`
`
`EXHIBIT 1005(A)
`EXHIBIT 1005(A)
`
`

`

`Airy. Docket: PAC/20632 US (4137-04700)
`
`Patent
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants: Amar Lulla, et al.
`
`Serial No.:
`
`10/518,016
`
`Filed:
`
`For:
`
`July 6, 2005
`
`COMBINATION OF AzELASTINE AND
`STEROIDS
`
`§
`§
`§
`§
`§
`§
`§
`§
`§
`
`Group Art Unit:
`
`1616
`
`Examiner: Kristie Latrice Brooks
`
`Confirmation No.: 4912
`
`Mail Stop: Amendment
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`CERTIFICATE OF EFS-WEB FILING
`
`I hereby certify
`is being
`this correspondence
`that
`electronically filed at the USPTO website to: Mail Stop
`Amendment, Commissioner for Paten s, P .. Box j450,
`A l eW lMOon 7 2:1:.
`.2..-bD"f
`
`Edith S. Shek
`
`AMENDMENTS AND RESPONSE TO
`OFFICE ACTION DATED JANUARY 23, 2009
`
`Dear Sir:
`
`In response to the Office Action dated January 23, 2009, Applicants respectfully request
`
`the following amendments to the above-identified application as follows. The changes made are
`
`shown by underlining the added text and striking through the deleted text.
`
`Amendments to the Claims are reflected in the listing of claims, which begins on page 2
`
`of this paper.
`
`Remarks/Arguments begin on page 10 of this paper.
`
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`Airy. Docket: PAC/20632 US (4137-04700)
`
`Patent
`
`AMENDMENTS TO THE CLAIMS
`
`Listing of Claims:
`
`1.
`
`(Currently Amended) A pharmaceutical formulation which comprises azelastine, or a
`
`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and
`
`fluticasone or a pharmaceutically acceptable ester thereofa steroid, or a pharmaceutically
`
`acceptable salt, solvate or physiologically flHlctional derivative thereof, which contains the
`
`fluticasone or a pharmaceutically acceptable ester thereof in an amount from about 50
`
`micrograms/ml to about 5 mg/ml of the formulation.
`
`2.
`
`(Original)
`
`A pharmaceutical formulation according to claim 1, wherein said azelastine
`
`is present as azelastine hydrochloride.
`
`3.
`
`(Canceled)
`
`4.
`
`(Currently Amended) A formulation according to claim 3claim 1, wherein the steroid
`
`pharmaceutically acceptable ester is beclomethasone propionate, mometasonefuroate, mometasone
`
`furoate monohydrate, fluticasone propionate or fluticasone valerate.
`
`5.
`
`(Canceled)
`
`6.
`
`(Currently Amended) A formulation according to claim 1, wherein the formulation has a
`
`particle size of less than abeut--10 µm.
`
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`-2-
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
`
`7.
`
`(Currently Amended) A formulation according to claim 1, which is a suspension
`
`containing 0.0005 to 2% (weight/weight of the formulation) of azelastine or a pharmaceutically
`
`acceptable salt of azelastine, and from 0.5 to 1.5% (weight/weight of the formulation) of
`
`fluticasone or a pharmaceutically acceptable ester thereofsaid steroid.
`
`8.
`
`(Currently Amended) A formulation according to claim 7, which contains from 0.001 to
`
`1 % (weight/weight of the formulation) azelastine, or salt thereof, and from 0.5% to 1.5%
`
`(weight/weight of the
`
`formulation)
`
`fluticasone or a pharmaceutically acceptable ester
`
`thereof steroid.
`
`9.
`
`(Previously Presented)A formulation according to claim 1, which also contains a
`
`surfactant.
`
`10.
`
`(Original)
`
`A formulation according to claim 9, wherein the surfactant comprises a
`
`polysorbate or poloxamer surfactant.
`
`11.
`
`(Previously Presented)A formulation according to claim 9, which contains from about 50
`
`micrograms to about 1 milligram of surfactant per ml of the formulation.
`
`12.
`
`(Previously Presented)A formulation according to claim 1, which also contains an isotonic
`
`agent.
`
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`

`At(Y. Docket: PAC/20632 US (4137-04700)
`
`Patent
`
`13.
`
`(Original)
`
`A formulation according to claim 12, wherein the isotonic agent comprises
`
`sodium chloride, saccharose, glucose, glycerine, sorbitol or 1,2-propylene glycol.
`
`14.
`
`(Previously Presented)A formulation according to claim 1, which also contains at least one
`
`additive selected from the group consisting of a buffer, a preservative, a suspending agent and a
`
`thickening agent.
`
`15.
`
`(Original)
`
`A formulation according to claim 14, wherein said preservative is selected
`
`from edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl
`
`mercury borate, or benzoic acid or a salt, a quaternary ammonium compound, or sorbic acid or a
`
`salt thereof.
`
`16.
`
`(Previously Presented)
`
`A
`
`formulation according
`
`to claim 14, wherein
`
`the
`
`suspending agent or
`
`thickening agent
`
`is selected from cellulose derivatives, gelatin,
`
`polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the
`
`basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, or pectin.
`
`17.
`
`(Previously Presented)A formulation according to claim 14, wherein the buffer comprises a
`
`citric acid-citrate buffer.
`
`18.
`
`(Currently Amended) A formulation according to claim 14, wherein the buffer maintains
`
`the pH of the aqueous phase at from 3 to 7, preferably 4.5 to about 6.5.
`
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`

`Atry. Docket: PAC/20632 US (4137-04700)
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`Patent
`
`19.
`
`(Previously Presented)A formulation according to claim 1, which is an aqueous suspension
`
`or solution.
`
`20.
`
`(Previously Presented)A formulation according to claim 1, which is in the form of an
`
`aerosol, an ointment, eye drops, nasal drops, a nasal spray, an inhalation solution and other forms
`
`suitable for nasal or ocular administration.
`
`21.
`
`(Original)
`
`A formulation according to claim 20, which is in the form of nasal drops or
`
`nasal spray.
`
`22.
`
`(Original)
`
`A formulation according to claim 20, which is in the form of an aerosol.
`
`23-24. (Canceled)
`
`25.
`
`(Previously Presented) A formulation according to claim 1, which is in the form of an
`
`insufflation powder.
`
`26.
`
`(Currently Amended) A pharmaceutical product according to claim 1, compnsmg (i)
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative
`
`thereof, provided in an aerosol formulation preferably together with a propellant typically suitable
`
`for MDI delivery, and (ii) fluticasone or a pharmaceutically acceptable ester thereofat least one
`
`steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative
`
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`Ato,. Docket: PAC/20632 US (4137-04700)
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`Patent
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`thereof, provided in an aerosol formulation preferably together with a propellant typically suitable
`
`for MDI delivery, as a combined preparation for simultaneous, separate or sequential use in the
`
`treatment of conditions for which administration of one or more anti-histamine and/or one or more
`
`steroid is indicated.
`
`27.
`
`(Previously Presented)An aerosol formulation preferably suitable for MDI delivery
`
`comprising the formulation of claim 1, together with a propellant.
`
`28.
`
`(Currently Amended) A pharmaceutical product comprising
`
`(i) azelastine, or a
`
`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided
`
`as an insufflation powder, and (ii) fluticasone or a pharmaceutically acceptable ester thereofat least
`
`one steroid, or a pharmaceutically acceptable salt, soh,ate or physiologically fooctional derivative
`
`thereof, provided as an insufflation powder, as a combined preparation for simultaneous, separate
`
`or sequential use in the treatment of conditions for which administration of one or more anti(cid:173)
`
`histamine and/or one or more steroid is indicated.
`
`29.
`
`(Currently Amended) An insufflation powder formulation comprising (i) azelastine, or a
`
`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii)
`
`fluticasone or a pharmaceutically acceptable ester thereofat least one steroid, or a pharmaceutically
`
`acceptable salt, solvate or physiologically functional derivative thereof, together with a
`
`pharmaceutically acceptable carrier or excipient therefor.
`
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`

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`A~. Docket: PAC/20632 US (4137-04700)
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`Patent
`
`30.
`
`(Currently Amended) A pharmaceutical product comprising the formulation according to
`
`claim 1, wherein (i) azelastine, or a pharmaceutically acceptable salt thereof, and (ii) viherein at
`
`least one steroid is selected from. the group consisting of beelom.ethasone, fluticasone, m.om.etasone
`
`and- or a pharmaceutically acceptable esters thereof, as a combined preparation with said azelastine
`
`for simultaneous, separate or sequential use in the treatment of conditions for which administration
`
`of one or more anti-histamine and/or one or more steroid is indicated.
`
`31-34. (Canceled)
`
`35.
`
`(Currently Amended) A
`
`pharmaceutical product
`
`comprising
`
`the pharmaceutical
`
`formulation of claim 1, wherein said azelastine
`
`is azelastine hydrochloride and said
`
`pharmaceutically acceptable estersteroid is fluticasone propionate, as a combined preparation for
`
`simultaneous, separate or sequential use in the treatment of conditions for which administration of
`
`one or more anti-histamine and/or one or more steroid is indicated.
`
`36.
`
`(Currently Amended) A pharmaceutical formulation according to claim 1, wherein said
`
`azelastine is azelastine hydrochloride and said pharmaceutically acceptable estersteroid 1s
`
`fluticasone propionate, together with a pharmaceutically acceptable carrier or excipient therefor.
`
`37.
`
`(Currently Amended) A
`
`pharmaceutical product
`
`compnsmg
`
`the pharmaceutical
`
`formulation of claim 1, wherein said azelastine
`
`is azelastine hydrochloride and said
`
`pharmaceutically acceptable estersteroid is fluticasone valerate, as a combined preparation for
`
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`Atry. Docket: PAC/20632 US (4137-04700)
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`Patent
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`simultaneous, separate or sequential use in the treatment of conditions for which administration of
`
`one or more anti-histamine and/or one or more steroid is indicated.
`
`38.
`
`(Currently Amended) A pharmaceutical formulation according to claim 1, wherein said
`
`azelastine is azelastine hydrochloride and said pharmaceutically acceptable estersteroid 1s
`
`fluticasone valerate, together with a pharmaceutically acceptable carrier or excipient therefor.
`
`39-43. (Canceled)
`
`44.
`
`(Currently Amended) A process of preparing a pharmaceutical product according to claim
`
`26, which process comprises providing (i) azelastine, or a pharmaceutically acceptable salt, solvate
`
`or physiologically functional derivative thereof, and (ii) fluticasone or a pharmaceutically
`
`acceptable ester thereofat least one steroid, or a pharmaceutically acceptable salt, solvate or
`
`physiologically functional derivative thereof, as a combined preparation for simultaneous, separate
`
`or sequential use in the treatment of conditions for which administration of one or more
`
`antihistamine and/or one or more steroid is indicated.
`
`45.
`
`(Currently Amended) A process of preparing a pharmaceutical formulation according to
`
`claim 1, which process comprises admixing a pharmaceutically acceptable carrier or excipient with
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative
`
`thereof, and fluticasone or a pharmaceutically acceptable ester thereofat least one steroid, or a
`
`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
`
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`

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`At(V. Docket: PAC/20632 US (4137-04700)
`
`Patent
`
`46-52. (Canceled)
`
`53.
`
`(New) A formulation according to claim 1, wherein the pharmaceutically acceptable ester
`
`is fluticasone propionate.
`
`54.
`
`(New) A formulation according to claim 1, wherein the pharmaceutically acceptable ester
`
`is fluticasone valerate.
`
`55.
`
`(New) A pharmaceutical product compnsmg (i) azelastine, or a pharmaceutically
`
`acceptable salt, solvate or physiologically functional derivative thereof, provided as a nasal spray,
`
`and (ii) fluticasone or a pharmaceutically acceptable ester thereof, provided as a nasal spray, as a
`
`combined preparation for simultaneous, separate or sequential use in the treatment of conditions
`
`for which administration of one or more anti-histamine and/or one or more steroid is indicated.
`
`56.
`
`(New) A nasal spray formulation compnsmg (i) azelastine, or a pharmaceutically
`
`acceptable salt, solvate or physiologically functional derivative thereof, and (ii) fluticasone or a
`
`pharmaceutically acceptable ester thereof, together with a pharmaceutically acceptable carrier or
`
`excipient therefor.
`
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`Atzy. Docket: PAC/20632 US (4137-04700)
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`Patent
`
`Status of Claims
`
`REMARKS/ARGUMENTS
`
`Claims 1, 4, 6, 7, 8, 18, 26, 28, 29, 30, 35, 36, 37, 38, 44, and 45 have been amended.
`
`Claims 3, 5, 23-24, 31-34, 39-43, and 46-52 have been canceled.
`
`New claims 53-56 have been added.
`
`Thus, claims 1, 2, 4, 6-22, 25-30, 35-38, 44-45, and 53-56 are currently pending in this
`
`application.
`
`Applicants hereby request further examination and reconsideration of the presently claimed
`
`application.
`
`Restriction Requirement
`
`Applicants affirm the election of group I, claims 1-22, 25-42 and 44-45. Furthermore,
`
`Applicants have amended the pending claims
`
`to recite the elected species, namely a
`
`pharmaceutical formulation comprising azelastine and fluticasone.
`
`New Claims
`
`Applicants have added new claims 53-54 directed to specific combinations of azelastine and
`
`specific pharmaceutically acceptable esters of fluticasone, which are supported by paragraph 0045
`
`of the published application. Further, Applicants have added new claims 55-56, which mirror
`
`existing claims 28 and 29, and are drawn to a nasal spray as disclosed by paragraph 0010 of the
`
`published application. The new claims are patentable for the reasons set forth below.
`
`Claim Rejections-35 U.S.C. § 112
`
`Claims 6 and 18 stand rejected under 35 U.S.C. § 112, second paragraph, as being indefinite
`
`for failing to particularly point out and distinctly claim the subject matter which applicant regards as
`
`the invention. Applicants have amended claim 6 to remove the term "about." Applicants have also
`
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`Atry. Docket: PAC/20632 US (4137-04700)
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`Patent
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`amended claim 18 to remove the recitation of a narrower range of values. In consideration of the
`
`foregoing, Applicants respectfully request withdrawal of the rejections.
`
`Claim Rejections - 35 U.S. C. § 102
`
`Claims 1, 2, 4, 7, 9-10, 12-21, 30-31, and 44-45 stand rejected under 35 U.S.C. § 102(b) as
`
`being anticipated by Cramer, European Patent No. 0780127 (hereinafter "Cramer"). Applicants
`
`note that claim 5 was not rejected as being anticipated by Cramer. Applicants have amended claim
`
`1 to incorporate the limitations of now canceled claim 5 and respectfully submit that claims 1, 2, 4,
`
`7, 9-10, 12-21, 30-31, and 44-45 are not anticipated by Cramer.
`
`Claim Rejections-35 U.S.C. § 103
`
`Claims 1, 2, and 6 stand rejected under 35 U.S.C. § 103(a) as being unpatentable over
`
`Malmqvist-Granlund, et al., U.S. Patent No. 6,391,340 (hereinafter "Malmqvist-Granlund').
`
`Applicants note that claim 5 was not rejected as being obvious in view of Malmqvist-Granlund.
`
`Applicants have amended claim 1 to incorporate the limitations of now canceled claim 5 and
`
`respectfully submit that claims 1, 2 and 6 are not obvious over Malmqvist-Granlund.
`
`Claims 5 and 35-38 stand rejected under 35 U.S.C. § 103(a) as being unpatentable over
`
`Cramer. Claims 22 and 26-27 stand rejected under 35 U.S.C. § 103(a) as being unpatentable over
`
`Cramer in view of Modi, U.S. Patent No. 6,294,153 (hereinafter "Modi"). Claims 28-29 stand
`
`rejected under 35 U.S.C. § 103(a) as being unpatentable over Cramer in view of Alfonso, et al.,
`
`U.S. Patent No. 6,017,963 (hereinafter "Alfonso"). Accordingly, the pending claims stand or fall on
`
`the above-recited application of the primary reference, Cramer, alone or in combination with the
`
`secondary references, Modi or Alfonso, to independent claims 1, 26, 28, and 29. Applicants
`
`respectfully submit the pending claims are patentable because the broad genus disclosed in the
`
`primary reference does not render obvious the Applicants' claimed species directed to a
`
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`Atty. Docket: PAC/20632 US (4137-04700)
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`Patent
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`pharmaceutical formulation comprising azelastine and fluticasone. Further, Applicants submit
`
`herewith objective evidence of nonobviousness in that the claimed species directed to a
`
`pharmaceutical formulation comprising azelastine and fluticasone displays unexpectedly beneficial
`
`properties, is commercially successful, and fills a long felt but unsolved need.
`
`The Legal Standard for Obviousness
`
`The MPEP provides that "establishing a prima facie case of obviousness" requires, "the
`
`clear articulation of the reason(s) why the claimed invention would have been obvious." See
`
`MPEP § 2142. The MPEP also acknowledges that "[t]he Supreme Court in KSR noted that the
`
`analysis supporting a rejection under 35 U.S.C. 103 should be made explicit." See MPEP § 2143.
`
`Moreover, in KSR Int'! Co. v. Teleflex, Inc., the United States Supreme Court explained
`
`that, "a patent composed of several elements is not proved obvious merely by demonstrating that
`
`each of its elements was, independently, known in the prior art," but, additionally whether "the
`
`claim extends to what is obvious." See KSR Int'! Co. v. Teleflex, Inc., 82 USPQ2d 1385, 1397
`
`(2007). Expounding on its edict, the Supreme Court went on to opine that an obviousness
`
`determination is based upon a "proper application of Graham," including consideration of
`
`"secondary factors" that may weigh against an obviousness determination. See KSR Int'! Co. v.
`
`Teleflex, Inc., 82 USPQ2d at 1399 (citing Graham v. John Deere Co. of Kansas City, et al., 383
`
`U.S. 1, 148 USPQ 459 (1966)). The Office Action states:
`
`[t]he factual inquiries set forth in Graham v. John Deere Co., 383
`U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a
`background for determining obviousness under 35 U.S.C. 103(a)
`are summarized as follows:
`
`1.
`2.
`
`3.
`
`Determining the scope and contents of the prior art.
`Ascertaining the differences between the prior art and the
`claims at issue.
`Resolving the level of ordinary skill in the pertinent art.
`
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`4.
`
`Considering objective evidence present in the application
`indicating obviousness or nonobviousness.
`
`See Office Action at 10. In an attempt to satisfy the factual inquiries set forth in Graham, the Office
`
`Action addresses the "determining the scope and contents of the prior art" and "ascertaining the
`
`differences between the prior art and the claims at issue" portions of the Graham factual inquiries.
`
`However, the Office Action is silent with regards to the "resolving the level of ordinary skill in the
`
`pertinent art" and "considering objective evidence present in the application indicating obviousness
`
`or nonobviousness" portions of the Graham factual inquiries.
`
`A. Cramer does not fairly suggest the elected species
`
`In ascertaining the difference in the prior art and claim 5, the Office Action acknowledges
`
`"Cramer does not exemplify a composition comprising azelastine and fluticasone." See Office
`
`Action at 12. As such, the Office Action retreats to a "rationale-based" obviousness rejection based
`
`on the conclusion that:
`
`one of ordinary skill in the art would have been motivated to make a
`composition comprising azelastine and fluticasone because Cramer
`suggests that the combination of a gluccocortoid (i.e. fluticasone)
`and antihistamine (i.e. azelastine) provide improved relief of
`symptoms
`associated with
`seasonal or perennial
`allergic
`rhinoconjunctivitis.
`
`See Office Action at 12.
`
`The Office Action then supports its "rationale-based" rejection by stating, "the claimed
`
`invention would have been prima facie obvious to one of ordinary skill in the art at the time the
`
`invention was made because the prior art is fairly suggestive of the claimed invention." See
`
`Office Action at 13 ( emphasis added). As noted previously, "establishing a prima facie case of
`
`obviousness" requires, "the clear articulation of the reason(s) why the claimed invention would
`
`have been obvious." See MPEP § 2142. The Office Action's conclusion does not support aprima
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`facie case of obviousness because the Office Action does not clearly articulate why the claimed
`
`invention would be obvious.
`
`The Office Action's reliance and discussion of Cramer does not articulate why the claimed
`
`pharmaceutical formulation comprising azelastine and fluticasone would be obvious in view of
`
`Cramer's general disclosure that mixtures of glucocorticoids and mixtures of antihstamines could
`
`be combined. The total number of possible glucocorticoids specified in Cramer is six
`
`(beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone and budesonide) and the
`
`total number of antihistamines is three (cetirizine, loratadine, azelastine). Accoringly, there is
`
`a total of eighteen different combinations disclosed in Cramer. The present application claims just
`
`one of these combinations, and it is common ground that this particular combination (fluticasone
`
`and azelastine) is not explicitly mentioned in Cramer. The number of possible combinations rises
`
`exponentially when considering the breadth of the disclosed combinations of racemates, salts, and
`
`mixtures of the glucocorticoid and antihistamine agents.
`
`As such, Cramer's disclosure cannot be "fairly suggestive of the claimed invention," see
`
`Office Action at 13, because, as the MPEP states, the rationale for supporting an obviousness
`
`determination requires, "choosing from a finite number of identified, predictable solutions, with a
`
`reasonable expectation of success." See MPEP § 2143; see also KSR Int'! Co. v. Teleflex, Inc., 82
`
`USPQ2d at 1397 (a combination of elements is obvious if "there are finite number of identified,
`
`predictable solutions, a person of ordinary skill has good reason to pursue."). Clearly, Cramer's
`
`recitation of the possibility of innumerous combinations of compounds does not disclose a "finite
`
`number of identified, predictable solutions." See id.
`
`Based on the foregoing, Applicants respectfully submit that the Office Action does not
`
`present a prima facie case of obviousness with regard to the instant claims.
`
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`B.
`
`Secondary considerations indicate that the combination of azelastine and fluticasone is
`
`nonobviousness
`
`Assuming, without conceding, that the Office Action's "rationale and motivation"
`
`discussion is sufficient, nevertheless, the Office Action's suggestion of a prima facie case of
`
`obviousness must fail because the unaddressed "secondary considerations" described below render
`
`the instant claims nonobvious. See KSR Int'! Co. v. Teleflex, Inc., 82 USPQ2d at 1399.
`
`Applicants provide herewith a Rule 1.132 declaration of inventor Geena Malhotra and the
`
`accompanying Exhibits A-C setting forth evidence of the following secondary considerations of
`
`nonobviousness.
`
`1.
`
`The combination ofazelastine and [luticasone displays unexpected, beneficial results
`
`A showing of unexpected results may rebut a prima facie case of obviousness, and is
`
`particularly applicable in the inherently unpredictable chemical arts where minor changes may
`
`yield substantially different results. See e.g., In re Soni, 34 USPQ2d 1684, 1687 (Fed. Cir. 1995).
`
`Exhibit A of the declaration demonstrates that the claimed pharmaceutical formulation comprising
`
`azelastine and fluticasone has unexpected and beneficial stability. As noted in paragraph 2 of the
`
`declaration:
`
`in Table II show that
`The results
`individual active materials ( e.g.,
`the
`azelastine.HCl, budesonide, and fluticasone propionate) have good stability, in that
`the impurity levels are fairly constant in all the tests. The results in Table II also
`show that the combination of azelastine and budesonide are relatively unstable, with
`varying, and high amounts of impurities developing during the tests. Surprisingly,
`the results for azelastine and fluticasone show good stability throughout the tests, as
`the amount of impurity remains constant and at a low level.
`
`These tests demonstrate that there is a clear unexpected advantage m product stability in
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`formulating azelastine with fluticasone rather than with other steroids such as budesonide.
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`At(Y. Docket: PAC/20632 US (4137-04700)
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`Patent
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`Improved product stability is extremely important in pharmaceutical compositions as is understood
`
`by those skilled in the art.
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`Furthermore, Exhibits B 1 and B3 of the declaration demonstrate that a pharmaceutical
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`formulation comprising azelastine and fluticasone has unexpected and beneficial efficacy when
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`administered to patients. Specifically, Exhibit Bl notes that the use of DUONASE (a commercial
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`pharmaceutical formulation comprising azelastine and fluticasone) "is very effective when
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`compared [to] the available other nasal sprays." Likewise, Exhibit B3 notes (with emphasis
`
`added):
`
`DUONASE Nasal Spray is very very effective in all types of allergic rhinitis.
`Especially in "Seasonal allergic rhinitis", Fluticasone alone or azelastine alone also
`has been tried. But single drug was not effective as compared with the combination
`of both i.e. "DUONASE Nasal Spray".
`
`Likewise, the remainder of the doctor statements in Exhibit B extol the therapeutic benefits of the
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`claimed pharmaceutical formulation comprising azelastine and fluticasone. Such recognition by
`
`skilled artisans of the merits of the invention is further evidence of nonobviousness. See Akzo N V
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`v. United States Int'l Trade Comm'n, 1 USPQ2d 1241, 1247 (Fed. Cir. 1986). These doctor
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`statements demonstrate a clear, unexpected advantage in treatment efficacy, namely that the
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`combination of azelastine and fluticasone provides a synergistic benefit in efficacy over azelastine
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`alone or fluticasone alone.
`
`As set forth above,
`
`the declaration provides strong evidence that the claimed
`
`pharmaceutical formulation comprising azelastine and fluticasone has unexpected and beneficial
`
`stability, and that upon administration to a patient, unexpected and beneficial enhanced efficacy is
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`observed. Accordingly, the claimed pharmaceutical formulation comprising azelastine and
`
`fluticasone is nonobvious in view of these unexpected results.
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`Atzy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`2.
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`The combination ofazelastine and fluticasone is commercially successful
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`Commercial success is a strong factor favoring nonobviousness. See e.g., Akzo NV. at
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`1246. As noted in paragraph 3 of the declaration, a pharmaceutical formulation comprising
`
`azelastine and fluticasonse is commercially available where approved as DUONASE nasal spray.
`
`The doctor statements set forth in Exhibit B provide further evidence of the commercial success of
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`DUONASE nasal spray. Furthermore, as noted in paragraph 5 of the declaration the present
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`application claiming a pharmaceutical formulation comprising azelastine and fluticasonse is
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`licensed to Meda Pharmaceuticals, which specializes in respiratory, allergy, and cough-cold
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`products. Given its expertise and knowledge in the field of treatment, the willingness of Meda
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`Pharmaceuticals to license the pending application is further evidence of the commercial success of
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`the claimed pharmaceutical formulation comprising azelastine and fluticasone. Accordingly, the
`
`claimed pharmaceutical formulation comprising azelastine and fluticasone is nonobvious in view
`
`of its commercial success.
`
`3.
`
`The combination ofazelastine and fluticasone fills a long-felt need
`
`As set forth in Graham, the existence of a long-felt and unsolved need in the art is further
`
`evidence of nonobviousness. Applicants note that Cramer was published on June 25, 1997, which
`
`was over 10 years ago. Nonetheless, as noted in paragraph 5 of the declaration, inventor Geena
`
`Malhotra is unaware of another commercially available pharmaceutical formulation comprising an
`
`antihistamine and a steroid. Likewise, the doctor statement of Exhibit B4 notes that:
`
`I have been using nasal sprays from the year 1993, ever since I joined my present
`institution.
`I have used Beclomethasone, Budesonide, Azelastine, Fluticasone,
`Mometasone, with oral antihistamines down the line till date.
`
`The present combination spray of a weak (non sedating component) Azelastine and
`fluticasone (steroid component) is complete by itself in my patients of chronic
`simple rhinitis following nasal + sinus polyposis surgery and those unwilling for
`surgery or unfit for surgery.
`
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`Such "( f]irsthand practical knowledge of unsolved needs in the art, by an expert, is evidence of the
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`state of the art." See In re Piasecki, 223 USPQ 785, 789 (Fed. Cir. 1984). Applicants respectfully
`
`submit that the evidence establishes a long-felt need dating back to 1993 that continued unsolved
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`even after the subsequent publication of Cramer in 1997. Applicants further submit that the lack
`
`of another commercially available pharmaceutical formulation comprising an antihistamine and a
`
`steroid further evidences a long-felt need and the failure of others to address the need prior to the
`
`present invention. Accordingly, the claimed pharmaceutical formulation comprising azelastine and
`
`fluticasone is nonobvious given that it meets the long-felt need outlined above.
`
`4.
`
`The secondary considerations require a finding of nonohviousness
`
`As set forth above, the claimed pharmaceutical formulation comprising azelastine and
`
`fluticasone displays unexpected, beneficial results; is commercially successful; and fills a long-felt
`
`need in the art. Accordingly, the totality of the secondary considerations requires a finding that the
`
`pending claims are not obvious, and therefore patentable, in view of the prior art ofrecord.
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`Airy. Docket: PAC/20632 US (4137-04700)
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`Patent
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`CONCLUSION
`
`Consideration of the foregoing amendments and remarks, reconsideration of the
`
`application, and withdrawal of the rejections are respectfully requested by Applicants. No new
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`matter is introduced by way of the amendment. It is believed that each ground of rejection raised
`
`in the Office Action dated January 23, 2009 has been fully addressed. If any fee is due as a result
`
`of the filing of this paper, please appropriately charge such fee to Deposit Account Number 50-
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`1515 of Conley Rose, P.C., Texas. If a petition for extension of time is necessary in order for this
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`paper to be deemed timely filed, please consider this a petition therefore.
`
`If a telephone conference would facilitate the resolution of any issue or expedite the
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`prosecution of the application, the Examiner is invited to telephone the undersigned at the
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`telephone number given below.
`
`Respectfully submitted,
`CONLEY ROSE, P.C.
`
`. 39,624
`
`ATTORNEY FOR APPLICANTS
`
`Date: - - - - - - - - - - -
`
`5601 Granite Parkway, Suite 750
`Plano, Texas 75024
`(972) 731-2288 (Telephone)
`(972) 731-2289 (Facsimile)
`
`57562 v3/4137.o4700
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`
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`EXHIBIT 1005(B)
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`
`
`GSK Exhibit 1005 - Page 21 of 342
`
`

`

`Atty Docket: PAC/20632 US (4131-04700)
`
`Pate11t
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicants: Amar Lulla, et al.
`
`Serial No.:
`
`10/518,016
`
`Filed:
`
`July 6, 2005
`
`For: COMBINATION OF AZELASTINE AND
`STEROIDS
`
`§
`§
`§
`§
`§
`§
`§
`§
`
`Group Art Unit:
`
`1616
`
`Examiner: Kristie Latrice Brooks
`
`Confirmation No.: 4912
`
`DECLARATION UNDER37 CFR § 1.132
`
`I, Geena Malhotra, hereby declare and say that:
`
`1.
`
`I am a co-inventor of the invention claimed in the above-identified patent application.
`
`2.
`
`Attached as Exhibit A is comparison data for five compositions:
`
`Column 1: Azelastine.HCI
`Column 2: Budesonide
`Column 3: Azelastine.HCI & Budesonide
`Column 4: Fluticasone Propionate
`Column 5: Azelastine.HCI and Fluticasone Propionate
`
`Table I of Exhibit A sets for the ingredient list for the five compositions. Table II of Exhibit A
`
`sets forth comparative stability data for the five compositions. The results in Table II show the
`
`impurity levels in the initial