Patent
`Attorney’s Docket No. 0056192-000024
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`MAIL STOP AMENDMENT
`
`Group Art Unit: 1623
`
`Examiner: JONATHAN S LAU
`
`Confirmation No.: 4092
`
`) ) ) ) ) ) ) )
`
`In re Patent Application of
`
`Nicholas Bodor etal.
`
`Application No.: 10/551,205
`
`Filed: November 14, 2006
`
`For: ORAL FORMULATIONS OF
`
`CLADRIBINE
`
`REPLY AND AMENDMENT
`
`Commissioner for Patents
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`In responseto the Office Action dated April 4, 2008, please first amend the
`
`above-identified patent application as follows:
`
`.
`Buchanan Ingersoll 4. Rooney Pc
`Attorneys & Government Relations Professionals
`Page 1 of 56
`
`Merck 2072
`TWi v Merck
`IPR2023-00050
`
`Page 1 of 56
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`

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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551 ,205
`Page 2
`
`AMENDMENTS TO THE SPECIFICATION:
`
`Please replace the paragraph at page 22, lines 8-16 of the specification with
`
`the following amended paragraph:
`
`The compositions of the invention are particularly suitable
`
`as modalities for the treatment of any cladribine-responsive disease. Several
`
`disease states responsive to cladribine are well-documented in the
`
`literature (see infra). For any target disease state, an effective amountof the
`
`complex cladribine-cyclodextrin cemples complex, j.e. the amorphous mixture
`
`of the optimized amorphous saturated cladribine-amorphous cyclodextrin
`
`complex with amorphous free cladribine as described above is used (e.g., an
`
`amount affective effective for the treatment of multiple sclerosis, rheumatoid
`
`arthritis, or leukemia).
`
`Please replace the paragraph at page 23, lines 7-28, of the specification with
`
`the following amended paragraph:
`
`Moreover, the route of administration for which the therapeutically
`
`effective dosages are taught in the literature should be taken into
`
`consideration. While the instant compositions optimize the bioavailability of
`
`cladribine following oral administration, it will be appreciated that even optimal
`
`bioavailability from oral dosage forms is not expected to approach
`
`bioavailability ebtain obtained after intravenous administration, particularly at
`
`early time points. Thus, it is often appropriate to increase a dosage
`
`suggested for intravenous administration to arrive at a suitable dosage for
`
`incorporation into a solid oral dosage form. At the presenttime, it is envisioned
`
`that, for the treatment of multiple sclerosis, 10 mg of cladribine in the instant
`
`complex cladribine-cyclodextrin complexin the instant solid dosage form
`
`would be administered once per day for a period of five to seven daysin the
`
`first month, repeated for another period of five to seven days in the second
`
`month, followed by ten months of no treatment. Alternatively the patient would
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 3
`
`be treated with 10 mg ofcladribine in the instant complex cladribine-
`
`cyclodextrin complexin the instant dosage form once perday for a period of
`five to seven days per monthfor a total of six months, followed by eighteen
`months of no treatment.
`Forfurtherdesing-infermation_seealse-U-S.
`
`
`ProvisionalPatent
`
`
`
`Page 3 of 56
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 4
`
`AMENDMENTS TO THE CLAIMS:
`
`This listing of claims will replace all prior versions, andlistings, of claims in the
`
`application:
`
`LISTING OF CLAIMS:
`
`1.
`
`(Currently Amended)
`
`A pharmaceutical composition comprising a
`
`complex cladribine-cyclodextrin complex which is an intimate amorphous admixture
`consisting 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,
`
`said composition comprising no significant amount of free crystalline cladribine
`
`therein.
`
`2.
`
`(Currently Amended)
`
`The pharmaceutical composition according
`
`to Claim 1, wherein the complex cladribine-cyclodextrin complex is saturated with
`
`cladribine.
`
`3.
`
`(Previously Presented)
`
`The composition according to Claim 1,
`
`wherein the amorphous cyclodextrin is hydroxypropyl-6-cyclodextrin,
`
`hydroxypropyl-y-cyclodextrin, randomly methylated B-cyclodextrin,
`
`carboxymethyl-B-cyclodextrin or sulfobuty!-B-cyclodextrin.
`
`4.
`
`(Previously Presented)
`
`The composition according to Claim 1,
`
`wherein the amorphous cyclodextrin is hydroxypropyl-8-cyclodextrin.
`
`5,
`
`(Previously Presented)
`
`The composition according to Claim 1,
`
`wherein the amorphous cyclodextrin is hydroxypropyl-y-cyclodextrin.
`
`6.
`
`(Previously Presented) The composition according to Claim 1,
`
`wherein the weight ratio of cladribine to amorphous cyclodextrin is from about 1:10 to
`
`about 1:16.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 5
`
`7.
`
`(Original)
`
`The composition according to Claim 6, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin.
`
`8.
`
`(Original)
`
`The composition according to Claim 7, wherein the
`
`weight ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:14.
`
`9.
`
`(Original)
`
`The composition according to Claim 7, wherein the
`
`weight ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:11.
`
`10.
`
`(Original)
`
`The composition according to Claim 6, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-y-cyclodextrin.
`
`11.
`
`(Currently Amended)
`
`The composition according to Claim Claim
`
`2, wherein the approximate molar ratio of cladribine to amorphous cyclodextrin
`
`corresponds to a point located on the curve of a phase solubility diagram for
`
`saturated complex cladribine-cyclodextrin complexes, said curve defining complex
`
`saturated complexes of cladribine in varying concentrations of the cyclodextrin.
`
`12.
`
`(Previously Presented)
`
`The composition according to Claim 1,
`
`wherein from about 30 to about 40 percent by weight of the cladribine is in the
`
`inclusion complex (a) and from about 70 to about 60 percent by weight of the
`
`cladribine is in the non-inclusion complex (b).
`
`13.
`
`(Withdrawn and Currently Amended)
`
`A method for enhancing the
`
`oral bioavailability of cladribine comprising orally administering to a subject in need
`
`thereof a pharmaceutical composition comprising a complex cladribine-cyclodextrin
`
`complex which is an intimate amorphous admixture consisting 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, said composition comprising no significant
`
`amountof free crystalline cladribine therein.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 6
`
`14.
`
`(Withdrawn and Currently Amended)
`
`The method according to
`
`Claim 13, wherein the complex cladribine-cyclodextrin complex is saturated with
`
`cladribine.
`
`15.
`
`(Withdrawn) The method according to Claim 13, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin,
`
`hydroxypropyl-y-cyclodextrin, randomly methylated B-cyclodextrin,
`
`carboxymethyl-B-cyclodextrin or sulfobutyl-B-cyclodextrin.
`
`16.
`
`(Withdrawn) The method according to Claim 13, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin.
`
`17.
`
`(Withdrawn) The method according to Claim 13, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-y-cyclodextrin.
`
`18.
`
`(Withdrawn) The method according to Claim 13, wherein the weight
`
`ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16.
`
`19.
`
`(Withdrawn) The method according to Claim 18, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin.
`
`20.
`
`(Withdrawn) The method according to Claim 19, wherein the weight
`
`ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:14.
`
`21.
`
`(Withdrawn) The method according to Claim 19, wherein the weight
`
`ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:11.
`
`22.
`
`(Withdrawn) The method according to Claim 18, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-y-cyclodextrin.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 7
`
`The method according to
`(Withdrawn and Currently Amended)
`23.
`Glaim-t+3 Claim 14, wherein the approximate molar ratio of cladribine to amorphous
`cyclodextrin correspondsto a point located on the curve of a phasesolubility
`diagram for saturated complex cladribine-cyclodextrin complexes, said curve
`
`defining complex saturated complexes of cladribine in varying concentrations of the
`
`cyclodextrin.
`
`24.
`
`(Withdrawn) The method according to Claim 13, wherein from about
`
`30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and
`from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion
`
`complex (b).
`
`25.
`
`(Withdrawn and Currently Amended)
`
`A methodfor the treatment of
`
`symptomsof a cladribine-responsive condition in a subject suffering from said
`
`symptoms comprising orally administering to said subject a pharmaceutical
`
`composition comprising a complex cladribine-cyclodextrin complex which is an
`
`intimate amorphous admixture consisting of (a) an amorphousinclusion 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, said composition comprising no significant amountof free
`
`crystalline cladribine therein.
`
`26.
`
`(Withdrawn and Currently Amended)
`
`The method according to
`
`Claim 25, wherein the complex cladribine-cyclodextrin complex is saturated with
`
`cladribine.
`
`2/7.
`
`(Withdrawn) The method according to Claim 25, wherein the
`
`cladribine-responsive condition is selected from the group consisting of multiple
`
`sclerosis, rheumatoid arthritis and leukemia.
`
`28.
`
`(Withdrawn) The method according to Claim 27, wherein the
`
`cladribine-responsive condition is multiple sclerosis.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 8
`
`29.
`
`(Withdrawn) The method according to Claim 25, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin,
`
`hydroxypropyl-y-cyclodextrin, randomly methylated B-cyclodextrin,
`
`carboxymethyl-B-cyclodextrin or sulfobuty!-B-cyclodextrin.
`
`30.
`
`(Withdrawn) The method according to Claim 25, wherein the weight
`
`ratio of cladribine to amorphous cyclodextrin is from about 1:10 to about 1:16.
`
`31.
`
`(Withdrawn) The method according to Claim 25, wherein the
`
`amorphous cyclodextrin is hydroxypropyl-B-cyclodextrin.
`
`32.
`
`(Withdrawn) The method according to Claim 31, wherein the weight
`
`ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:14.
`
`33.
`
`(Withdrawn) The method according to Claim 31, wherein the weight
`
`ratio of cladribine to hydroxypropyl-B-cyclodextrin is about 1:11.
`
`34.
`
`(Withdrawn) The method according to Claim 25, wherein the
`
`amorphous cyclodextrin is hydropropyl-y-cyclodextrin.
`
`35.
`
`(Withdrawn) The method according to Claim 25, wherein from about
`
`30 to about 40 percent by weight of the cladribine is in the inclusion complex (a) and
`
`from about 70 to about 60 percent by weight of the cladribine is in the non-inclusion
`
`complex (b).
`
`36.-55.
`
`(Cancelled)
`
`56.
`
`(Currently Amended)
`
`A complex cladribine-cyclodextrin complex
`
`which is an intimate amorphous admixture consisting 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.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 9
`
`57.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 56, saturated with cladribine.
`
`58.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 56, wherein the amorphous cyclodextrin is
`
`hydroxypropyl-B-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated
`
`B-cyclodextrin, carboxymethyl-B-cyclodextrin or sulfobutyl-B-cyclodextrin.
`
`59.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 56, wherein the amorphous cyclodextrin is
`
`hydroxypropyl-8-cyclodextrin.
`
`60.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 56, wherein the amorphous cyclodextrin is
`
`hydroxypropyl-y-cyclodextrin.
`
`61.
`
`The complex cladribine-cyclodextrin
`complex according to Claim 56, wherein the weight ratio of cladribine to amorphous
`
`(Currently Amended)
`
`cyclodextrin is from about 1:10 to about 1:16.
`
`62.
`
`The complex cladribine-cyclodextrin
`complex according to Claim 61, wherein the amorphous cyclodextrin is
`
`(Currently Amended)
`
`hydroxypropyl-B-cyclodextrin.
`
`63.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 62, wherein the weight ratio of cladribine to
`
`hydroxypropyl-8-cyclodextrin is about 1:14.
`
`64.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 62, wherein the weightratio of cladribine to
`
`hydroxypropyl-8-cyclodextrin is about 1:11.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 10
`
`65.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 61, wherein the amorphous cyclodextrin is
`
`hydroxypropyl-y-cyclodextrin.
`
`66.
`
`(Currently Amended)
`
`The complex cladribine-cyclodextrin
`
`complex according to Claim 56, wherein from about 30 to about 40 percent by weight
`
`of the cladribine is in the inclusion complex (a) and from about 70 to about 60
`
`percent by weight of the cladribine is in the non-inclusion complex (b).
`
`67.
`
`(Withdrawn and Currently Amended) A processfor the preparation of
`
`a complex cladribine-cyclodextrin complex as claimed in Claim 56, which comprises
`
`the steps of:
`
`(i)
`
`combining cladribine and an amorphous cyclodextrin in water at a
`
`temperature of from about[[40]] 45 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.
`
`68.
`
`(Withdrawn) A process according to Claim 67, further comprising a
`
`filtration step following step(ii).
`
`69.
`
`(Withdrawn) A process according to Claim 67, wherein step(i) is
`
`performed at a temperature of from about 45 to about 60°C.
`
`70.
`
`(Withdrawn) A process according to Claim 67, wherein step (i) is
`
`performed at a temperature of from about 45 to about 50°C.
`
`71.
`
`(Withdrawn) A process according to Claim 69, wherein step (i) is
`
`performedwith stirring.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 11
`
`72.
`
`(withdrawn) A process according to Claim 71, wherein step (i) is
`
`performed for a period of from about 6 to about 9 hours.
`
`73.
`
`(Withdrawn) A process according to Claim 67, wherein step(ii) is
`
`performed for a period of from about 6 to about 9 hours.
`
`74,
`
`(Withdrawn) A process according to Claim 67, wherein step(iii)
`
`comprises an initial freezing stage in which the solution is cooled to from about -40 to
`
`about -80° C, and held at said temperature for a period of from about 2 to about 4
`
`hours.
`
`75.
`
`(Withdrawn) A process according to Claim 74, wherein, in theinitial
`
`freezing stage of step(iii), the solution is cooled to about -45°C.
`
`(Withdrawn) A process according to Claim 67, wherein 12.00 parts by
`76.
`weight of cladribine and 172.50 parts by weight of hydroxypropyl-B-cyclodextrin are
`
`introduced in step (i).
`
`77.|(Withdrawn) A process according to Claim 67, wherein 16.35 parts by
`weight of cladribine and 172.50 parts by weight of hydroxypropyl-B-cyclodextrin are
`
`introducedin step(i).
`
`78.|(Withdrawn) A process according to Claim 76, wherein 825 parts by
`
`volume of water are introducedin step (i).
`
`79.
`
`(Withdrawn) A process according to Claim 67, wherein the
`
`lyophilization step (iii) comprises:
`(a)
`an initial freezing stage in which the complexation solution is brought to
`
`from about -40°C to about -80°C for approximately 2 to 4 hours;
`
`(b) a primary drying stage at about -25°C for approximately 80 to 90 hours;
`
`and
`
`(c) a secondary drying stage at about 30°C for approximately 15 to 20 hours.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 12
`
`(Withdrawn) A process according to Claim 79, wherein stage (a) of the
`80.
`lyophilization is conducted at about -45°C for approximately 3 to 4 hours.
`
`(Withdrawn) A process according to Claim 79, wherein stage (b) of the
`81.
`lyophilization is conducted under a pressure of about 100 mTorr.
`
`82.
`
`(Currently Amended)
`
`A pharmaceutical composition obtainable by
`
`a process comprising the stepsof:
`
`(i)
`
`combining cladribine and an amorphous cyclodextrin in water at a
`
`temperature of from about [[40]] 45 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;
`
`(iii)|lyophilizing the cooled solution to afford an amorphous product; and
`
`(iv)
`
`formulating the amorphous productinto a solid oral dosage form.
`
`83.
`
`(Original)
`
`A pharmaceutical composition according to Claim 82,
`
`wherein the process further comprisesa filtration step following step (i) or (ii).
`
`84.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein step(i) of the process is performed at a temperature of from about
`
`45 to about 60°C.
`
`85.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein step (i) of the process is performed at a temperature of from about
`
`45 to about 50°C.
`
`86.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 84, wherein step (i) of the process is performed with stirring.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 13
`
`A pharmaceutical composition according to Claim 86,
`(Original)
`87.
`wherein step (i) of the process is performed for a period of from about 6 to about 9
`
`hours.
`
`A pharmaceutical composition according to
`(Previously Presented)
`88.
`Claim 82, wherein step(ii) of the process is performed for a period of from about 6 to
`
`about 9 hours.
`
`89.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein step(iii) comprises an initial freezing stage in which the solution is
`
`cooled to from about -40 to about -80°C, and held at said temperature for a period of
`
`from about 2 to about 4 hours.
`
`90.
`
`(Original)
`
`A pharmaceutical composition according to Claim 89,
`
`wherein, in theinitial freezing stage of step (iii), the solution is cooled to about -45°C.
`
`91.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein 12.00 parts by weight of cladribine and 172.50 parts by weightof
`
`the hydroxypropyl-B-cyclodextrin are introduced in step (i) of the process.
`
`92.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein 16.35 parts by weight of cladribine and 172.50 parts by weight of
`
`the hydroxypropyl-8-cyclodextrin are introduced in step (i) of the process.
`
`93.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 91, wherein 825 parts by volume of water are introducedin step (i) of the
`
`process.
`
`94.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein the lyophilization step(iii) of the process comprises:
`
`(a) an initial freezing stage in which the complexation solution is brought to
`
`from about -40°C to about -80°C for approximately 2 to 4 hours;
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 14
`
`(b) a primary drying stage at about -25°C for approximately 80 to 90 hours;
`
`and
`
`(c) a secondary drying stage at about 30°C for approximately 15 to 20 hours.
`
`95.
`
`(Original)
`
`A pharmaceutical composition according to Claim 94,
`
`wherein stage (a) of the lyophilization is conducted at about -45°C for approximately
`
`3 to 4 hours.
`
`96.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 94, wherein stage (b) of the lyophilization is conducted under a pressure of
`
`about 100 mTorr.
`
`97.
`
`(Previously Presented)
`
`A pharmaceutical composition according to
`
`Claim 82, wherein the formulation step (iv) of the process comprises blending the
`
`complex with magnesium stearate and compressing into tablets.
`
`98.
`
`(Original)
`
`A pharmaceutical composition according to Claim 97,
`
`wherein magnesium stearate is pre-mixed with sorbitol powder before blending with
`
`the complex.
`
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 15
`
`REMARKS
`
`Entry of the foregoing and reexamination and reconsideration of the subject
`
`application, as amended, pursuantto and consistent with 37 C.F.R. § 1.112, are
`
`respectfully requested in light of the following remarks.
`
`Applicants appreciate the Examiner's acceptance of the drawing asfiled.
`
`THE DRAWINGS
`
`INFORMATION DISCLOSURE STATEMENTS
`
`Applicants thank the Examiner for considering the four Information Disclosure
`
`Statements previously filed herein.
`
`FILING DATES TO WHICH CLAIMS ARE ENTITLED
`
`The Examiner has assessedthe filing dates to which he believes the claims
`
`which he has examinedare entitled. Thus, Claims 1-12, 56-66 and 82-98 have been
`
`assessed by the Examinerin regard to the earliest filing date to which he believes
`
`they are entitled.
`Applicants have amended Claim 82 hereinabove sothat step (i) is conducted
`at a temperature from about 45 to about 80°C rather than from about 40 to about
`80°C as previously recited. This revised range is not only supported by the instant
`application (e.g., page 13, lines 21-25) but also by page 12, lines 20-23, of
`Provisional AppIn. No. 60/541 ,247, filed February 4, 2004; moreover, step (ii) is
`disclosed at least on page 14, line 3 and in Example 2 of 60/541,247; step(iii) at
`least on page 14, line 6 and Example 2 of 60/541,247; and step (iv) at least on page
`17, lines 25-27, page 18, lines 7-10 and Example 3 of 60/541,247. Claim 88 is
`supported at least by page 12, lines 20-22 of 60/541,247. Thus, applicants concur
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`with the Examinerthat the filing dates of Claims 1-11, 56-65, 84, 86 and 87 are the
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`filing date of Application No. 60/541 ,247, filed February 4, 2004, but add that the
`filing dates of Claims 82 and 88 are also the February 4, 2004filing date of
`Application No. 60/541,247.
`Applicants concur with the Examiner's assessmentthat Claims 12, 66, 83, 85
`and 89 are entitled to the effective filing date of the present application; however, as
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`Page 15 of 56
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`Page 15 of 56
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 16
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`a national phase application, this application and thus Claims 12, 66, 83, 85 and 89
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`are entitled to the international filing date of PCT/US04/09387, that is, March 26
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`2004. The Examiner's reference to November 14, 2006 as thefiling date for these
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`claimsis incorrect, that date simply being the date on which the requirements of the
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`last of the 371(c)(1), (c)(2) and (c)(4) requirements were received by the USPTO.
`
`In
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`the official Notice of Acceptance of Application under 35 U.S.C. 371 and 37 C.F.R.
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`1.495, it is clearly stated: "The filing date of the aboveidentified application is the
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`international filing date of the international application (Article 11(3) and 35 U.S.C.
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`363)."
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`Despite the foregoing, it is not understood why the Examiner hasfound it
`
`necessary to assessthe priority dates of the examined claims, as no art has been
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`cited which would make it necessary to make such an assessment.
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`ELECTIONS/RESTRICTIONS
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`Applicants’ election, with traverse, of the invention of Group |, Claims 1-12,
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`56-66 and 82-98 has been acknowledged and acted upon. Applicants continue to
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`maintain that the amorphous nature of the various entities which make up the
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`complex, that is the intimate amorphous admixture of (a) an amorphous inclusion
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`complex of cladribine with amorphous cyclodextrin and (b) amorphous free cladribine
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`associated with amorphous cyclodextrin as a non-inclusion complex whichis
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`formulated into a solid dosage form is not disclosed or suggested by Schultz etal.
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`even when read in conjunction with WO 97/18839, as Schultz et al.'s melt extrusion
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`product would not be inherently the same as applicants’ Claim 1 product. Applicants’
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`reasons for so stating are set forth in the discussion of the references herein below.
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`Based on the discussion below, applicants submit that because the elected claims
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`are in fact patentable over the art of record, there is indeed the unifying feature to all
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`of the claims which applicants pointed to earlier. Therefore, the withdrawn claims
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`should be rejoined and examined.
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`OBJECTIONS TO THE SPECIFICATION
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`The disclosure has been objected to becauseof the blanks identifying
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`provisional application numbers on page 23. By the foregoing amendment,
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`Page 16 of 56
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`Page 16 of 56
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`Attorney's Docket No. 0056192-000024
`Application No. 10/551,205
`Page 17
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`applicants have deleted the entire sentence containing the blanks because the
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`applications in question have been abandoned.
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`The disclosure has also been objected to because of a typographical error on
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`page 22, line 12. Applicants have corrected the error by the foregoing amendment.
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`It is believed that these amendments overcomethe objections to the
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`specification.
`
`CLAIM REJECTIONS- 35 U.S.C. § 112
`
`Claims 2, 11 and 57 are also rejected under 35 U.S.C. § 112, second
`
`paragraph, as being indefinite because of use of the term "saturated." Applicants
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`submit that the claims are indeed clear and particularly point out and distinctly claim
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`whatapplicants regard astheir invention.
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`The Federal Circuit has made it very clear that definiteness of claim language
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`must not be analyzed in a vacuum butrather (1) in light of applicants’ specification,
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`(2) in light of the prior art, and (3) in light of the manner in which the claims would be
`
`interpreted by oneof ordinary skill in the relevant art. When analyzed in accord with
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`Federal Circuit decisions, applicants’ claims are definite. Applicants' claims are
`
`understandable and define what they regard as their invention; according to the
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`C.C. P.A. decision /n re Kamalet al. (CCPA 1968) 158 USPQ 120, such claims meet
`
`the requirements of the second paragraph of 35 U.S.C. § 112.
`
`In an effort to make
`
`these claims and others containing similar language even clearer, applicants have
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`modified the language that refers to the saturated complexes to makeit clear thatit
`
`is the complex cladribine-cyclodextrin complexes which are saturated. Applicants
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`have also modified the language of Claim 11; it would of course be apparent to the
`
`person of ordinary skill that applicants were referring to a point on the curve of the
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`phase solubility diagram. The claims as amended have the same scopeas prior to
`
`the amendment; these are not narrowing amendments but merely clarification of the
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`subject matter to which the claims were previously directed.
`
`The Examiner has noted that the term "saturated" is not defined in the claims,
`
`but applicants submit thatit is the function of the specification, not the claims, to
`
`define terms. Applicants have certainly explained what they mean by saturated, not
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`only by the disclosure at page 10, lines 1-13, but also by the disclosure at page 6,
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`Page 17 of 56
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`Page 17 of 56
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 18
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`line 20 to page7, line 2; by the disclosure beginning at page 13, line 14 through
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`page 14, line 16, which details the procedure used to develop the phase solubility
`
`curve; and by the disclosure at page 15, lines 5-29. Very specific information is
`
`given, not only as to time and temperature and subsequentfiltration, on page 13,
`
`lines 21-26, but also in the discussion extending from page 16, line 1 to page 17,
`
`line 14. The phasesolubility diagram and the discussion of the phase solubility
`diagram in Example 1 (and by reference, the complexation portion of Example 2)
`describe exactly how this phase solubility diagram/curve was generated. One of
`ordinary skill need only select a point on the phase solubility curve to identify the
`proportion of cladribine and cyclodextrin appropriate for the described saturated
`complexes for the conditions used in applicants’ study. Alternatively, one of ordinary
`skill can repeat applicants' study to obtain the same curve, or can create his/her own
`phasesolubility diagram for other conditions which he/she selects. The pointis that
`applicants' work is reproducible, based on the teachingsof their specification;
`selection of the same conditions as describedwill afford the same results; thus, the
`
`meaning of the claims which use the word "saturated" and which refer to the phase
`solubility diagram is clear to one of ordinary skill. As to the Examiner's complaint
`that no standard is given such as temperature, pressure or solvent, this is manifestly
`
`untrue forit is perfectly clear that the solvent disclosed in the specification is water
`and that the temperature and time are discussed with particularity in the
`specification, including the Examples, as already pointed out. Pressure is not
`mentioned because the work was carried out at atmospheric pressure, as would be
`
`understood by the skilled worker (who would know that pressure need beindicated
`onlyif it deviates from atmospheric pressure). Therefore, while there is no need to
`determine the amounts for each composition, at least when the cyclodextrin is
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`hydroxypropyl-B-cyclodextrin or even hydroxypropyl-y-cyclodextrin (page 17, lines 9-
`14) and the phasesolubility curve provided by applicants can be used, it would be a
`very routine matter for one of ordinary skill to create such a curve for other
`amorphouscyclodextrins or to merely combinecladribine with the chosen
`cyclodextrin using the conditions specified by applicants and then remove excess
`cladribine. This is a simple procedure given all of applicants’ teachings; it is not
`
`rocket science but rather is well within the skill in the art.
`
`Page 18 of 56
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`Page 18 of 56
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`Attorney’s Docket No. 0056192-000024
`Application No. 10/551,205
`Page 19
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`For at least the reasons set forth above, applicants submit that the 35 U.S.C.
`
`§ 112, second paragraph, rejection is untenable and should be withdrawn.
`
`CLAIM REJECTIONS- 35 U.S.C. § 102
`
`Claims 1-15, 11, 56-60, 82-90 and 84-98 have been rejected under 35 U.S.C.
`
`§ 102(b) as being anticipated by Schultz et al. U.S. Patent No. 6,194,395, as
`
`evidenced by Baert et al. WO 97/18839.
`
`Before discussing the cited references, applicants wouldlike to discuss the
`
`amendments madeto the claims hereinabove which makeclearer what applicants
`
`regard as their invention. The Examiner is thanked for his very thorough review of
`
`the specification and the claim language, which has made it possible for applicants
`
`to see that someoftheir original language might have been open to misinterpretation
`
`while other language could be interpreted more broadly than they had intended. The
`
`amendments to Claims 2, 11 and 57 (as well as to withdrawn claims containing
`
`corresponding language)clarify thatit is the entire complex cladribine-cyclodextrin
`
`complex which is saturated and that the point is located on the curve defining the
`
`saturated complexesas in the Figure. Applicants have also amended Claims 1 and
`
`56 (and thus their dependentclaims as well), as well as corresponding withdrawn
`
`claims, so that both Claims 1 and 56 now specify that the complex cladribine-
`
`cyclodextrin complex is an intimate amorphous admixture consisting 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. This of course excludes anything else from the complex. Claim
`
`1, drawn to a pharmaceutical composition comprising the complex, has been further
`
`amended (as have the withdrawn claims containing corresponding language) to
`
`specify that the composition comprises no significant amountof free crystalline
`
`cladribine therein. This means that no significant amount of free cladribine can be
`
`detected considering the sensitivity of the analytical method; see Example 2, page
`
`31, lines 3-13, where this language finds specific support. Applicants teach
`
`throughoutthis application that free crystalline cladribine which is not in the complex
`
`is excluded; see for example, page 13, lines 19-28; page 16, lines 1-12 and 13-28;
`
`page 20, li