Patent
`Attorney Docket No. 0056192-000067
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`REQUEST FOR FILING CONTINUATION/ DIVISIONAL
`APPLICATION UNDER 37 C.F.R. § 1.53(b)
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Customer Number 21839
`
`Sir:
`
`0
`
`NON-PUBLICATION IS REQUESTED. A CERTIFICATION IS BELOW.
`
`IZI continuation D divisional application under 37 C.F.R. § 1.53(b) of
`This is a request for filing a
`the following pending application, Application No. 10/551,205, filed November 14. 2006 entitled ORAL
`FORMULATIONS OF CLADRIBINE
`
`by the following named inventor(s):
`Nicholas S. BODOR
`Yogesh DANDIKER
`
`D
`
`D
`
`D
`
`D
`
`D
`
`1.
`
`2.
`
`The entire disclosure of the prior application from which a copy of the oath or declaration is
`supplied herewith is considered as being part of the disclosure of the accompanying
`application and is hereby incorporated by reference therein.
`
`Applicant(s) hereby requests that the above-captioned application NOT BE PUBLISHED
`under 35 U.S.C. § 122(b) and 37 C.F.R. § 1.211. The undersigned hereby certifies that the
`invention disclosed in this application has not and will not be the subject of an application
`filed in another country, or under a multilateral international agreement, that requires
`publication at eighteen (18) months after filing.
`
`This application is being filed by less than all the inventors named in the prior application. In
`accordance with 37 C.F.R. § 1.63(d)(2), the Commissioner is requested to delete the name(s}
`of the following person or persons who are not inventors of the invention being claimed in this
`application.
`
`This application is being filed by more than all the inventors named in the prior application. In
`accordance with 37 C.F.R. § 1.63(d)(5), a new oath or declaration is enclosed, and the
`Commissioner is requested to add the name(s) of the following person or persons who are
`inventors of the invention being claimed in this application.
`
`Applicant(s) suggests Figure 1 for inclusion on the front page of the patent application
`publication and patent.
`
`Applicant{s) requests that the published application include the following assignment
`information: Ares Trading, S.A., Aubonne, Switzerland.
`
`Small entity status is claimed.
`
`□
`
`Enclosed is a copy of the prior Application No. _______ as originally filed on
`______ _, including copies of the specification, claims, drawings and the executed
`oath or declaration as filed.
`
`Enclosed is a revised prior application and a copy of the prior executed oath or declaration as
`filed. No new matter has been added to the revised application.
`
`Buchanan Ingersoll 1~, Rooney PC
`
`Attorneys & Government Relations Professionals
`
`Exhibit
`
`Hopewell EX 1058
`
`02/15/24 - EW
`
`exhibitsticker.com
`
`Hopewell EX1058
`Hopewell v. Merck
`IPR2023-00481
`
`1
`
`

`

`Continuation/Divisional Patent Application Transmittal Letter
`Application No. unassigned
`Attorney Docket No. 0056192-000067
`Page2
`The filing fee has been calculated as follows D and in accordance with the enclosed
`Preliminary Amendment:
`
`3.
`
`Basic Application Filing Fee (1011)
`
`Examination Fee (1311)
`
`Search Fee (1111)
`
`No. of
`Claims
`Total Claims
`64
`Minus 20=
`Independent Claims
`Minus 3=
`4
`If multiple dependent claims are presented, add 390
`
`Extra
`Claims
`44
`1
`
`Rate
`
`X $ 52 (1202)
`X $ 220 (1201)
`
`App. Size Fee (app + dwgs. exceeding 100 sheets) - $270 for each 50 sheets
`(1081)
`
`Total Application Fee
`
`D Small Entity Status claimed - subtract 50% of Total Application Fee
`
`Add Assignment Recording Fee of$ 40 if Assignment document is enclosed
`
`TOTAL APPLICATION FEE DUE
`
`FEES
`
`330
`220
`
`540
`
`2288
`220
`0
`
`0
`
`3598
`
`0
`
`0
`
`3598
`
`$
`
`$
`
`$
`
`$
`
`$
`
`$
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`This application is being filed without a filing fee.
`
`Charge ______ to Deposit Account No. 02-4800 for the fee due.
`
`Charge $ 3598 to credit card.
`
`The Director is hereby authorized to charge any appropriate fees under 37 C.F.R. §§ 1.16,
`1.17 and 1.21 that may be required by this paper, and to credit any overpayment, to Deposit
`Account No. 02-4800.
`
`New drawings are enclosed.
`
`Applicant(s) claims priority under 35 U.S.C. §§ 119 of the following application(s):
`
`Country
`
`Appl. No.
`
`Filing Date
`MM-DD-YYYY
`
`MM-DD-YYYY
`
`D
`
`The certified copy of the priority application:
`D
`
`is enclosed.
`
`2
`
`

`

`Continuation/Divisional Patent Application Transmittal Letter
`Application No. unassigned
`Attorney Docket No. 0056192-000067
`Page 3
`
`□
`
`D
`
`was filed on _______ in prior Application No. ______ _, filed on
`______ _, and acknowledged by the Examiner on
`in
`Paper No. ______ _
`
`was filed in the International Bureau and acknowledged by the Examiner on
`_______ in ______ _
`
`D
`has not yet been filed.
`A Preliminary Amendment is enclosed.
`
`An Information Disclosure Statement, Form Substitute PTO-1449 and (2) documents are
`enclosed.
`
`10.
`
`11.
`
`□
`[8J
`
`12. □
`
`A General Authorization of Payment of Fees and Petitions for Extensions of Time is
`enclosed.
`
`13.
`
`14.
`
`15.
`
`[8J
`
`□
`[8J
`
`a.
`b.
`
`C.
`
`An Application Data Sheet.
`
`Also enclosed is ______ _
`
`The power of attorney in the prior application is to Customer Number 21839.
`D
`D
`
`The power appears in the original papers in the prior application.
`Since the power does not appear in the original papers, a copy of the power in the
`prior application is enclosed.
`Address all future communications to: (may only be completed by applicant,
`attorney, or agent of record)
`Buchanan Ingersoll & Rooney pc
`Customer Number 21839
`
`[8J
`
`Date: January 7, 2011
`
`Customer No. 21839
`703 836 6620
`
`By 1141 l::Jt~ fi::A'!(u,;t,r./
`
`Mary atherine Baum ister
`Registration No. 26254
`
`D inventor(s)
`D assignee of complete interest
`[8J attorney or agent of record
`D filed under 37 C.F.R.§ 1.34(a)
`
`3
`
`

`

`APPLICATION DATA SHEET
`
`Application Information
`
`Application Number::
`
`Filing Date::
`
`January 7, 2011
`
`Application Type::
`
`Subject Matter::
`
`Regular
`
`Utility
`
`Suggested Classification::
`
`Suggested Group Art Unit::
`
`CD-ROM or CD-R?::
`
`Number of CD Disks::
`
`Number of Copies of CDs::
`
`Sequence Submission?::
`
`Computer Readable Form (CRF)?::
`
`Number of Copies of CRF::
`
`Title::
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`Attorney Docket Number::
`
`0056192-000067
`
`Request for Early Publication?::
`
`Request for Non-Publication?::
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets::
`
`Small Entity?::
`
`Latin Name::
`
`No
`
`No
`
`1
`
`1
`
`No
`
`Page# 1
`
`Initial 01/07/11
`
`4
`
`

`

`Variety Denomination Name::
`
`Petition Included?::
`
`No
`
`Petition Type::
`
`Licensed US Govt. Agency::
`
`Contract or Grant Numbers::
`
`Secrecy Order in Parent Appl.?::
`
`No
`
`Applicant Information
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`United States
`
`Status::
`
`Given Name::
`
`Middle Name::
`
`Family Name::
`
`Name Suffix::
`
`Full Capacity
`
`Nicholas
`
`S.
`
`BODOR
`
`City of Residence::
`
`Bal Harbour
`
`State or Province of Residence::
`
`Florida
`
`Country of Residence::
`
`United States
`
`Street of Mailing Address::
`
`10225 Collins Avenue
`Unit 1002/1004
`
`City of Mailing Address::
`
`Bal Harbour
`
`State or Province of Mailing
`Address::
`
`Florida
`
`Page# 2
`
`Initial 01/07/11
`
`5
`
`

`

`Country of Mailing Address::
`
`United States
`
`Postal or Zip Code of Mailing
`Address::
`
`33154
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`United Kingdom
`
`Status::
`
`Given Name::
`
`Middle Name::
`
`Family Name::
`
`Name Suffix::
`
`Full Capacity
`
`Yogesh
`
`DANDIKER
`
`City of Residence::
`
`Toronto
`
`State or Province of Residence::
`
`Country of Residence::
`
`Canada
`
`Street of Mailing Address::
`
`57 Fenn Avenue
`
`City of Mailing Address::
`
`Toronto
`
`State or Province of Mailing
`Address::
`
`Country of Mailing Address::
`
`Canada
`
`Postal or Zip Code of Mailing
`Address::
`
`M2L 1M9
`
`Page# 3
`
`Initial 01/07/11
`
`6
`
`

`

`Correspondence Information
`
`Correspondence Customer Number:: 21839
`
`Phone Number::
`
`Fax Number:
`
`(703) 836-6620
`
`(703) 836-2021
`
`Representative Information
`
`Representative Customer Number:: 21839
`
`Domestic Priority Information
`
`Application::
`
`Continuity Type::
`
`Parent Application::
`
`This Application
`
`Continuation of
`
`10/551,205
`
`Parent Filing
`Date::
`
`November 14,
`2006
`
`10/551,205
`
`National Stage of
`
`PCT /US2004/009387
`
`March 26, 2004
`
`PCT /US2004/009387 Claims benefit under 35
`U.S.C. §119(e) of
`
`PCT /US2004/009387 Claims benefit under 35
`U.S.C. §119(e) of
`
`PCT /U S2004/009387 Claims benefit under 35
`U.S.C. §119(e) of
`
`60/458,922
`
`March 28, 2003
`
`60/484,756
`
`July 2, 2003
`
`60/541,247
`
`Feb 4, 2004
`
`Page# 4
`
`Initial 01/07/11
`
`7
`
`

`

`Foreign Priority l_nformation
`
`Country::
`
`Application Number::
`
`Filing Date:: Priority
`Claimed::
`
`Assignee Information
`
`Assignee Name::
`
`ARES TRADING S.A.
`
`Street of Mailing Address::
`
`Zone lndustrielle d l'Ouriettaz
`
`City of Mailing Address::
`
`Aubonne
`
`State or Province of Mailing
`Address::
`
`Country of Mailing Address::
`
`Switzerland
`
`Postal or Zip Code of Mailing
`Address::
`
`CH-1170
`
`Respectfully submitted,
`
`BUCHANAN INGERSOLL & .ROONEY PC
`
`Date: January 7, 2011
`
`By:
`
`Customer No. 21839
`703 836 6620
`
`Page# 5
`
`Initial 01/07/11
`
`8
`
`

`

`Anorney Docket No. 033935-021
`
`COMBINED DECLARATION AND POWER OF ATTORNEY
`FOR UTILITY OR DESIGN PATENT APPLICATION
`
`As a below named inventor, I hereby declare that:
`
`My residence, post office address and citizenship are as stated below next to fTIY name;
`
`I believe I am the original, first and sole inventor (if only one name is listed below) or an original, first
`and joint inventor (if plural names are listed below) of the subject matter which is claimed and for
`which a patent is sought on the invention entitled:
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`the specification of which (check only one item below):
`D
`is attached hereto.
`D was filed as United States Patent application Number ____ _
`on __________ and was amended on
`__________ (if applicable).
`
`[XI was filed as PCT International application Number
`on
`March 26,
`PCT/US2004/009387
`2004
`and was amended on
`__________ (if applicable).
`
`I hereby state that I have reviewed and understand the contents of the above-identified specification,
`including the claims, as amended by any amendment referred to above.
`
`I acknowledge · the duty to disclose to the Office all information known to me to be material to
`patentability as defined in Title 37, Code of Federal Regulations, § 1.56.
`
`I hereby claim foreign priority benefits under Title 35, United States Code, §§ 119 (a}-(d), 172 or
`365(a) of any foreign application(s) for patent or inventor's certificate or of any international (PCT)
`application(s) designating at least one country other than the United States of America listed below
`and have also identified below any foreign application(s) for patent or inventor's certificate or any PCT
`international (PCT) appllcation(s) designating at least one country other than the United States of
`America filed by me on the same subject matter having a filing date before that of the appllcation(s) of
`which priority is claimed:
`
`PRIOR FOREIGN/PCT APPLICATION(S) AND ANY PRIORITY CLAIMS UNDER 35 U.S.C. §§119(a)-(d), 172 or 365(a):
`PRIORITY CLAIMED
`UNDER 35 U.S.C.
`&~ 119, 172 OR 365(a)
`Yes
`No
`
`COUNTRY
`(if PCT, indicate "PCT")
`
`APPLICATION NUMBER
`
`DATE OF FILING
`(MM/DD/YYYY)
`
`Buchanan Ingersoll PC
`,,no,~riEvs
`;n,:lu<lin~ ;,l!r,rM\'> from nurns Donne Swecker & Molhb
`
`(8/05)
`
`9
`
`

`

`Combined Declaration and Power of Attorney
`For Utility or Design Patent Application
`Attorney Docket No. 033935-021
`Page 2 of 2
`
`I hereby appoint the attorneys and agents associated with the following PTO Customer Number of
`Buchanan Ingersoll PC (including attorneys from Burns, Doane, Swecker & Mathis) to prosecute said
`application and to transact all business in the P,atent and Trademark Office connected therewith and
`to file, prosecute and transact all business in connection with international applications directed to .
`said invention:
`·
`
`· Customer Number 2 1 8 3 9
`
`I hereby declare that all statements made herein of my own knowledge are true and that all
`statements made on information and belief are believed to be true; and further that these statements
`were made with the knowledge that willful false statements and the like so made are punishable by
`fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such
`willful false statements may jeopardize the validity of the application or any patent issued thereon.
`
`FULL NAME OF SOLE OR FIRST INVENTOR
`
`Nicholas S. Bodor
`
`Siqnature
`
`Date
`
`L-~ < ; ,~
`I\- \4--oll('
`
`Residence (Citv, State, Countrv)
`
`Bal Harbour, Florida, US
`
`Citizenshio
`
`Mailinq Address
`
`United States
`
`10225 Collins Avenue, Unit 1002/1004
`
`Citv, State, ZIP, Country
`FULL NAME SECOND INVENTOR, IF ANY
`
`Bal Harbour, Florida 33154, US
`Yoqesh Dandiker
`
`/A-.....A-1',./}
`
`,
`
`A.~ ·vL
`r
`•
`-
`- ,
`I .Jtn. AA.~ M'll
`
`1M...,
`
`~~~
`l~ ii t,£'"'
`--ro IJ_. -,-.,
`-
`l
`I
`,., C/-,_. ,._,
`United Kingdom
`. -
`-
`-r.;..n.- I:..-, ...
`
`'
`
`Sianature
`
`Date
`Residence (Citv, State, Country)
`
`Citizenship
`
`Mailina Address
`
`City, State, ZIP, Country
`FULL NAME OF THIRD INVENTOR, IF ANY
`
`Siqnature
`
`Date
`
`Residence {City, State, Country)
`
`Citizenshio
`Mailinq Address
`Citv, State, ZIP, Country
`
`Buchanan Ingersoll PC
`
`0.nomlE'tS
`!i1Llm1Jnn ut1'ill1il}'! tmm Uum.s Donne Swecker & Mothfs
`
`10
`
`

`

`-1-
`
`5
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`CROSS-REFERENCE TO EARLIER APPLICATIONS
`
`10
`
`This application is a continuation of prior copending US Application No.
`
`10/551,205 filed November 14, 2006, now allowed, which is the US national
`
`stage of International Application No. PCT/US2004/009387, filed March 26,
`
`2004, which claims benefit under 35 U.S.C. § 119(e) of United States Provisional
`
`Application No. 60/458,922, filed March 28, 2003; of United States Provisional
`
`Application No. 60/484, 756, filed July 2, 2003; and of United States Provisional
`
`.
`Application No. 60/541,247, filed February 4, 2004, all of said applications being
`.
`· hereby incorporated_ by reference herein in their entireties and relied upon.
`
`BACJ<GROUND OF THE INVENTION
`
`15
`
`Cladribine, which is an acid-labile drug, has the chemical structure as
`r·
`set forth below:
`
`20
`
`It is also known as 2-chloro-2'-deoxyadenosine or 2-CdA. Cladribine exists
`as a white, nonhydroscopic, crystalline powder, consisting of individual
`crystals and of crystalline aggregates.
`Cladribine is an antimetabolite which has use in the treatment of
`lymphoproliferative d_isorders. It has been used to treat experimental ·
`leukemias such as L 1210 and clinically for hairy celJ leukemia and chronic
`lymphocytic leukemia as well as Waldenstrom's macroglobulinaemia. It has
`
`11
`
`

`

`-2-
`
`also been used as an immunosuppressive agent and as a modality for the
`treatment of a variety of autoimmune conditions including rheumatoid
`arthritis, inflammatory bowel disease (e.g., Crohn's disease, ulcerative
`colitis) and multiple sclerosis (see e.g., J. Liliemark, Clin. Parmacokinet,
`32(2): 120-131, 1997). It has also been investigated, either experimentally
`or clinically in, for example, lymphomas, Langerhan's cell histiocytosis, lupus
`erythematosus, chronic plaque psoriasis, Sezary syndrome, Bing-Neel
`syndrome, recurrent glioma, and solid tumors.
`
`Oral delivery of drugs is often preferred to parenteral delivery for a
`variety of reasons, foremost patient compliance, or for cost or therapeutic
`considerations. Patient compliance is enhanced insofar as oral dosage
`forms alleviate repeated health care provider visits,. or the discomfort of
`injections or proionged infusion times associated with some active dr';JQS. At
`a time of escalating health care costs, the reduced costs associated with oral
`administration versus parenteral administration costs gain importance. The
`cost of parenteral administration is much hig!ier due to the requirement that
`a health care professional administer the cladribine in the health care
`provider setting, which also includes all attendant costs associated with such
`administration. Furthermore, in certain instances, therapeutic considerations
`such as the need for a slow release of cladribine over a prolonged period of
`time may be practically met only by oral or transmucosal delivery.
`
`However, to date the oral delivery of cladribine has been plagued by
`low bioavailability {see, e.g., J. Liliemark et al., J. Clin. Oncol., 10(10): 1514-
`1518, 1992), and suboptimal interpatient variation (see, e.g., J. Liliemark,
`Clin. Phannacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al.
`reporting poor absorption and pH dependent lability (Arch. /mmunol. et
`Therapiae Exper., 42: 13-15, 1994).
`
`Cyclodextrins are cyclic oligosaccharides composed of cyclic a-(1~4)
`linked D-glucopyranose units. Cyclodextrins with six to eight units have
`
`5
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`25
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`12
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`

`

`-3-
`been named a-, 13- and y-cyclodextrin, respectively. The number of units
`determines the size of the cone-shaped cavity which characterizes
`cyclodextrins and into which drugs may be included to form stable
`complexes. A number of derivatives of a-, 13- and v-cyclodextrin are known
`in which one or more hydroxyl groups is/are replaced with ether groups or
`other radicals. These compounds are thus known complexing agents and
`have been previously used in the pharmaceutical field to form inclusion
`complexes with water-insoluble drugs and to thus solubilize them in aqueous
`media.
`
`Recently, Schultz et al., in U.S. Patent No. 6,194,395 B1, have
`described complexing and solubilizing cladribine with cyclodextrin. The
`Schultz et al. patent primarily addresses the problems inherent in previously
`described aqueous formulations of cfadribine, particularly for subcutaneous
`and intramuscular injection. Schultz et al. have found that cladribine is not
`only significantly more soluble in aqueous media when formulated with
`cyclodextrin, but also is more stable against acid-catalyzed hydrolysis when
`combined with cyclodextrin. The latter finding is taught to be of particular
`benefit in the formulation of solid oral dosage forms, where the compound
`would normally undergo hydrolysis in the acid pH of the stomach contents.
`Schultz et al. do not appear to have described any actual work in connection
`with solid oral dosage forms. In fact, they describe only one method of
`preparing the solid dosage form, which is a melt extrusion process, in which
`the cladribine and cyclodextrin are mixed with other optional additives and
`then heated until melting occurs. Furthermore, the broad dosage ranges of
`1 mg to 15 mg of cladribine and 100 mg to 500 mg of cyclodextrin listed in
`the patent sugg~st no criticality to the particular amount of cyclodextrin to be
`present with a given amount of cladribine in a solid oral dosage form.
`Indeed, these dosage ranges include many combinations which may be
`suitable as mixtures but not for complex formation. For example, a ratio of 1
`mg of cladribine to 500 mg of cyclodextrin contains too much cyclodextrin, so
`
`5
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`20
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`

`-4-
`
`that the drug would not readily leave the complex and achieve its therapeutic
`function. On the other hand, 15 mg of cladribine and only 100 mg of
`cyclodextrin would not be enough to complex that amount of cladribine.
`
`The Schultz et al. patent does suggest improving the stability of
`cladribine in oral dosage forms by combining/complexing it with cyclodextrin,
`but does not suggest improving the drug's oral bioavailability by such means;
`in fact, the patent does not describe or suggest a method for enhancing or
`maximizing the bioavailability of cladribine from a solid oral dosage form of
`cladrlbine and cyclodextrin, or a composition specially designed to do so.
`
`Many workers have studied the solubility of specific drugs in water
`containing various concentrations of selected cyclodextrins in order to
`demonstrate that increasing concentrations of cyclodextrins increase the
`solubility of the drugs at selected temperatures and pH levels, as for
`example reported in the Schultz et al. patent. Phase solubility studies have
`also been performed by various workers in order to elucidate the nature of
`the complex formation, for example, whether the cyclodextrin and drug form
`a 1 :1 complex or a 1 :2 complex; see, for example, Harada et al. U.S. Patent
`No. 4,497,803, relating to inclusion complexes of lankacidin-group antibiotics
`with cyclodextrin, and Shinoda et al. U.S. Patent No. 4,478,995, relating to a
`complex of an acid addition salt of (2'-benzyloxycarbonyl)phenyl trans-4-
`guanidinomethylcyclohexanecarboxylate with a cyclodextrin.
`
`While Schultz et al. teach that a cladribine-cyclodextrin complex
`improves the water solubility and acid stability of cladribine, the art does not
`suggest how to maximize or enhance the benefits of the complexation in
`terms of bioavailability and interpatient variation when the complex is to be
`administered in a solid oral dosage form.
`
`5
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`

`

`-5-
`
`SUMMARY OF THE INVENTION
`
`It has now been found that amorphous cyclodextrins can be combined
`with cladribine to form a particularly advantageous product which can be
`incorporated into a solid oral dosage form. This product is a complex
`cladribine-cyclodextrin complex, and the solid oral dosage form containing it
`improves oral bioavailability and/or achieves tower interpatient and/or
`intrapatient variation of the drug.
`
`The present invention provides a complex cladribine.:cyclodextrin
`complex which is an intimate amorphous admixture of (a) an amorphous
`inclusion complex of cladribine with an amorphous cyclodextrin and (b)
`amorphous free cladribine associated with amorphous cyclodextrin as a non(cid:173)
`inclusion complex, and a pharmaceutical composition comprising said
`complex, formulated into a solid oral dosage form. Thus, the cyclodextrin
`itself is amorphous, the inclusion complex with cladribine is amorphous (and
`is preferably saturated with cladribine) and the free cladribine which forms
`the non-inclusion complex is amorphous.
`
`The invention also provides a method for increasing or enhancing the
`oral bioavailability of 9ladriblne comprising orally administering to a subject in
`need thereof, a pharmaceutical composition comprising a complex
`cladribine-cycfodextrin· complex which is an intimate amorphous admixture of
`(a) an amorphous inclusion complex of cladribine with an amorphous
`cyclodextrin and (b) amorphous free cladribine associated with amorphous
`cyclodextrin as a non-inclusion complex, formulated into a solid oral dosage
`form which maximizes the amount of cladribine in the inclusion and non-
`inclusion complexes.
`
`The invention further provides for treatment of conditions responsive
`to administration of cladribine in mammals by administering thereto the
`composition of the invention. Use of cladribine in the preparation of the
`pharmaceutical compositions of the invention for administration to treat
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`cladribine-responsive conditions and for enhancing the oral bioavailability of
`cladribine is also provided.
`
`Still further, the invention provides a process for the preparation of a
`complex cladribine-cyclodextrin complex which comprises the steps of:
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`(i) combining cladribine and an amorphous cyclodextrin in water at a
`temperature of from about 40 to about 80°C and maintaining said
`temperature for a period of from about 6 to about 24 hours;
`
`(ii) cooling the resultant aqueous solution to room temperature; and
`
`(iii) lyophilizing the cooled solution to afford an amorphous product.
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`In yet a further aspect the invention provides a pharmaceutical
`composition obtainable by a process comprising the steps of:
`
`(i) combining cladribine and an amorphous cyclodextrin in water at a
`temperature of from about 40 to about 80°C and maintaining said
`temperature for a period of from about 6 to about 24 hours;
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`(ii) cooling the resultant aqueous solution to room temperature;
`
`(iii) fyophilizing the cooled solution to afford an amorphous product;
`
`and
`
`(iv) formulating the amorphous product into a solid oral dosage form.
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`BRIEF DESCRIPTION OF THE DRAWING
`
`A more complete appreciation of the invention and its many attendant
`advantages will be readily understood by reference to the following detailed
`description and the accompanying drawing, wherein the sole Figure is a
`graphical representation of the results of a phase solubility study where
`various molar concentrations of hydroxypropyl-(3-cyclodextrin (HPJ3CD) are
`
`plotted against various cladribine molar concentrations, with(•) representing
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`the data points obtained for complexation und~r conditions specified in
`EXAMPLE 2 below.
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`-7-
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`DETAILED DESCRIPTION OF THE INVENTION
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`Throughout the instant specification and claims, the following
`definitions and general statements are applicable.
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`The patents, published applications, and scientific literature referred
`to herein establish the knowledge of those with skill in the art and are hereby
`incorporated by referenpe in their entirety to the same extent as if each was
`specifically and individually indicated to be incorporated by reference. Any
`conflict between any reference cited herein and the specific teachings of this
`specification shall be resolved in favor of the latter. Likewise, any conflict
`between an art-understood definition of a word or phrase and a definition of
`the word or phrase as specifically taught in this specification shall be
`resolved in favor of the fatter.
`
`The term "inclusion complex'' as used herein refers to a complex of
`cladribine with the selected cyclodextrin wherein the hydrophobic portion of
`the cfadribine molecule (the nitrogen-containing ring system) is inserted into
`the hydrophobic cavity of the cyclodextrin molecule. This is often referred to
`simply as a cyclodextrin complex of the drug.
`
`The term·"non-inclusion complex" refers to a complex which is not an
`inclusion complex; rather than the hydrophobic portion of cladribine being
`inserted in the cyclodextrin cavity, the non-inclusion complex is formed
`primarily by hydrogen-bonding of the hydroxyls and amino group on "free"
`cladribine, (i.e. cladribine not in the inclusion complex) to the hydroxyls on
`the exterior of the cyclodextrin torus (e.g. in the case of hydroxypropyl-(3-
`cyclodextrin, hydroxypropyl and hydro)cyl groups on the glucose rings). This
`is a more loosely-held association than an inclusion complex.
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`-8-
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`As used herein, whether in a transitional phrase or in the body of a
`claim, the terms "comprise(s)" and "comprising" are to be interpreted as
`having an open-ended meaning. That is, the terms are to be interpreted
`synonymously with the phrases "having at least" or "including at least".
`When used in the context of a process, the term "comprising" means that the
`process includes at least the recited steps, but may include additional steps.
`When used in the context of a composition, the term "comprising" means
`that the composition includes at least the recited features or components,
`but may also include additional features or components.
`
`The terms "consists essentially of' or 11consisting essentially of' have a
`partially closed meaning, that is, they do not permit inclusion of steps or
`features or components which would substantially change the essential
`characteristics of a process or composition; for example, steps or features or
`components which would significantly interfere with the desired properties of
`the compositions described herein, i.e., the process or composition is limited
`to the specified steps or materials and those which do not materially affect
`the basic and novel characteristics of the invention. The basic and novel
`features herein are the provision of a complex cladribine-cyclodextrin
`complex which is an intimate. amorphous admixture of (a) an amorphous
`inclusion complex of cladribine with an amorphous cyclodextrin and (b)
`amorphous free cladribine a~sociated with amorphous cyclodextrin as a non(cid:173)
`inclusion complex, formulated into a solid oral dosage form, so as to provide
`improved bioavaifability and/or lower interpatient and/or intrapatient variation
`following administration. Essential to the invention is the combination of the
`amorphous nature of the starting cyclodextrin, and the level of water
`solubility exhibited by cladribine (about 5 mg/ml at room temperature), and
`consequently its capability for hydrogen bonding, which can be tal<en
`advantage of under particular conditions described hereinafter, and which
`afford a special amorphous mixture uniquely well-suited for optimizing the
`oral bioavailability of cladribine.
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`-9-
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`The terms "consists of' and "consists" are closed terminology and
`allow only for the inclusion of the recited steps or features or components.
`
`As used herein, the singular forms "a," "an" and "the" specifically also
`encompass the plural forms of the terms to· which they refer, unless the
`content clearly dictates otherwise.
`
`The term "about' is used herein to means approximately, in the region
`of, roughly, or around. When the term "about" is used in conjunction with a
`numerical range, it modifies that range by extending the boundaries above
`and below the numerical values set forth. In general, the term "about" or
`"approximately'' is used herein to modify a numerical value above and below
`the stated value by a variance of 20%.
`
`The term "amorphous" is used herein to refer to a noncrystalline solid.
`The cyclodextrins encompassed herein themselves are amorphous because
`they are each composed of a multitude of individual isomers, and their
`complexes with cladribine are also amorphous. Further, conditions for
`complexation can be selected {elevated temperature and prolonged
`complexation times, as described hereinafter) so that a supersaturated
`cladribine solution will be formed. When cooled, because of the amorphous
`nature of the complex and the cyclodextrin, some excess free cladribine
`does not precipitate but rather is trapped in amorphous form in intimate
`admixture with the (preferably saturated) amorphous cladribine-cyclodextrin
`inclusion complex. This excess cladribine forms a loosely-held association,
`or non-inclusion complex, with the cyclodextrin through hydrogen bonding.
`This, then, further increases the amount of cladribine in the product; this
`additional cladribine, because it is amorphous and also because it is i_n
`intimate admixture with the amorphous inclusion complex, is expected to be
`somewhat protected from degradation by stomach acid (although it may not
`be as protected as the cladribine which is in the form of the inclusion
`complex).
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`The term "saturated" when used in conjunction with a complex of
`cladribine in amorphous cyclode}(trin means that the complex is saturated
`with cladribine, that is, the complex contains the maximum amount of
`cladribine which can be complexed (by means of both inclusion and non-
`inclusion complexes) with a given amount of cyclodextrin under the
`conditions of complexation used. A phase solubility study can be used to
`provide this information, as described in more detail hereinafter. (Conditions
`for the complexation are also described in more detail below.) Alternatively,
`a saturated complex may be arrived at empirically by simply adding
`cladribine to an aqueous solution of the selected cyclodextrin until no more
`cladribine goes into solution; ultimately, excess cladribine, if any, is removed
`(by filtration or centrifugation) and the solution lyophilized to provide the dry
`saturated complex.
`
`The expression "substantially' 1 as in 11substantially free" means within
`20% of the exact calculated amount, preferably within 10%, most preferably
`within 5%.
`
`The term "interpatient variability" refers to variation among patients to
`which a drug is administered. The term "intrapatient variability" refers to
`variation experienced by a single patient when dosed at different times.
`
`As used herein, the recitation of a numerical range for a variable is
`intended to convey that the invention may be practiced with the variable
`equal to any of the values within that range. Thus, for a variable which is
`inherently discrete, the variable can be equal to any integer value of the
`numerical range, including the e