Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 1 of 35 PageID #: 302
`Case 1:15-cv—00697-RGA Document 39-5 Filed 01/29/16 Page 1 of 35 PagelD #: 302
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`EXHIBIT 5
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`EXHIBIT 5
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 2 of 35 PageID #: 303
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 2 of 35 PagelD #: 303
`Atty. Docket No. 0773503344
`U.Si Serial No. $843,672
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s)
`
`: Roychowdhury et‘ at.
`
`Customer No.
`
`:
`
`62965
`
`Serial No.
`
`Filed
`
`:
`
`:
`
`133433372
`
`Confirmation No.
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`: 3876
`
`January 4, 2012
`
`Group Art Unit
`
`:
`
`l629
`
`Examiner
`
`: Polansky, Gregg
`
`For
`
`: DEXMEDETOMIDINE PREMIX FORMULATION
`
`RESPONSE TO OFF ICE ACTION AND
`
`STATENIENT OF THE SUBSTANCE OF THE INTERVIEW
`
`FILED ELECTRONICALLY VIA EFS
`Mail Stop Amendment
`Commissioner for Patents
`
`PO- Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`In response to the Office Action dated February 13, 2012, Applicants request consideration
`
`of the Following amendments and remarks. Applicants believe no fee is due. However, if any fee
`
`is required in connection with this communication, or ifauy overpayment has been made, please
`
`charge any deficiency or credit any overpayment made, to Deposit Account No. 02-4377.
`
`Amendments to the Claims begin on page 2 of this paper.
`
`Remarks begin on page 3 of this paper.
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`HOSPIRA_00000226
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 3 of 35 PageID #: 304
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 3 of 35 PagelD #: 304
`Atty. Docket No. 0773500344
`US. Serial No. 13(343,672
`
`AMENDMENTS TO THE CLAIMS
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`The listing of claims provided below will replace all prior versions, and listings, of claims
`
`in the application.
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`1 . (Currently amended) A pharmaceutical composition comprising dexmcdetomidine or a
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`phamtaecutically acceptable salt thereof at a concentration of about 4 pg/mL, wherein the
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`composition is formulated as a liquid for parenteral administration to a subject, and wherein the
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`composition is disposed within a sealed glass container as a readyth use premixture.
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`2. (Original) The pharmaceutical composition of claim 1, further comprising sodium
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`chloride at a concentration ol‘between about 0.01 and about 2.0 weight percent.
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`3. (Original) The pharmaceutical composition of claim 2, wherein the sodium chloride is
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`present at a concentration of about 0.9 weight percent.
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`4. (Original) The pharmaceutical composition of claim 1, wherein the compositicm is
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`formulated as a total volume selected from the group consisting of 20 mL, 50 ml. and 100 tnl..
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`HOSPIRA_00000227
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 4 of 35 PageID #: 305
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 4 of 35 PagelD #: 305
`Atty. Docket No, 0773500344
`LLS. Serial No. 133343.67?
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`was
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`Reconsideration is respectfully requested. Claim 1 is amended to recite sealed glass
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`container and a ready to use premixtttre. The amendments to claim I are fully supported by the
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`claims as originally filed and by the specification, including for example, at page 5, paragraph
`
`[0025]; and page 13, paragraph [0060] of the application. Accordingly, Claims 14 remain
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`currently pending- The amendments to claim 1 do not constitute new matter.
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`I.
`
`Statement of the Substance of the Interview
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`In accordance with 3? C.F.R. § 1.2 and M.P.E.P. § 713.04, Applicants respectfully submit
`
`this Statement of the Substance of the Interview in reply to the Interview Summary mailed on
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`March 6, 2012, for the above referenced patent application.
`
`Applicants acknowledge with appreciation the courtesy extended by Examiner Gregg
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`Polansky and Primary Examiner James Anderson during the telephone interview on February 28,
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`2012 with Dennis Bissonnctte, Sandra Lee and Jennifer Flory, and for their careful consideration
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`of this application and claims. Applicants have rushed and reviewed the Interview Summary,
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`and provide the following statements to supplement and clarify the summary provided by the
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`Examiners.
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`As evident from the Interview Summary, the pending claims were discussed in View of tho
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`rejections ofrecord under 35 U.S.C. §§ 1020:) and 103(a). Specifically, the reference
`
`“Dexmedetomidinc HCL Draft Labeling: PrecedexTM Dcxmedctomidinc Hydrochloride
`
`Injection,” FDA approved label (dated December 17, 1999, and available online July 26. 2001,
`
`pages 1-13) cited in the rejections ofrecord was discussed.
`
`Although no consensus was reached, Applicants noted that the claims are directed to a
`
`composition comprising 4 pga’niL dexmedetomidine that is a premixture, which does not require
`
`dilution prior to administration to a subject. The claimed composition differs from the
`
`formulation described by the cited reference, which requires dilution to a concentration of 4
`
`1.13me dexmedetomidine prior to administration to a patient. As such, Applicants maintained that
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`unlike the claimed composition, the formulation disclosed by the cited reference is not a ready to
`
`use premixttu'e.
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`HOSPIRA_00000228
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 5 of 35 PageID #: 306
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 5 of 35 PagelD #: 306
`Atty. Docket No. 0?7350.0344
`[1.8. Serial No. 13843.6?2
`
`II.
`
`Rejection Under 35 U.S.C. § 1021b)
`
`Claims l-4 stand rejected under 35 U.S.C. § 102(b) as allegedly anticipated by
`
`“Dexmedetomidine HCL Draft Labeling: PrecedeaTM Dexmedetomidine Hydrochloride
`
`Injection,” FDA approved label (dated December 17, 1999, and available online July 26, 2001,
`
`pages 1—13) (hereafter, “the Draft Labeling”). According to the Examiner, the Draft Labeling
`
`discloses a composition comprising a hydrochloride (HCl) salt of dexmedetomidine (Precedex)
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`that is formulated as a sterile aqueous liquid (in 0.9% NaCl solution) for intravenous infusion (is. ,
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`parenteral administration) to a patient, wherein the dexmedetomidine EC! is present at a
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`concentration of 118 pg/mL (which corresponds to 100 pg/mL dexmedetomidine). According to
`
`the Examiner, the Draft Labeling discloses that prior to administration to a patient, the formulation
`
`is diluted with 0.9% NaCl solution to achieve a 4 pgfml. dexmedetomidine formulation in a total
`
`volume of 50 mL. The Examiner further alleges that the dilution step would be performed in
`
`either a scaled or unsealed container. The Examiner states that in order to maintain the sterility of
`
`the composition for parenteral administration, an artisan of ordinary skill would have diluted the
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`composition in a sealed container. Accordingly, the Examiner contends that the diluted
`
`composition describes all the elements of the claims.
`
`Applicants respectfully traverse the rejection. Anticipation requires that each and every
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`element of the rejected claim(s) be disclosed in a single prior art reference. See M.P.E.P. § 2131.
`
`“A claim is anticipated only if each and every element as set forth in the claim is found, either
`
`expressly or inherently described, in a single prior art reference.” Verdegaal Bros. 1:. Union Oil
`
`Co. ofCaZifor-nia, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1937). Every element of
`
`the claimed invention must literally be present and arranged as in the claim. Perkin Elmer Corp.
`
`v. Computervisr‘on Corp, 732 F.2d 888, 894, 221 USPQ 669, 673 (Fed. Cir. 1984).
`
`Independent claim 1 is hereby amend ed to recite a pharmaceutical composition comprising
`
`dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 4
`
`pgi’ml., wherein the composition is disposed within a sealed gig container as a ready to use
`
`premixture. The claims are not anticipated by the Draft Labeling because the reference does not
`
`disclose all the elements of the claims. For example, the Draft Labeling does not disclose a
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`composition comprising about 4 ngKmL dexmedetornidinc, or a pharmaceuticaily acceptable salt
`
`thereof, wherein the composition is disposed within a sealed glass container as a ready to use
`
`premixture.
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`HOSPIRA_00000229
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 6 of 35 PageID #: 307
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 6 of 35 PagelD #: 307
`Atty. Docket No. 0773500344
`11.5. Serial No. 133341672
`
`With regard to the claims” recitation that the composition is disposed within a sealed
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`container, the Examiner states that the 100 ugfrnli composition of the Draft Labeling could only
`
`be diluted in either a sealed or an unsealed container. Applicants note that the Draft Labeling is
`
`silent regarding any dilution container. The Examiner relies on In re Schauman, 572 F.2d 312,
`
`197 USPQ 5 (CCPA 1978), as supporting the contention that the claim element ofa “sealed
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`container” is anticipated by the cited reference because the reference allegedly discloses a genus
`
`ofcontainer with only a limited number of options (£2. , dilution in a sealed or an unsealed
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`container}, wherein the limited number of options are closely related to each other in structure,
`
`and possess the same properties of the claim element. However, as noted above, the Draft
`
`Labeling does not recite any genus of container into which the concentrated composition is
`
`diluted. Accordingly, Applicants note the Examiner’s position must be based on a theory of
`
`inherent anticipation.
`
`In order for a reference to inherently anticipate a limitation, however, that limitation must
`
`necessarily be present in the disclosure. See. e.g., Expat-re Levy, 17 USPQ2d 1461, 1464 (Ed.
`
`Pat. App. & Inter. 1990).
`
`lnherency may not be established by probabilities or possibilities. See,
`
`ag, In re Robertson, 169 F.3d 743, 745, 49 USPQZd 1949, 1950-51 (Fed. Cir. 1999). For
`
`example, a feature is not inherent if it is a mere probability that the limitation would appear in the
`
`prior art. See, e.g., In re Robertson. l69 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir.
`
`1999). That a limitation may result in a prior art reference from a given set of circumstances is
`
`insufficient to prove anticipation. See, 9.53., In re Ry'ckoerr, 9 F.3d 1531, 1534, 28 USPQ2d 1955,
`
`195? (Fed- Cir. 1993); and M.P.E.P. § 2112.
`
`Applicants respectfully submit that the Office Action fails to make a showing based on the
`
`Draft Labeling that meets this standard. As noted above, the claims as amended are directed to a
`
`pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt
`
`thereof at a concentration of about 4 ng/inL, wherein the composition is disposed within a sealed
`
`glass container as a ready to use premixture. As discussed above, the Drafi Labeling does not
`
`disclose a 4 ttg/mL ready to use premixture that is disposed within a sealed glass container.
`
`Furthermore, a 4 ug/mL ready to use premixture that is disposed within a sealed glass container is
`
`not inherent to the Draft Labeling because the reference does not disclose a 4 pg/rnL ready to use
`
`premixture that is necessarily disposed within a sealed glass container. Assuming orgnendo, with
`
`reference to the Examiner‘s own logic and interpretation of the Draft Labeling, the Examiner
`
`_5_
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`HOSPIRA_00000230
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 7 of 35 PageID #: 308
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 7 of 35 PagelD #: 308
`Atty. Docket No. 0773503344
`U.S. Serial No. 13/343,672
`
`states that “2 options are available to the artisan practicing the dilution instructions ol’the
`
`reference: (1 ) mixing the solution in a sealed container, or (2) mixing the solution in an unsealed
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`container." (See the Office Action, p. 4}. Accordingly, any conclusion that the dilutiOn would be
`
`diaposed within a sealed glass container is based on a mere probability that the skilled artisan
`
`would prepare the dilution in a sealed glass container and not in an unsealed container. However,
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`inherency may not be established by probabilities or possibilities, and as such, a conclusion that is
`
`based on mere probability is without merit and lacks basis to support a finding of inherent
`
`anticipation. See, e.g., In re Robertson. 169 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir.
`
`1999).
`
`For at least these reasons, Applicants submit that the Drafi Labeling does not describe all
`
`the elements of the amended claims, and as such, cannot anticipate the claims. Accordingly,
`
`Applicants respectfully request that the rejection be withdrawn.
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`III.
`
`Re'ection Under 35 U.S.C.
`
`103 a
`
`As an alternative to the rejection under 35 U.S.C. § 102(b) described above, the Examiner
`
`has rejected claims l-4 under 35 U.S.C. § 103(a) as allegedly obvious over the Draft Labeling.
`
`The Examiner relies on the Drafi Labeling as described above, and further states that the claims
`
`are primofocie obvious over the Draft Labeling in View of the reference's disclosure that the 100
`
`ug/mL dexmedetomidine formulation must be diluted with 0.9% saline to produce a 4 nga’mL
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`dcxrnedctomidine formulation prior to administration to a patient. According to the Examiner, it
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`would have been obvious for one of ordinary skill in the art to dilute the 100 .ug/mL.
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`dexmcdctomidine formulation in a sealed container in order to maintain the sterility of' the
`
`formulation.
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`Applicants respectfully traverse the rejection. To support an assertion of obviousness, the
`
`Examiner must show that “all the claimed elements were known in the prior art and one skilled in
`
`the art could have combined the elements as claimed by knowu methods with no change in their
`
`respective functions, and the combination yielded nothing more than predictable results to one of
`
`ordinary skill in the art.” See M.P.E.P § 2143. See also KSR International Co. v. Teleflex Inc. ,
`
`550 US. 398 (2007).
`
`As described previously, independent claim I is amended herein to recite a pharmaceutical
`
`composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a
`
`-6-
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`HOSPIRA_00000231
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 8 of 35 PageID #: 309
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 8 of 35 PagelD #: 309
`Any. Docket No. 073500344
`U.S. Serial No. 0.04.1672
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`concentration of about 4 uglmL, wherein the composition is disposed within a sealed glass
`
`container as a ready to use premixture.
`
`In contrast to the claims, the Draft Labeling does not
`
`suggest or describe that the diluted 4 rig/ml. dexmedetornidine composition is disposed within a
`
`sealed glass container. Rather, the reference discloses that the dcxmcdetomidine composition is
`
`diluted to 4 uglmL prior to administration to a subject. (See, the Draft Labeling, p. 12). Because
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`the diluted composition is administered to a subject by an intravenous infusion (see. (2.3., the Draft
`
`Labeling, p. I), an artisan of ordinary skill would have diluted the dexmedetomidine in a device
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`for infusion, such as a plastic infusion bag or plastic syringe, and not disposed the 4 pg,me
`
`dilution in a sealed glass container. Applicants note that the Examiner has recognized that an
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`infusion bag would be a likely container for diluting the composition in preparation for
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`administration to a subject, as evidenced by the Examiner’s statement that the composition could
`
`be diluted by “injecting 2 mL of the concentrate into an intravenous bag containing 43 mL
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`isotonic saline.” (See the Applicant-Initiated Interview Summary dated March 6, 2012, p. 2). The
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`Examiner provides no basis or evidence to suggest that an artisan ofordinary skill would prepare
`
`the dilution in a sealed glass container as claimed.
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`Additionally, Applicants note that a primary difference between the claimed 4 pglmL
`
`premixture composition and the 4 rig/ml. diluted composition described by the Draft Labeling, is
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`that the claimed composition is a ready to use premiidurc that does not require any dilution or
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`reconstitution prior to administration to a subj ect. (See the specification, p. 5, paras. [0024]-
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`[0025]). Accordingly, upon withdrawing the claimed composition from a sealed glass container,
`
`an artisan of ordinary skill can administer the composition directly to a subject.
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`In centrast, the
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`composition described by the Draft Laheling is not suitable for administering to a patient upon
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`withdrawing the composition from a sealed container 010., a 2 mL vial or ampoule which the
`
`concentrated 100 uglinL formulation is stored in, see the Draft Labeling, p. 13). Rather, after
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`withdrawing the concentrated 100 ug/mL composition from a sealed container, the composition
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`must be diluted prior to administration to a subject.
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`Applicants also submit that the claimed ready to use premixture composition provides for
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`surprising and unexpected advantages over the diluted 4 pgme composition described by the
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`Draft Labeling. For example, the claimed ready to use 4 pg,me premixture composition provides
`
`for advantages with regard to the ability to store the composition over prolonged periods of time,
`
`while maintaining a stable formulation. Such advantages over the diluted composition of the
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`-7-
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`HOSPIRA_00000232
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 9 of 35 PageID #: 310
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 9 of 35 PagelD #: 310
`Atty. Docket No. 0773500344
`us. Serial No. Boom
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`Draft Labeling is further evidence of the non-obviousness of the claims over the cited reference.
`
`(See M.P.E.P. § 71602090). For example, as described by the present application, the claimed
`
`pharmaceutical formulation “can be stable under the conditions of manufacture and storage and
`
`can be preserved against the contaminating action of microorganiSrns such as bacteria and fungi.”
`
`(See the Specification, p. 8, para. [0038]). The ability to store the claimed composition for
`
`prolonged periods of time are shown in at least Examples 1 and 3 of the application, which
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`demonstrate that the claimed ready to use 4 ug/mL premixture composition was stable for up to 9
`
`months when stored in a glass container. As described in Example 1, a 4 pg/mL premixture
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`lbrtnulation stored in glass Vials and ampoulcs maintained a higher level of potency after a 5
`
`month storage period compared to storage in plastic, CR3 or PVC containers. (See, the
`
`specification, pp. 18-20, paras. [0086] — [0088]). As described by Table 1, when stored in glass
`
`vials or ampoules, the 4 pg/rnL premixture maintained over 98% potency after 5 months.
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`However, when stored in plastic or PVC containers, which include plastic syringes and plastic
`
`bags, the potency was reduced by as much as 20% after only a two-week storage period. (See the
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`specifieatiori, pp. 19-20, Table 1). Similarly. Example 3 discloses that the potency of the claimed
`
`4 ugme premixture composition maintained relati ver unchanged after being stored in glass vials
`
`and ampoules at 25°C for 9 months.
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`(See the specification, Example 3, pp. 22-23, para. [0095]).
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`In contrast, the Draft Labeling discloses that the concentrated 100 ug/mL
`
`dexmedetomidine composition is suitable for storage, and not the diluted 4 tight-ii. composition-
`
`(See the Draft Labeling, p. l3). Furthermore, as described by the FDA Memorandum by Cynthia
`
`G, McCormick, M.D., dated November 30, 1999,111 connection with the Medical Reviews 01‘ the
`
`Precedex (dexmcdetomidine hydrochloride injection) Application No. 21-038 submitted to the
`
`FDA, and available on the FDA website July 26, 2001 (hereafter, “the Memorandum,“ Exhibit A,
`
`and a copy of which is submitted herewith in an Information Disclosure Statement), the undiluted
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`dexmedetomidine composition is manufactured through an “aseptic fill and terminal sterilization
`
`by autoclave," (see, the Memorandum, p. 8, third para), and as sueh, is suitable for storage.
`
`However, once diluted for administration, the diluted composition is stable for only 24 hours. See
`
`the Memorandum, p. 8, para. 4, stating: “The drug product is prepared for use by diluting it with
`
`sterile 0.9% sodium chloride solution for injection after which it is stable for 24 hours” (emphasis
`
`added). Thus, unlike the claimed ready to use 4 pg/ml. premixturc composition, which can be
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`HOSPIRA_00000233
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`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 10 of 35 PagelD #: 311
`Atty. Docket No. 077350.0344
`LLS. Serial No. 13841672
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`stored for prolonged periods of time, the diluted composition described by the Draft Labeling is
`
`prepared for use within a 24 hour period, and is not a formulation suitable for prolonged storage.
`
`Accordingly, the memorandum provides further evidence that formulating the claimed 4
`
`ttg/rnL composition as a ready to we premixturc provides for surprising and unexpected
`
`advantages over the dilution described by the Draft Labeling. While diluting a 100 pg/mL
`
`concentrate to a 4 pg/mL dilution produces a composition that is stable and useable for a 24 hour
`
`period afier dilution, the claimed 4 ugme ready to use premixture can be stored for at least 9
`
`months in a sealed glass container. Such a characteristic is not suggested or disclosed by the cited
`
`reference, as evidenced by the Memorandum. Rather, in contrast, an artisan of ordinary skill
`
`would understand that a diluted 4 pgr'mL composition is only stable and useable for up to 24
`
`hours.
`
`Additionally, in View of the Draft Labeling’s disclosure as a whole, an artisan of ordinary
`
`skill would understand that the diluted 4 ugz’mL formulation is fonnulated for immediate
`
`administration to a subject, and not suitable for prolonged storage. For example, the Draft
`
`Labeling discloses that the composition is “preservative-flee and contains no additives or
`
`chemical stabilizers." (See the Draft Labeling, p. 1). Thus, the artisan would have had no
`
`expectation that the formulation is suitable for storage. Additionally, the diluted composition is
`
`intended for a single use only, and further, such a single use can only be for a period of, at most,
`
`24 hours.
`
`(See the Draft Labeling, pp. 12 and 13). As such, the artisan would understand that any
`
`portion of the diluted composition that is not administered to a subject, or that remains after a 24
`
`hour dosing period, cannot be stored for later use. Finally, contamination with impurities is a
`
`greater concern for compositions diluted to a low concentration. “Since the drug is present at
`
`such a low concentration 4 ugme, even ppb leveis of impurities would have a significant
`
`contribution toward the impurity limit.” (See the specification, p. 32, para. [00115]).
`
`Accordingly, the skilled artisan would be motivated to immediately use the diluted composition
`
`once prepared, and not store the dilution since storage could increase the risk of contamination,
`
`2.3., microbe growth resulting from contamination during dilution.
`
`In View of the advantages of the claimed ready to use 4 uga‘mL premixture composition
`
`over the diluted composition disclosod by the Draft Labeling with regard to storage and stability
`
`over prolonged periods of time, and further, in View of the Draft Labeling’s failure to provide an
`
`artisan of ordinary skill with any suggestion or motivation to dispose the diluted 4 ug/mL
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`_9_
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`HOSPIRA_00000234
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 11 of 35 PageID #: 312
`Case 1:15-cv-OO697-RGA Document 39-5 Filed 01/29/16 Page 11 of 35 PagelD #: 312
`Any, Docket No. 077350.0344
`US. Serial No. I33343,672
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`composition in a glass container, Applicants submit that the claims are not obvious over the cited
`
`reference, and respectfitlly request that the rejection be withdrawn.
`
`IV.
`
`ConclusiOn
`
`in view of the above amendments and remarks,
`
`it
`
`is respectfully requested that the
`
`application be reconsidered and that all pending claims be allowed and the case passed to issue. If
`
`there are any other issues remaining which the Examiner believes could be resolved through either
`
`a Supplemental Response or in a telephone call with the tmdersigned, the Examiner is invited to
`
`call the undersigned at the telephone number indicated below.
`
`Applicants believe that no fee is due in connection with the filing of this paper. However,
`
`if any feas are due, or ii‘any overpayment has been made, in connection with the filing of this
`
`response, the Commissioner is authorized to charge any such fees or credit an},r overpayment
`
`made, to our Deposit Account No, 02—4377.
`
`Marcia
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`2642’
`
`Date
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`_
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`Respectfully submitted,
`
`BAKER BUTTS L.L,P.
`
`Dennis M. Bissonnette
`
`Patent Office Reg. No. 61,910
`
`Sandra S. Lee
`
`Patent Office Reg. No. 51,932
`
`30 Rockefeller Plaza
`44th Floor
`
`New York, NY 10112-4498
`212-408-2500
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`-10-
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`HOSPIRA_00000235
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 12 of 35 PageID #: 313
`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 12 of 35 PagelD #: 313
`Atty. Docket No. WTBSDOEM
`[1.8. Serial No. {3843,672
`
`EXHIBIT A
`
`-11-
`
`HOSPIRA_00000236
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`
`

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`HOSPIRA_00000237
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 14 of 35 PageID #: 315
`Case 1215-CV-00697-RGA_ D_Ocument_3_9.;5__Elled_Ol/29/16 Page 14 of 35 PagelD #: 315
`“31033 -
`in #21—038
`HFD-l70
`K13
`_
`Illlllfilllllllllllllllllm
`llllllllllllllllllll!ll
`
`mugge-
`'FJJ“
`unuu n erE: Precedex (dexmedetomidine no: Injection)
`{31:11:
`MM 5 ,z’
`
`APPLICANT: ABBOTT LABORATORIES
`
`CHEMICAL & THERAPEUTIC CLAS'Szl S
`
`. Review C Acles
`
`Review Cycle: 1
`Submission Dale:l2-18-9B
`Receipt Date: 12-18-93
`Goal [Islands-99
`Action:AP
`
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`Rev/low Cycle: 2
`Submission Date:
`Receipt Date:
`Goal Date:
`-
`
`Review Cycle: 4
`- Submission Dute:
`Receipt Date:
`Goal Date:
`Action:
`
`Action: Review Cycle: 3
`MICROIHGLOGIST: Patricia Hughes. Ph.D.
`
`PROJECT MANAGER! C50 :Susmite Samanta
`Phone u 3: Office Room #:301427-74l0. 93-45
`
`MEDICAL:Patricia Hartwell. M.D.. M.B.A.
`
`CHEMISTRY:MichaeI Theodoraltis. Ph-D.
`
`'
`
`..
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`._
`
`-
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`.
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`Volume 2 of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`Pharmacologyn'oxicology volume #(s): 4
`
`
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`HOSPIRA_00000238
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 15 of 35 PageID #: 316
`r__Case_l;15-ctb0069LRGA_Documont—39-5—Filed—91/29/16 Page 15 of 35 PagelD #: 316
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`ODE 1] ACTION PACKAGE TABLE or CONTENTS
`
`Application #21-038
`Drug Nmethrecedex (dexmedetomidine Hydrochloride injection ), 2 ml. ampulei’Z ml. vial, 100
`
`meg/ml.
`
`Applicant: Abbott Laboratories
`
`Chemfl'her. Type: 1 S
`
`CSOFPM: Susmita Samanta
`
`Phone: 301-327-7410
`
`HFD-l70
`
`Original Application Date: December 18, 1993 Original Receipt Date: December 18, 1998
`
`CURRENTUSER FEE GOAL DATE: December 18. l999DateTableol‘ContentsCompleted:9il3/99
`
`Minna:
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`‘
`
`Tab A—l
`Tab A—E
`
`Action Lettetis)
`Phase 4 Commitments:
`
`Current Action:AP " -
`
`i
`
`X {completed}.
`_ NA (not applicable}.
`or Comment
`
`a. Copy of applicants communication committing to Phase 4
`
`b. Agency Correspondence requesting Phase 4 Commitments
`
`c. 24! hour alert memorandum .......................................................
`
`Tab A-J
`
`Tab Ant
`
`Tab A-S
`
`Tab A~6
`Tab A“?
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`Tab A-E
`
`Tab A-9
`Tab PM o
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`Tab A-l 1
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`
`
`.FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
`
`a. Package Insert
`b. Immediate Container and Carton Labels
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`Original Proposed Labeling
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`Foreign Labeling:
`
`a. Foreign Marketing
`
`b. Foreign Labeling and Review(s)
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`Labeling and Nomenclature Commince's.deenarne Review
`Summary Memoranda (e.g., Division Director, Group Leader, Office) .........
`
`Copy of Patent Statement ................................................................ ..
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`Exclusivity Checklist (and any requests for exclusivity)
`
`Belling-115m Statements ......................................................................
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`Correspondences, Faxes, & Tclecons ................................................. ..
`Min_mes._§rmeenngs:
`a. End-of-Phase 11 meeting ...........................................................
`
`b. Pre-NDA meeting{s)
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`e. Filing meeting ..................................................................... ..
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`d. Other meetings .................................................................... ..
`
`Advisory Committee Meeting:
`
`a. Quesfions Considered by the committee .......................................
`
`b. Li_5_t of Attendees .................................................................. ..
`
`Tab A- 12
`
`Project Management Administrative Information (optional)........................
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`
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`HOSPIRA_00000239
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 16 of 35 PageID #: 317
`C_ase 1:15-_cv-00697-_R£A_DQQJ.menL39;5_EiLed—01/29/16 Page 16 Of 35 PagelD #: 317
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`ODE II ACTION PACKAGE TABLE or CONTENTS (continued)
`
`Application #21-038 Drug Name: Demedetomidine HCL
`
`Simian};
`
`Tab B«I
`
`Clinicai Reviews and Memoranda ..................................................... ..
`
`_
`
`X (completed).
`NA (not applicable}.
`or Comment
`
`
`
`Tab 8-2
`
`Safety Update Reviews .....................................................................
`
`Tab B-3
`
`- Pediatric Page
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`Tab 3—4
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`Statistical (Clinical) Review and Memoranda ..................... ..Z ................ ..
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`Tab B-S
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`_ Biopharmaceutics Review and Memoranda
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`Tab B-IS
`Tab 8-7
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`Abuse Liability Review
`DSI Audits .................................................................................. ..
`
`Tab 8-8
`- Tab 3-?
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`Summary of Efficacy (from the summary volume oftheiiigplieetioo)
`Summary ofSafcty (from the summary volume oftbe application]
`
`ms;
`
`El
`
`.
`
`M
`
`.
`I
`E
`1mm
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`I c I
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`I
`
`[Ch 1C]
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`X {completed}.
`N/A (not applicable),
`or Comment
`
`Tab (3-!
`Tab 02
`
`CMC Reviews and Memoranda
`DMF Reviews ............................................................................ ..
`
`Tab 03
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`EA Reviews/FONS!
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`Tab (2-4
`
`M icro Review (validation of sterilization) .............................................
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`.-
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`Tab C-S
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`Statistical Review ofdrug stability ..... ... ..... .....L‘...................................
`
`-
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`Tab C -6
`Ta'o C-7
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`Inapection of facilities => Decision:
`Date:
`Methods Validation Information ...................................................
`
`Mount
`
`_
`.
`.I
`.
`I
`_
`we a. WWW -
`
`X (completed).
`NA (not applicable).
`or Comment
`
`Tab D~I
`Tab D—Z
`Tab [DI-3
`
`qupnagélogyfl'oxicology Reviews and Memoranda ............................. ..
`Carcinogenicity Review (Statistical) ....................................................
`CACIExecutive Committee Report ................................................... ..
`
`_
`
`ADDITIONAL NOTES:
`
`'
`
`
`
`i
`I
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`
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`HOSPIRA_00000240
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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 17 of 35 PageID #: 318
`,__Case '
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`+flll'q‘v'
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`ia K:
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`K
`EDA CENTER FOR DRUG EVALUATION AND RESEARCH
`W"
`DIVISION 0!“Was. CRITIan CARE, an]: ADDICI'ION DRUG Hoovers
`
`RFD-170, Room 93-45, 5600 Fishers Lane. Rockviflexifl) 20857
`
`Tel:(301) 827-7410
`
`maton
`
`to:
`
`John K. Jenkins, MD
`Director,
`Ofice of Drug Evaluation II
`
`Division Fiie: NDA it 21—038
`
`from: CynthiaG. McCormick, MD
`
`. Director, Division orAnesmetici,’ Critical Care
`Products
`
`d Addiction Drug
`
`subject: Dennedetomidine NDA
`
`date: November 30, 1999
`
`This memorandum summarizes for the file the basis for the approwa] action recommended
`by the Division of Anesthetics, 'Criticfl'Care, and Addiction Drug Products for NBA #21-
`038, Deionedetomedine HCl for Injection, a sedafivoitypnonc agent intended for use in
`the intensive care setting.
`'
`'
`'
`"
`
`Background
`Demedetomidine is the dextro-enantiomer of the racemic mixture, tocot-.tomidinel and a
`selectivoa-l-adrenoreceptor agonist. It has been shown in Standard animal models of
`efficacy to have mndolytic activity (0.3-1!) uykg IV), analgesic activin (3-6 ugfkg IV),
`and sedative properties (IQ—3O uglkg IV) in a dose-related manner in mice, rats and dogs.
`Dexmedetoriiidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivei'ed by continuous intravenous
`infusion.
`
`
`
`It was anticipated that dmedetonfidine woold provide efl‘ects similar to those of
`clonidine, also an u-Z-cdrenergic agonist which has been used as an anesthetic adjovtmt
`producing analgesia and sedation, and purported to decrease anesthetic requirements and
`
`1 Medetomidine is a veterinary sedative widely avaflebie in Europe and approved in the US
`in 1997.
`‘
`.-
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`HOSPIRA_00000241
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`

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`Case 1:15-cv-00697-RGA Document 39-5 Filed 01/29/16 Page 18 of 35 PageID #: 319
`——€ase—1115:CV=06697=RGA—-Document 3%- -FH-ed 01/29/16 Page 18 of 35 PagelD #: 319
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`improve hemodynamic stability. The theoretical basis for the use of the or-Z-adre