Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`First Named Inventor: Jiang
`
`Application No.: 13/597,884
`
`Filed: August 29, 2012
`
`Title: Levothyroxine Formulations
`
`Art Unit: 1627
`
`Examiner: Kara R. McMillian
`
`Docket No.: FKA01 007 US
`
`AMENDMENT AND RESPONSE UNDER 37 C.F.R. § 1.116
`
`Mail Stop RCE
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Dear Sir:
`
`This communication responds to the Office Action mailed on April 3, 2013.
`
`Applicants respectfully request that Examiner McMillian reconsider the rejections in
`
`view of the following amendments and remarks. This paper is believed to be timely
`
`filed.
`
`Amendments to the Claims are reflected in the listing of claims beginning on
`
`page 2.
`
`Remarks begin on page 7.
`
`Declaration pursuant to 37 CFR § 1.132 is included with the response.
`
`Mylan Ex 1037, Page 1
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`IN THE CLAIMS:
`
`PATENT
`Docket No. FKA01_007_US
`
`In accord with Rule § 1.121, a complete claim listing is presented below. A
`
`status identifier (Original) or (Currently Amended) precedes each claim. The changes
`
`in amended claims are shown by strikethrough or double brackets for deleted material,
`
`and by underlining for added material.
`
`1. (cid:9)
`
`(Currently Amended) (cid:9)
`
`A composition, comprising:
`
`from 100 to 500 micrograms of levothyroxine sodium, and
`
`from 1 to 5 milligrams mannitol;
`
`where the composition is a lyophilized solid.
`
`2.
`
`(Original) (cid:9)
`
`The composition of claim 1, where the amount of mannitol is from 2
`
`to 4 milligrams.
`
`3.
`
`(Original) (cid:9)
`
`The composition of claim 1, where the amount of mannitol is from
`
`2.9 to 3.1 milligrams.
`
`4.
`
`(Original) (cid:9)
`
`The composition of claim 1, further comprising a phosphate buffer.
`
`5.
`
`(Original) (cid:9)
`
`The composition of claim 4, further comprising a base;
`
`where, when the composition is reconstituted in 5 milliliters of 0.9% aqueous
`
`sodium chloride, the pH of the reconstituted liquid is from 9.5 to 11.5.
`
`6.
`
`(Original) (cid:9)
`
`The composition of claim 5, where the amount of mannitol is from
`
`2.9 to 3.1 milligrams.
`
`7.
`
`(Original) (cid:9)
`
`The composition of claim 5, where the composition is formed by
`
`forming a liquid mixture by combining
`
`the levothyroxine sodium,
`
`2
`
`Mylan Ex 1037, Page 2
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`the mannitol,
`
`dibasic sodium phosphate,
`
`a solvent comprising water, and
`
`a base; and
`
`lyophilizing the liquid mixture.
`
`8.
`
`(Original) (cid:9)
`
`The composition of claim 7, where the amount of dibasic sodium
`
`phosphate in the liquid mixture is from 400 to 600 micrograms.
`
`9.
`
`(Original) (cid:9)
`
`The composition of claim 1, where when the composition is stored at
`
`25 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine over a
`
`period of 12 months.
`
`10.
`
`(Original) (cid:9)
`
`The composition of claim 1, where when the composition is stored at
`
`40 °C, at most 0.20% of the levothyroxine sodium is converted to liothyronine over a
`
`period of 3 months.
`
`11.
`
`(Currently Amended) (cid:9)
`
`A composition, comprising:
`
`from 100 to 200 micrograms of levothyroxine sodium, and
`
`mannitol;
`
`where the mass ratio of mannitol to levothyroxine sodium is at most 40:1, and
`
`the composition is a lyophilized solid.
`
`12.
`
`(Original) (cid:9)
`
`The composition of claim 11, where the amount of levothyroxine
`
`sodium is about 100 micrograms.
`
`13.
`
`(Original) (cid:9)
`
`The composition of claim 12, where the mass ratio of mannitol to
`
`levothyroxine sodium is at most 30:1.
`
`14. (cid:9)
`
`(Original) (cid:9)
`
`The composition of claim 13, further comprising a phosphate buffer.
`
`-3
`
`Mylan Ex 1037, Page 3
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`15.
`
`(Original) (cid:9)
`
`The composition of claim 14, where the composition is formed by
`
`forming a liquid mixture by combining
`
`the levothyroxine sodium,
`
`the mannitol,
`
`dibasic sodium phosphate, and
`
`a solvent comprising water; and
`
`lyophilizing the liquid mixture.
`
`16.
`
`(Original) (cid:9)
`
`The composition of claim 15, where the amount of dibasic sodium
`
`phosphate in the liquid mixture is from 400 to 600 micrograms.
`
`17.
`
`(Original) (cid:9)
`
`The composition of claim 11, where the amount of levothyroxine
`
`sodium is about 200 micrograms.
`
`18.
`
`(Original) (cid:9)
`
`The composition of claim 17, where the mass ratio of mannitol to
`
`levothyroxine sodium is at most 15:1.
`
`19.
`
`(Original) (cid:9)
`
`The composition of claim 18, further comprising a phosphate buffer.
`
`20.
`
`(Original) (cid:9)
`
`The composition of claim 19, where the composition is formed by
`
`forming a liquid mixture by combining
`
`the levothyroxine sodium,
`
`the mannitol,
`
`dibasic sodium phosphate, and
`
`a solvent comprising water; and
`
`lyophilizing the liquid mixture.
`
`21.
`
`(Original) (cid:9)
`
`The composition of claim 20, where the amount of dibasic sodium
`
`phosphate in the liquid mixture is from 400 to 600 micrograms.
`
`-4
`
`Mylan Ex 1037, Page 4
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`22.
`
`(Original) (cid:9)
`
`The composition of claim 11, where when the composition is stored
`
`at 25 °C, at most 0.20°/0 of the levothyroxine sodium is converted to liothyronine over a
`
`period of 12 months.
`
`23.
`
`(Original) (cid:9)
`
`The composition of claim 11, where when the composition is stored
`
`at 40 °C, at most 0.20°/0 of the levothyroxine sodium is converted to liothyronine over a
`
`period of 3 months.
`
`24.
`
`(Currently Amended) (cid:9)
`
`A composition, comprising:
`
`about 500 micrograms of levothyroxine sodium, and
`
`mannitol;
`
`where the mass ratio of mannitol to levothyroxine sodium is at most 10:1, and
`
`the composition is a lyophilized solid.
`
`25.
`
`(Original) (cid:9)
`
`The composition of claim 24, where the mass ratio of mannitol to
`
`levothyroxine sodium is at most 6:1.
`
`26.
`
`(Currently Amended) (cid:9)
`
`The composition of claim 25, further comprising a
`
`phosphate buffer;_
`
`27.
`
`(Original) (cid:9)
`
`The composition of claim 26, where the composition is formed by
`
`forming a liquid mixture by combining
`
`the levothyroxine sodium,
`
`the mannitol,
`
`dibasic sodium phosphate, and
`
`a solvent comprising water; and
`
`lyophilizing the liquid mixture.
`
`28.
`
`(Original) (cid:9)
`
`The composition of claim 27, where the amount of dibasic sodium
`
`phosphate in the liquid mixture is from 400 to 600 micrograms dibasic sodium phosphate.
`
`5
`
`Mylan Ex 1037, Page 5
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`29.
`
`(Original) (cid:9)
`
`The composition of claim 24, where when the composition is stored
`
`at 25 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine over a
`
`period of 12 months.
`
`30.
`
`(Original) (cid:9)
`
`The composition of claim 24, where when the composition is stored
`
`at 40 °C, at most 0.15% of the levothyroxine sodium is converted to liothyronine over a
`
`period of 3 months.
`
`6
`
`Mylan Ex 1037, Page 6
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`Status of the Claims
`
`PATENT
`Docket No. FKA01_007_US
`
`REMARKS
`
`Claims 1-30 are pending. Claims 1, 11, 24, and 26 are amended. The
`
`application is no longer under Track I prioritized examination as a final rejection was
`
`issued.
`
`Support for the Amendment
`
`Support for the amendments to claims 1, 11, and 24 is found in the originally
`
`filed dependent claims 7, 15, 20, and 27. Additional description regarding
`
`lyophilization is found in paragraphs [0014] and [0018] of the specification, for
`
`example. Paragraph [0014] states that the solid composition is formed through
`
`lyophilization, while paragraph [0018] defines lyophilization. Claim 26 is amended to
`
`correct a typographical error. Thus, no new matter has been added. In view of the
`
`following amendments and remarks, Applicants respectfully request reconsideration of
`
`the application.
`
`Interview Summary
`
`Applicants would like to thank Examiner McMillian for the courteous and
`
`helpful discussion with Applicants' representatives on April 30, 2013. Independent
`
`claim 1 was discussed with respect to the cited references in the context of the
`
`outstanding obviousness rejection. Applicants' representatives also discussed that
`
`evidence from the specification of non-obviousness was presented in Applicants'
`
`response of February 11, 2013. Applicants' representatives discussed the results
`
`depicted in FIGs. 2 and 3 of the specification as highlighted in the response, which
`
`show that the stability of levothyroxine in the claimed compositions was surprising and
`
`unexpected in view of conventional injectable formulations. An agreement regarding
`
`the claims was not reached during the interview.
`
`Applicants also would like to thank Examiner McMillian and Supervisor
`
`Padmanabhan for the courteous and helpful discussion with Applicants' representatives
`
`7
`
`Mylan Ex 1037, Page 7
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`on May 29, 2013. During this discussion, the independent claims were discussed in
`
`relation to Mitra, Bedford, and Collier in the context of the outstanding obviousness
`
`rejection. Applicants discussed the requirements for a prima facie rejection and for
`
`maintaining an obviousness rejection in the face of evidence from the specification of
`
`unexpected results. Potential amendments to the independent claims were discussed
`
`to further distinguish the inventions from the cited art. Applicants' representatives
`
`agreed to submit a response with declaratory support. An agreement regarding the
`
`claims was not reached during the interview.
`
`Applicants also would like to thank Examiner McMillian for discussing a draft
`
`declaration under 37 CFR § 1.132 and proposed claim amendments with Applicants'
`
`representative on July 26, 2013. The contents of the declaration and proposed claim
`
`amendments were discussed in the context of unexpected results and the independent
`
`claims. An agreement regarding the claims was not reached during the interview.
`
`Applicants agreed to file a RCE including the signed declaration and proposed claim
`
`amendments.
`
`REQUEST FOR RECONSIDERATION
`
`In lyophilized solid compositions including levothyroxine sodium and mannitol,
`
`the stability of levothyroxine may be improved by lowering the mass of mannitol
`
`and/or the mass ratio of mannitol to levothyroxine sodium to a level below that of
`
`conventional levothyroxine compositions. (Specification, par. [0032]). Conventional
`
`levothyroxine lyophilized solid compositions include 10 milligrams (mg) mannitol and
`
`either 200 or 500 micrograms (,ug) levothyroxine sodium, corresponding to mass ratios
`
`of mannitol to levothyroxine sodium (M:L) of 50:1 and 20:1, respectively. Surprisingly,
`
`improved stability of levothyroxine was obtained by lowering the amount of mannitol
`
`to 1 to 5 mg. In compositions having either 200 or 500 ,ug levothyroxine sodium, this
`
`range of mannitol corresponds to M:L ratios of from 5:1 to 25:1 or from 2:1 to 10:1,
`
`respectively. (Specification, par. [0025]).
`
`8
`
`Mylan Ex 1037, Page 8
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`As amended, independent claims 1, 11, and 24 are directed to lyophilized solid
`
`compositions including levothyroxine sodium and mannitol, where the amount of
`
`mannitol is lowered in relation to conventional compositions, but the stability of the
`
`levothyroxine is increased in relation to the conventional compositions. Each
`
`independent claim recites different lowered mannitol compositions. Claim 1 recites
`
`that the lyophilized solid includes from 100 to 500 micrograms of levothyroxine
`
`sodium and from 1 to 5 milligrams mannitol. Claim 11 recites that the lyophilized
`
`solid includes from 100 to 200 micrograms of levothyroxine sodium and mannitol,
`
`where the mass ratio of mannitol to levothyroxine sodium is at most 40:1. Claim 24
`
`recites that the lyophilized solid includes about 500 micrograms of levothyroxine
`
`sodium and mannitol, where the mass ratio of mannitol to levothyroxine sodium is at
`
`most 10:1.
`
`§ 103. The Claims are Not Obvious in View of the Cited Art
`
`The rejection of all the pending claims as obvious over U.S. 5,955,105 to Mitra
`
`et al. (Mitra) or over the Bedford Laboratories Product label dated May 2003 (Bedford)
`
`or over Collier et al., "Influence of Formulation and Processing Factors on Stability of
`
`Levothyroxine Sodium Pentahydrate", APPS PharmSiTech 11(2), 2010, 818-825
`
`(Collier) is respectfully traversed.
`
`As established by the included declaration under 37 CFR § 1.132 from the
`
`inventors of the present application, the cited references fail to teach lyophilized solid
`
`compositions including the claimed critical relative amounts of levothyroxine sodium
`
`and mannitol. Neither do the cited references, alone or in combination, provide any
`
`motivation to adjust or to try to adjust the concentration of a single excipient in an
`
`attempt to affect levothyroxine stability in a lyophilized solid composition, nor that
`
`levothyroxine stability could be affected with such adjustment. As the references are
`
`silent in this regard, an expectation of successfully increasing levothyroxine stability
`
`with such adjustment could not exist as the references teach that excipient type, not
`
`9
`
`Mylan Ex 1037, Page 9
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`PATENT
`Docket No. FKA01_007_US
`
`relative excipient amount, affect stability of the resulting compositions. (See Collier, for
`
`example).
`
`The declaration also establishes that both the type of stability result and the
`
`degree of stability result obtained from the relative amounts of mannitol to
`
`levothyroxine of Tables 1-3 of the specification were unexpected and of practical
`
`significance, as a longer shelf life was achieved for the lyophilized solid. The stability
`
`results obtained from the relative amounts of mannitol to levothyroxine provided in
`
`Tables 1-3 of the specification were unexpected at least because the inventors expected
`
`a formulation in accord with Bedford to have the desired stability.
`
`The declaration also establishes that lyophilized solids have different physical
`
`structures and reactivities than a solid that is dissolved in liquid or than a solid that is
`
`compressed to form a tablet. Thus, any document or study that discusses levothyroxine
`
`stability in water or in a compressed tablet would not be referenced or helpful for
`
`developing a lyophilized formulation of levothyroxine.
`
`In view of the proffered evidence of unexpected results, the Office may no
`
`longer maintain the assertion that the limitations of the pending claims are obvious over
`
`the cited art, and Applicants respectfully request withdrawal of the rejection under
`
`35 USC § 103.
`
`-10-
`
`Mylan Ex 1037, Page 10
`
`

`

`Serial No. 13/597,884 (cid:9)
`
`Conclusion
`
`PATENT
`Docket No. FKA01_007_US
`
`The Applicants believe the Examiner's concerns have been addressed to
`
`overcome the rejections. Upon the indication of allowable subject matter, the
`
`Examiner is respectfully requested to telephone Jonathan M. Blanchard at (312) 612-
`
`6700 to resolve any outstanding issues as expeditiously as possible so the case may be
`
`passed to issue.
`
`August 9, 2013 (cid:9)
`Date (cid:9)
`
`Blanchard & Associates
`566 West Adams Street
`Suite 600
`Chicago, IL 60661
`Docketing@blanchard-patent.corn
`Tel. (312) 612-6700
`
`Respectfully Submitted,
`
`/Jonathan M. Blanchard, Reg. No. 48927/
`Jonathan M. Blanchard, Ph.D.
`Patent Attorney
`Reg. No. 48,927
`
`-11-
`
`Mylan Ex 1037, Page 11
`
`