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.: FKA01 007 US
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`AMENDMENT AND RESPONSE UNDER 37 C.F.R. § 1.116
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`Mail Stop AF
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Dear Sir:
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`This communication responds to the Office Action mailed on September 8, 2014.
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`Applicant respectfully requests that Examiner McMillian reconsider the rejections in view
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`of the following amendments and remarks.
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`Amendments to the Claims are reflected in the listing of claims beginning on
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`page 2.
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`Remarks begin on page 6.
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`Declaration pursuant to 37 CFR § 1.132 of Arunya Usayapant is included with the
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`response.
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`1
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`Mylan Ex 1026, Page 1
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`Serial No. 13/597,884 (cid:9)
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`IN THE CLAIMS:
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`PATENT
`Docket No. FKA01_007_US
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`In accord with Rule § 1.121, a complete claim listing is presented below. A status
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`identifier (Original), (Previously Presented), or (Currently Amended) precedes each claim.
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`The changes in amended claims are shown by strikethrough or double brackets for deleted
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`material, and by underlining for added material.
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`1.-10. (Canceled)
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`(Currently Amended) A composition, comprising:
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`from 100 to 200 about 100 or about 200 micrograms of levothyroxine sodiumi
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`a phosphate buffer,—Land
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`from 2 to 4 milligrams of mannitol
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`where the mass ratio of mannitol to lcvothyroxinc sodium is from 1:1 to 40:1, and
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`the composition is a lyophilized solid.
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`12.
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`(Currently Amended) The composition of claim 11, where the amount of
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`levothyroxine sodium is about 100 micrograms and the mass ratio amount of mannitol to
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`lcvothyroxinc sodium is about 3043 milligrams.
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`13.
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`(Currently Amended) The composition of claim 11, where the amount of
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`levothyroxine sodium is about 200 micrograms and the mass ratio amount of mannitol to
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`lcvothyroxinc sodium is about 15:13 milligrams.
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`14.
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`(Previously Presented) The composition of claim 12, where the phosphate buffer is
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`dibasic sodium phosphate in an amount from 400 to 600 micrograms.
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`15.
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`(Original) The composition of claim 14, where the composition is formed by
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`forming a liquid mixture by combining
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`the levothyroxine sodium,
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`the mannitol,
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`-2
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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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`dibasic sodium phosphate, and
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`a solvent comprising water; and
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`lyophilizing the liquid mixture.
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`16.
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`(Previously Presented) The composition of claim 11, where when the composition
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`is stored at 25 °C, at most 0.20°/0 of the levothyroxine sodium is converted to liothyronine
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`over a period of 12 months.
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`17.
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`(Previously Presented) The composition of claim 11, where when the composition
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`is stored at 40 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine
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`over a period of 3 months.
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`18.
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`(Currently Amended) The composition of claim 14, where when the composition is
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`stored at 25 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine
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`over a period of 12 months.
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`19.
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`(Previously Presented) The composition of claim 13, where the phosphate buffer is
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`dibasic sodium phosphate in an amount from 400 to 600 micrograms.
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`20.
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`(Original) The composition of claim 19, where the composition is formed by
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`forming a liquid mixture by combining
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`the levothyroxine sodium,
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`the mannitol,
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`dibasic sodium phosphate, and
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`a solvent comprising water; and
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`lyophilizing the liquid mixture.
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`21.
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`(Previously Presented) The composition of claim 14, where when the composition
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`is stored at 40 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine
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`over a period of 3 months.
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`3
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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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`22.
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`(Previously Presented) The composition of claim 19, where when the composition
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`is stored at 25 °C, at most 0.20°/0 of the levothyroxine sodium is converted to liothyronine
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`over a period of 12 months.
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`23.
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`(Previously Presented) The composition of claim 19, where when the composition
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`is stored at 40 °C, at most 0.20°/0 of the levothyroxine sodium is converted to liothyronine
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`over a period of 3 months.
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`24.
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`(Currently Amended) A composition, comprising:
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`about 500 micrograms of levothyroxine sodium,,i
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`a phosphate buffer,—Land
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`from 2 to 4 milligrams of mannitol
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`where the mass ratio of mannitol to lcvothyroxinc sodium is from 2:1 to 10:1, and
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`the composition is a lyophilized solid.
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`25.
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`(Currently Amended) The composition of claim 24, where the mass ratio amount of
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`mannitol to lcvothyroxinc sodium is about 643 milligrams.
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`26.
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`(Previously Presented) The composition of claim 25, where the phosphate buffer is
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`dibasic sodium phosphate in an amount from 400 to 600 micrograms.
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`27.
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`(Original) The composition of claim 26, where the composition is formed by
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`forming a liquid mixture by combining
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`the levothyroxine sodium,
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`the mannitol,
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`dibasic sodium phosphate, and
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`a solvent comprising water; and
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`lyophilizing the liquid mixture.
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`-4
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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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`28.
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`(Previously Presented) The composition of claim 24, where when the composition
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`is stored at 25 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine
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`over a period of 12 months.
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`29.
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`(Previously Presented) The composition of claim 26, where when the composition
`
`is stored at 25 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine
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`over a period of 12 months.
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`30.
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`(Previously Presented) The composition of claim 26, where when the composition
`
`is stored at 40 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine
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`over a period of 3 months.
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`31.
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`(Previously Presented) The composition of claim 24, where when the composition
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`is stored at 40 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine
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`over a period of 3 months.
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`32.-39. (Canceled).
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`5
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`Serial No. 13/597,884 (cid:9)
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`The Pending Claims
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`PATENT
`Docket No. FKA01_007_US
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`REMARKS
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`Claims 11-31 currently are pending and subject to examination.
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`Support for the Amendment
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`Claim 11 is amended to specify that the amount of levothyroxine sodium is about
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`100 pig or about 200 pig and the amount of mannitol is from 2 to 4 mg. Claim 24 is
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`amended to specify that the amount of mannitol is from 2 to 4 mg. These amendments are
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`supported by the specification at, e.g., paragraphs 0027, 0031, 0033, and 0034. Claims
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`12, 13, and 25 are amended to specify that the amount of mannitol is about 3 mg, as
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`supported by the specification at, e.g., paragraphs 0031, 0033, and 0034. Claim 18 is
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`amended to include the inadvertently omitted "when" at the start of the clause. Claims 32-
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`39 are canceled without prejudice to their pursuit in a continuing application. No new
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`matter is added by way of these amendments. These amendments are made to facilitate
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`prosecution of the current application and are not an admission that the original claims are
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`not patentable.
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`Applicant requests entry of the Declaration Under 37 C.F.R. § 1.132 of Dr. Arunya
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`Usayapant (hereinafter "the Dr. Usayapant declaration") filed herewith. Some of the data
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`described in the Dr. Usayapant declaration was obtained as recently as October 2014.
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`Accordingly, the Dr. Usayapant declaration filed herewith could not have been presented
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`to the Office earlier (see 37 C.F.R. § 1.116(e)). While discussed during the interview,
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`Applicant does not believe an AFCP 2.0 request may be properly filed with this response,
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`as the declaration includes newly obtained information.
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`The Office Action
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`Claims 11-39 are rejected under 35 U.S.C. § 103(a) as obvious over Bedford
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`Laboratories, "Levothyroxine Sodium For Injection", 2003 ("Bedford") in view of Collier et
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`al. (AAPS PharmSciTech., 11(2): 818-825 (2010) ("Collier")), Baheti et al. (J. Excip. Food
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`Chem., 1(1): 41-54 (2010) ("Baheti")), and Kim et al. (J. Pharm. Sci., 87(8): 931-935 (1998)
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`6
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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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`("Kim")). Applicant respectfully requests reconsideration of this rejection in view of the
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`claim amendments and remarks that follow.
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`Summary of the Examiner Interview
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`Applicant thanks Examiners McMillian and Padmanabhan for the courtesies
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`extended during the in-person interview held on December 16, 2014, with one of the
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`inventors of the present application, Dr. Arunya Usayapant, a patent agent employed with
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`the assignee of the present application, Dr. Tim Carlson, and the undersigned attorney.
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`The interview included a discussion of the unexpected results described in the Dr.
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`Usayapant declaration filed herewith in view of the limitations of the independent and
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`dependent claims.
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`Discussion of the Remaining Obviousness Rejection
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`Applicant continues to disagree that the Office has demonstrated a prima facie case
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`of obviousness of the subject matter recited in the prior and amended claims in view of the
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`combination of cited references. Applicant has set forth this position in multiple prior
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`responses, including the most recent filed on June 6, 2014. Nevertheless, in order to
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`advance prosecution, Applicant has amended the claims to focus specifically on the
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`unexpected results described in the specification and in the Dr. Usayapant declaration.
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`The Dr. Usayapant declaration establishes that prior to the present invention, Dr.
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`Usayapant was unaware of teaching in the art regarding the instability of lyophilized
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`pharmaceutical products comprising 200 pig or 500 pig 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', e.g., the SYNTHROID° (levothyroxine sodium) Injection as
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`described in the 1971 publication of the Physicians' Desk Reference (attached), the
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`LEVOTHROID° (levothyroxine sodium) Injection as described in the 1986 publication of
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`the Physicians' Desk Reference (attached), or the product disclosed in Bedford (see the Dr.
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`Usayapant declaration at paragraph 8).
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`I Thyroid treatments were known prior to the enactment of the Food, Drug, and Cosmetic Act in 1938.
`Therefore, drug products containing levothyroxine were "grandfathered," and drug manufacturers were not
`required to obtain official FDA approval prior to marketing.
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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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`The Dr. Usayapant declaration also establishes that a person of ordinary skill in the
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`art would not consider a reference directed to levothyroxine stability in water or in a
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`compressed tablet, such as Collier, to be relevant to the development of a stable,
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`lyophilized solid composition. (see the Dr. Usayapant declaration at paragraph 7). In this
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`regard, it is noted that according to the Center For Drug Evaluation and Research the U.S.
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`Food and Drug Administration ("FDA") granted SYNTHROID° (levothyroxine sodium)
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`tablets for oral administration a shelf-life of 9 or 10 months upon approval in approximately
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`July of 2002 (Center for Drug Evaluation and Research, Approval Package for Application
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`Number NDA 21-402, pp. 10-11) (attached). In contrast, the lyophilized solid
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`levothyroxine sodium compositions of the amended claims have a shelf-life of 18-24
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`months (see the Dr. Usayapant declaration at paragraph 17).
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`Considering the lack of an understanding that the grandfathered levothyroxine
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`sodium for injection products were unstable, and the differences in stability of
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`levothyroxine in an oral tablet as compared with a lyophilized product, one of ordinary
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`skill in the art would not have been motivated to reduce the amount of mannitol in the
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`compositions disclosed in Bedford in view of Baheti, Kim, and/or Collier, with a reasonable
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`expectation of arriving at a more stable product.
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`Moreover, the unexpected stabilizing effects provided by the specific amounts of
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`mannitol and levothyroxine sodium present in the compositions recited in the amended
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`claims are of statistical and practical significance. The Dr. Usayapant declaration
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`establishes that a commercial product according to the amended claims has a statistically
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`significant greater potency following storage for 18 or 24 months at 25 °C as compared to
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`a commercial product having the same composition as disclosed in Bedford (see the Dr.
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`Usayapant declaration at paragraphs 14-16).
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`In addition, the commercial products according to the amended claims have a shelf-
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`life of 24 months, whereas the commercial products having the compositions disclosed in
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`Bedford have a shelf life of 18 months (see the Dr. Usayapant declaration at paragraph 17).
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`The extended shelf-life of the commercial products according to the amended claims
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`provides numerous practical advantages to a drug manufacturer and the health care system
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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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`as a whole, such as reduced manufacturing burden, increased availability of personnel,
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`equipment, materials, etc. for the manufacture of other drug products, and reduced costs
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`due to improved supply chain efficiencies.
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`Applicant respectfully submits that the superior stability and extended shelf-life of
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`the compositions according the amended claims are unexpected, and are sufficient to
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`overcome a prima facie case of obviousness. In view of the foregoing, withdrawal of the
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`obviousness rejection is respectfully requested in regard to the pending claims as amended.
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`Conclusion
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`Applicant respectfully submits that the patent application is in condition for
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`allowance. If, in the opinion of the Examiner, a telephone conference would expedite the
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`prosecution of the subject application, the Examiner is invited to call Jonathan M.
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`Blanchard at 312-612-6700.
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`Respectfully Submitted,
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`/Jonathan M. Blanchard, Reg. No. 48927/
`Jonathan M. Blanchard, Ph.D.
`Patent Attorney
`Reg. No. 48,927
`
`December 23, 2014
`Date
`
`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, IL 60661
`Docketing@blanchard-patent.com
`Tel. (312) 612-6700
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`9
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`Mylan Ex 1026, Page 9
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