Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01_007_US
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`First Named Inventor: Jiang
`Application No.: 13/597,884
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`Filed: August 29, 2012
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`Title: Levothyroxine Formulations
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`Art Unit: 1627
`Examiner: Kara R. McMillian
`Docket No.: FKA01_007_US
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`DECLARATION UNDER 37 C.F.R. § 1.132
`
`Mail Stop AF
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`We, Zhi-Qiang Jiang, Arunya Usayapant, and George Monen, declare as follows:
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`1. We are the inventors of the subject matter claimed in the above-identified
`U.S. Patent Application.
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`2. We have assigned the above-identified U.S. Patent Application to
`Fresenius Kabi USA, LLC.
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`At the time of the invention of the subject matter claimed in the above-
`3.
`identified U.S. Patent Application, we were employees of Fresenius Kabi USA, LLC and
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`continue to be employees of Fresenius Kabi USA, LLC on the date of our signatures
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`below.
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`4. When we performed the research leading to the filing of the instant patent
`application, we were unaware of any study showing that different excipient amounts
`would have significant effect on levothyroxine stability in lyophilized solids, instead
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`believing that excipient type was most important to levothyroxine stability.
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01_007_US
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`5. When performing this research, we were unexpectedly surprised by the
`type of stability results obtained from the data presented in Tables 1-3 and Figures 2
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`and 3 of our patent application. The tables and figures show that at the higher 10 mg
`mannitol level, increasing amounts of mannitol in relation to levothyroxine adversely
`affected levothyroxine stability in a somewhat linear manner, while at the lower 3 mg
`mannitol level, a significant and wholly unexpected departure from this degradation
`linearity was observed over the attempted levothyroxine concentrations. Thus, after
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`seeing the degradation trend at the higher mannitol concentration, the break from
`linearity and substantial flattening due to the stability uniformity observed at the lower
`mannitol concentration was surprising and much greater than expected.
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`6. We also were unexpectedly surprised by the difference in the degree of
`levothyroxine degradation when the high and low mannitol concentrations were
`compared. From the low mannitol concentration stability results of Table 2, the %T3
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`increased from 0.12 % [(0.12+0.12+0.12)13] to approximately 0.131 %
`[(0.13+0.13+0.133)/3] over a 3 month period when all T3 percentages at the different
`levothyroxine concentrations were averaged. This represented an approximate 9%
`degradation over the 3 month period at 40° C [(0.131-0.12)/0.12*100]. In contrast, from
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`the high mannitol concentration stability results of Table 3, the %T3 increased from
`0.173 % [(0.17+0.18+0.17)/3] to approximately 0.286 % [(0.403+0.253+0.203)/3] over a
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`3 month period when all T3 percentages at the different levothyroxine concentrations
`were averaged. This represented an approximate 65% degradation over the 3 month
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`period at 40° C [(0.286-0.173)/0.173*100]. A greater than 7-fold increase in
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`levothyroxine degradation at the higher mannitol concentrations in relation to the lower
`mannitol ranges was surprising and much greater than expected.
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`7. We also were unexpectedly surprised to find that similar levothyroxine
`stability was observed at the lower mannitol concentration for each levothyroxine
`concentration. In view of the relatively wide separations between the stability of the
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`higher mannitol concentration samples at each levothyroxine concentration, the
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`uniformity of the stability achieved at the lower mannitol concentration (substantially
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01_007_US
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`levothyroxine concentration independent) also was unexpected. As discussed in
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`paragraph 35 of the application, the stability of the higher mannitol concentration
`samples varied by approximately 90% over a 3 month period, while the lower mannitol
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`concentration samples varied by approximately 6% over the 3 month period. The
`surprising difference in the relatively large amount of stability variance at the high
`mannitol concentration in relation to the substantial lack of stability variance at the low
`mannitol concentration observed in Figures 2 and 3 of the patent application was
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`unexpected. A fifteen-fold decrease in stability variance at the lower mannitol
`concentration in relation to the higher mannitol concentration was surprising and much
`greater than expected.
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`A lyophilized solid has a different physical structure and reactivity than a
`8.
`solid that is dissolved in liquid or than a solid that is compressed to form a tablet. A
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`lyophilized solid is extremely dry, as during the lyophilizing process water is frozen and
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`removed under high vacuum from the solid. Thus, the reactivity of a solid in a liquid in
`comparison to a lyophilized solid cannot be directly compared. When a lyophilized solid
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`is formed, the vacuum removal of the frozen water and other volatile solvents leaves
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`gaps or pores in the resulting solid. This is very different from a solid that is tightly
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`compressed to form a tablet by the substantial removal of gaps or pores. Thus, the
`reactivity of a solid that is compressed to form a tablet in comparison to a lyophilized
`solid cannot be directly compared. Furthermore, as a lyophilized solid is formed from
`the removal of solvent directly, the lyophilized solid also has a different physical
`structure than would result from crystallization or precipitation of the solid from the
`solvent. Lyophilized solids have unique physical structures and reactivities in
`comparison to other solid forms.
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`9.
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`Any document or study that discusses levothyroxine stability in water or in
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`a compressed tablet would not be referenced or helpful for developing a lyophilized
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`formulation of levothyroxine.
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`10. We have reviewed and understand the contents of the cited documents
`1) U.S. Patent No. 5,955,105 to Mitra et al. (Mitra); 2) Bedford Laboratories,
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`"Levothyroxine Sodium For Injection", 2003 (Bedford); and 3) Collier et al., "Influence of
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`Formulation and Processing Factors on Stability of Levothyroxine Sodium
`Pentahydrate", APPS PharmSiTech 11(2), 2010, 818-825 (Collier).
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`It is our conclusion that these documents cited against the claims of our
`11.
`patent application fail to teach lyophilized solid compositions including the claimed
`critical relative amounts of levothyroxine sodium and mannitol and that direct
`comparison of the presently claimed inventions to the closest cited art is not possible.
`These cited documents also are silent regarding how a change in the amount of
`excipient in relation to the amount of levothyroxine might affect the stability of the
`levothyroxine.
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`12. Mitra discloses tablets containing levothyroxine sodium and one or more
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`excipients. The ratio of levothyroxine sodium to mannitol in the tablets may be from 1:0
`to 1:2,500. Mitra fails to teach whether the presence, absence or concentration of
`mannitol has any effect on the stability of levothyroxine in the tablets. Mitra does not
`disclose or suggest our claimed critical relative amounts of levothyroxine sodium and
`mannitol in a lyophilized solid. Mitra also is silent regarding levothyroxine stability in
`lyophilized solids.
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`13. Bedford discloses a solid composition for use in forming injectable
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`formulations of levothyroxine sodium. The amount of levothyroxine sodium described in
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`Bedford is either 200 or 500 pg, and the amount of mannitol is 10 mg (page 1, 3rd
`paragraph). Bedford does not disclose or suggest our claimed critical relative amounts
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`of levothyroxine sodium and mannitol in a lyophilized solid. Bedford also is silent
`regarding levothyroxine stability in lyophilized solids.
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`14. Collier discloses that crospovidone, povidone, and sodium laurel sulfate
`caused a greater than 80% degradation of levothyroxine sodium in the presence of
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`moisture in selected 1:1 or 1:10 ratios and should be avoided. (Collier, p. 823 & Table
`1). Collier also discloses that when in water a 1:10 ratio of levothyroxine sodium and
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`mannitol powders showed a close to 50% degradation of the levothyroxine sodium after
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`Docket No. FKA01_007_US
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`28 days. (Collier, p. 822 & Table 1). Other compounds showing similar degradation as
`mannitol in the hands of Collier were microcrystalline cellulose, and confectioner's
`sugar. Collier also discloses that when in water colloidal silicon dioxide, magnesium
`stearate, acacia, lactose monohydrate, croscarmellose sodium, corn starch, and sodium
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`starch glycolate in selected ratios of 1:1 or 1:100 showed a less than 50% degradation
`of the levothyroxine sodium after 28 days. (Collier, p. 822 & Table 1). Collier teaches
`that the preferred excipients for use with levothyroxine in water are colloidal silicon
`dioxide, magnesium stearate, acacia, lactose monohydrate, croscarmellose sodium,
`corn starch, and sodium starch glycolate. Thus, Collier does not disclose our claimed
`critical relative amounts of levothyroxine sodium and mannitol of Applicants' claims in a
`lyophilized solid. Collier also is silent regarding levothyroxine stability in lyophilized
`solids.
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`15.
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`In the development of our formulation, we initially thought the Bedford
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`formulation (200 or 500 pg/vial Levothyroxine with 10 mg of mannitol and tribasic
`sodium phosphate) would have the desired stability. Our first "lab batch" made in
`accord with Bedford included 500 pg per vial of levothyroxine sodium and appeared
`promising. Based on this data from this lab batch trial, we expected that results would
`be similar for 100 or 200 pg per vial of levothyroxine. With the data in hand for the lab
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`batches, we had a high degree of confidence and decided to develop full scale
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`"commercial batches" of levothyroxine/mannitol. Commercial batches are
`approximately 100 times the amount of a "lab batch" and are substantially more
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`expensive to make: Each commercial batch used 10 mg of mannitol with varying
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`amounts of levothyroxine sodium (100, 200, or 500 pg/vial).
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`16. Unexpectedly, all three "commercial batches" including 10 mg of mannitol
`with varying amounts of levothyroxine (100, 200, or 500 pg/vial) were unacceptable.
`The impurity profiles of these batches were too high. In our experience, a high impurity
`profile suggests that the drug would not be safe or effective. Additionally, the high
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`impurity profiles may result in the Federal Drug Administration ("FDA") having issues in
`providing approval for commercial sale of the drug. In fact, the FDA commented that
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`the levothyroxine formulation according to Bedford created irritation at the point of
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`injection.
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`In order to conduct studies and evaluate the cause of the impurities, we
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`17.
`staffed 10 scientists in our lab on this project and evaluated several factors on the
`formulation.
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`18. After expending considerable resources and approximately 6 months of
`time testing various factors in the lab, we were surprised to discover that the 1 to 5 mg
`mannitol range is critical to the substantially improved stability results observed for
`lyophilized solid compositions including from 100 to 500 micrograms of levothyroxine
`sodium. Our effort and time spent on development was far from routine in discovering
`the criticality of the claimed amounts and ratios of levothyroxine and mannitol. To date,
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`the formulations we have developed have no known irritation at the point of injection.
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01_007_US
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`19. (cid:9) We hereby declare that all statements made herein of our 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
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`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.
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`06r/c7A-0-0
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`Date
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`Declarant: Zhi-Qiang Jiang
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`Dat (cid:9)
`
`Declarant: Arunya Usa pant
`
`1 7113
`Date
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`
`
`
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`George Declarant: George Monen
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`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, IL 60661
`Docketing@blanchard-patent.com
`Tel. 312-612-6700
`
`Mylan Ex 1014, Page 7