Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant(s)
`
`Roychowdhury et al.
`
`Customer No.
`
`Serial No.
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`13/541,524
`
`Confirmation No.
`
`Filed
`
`July 3, 2012
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`Group Art Unit
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`62965
`
`8238
`
`1629
`
`Examiner
`
`Polansky, Gregg
`
`For
`
`DEXMEDETOMIDINE PREMIX FORMULATION
`
`RESPONSE TO OFFICE ACTION
`
`FILED ELECTRONICALLY VIA EFS
`Mail Stop Amendment
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`In response to the Office Action dated August 17, 2012, Applicants request consideration
`
`of the following remarks. Applicants believe no fee is due. However, if any fee is required in
`
`connection with this communication, please charge any deficiency, to Deposit Account No. 02-
`
`4377.
`
`A Listing of the Claims begin on page 2 of this paper.
`
`Remarks begin on page 3 of this paper.
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`The listing of claims provided below will replace all prior versions and listings of claims in
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`LISTING OF THE CLAIMS
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`the application.
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`Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
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`1. (Original) A ready to use liquid pharmaceutical composition for parenteral
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`administration to a subject, comprising dexmedetomidine or a pharmaceutically acceptable salt
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`thereof at a concentration of about 0.005 to about 50 µg/mL disposed within a sealed glass
`
`container.
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`2. (Original) The ready to use liquid pharmaceutical composition of claim 1, wherein the
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`dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 0.05
`
`to about 15 ug/mL.
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`3. (Original) The ready to use liquid pharmaceutical composition of claim 1, wherein the
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`dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 0.5 to
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`about 10 ug/mL.
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`4. (Original) The ready to use liquid pharmaceutical composition of claim 1, wherein the
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`dexmedetomidine or pharmaceutically acceptable salt thereof is at a concentration of about 1 to
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`about 7 ug/mL.
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`5. (Original) The ready to use liquid pharmaceutical composition of claim 1, further
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`comprising sodium chloride at a concentration of between about 0.01 and about 2.0 weight
`
`percent.
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`6. (Original) The ready to use liquid pharmaceutical composition of claim 5, wherein the
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`sodium chloride is present at a concentration of about 0.9 weight percent.
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`7. (Original) The ready to use liquid pharmaceutical composition of claim 1, wherein the
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`composition is formulated as a total volume selected from the group consisting of 20 mL, 50 mL
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`and 100 mL.
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`Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
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`REMARKS
`
`Reconsideration is respectfully requested. Claims 1-7 are currently pending. No
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`amendments have been introduced into the claims. Accordingly, no new matter has been
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`introduced in this response.
`
`I.
`
`Rejections Under 35 U.S.C. § 103(a)
`
`A.
`
`U.S. Patent Application Publication No. 2011/0230534 as evidenced by a
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`Precedex® Package Insert, U.S. Patent No. 6,806,291, U.S. Patent No. 5,716,988,
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`and a Xylocaine® Package Insert
`
`Claims 1-7 stand rejected under 35 U.S.C. § 103(a) as allegedly obvious over U.S. Patent
`
`Application Publication No. 2011/0230534 to Miyawaki et al. (hereafter, "Miyawaki") as
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`evidenced by the Precedex® Package Insert, U.S. Patent No. 6,806,291 to Sunkel et al. (hereafter,
`
`"Sunkel"), U.S. Patent No. 5,716,988 to Ibrahim et aL (hereafter, "Ibrahim"), and the Xylocaine®
`
`Package Insert.
`
`The Examiner contends that Miyawaki discloses a kit for a ready to use parenterally
`
`administered local anesthesia, which allegedly includes a local anesthetic agent and
`
`dexmedetomidine or a salt thereof. According to the Examiner, the dexmedetomidine can be at a
`concentration ofbetween lx10- 10 M and lx10-6 M (i.e., 2xI0- 5 µg/mL to 0.2 µg/mL), or at specific
`concentrations such as 4x10-6 M (i.e., 0.8 µg/mL), wherein the dexmedetomidine is prepared from
`
`a Precedex® stock solution of dexmedetomidine hydrochloride that is diluted with 0.9% sodium
`
`chloride solution to achieve the desired dexmedetomidine concentrations. The Examiner alleges
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`that the 0.8 µg/mL concentration of dexmedetomidine disclosed by Miyawaki reads on claim 4
`
`because 0.8 µg/mL "is about 1 µg/mL," as recited by claim 4.
`
`The Examiner concedes that Miyawaki does not suggest or describe disposing the
`
`parenteral compositions described by the reference within a sealed glass container. However, the
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`Examiner relies on the Precedex® Package Insert, the Xylocaine® Package Insert, Sunkel and
`
`Ibrahim as evidence that disposing parenteral compositions in sealed glass containers is common
`
`and well known in the art. According to the Examiner, the Precedex® Package Insert describes a
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`100 µg/mL dexmedetomidine hydrochloride solution disposed within sealed glass vials that is
`
`diluted to 4 µg/mL with 0.9% sodium chloride solution for use_ The Examiner also purports that
`
`the Xylocaine® Package Insert discloses a lidocaine HCI solution provided in glass ampoules and
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`Atty. Docket No. 077350.0355
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`vials at various concentrations and volumes. Further, the Examiner asserts that Sunkel discloses
`
`pharmaceutical compositions for parenteral administration, which may comprise
`
`dexmedetomidine, contained in glass ampoules and vials. Lastly, the Examiner alleges that
`
`Ibrahim discloses compositions comprising oxaliplatinum contained in 50 mL sealed glass vials.
`
`The Examiner concludes that it would have been obvious to provide the diluted
`
`dexmedetomidine composition described by Miyawaki in sealed glass containers since it allegedly
`
`was a common and predictable method of providing parenteral pharmaceutical compositions.
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`Furthermore, the Examiner contends that there are a limited number of options available with
`
`regard to the material for the container, and as such, the skilled artisan would envisage disposing
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`the dilution in a glass container. Additionally, the Examiner alleges that it would have been
`
`obvious to use a sealed glass storage container to preserve the sterility of the dilution.
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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.,
`
`550 U.S. 398, 127 S. Ct. 1727, 82 (2007). Applicants submit that the claims are not obvious over
`
`the cited references because the combined disclosure of the cited references does not suggest or
`
`describe all of the claims elements. Furthermore, practicing the claims results in surprising and
`
`unexpected advantages with regard to stability of the claimed composition over the prior art,
`
`which is indisputable evidence of the non-obviousness of the claims over the cited references.
`
`Independent claim 1 recites a ready to use liquid pharmaceutical composition for
`
`parenteral administration to a subject, comprising dexmedetomidine or a pharmaceutically
`
`acceptable salt thereof at a concentration of about 0. 005 to about 50 µg/mL disposed within a
`
`sealed glass container. In contrast to the claims, as conceded by the Examiner, Miyawaki does
`
`not suggest or describe that the diluted dexmedetomidine compositions recited by the reference
`
`are disposed within a sealed glass container. Rather, Miyawaki discloses a kit for the preparation
`
`of a composition for local anesthesia, wherein the composition includes a local anesthetic agent,
`
`and an o.2 receptor agonist, such as dexmedetomidine. The kit provides for the combination of
`components into a single composition in advance of its use for local anesthesia (see Miyawaki,
`page 2, paragraphs [0024] - [0031 J; and page 9, paragraph [0095]).
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`Atty. Docket No. 077350.0355
`U.S. Serial No. IJ,'541,524
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`Importantly, contrary to the Examiner's assertions, Applicants submit that none of the
`
`Precedex® Package Insert, Sunkel, Ibrahim or the Xylocaine® Package Insert provide an artisan
`
`of ordinary skill with guidance, suggestion, or motivation to prepare the diluted dexmedetomidine
`
`compositions described by Miyawaki in a sealed glass container.
`
`With regard to the Precedex® Package Insert, the reference does not suggest or describe a
`
`composition comprising about 0.005 to about 50 µg/mL dexmedetomidine, or a pharmaceutically
`
`acceptable salt thereof, wherein the composition is disposed within a sealed glass container as a
`
`ready to use premixture. In contrast, the Precedex® Package Insert discloses a dexmedetomidine
`
`composition that is supplied as a 100 µg/mL concentration that must be diluted to 4 µg/mL prior
`
`to administration to a subject. (See the Precedex® Package Insert, page 1, col. 1 ). The reference
`
`does not suggest or describe that the dexrnedetomidine would have been diluted into a sealed
`
`glass container. Rather, because the diluted composition is administered to a subject by an
`
`intravenous infusion (see, e.g., the Precedex® Package Insert, page 1, col. 1 ), an artisan of
`
`ordinary skill would have diluted the dexmedetornidine in a device for infusion, such as a plastic
`
`infusion bag or plastic syringe, and would not have disposed the 4 µg/mL dilution into a sealed
`
`glass container. The Examiner provides no basis or evidence to suggest that an artisan of ordinary
`
`skill would have prepared the dilution in a sealed glass container as claimed. Furthermore,
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`Applicants note that in rejecting the claims as allegedly being obvious over the Precedex®
`
`Package Insert (see the Office Action, item 8, page 9; and section I(C), below), the Examiner
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`concedes that the Precedex® Package Insert does not suggest or describe disposing the diluted 4
`
`µg/mL dexmedetomidine composition in a sealed glass container. Thus, in view of the
`
`Precedex® Package Insert, the artisan would not have been motivated to prepare the diluted
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`dexmedetomidine composition described by Miyawaki in a sealed glass container.
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`Additionally, Applicants note that the Precedex® Package Insert describes
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`dexmedetomidine compositions for intravenous administration to a subject. (See the Precedex®
`
`Package Insert, page 1, col. 1 ). In contrast, Miyawaki is directed to compositions for injection
`
`that produce a local anesthetic effect. (See Miyawaki, page 4, paragraph [0048]). Miyawaki does
`
`not suggest or describe that such compositions can be administered via an intravenous infusion.
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`Thus, an artisan of ordinary skill would not have been motivated to combine the features of an
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`intravenous formulation described by the Precedex® Package Insert with a composition
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`formulated for local injection, as described by Miyawaki.
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`Atty. Docket No. 077350.0355
`U.S. Serial No. J 3i54 l ,524
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`With regard to the references cited by the Examiner, only Miyawaki and the Precedex®
`
`Package Insert provide any disclosure related to formulating dexmedetomidine at specific
`
`concentrations for use. As evidenced by Miyawaki and the Precedex® Package Insert,
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`dexmedetomidine is presently supplied as a 100 µg/mL concentrated solution, and must be diluted
`
`to a lower concentration for use. Applicants note that a primary difference between the claimed
`
`ready to use premixture composition and the diluted composition described by the cited references
`
`is 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, page 5, paragraphs
`
`[0024]-[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. In
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`contrast, the compositions described by the cited references are not suitable for administering to a
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`patient upon withdrawing the composition from a sealed container (i.e., a 2 mL vial or ampoule in
`
`which the concentrated 100 µg/mL formulation is stored in, see the Precedex® Package Insert,
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`page 1, col. 1 ). Rather, after withdrawing the concentrated 100 µg/mL composition from a sealed
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`container, the composition must be diluted prior to administration to a subject.
`
`Applicants also submit that the claimed ready to use premixture composition provides for
`
`surprising and unexpected advantages over the diluted compositions described by the cited
`
`references. For example, the claimed ready to use composition provides for advantages with
`
`regard to the ability to store the composition over prolonged periods of time, while maintaining a
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`stable formulation. Such advantages over the diluted compositions of the cited references is
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`further evidence of the non-obviousness of the claims over the cited references. (See M.P.E.P. §
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`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
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`against the contaminating action of microorganisms such as bacteria and fungi." (See the
`
`specification, page 8, paragraph [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 a 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
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`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, pages 18-
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`20, paragraphs [0086] - [0088]). As described by Table 1, when stored in glass vials or ampoules,
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`Atty. Docket No. 077350.0355
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`the 4 µg/rnL premixture maintained over 98% potency after 5 months. However, when stored in
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`plastic or PVC containers, which include plastic syringes and plastic bags, the potency was
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`reduced by as much as 20% after only a two-week storage period. (See the specification, pages
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`19-20, Table 1 ). Similarly, Example 3 discloses that the potency of the 4 µg/mL premixture
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`composition maintained relatively unchanged after being stored in glass vials and ampoules at
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`25°C for 9 months. (See the specification, Example 3, pages 22-23, paragraph [0095]).
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`In contrast, the Precedex® Package Insert discloses that the concentrated 100 µg/mL
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`dexmedetomidine composition is suitable for storage, and not the diluted 4 µg/mL composition.
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`(See the Precedex® Package Insert, page 23, section 16). Furthermore, as described by the FDA
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`Memorandum by Cynthia G. McCormick, M.D., dated November 30, 1999, in connection with
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`the Medical Reviews of the Precedex (dexmedetomidine hydrochloride injection) Application No.
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`21-038 submitted to the FDA, and available on the FDA website July 26, 2001 (hereafter, "the
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`Memorandum," a copy of which was submitted July 3, 2012 in an Information Disclosure
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`Statement Not In Support Of Accelerated Examination Support Document And Petition To Make
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`Special), the undiluted dexmedetomidine composition is manufactured through an "aseptic fill and
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`terminal sterilization by autoclave," (see, the Memorandum, page 8, third paragraph), and as such,
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`is suitable for storage. However, once diluted for administration, the diluted composition is stable
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`for only 24 hours. (See the Memorandum, page 8, paragraph 4, stating: "The drug product is
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`prepared for use by diluting it with sterile 0.9% sodium chloride solution for injection after which
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`it is stable for 24 hours" (emphasis added)). Thus, unlike the claimed ready to use premixture
`
`composition, which can be stored for prolonged periods of time, the diluted composition
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`described by the cited references is prepared for use within a 24-hour period, and is not a
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`formulation suitable for prolonged storage.
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`Accordingly, the memorandum provides further evidence that formulating the claimed
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`composition as a ready to use premixture provides for surprising and unexpected advantages over
`
`the dilutions described by the cited references. While diluting the 100 µg/mL concentrate
`
`produces a composition that is stable and useable for a 24-hour period after dilution, the claimed
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`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 references, as evidenced by the
`
`Memorandum. Rather, in contrast, an artisan of ordinary skill would understand that a diluted
`
`dexmedetomidine composition is only stable and useable for up to 24 hours.
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`Atty. Docket No. 077350.0355
`U.S. Serial No. !3/541,524
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`Additionally, in view of the Precedex® Package Insert's disclosure as a whole, an artisan
`
`of ordinary skill would understand that a diluted dexmedetomidine formulation is formulated for
`
`immediate administration to a subject, and not suitable for prolonged storage. For example, the
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`Precedex® Package Insert discloses that the composition is "preservative-free and contains no
`
`additives or chemical stabilizers." (See the Precedex® Package Insert, page 16, first paragraph).
`
`Thus, the artisan would have had no expectation that the diluted formulation is suitable for
`
`storage. Additionally, the diluted composition is intended for a single use only, and further, such
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`a single use can only be for a period of, at most, 24 hours. (See the Precedex® Package Insert,
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`page 1, col. I). As such, the artisan would understand that any portion of the diluted composition
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`that is not administered to a subject, or that remains after a 24-hour dosing period, cannot be
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`stored for later use. Finally, contamination with impurities is a greater concern for compositions
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`diluted to a low concentration. "Since the drug is present at such a low concentration ... even
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`ppb levels of impurities would have a significant contribution toward the impurity limit." (See the
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`specification, page 32, paragraph [00115]). Accordingly, the skilled artisan would have been
`
`motivated to immediately use the diluted composition once prepared, and not store the dilution
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`since storage could increase the risk of contamination, e.g., microbe growth resulting from
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`contamination during dilution.
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`Furthermore, as described in the Declaration of H uailiang Wu (hereafter, "the
`
`Declaration"), submitted herewith as Attachment A, storing a ready to use dexmedetomidine
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`composition at concentrations of 1, 10, 15 and 50 µg/mL in glass containers surprisingly
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`increased the stability of the dexmedetomidine compositions compared to storage in plastic PVC
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`bags. Specifically, as described by the Declaration, the potency of the 1 µg/mL
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`dexmedetomidine formulation decreased by 1.82% about 12 hours after being disposed in a PVC
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`storage bag (preTS), and by 7.81% (T=O) following autoclave compared to control. After storage
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`for three days in a PVC bag at 25°C and 40°C, the potency of the 1 µg/mL formulation decreased
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`by 8.05% and 8.83%, respectively, compared to control. Similarly, the potency of the 10, 15 and
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`50 µg/mL formulations stored in PVC bags decreased by 5.84%, 5.54% and 4.32% following
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`autoclave, respectively, compared to control. After storage for three days in PVC bags at 25°C,
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`the potency of the three concentrations decreased by 6.24%, 6.17% and 5.26%, respectively,
`
`compared to control. After storage for three days in PVC bags at 40°C, the potency of the three
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`concentrations decreased by 6.28%, 6.62% and 5.36%, respectively, compared to control.
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`Atty. Docket No. 077350.0355
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`In contrast, when the dexmedetomidine compositions were stored in glass containers, the
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`potency of the dexmedetomidine was maintained. When stored in glass vials, none of the four
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`concentrations of dexmedetomidine experienced any loss in potency after disposing the
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`formulations in glass vials or after autoclaving, compared to control. After storage for 3 days in
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`glass vials at 25°C, the decrease in potency of the I, 10, 15 and 50 µg/mL dexmedetomidine
`
`compositions were 0%, 0%, 0.39% and 0.44%, respectively, compared to control. After storage
`
`for 3 days in glass vials at 40°C, the decrease in potency of the 1, 10, 15 and 50 µg/mL
`
`dexmedetomidine compositions were 0.42%, 0%, 0.27% and 0.51 %, respectively, compared to
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`control.
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`Thus, as described by the Declaration, storing a ready to use formulation of
`
`dexmedetomidine at concentrations recited by the claims in glass containers resulted in an
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`unexpected reduction in potency loss of the dexmedetomidine composition compared to storage in
`
`plastic PVC containers. Storing the formulations in PVC containers resulted in a decrease in
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`dexmedetomidine potency after disposition within the containers, after autoclave, and after a
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`three-day storage period at 25°C or 40°C. The maximum detectable loss in potency of the
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`samples stored in PVC containers after the three-day storage period was 8.83%, whereas the glass
`
`containers showed a maximum loss of only 0.51 %.
`
`Similarly, as described by the Declaration, when the dexmedetomidine compositions
`
`described above were stored at ambient temperature in glass containers or PVC containers without
`
`autoclaving, the compositions stored in glass containers were more stable over a 24-hour storage
`
`period. For example, when stored for 24 hours in PVC containers, the I, 10, 15 and 50 µg/mL
`
`dexmedetomidine compositions experienced a decrease in potency of 1.48%, 1.22%, 1.06% and
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`1. 78%, respectively, compared to control. In contrast, when stored for 24 hours in glass
`
`containers, the potency of the I, 10, 15 and 50 µg/mL dexmedetomidine compositions only
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`decreased by 0%, 0.56%, 0.24% and 0%, respectively, compared to control.
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`Thus, maintaining the potency of a ready to use dexmedetomidine composition during
`
`autoclave is dependent at least upon the type of container the composition is disposed in. As
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`described by the Declaration, storing the ready to use dexmedetomidine composition in a glass
`
`container reduced potency loss compared to plastic PVC containers during autoclave.
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`Additionally, as described by the Declaration, storing the ready to use composition in glass
`
`containers inhibited additional potency loss during prolonged storage of the composition. As
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`Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
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`described previously, an undiluted dexmedetomidine pharmaceutical composition for parenteral
`
`use is manufactured through an "aseptic fill and terminal sterilization by autoclave," (see, the
`
`Memorandum, page 8, third paragraph). Such a manufacturing process provides a sterile solution
`
`that is suitable for storage and safe to dilute for administering to patients. As discussed
`
`previously, and described by the Declaration, the ready to use composition recited by the claims is
`
`also suitable for storage, and formulated for administration to patients. However, unlike the
`
`composition described by the Memorandum, the claimed dexmedetomidine composition does not
`
`require dilution prior to administration to a patient. Because the claimed dexmedetomidine
`
`composition is formulated as a "ready to use" composition, sterilizing the composition during
`
`manufacture through, for example, autoclaving, would be required to produce a composition that
`
`is safe for parenteral administration to a patient.
`
`As described by Examples 1 and 2 of the application, and further, as described by the
`
`Declaration, ready to use dexmedetomidine compositions at concentrations recited by the claims
`
`were more stable over prolonged periods of time when stored in glass containers compared to
`
`storage in plastic PVC containers. Such an increase in stability was detectable whether the
`
`compositions were autoclaved, for example, as during the manufacture of a dexmedetomidine
`
`composition for parenteral use, or not before storage. Such an increase in stability achieved by
`
`storing a ready to use dexmedetomidine compositions in a class container is a surprising and
`
`unexpected result of practicing the claims, and is evidence of the non-obviousness of the claims
`
`over the cited references. (See M.P.E.P. § 716.02(a)).
`
`With regard to Sunkel, Applicants note that this reference is directed to pharmaceutical
`
`compositions comprising SCP-M series compounds. (See Sunkel, col. 2, line 1 to col. 3, line 3).
`
`SCP-M series compounds are different compounds that are structurally unrelated to
`dexmedetomidine, and as such, an obviousness rejection based on a property of the structurally
`
`unrelated SCP-M series compounds (e.g., storability in a sealed glass container), would be
`
`improper. Generalizing characteristics and properties of a chemical entity to a structurally
`
`unrelated chemical entity is not proper, and can not form a basis for an obviousness rejection.
`
`This inability to generalize characteristics and properties of different chemical entities is
`
`recognized by the USPTO. For example, as described by M.P.E.P. § 2144.09, a rejection based
`
`on obviousness is "founded on the expectation that compounds similar in structure will have
`
`similar properties." (See M.P.E.P. § 2144.09(1)). Because SCP-M series compounds are different
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`Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
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`chemical entities from dexmedetomidine, with different chemical structures, it would be improper
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`to base an obviousness rejection on the conclusion that storage conditions applicable to SCP-M
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`series compounds would be suitable for a diluted dexmedetomidine composition. Thus, the
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`reference's disclosure that SCP-M series compounds can be stored in a glass container provides
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`an artisan of ordinary skill with no guidance or suggestion that such storage conditions would
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`have been applicable to a diluted dexmedetomidine composition. Furthermore, as described in
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`greater detail above, dexmedetomidine itself exhibits different properties with regard to stability
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`when formulated as a concentrated stock solution, and after dilution for use. Thus, the disclosure
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`of Sunkel provides an artisan of ordinary skill with no suggestion or motivation to dilute the
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`dexmedetomidine of Miyawaki into a sealed glass container.
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`Applicants also submit that Sunkel provides no suggestion or disclosure that storage in a
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`glass container provides for any advantages over storage in other containers, such as, for example,
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`a plastic container. In contrast, as described above, the ready to use dexmedetomidine
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`formulations of the present application exhibited surprising and unexpected advantages with
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`regard to stability when stored in a sealed glass container, compared to storage in a plastic
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`container. Such a surprising and unexpected advantage is evidence of the non-obviousness of the
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`claims of the application over the cited references.
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`With regard to Ibrahim and the Xylocaine® Package Insert, Applicants note that these two
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`references are directed to compositions comprising oxaliplatinum (see Ibrahim, col. 3, lines 45-
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`62) and lidocaine HCl (see the Xylocaine® Package Insert, page 1, first paragraph), respectively.
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`The references provide no disclosure related to dexmedetomidine or to compositions comprising
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`dexmedetomidine. Each of the oxaliplatinum and lidocaine compounds described by Ibrahim and
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`the Xylocaine® Package Insert are different compounds that are each structurally unrelated to
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`dexmedetomidine. Accordingly, any property of either oxaliplatinum or lidocaine HCl, for
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`example, with regard to storage conditions, can not be generalized to dexmedetomidine. (See
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`M.P.E.P. § 2144.09(1)). Additionally, as described above, the inability to generalize properties of
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`one chemical compound to another is further evidenced by dexmedetomidine itself, which
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`exhibits different properties with regard to stability when formulated as a concentrated stock
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`solution, and after dilution for use. Thus, Ibrahim and the Xylocaine® Package Insert's disclosure
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`that oxaliplatinum and lidocaine, respectively, can be stored in a glass container provides an
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`NY02:754562.l
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1049 – Page 11
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`

`

`Atty. Docket No. 077350.0355
`U.S. Serial No. 13/541,524
`
`artisan of ordinary skill with no guidance or suggestion to store a diluted dexmedetomidine
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`composition in a glass container.
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`Additionally, Applicants note that some of the lidocaine compositions described by the
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`Xylocaine® Package Insert comprise methyl paraben as an antiseptic preservative, sodium
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`metabisulfide as an antioxidant, and citric acid as a stabilizer. (See Xylocaine® Package Insert,
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`page 1, Description). In contrast, Miyawaki does not suggest or describe that the diluted
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`dexmedetomidine composition described by the reference includes any preservatives,
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`antioxidants, or stabilizers. Thus, when formulating different chemical entities into
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`pharmaceutical compositions, some chemical entities, such as certain lidocaine compositions
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`described by the Xylocaine® Package Insert, require additional ingredients to successfully
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`formulate the pharmaceutical compositions, while other chemical entities, such as the
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`dexmedetomidine described by Miyawaki, do not. Accordingly, an artisan of ordinary skill would
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`have had no motivation to combine the disclosure of the Xylocaine® Package Insert with
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`Miyawaki since different chemical entities can require different conditions to successfully
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`formulate a pharmaceutical composition.
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`Furthermore, Applicants note that the Examiner alleges that "there are only a limited
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`number of options available to the artisan with regard to the material of the container" in which
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`the composition described by Miyawaki can be stored in. (See the Office Action, page 5). Thus,
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`according to the Examiner, it would have been obvious to the artisan to envisage storing the
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`diluted dexmedetomidine composition described by Miyawaki in a sealed glass container.
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`Applicants respectfully disagree. In addition to glass, there are numerous materials from
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`which a container for a pharmaceutical composition can be manufactured from. For example, a
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`non-limiting list of examples include but are not limited to polypropylene, polyethylene, cyclo(cid:173)
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`olefin copolymer, polyolefin, polyester, and polyvinyl chloride -- all of which are materials that
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`can be used for manufacturing containers for pharmaceutical compositions. (See the specification,
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`page 13, paragraph [0060], and Examples 1 and 2, pages 18-22; see, also, Petersen, "Trends in
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`Pharmaceutical Primary Packaging for Injectables - Solutions for New Challenges," Drug
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`Development and Delivery, Issue Date: September 2012, Posted On: 9/5/2012, (hereafter,
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`"Petersen"), submitted herewith in an Information Disclosure Statement Not In Support Of
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`Accelerated Examination Support Document And Petition To Make Special). However, as
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`discussed above, none of the cited references provide any suggestion or guidance to store a diluted
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`NY02 754562. l
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`Petition for Inter Partes Review of US 8,338,470
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