Doc Code: TRACK1.REQ
`Document Description: TrackOne Request
`
`PTO/AlA/424 (04-14)
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`
`UNDER 37 CFR 1.102(e) (Page 1 of 1)
`
`PIN d
`
`-
`
`N
`
`"
`
`IA I'
`
`I'
`
`N
`
`D
`
`'f
`
`CO-ADMINISTRATION OF STEROIDS AND ZOLEDRONIC ACID TO PREVENT AND TREAT PAIN
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`1. The processing fee set forth in 37 CFR 1.17(i)(1) and the prioritized examination fee set forth in
`37 CFR 1.17(c) have been filed with the request. The publication fee requirement is met
`because that fee, set forth in 37 CFR 1.18(d), is currently $0. The basic filing fee, search fee,
`and examination fee are filed with the request or have been already been paid.
`I understand
`that any required excess claims fees or application size fee must be paid for the application.
`
`I understand that the application may not contain, or be amended to contain, more than four
`independent claims, more than thirty total claims, or any multiple dependent claims, and that
`any request for an extension of time will cause an outstanding Track | request to be dismissed.
`
`3. The applicable box is checked below:
`
`Ori
`
`inal Ao olication Track One - Prioritized Examination under ~
`
`i.
`
`(a) The application is an original nonprovisional utility application filed under 35 U.S.C. 111(a).
`This certification and request is being filed with the utility application via EFS—Web.
`___OR___
`
`(b) The application is an original nonprovisional plant application filed under 35 U.S.C. 111(a).
`This certification and request is being filed with the plant application in paper.
`
`ii. An executed inventor’s oath or declaration under 37 CFR 1.63 or 37 CFR 1.64 for each
`
`inventor, g the application data sheet meeting the conditions specified in 37 CFR 1.53(f)(3)(i) is
`filed with the application.
`
`Re uest for Continued Examination - Prioritized Examination under
`
`.
`
`'
`
`A request for continued examination has been filed with, or prior to, this form.
`If the application is a utility application, this certification and request is being filed via EFS-Web.
`The application is an original nonprovisional utility application filed under 35 U.S.C. 111(a), or is
`a national stage entry under 35 U.S.C. 371.
`. This certification and request is being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`No prior request for continued examination has been granted prioritized examination status
`under 37 CFR 1.102(e)(2).
`
`
`
`
`Signature/Brent A. Johnson/
`DateNovember 21, 2016
`
`Name
`(Print/Typed)
`
`Brent A. Johnson
`
`Practi‘imr
`Registration Number
`
`51851
`
`This form must be signed in accordance with 37 CFR 1.33. See 37 CFR 1.4(d) for signature requirements and certifications.
`Note:
`Submit multile forms if more than one sinature is re-uired. *
`
`*Total of
`
`1
`
`forms are submitted.
`
`Griin. Exh. 1033
`
`PGR for U.S. Patent No. 10,052,338
`
`1
`
`Grün. Exh. 1033
`PGR for U.S. Patent No. 10,052,338
`
`

`

`Privacy Act Statement
`
`The Privacy Act of 1974 (P.L. 93-579) requires that you be given certain information in connection with your
`submission of the attached form related to a patent application or patent. Accordingly, pursuant to the requirements of
`the Act, please be advised that: (1) the general authority forthe collection ofthis information is 35 U.S.C. 2(b)(2); (2)
`furnishing ofthe information solicited is voluntary; and (3) the principal purpose for which the information is used by the
`US. Patent and Trademark Office is to process and/or examine your submission related to a patent application or
`patent.
`If you do not furnish the requested information, the US Patent and Trademark Office may not be able to
`process and/or examine your submission, which may result in termination of proceedings or abandonment ofthe
`application or expiration of the patent.
`
`The information provided by you in this form will be subject to the following routine uses:
`
`1. The information on this form will be treated confidentially to the extent allowed underthe Freedom of
`Information Act (5 U.S.C. 552) and the Privacy Act (5 U.S.C 552a). Records from this system of records may
`be disclosed to the Department ofJustice to determine whether disclosure ofthese records is required by the
`Freedom of Information Act.
`A record from this system of records may be disclosed, as a routine use, in the course of presenting evidence
`to a court, magistrate, or administrative tribunal, including disclosures to opposing counsel in the course of
`settlement negotiations.
`A record in this system of records may be disclosed, as a routine use, to a Member of Congress submitting a
`request involving an individual, to whom the record pertains, when the individual has requested assistance from
`the Member with respect to the subject matter ofthe record.
`A record in this system of records may be disclosed, as a routine use, to a contractor ofthe Agency having
`need forthe information in orderto perform a contract. Recipients of information shall be required to comply
`with the requirements of the Privacy Act of 1974, as amended, pursuant to 5 U.S.C. 552a(m).
`A record related to an International Application filed underthe Patent Cooperation Treaty in this system of
`records may be disclosed, as a routine use, to the International Bureau ofthe World Intellectual Property
`Organization, pursuant to the Patent Cooperation Treaty.
`A record in this system of records may be disclosed, as a routine use, to another federal agency for purposes
`of National Security review (35 U.S.C. 181) and for review pursuant to the Atomic Energy Act (42 U.S.C.
`218(c)).
`A record from this system of records may be disclosed, as a routine use, to the Administrator, General
`Services, or his/her designee, during an inspection of records conducted by GSA as part ofthat agency’s
`responsibility to recommend improvements in records management practices and programs, under authority of
`44 U.S.C. 2904 and 2906. Such disclosure shall be made in accordance with the GSA regulations governing
`inspection of records forthis purpose, and any other relevant (i.e., GSA or Commerce) directive. Such
`disclosure shall not be used to make determinations about individuals.
`A record from this system of records may be disclosed, as a routine use, to the public afler either publication of
`the application pursuant to 35 U.S.C. 122(b) or issuance ofa patent pursuant to 35 U.S.C. 151. Further, a
`record may be disclosed, subject to the limitations of 37 CFR 1.14, as a routine use, to the public ifthe record
`was filed in an application which became abandoned or in which the proceedings were terminated and which
`application is referenced by either a published application, an application open to public inspection or an issued
`patent.
`A record from this system of records may be disclosed, as a routine use, to a Federal, State, or local law
`enforcement agency, if the USPTO becomes aware of a violation or potential violation of law or regulation.
`
`2
`
`

`

`1/14
`
`195880330227
`
`180
`
`150
`
`140
`
`129
`
`100
`
`so
`
`
`
`MeanPawCcmpresgicmThreshoidg(g)
`
`Fifi; ’E
`
`Vemcm
`@
`------wu- Zciedmnic acid 18 mg/msq.
`.»
`Zomdronk2acfl 1201Tghnsq.
`x
`Zciedmnic acid 900 rrg/msq.
`
`
`
`Day?
`BL
`
`Day1
`(9.5m)
`
`Day1
`(1hr)
`
`Day1
`(Shfi
`
`DayZ
`BL
`
`Dayz
`(1hfi
`
`Dayfi
`BL
`
`DayB
`(1hfi
`
`3
`
`

`

`2/14
`
`195880330227
`
`30%
`
`%Reversaia?ArthitisPain 2%
`
`40%
`
`19%
`
`Zciedmnic
`
`acid 54
`2
`
`mg/m
`
`Zaiedmnic
`
`acid 360
`2
`
`mgim
`
`6%
`
`Fifi. 2A
`
`4
`
`

`

`3/14
`
`195880330227
`
`
`
`UE‘s‘é‘sfi‘Afhreshaid(g;
`
`29:13
`
`250
`
`23x;
`
`1m
`
`21$
`
`193
`
`Narmal Paw
`
`VehECEe
`
`Zniedmnic
`Zniedmnic
`acid 54 mgj’n‘i2 acid 350 rragjrw‘a2
`
`159
`
`Hi3. EB
`
`5
`
`

`

`4/14
`
`195880330227
`
`cantrm
`
`%Changevs.
`
`Pain
`
`Edema
`
`Warmth
`
`Weight
`
`Beafing
`
`6
`
`

`

`5/14
`
`195880330227
`
`£93mThreshaid{g} awwwa‘mmwmm
`Hindpaw
`
`Vehicie
`
`Zaiedrcnic acid
`
`PEG. 4
`
`Q Left Paw (Nmmai)
`
`fi Right Paw (Fracture)
`
`7
`
`

`

`6/14
`
`195880330227
`
`
`
`WeightBearing
`
`(%2
`
`Vehide
`
`Zciedmnéc acid
`
`8
`
`

`

`7/14
`
`195880330227
`
`{mm}
`
`PawThEckneSs{Zhange
`
`Vehicie
`
`Zafledmnic acid
`
`9
`
`

`

`8/14
`
`195880330227
`
`{g/199ml}
`Scfiubmty
`
`Zfifledmnic add
`
`Bisadium zefledmnate
`
`tetrahyd rate
`
`PEG. 3’
`
`10
`
`10
`
`

`

`9/14
`
`195880330227
`
`m\\\\\w15€§ mg ~ Disadéum mfiarfi masts
`
`«~\\~m15{§ mg - Eaiemémnia MM
`
`\\\
`
`
`2's
`
`
`
`F5823. 3
`
`11
`
`11
`
`
`
`

`

`18/14
`
`195880330227
`
`
`
`
`
`
`
`
`
`Ma» 5’»
`
`fl
`
`§
`
`L
`
`i
`i
`1
`i
`
`”a? M
`i
`a
`5
`~....
`“I
`m
`a: 12 i
`g
`!
`"a m
`:3
`a
`:3:
`'
`+4
`8 "1
`.92.
`i
`Q R
`g
`g b
`=
`4 _‘
`
`,,
`
`j
`
`.
`
`‘
`
`“I
`
`I “
`
`r
`
`a
`g“““““““““““
`
`.y'
`
`“as;
`
`,
`,5
`1;”
`
`‘1
`
`1
`
`“F
`
`.49 a
`
`m ,— "
`
`,. _, ‘“ °"” '“ '” _,.
`.....................................
`
`""""""""""""
`
`““““
`
`was mg [Eisedium Saki
`
`------- 56 mg Diacid
`fl
`_
`‘
`,
`-- - 71 mg Disodium bait
`
`l":
`m
`
`i
`
`i
`.
`{3 +7”:77777rww77777F"’1""’1""T’"’1""’r’"’T""r""1""’Y""T’W’1’"’T""T""r""1’""r777777777‘177777r’W‘v?????r""IW"’Y"”r”"1"”r””1
`G
`”330.0
`23633
`3005
`409-3
`5960.
`8883
`{tempressiaa Fame £33253
`
`12
`
`12
`
`

`

`11/14
`
`195880330227
`
`Ehanga if: VAS Pam Scare fiamgared m fiaceha
`wifih zafiefimfififi Add Treatmmt
`
`GARE Grade €15
`
`GEERSE Grams “L2
`
`
`WASChangevs.PiacefimEmmi {.032::C?)
`
`
`
`91.2. N C?
`
`4334}
`
`
`
`45.6}
`
`FEG. ”$9
`
`13
`
`13
`
`

`

`12/14
`
`195880330227
`
`{Shange if: ‘e’AS @aifi 3mm Eamgared m Bagefiifig
`wifih zafiefimfififi Add Treatmmt
`
`(EARS! firade 2
`QARSE mafia I
`{EARSE Grazia i3
`
`
`8.3
`
`.fiaseiineimm) I
`
`
`
`VA?»fihangeus
`
`wL?! C?)
`
`~23.§
`
`14
`
`14
`
`

`

`13/14
`
`195880330227
`
`9
`
`an“
`
`Rnuws@mmmEmuCwmgaSiRQm.mm
`
`2B
`
` emmmm(mmL...“ma.
`
`
`«aac%,r
`
`av
`
`map
`
`Be
`
`
`
` ET:H»vs:S332“wt5MBAasVcmWma“3mm%ST%umcat
`
`9A5ammna\\\\0\
`gE.BA
`
`cmfluxA\Mnmm“\mxxmmn“\m“mm\x
`
`aan“E
`
`
`
`NEE“Swamimymmcmguma}
`
`flflam.fl3Enu”fl5onmy.2A»506fluu_Eu.11.4I“,1«or.
`
`FEG
`
`.“EZ
`
`
`
`15
`
`15
`
`
`

`

`{M}
`
`3833
`
`$8.9
`
`-6{§fl
`
`39.3
`
`
`
`
`
`.Piacebca{mmaj
`
`v R3833
`
`geus
`
`1283?
`
`1433.3
`
`8M5.AreaEthan
`
`)
`
`14/14
`
`195880330227
`
`Chafige $53 EML Leasing“: Size Cammreci m Fiamha
`Wm: Emedmnig Add Treatment
`
`QéRSE Graefie £3
`
`GARSS Grade 1—2
`
`
`
`..\ m .
`..
`\\E3\\.\\\“.\\\ER\\\\\‘.\\
`\i w \N's;
`w \\ w
`~\Q
`‘
`
`16
`
`16
`
`

`

`CO-ADMINISTRATION 0F STEROIDS AND ZOLEDRONIC ACID TO PREVENT AND
`
`Patent Application
`195860300227 CIP
`
`TREAT PAIN
`
`inventors: Herriot Tabuteau
`
`CROSSREFERENCE "m RELATED APPLECATEQNS
`
`[0001]
`
`This application is a continuation-in-part of U.S. Pat. App. No. 14/530,556, filed
`
`October 31, 2014, which is a continuation-in-part of U.S. Pat. App. No. 14/279,229, filed May
`
`15, 2014, now US. Patent No. 9,034,889, which is a continuation of US. Pat. App. No.
`
`14/063,979, filed October 25, 2013, now US. Patent No. 8,802,658, which is a continuation-
`
`in-part of U.S. Pat. App. No. 13/894,274, filed May 14, 2013, now abandoned, which claims
`
`the benefit of U.S. Prov. App. No. 61/646,538, filed May 14, 2012; and this application is also
`
`a continuation-in-part of International Pat. App. No. PCT/U82015/032739, filed May 27, 2015,
`
`all of which are incorporated by reference in their entireties herein.
`
`SUMMARY
`
`[0002]
`
`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.
`
`[0003]
`
`Patchy osteoporosis and bone marrow edema may result from osteoclast
`
`hyperactivity. Zoledronic acid is a potent inhibitor of bone resorption and osteoclast activity.
`
`Nitrogen containing bisphosphonates, such as zoledronic acid, also inhibit the mevalonate
`
`pathway in the osteoclast thereby interrupting normal osteoclast function.
`
`[0004]
`
`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.
`
`[0005]
`
`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.
`
`[0006]
`
`Some embodiments include a 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.
`
`17
`
`17
`
`

`

`Patent Application
`195860300227 CIP
`
`[0007]
`
`Some embodiments include a dosage form comprising zoledronic acid in
`
`an acid or a salt form, such as 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 ngoh/mL to about 2000 ngoh/mL to a
`
`human being to which the dosage form is administered.
`
`[0008]
`
`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.
`
`[0009]
`
`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
`unenhanced.
`
`is substantially
`
`[0010]
`
`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.
`
`[0011]
`
`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.
`
`[0012]
`
`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.
`
`[0013]
`
`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%.
`
`[0014]
`
`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.
`
`18
`
`18
`
`

`

`Patent Application
`1958601100227 CIP
`
`[0015]
`
`Some embodiments include a method of relieving inflammatory pain
`
`comprising administering an oral dosage form containing zoledronic acid to a mammal in
`need thereof.
`
`[0016]
`
`In some embodiments,
`
`the mammal receives a total monthly dose of
`
`zoledronic acid that is about 800 mg/m2 or less.
`
`[0017]
`
`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.
`
`[0018]
`
`Some embodiments include a method of relieving inflammatory pain
`
`comprising orally administering zoledronic acid to a mammal in need thereof.
`
`[0019]
`
`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.
`
`[0020]
`
`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 ofthe mammal.
`
`BRIEF DESCRIPTEQN GF QRAWINGS
`
`[0021]
`
`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.
`
`[0022]
`
`FIG. 2A is a graph depicting reversal of arthritis pain for two different
`
`doses of zoledronic acid in a rat model of arthritis pain.
`
`[0023]
`
`FIG. ZB is a graph depicting pain thresholds for two different doses of
`
`zoledronic acid in a rat model of arthritis pain.
`
`[0024]
`
`FIG. 3 is a graph summarizing the results for vehicle and zoledronic acid
`
`treated rats in a rat model of complex regional pain syndrome.
`
`[0025]
`
`FIG. 4 depicts hindpaw pain thresholds for vehicle and zoledronic acid
`
`treated rats in a rat model of complex regional pain syndrome.
`
`[0026]
`
`FIG. 5 depicts weight bearing for vehicle and zoledronic acid treated rats
`
`in a rat model of complex regional pain syndrome.
`
`[0027]
`
`FIG. 6 depicts paw thickness change for vehicle and zoledronic acid
`
`treated rats in a rat model of complex regional pain syndrome.
`
`[0028]
`
`FIG. 7 depicts the aqueous solubility of disodium zoledronate tetrahydrate
`
`as compared to the diacid form of zoledronic acid.
`
`19
`
`19
`
`

`

`Patent Application
`195860300227 CIP
`
`[0029]
`
`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.
`
`[0030]
`
`FIG. 9 depicts the compressibility of dosage forms containing zoledronic
`
`acid in the disodium salt form as compared to the diacid form.
`
`[0031]
`
`FIG. 10 depicts the change in VAS pain score compared to placebo at
`
`three months with zoledronic acid treatment in patients with osteoarthritis of the knee, bone
`
`marrow lesions, and different degrees ofjoint space narrowing.
`
`[0032]
`
`FIG. 11 depicts the change in VAS pain score compared to baseline at
`
`three months with zoledronic acid treatment in patients with osteoarthritis of the knee, bone
`
`marrow lesions, and different degrees ofjoint space narrowing.
`
`[0033]
`
`FIG. 12 depicts the change in VAS pain score compared to placebo at
`
`in different subgroups of patients with
`three months with zoledronic acid treatment
`osteoarthritis of the knee and bone marrow lesions.
`
`[0034]
`
`FIG. 13 depicts the change in BML lesion size compared to placebo at six
`
`months with zoledronic acid treatment
`
`in patients with osteoarthritis of the knee, bone
`
`marrow lesions, and different degrees ofjoint space narrowing.
`
`DE?A¥LED DESCRIPTION
`
`[0035]
`
`Inhibitors of osteoclast activity include 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
`
`ibandronic acid, risedronate or risedronic acid, cimadronate or cimadronic acid, zoledronate
`
`or zoledronic acid, etidronate or etidronic acid, clodronate or clodronic acid, tiludronate or
`
`tiludronic acid, etc.
`
`[0036]
`
`RANK/RANKL antagonists may be
`
`inhibitors of osteoclast
`
`activity.
`
`RANK/RANKL antagonists include but are not limited to OPG (osteoprotegerin) or a variant
`
`thereof, an anti-RANKL antibody such as denosumab, a monoclonal anti-RANKL antibody, a
`
`small interfering RNA, a microRNA, a precursor molecule, a ribozyme, an antisense nucleic
`
`acid, or an aptamer targeting RANKL. Antibodies such as AB-25E9, small molecules, small
`
`interfering RNAs, microRNAs, precursor molecules, ribozymes, antisense nucleic acids, or
`
`aptamers that target the cell-surface protein Siglec-15 may be osteoclast inhibitors.
`
`[0037]
`
`Some Bruton's tyrosine kinase (BTK)
`
`inhibitors may be inhibitors of
`
`osteoclast activity. BTK inhibitors can include ONO-4059;
`
`ibrutinib; Benzo[b]thiophene-2—
`
`carboxamide, N-[3-[6-[[4-[(2R)-1,4-dimethyl-3-oxo-2—piperazinyl]phenyl]amino]-4,5-dihydro-4-
`
`4
`
`20
`
`20
`
`

`

`Patent Application
`1958603.00227 CIP
`
`methyl-5-oxo-2—pyrazinyl]-2—methy|pheny|]-4,5,6,7-tetrahydr0-
`
`(GDC-0834);
`
`RN-486;
`
`Benzamide,
`
`4-(1,1-dimethylethyI)-N-[3-[8-(phenylamino)imidazo[1,2-a]pyrazin-G-yl]phenyl]-
`
`(Gel-560);
`
`Benzamide,
`
`N-[3-[4,5-dihydro-4-methyI-6-[[4-(4-morpholinylcarbony|)phenyl]
`
`amino]-5-oxo-2-pyraziny|]-2-methylphenyI]-4-(1,1-dimethylethyl)-
`
`(CGI-1746CAS Registry
`
`No.
`
`910232-84-7); HM-71224; 2-Propenamide, N-[3-[[5-fluoro-2-[[4—(2-methoxyethoxy)
`
`phenyl]amino]—4-pyrimidinyl]amino]phenyl]— (CC-292, CAS Registry No. 1202757—89-8); 2-
`
`Pyridinecarboxamide,
`
`4-[4-[[5-fluoro-4-[[3-[(1-oxo-2-propen-1-y|)amino]phenyl]amino]—2—
`
`pyrimidinyl]amino]phenoxy]-N-methy|— (CNX-774, CAS Registry No. 1202759-32—7), AVL-
`
`101 (CAS Registry No. 1552307-34—2), AVL-291 (CAS Registry No. 1552307-35-3), and
`
`AVL-292
`
`(CA8 Registry No.
`
`1552307-36—4),
`
`[N-(2-chloro-6-methylphenyI)-2-(6-(4-(2-
`
`hydroxyethyl)
`
`piperazin-1-y|)-2-methy|pyrimidin-4-ylamino)thiazoIe-5-carboxamide]
`
`(dasatinib), alpha-cyano-beta-hydroxy-beta-methyI-N-(Z,5-bromophenyl) propenamide (LFM-
`
`A13), and ONO-WG-307.
`
`H
`N
`
`LFM—A13
`
`N
`
`N
`f \ \
`N / /
`
`N
`
`NH2
`
`0
`
`Ibrutinib
`
`5
`
`21
`
`21
`
`

`

`Patent Application
`1958603.00227 CIP
`
`O
`
`—N/—\N—
`
`I
`
`HN
`
`8
`
`[I \H
`
`O
`
`{£4
`NH
`
`E/
`
`N\
`
`N
`/
`GDC-0834
`
`o
`
`HN
`
`N/
`
`/N
`
`\ NJ
`
`\ N
`
`NYN
`
`Dasatinib
`
`HN
`
`0
`
`CGI-560
`
`6
`
`22
`
`22
`
`

`

`CGl-1746
`
`Patent Application
`1958603.00227 CIP
`
`O\/\ /
`
`O
`
`N
`
`H
`
`H
`
`O fill/AI”
`\ A
`VKN
`N
`N
`
`F
`
`H
`
`CC-292
`
`F
`
`N
`
`H
`
`\ A
`N
`
`N
`
`H
`
`CNX—774
`
`O
`
`O
`
`\
`
`N
`
`VKN
`
`H
`
`[0038]
`
`Inhibitors of osteoclast activity 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.
`
`[0039]
`inhibitors:
`
`The compounds containing Ion 1 or
`
`Ion 2 may also be osteoclast
`
`+
`
`2
`/=\
`O
`PO3H2
`)K/N\ N
`V OH
`
`PO H
`3
`
`“0
`
`Ion 1
`
`+
`
`PO H
`
`H o P
`2
`3 HO
`
`NVN
`
`P03H2
`OH
`
`Ion 2
`
`23
`
`23
`
`

`

`Patent Application
`19586030027 CIP
`
`[0040]
`
`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.
`
`[0041]
`
`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.
`
`[0042]
`
`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.
`
`[0043]
`
`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.
`
`[0044]
`
`An osteoclast inhibitor, such as a bisphosphonate, e.g. zoledronic acid,
`
`may also be used to treat bone fractures or to enhance the healing of bone fractures.
`
`[0045]
`
`In some embodiments, zoledronic acid or another bisphosphonate may
`
`also be administered orally to relieve neuropathic pain,
`
`including diabetic peripheral
`
`24
`
`24
`
`

`

`Patent Application
`195360300227 CIP
`
`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.
`
`[0046]
`
`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 ofthe
`
`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.
`
`[0047]
`
`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 ofthe hip.
`
`[0048]
`
`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
`
`arthropathies
`
`including Charcot’s
`
`foot,
`
`axial
`
`spondyloarthritis
`
`including
`
`ankylosing
`
`spondylitis, and SAPHO syndrome.
`
`[0049]
`
`In some embodiments, a human being that is treated for a disease or
`
`condition, such as an inflammatory condition, eg. arthritis or CRPS, by an osteoclast
`
`inhibitor, such as a bisphosphonate, eg. an oral dosage form of zoledronic acid, has an age
`
`of at
`
`least 18 years, at
`
`least 50 years (including a male of at
`
`least 50 years), a
`
`postmenopausal female, about 10 years to about 90 years, about 20 years to about 80
`
`years, about 30 years to about 75 years, about 40 years to about 70 years, about 1 year to
`
`about 16 years, or about 80 years to about 95 years.
`
`In some embodiments, the human
`
`being is a male at least 50 years of age or postmenopausal female, with knee osteoarthritis
`
`(OA) and bone marrow lessions (BMLs), having moderate or worse knee pain.
`
`[0050]
`
`In some embodiments, a human being that is treated for a disease or
`
`condition, such as an inflammatory condition, eg. arthritis, by an osteoclast inhibitor, such as
`
`25
`
`25
`
`

`

`Patent Application
`195860300227 CIP
`
`a bisphosphonate, e.g. 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.
`
`[0051]
`
`In some embodiments, the arthritis affects a knee, an elbow, a finger, a
`
`wrist, a shoulder, an ankle, the spine, or a hip.
`
`[0052]
`
`For treatment of arthritis or joint pain, such as knee pain,
`
`in some
`
`embodiments the person being treated has OARSI Grade 0, or Kellgren and Lawrence
`
`Grades 0 or 1,joint space narrowing.
`
`[0053]
`
`In some embodiments, the person has lesions, such as bone marrow
`
`lesions.
`
`In some embodiments the person being treated for bone marrow lesions has
`
`normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0 or 1,joint
`
`space narrowing.
`
`[0054]
`
`In some embodiments, the person has baseline pain intensity of 5 or
`
`greater measured using the 0-10 numerical rating scale (NR8), or 50 mm or greater using
`
`the 100 mm visual analog scale (VAS). In some embodiments the person being treated for
`
`pain has normal joint space knee pain, OARSI Grade 0, or Kellgren and Lawrence Grades 0
`
`or 1, joint space narrowing.
`
`[0055]
`
`Bone marrow lesions
`
`(BMLs)
`
`include regional bone marrow signal
`
`intensity alterations on magnetic resonance imaging (MRI). BMLs can be present in the knee
`
`and can be an important feature of osteoarthritis of the knee. BMLs have also been
`
`described in other
`
`rheumatic conditions such as rheumatoid arthritis, osteonecrosis,
`
`ankylosing spondylitis, and transient osteoporosis of the hip and are often referred to as
`
`bone marrow edema (BME).
`
`[0056]
`
`In some embodiments, a person being treated for arthritis, such as with
`
`zoledronic acid, has osteoarthritis of the knee associated with bone marrow lesions.
`
`In some embodiments, an inhibitor of osteoclast activity can be used to
`[0057]
`treat bone marrow lesions.
`
`[0058]
`
`In some embodiments, an inhibitor of osteoclast activity can be used to
`
`treat bone marrow lesions of the knee, shoulder, ankle, wrist, hand, fingers, spine, or hip.
`
`[0059]
`
`Commonly used measures of pain intensity include the visual analog
`
`scale (VAS) and the numerical rating scale (NRS). With the VAS approach, patients rate the
`
`severity of their pain by marking a point on a 10-cm (or 100 mm) VAS (0=no pain and
`
`10=worst possible pain). With the NRS approach, patients rate the severity of their pain by
`
`verbally responding to a 10-point NRS (O=no pain and 10=worst possible pain). VAS and
`
`NRS scores have been shown to be strongly correlated (slope of regression line, 1.01),
`
`10
`
`26
`
`26
`
`

`

`Patent Application
`195860300227 CIP
`
`indicating that a score on the 10-cm VAS is equivalent to the same score on 10-point NRS
`
`(Bijur PE et al. Acad Emerg Med 2003; 10:390-392). For example, a VAS score of 5 cm (or
`
`50 mm) is equivalent to an NRS score of 5. Knee pain in a person with a VAS score of 5 cm
`
`or 50 mm or higher, or an NRS score of 5 or higher, may be referred to herein as moderate
`
`to severe knee pain.
`
`[0060]
`
`In some embodiments, the patient suffering from pain,
`
`inflammation, a
`
`similar condition, or any of the conditions described herein, has an NRS of 5 or greater, or a
`
`VAS of 5 cm or greater. In some embodiments, the patient has an NRS of4 or greater, or a
`
`VAS of 4 cm or greater. In some embodiments, the patient has an NRS of 6 or greater, or a
`
`VAS of 6 cm or greater. In some embodiments, the patient has an NRS of 7 or greater, or a
`
`VAS of 7 cm or greater. In some embodiments, the patient has an NRS of about 1, about 2,
`
`about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10.
`
`In some
`
`embodiments, the patient has a VAS of about 1 cm, about 2 cm, about 3 cm, about 4 cm,
`
`about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, or about 10 cm.
`
`[0061]
`
`For knee pain or pain associated with bone marrow lesions,
`
`in some
`
`embodiments, treatment with a nitrogen-containing bisphosphonate such as zoledronic acid
`
`may decrease the visual analog (VAS) pain score measured using a 100 mm scale, by at
`
`least about 5 mm, at least about 8 mm, at least about 10 mm, at least about 15 mm, up to
`
`about 50 mm, or up to about 100 mm.
`
`In some embodiments, the VAS score, may be
`
`decreased by at least about 5 mm, at least about 8 mm, at least about 10 mm, at least about
`
`15 mm, up to about 50 mm, or up to about 100 mm, as compared to a placebo.
`
`[0062]
`
`Treatment with a nitrogen-containing bisphosphonate such as zoledronic
`
`acid may decrease the numerical rating scale (NR8) pain score measured using a 0-10
`
`scale, by at least about 0.1, at least about 0.5, at least about 0.8, at least about 1, at least
`
`about 1.5, up to about 5, or up to about 10.
`
`In some embodiments, the NRS score may be
`
`decreased by at least about 0.1, at least about 0.5, at least about 0.8, at least about 1, at
`
`least about 1.5, up to about 5, or up to about 10, as compared to a placebo.
`
`[0063]
`
`In some embodime