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
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`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
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`Examiner: Kara R. McMillian
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`Docket No.: FKA01007US
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`DECLARATION UNDER 37 C.F.R. § 1.132 OF LEONARD J. CHYALL
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`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 223134450
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`I, Leonard J. Chyall do hereby declare as follows:
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`1.
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`I received a Ph.D. degree in Chemistry in 1991 from the University of
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`Minnesota in Minneapolis, Minnesota and a B.A. degree in Chemistry in 1986 from Oberlin
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`College in Oberlin, Ohio. Since 2000, I have worked in various capacities as a research and
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`development chemist in the pharmaceutical field. I have extensive experience in the
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`chemistry aspects of the development of pharmaceutical drug substances and drug
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`products.
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`2.
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`Since 2011, I have been employed at Chyall Pharmaceutical Consulting, LLC,
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`which is my independent consulting company. Prior to my current position, I was
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`employed at Aptuit, Inc. (formerly SSCI, Inc.) in West Lafayette, Indiana in the following
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`roles: Director (2010-2011), Principal (2007-2010), Senior Research Investigator (2003-
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`2006), and Research Investigator (2000-2003). Prior to Aptuit, I was employed as a
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`Research Chemist at Great Lakes Chemical (now Chemtura) in West Lafayette, Indiana,
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`from 1996-2000.
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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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`3.
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`As of August 30, 2011, which I understand is the earliest possible effective
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`filing date for the subject patent application, I was actively engaged in scientific research in
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`the development of pharmaceutical products, including lyophilized pharmaceutical
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`products to which the subject patent application pertains. I am aware of the general
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`knowledge available in the field of lyophilization and of the skill level of the ordinary
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`artisan in the field of lyophilization as it exists today and as it existed as of August 30, 2011.
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`4.
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`A copy of my curriculum vitae is attached as Exhibit A.
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`5.
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`I am being compensated by Fresenius Kabi USA for my time spent preparing
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`this declaration. I have no financial interest in Fresenius Kabi USA, nor in the outcome of
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`this prosecution. I do not personally know the inventors listed on the subject patent
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`application. I offer my opinions on this matter as an independent pharmaceutical
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`consultant. In addition to the materials cited here, I have relied on my general knowledge
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`and education in this subject matter along with my 14 years of experience in the
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`pharmaceutical industry.
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`6.
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`I have reviewed the subject patent application. I understand that the
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`pending claims are directed to a lyophilized solid composition containing levothyroxine
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`sodium, a phosphate buffer, and mannitol, wherein the levothyroxine sodium and mannitol
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`are present in particular amounts and ratios with respect to one another.
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`7.
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`I have reviewed the Office Action dated March 6, 2014, and the references
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`cited therein, namely: 1) Bedford Laboratories, "Levothyroxine Sodium For Injection",
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`2003 ("Bedford"); 2) Collier et al., "Influence of Formulation and Processing Factors on
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`Stability of Levothyroxine Sodium Pentahydrate," MPS PharmSciTech., 11(2): 818-825
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`(2010) ("Collier"); 3) Baheti et al., "Excipients Used in Lyophilization of Small Molecules,"J.
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`Excip. Food Chem., 1(1): 41-54 (2010) ("Baheti"); and 4) Kim et al., "The Physical State of
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`Mannitol after Freeze-Drying: Effects of Mannitol Concentration, Freezing Rate, and a
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`Noncrystallizing Cosolute,"/ Pharm. Sci., 87(8): 931-935 (1998) ("Kim"). I have also
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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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`conducted a scientific literature review concerning the stability of sodium levothyroxine
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`pharmaceutical compositions.
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`8.
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`It is my understanding that the Examiner believes the teachings of Baheti and
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`Kim suggest to one of ordinary skill in the art that increasing the ratio of mannitol to
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`levothyroxine would lead to an increase in the crystallization of mannitol which, in turn,
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`would destabilize levothyroxine (Office Action at pg. 12, para. 2 - pg. 13, para. 2 and pg. 15,
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`para. 1-2). Therefore, the Examiner believes that it would have been obvious to one of
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`ordinary skill in the art to reduce the amount of mannitol in a lyophilized solid in order to
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`stabilize levothyroxine.
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`9.
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`I respectfully disagree with the Examiner's views of the teachings of the cited
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`references as a whole, and the general knowledge in the field of lyophilization at the time of
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`the invention. Given below are my opinions concerning how a skilled artisan would view
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`these teachings with respect to the claims of the subject patent application.
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`10. Baheti discloses: "Crystallization of the bulking agent, however, might
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`adversely affect the physical stability of the product in certain instances, for which, an
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`amorphous bulking agent would be preferred" (pg. 46, col. 2) (emphasis added). In
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`support of this statement, Baheti references an article by Herman et al. (Pharm. Res., 11:
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`1467-1473 (1994) ("Herman")). The Herman article discloses that the rate of hydrolysis of
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`methylprednisolone sodium succinate increased as the ratio of mannitol to drug increased
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`from 1 to 1 to 5.25 to 1 in a freeze-dried composition (pg. 1468, col. 1, and Figure 1).
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`11.
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`It is my understanding that the Examiner has correlated the Herman studies
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`concerning the hydrolytic stability of lyophilized methylprednisolone sodium succinate
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`compositions to the stability of sodium levothyroxine compositions. I do not believe that
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`the findings of Herman are relevant to a lyophilized solid levothyroxine composition for
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`several reasons. The reactivity of water toward a given organic molecule is related to both
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`the identity and the specific reactivity of the functional groups within a given molecule.
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`Serial No. 13/597,884 (cid:9)
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`The different functional groups of different molecules will necessarily involve different
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`rates of reaction with water, presuming any reaction even occurs.
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`12. Methylprednisolone sodium succinate and levothyroxine are unrelated in
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`chemical structure and will therefore have different hydrolytic stability profiles. Most
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`importantly, the degradation pathways for methylprednisolone sodium succinate in the
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`presence of water are not possible for sodium levothyroxine due to these differences in
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`chemical structure. Methylprednisolone sodium succinate degrades primarily by ester
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`hydrolysis (pg. 1468, col. 1). In contrast, levothyroxine degrades primarily by deiodination
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`of levothyroxine to liothyronine (subject patent application at paragraph 0033, and Figs. 2
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`and 3). The mechanism of ester hydrolysis involves attack of the carbonyl group (C=0) of
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`the ester followed by cleavage of the C-0 bond between the acyl group and the oxygen
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`atom.
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`13. The ester hydrolysis mechanism that is operative in the degradation of
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`methylprednisolone sodium succinate is completely different than the proposed
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`mechanisms of the deiodination of sodium levothyroxine in the presence of water, which
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`involves cleavage of a carbon-iodine (C-1) bond. Won has studied the aqueous stability
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`sodium levothyroxine under various conditions and has proposed at least two mechanisms
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`for the deiodination of the molecule. Won, CM. "Kinetics of Degradation of Levothyroxine
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`in Aqueous Solution and in Solid State," Pharm. Res., 9: 131-137 (1992) ("Won"). The
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`deiodination reaction was found to have a sigmoidal pH dependence (Fig. 3), which is
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`different than that for the ester hydrolysis of methylprednisolone sodium succinate. The
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`Won studies were conducted using an excess of water and, therefore, the effect of trace
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`amounts of water in lyophilized sodium levothyroxine compositions cannot be
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`extrapolated from Won.
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`14. The Examiner has pointed to the better stability of methylprednisolone
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`sodium succinate observed by Herman in the formulations that contained a greater amount
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`of the drug relative to mannitol. Figure 1 of Herman provides a graph of the stabilities of
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`these compositions. Upon review of the data contained in Herman, it is my opinion that
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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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`compositions that contain relatively less mannitol are not necessarily more stable than the
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`compositions that contain greater relative amounts of mannitol. Figure 1 shows the
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`stability of methylprednisolone sodium succinate over time. Notably, the amount of
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`degradation over time provides roughly parallel lines for both mannitol formulations (open
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`and closed triangles in Figure 1 of Herman). The initial measurements of the free
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`methylprednisolone degradation product show that the starting amount of the degradation
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`product was much higher for the 40 mg drug sample (5.25:1 mannitol:drug) (closed
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`triangle), which has offset all subsequent measurements by this amount. Therefore, it is
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`my opinion that any differences in the stability of the methylprednisolone sodium
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`succinate samples as a function of added mannitol are slight. Regardless of the effect of
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`mannitol concentration on methylprednisolone sodium succinate, it is my opinion that
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`whatever mechanism to account for the instability of the drug toward water cannot be
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`operative for the degradation of sodium levothyroxine due to the differences in chemical
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`structure for the two drugs.
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`15.
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`I also do not believe the teachings of Kim are relevant to the understanding
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`of the stability of sodium levothyroxine in the presence of mannitol in a lyophilized
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`composition. Kim discloses: "The physical state of mannitol during and after freeze-drying
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`is particularly important in protein formulations where mannitol is present as a
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`lyoprotectant. Izutsu et al., using three different model proteins, demonstrated that
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`recovery of activity is inversely related to the degree of crystallinity of mannitol" (pg. 931,
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`col. 2) (emphasis added). The impact of mannitol crystallinity on the biological activity of a
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`protein in a freeze-dried preparation has no relation to the impact of mannitol crystallinity
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`on the stability of a low molecular weight organic molecule, such as levothyroxine.
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`16. Kim also discloses that the relative concentration threshold above which
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`crystalline mannitol is observed in a freeze-dried composition comprising mannitol and a
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`cosolute is 30% w/w (pg. 933, col. 2). The relative concentration of mannitol in the
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`exemplary freeze-dried compositions of the invention containing 3 mg mannitol disclosed
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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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`in the specification of the subject patent application is at least 75% w/w1. In addition,
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`Tables 2 and 3 and Figures 2 and 3 of the subject patent application demonstrate no
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`differences in the stability of the solid levothyroxine compositions according to the pending
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`claims over a relative mannitol concentration range of 75% w/w to 83% w/w2. Thus, the
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`increased stability of the solid compositions according to the pending claims as compared
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`to conventional solid levothyroxine compositions containing 10 mg mannitol cannot simply
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`be attributable to a predictable change in the degree of crystallinity of mannitol - as
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`suggested by the Examiner - in view of Kim, which discloses that mannitol is crystalline
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`when present in freeze-dried compositions at 30% w/w or greater.
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`17.
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`If anything, the general knowledge in the art at the time of the invention
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`would have suggested to one of ordinary skill in the art that increasing the crystallization of
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`mannitol would be beneficial for a lyophilized solid, thus effectively teaching away from the
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`pending claims of the subject patent application. For example, Searles, JA. "Freezing and
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`Annealing Phenomena in Lyophilization." Freeze Drying/Lyophilization of Pharmaceutical
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`and Biological Products, 3rd Edition. Ed. Louis Rey, Ed. Joan C. May. London: Informa
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`Healthcare, 2010. 52-81 discloses:
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`Mannitol is of great interest because it is widely used as a bulking agent for
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`lyophilization, but it is only effective as a bulking agent when in the
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`crystalline form.
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`(page 71, paragraph 1).
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`18. Collier is directed to the stability of levothyroxine in pharmaceutical tablets
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`intended for oral administration. Collier discloses that levothyroxine has greater stability
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`in the presence of 5% moisture when mixed with the tabletting excipients colloidal silicon
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`dioxide, magnesium stearate, acacia, confectioner's sugar, talc, lactose monohydrate,
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`A solid composition comprising 500 pg levothyroxine, 500 p.g dibasic sodium phosphate, and 3 mg mannitol
`contains 75% w/w mannitol ([3 mg mannitol / (0.5 mg levothyroxine + 0.5 mg dibasic sodium phosphate + 3 mg
`mannitol)] x 100).
`2 A solid composition comprising 100 p,g levothyroxine, 500 p.g dibasic sodium phosphate, and 3 mg mannitol
`contains 83.3% w/w mannitol ([3 mg mannitol / (0.1 mg levothyroxine + 0.5 mg dibasic sodium phosphate + 3 mg
`mannitol)] x 100).
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`croscarmellose sodium, and sodium starch glycolate than it does when mixed with
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`mannitol (see, e.g., Fig. 3 and Table IV). Other than mannitol and lactose monohydrate,
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`none of the excipients tested in Collier are FDA-approved for use in a composition intended
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`for intravenous administration. Accordingly, one of ordinary skill in the art would not have
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`considered Collier in the development of a lyophilized solid composition for intravenous
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`administration, including the disclosure of a levothyroxine-mannitol ratio of 1:10, since
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`Collier undoubtedly is directed to pharmaceutical tablets intended for oral administration.
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`19.
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`I do not believe that any of Bedford, Baheti, Herman, Kim, or Collier, alone or
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`in combination, or the common knowledge in the art at the relevant time, would have
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`motivated one of ordinary skill in the art to reduce the amount of mannitol in the
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`composition of Bedford with a reasonable expectation of obtaining a more stable product.
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`20.
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`I have reviewed the results described in the specification of the subject
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`patent application, including paragraphs 0033-0049, Tables 1-3, and Figs. 1-2. In my
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`opinion, the increased stability of the lyophilized solid compositions comprising 3 mg
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`mannitol and 100 pig, 200 pig, or 500 pig levothyroxine as compared to conventional
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`lyophilized solid composition comprising 10 mg mannitol and 100 pig, 200 lig, or 500 lig
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`levothyroxine is surprising, and would not have been expected in view of the cited
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`references or the common knowledge in the art at the relevant time.
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`21.
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`I hereby declare that all statements made herein of my own knowledge are
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`true and that all statements made on information and belief are believed to be true; and
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`further that these statements were made with the knowledge that willful false statements
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`and the like so made are punishable by fine or imprisonment, or both, under Section 1001
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`of Title 18 of the United States Code and that such willful false statements may jeopardize
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`the validity of the application or any patent issued thereon.
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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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`Jor\e, g aol Li
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`Date (cid:9)
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`cfery,,,,k 01- efi,,,,Q2
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`Leonard J. Chyall, Ph.D.
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`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, IL 60661
`Docketing@blanchard-patentcom
`Tel. 312-612-6700
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