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. § 1.111
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`Mail Stop Amendment
`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 March 6, 2014.
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`Applicants respectfully request that Examiner McMillian reconsider the rejections in view
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`of the following amendments and remarks. This paper is believed to be timely filed.
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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 7.
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`Declaration pursuant to 37 CFR § 1.132 of Leonard J. Chyall is included with the
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`response.
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`Mylan Ex 1035, 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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`11.
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`(Currently Amended) A composition, comprising:
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`from 100 to 200 micrograms of levothyroxine sodium
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`a phosphate buffer, and
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`mannitol;
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`where the mass ratio of mannitol to levothyroxine sodium is at most 10:1 from 1:1
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`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 of mannitol to
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`levothyroxine sodium is about 30:1.
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`13.
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`(Currently Amended) The composition of claim 12 claim 11, where the amount of
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`levothyroxine sodium is about 200 micrograms and the mass ratio of mannitol to
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`levothyroxine sodium is at most 30:1 about 15:1.
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`14.
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`(Currently Amended) The composition of claim 13, further comprising a claim 12,
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`where the phosphate buffer is dibasic sodium phosphate in an amount from 400 to 600
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`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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`Serial No. 13/597,884 (cid:9)
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`PATENT
`Docket No. FKA01 007 US
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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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`16.
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`(Currently Amended) The composition of claim 15, where the amount of dibasic
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`sodium phosphate in the liquid mixture is from 100 to 600 micrograms claim 11, where
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`when the composition is stored at 25 °C, at most 0.20°/0 of the levothyroxine sodium is
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`converted to liothyronine over a period of 12 months.
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`17.
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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 when the composition is stored at 40 °C, at
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`most 0.20°/0 of the levothyroxine sodium is converted to liothyronine over a period of 3
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`months.
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`18.
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`(Currently Amended) The composition of claim 17, where the mass ratio of
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`mannitol to levothyroxine sodium is at most 15:1 claim 14, when the composition is stored
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`at 25 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine over a
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`period of 12 months.
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`19.
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`(Currently Amended) The composition of claim 18, further comprising a claim 13,
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`where the phosphate buffer is dibasic sodium phosphate in an amount from 400 to 600
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`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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`Serial No. 13/597,884 (cid:9)
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`lyophilizing the liquid mixture.
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`PATENT
`Docket No. FKA01 007 US
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`21. (cid:9)
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`(Currently Amended) The composition of claim 20, where the amount of dibasic
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`sodium phosphate in the liquid mixture is from 100 to 600 micrograms claim 14, where
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`when the composition is stored at 40 °C, at most 0.20010 of the levothyroxine sodium is
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`converted to liothyronine over a period of 3 months.
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`22.
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`(Currently Amended) The composition of claim 11 claim 19, where when the
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`composition is stored at 25 °C, at most 0.20% of the levothyroxine sodium is converted to
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`liothyronine over a period of 12 months.
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`23.
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`(Currently Amended) The composition of claim 11 claim 19, where when the
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`composition is stored at 40 °C, at most 0.20% of the levothyroxine sodium is converted to
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`liothyronine 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,
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`a phosphate buffer, and
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`mannitol;
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`where the mass ratio of mannitol to levothyroxine sodium is at most 10:1 from 2:1
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`to 10:1, and 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 of
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`mannitol to levothyroxine sodium is at most about 6:1.
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`26.
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`(Currently Amended) The composition of claim 25, further comprising a where the
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`phosphate buffer is 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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`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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`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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`28. (cid:9)
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`(Currently Amended) The composition of claim 27, where the amount of dibasic
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`;odium phosphate in the liquid mixture is from 400 to 600 micrograms dibasic sodium
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`phosphate claim 24, where when the composition is stored at 25 °C, at most 0.15% of the
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`levothyroxine sodium is converted to liothyronine over a period of 12 months.
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`29.
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`(Currently Amended) The composition of claim 21 claim 26, where when the
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`composition is stored at 25 °C, at most 0.15% of the levothyroxine sodium is converted to
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`liothyronine over a period of 12 months.
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`30.
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`(Currently Amended) The composition of claim 24 claim 26, where when the
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`composition is stored at 40 °C, at most 0.15% of the levothyroxine sodium is converted to
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`liothyronine over a period of 3 months.
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`31.
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`(New) The composition of claim 24, where when the composition is stored at 40
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`°C, at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period
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`of 3 months.
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`32.
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`(New) The composition of claim 11, where the mass ratio of mannitol to
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`levothyroxine sodium is from 5:1 to 35:1.
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`33.
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`(New) The composition of claim 32, where when the composition is stored at 25
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`°C, at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period
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`of 12 months.
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`34.
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`(New) The composition of claim 32, where the phosphate buffer is dibasic sodium
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`phosphate in an amount from 400 to 600 micrograms.
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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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`35.
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`(New) The composition of claim 34, where when the composition is stored at 25
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`°C, at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period
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`of 12 months.
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`36.
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`(New) The composition of claim 24, where the mass ratio of mannitol to
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`levothyroxine sodium is from 4:1 to 8:1.
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`37.
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`(New) The composition of claim 36, where when the composition is stored at 25
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`°C, at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period
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`of 12 months.
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`38.
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`(New) The composition of claim 36, where the phosphate buffer is dibasic sodium
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`phosphate in an amount from 400 to 600 micrograms.
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`39.
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`(New) The composition of claim 38, where when the composition is stored at 25
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`°C, at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period
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`of 12 months.
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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 11-39 currently are pending and subject to examination. The application
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`presently is under Track I prioritized examination.
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`Support for the Amendment
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`Claims 11 and 24 have been amended to specify a phosphate buffer, as supported
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`by the specification at, e.g., paragraph 0029. Claims 11-13 and 24 have been amended to
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`specify a range of mass ratios of mannitol to levothyroxine, as supported by the
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`specification at, e.g., paragraph 0031. Support for the limitation of from 2:1 to 10:1 in
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`claim 24 is derived from the explicit disclosure of a range of mannitol from 1 to 5 mg
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`recited in paragraph 0031 of the specification. Claims 14, 19, and 26 have been amended
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`to specify a type and amount of phosphate buffer, as supported by the specification at, e.g.,
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`paragraph 0029. Claims 16-18, 21, and 28 have been amended to specify storage stability
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`parameters, as supported by the specification at, e.g., paragraphs 0041-0042. Claims 13,
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`14, 16, 18, 19, 21-23, 25, 29, and 30 have been amended to change dependencies and/or
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`grammar. New claims 31-39 recite a range of mass ratios of mannitol to levothyroxine, a
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`type and amount of phosphate buffer, and/or storage stability parameters, which are
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`supported at least by the above-referenced portions of the specification. Support for the
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`limitation of from 4:1 to 8:1 in claim 36 is derived from the explicit disclosure of a range of
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`mannitol from 2 to 4 mg recited in paragraph 0031 of the specification. Claims 1-10 have
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`been canceled without prejudice. No new matter has been added by way of these
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`amendments.
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`The Office Action
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`Claims 1-30 are rejected under 35 U.S.C. § 103(a) as allegedly obvious over
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`Bedford Laboratories, "Levothyroxine Sodium For Injection", 2003 ("Bedford") in view of
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`Collier et al. (RAPS PharmSciTech., 11(2): 818-825 (2010) ("Collier")), Baheti et al. (J.
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`Excip. Food Chem., 1(1): 41-54 (2010) ("Baheti")), and Kim et al. (I. Pharm. Sci., 87(8): 931-
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`935 (1998) ("Kim")).
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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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`Applicants respectfully request reconsideration of this rejection in view of the claim
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`amendments and remarks set forth herein.
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`Discussion of the Obviousness Rejection
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`The Office acknowledges that Bedford does not disclose the amounts of mannitol
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`recited in the pending claims. However, the Office alleges that Baheti and Kim suggest to
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`one of ordinary skill in the art that changing the amount of mannitol in a lyophilized solid
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`levothyroxine composition would stabilize the levothyroxine, and that Collier suggests a
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`mannitol to levothyroxine ration of 10:1 in a lyophilized solid levothyroxine composition.
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`Applicants traverse the rejection for the following reasons.
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`For subject matter defined by a claim to be considered obvious, the Office must
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`demonstrate that the differences between the claimed subject matter and the prior art "are
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`such that the subject matter as a whole would have been obvious at the time the invention
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`was made to a person having ordinary skill in the art to which said subject matter pertains."
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`35 U.S.C. § 103(a); see also Graham v. John Deere Co., 383 U.S. 1, 148 U.S.P.Q. 459
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`(1966). The ultimate determination of whether an invention is or is not obvious is based
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`on certain factual inquiries including: (1) the scope and content of the prior art, (2) the level
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`of ordinary skill in the art, (3) the differences between the claimed invention and the prior
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`art, and (4) objective evidence of nonobviousness. Graham, 383 U.S. at 17-18, 148
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`U.S.P.Q. at 467.
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`1. Scope and Content of the Prior Art
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`Applicants submit herewith a Declaration Under 37 C.F.R. § 1.132 of Dr. Leonard J.
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`Chyall ("the Dr. Chyall declaration"), which summarizes the relevant portions of the
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`references cited by the Office and the general knowledge in the field of lyophilization at
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`the time of the invention. As explained by Dr. Chyall, the Office has mischaracterized the
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`disclosures of the references and has made interpretations that lack factual bases and are
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`inconsistent with the interpretations that would be made by one of ordinary skill in the art.
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`Bedford discloses a lyophilized composition containing 200 aug levothyroxine, 10
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`mg mannitol, and 0.7 mg tribasic sodium phosphate wherein the ratio of mannitol to
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`PATENT
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`levothyroxine is 50:1. Bedford also discloses a lyophilized composition containing 500 ,ug
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`levothyroxine, 10 mg mannitol, and 0.7 mg tribasic sodium phosphate wherein the ratio of
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`mannitol to levothyroxine is 20:1. The Office acknowledges that Bedford does not disclose
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`the ratios of mannitol to levothyroxine recited in the pending claims.
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`Baheti makes a generic statement that crystallization of a bulking agent "might"
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`adversely affect the stability of a drug "in certain instances" (pg. 46, col. 2), while
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`referencing an article by Herman et al. (Pharm. Res., 11: 1467-1473 (1994) ("Herman")),
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`which is of record in the present application. The only support for the generic
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`statement made by Baheti is derived from the stability of methylprednisolone sodium
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`succinate, as tested in Herman.
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`Kim merely discloses that the degree of mannitol crystallinity in a lyophilized solid
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`can affect protein activity (pg. 931, col. 2).
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`As explained by Dr. Chyall, given that the chemical structures and degradation
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`pathways of methylprednisolone sodium succinate, proteins, and levothyroxine are
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`completely unrelated to one another, one of ordinary skill in the art would not have
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`interpreted Baheti, Herman, or Kim as suggesting that decreasing the crystallization of
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`mannitol would be beneficial for the stability of levothyroxine in a lyophilized solid
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`composition.
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`Collier is directed to the stability of levothyroxine in pharmaceutical tablets for oral
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`administration. Collier discloses that levothyroxine demonstrated greater stability when
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`mixed with the tabletting excipients colloidal silicon dioxide, magnesium stearate, acacia,
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`confectioner's sugar, talc, lactose monohydrate, croscarmellose sodium, and sodium starch
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`glycolate than it did when mixed with mannitol (see, e.g., Fig. 3 and Table IV). Collier also
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`discloses that a levothyroxine to mannitol ratio of 1:10 is used in pharmaceutical tablets.
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`2. Level of Ordinary Skill in the Art
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`For the purposes of the analysis here, and for the sake of argument, the level of
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`ordinary skill can be considered to be relatively high, such that a person of ordinary skill in
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`PATENT
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`the art would have an advanced degree and/or at least a few years of experience in the
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`relevant field.
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`3. Differences Between the Claimed Invention and the Prior Art
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`The present invention, as defined by independent claims 11 and 24, is directed to a
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`lyophilized solid composition comprising levothyroxine sodium, a phosphate buffer, and
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`mannitol, wherein the levothyroxine and mannitol are present in particular mass ratios.
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`Each of the remaining claims subject to the obviousness rejection is directly or indirectly
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`dependent on claim 11 or 24.
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`The mass ratios of mannitol to levothyroxine recited in the pending claims are
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`reduced relative to Bedford. As discussed in detail above and in the Dr. Chyall
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`declaration, the prior art does not suggest that it would be beneficial to reduce the amount
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`of mannitol in a lyophilized solid levothyroxine composition.
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`The theory of the Office that Baheti, Herman, and Kim suggest that reducing the
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`amount of mannitol in a lyophilized solid would reduce the crystallinity of mannitol
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`thereby stabilizing the levothyroxine is not supported by the disclosure of the cited
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`references themselves, or the general knowledge in the art at the time of the invention. If
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`anything, the prior art teaches away from reducing the crystallinity of mannitol in a
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`lyophilized drug product. For example, Searles, JA. "Freezing and Annealing Phenomena
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`in Lyophilization." Freeze Drying/Lyophilization of Pharmaceutical and Biological
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`Products, 3' Edition. Ed. Louis Rey, Ed. Joan C. May. London: Informa Healthcare, 2010.
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`52-81 (cited in the Information Disclosure Statement submitted herewith) discloses,
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`"[m]annitol 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 crystalline form" (pg.
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`71, para. 1).
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`Moreover, Applicants note that Kim also discloses that the weight ratio of mannitol
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`to cosolute in a lyophilized composition is related to mannitol crystallinity. In this regard,
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`Kim discloses that the relative concentration threshold above which crystalline mannitol is
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`observed in a lyophilized composition comprising mannitol and a cosolute is 30% why
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`(pg. 933, col. 2). The pending claims of the present invention recite a relative
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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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`concentration of mannitol that is greater than the threshold for mannitol crystallinity
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`disclosed in Kim. Therefore, even assuming, arguendo, levothyroxine is affected by
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`mannitol crystallinity in a lyophilized solid, one of ordinary skill in the art would not have
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`been motivated to select the mass ratios recited in the pending claims in view of Kim, since
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`mannitol would still be expected to be in crystalline form.
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`Collier also does not provide any motivation for one of ordinary skill in the art to
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`reduce the amount of mannitol in a lyophilized solid levothyroxine composition. The
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`Office acknowledges that Collier does not disclose a lyophilized composition comprising
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`mannitol and levothyroxine. However, the Office nevertheless asserts that the "teachings
`
`of Collier et al. are very relevant to the claimed invention" (Office Action at pg. 7, para. 2),
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`including the levothyroxine to mannitol ratio of 1:10 used in pharmaceutical tablets.
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`Applicants strongly disagree with the Office regarding the relevance of Collier to the
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`present invention, a sentiment which is supported by the Dr. Chyall declaration and the
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`Declaration Under 37 C.F.R. § 1.132 of Zhi-Qiang Jiang, Arunya Usayapant, and George
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`Monen filed on August 9, 2013 ("the Jiang et al. declaration").
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`If, however, the Office continues to believe that Collier is "very relevant to the
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`claimed invention," Applicants respectfully request that the Office explain why one of
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`ordinary skill in the art would not have chosen to replace the mannitol in the solid
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`levothyroxine composition of Bedford with the colloidal silicon dioxide, magnesium
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`stearate, acacia, confectioner's sugar, talc, lactose monohydrate, croscarmellose sodium, or
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`sodium starch glycolate of Collier, rather than change the amount of mannitol, given that
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`each of these tabletting excipients promoted greater levothyroxine stability than mannitol.
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`The only way in which the combined disclosures of the cited references can be
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`considered as teaching or suggesting the present invention as defined by the pending
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`claims is through the use of hindsight, i.e., with the knowledge of the present application
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`and the invention as claimed therein. It is impermissible for the Patent Office to engage in
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`hindsight reconstruction of the claimed invention by using Applicants' invention as a
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`template and selecting and combining elements from references to fill in that template.
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`See In re Gorman, 933 F.2d 982, 18 U.S.P.Q.2d 1885 (Fed. Cir. 1991).
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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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`4. Objective Evidence of Unobviousness
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`As described in the specification of the present application, Applicants have
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`discovered that compositions according to the present invention having at least 30% less,
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`and up to 900!o less, mannitol than conventional lyophilized levothyroxine compositions
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`provide for substantial increases in stability.
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`These results were brought to the attention of the Office in a response to Office
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`Action filed on February 11, 2013, and in the Jiang et al. declaration filed on August 9,
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`2013, wherein it was stated that that the approximate 7- to 15-fold improvement in stability
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`achieved by lowering the amount of mannitol was surprising and unexpected in view of
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`the conventional amount of mannitol included in lyophilized solid levothyroxine
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`compositions.
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`The Dr. Chyall declaration accompanying this response establishes that neither the
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`newly cited references (Baheti and Kim) nor the prior art as a whole provides any teaching
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`that would render the stability results obtained from the claimed compositions any less
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`unexpected.
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`5. Consideration of the Graham Factors Together
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`The courts have held that there must exist some credible reason for one of ordinary
`
`skill in the art to combine the prior art teachings in the manner necessary to arrive at the
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`claimed invention. See, e.g., KSR Int'l v. Teleflex Inc., 550 U.S. 398,418, 82 U.S.P.Q.2d
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`1385, 1396 (2007) (there is a need "to determine whether there was an apparent reason to
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`combine the known elements in the fashion claimed by the patent at issue"); In re Kotzab,
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`217 F.3d 1365, 1371, 55 U.S.P.Q.2d 1313, 1317 (Fed. Cir. 2000) ("Particular findings
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`must be made as to the reason the skilled artisan, with no knowledge of the claimed
`
`invention, would have selected these components for combination in the manner
`
`claimed.").
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`Here, the Office has failed to identify any credible reason why one of ordinary skill
`
`in the art would have "picked and chosen" the particular elements disclosed in the cited
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`references identified by the Office and then combined those elements in the manner
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`necessary to arrive at the invention recited in the pending claims. Contrary to the
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`Serial No. 13/597,884 (cid:9)
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`PATENT
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`assertions of the Office, Applicants submit that one of ordinary skill in the art — without
`
`hindsight knowledge of the present invention — would not have had a credible reason to
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`modify the amount of mannitol in the compositions disclosed in Bedford in view of Baheti,
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`Kim, and/or Collier, much less in a manner to arrive at the mass ratios of mannitol to
`
`levothyroxine recited in the pending claims.
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`In any event, the unexpected stabilizing effect provided by mass ratio of mannitol to
`
`levothyroxine present in the compositions recited in the pending claims further evidences
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`the unobviousness of the present invention and serves to rebut any prima facie case of
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`obviousness made out by the Office.
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`Considering all of the Graham factors together, it is clear that the present invention
`
`would not have been obvious to one of ordinary skill in the art at the relevant time in view
`
`of the combination of cited references. Accordingly, the obviousness rejection should be
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`withdrawn.
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`Conclusion
`
`Applicants respectfully submit that the patent application is in condition for
`
`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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`June 6, 2014 (cid:9)
`Date (cid:9)
`
`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, IL 60661
`Docketing@blanchard-patent.com
`Tel. (312) 612-6700
`
`Respectfully Submitted,
`
`/Jonathan M. Blanchard, Reg. No. 48927/
`Jonathan M. Blanchard, Ph.D.
`Patent Attorney
`Reg. No. 48,927
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