Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s)
`
`Roychowdhury et al.
`
`Customer No.
`
`62965
`
`Serial No.
`
`13/343,672
`
`Confirmation No.
`
`3876
`
`Filed
`
`January 4, 2012
`
`Group Art Unit
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`1629
`
`Examiner
`
`Polansky, Gregg
`
`For
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`DEXMEDETOMIDINE PREMIX FORMULATION
`
`RESPONSE TO OFFICE ACTION AND
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`STATEMENT OF THE SUBSTANCE OF THE INTERVIEW
`
`FILED ELECTRO NI CALLY VIA EFS
`Mail Stop Amendment
`Commissioner for Patents
`P.O. 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
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`is required in connection with this communication, or if any 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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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 1
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`AMENDMENTS TO THE CLAIMS
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`The listing of claims provided below will replace all prior versions, and listings, of claims
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`in the application.
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`1. (Currently amended) A pharmaceutical composition comprising dexmedetomidine or a
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`pharmaceutically acceptable salt thereof at a concentration of about 4 µg/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 ready to 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 of 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 composition is
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`formulated as a total volume selected from the group consisting of 20 mL, 50 mL and 100 mL.
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`REMARKS
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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 premixture. The amendments to claim 1 are fully supported by the
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`claims as originally filed and by the specification, including for example, at page 5, paragraph
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`[0025]; and page 13, paragraph [0060] of the application. Accordingly, Claims 1 A remain
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`currently pending. The amendments to claim 1 do not constitute new matter.
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`I.
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`Statement of the Substance of the Interview
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`In accordance with 37 C.F.R. § 1.2 and M.P.E.P. § 713.04, Applicants respectfully submit
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`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.
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`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 Bissonnette, Sandra Lee and Jennifer Flory, and for their careful consideration
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`of this application and claims. Applicants have received 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 the
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`rejections of record under 35 U.S.C. §§ 102(b) and 103(a). Specifically, the reference
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`"Dexmedetomidine HCL Draft Labeling: Precedex™ Dexmedetomidine Hydrochloride
`
`Injection," FDA approved label (dated December 17, 1999, and available online July 26, 2001,
`
`pages 1-13) cited in the rejections of record was discussed.
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`Although no consensus was reached, Applicants noted that the claims are directed to a
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`composition comprising 4 µg/mL dexmedetomidine that is a premixture, which does not require
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`dilution prior to administration to a subject. The claimed composition differs from the
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`formulation described by the cited reference, which requires dilution to a concentration of 4
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`µg/mL 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
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`use premixture.
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`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 3
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`II.
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`Rejection Under 35 U.S.C. § 102(b)
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`Claims 1-4 stand rejected under 35 U.S.C. § 102(b) as allegedly anticipated by
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`"Dexmedetomidine HCL Draft Labeling: Precedex™ 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
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`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 (i.e.,
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`parenteral administration) to a patient, wherein the dexmedetomidine HCl is present at a
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`concentration of 118 µg/mL (which corresponds to 100 µg/mL dexmedetomidine). According to
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`the Examiner, the Draft Labeling discloses that prior to administration to a patient, the formulation
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`is diluted with 0.9% NaCl solution to achieve a 4 µg/mL dexmedetomidine formulation in a total
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`volume of 50 mL. The Examiner further alleges that the dilution step would be performed in
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`either a sealed or unsealed container. The Examiner states that in order to maintain the sterility of
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`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
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`composition describes all the elements of the claims.
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`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.
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`"A claim is anticipated only if each and every element as set forth in the claim is found, either
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`expressly or inherently described, in a single prior art reference." Verdegaal Bros. v. Union Oil
`
`Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987). Every element of
`
`the claimed invention must literally be present and arranged as in the claim. Perkin Elmer Corp.
`
`v. Computervision Corp., 732 F.2d 888, 894, 221USPQ669, 673 (Fed. Cir. 1984).
`
`Independent claim 1 is hereby amended to recite a pharmaceutical composition comprising
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`dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 4
`
`µg/mL, wherein the composition is disposed within a sealed glass container as a ready to use
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`premixture. The claims are not anticipated by the Draft Labeling because the reference does not
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`disclose all the elements of the claims. For example, the Draft Labeling does not disclose a
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`composition comprising about 4 µg/mL dexmedetomidine, or a pharmaceutically acceptable salt
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`thereof, wherein the composition is disposed within a sealed glass container as a ready to use
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`premixture.
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`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 4
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`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 µg/mL composition of the Draft Labeling could only
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`be diluted in either a sealed or an unsealed container. Applicants note that the Draft Labeling is
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`silent regarding any dilution container. The Examiner relies on In re Schauman, 572 F.2d 312,
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`197 USPQ 5 (CCPA 1978), as supporting the contention that the claim element of a "sealed
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`container" is anticipated by the cited reference because the reference allegedly discloses a genus
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`of container with only a limited number of options (i.e., 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,
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`and possess the same properties of the claim element. However, as noted above, the Draft
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`Labeling does not recite any genus of container into which the concentrated composition is
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`diluted. Accordingly, Applicants note the Examiner's position must be based on a theory of
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`inherent anticipation.
`
`In order for a reference to inherently anticipate a limitation, however, that limitation must
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`necessarily be present in the disclosure. See, e.g., Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd.
`
`Pat. App. & Inter. 1990). Inherency may not be established by probabilities or possibilities. See,
`
`e.g., In re Robertson, 169 F.3d 743, 745, 49 USPQ2d 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, 169 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, e.g., In re Rijckaert, 9 F.3d 1531, 1534, 28 USPQ2d 1955,
`
`1957 (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
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`pharmaceutical composition comprising dexmedetomidine or a pharmaceutically acceptable salt
`
`thereof at a concentration of about 4 µg/mL, wherein the composition is disposed within a sealed
`
`glass container as a ready to use premixture. As discussed above, the Draft Labeling does not
`
`disclose a 4 µg/mL ready to use premixture that is disposed within a sealed glass container.
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`Furthermore, a 4 µg/mL ready to use premixture that is disposed within a sealed glass container is
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`not inherent to the Draft Labeling because the reference does not disclose a 4 µg/mL ready to use
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`premixture that is necessarily disposed within a sealed glass container. Assuming arguendo, with
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`reference to the Examiner's own logic and interpretation of the Draft Labeling, the Examiner
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`states that "2 options are available to the artisan practicing the dilution instructions of the
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`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
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`disposed within a sealed glass container is based on a mere probability that the skilled artisan
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`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
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`based on mere probability is without merit and lacks basis to support a finding of inherent
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`anticipation. See, e.g., Jn re Robertson, 169 F.3d 743, 745, 49 USPQ2d 1949, 1950-51 (Fed. Cir.
`
`1999).
`
`For at least these reasons, Applicants submit that the Draft Labeling does not describe all
`
`the elements of the amended claims, and as such, cannot anticipate the claims. Accordingly,
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`Applicants respectfully request that the rejection be withdrawn.
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`III. Rejection Under 35 U.S.C. § 103{a)
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`As an alternative to the rejection under 35 U.S.C. § 102(b) described above, the Examiner
`
`has rejected claims 1-4 under 35 U.S.C. § 103(a) as allegedly obvious over the Draft Labeling.
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`The Examiner relies on the Draft Labeling as described above, and further states that the claims
`
`are primafacie obvious over the Draft Labeling in view of the reference's disclosure that the 100
`
`µg/mL dexmedetomidine formulation must be diluted with 0.9% saline to produce a 4 µg/mL
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`dexmedetomidine 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 µg/mL
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`dexmedetomidine formulation in a sealed container in order to maintain the sterility of the
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`formulation.
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`Applicants respectfully traverse the rejection. To support an assertion of obviousness, the
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`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 known 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.,
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`550 U.S. 398 (2007).
`
`As described previously, independent claim 1 is amended herein to recite a pharmaceutical
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`composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof at a
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`concentration of about 4 µg/mL, 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 µg/mL dexmedetomidine composition is disposed within a
`
`sealed glass container. Rather, the reference discloses that the dexmedetomidine composition is
`
`diluted to 4 µg/mL 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, e.g., the Draft
`
`Labeling, p. 1 ), 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 µg/mL
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`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
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`be diluted by "injecting 2 mL of the concentrate into an intravenous bag containing 48 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 of ordinary skill would prepare
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`the dilution in a sealed glass container as claimed.
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`Additionally, Applicants note that a primary difference between the claimed 4 µg/mL
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`premixture composition and the 4 µg/mL diluted composition described by the Draft Labeling, is
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`that the claimed composition is a ready to use premixture that does not require any dilution or
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`reconstitution prior to administration to a subject. (See the specification, p. 5, paras. [0024](cid:173)
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`[0025]). Accordingly, upon withdrawing the claimed composition from a sealed glass container,
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`an artisan of ordinary skill can administer the composition directly to a subject. In contrast, the
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`composition described by the Draft Labeling is not suitable for administering to a patient upon
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`withdrawing the composition from a sealed container (i.e., a 2 mL vial or ampoule which the
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`concentrated 100 µg/mL formulation is stored in, see the Draft Labeling, p. 13). Rather, after
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`withdrawing the concentrated 100 µg/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 µg/mL composition described by the
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`Draft Labeling. For example, the claimed ready to use 4 µg/mL premixture composition provides
`
`for advantages with regard to the ability to store the composition over prolonged periods of time,
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`while maintaining a stable formulation. Such advantages over the diluted composition of the
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`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 7
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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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. § 716.02(a)). 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 microorganisms such as bacteria and fungi."
`
`(See the specification, p. 8, para. [0038]). The ability to store the claimed composition for
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`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 µg/mL premixture composition was stable for up to 9
`
`months when stored in a glass container. As described in Example 1, a 4 µg/mL premixture
`
`formulation stored in glass vials and ampoules 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 µg/mL 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
`
`specification, pp. 19-20, Table 1). Similarly, Example 3 discloses that the potency of the claimed
`
`4 µg/mL premixture composition maintained relatively unchanged after being stored in glass vials
`
`and ampoules at 25°C for 9 months. (See the specification, Example 3, pp. 22-23, para. [0095]).
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`In contrast, the Draft Labeling discloses that the concentrated 100 µg/mL
`
`dexmedetomidine composition is suitable for storage, and not the diluted 4 µg/mL composition.
`
`(See the Draft Labeling, p. 13). Furthermore, as described by the FDA Memorandum by Cynthia
`
`G. McCormick, M.D., dated November 30, 1999, in connection with the Medical Reviews of the
`
`Precedex ( dexmedetomidine 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 such, is suitable for storage.
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`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 µg/mL premixture composition, which can be
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`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 8
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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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
`
`µg/mL composition as a ready to use premixture provides for surprising and unexpected
`
`advantages over the dilution described by the Draft Labeling. While diluting a 100 µg/mL
`
`concentrate to a 4 µg/mL dilution produces a composition that is stable and useable for a 24 hour
`
`period after dilution, the claimed 4 µg/mL 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 µg/mL composition is only stable and useable for up to 24
`
`hours.
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`Additionally, in view of the Draft Labeling's disclosure as a whole, an artisan of ordinary
`
`skill would understand that the diluted 4 µg/mL formulation is formulated for immediate
`
`administration to a subject, and not suitable for prolonged storage. For example, the Draft
`
`Labeling discloses that the composition is "preservative-free 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
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`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 µg/mL, even ppb levels 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,
`
`e.g., microbe growth resulting from contamination during dilution.
`In view of the advantages of the claimed ready to use 4 µg/mL premixture composition
`
`over the diluted composition disclosed 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 µg/mL
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`Atty. Docket No. 077350.0344
`U.S, Serial No. 13/343,672
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`composition in a glass container, Applicants submit that the claims are not obvious over the cited
`
`reference, and respectfully 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
`
`3 Supplemental Response or in a telephone call with the undersigned, 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 fees are due, or if any overpayment has been made, in connection with the filing of this
`
`response, the Commissioner is authorized to charge any such fees or credit any overpayment
`
`made, to our Deposit Account No. 02—43 77.
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`Mack 6,20%.
`
`
`Date
`
`Respectfully submitted,
`
`BAKER BOTTS L.L.P.
`
`09/ /7497"
`
`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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`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 10
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`Atty. Docket No. 077350.0344
`U.S. Serial No. 13/343,672
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`EXHIBIT A
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`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 11
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`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 12
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`APPLICANT: ABBOTT LABORATORIES
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`"Ms"
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`CHEMICAL & THERAPEUTIC CLA‘SS:IS
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`Review Cycle: 1
`Submission DII::12~18-98
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`.-
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`—
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`. Receipt Date: 1248-98
`Goal Date:12-18-99
`Action:AP
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`Review Cycle: 3
`Submission Date:
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`Receipt Date:
`Goal Date:
`Action:
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`Action:
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`. RevieWC .cles
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`Review Cycle: 2
`Submission Date:
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`Receipt Date:
`Goal Date:
`_
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`Review CYele: 4
`~ Submission Date:
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`Receipt Date:
`Goal Date:
`Action:
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` PROJECT MANAGER! CSO :Susmita Samanta
`Phone 3 & Office Room #:301v827-7410. 93-45
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`ABUSE LIABILITY: BeUnda A. Hayes. Ph-D.
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`Volume 2 of 4
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`Administrative volume #(s): 1
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`CMC volume #(s): 3
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`Amneal Pharmaceuticals LLC — Exhibit 1012 — Page 13
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`ODE It ACTION PACKAGE TABLE OF CONTENTS
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`Application #21-038
`Drug Nameszrecedex (dexmedetornidine Hydrochloride injection), 2 ml. ampule/Z mI. vial, 100
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`meg/ml.
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`Applicant: Abbott Laboratories
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`Chemeher. Type: 1 S
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`C SO/PM: Susmita Samanta
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`Phone: 301-827-7410
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`HFD-l 70
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`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
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`CURRENTUSER FEE GOAL DATE: December 18, l999DateTableofContentsCompleted29/13/99
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`" Sultana;
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`'
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`X (completed).
`NA (not applicable)-
`or Comment
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`Tab A-l
`' Tab A-Z
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`Action Letter(s)
`Phase 4 Commitments:
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`Current ActionzAP " r
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`a. Copy of applicants communication committing to Phase 4 .............
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`b. Agency Correspondence requesting Phase 4 Commitments .............. ..
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`Tab A-3
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`.FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
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`a. Package Insert ..............................................................
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`b. Immediate Container and Carton Labels .'. ................................... ..
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`Tab A-d
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`Original Proposed Labeling ............................................................. ..
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`Tab A-S
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`Foreign Labeling:
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`’
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`'
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`a. Foreign Marketing History........................................................
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`b. Foreign Labeling and Review(s) .......... .I: .............
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`................... ..
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`‘
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`Tab A~6
`Tab A-7
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`Labeling and Nomenclature Comminee’s.Tradenarne Review ................... ..
`Summary Memoranda (e.g., Division Director, Group Leader, Office) ....... ..
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`Tab A-E
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`Copy of Patent Statement ..................................................................
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`Exclusivin Checklist (and any requests for exclusivity) ........................... ..
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`Debgment Statements ......................................................................
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`CorrespOndences, Faxes, 8L Telecons ...................................................
`Tab A-9
`Tab A- l 0 Minutesgif Meetings:
`a. End-of-Phase II meeting ...........................................................
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`b. Pre-NDA meeting(s) ............................................................. ..
`c. Filing meeting ...............................................................
`......
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`d. Other meetings .................................................................... ..
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`Tab A-l 1
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`Advisory Committee Meeting:
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`3. Questions Considered by the committee ..................................... ..
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`b. Li_st of Attendees .................................................................. ..
`c. 24; hour alert memorandum ............_...........................................
`Project Management Administrative Information (optional).........................
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`Tab A-IZ
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 14
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`ODE II Amen PACKAGE TABLE OF CONTENTS (continued)
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`Application #21-038 Drug Name: Dexniedetomidine HCL
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`W
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`X (completed).
`N/A (n0! applicable),
`or Comment
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`Tab 8-}
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`Clinical Reviews and Memoranda ..................................................... ..
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`Tab B—Z
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`Safety Update Reviews .....................................................................
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`Tab Bv3
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`‘ Pediatric Page .................................................. -._. ....................... ..
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`Tab 8-4
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`Statistical (Clinical) Review and Memoranda ..................... .5. ................ ..
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`Tab B-S
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`_ Biopharmaeeutics Review and Memoranda .......................................... ..
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`Tab 3-6
`Tab 8-7
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`Abuse Liability Review ............................:..................................... ..
`051 Audits .................................................................................. ..
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`Tab 843
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`Summary of Efficacy (from the summary volume ofthejé'gplieation)
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`.
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`- Tab 8-9
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`Summary of Safety (from the summary volume of the application) ................... ..
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`
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`SESflQILCl
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`Cl
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`.
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`I
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`n I
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`E
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`I
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`.
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`I C I
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`I
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`[CD 1:]
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`X (completed).
`N/A (not applicable),
`or Comment
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`Tab (3-!
`Tab 02
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`CMC Reviews and Memoranda .........................................................
`DMF Reviews ............................................................................ ..
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`Tab C~3
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`EA Reviews/FONSI ..................................................................... ..
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`Tab 04
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`Micro Review (validation of sterilization) ........................................... ..
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`Tab 05
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`StatiStical Review of drug stability ................
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`................................. ..
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`~
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`Tab C-6
`Tab C-7
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`Inspection of facilities => Decision:
`Date:
`Methods Validation Information ...................................................
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`mm;
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`Tab 0-]
`Tab D—2
`Tab D-3
`
`I
`.
`._
`.
`'
`t
`.-= a. WWW -
`_
`Pbapnacélogyfloxicology Reviews and Memoranda ...............................
`Carcinogenicity Review (statistical) .............................
`.....................
`GAG/Executive Committee Repon .....................................................
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`_
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`X (completed),
`NA (not applicable).
`or Comment
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`ADDITIONAL NOTES:
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`'
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`l
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`!
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLc — Exhibit 1012 — Page 15
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`,__-------------------------·---~---
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`(?.
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`'~ FDA CENTER FOR DRUG EVALUATION AND RESEARCH
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`DMSION OF A.NESTHETICS, CRITICAL CARE, A.ND ADDICTION DRUG PR~nucrs
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`HFD-170, Room 9B-45, 5600 Fishers lmte, Rockville MD 20857
`Te1:(301) 827-7410
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`MEMORANDUM
`JolmK. Jenkins, MD
`to:
`_ . Director,
`Office of Drug Evaluation II
`
`...
`
`Division File: NDA # 21-038
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`from: Cynthia G. Mccormic~ MD
`
`. \S\
`Director, Division of Anestheticf. Critical Care Jnd Addiction Drug
`Products
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`subject: Dexmedetomidine NDA
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`date: November 30, 1999
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`This memorandum summarizes for the file the basis for the approval actiori recommended
`by the Division of Anesthetics,. Critical Care, and Addiction Drug Products for NDA #21-
`038, Dexmedetomedine HCI for Injection. a sedative/hypnotic agent intended for use in
`the intensive care setting.
`· ·
`·
`..
`
`Background
`Dexmedetomidine is the dextro-enantiomer of the racemic mixture, medetomidine1 and a
`selectivo-.s.-2.-adrenoreceptor agonist. It has been shown in standard animal models of
`efficacy to have anxiolytic activity (0.3-2.0 µg/kg IV), analgesic activity (3-6 µg/kg IV),
`and sedative.properties (10-30 µg/kg IV) in a dose-related manner in mice, rats and dogs.
`Dexmedetoffiidine was developed in humans primarily for its sedative properties and was
`studied as a sedative in the intensive care setting, delivered by continuous intravenous
`infusion.
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`It was anticipated that dexmedetomidine would provide effects similar to those of
`clonidine, also an 0:·2·adrenergic agonist which has been used as an anesthetic adjuvant
`producing analgesia and sedation, a.r.d purported to decrease anesthetic requirements and
`
`1 Medetomic;Wte is a veterinary sedative v.idely available in Europe and approved in the US
`in 1997.
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`.
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`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1012 – Page 16
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`improve hemodynamic stability. The theoretical basis for the use of the o:-2-adrenergic
`··agonists as adjunctive medications is that they are thought to act as neuromodulators,
`regulating central (rneduJiary) cardiovascular or peripheral vasomotor responses such as
`those to anesthetics, thus producing an anesthetic-sparing effect. These effects were not
`specifically characterized for approval purposes, although some exploratory studies were
`undertaken during early development.
`