Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01007_US
`
`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.: FKA01_007_US
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`DECLARATION UNDER 37 C.F.R. § 1.132 OF ARUNYA USAYAPANT
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`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`I, Arunya Usayapant do hereby declare as follows:
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`1.
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`I am one of the named inventors on the present patent application.
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`2.
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`I received a Ph.D. degree in Pharmaceutical Sciences in 1991 from Northeast
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`Louisiana University in Monroe, LA, and a B.S. degree in Pharmacy in 1982 from
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`Chulalongkorn Mahawitthayalai in Bangkok, Thailand.
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`3.
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`I have over 15 years of formulation and development experience in the
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`pharmaceutical industry. Since 2007, I have been employed at Fresenius Kabi USA
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`(formerly APP Pharmaceuticals), which is the assignee of the present patent application, in
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`the following roles: Senior Manager (2013-present), Manager (2008-2013), and Principal
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`Scientist (2007-2008). Prior to my current employer, I was employed as a Senior Principal
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`Scientist at Morton Grove Pharmaceuticals (now Wockhardt USA) in Morton Grove, IL, from
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`2004-2006; as a Senior Scientist at Wyeth Consumer Healthcare in Richmond, VA, from
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`1998-2004; as an Assistant Professor at Chicago College of Pharmacy in Downers Grove, IL,
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`from 1992-1998; and as an Assistant Professor at Northeast Louisiana University from
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`1991-1992.
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`Mylan Ex 1013, Page 1
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`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01007_US
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`4.
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`I am aware of the general knowledge available in the field of lyophilized
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`pharmaceutical products and of the skill level of the ordinary artisan in the field of
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`lyophilized pharmaceutical products as it exists today and as it existed at the time of the
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`invention of the subject matter claimed in the present patent application.
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`5.
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`I understand that the currently pending claims are directed to a lyophilized
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`solid composition containing 100 1.1g, 200 lig, or 50011g levothyroxine sodium, a phosphate
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`buffer, and from 2 to 4 mg mannitol or, more specifically, about 3 mg mannitol.
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`6.
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`I have reviewed the Office Action dated September 8, 2014, and the
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`references cited therein, namely: 1) Bedford Laboratories, "Levothyroxine Sodium For
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`Injection", 2003 ("Bedford"); 2) Collier et al., "Influence of Formulation and Processing
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`Factors on Stability of Levothyroxine Sodium Pentahydrate," MPS PharinSciTech., 11(2):
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`818-825 (2010) ("Collier"); 3) Baheti et al., "Excipients Used in Lyophilization of Small
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`Molecules,"/ Excip. Food Chem., 1(1): 41-54 (2010) ("Baheti"); and 4) Kim et al., "The
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`Physical State of Mannitol after Freeze-Drying: Effects of Mannitol Concentration, Freezing
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`Rate, and a Noncrystallizing Cosolute,"J. Pharin. Sci., 87(8): 931-935 (1998) ("Kim").
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`7.
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`A lyophilized solid has a different physical structure and reactivity than a
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`solid that is dissolved in a liquid or than a solid that is compressed to form a tablet; thus,
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`the reactivity of a solid in a liquid and a lyophilized solid cannot be directly compared. In
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`my opinion, a person of ordinary skill in the art would not consider a reference directed to
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`levothyroxine stability in water or in a compressed tablet to be relevant to the
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`development of a stable lyophilized solid composition.
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`8.
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`Prior to the present invention, I was unaware of any publication or general
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`knowledge in the art that disclosed or otherwise suggested that the lyophilized
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`pharmaceutical products comprising 200 j.tg or 500 mg levothyroxine sodium and at least
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`10 mg mannitol - which had been marketed in the United States since at least 1971 as
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`grandfathered products - had undesirable impurity profiles.
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01007_US
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`9.
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`The results described in the specification of the present patent application
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`demonstrate that reduced amounts of the impurity liothyronine (T3) are formed following
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`storage fort-3 months at 40 °C or for 2-4 weeks at 55 °C of lyophilized solid compositions
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`comprising 100 [ig levothyroxine sodium and 2 mg, 3 mg, or 4 mg mannitol as compared to
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`conventional lyophilized solid composition comprising 100 lig levothyroxine sodium and
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`10 mg mannitol (see paragraphs 0033-0036 and Table 1 of the specification).
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`10. The results described in the specification of the present patent application
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`also demonstrate that reduced amounts of liothyronine are formed following storage for 3-
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`6 months at 40 °C or for 12-18 months at 25 °C of lyophilized solid compositions
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`comprising 100 pg, 200 p.g, or 500 j.i.g levothyroxine sodium and 3 mg mannitol (hereinafter
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`referred to as "compositions of the invention" or simply "invention") as compared to
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`conventional lyophilized solid compositions comprising 10 mg mannitol and 100 vtg, 200
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`lig, or 500 1.1g levothyroxine sodium (hereinafter referred to as the "conventional
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`compositions" or simply "conventional") (see paragraphs 0037-0049, Tables 2-3, and Figs.
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`2-3 of the specification).
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`11. The stability experiments of the compositions of the invention were
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`extended to 24 months at 25 °C. The stability experiments of the conventional
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`compositions were terminated at 18 months, since the increasing amounts of liothyronine
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`impurities were indicative of unstable products. The results of the extended stability
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`experiments are described herein as follows.
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`12. The amount of liothyronine impurity present following storage for 24
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`months at 25 °C of the compositions of the invention comprising 100 hg, 200 p.g, or 500 lig
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`levothyroxine sodium was 0.13% (see Exhibit A attached hereto at Figs. 1A-1C), which
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`represented a minimal (8%) increase in the amount of liothyronine impurity over the 24
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`month storage period. In contrast, the amounts of liothyronine impurity present following
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`storage for 18 months at 25 °C of conventional compositions comprising 100 hg, 200 hg, or
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`500 p.g levothyroxine sodium were 0.25%, 0.25%, and 0.18%, respectively (see Exhibit A at
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01007_US
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`Figs. 1A-1C), which represented a substantial (6%-47%) increase in the amount of
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`liothyronine impurity over the 18 month storage period.
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`13.
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`In my opinion, the results described in the specification of the present
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`application and as supported by Figs. 1A-1C in Exhibit A attached hereto are unexpected in
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`view of the combination of cited references and the general knowledge in the art, since I
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`was unaware of any study demonstrating that reducing the amount of mannitol would have
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`affected levels of liothyronine impurity in a lyophilized solid levothyroxine composition.
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`14.
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`In 2011, the United States Food and Drug Administration ("FDA") approved
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`Fresenius Kabi USA's New Drug Application (NDA) 202231 for Levothyroxine Sodium for
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`Injection containing 100 jig, 200 jig, or 500 tg levothyroxine sodium, 3 mg mannitol, and a
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`phosphate buffer, which correspond to compositions of the invention. Prior to 2011,
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`Fresenius Kabi USA manufactured and sold a grandfathered Levothyroxine Sodium for
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`Injection product containing 200 jig or 500 jig levothyroxine sodium, 10 mg mannitol, and
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`a phosphate buffer (hereinafter referred to as "compositions of the prior art" or simply
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`"prior art"). The prior art compositions previously sold by Fresenius Kabi USA are
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`substantially similar to the compositions described in Bedford.
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`15.
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`I have reviewed stability testing summaries compiled at Fresenius Kabi USA
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`of commercial-scale preparations of compositions of the invention (200 jig/vial
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`levothyroxine sodium) and compositions of the prior art (200 jig/vial levothyroxine
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`sodium). Summaries of the stability assay and certain test results are described herein as
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`follows.
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`16. All vials were stored at 25±2 °C, 60± 5% relative humidity in an inverted
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`position for 18 or 24 months. Prior to storage and at the end of the storage period, the
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`amount of levothyroxine present in each vial was calculated by a high-performance liquid
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`chromatography method. After 18 months, the prior art compositions exhibited, on
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`average, a loss of approximately 7.7% of the initial amount of levothyroxine. In contrast,
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`the compositions of the invention did not exhibit, on average, any loss of levothyroxine (see
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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01007_US
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`Exhibit A at Fig. 2). Similarly, at 24 months, the prior art compositions exhibited a loss of
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`approximately 8.8% of the initial amount of levothyroxine, whereas the compositions of
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`the invention still did not exhibit any loss of levothyroxine (see Exhibit B at Fig. 2).
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`17.
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`The current Fresenius Kabi USA Levothyroxine Sodium for Injection product
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`marketed under NDA 202231 (invention) has a shelf-life of 24 months, whereas the
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`previous Fresenius Kabi USA Levothyroxine Sodium for Injection marketed as a
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`grandfathered product (prior art) had a shelf-life of 18 months.
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`18. Based upon my experience, I believe that the FDA would not have approved
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`an NDA for a conventional lyophilized solid composition comprising 200 lig or 500 ug
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`levothyroxine sodium and 10 mg mannitol, such as the grandfathered Fresenius Kabi USA
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`or Bedford product. In my opinion, the FDA would have considered the increased
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`impurities and decreased potency following storage problematic, especially for a drug
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`product containing a highly potent active pharmaceutical ingredient, such as levothyroxine.
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`19.
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`In my opinion, the superior stability and extended shelf-life of the
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`compositions of the invention as compared to the prior art compositions are unexpected in
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`view of the combination of cited references and the general knowledge in the art, as I was
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`unaware of any study suggesting that reducing the amount of mannitol in a lyophilized
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`solid composition would have positively affected levothyroxine potency following storage,
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`much less extend the shelf-life of a commercial product.
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`20.
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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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`Mylan Ex 1013, Page 5
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`3erioi No. 13.15s.V.A18,4 (cid:9)
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`. PATENT
`No. :F. KA01.5.)07_0
`
`fiee *4. St3 ,
`.si (cid:9)
`Date (cid:9)
`
`
`
`Arunya Usayapant., Ph,D.
`
`Blanchard & Associates
`$86 West Adams Street.
`Suite 600
`Chicago, IL 60661
`Docketing fa.s.Cianchard-patent.00m
`T&..312-.612-6700
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`Mylan Ex 1013, Page 6
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`(cid:9)
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`Exhibit A
`Exhibit A
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`Mylan Ex 1013, Page 7
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`Mylan Ex 1013, Page 7
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`n initial
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`12 months
`
`• 18 months
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`Z 24 months
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`n initial
`
`12 months
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`• 18 months
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`P2 24 months
`
`n initial
`
`gg 12 months
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`O 18 months
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`2 24 months
`
`Conventional
`
`Invention
`
`Conventional Invention
`
`0.4 (cid:9)
`0.35 (cid:9)
`0.3
`0.25
`0.2 (cid:9)
`0.15 (cid:9)
`0.1
`
`0.05
`0 (cid:9)
`
`
`
`
`
`
`
`
`
`0.3
`
`0.25
`
`0.2
`
`0.15
`
`0.1
`
`0.05
`
`0
`
`0.25
`
`0.2
`
`0.15
`
`0.1
`
`0.05
`
`% liothyronine impurity
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`% liothyronine impurity
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`% liothyronine impurity
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`Fig. 1A
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`Fig. 1B
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`Fig. 1C
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`0 I
`Conventional Invention
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`Figure 1. Bar graphs depicting amounts of liothyronine impurity present following storage of
`lyophilized solid compositions comprising 100 ug levothyroxine (Fig. 1A), 200 [..tg levothyroxine
`(Fig. 1B), or 500 1.1g levothyroxine (Fig. 1C) and either 10 mg of mannitol ("Conventional") or 3
`mg mannitol ("Invention"). NT = not tested.
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`Mylan Ex 1013, Page 8
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`(cid:9)
`(cid:9)
`(cid:9)
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`Fig. 2
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`Prior Art
`
`0 Invention
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`12
`
`10
`
`8
`
`6
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`4
`
`2
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`0
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`-2
`
`-4
`
`% loss levothyroxine
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`18 months 24 months
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`Figure 2. Bar graph depicting loss in levothyroxine following storage for 18 or 24 months of
`commercial-scale lyophilized solid compositions comprising 200 pg levothyroxine and 10 mg
`of mannitol ("Prior Art") or 3 mg mannitol ("Invention"). Data represent means ± standard
`deviation (n = 3-7). * p < 0.01 versus Prior Art by Student's T-test.
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`Mylan Ex 1013, Page 9
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