UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O.Box 1450
`Alexandria, VirgLnia 22313-1450
`www.uspto.gov
`
`I
`
`APPLICATION
`NUMBER
`61/529,084
`
`G or (cid:9)
`FILIN
` DATE
`371(c)
`08/30/2011
`
`I
`
`ART
`GRUPNIT
`
`I
`
`FIL FEE RECD
`220 (cid:9)
`
`I (cid:9)
`
`ATTY.DOCKET.NO (cid:9)
`APP01_007_PRO
`
`ITOT CLAIMS I IND CLAIMS
`
`66140
`BLANCHARD & ASSOCIATES
`566 WEST ADAMS STREET
`SUITE 600
`CHICAGO, IL 60661
`
`CONFIRMATION NO. 3754
`FILING RECEIPT
`
`Date Mailed: 09/13/2011
`
`Receipt is acknowledged of this provisional patent application. It will not be examined for patentability and will
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Fees transmitted by check or draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please submit
`a written request for a Filing Receipt Correction. Please provide a copy of this Filing Receipt with the
`changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please submit
`any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processes the reply
`to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`Applicant(s)
`
`Zhi-Qiang Jiang, Skokie, IL;
`Arunya Usayapant, Mundelein, IL;
`George Monen, Woodridge, IL;
`Power of Attorney:
`Jonathan Taylor--48338
`
`If Required, Foreign Filing License Granted: 09/12/2011
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/529,084
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`Title
`
`Levothyroxine Formulations
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`page 1 of 3
`
`Mylan Ex 1027, Page 1
`
`(cid:9)
`

`

`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`LICENSE FOR FOREIGN FILING UNDER
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`Title 35, United States Code, Section 184
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`Title 37, Code of Federal Regulations, 5.11 & 5.15
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`GRANTED
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`The applicant has been granted a license under 35 U.S.C. 184, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
`page 2 of 3
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`Mylan Ex 1027, Page 2
`
`

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`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControl, Department of
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`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
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`U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
`page 3 of 3
`
`Mylan Ex 1027, Page 3
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`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 09/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
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`Provisional Application for Patent Cover Sheet
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
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`Inventor(s)
`
`Inventor 1
`
`Remove
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`Zhi-Qiang
`
`Inventor 2
`
`Jiang
`
`Skokie
`
`IL
`
`US
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`Remove
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`Arunya
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`Usayapant
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`Mundelein
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`IL
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`Woodridge
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`generated within this form by selecting the Add button.
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`Add
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`Title of Invention
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`Levothyroxine Formulations
`
`Attorney Docket Number (if applicable)
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`APP01_007_PRO
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`Direct all correspondence to (select one):
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`C) The address corresponding to Customer Number
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`0 Firm or Individual Name
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`Customer Number
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`66140
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`The invention was made by an agency of the United States Government or under a contract with an agency of the United
`States Government.
`
`C) No.
`
`0 Yes, the name of the U.S. Government agency and the Government contract number are:
`
`EFS - Web 1.0.1
`
`Mylan Ex 1027, Page 4
`
`

`

`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (SB16)
`
`PTO/SB/16 (11-08)
`Approved for use through 09/30/2010 OMB 0651-0032
`U.S. Patent and Trademark Office: U.S. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
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`0 Yes, applicant qualifies for small entity status under 37 CFR 1.27
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`C) No
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`Signature
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`Please see 37 CFR 1.4(d) for the form of the signature.
`
`Signature
`
`/Jonathan P. Taylor, Reg. No. 48,338/
`
`Date (YYYY-MM-DD)
`
`2011-08-30
`
`First Name
`
`Jonathan P.
`
`Last Name
`
`Taylor
`
`Registration Number
`(If appropriate)
`
`48338
`
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`EFS - Web 1.0.1
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`Mylan Ex 1027, Page 5
`
`

`

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`Mylan Ex 1027, Page 6
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`PROVISIONAL APPLICATION FOR UNITED STATES LETTERS PATENT
`
`TITLE: (cid:9)
`
`Levothyroxine Formulations
`
`INVENTORS:
`
`Zhi-Qiang Jiang
`Arunya Usayapant
`George Monen
`
`REPRESENTATIVE: (cid:9)
`
`Jonathan P. Taylor, Ph.D.
`Reg. No. 48,338
`
`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, Illinois 60661
`
`Mylan Ex 1027, Page 7
`
`(cid:9)
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`LEVOTHYROXINE FORMULATIONS
`
`BACKGROUND
`
`[1]
`
`A healthy thyroid produces hormones that regulate multiple metabolic
`
`processes and that play important roles in growth and development, in maturation of
`
`the central nervous system and bone including augmentation of cellular respiration and
`
`thermogenesis, and in metabolism of proteins, carbohydrates and lipids. The thyroid
`
`accomplishes its regulation functions by producing the hormone L-triiodothyronine
`
`(liothyronine; T3) and L-thyroxine (levothyroxine; T4).
`
`[2]
`
`Thyroid hormones are believed to exert their physiologic actions through
`
`control of DNA transcription and protein synthesis. It is presently believed that the T3
`
`and T4 hormones diffuse into the cell nucleus and bind to thyroid receptor proteins
`
`attached to DNA. This hormone nuclear receptor complex then activates gene
`
`transcription and synthesis of messenger RNA and cytoplasmic proteins. The
`
`physiological actions of thyroid hormones are believed to be produced predominantly
`
`by T3, approximately 80% of which is derived from T4 by deiodination in peripheral
`
`tissues.
`
`[3]
`
`Both T3 and T4 are stored in the thyroid colloid as thyroglobulin adducts
`
`with serum proteins. Once secreted by the thyroid, T3 and T4 primarily exist in the
`
`circulatory system as their thyroglobulin adducts, and are in equilibrium with small
`
`amounts (<1°/o) of the unbound hormones, which are the metabolically active species.
`
`T4 has higher serum levels, slower metabolic clearance, and a longer half-life than T3,
`
`which may be due to the higher affinity of serum proteins for T4 compared to T3.
`
`[4]
`
`A patient who has had their thyroid gland removed, or whose thyroid
`
`gland functions at an undesirably low level (hypothyroidism), may be treated with a
`
`daily administration of 50 — 100 micrograms (pg) of levothyroxine sodium. Formal
`
`names for levothyroxine sodium include 4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodo-L-
`
`1
`
`Mylan Ex 1027, Page 8
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`phenylalanine sodium, and L-tyrosine-0-(4-hydroxy-3,5-diiodopheny1)-3,5-diiodo-
`
`monosodium salt. The chemical structure of levothyroxine is shown in FIG. 1.
`
`[5]
`
`Administration of levothyroxine sodium provides T4 to a patient. Once
`
`absorbed by the organism, the administered T4 behaves identically to T4 that otherwise
`
`would be secreted by the thyroid gland of the patient, and binds to the same serum
`
`proteins, providing a supply of circulating T4-thyroglobulin in the patient. The
`
`administered T4 is deiodinated in vivo to T3. As a result, a patient receiving
`
`appropriate doses of levothyroxine sodium will exhibit normal blood levels of T3, even
`
`when the patient's thyroid gland has been removed or is not functioning.
`
`[6]
`
`Levothyroxine sodium for injection is a sterile lyophilized product for
`
`parenteral administration of levothyroxine sodium for thyroid replacement therapy.
`
`Levothyroxine sodium for injection is particularly useful when thyroid replacement is
`
`needed on an urgent basis, for short term thyroid replacement, and/or when oral
`
`administration is not possible, such as for a patient in a state of myxedema coma.
`
`[7]
`
`Conventional formulations of levothyroxine sodium for injection are
`
`preservative-free lyophilized powders containing synthetic crystalline levothyroxine
`
`sodium and the excipients mannitol, tribasic sodium phosphate, and sodium hydroxide.
`
`These conventional formulations typically contain either 200 ,ug or 500 ,ug of
`
`levothyroxine sodium. Administration of the product involves reconstitution of the
`
`lyophilized powder in 5 milliliters (mL) of 0.9% sodium chloride injection (USP), to
`
`provide injectable solutions having levothyroxine sodium concentrations of 40
`
`micrograms per milliliter (pg/mL) or 100 ,ug/mL, respectively.
`
`[8]
`
`One drawback to conventional formulations of levothyroxine sodium for
`
`injection is the possibility of irritation at the injection site of the patient. Another
`
`drawback to the conventional formulations is that the excipient tribasic sodium
`
`phosphate is not typically approved by the U.S. Food and Drug Administration (FDA)
`
`for use in injectable formulations, but rather is limited to use in buccal delivery of
`
`pharmaceuticals.
`
`2
`
`Mylan Ex 1027, Page 9
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`[009] (cid:9)
`
`It is desirable to provide a new formulation that can reduce the likelihood
`
`of irritation upon injection, but which maintains the stability of the levothyroxine. It is
`
`also desirable for the new formulation to be convenient to store, to reconstitute, and to
`
`administer to a patient.
`
`SUMMARY
`
`[0010] (cid:9)
`
`In one aspect, the invention provides a composition that includes
`
`levothyroxine sodium and mannitol. The composition is a solid and is substantially free
`
`of tribasic sodium phosphate.
`
`[0011] (cid:9)
`
`In another aspect of the invention, there is a method of making a solid
`
`composition that includes forming a liquid mixture including a solvent, levothyroxine
`
`sodium and mannitol, where the liquid mixture includes substantially no tribasic
`
`sodium phosphate. The method further includes lyophilizing the liquid mixture.
`
`[0012] (cid:9)
`
`In another aspect of the invention, there is a solid composition, which is
`
`formed by a method that includes combining ingredients to form a liquid mixture, and
`
`lyophilizing the liquid mixture. The ingredients include a solvent, levothyroxine
`
`sodium, mannitol, and substantially no tribasic sodium phosphate.
`
`[0013] (cid:9)
`
`In another aspect of the invention, there is a composition that includes
`
`levothyroxine sodium, mannitol and dibasic sodium phosphate. The composition is a
`
`solid, and the mass ratio of mannitol to levothyroxine sodium is at most 40:1.
`
`[0014] (cid:9)
`
`In another aspect of the invention, there is a method of making a solid
`
`composition that includes forming a liquid mixture including a solvent, levothyroxine
`
`sodium, mannitol and dibasic sodium phosphate; and lyophilizing the liquid mixture.
`
`[0015] (cid:9)
`
`In another aspect of the invention, there is a solid composition, which is
`
`formed by a method that includes combining ingredients to form a liquid mixture, and
`
`lyophilizing the liquid mixture. The ingredients include a solvent, levothyroxine
`
`3
`
`Mylan Ex 1027, Page 10
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`sodium, mannitol and dibasic sodium phosphate. The mass ratio of mannitol to
`
`levothyroxine sodium in the liquid mixture is at most 40:1.
`
`[0016] (cid:9)
`
`To provide a clear and more consistent understanding of the specification
`
`and claims of this application, the following definitions are provided.
`
`[0017] (cid:9)
`
`The term "mass ratio" of two substances means the mass of one substance
`
`(S1) relative to the mass of the other substance (S2), where both masses have identical
`
`units, expressed as S1 :S2.
`
`[0018] (cid:9)
`
`The term "lyophilizing" means removing from a solution or an emulsion
`
`one or more substances having the lowest boiling points by freezing the solution or
`
`emulsion and applying a vacuum to the frozen mixture.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0019] (cid:9)
`
`The invention can be better understood with reference to the following
`
`drawing and description. The components in the figure are not necessarily to scale and
`
`are not intended to accurately represent molecules or their interactions, emphasis
`
`instead being placed upon illustrating the principles of the invention. Moreover, in the
`
`figure, like referenced numerals designate corresponding parts throughout the different
`
`views.
`
`[0020] (cid:9)
`
`FIG. 1 depicts a chemical structure of levothyroxine sodium.
`
`DETAILED DESCRIPTION
`
`[0021] (cid:9)
`
`Lyophilized formulations that include levothyroxine sodium and
`
`mannitol, and that are substantially free of tribasic sodium phosphate, can protect
`
`levothyroxine from degradation. These formulations also can maintain a consistent
`
`level of pure levothyroxine regardless of the dosage in the formulation. Reconstitution
`
`of the lyophilized formulations with a carrier liquid yields injectable liquids having
`
`ingredients that are more acceptable than those in conventional formulations.
`
`Maintaining the mass ratio of mannitol to levothyroxine sodium in the formulations at a
`
`- 4 -
`
`Mylan Ex 1027, Page 11
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`level of less than 50:1 can provide for acceptable levels of levothyroxine stability,
`
`which otherwise would not be maintained in formulations having a higher relative
`
`amount of mannitol. Moreover, lowering the phosphate content of the reconstituted
`
`composition may reduce the likelihood of irritation at the injection site of the patient.
`
`[0022] (cid:9)
`
`A levothyroxine composition may include levothyroxine sodium,
`
`mannitol, and optionally one or more other substances, where the composition is a
`
`solid and is substantially free of tribasic sodium phosphate. The solid composition may
`
`be prepared by forming a liquid mixture containing a solvent, levothyroxine sodium
`
`and mannitol, and lyophilizing the liquid mixture. Forming a liquid mixture for use in
`
`preparing the solid composition may include combining ingredients including a solvent,
`
`levothyroxine sodium and mannitol. The liquid mixture may be substantially free of
`
`tribasic sodium phosphate.
`
`[0023] (cid:9)
`
`A levothyroxine composition may include levothyroxine sodium,
`
`mannitol, dibasic sodium phosphate and optionally one or more other substances,
`
`where the composition is a solid. The mass ratio of mannitol to levothyroxine sodium
`
`preferably is at most 40:1. The solid composition may be prepared by forming a liquid
`
`mixture containing a solvent, levothyroxine sodium, mannitol and dibasic sodium
`
`phosphate, and lyophilizing the liquid mixture. Forming a liquid mixture for use in
`
`preparing the solid composition may include combining ingredients including a solvent,
`
`levothyroxine sodium, mannitol and dibasic sodium phosphate.
`
`[0024] (cid:9)
`
`The stability of levothyroxine in solid formulations is surprisingly and
`
`unexpectedly dependent on the type and relative amounts of certain excipients. For
`
`example, solid compositions of levothyroxine that differ from conventional formulations
`
`only in the type and/or amount of sodium phosphate can exhibit increased instability of
`
`the levothyroxine when stored at temperatures of 25 °C or 40 °C. Table 1 lists the
`
`ingredients of conventional formulations containing tribasic sodium phosphate, and of
`
`modified formulations containing dibasic sodium phosphate. For a given formulation,
`
`the listed ingredients were combined with water for injection (USP) for a total volume
`
`of 1 mL, and then lyophilized to provide solid powders substantially free of water.
`
`- 5 -
`
`Mylan Ex 1027, Page 12
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`Table 1: Composition of lyophilized levothyroxine sodium formulations.
`
`Conventional
`
`A (cid:9)
`
`B
`
`Modified
`
`C
`
`D
`
`E
`
`Levothyroxine sodium, USP
`
`200 pg
`
`500 pg
`
`100 pg
`
`200 pg
`
`500 pg
`
`Mannitol, USP
`
`10 mg
`
`10 mg
`
`10 mg
`
`10 mg
`
`10 mg
`
`Tribasic sodium phosphate
`
`700 pg
`
`700 pg
`
`Dibasic sodium phosphate
`
`Sodium hydroxide
`
`500 pg
`
`500 pg
`
`500 pg
`
`- - - to pH 11.8 ± 0.1 - (cid:9) - (cid:9) -
`
`[0025] (cid:9)
`
`The stability of the levothyroxine in modified formulations C, D and E
`
`was analyzed. Samples of each formulation were stored in vials at temperatures of 25
`
`°C or 40 °C, with some samples stored upright and other samples stored inverted. The
`
`stability of the levothyroxine in the formulations over time was determined by
`
`measuring the amount of liothyronine (T3) in a sample, as this is a degradation product
`
`of levothyroxine (T4). The results of these measurements are listed in Table 2, below.
`
`Table 2: Concentration of T3 impurity in levothyroxine sodium formulations.
`
`Formulation:
`
`C
`
`% T3
`
`D
`
`E
`
`Time
`(mo.)
`
`0
`
`2
`
`Temp.
`
`Inverted
`
`Upright (cid:9)
`
`Inverted
`
`Upright (cid:9)
`
`Inverted
`
`Upright
`
`0.17
`
`0.17 (cid:9)
`
`0.18
`
`0.18
`
`0.19
`
`0.17
`
`0.18
`
`0.17
`
`0.17
`
`3
`
`6
`
`9
`
`12
`
`18
`
`1
`
`2
`
`3
`
`25 °C
`
`40 °C
`
`0.20
`
`0.24
`
`0.28
`
`0.20
`
`0.35
`
`0.25
`
`0.34
`
`0.22
`
`0.44
`
`0.18
`
`0.20
`
`0.24
`
`0.20
`
`0.25
`
`0.25
`
`0.26
`
`0.28
`
`0.33
`
`0.20
`
`0.22
`
`0.25
`
`0.24
`
`0.29
`
`0.35
`
`0.34
`
`0.30
`
`0.57
`
`6
`
`0.19
`
`0.21
`
`0.24
`
`0.21
`
`0.24
`
`0.21
`
`0.23
`
`0.32
`
`0.18
`
`0.19
`
`0.18
`
`0.20
`
`0.18
`
`0.19
`
`0.19
`
`0.19
`
`0.17
`
`0.20
`
`0.19
`
`0.19
`
`0.21
`
`0.20
`
`0.21
`
`0.20
`
`Mylan Ex 1027, Page 13
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`[0026] (cid:9)
`
`Each of formulations C, D and E included 0.17 — 0.18% T3 at the
`
`beginning of the testing. The amount of T3 increased over time in formulations C and
`
`D, whereas the amount of T3 in formulation E remained relatively stable. During
`
`storage at room temperature (25 °C), the amount of T3 in formulation C increased over
`
`a period of 18 months to 0.35% for upright storage, and to 0.25% for inverted storage.
`
`Under the same conditions, the amount of T3 in formulation D increased less rapidly, to
`
`0.24% for upright storage and to 0.25% for inverted storage over a period of 18 months.
`
`In contrast, the amount of T3 in formulation E was relatively stable under the same
`
`conditions, increasing only to 0.21 % for upright storage and to 0.18% for inverted
`
`storage over a period of 18 months.
`
`[0027] (cid:9)
`
`These stability trends were more pronounced at a higher storage
`
`temperature, with the amount of T3 in formulations C and D reaching higher levels and
`
`increasing more rapidly than at room temperature. During storage at 40 °C, the amount
`
`of T3 in formulation C increased over a period of 3 months to 0.57% for upright
`
`storage, and to 0.44% for inverted storage. Under the same conditions, the amount of
`
`T3 in formulation D increased less rapidly, to 0.32% for upright storage and to 0.33%
`
`for inverted storage over a period of 3 months. In contrast, formulation E appeared
`
`largely unaffected by the temperature increase. The amount of T3 in formulation E was
`
`relatively stable at 40 °C for 3 months, increasing only to 0.20% for upright storage and
`
`to 0.19% for inverted storage.
`
`[0028] (cid:9)
`
`The instability of levothyroxine in the modified formulations C and D was
`
`unexpected in view of the behavior of the conventional formulations A and B. During
`
`storage at 25 °C for a period of from 4 to 19 months, the amount of T3 in formulation A
`
`varied from 0.16 — 0.34%, but did not exhibit an increase over time. Likewise, the
`
`amount of T3 in formulation B varied from 0.22 — 0.27% during storage at 25 °C for a
`
`period of from 8 to 28 months, but did not exhibit an increase over time.
`
`[0029] (cid:9)
`
`The instability of levothyroxine in the modified formulations C and D also
`
`was unexpected in view of the nature of the differences in the formulations relative to
`
`conventional formulations A and B. The amounts of mannitol in the conventional and
`
`- 7 -
`
`Mylan Ex 1027, Page 14
`
`

`

`EFS (cid:9)
`Date of Deposit: August 30, 2011 (cid:9)
`
`PATENT
`B&A Docket No. APP01007PRO
`
`modified formulations were identical (10 mg), and the pH values of the formulations
`
`prior to lyophilization also were constant (11.8 ± 0.1). Modified formulation C
`
`included half the amount of levothyroxine sodium (100 pg) as conventional formulation
`
`A (200 pg), but a change in the levothyroxine sodium level by a factor of 2 has not
`
`historically resulted in a substantial change in stability. For example, conventional
`
`formulation A has less than half the amount of levothyroxine sodium as conventional
`
`formulation B, but the two formulations have not sho