IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Docket No.: ASZD-P02-617
`(PATENT)
`
`~~~fu re Patent Application of:
`Dearn et al.
`
`Application No.: 10/854959
`
`Filed: May 27, 2004
`
`Confirmation No. 7301
`
`Art Unit: 1616
`
`Examiner: Pryor, Alton Nathaniel
`
`For: PHARMACEUTICAL FORMULATIONS
`CONTAlliTNGZOLMITRWTAN
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Declaration Under 37 C.F.R. § 1.132 o(Dr. Ed Cahill
`
`Sir:
`
`I, Dr. Ed Cahill, of24 Adey Road, Lymm, Cheshire WA139QX, United Kingdom, hereby declare as
`follows:
`
`1.
`
`I am a Manager of Product Development for AstraZeneca.
`
`I have ten years of experience in the pharmaceutical industry developing both liquid and solid
`2.
`dosage forms. I have a Bachelor of Science Degree in Combined Science (Biochemistry) from the
`Polythenic ofNorth London, an MSc degree in Toxicology from the University of Surrey, U.K., and a
`Ph.D. degree in the Pharmaceutical Sciences from the University ofNottingham, U.K. In addition, I was
`a visiting lecturer from at John Moores University in Liverpool, U.K. and have authored six peer(cid:173)
`reviewed scientific articles.
`
`Experiments were performed under my direction (depicted as Exhibit A attached hereto), to
`3.
`compare the stability. of zolmitriptan at different pHs using citric acid buffers.
`
`4.
`These experiments indicate that the amount of zolmitriptan degradation products upon
`prolonged storage was significantly less at a pH below 6, for example at pH 5.0 and 3.0, as compared to
`pH 7.4 or to pH 7.0. ·
`
`9835952_l.DOC
`
`Page 1 of 4
`
`AstraZeneca Exhibit 2025
`Lannett v. AstraZeneca
`IPR2015-01629
`
`

`
`•.
`
`..
`
`I hereby declare that all statements made herein of my own knowledge are true and that all
`5.
`statements made on information and belief are believed to be true; and further that these statements are
`made with knowledge that Willful false statements and the like so made are punishable by fine or
`imprisonment, or both, under Section 1001 of Title :xvm of the United States Code and that willful false
`statements may jeopardize the validity of this Application for Patent or any patent issuing thereon.
`
`.
`
`.
`
`Ed Cahill
`
`Signature: ~ c::!'f_t/
`
`9835952_1.DOC
`
`Page 2 of 4
`
`

`
`•.:
`
`Exhibit A
`
`Stability studies of zolm.itriptan at different pHs using citric acid buffers have been performed by
`AstraZeneca to show that intranasal formulations ofzolmitriptan are significantly more the
`chemically storage stable below pH 7, particularly below pH 6.0. The formulations were
`prepared by dissolving zolmitriptan in a solution of citric acid, adding sufficient of a solution of
`disodium phosphate to give the required pH and diluting to the required volume with water; The
`formulations and study conditions are described in the sections below.
`
`STUDY I
`
`fu Study 1, solutions with a nominal zolmitriptan concentration of25 mglml (2.5mg/ dose) were
`prepared at pH 3.0, pH 5.0 and pH 7.4. These solutions were tested for levels of degradation
`products after storage at 50°C for 8 weeks in darkness.
`
`Study 1 Formulation compositions
`
`Zolmitriptan
`Citric Acid
`(anhydrous)
`Disodium
`Phosphate
`( dodecahydrate)
`0.2M
`Water for injection
`
`pH3.0
`2.5mg
`3.2mg
`
`pHS.O
`2.5mg
`1.3 mg
`
`pH7.4
`2.5mg
`0.6mg
`
`q.s. to pH 3.0
`
`q.s. to pH 5.0
`
`q.s. to pH 7.4
`
`to lml
`
`to lml
`
`to lml
`
`The results of the degradation products analysis are given in the following table:
`
`p d
`d
`.
`
`SdlR I I hD tu ly
`fter storage at 50°C for 8 weeks.
`ro ucts a
`: esu ts or t e egra at10n
`Degradation Products (% w/w)
`2.5
`2.4
`7.4
`
`pH3
`pHS
`pH7.4
`
`STUDIES 2 and 3
`
`fu Studies 2 and 3, solutions with a nominal zolmitriptan concentration of 50 mglml (Smg/ dose)
`were prepared at pH 3, pH 5 and pH 7. These solutions were tested for degradation products after
`storage at 50°C for 8 weeks in darkness (Study 2) and 25°C for 26 weeks in darkness (Study 3),
`respectively.
`
`Studies 2 and 3 Formulation Compositions
`
`I pH3.0
`
`Smg
`
`I pHS.O
`
`Smg
`
`Smg
`
`I Zolmitriptan
`
`9835952_l.DOC
`
`Page 3 of 4
`
`

`
`Citric Acid
`(anhydrous)
`Disodium
`Phosphate
`( dodecahydrate)
`0.2M
`Water for injection
`
`8.7mg
`
`2.6mg
`
`1.6 mg
`
`q.s to pH 3.0
`
`q.s to pH 5.0
`
`q.s to pH 7.0
`
`to 1 m1
`
`to 1 ml
`
`to 1 ml
`
`The results of the degradation products analysis at each of the two conditions are given in the
`following tables:
`
`Study 2: Results for the Degradation Products after storage at 50°C for 8 weeks.
`
`pH3.0
`pHS.O
`pH7.0
`
`Degradation Products(% w/w)
`1.9
`2.1
`3.6
`
`Study 3: Results for the Degradation Products after storage at 25°C for 26 weeks.
`
`pH3.0
`pHS.O
`_l)_H 7.0
`
`Degradation Products (% w/w)
`1.8
`1.0
`5.0
`
`Method ofAnalysis:
`HPLC was used to measure the degradation products in Study 1 and 2. A 15 em x 5 mrn
`Spherisorb S30DS-2 column operating at a temperature of 40°C with an eluant consisting of
`1730 part Water, 270 parts Acetonitrile, 2 parts Trifluoroacetic acid and 0.5 part Triethylamine
`was used at a flow rate of 1.6 mllmin. Detection was by UV at a wavelength of 210 nm.
`
`The improved chemical storage stability achieved by the present invention is evident from a
`comparison of the data in Studies 1, 2 and 3. Study 1 clearly shows that after 8 weeks at 50°C in
`darkness 7.4% degradation products were measured in the zolmitriptan formulation when the pH
`was 7.4 while at pH 5.0 and 3.0, respectively, the degradation products were only 2.4 and 2.5,
`respectively. Using twice the amount ofzolmitriptan in the Study 2 formulation and preparing
`the study under the same conditions as Study 1 with regard to time, temperature and darkness,
`the degradation products obtained were 3.6% at pH 7.0, 2.1% at pH 5.0 and 1.9% at pH 3.0.
`Using an identical zolmitriptan formulation in Study 3 as in Study 2 but storage at 25°C in
`darkness for 26 weeks, the obtained degradation products were 5.0 at pH 7 .0, 1.0 at pH 5.0 and
`1.8 at pH 3.0. These studies clearly show the amount of storage degradation products were
`significantly less at pH below 6, specifically at pH 5.0 and 3.0 compared to pH 7.4 and 7 .0.
`
`9835952 _l.DOC
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`Page 4 of 4