as zoledronic acid, by structure, name, or any other means, includes
`
`pharmaceutically acceptable salts, such as the disodium salt; alternate solid
`
`forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other
`
`chemical species that may rapidly convert to a compound described herein under
`
`conditions in which the compounds are used as described herein.
`
`1’]
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`Patent Application
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`
`[054]
`
`In some embodiments, zoledronic acid is administered in a
`
`dosage form comprising a salt form, such as a salt of a dianion of zoledronic
`
`acid.
`
`In some embodiments, zoledronic acid is administered in a dosage form
`
`comprising a disodium salt form of zoledronic acid.
`
`In some embodiments,
`
`zoledronic acid is administered in a sodium salt form, such as a monosodium
`
`salt