:~~= for Form
`
`U.S. DEPARf¥ENT OF COMMERCE PATENT ANO TRADEMARK OFFICE
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US}
`CONCERNING A FILING UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION NO.
`PCT/US2004/009387
`TITLE OF INVENTION
`
`March 26,12004
`'
`
`JC06 Rec'd PCT/PTO 2 8 SEP zoo,
`
`ATTORNEY'S DOCKET NUMBER
`033935-021
`
`PRIORITY DATE CLAIMED
`March 28, 2003
`
`I INTERNATIONAL FILING PATE
`
`/
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`APPLICANT($) FOR DO/EO/US
`Nicholas S. BODOR and Yogesh DANDIKER
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`1. IBI This is a FIRST submission to items concerning a filing under 35 U.S.C. 371.
`2. D This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`3. IBI This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission must include items (5),
`(6), (9) and (22) indicated below.
`4. D The US has been elected by the expiration of 19 months from the priority date (Article 31).
`!BJ A copy of the International Application as filed (35 U.S.C. 371 (c)(2))
`5.
`a. IBI is attached hereto (required only if not communicated by the International Bureau).
`b. D has been communicated by the International Bureau.
`c. IBI is not required, as the application was filed in the United States Receiving Office (RO/US).
`g. D An English language translation of the International Application as filed (35 U.S.C. 371 (c)(2))
`a. D is attached hereto.
`b. D has been previously submitted under 35 U.S.C. 154(d)(4).
`·-
`7. IBI Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371 (c)(3))
`a. D are attached hereto (required only if not communicated by the International Bureau).
`b. D have been communicated by the International Bureau.
`c. D have not been made; however, the time limit for making such amendments has NOT expired.
`d. IBI have not been made and will not be made.
`8. D An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
`9. D An oath or declaration of the inventor(s) (35 U.S.C. 371(c)(4)).
`10. D An English language tranlation of the annexes of the International Preliminary Examination Report under
`PCT Article 36 (35 U.S.C. 371 (c)(5)).
`
`A FIRST preliminary amendment.
`
`A SECOND or SUBSEQUENT preliminary amendment.
`
`Items 11 to 21 below concern document(s) or information included:
`11. D An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`12. 0
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`13_ 1B1
`14. 0
`15. 0
`16. 0
`A change of power of atJorney and/or address letter.
`17. D A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2 and 37 C.F.R. 1.821 - 1.825.
`18. D A second copy of the published international application under 35 U.S.C. 154(d)(4).
`19. D A second copy of the English language translation of the international application under 35 U.S.C, 154(d)(4).
`20. IBI Other items or information: _A'-=pp=l=ica=li=on'-'--"D'--=a""ta~S~h~ee=t~. __________________________ _
`
`A substitute specificati,on.
`
`Page 1 of 2
`
`Exhibit
`
`Hopewell EX 1057
`
`02/15/24 - EW
`
`exhibitsticker.com
`
`Exhibit #:
`
`Hopewell EX 1057
`
`02/15/24
`
`exhibitsticker.com
`
`Hopewell EX1057 (Part 1 of 2)
`Hopewell v. Merck
`IPR2023-00480
`
`1
`
`

`

`JC12 Rec'd PCT/PTC 2 8 SEP 2005
`U.S. APPLICAlOONJ·s~1ee,Cn 1'il INTERNATIONAL APPLICATION NO.
`I ATTORNEY'S DOCKET NUMBER
`
`PCT/US2004/009387
`
`033935-021
`CALCULATIONS PTO USE ONLY
`
`21. 0 Applicant(s) requests that the published application include the following assignment
`information:
`IVAX Comoration
`44QQ BiS~l£n!i! BQ!,!l!;!Vj;!rQ
`Miami EIQdga JJl JZ !JS
`
`22. m) The following fees are submitted:
`
`Basic Filing Fee (1631)
`
`Surcharge of $130.00 (1617) for furnishing the oath or declaration later than
`mnnlhc, frnm the c<>rl;oc,I rl<>it non orioritv n,:,lo ('>.7 ri::-1 1 AQ?fo\\
`NUMBER FILED
`CLAIMS
`NUMBER EXTRA
`78
`~20 =
`58
`Total Claims
`~3 =
`Independent Claims
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`6
`
`3
`
`Examination Fee
`
`Search Fee
`
`0 20 m) 30
`
`RATE
`X $50.00 (1615)
`
`$
`
`X $200.00 (1614)
`+ $360.00 (1616)
`
`+ $200.00 (1633)
`
`+ $500.00 (1632)
`
`0
`
`App. Size Fee (add $250.00 for each add'I 50 sheets exceeding 100 sheets)
`TOTAL OF ABOVE CALCULATIONS=
`Applicant daims small entity status. See 37 CFR 1.27. The fees indicated above
`are reduced by 1 /2.
`
`+
`SUBTOTAL=
`Processing fee of $130.00 (1618) for furnishing the English translation later than 020 030
`months from the earliest claimed priority date (37 CFR 1.492(f)).
`
`TOTAL NATIONAL FEE=
`Fee for recording the enclosed assignment (37 CFR 1.21 (h)). The assiQnment must be
`accomoanied by an aooropriate cover sheet (37 CFR 3.28, 3.31 ). $40.00 (8021) per property +
`TOTAL FEES ENCLOSED=
`
`$ 300.00
`
`$ 130.00
`
`$2,900.00
`
`$600.00
`
`$ 200.00
`
`$ 500.00
`
`$4,630.00
`
`$ 0.00
`
`$ 4,630.0C
`
`$0.00
`
`$ 4,630.0C
`
`$4,630.00
`Amount to be
`refunded:
`charged:
`
`l2SI A check in the amount of
`a.
`$4,630.00
`b. □ Please charge my Deposit Account No.
`duplicate copy of this sheet is enclosed.
`
`to cover the above fees is enclosed.
`
`02-4800
`
`in the amount of
`
`to cover the above fees. A
`
`C. ~ The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment to
`02-4800
`. A duplicate copy of this sheet is enclosed.
`Deposit Account No.
`
`d. 0 Charge
`
`to credit card. Form PTO-2038 is attached.
`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR 1.137(a)
`or {b)) must be filed and granted to restore the application to pending status.
`
`SEND ALL CORRESPONDENCE TO:
`
`Burns, Doane, Swecker & Mathis, L.L.P.
`P.O. Box 1404
`Alexandria, Virginia 22313-1404
`(703) 836-6620
`
`Page 2 of 2
`
`t:zffj!L,,,~
`
`Ma!}'. Katherine Baumeister
`
`NAME
`
`26,254
`REGISTRATION NO.
`
`Seetember 28, 2005
`DATE
`
`2
`
`

`

`:~~= for Form
`
`U.S. DEPARf¥ENT OF COMMERCE PATENT ANO TRADEMARK OFFICE
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US}
`CONCERNING A FILING UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION NO.
`PCT/US2004/009387
`TITLE OF INVENTION
`
`March 26,12004
`'
`
`JC06 Rec'd PCT/PTO 2 8 SEP zoo,
`
`ATTORNEY'S DOCKET NUMBER
`033935-021
`
`PRIORITY DATE CLAIMED
`March 28, 2003
`
`I INTERNATIONAL FILING PATE
`
`/
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`APPLICANT($) FOR DO/EO/US
`Nicholas S. BODOR and Yogesh DANDIKER
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`1. IBI This is a FIRST submission to items concerning a filing under 35 U.S.C. 371.
`2. D This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`3. IBI This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission must include items (5),
`(6), (9) and (22) indicated below.
`4. D The US has been elected by the expiration of 19 months from the priority date (Article 31).
`!BJ A copy of the International Application as filed (35 U.S.C. 371 (c)(2))
`5.
`a. IBI is attached hereto (required only if not communicated by the International Bureau).
`b. D has been communicated by the International Bureau.
`c. IBI is not required, as the application was filed in the United States Receiving Office (RO/US).
`g. D An English language translation of the International Application as filed (35 U.S.C. 371 (c)(2))
`a. D is attached hereto.
`b. D has been previously submitted under 35 U.S.C. 154(d)(4).
`·-
`7. IBI Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371 (c)(3))
`a. D are attached hereto (required only if not communicated by the International Bureau).
`b. D have been communicated by the International Bureau.
`c. D have not been made; however, the time limit for making such amendments has NOT expired.
`d. IBI have not been made and will not be made.
`8. D An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
`9. D An oath or declaration of the inventor(s) (35 U.S.C. 371(c)(4)).
`10. D An English language tranlation of the annexes of the International Preliminary Examination Report under
`PCT Article 36 (35 U.S.C. 371 (c)(5)).
`
`A FIRST preliminary amendment.
`
`A SECOND or SUBSEQUENT preliminary amendment.
`
`Items 11 to 21 below concern document(s) or information included:
`11. D An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`12. 0
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`13_ 1B1
`14. 0
`15. 0
`16. 0
`A change of power of atJorney and/or address letter.
`17. D A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2 and 37 C.F.R. 1.821 - 1.825.
`18. D A second copy of the published international application under 35 U.S.C. 154(d)(4).
`19. D A second copy of the English language translation of the international application under 35 U.S.C, 154(d)(4).
`20. IBI Other items or information: _A'-=pp=l=ica=li=on'-'--"D'--=a""ta~S~h~ee=t~. __________________________ _
`
`A substitute specificati,on.
`
`Page 1 of 2
`
`3
`
`

`

`JC12 Rec'd PCT/PTC 2 8 SEP 2005
`U.S. APPLICAlOONJ·s~1ee,Cn 1'il INTERNATIONAL APPLICATION NO.
`I ATTORNEY'S DOCKET NUMBER
`
`PCT/US2004/009387
`
`033935-021
`CALCULATIONS PTO USE ONLY
`
`21. 0 Applicant(s) requests that the published application include the following assignment
`information:
`IVAX Comoration
`44QQ BiS~l£n!i! BQ!,!l!;!Vj;!rQ
`Miami EIQdga JJl JZ !JS
`
`22. m) The following fees are submitted:
`
`Basic Filing Fee (1631)
`
`Surcharge of $130.00 (1617) for furnishing the oath or declaration later than
`mnnlhc, frnm the c<>rl;oc,I rl<>it non orioritv n,:,lo ('>.7 ri::-1 1 AQ?fo\\
`NUMBER FILED
`CLAIMS
`NUMBER EXTRA
`78
`~20 =
`58
`Total Claims
`~3 =
`Independent Claims
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`
`6
`
`3
`
`Examination Fee
`
`Search Fee
`
`0 20 m) 30
`
`RATE
`X $50.00 (1615)
`
`$
`
`X $200.00 (1614)
`+ $360.00 (1616)
`
`+ $200.00 (1633)
`
`+ $500.00 (1632)
`
`0
`
`App. Size Fee (add $250.00 for each add'I 50 sheets exceeding 100 sheets)
`TOTAL OF ABOVE CALCULATIONS=
`Applicant daims small entity status. See 37 CFR 1.27. The fees indicated above
`are reduced by 1 /2.
`
`+
`SUBTOTAL=
`Processing fee of $130.00 (1618) for furnishing the English translation later than 020 030
`months from the earliest claimed priority date (37 CFR 1.492(f)).
`
`TOTAL NATIONAL FEE=
`Fee for recording the enclosed assignment (37 CFR 1.21 (h)). The assiQnment must be
`accomoanied by an aooropriate cover sheet (37 CFR 3.28, 3.31 ). $40.00 (8021) per property +
`TOTAL FEES ENCLOSED=
`
`$ 300.00
`
`$ 130.00
`
`$2,900.00
`
`$600.00
`
`$ 200.00
`
`$ 500.00
`
`$4,630.00
`
`$ 0.00
`
`$ 4,630.0C
`
`$0.00
`
`$ 4,630.0C
`
`$4,630.00
`Amount to be
`refunded:
`charged:
`
`l2SI A check in the amount of
`a.
`$4,630.00
`b. □ Please charge my Deposit Account No.
`duplicate copy of this sheet is enclosed.
`
`to cover the above fees is enclosed.
`
`02-4800
`
`in the amount of
`
`to cover the above fees. A
`
`C. ~ The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment to
`02-4800
`. A duplicate copy of this sheet is enclosed.
`Deposit Account No.
`
`d. 0 Charge
`
`to credit card. Form PTO-2038 is attached.
`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR 1.137(a)
`or {b)) must be filed and granted to restore the application to pending status.
`
`SEND ALL CORRESPONDENCE TO:
`
`Burns, Doane, Swecker & Mathis, L.L.P.
`P.O. Box 1404
`Alexandria, Virginia 22313-1404
`(703) 836-6620
`
`Page 2 of 2
`
`t:zffj!L,,,~
`
`Ma!}'. Katherine Baumeister
`
`NAME
`
`26,254
`REGISTRATION NO.
`
`Seetember 28, 2005
`DATE
`
`4
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-1-
`
`ORAL FORMULATIONS OF CLADRIBINE
`
`FIELD OF THE INVENTION
`
`5
`
`The invention relates to a composition comprising a complex
`-
`.
`cladribine-cyclodextrin complex formulated into a solid oral dosage form and
`to a method for enhancing the oral bioavailability of cladribine.
`
`BACKGROUND OF THE INVENTION
`
`Cladribine, which is an acid-labile drug, has the chemical structure as
`set forth below:
`
`10
`
`OH
`
`15
`
`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 disorders. It has been used to treat experimental ·
`leukemias such as L 1210 and clinically for hairy cell leukemia and chronic
`lymphocytic leukemia as well as Waldenstrom's macroglobulinaemia. It has
`
`5
`
`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-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, C/in. 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 dn_Jgs. 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 higher 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. Oneal., 10(10): 1514-
`1518, 1992), and suboptimal interpatient variation {see, e.g., J. Liliemark,
`Clin. Pharmacokinet, 32 (2): 120-131, 1997). See also, A. Tarasuik, et al.
`reporting poor absorption and pH dependent !ability (Arch. lmmunol. et
`Therapiae Exper., 42: 13-15, 1994).
`
`Cyclodextrins are cyclic oligosaccharides composed of cyclic a-(1---+4)
`linked 0-glucopyranose units. Cyclodextrins with six to eight units have
`
`5
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`10
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`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-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 y-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 81, have
`described complexing and solubilizing cladribine with cyclodextrin. The
`Schultz et al. patent primarily addresses the problems inherent in previously
`described aqueous formulations of cladribine, 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
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`15
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`WO 2004/087101
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`PCT/US2004/009387
`
`-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
`cladribine 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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`10
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`15
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`20
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`25
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`

`WO 2004/087101
`
`PCT/0S2004/009387
`
`-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 lower 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 bioavaifability of ~ladribine comprising orally administering to a subject in
`need thereof, a pharmaceutical composition comprising 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-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
`
`5
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`
`15
`
`20
`
`25
`
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`

`

`WO 2004/087101
`
`PCT/US2004/009387
`
`-6-
`
`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:
`
`5
`
`(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.
`
`10
`
`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;
`
`15
`
`(ii) cooling the resultant aqueous solution to room temperature;
`
`(iii) lyophilizing the cooled solution to afford an amorphous product;
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`and
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`(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-l3-cyclodextrin (HPJ3CD) are
`
`plotted against various cladribine molar concentrations, with ( •) representing
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`the data points obtained for complexation under conditions specified in
`EXAMPLE 2 below.
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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 referen.ce 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 latter.
`
`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 cfadribine 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 cycfodextrin torus (e.g. in the case of hydroxypropyl-'3-
`cyclodextrin, hydroxypropyl and hydroxyl groups on the glucose rings). This
`is a more loosely-held association than an inclusion complex.
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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 "consisting 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 associated 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 taken
`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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`The terms "consists or 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.
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`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 in
`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 cyclodextrin 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', as in "substantially 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 end-points of the range. Similarly, for a
`variable which is inherently continuous, the variable can be equal to any real
`value of the numerical range, including the end-points of the range. As an
`example, a variable which is described as having values between O and 2,
`can be 0, 1 or 2 for variables which are inherently discrete, and can be 0.0,
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`0.1, 0.01, 0.001, or any other real value for variables which are inherently
`continuous.
`
`In the specification and claims, the singular forms include plural
`referents unless the context clearly dictates otherwise. As used herein,
`unless specifically indicated otherwise, the word "or" is used in the "inclusive"
`sense of "and/or" and not the "exclusive" sense of "either/or."
`
`Technical and scientific terms used herein have the meaning
`commonly understood by one of skill in the art to which the present invention
`pertains, unless otherwise defined. Reference is made herein to various
`methodologies and materials known to those of skill in the art. Standard
`reference works setting forth the general principles of pharmacology include
`Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th
`Ed., McGraw Hill Companies Inc., New York (2001).
`
`Reference is made hereinafter in detail to specific embodiments of the
`invention. While the invention will be described in conjunction with these
`specific embodiments, it will be understood that it is not intended to limit the
`invention to such specific embodiments. On the contrary, it is intended to
`cover alternatives, m