Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 1 of 63 PageID #: 397
`Case 1:14—cv—O1453—LPS Document 43-6 Filed 10/22/15 Page 1 of 63 Page|D #: 397
`
`
`
`EXHIBIT 11
`
`EXHIBIT 11
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 2 of 63 PageID #: 398
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Ofiice
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 223l3- 1450
`VVV/W.l]Sp[0.g0V
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO.
`
`CONFIRMATION NO.
`
`10/518.016
`
`07/06/2005
`
`Amar Lulla
`
`30652
`7590
`comm ROSE, pc.
`5601 GRANITE PARKWAY, SUITE 750
`PLANO, TX 75024
`
`04/23/2010
`
`PAC/20632 US
`(4137—04700)
`
`4912
`
`BROOKS» KRISTIE LATRICE
`ART UNIT
`PAPER NUMBER
`
`1616
`
`MAIL DATE
`
`04/28/2010
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL—90A (Rev. 04/07)
`
`M ED_DYM_0O000577
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 3 of 63 PageID #: 399
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 3 of 63 PagelD #: 399
`Application No.
`Applicant(s)
`
`Office Action Summary
`
`10/518,016
`LULLA ET AL.
`
`Examine,
`Art Unit
`KRISTIE L. BROOKS
`1616
`
`-- The MAILING DA TE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE Q MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`- Extensions of time may be available under the provisions of 37 CFR 1.136(a).
`In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`lf NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`-
`- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`Status
`
`HE Responsive to communication(s) filed on 23 July 2009.
`
`2a)IZ] This action is FINAL.
`
`2b)l:I This action is non-final.
`
`3)I:] Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`Disposition of Claims
`
`4)E C|aim(s) 1 2 4 6-22 25-30 35-38 44 45 and 53-56 is/are pending in the application.
`
`4a) Of the above claim(s)
`
`is/are withdrawn from consideration.
`
`5)I:I C|aim(s)j is/are allowed.
`
`6)lZ C|aim(s) 1 2 4 6-22 25-30 35-38 44 45 and 53-56 is/are rejected.
`
`7)I:] C|aim(s)j is/are objected to.
`
`8)I:I C|aim(s)j are subject to restriction and/or election requirement.
`
`Application Papers
`
`9)I:I The specification is objected to by the Examiner.
`
`10)E] The drawing(s) filed on j is/are: a)l:I accepted or b)[:I objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d).
`
`11)I:I The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
`
`Priority under 35 U.S.C. § 119
`
`12)Ij Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`
`a)EI All b)D Some * c)E] None of:
`
`1.I:I Certified copies of the priority documents have been received.
`
`2.[:I Certified copies of the priority documents have been received in Application No. T
`
`3.l:I Copies of the certified copies of the priority documents have been received in this National Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`
`* See the attached detailed Office action for a list of the certified copies not received.
`
`Attach ment(s)
`
`1) E Notice of References Cited (PTO-892)
`2) El Notice of Draftsperson‘s Patent Drawing Review (PTO-948)
`3) IZI Information Disclosure Statement(s) (PTOISB/O8)
`
`Paper No(s)/Mail Date 7/23/09'8/7/09.
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 08-06)
`
`Office Action Summary
`
`4) El Interview Summary (PTO-413)
`Paper N0(S)/M8“ Data j
`5) I:I Notice of Informal Patent Application
`6) El Other: j.
`
`Part of Paper No./Mail Date 20091029
`
`M ED_DYM_0O000578
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 4 of 63 PageID #: 400
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 4 of 63 PagelD #: 400
`
`Application/Control Number: 10/518,016
`
`Page 2
`
`Art Unit: 1616
`
`DETAILED ACTION
`
`Status of Application
`
`1.
`
`Claims 1, 2, 4, 6-22, 25-30, 35-38, 44-45 and 53-56 are pending. Claims
`
`53—56 are new.
`
`2.
`
`Receipt and consideration of Applicants remarks/arguments submitted on
`
`July 23, 2009 is acknowledged.
`
`3.
`
`Rejections not reiterated from the previous Office Action are hereby
`
`withdrawn. The following rejections are either reiterated or newly applied. They
`
`constitute the complete set of rejections presently being applied to the instant
`
`application.
`
`Claim Rejections - 35 USC § 103
`
`4.
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for
`
`all obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described
`as set forth in section 102 of this title, if the differences between the subject matter sought to
`be patented and the prior art are such that the subject matter as a whole would have been
`obvious at the time the invention was made to a person having ordinary skill in the art to which
`said subject matter pertains. Patentability shall not be negatived by the manner in which the
`invention was made.
`
`The 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.
`
`M ED_DYM_0O000579
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 5 of 63 PageID #: 401
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 5 of 63 PagelD #: 401
`
`Application/Control Number: 10/518,016
`
`Page 3
`
`Art Unit: 1616
`
`4.
`
`Considering objective evidence present in the application indicating
`obviousness or nonobviousness.
`
`5.
`
`Claims 1-2, 4, 7-21, 30, 35-38, 44-45, and 53-56 are rejected under
`
`U.S.C. 103(a) as being unpatentable over Cramer (EP 0780127).
`
`Applicant claims a pharmaceutical formulation which comprises
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically
`
`functional derivative thereof and fluticasone, or a pharmaceutically acceptable
`
`ester thereof, wherein fluticasone or a pharmaceutically acceptable ester thereof
`
`in an amount from about 50micrograms/ml to about 5mg/ml of the formulation.
`
`Determination of the scope and content of the prior art (MPEP 2141.01)
`
`Cramer teaches a nasal spray composition comprising about 0.001 to
`
`about 0.2% concentration of a glucocorticosteroid (i.e. beclomethasone,
`
`flunisolide, triamcinolone, fluticasone, mometasone, bedusonide and
`
`pharmaceutically acceptable salts), 0.01 to about 4% concentration of an
`
`antihistamine (i.e. azelastine or pharmaceutically acceptable salt thereof, and an
`
`intranasal carrier (see the abstract and page 2 lines 36-45). The composition
`
`may contain isotonic agents such as citric acid, boric acid, propylene glycol, etc.,
`
`thickening agents such as xanthan gum, microcrystalline cellulose,
`
`carboxymethyl cellulose, hydroxypropyl cellulose, etc., humectants such as
`
`sorbitol, propylene glycol, polyethylene glycol, etc. and preservatives such as
`
`M ED_DYM_0O000580
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 6 of 63 PageID #: 402
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 6 of 63 PagelD #: 402
`
`Application/Control Number: 10/518,016
`
`Page 4
`
`Art Unit: 1616
`
`benzyl alcohol, phenylethyl alcohol, and quaternary ammoniums such as
`
`benzalkonium chloride (see page 4 lines 50-58 and page 5 lines 1-22). The
`
`composition may contain surfactants such as Polysorbate 80, Octoxynol, etc.
`
`(see page 5 lines 11-16). The pH of the composition is from about 4.5 to about 9
`
`(see page 2 lines 57-58). The composition may be formulated into a nasal
`
`solution (for use as drops or a spray), a nasal suspension, ointment, or gel (see
`
`page 3 lines 43-47). Typically the dosage units may be prepared to deliver
`
`0.5mcg to about 100mcg of the glucocorticoid and 5mcg to about 1000mcg of the
`
`antihistamine spray (see page 3 lines 58 and page 4 lines 1-2).
`
`Example Ill discloses an intranasal pharmaceutical composition prepared by
`
`combining the following components utilizing conventional mixing techniques,
`
`shown below:
`
`
`
`2s~:=§:S
`
`(see page 6, Example lll).
`
`Ascertainment of the difference between the prior art and the claims (MPEP
`
`2141.02)
`
`Cramer does not exemplify a composition comprising azelastine and
`
`fluticasone.
`
`M ED_DYM_0O000581
`
`
`
`Smflmirmkxw amtmids
`L§.$§.§
`
`
`a§;€4§t2'i:>3§:m’3 HES’
`g pmyssrtxataw
`§
`3.9;;-.a'.:«i§x‘.a'n
`hj<pC§r§)i(:y1:\{<:<g;‘§3 m£:£h;)§IE$§l$31.s:iQ:‘~§
`
`§
`E
`€i5§xx,~:.€l:s°.t£t\~’:Fi:§\2‘$‘?§ii‘1$t;~:\tI‘§ms‘:_t!$=s::
`E
`§1€i>‘\,.~‘,:\‘:*F$i‘.‘<>‘I:§£.irEi=53§‘£§Ck:“étk*
`E
`
`
`§ 2;... tcs.§iKSE§§t3i‘i mew ..
`
`
`:*.§}~{t{§
`‘i.$~i?-‘.‘>
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 7 of 63 PageID #: 403
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 7 of 63 PagelD #: 403
`
`Application/Control Number: 10/518016
`
`Page 5
`
`Art Unit: 1616
`
`Finding of prima facie obviousness Rational and Motivation (MPEP
`
`2142-2143)
`
`However, 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 glucocorticoid (i.e. fluticasone) and an
`
`antihistamine (i.e. azelastine) provide improved relief of symptoms associated
`
`with seasonal or perennial allergic rhinoconjunctivitis.
`
`Thus, it would have been obvious to one of ordinary skill in the art at the
`
`time the claimed invention was made to make a composition comprising
`
`azelastine and fluticasone for the purpose of providing intranasal compositions
`
`with improved effectiveness in the treatment of seasonal or perennial allergic
`
`rhinoconjunctivitis.
`
`Although Cramer does not specifically teach the instantly claimed ester (or
`
`salt) forms of fluticasone (i.e. fluticasone valerate or fluticasone propionate),
`
`Cramer suggest that fluticasone can be present in a pharmaceutically acceptable
`
`salt form. It would have been obvious to one of ordinary skill in the art to utilize
`
`fluticasone in any pharmaceutically acceptable salt form that would be
`
`therapeutically beneficial to fluticasone. Further, it is known in the art that
`
`pharmaceutically acceptable salt forms can include hydrochloride, propionate,
`
`valerate salt, etc. (as evidenced by Link et al. US 6,583,180, see column 183
`
`lines 38-67).
`
`M ED_DYM_0O000582
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 8 of 63 PageID #: 404
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 8 of 63 PagelD #: 404
`
`Application/Control Number: 10/518,016
`
`Page 6
`
`Art Unit: 1616
`
`Therefore, 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.
`
`7.
`
`Claims 22 and 26-27 are rejected under U.S.C. 103(a) as being
`
`unpatentable over Cramer (EP 0780127) in view of Modi (US 6,294,153).
`
`Applicant claims a pharmaceutical formulation which comprises
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically
`
`functional derivative thereof and fluticasone, or a pharmaceutically acceptable
`
`ester thereof, wherein fluticasone or a pharmaceutically acceptable ester thereof
`
`in an amount from about 50micrograms/ml to about 5mg/ml of the formulation.
`
`Determination of the scope and content of the prior art (MPEP 2141.01)
`
`Cramer teaches a nasal spray composition comprising about 0.001 to
`
`about 0.2% concentration of a glucocorticosteroid (i.e. beclomethasone,
`
`flunisolide, triamcinolone, fluticasone, mometasone, bedusonide and
`
`pharmaceutically acceptable salts), 0.01 to about 4% concentration of an
`
`antihistamine (i.e. azelastine or pharmaceutically acceptable salt thereof, and an
`
`intranasal carrier (see the abstract and page 2 lines 36-45). The composition
`
`may contain isotonic agents such as citric acid, boric acid, propylene glycol, etc.,
`
`thickening agents such as xanthan gum, microcrystalline cellulose,
`
`M ED_DYM_0O000583
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 9 of 63 PageID #: 405
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 9 of 63 PagelD #: 405
`
`Application/Control Number: 10/518,016
`
`Page 7
`
`Art Unit: 1616
`
`carboxymethyl cellulose, hydroxypropyl cellulose, etc., humectants such as
`
`sorbitol, propylene glycol, polyethylene glycol, etc. and preservatives such as
`
`benzyl alcohol, phenylethyl alcohol, and quaternary ammoniums such as
`
`benzalkonium chloride (see page 4 lines 50-58 and page 5 lines 1-22). The
`
`composition may contain surfactants such as Polysorbate 80, Octoxynol, etc.
`
`(see page 5 lines 11-16). The pH of the composition is from about 4.5 to about 9
`
`(see page 2 lines 57-58). The composition may be formulated into a nasal
`
`solution (for use as drops or a spray), a nasal suspension, ointment, or gel (see
`
`page 3 lines 43-47). Typically the dosage units may be prepared to deliver
`
`0.5mcg to about 100mcg of the glucocorticoid and 5mcg to about 1000mcg of the
`
`antihistamine spray (see page 3 lines 58 and page 4 lines 1-2).
`
`Example Ill discloses an intranasal pharmaceutical composition prepared by
`
`combining the following components utilizing conventional mixing techniques,
`
`shown below:
`
`
`
`
`
`aateztmisfia
`+3.z+3ia::§tm M.£;¢§
`
`
`;2cxya::sz2a,sza
`3
`§ giytstefin
`8’7‘u.€5Ef‘I~‘_.I'|E:Tt3l§L:El<‘;\<$&%
`t132\:5.{€.3?-:§°;:u‘e:35‘.S¥§
`s:§'i:5c:si:!§s:t
`séhyflsnaflimmiw l.~§Il¥$.Q33>‘.f&EEi:;
`
`;
`§
`
`u
`E X "
`E
`
`(see page 6, Example Ill).
`
`uimzsa wasiar
`
`Ascertainment of the difference between the prior art and the claims (MPEP
`
`2141.02)
`
`M ED_DYM_0O000584
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 10 of 63 PageID #: 406
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 10 of 63 PagelD #: 406
`
`Application/Control Number: 10/518,016
`
`Page 8
`
`Art Unit: 1616
`
`Cramer does not exemplify a nasal composition further comprising a
`
`propellant. This deficiency is cured by the teachings of Modi.
`
`Modi teaches aerosol formulations for nasal delivery comprising
`
`pharmaceutical agents (i.e. anti-inflammatories, steroids, etc.), water, excipients
`
`and a propellant (see the abstract and column 3 lines 30-40). Improved
`
`penetration and absorption of the formulations can be achieved by mixing the
`
`formulation with propellants such as tetrafluroethane, etc., especially when
`
`delivered through aerosol devices (i.e. MDI). (see column 2 lines 5-24).
`
`Finding of prima facie obviousness Rational and Motivation (MPEP
`
`2142-2143)
`
`One of ordinary skill in the art would have been motivated to make a
`
`composition further comprising a propellant because Modi suggests that adding
`
`propellants to nasal formulations can increase penetration and absorption in the
`
`nasalcavny.
`
`Thus, it would have been obvious to one of ordinary skill in the art at the
`
`time the claimed invention was made to make a composition further comprising a
`
`propellant for the purpose of increasing penetration of active formulations into the
`
`nasalcavhy.
`
`Therefore, 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.
`
`M ED_DYM_0O000585
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 11 of 63 PageID #: 407
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 11 of 63 PagelD #: 407
`
`Application/Control Number: 10/518,016
`
`Page 9
`
`Art Unit: 1616
`
`8.
`
`Claims 1-2 and 6 are rejected under U.S.C. 103(a) as being unpatentable
`
`over Cramer (EP 0780127) in view of Fassberg et al. (US 6,416,743).
`
`Applicant claims a pharmaceutical formulation which comprises
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically
`
`functional derivative thereof and fluticasone, or a pharmaceutically acceptable
`
`ester thereof, wherein fluticasone or a pharmaceutically acceptable ester thereof
`
`in an amount from about 50micrograms/ml to about 5mg/ml of the formulation.
`
`Determination of the scope and content of the prior art (MPEP 2141.01)
`
`Cramer teaches a nasal spray composition comprising about 0.001 to
`
`about 0.2% concentration of a glucocorticosteroid (i.e. beclomethasone,
`
`flunisolide, triamcinolone, fluticasone, mometasone, bedusonide and
`
`pharmaceutically acceptable salts), 0.01 to about 4% concentration of an
`
`antihistamine (i.e. azelastine or pharmaceutically acceptable salt thereof, and an
`
`intranasal carrier (see the abstract and page 2 lines 36-45). The composition
`
`may contain isotonic agents such as citric acid, boric acid, propylene glycol, etc.,
`
`thickening agents such as xanthan gum, microcrystalline cellulose,
`
`carboxymethyl cellulose, hydroxypropyl cellulose, etc., humectants such as
`
`sorbitol, propylene glycol, polyethylene glycol, etc. and preservatives such as
`
`benzyl alcohol, phenylethyl alcohol, and quaternary ammoniums such as
`
`benzalkonium chloride (see page 4 lines 50-58 and page 5 lines 1-22). The pH of
`
`M ED_DYM_0O000586
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 12 of 63 PageID #: 408
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 12 of 63 PagelD #: 408
`
`Application/Control Number: 10/518,016
`
`Page 10
`
`Art Unit: 1616
`
`the composition is from about 4.5 to about 9 (see page 2 lines 57-58). The
`
`composition may be formulated into a nasal solution (for use as drops or a
`
`spray), a nasal suspension, ointment, or gel (see page 3 lines 43-47). Typically
`
`the dosage units may be prepared to deliver 0.5mcg to about 100mcg of the
`
`glucocorticoid and 5mcg to about 1000mcg of the antihistamine spray (see page
`
`3 lines 58 and page 4 lines 1-2).
`
`Example Ill discloses an intranasal pharmaceutical composition prepared by
`
`combining the following components utilizing conventional mixing techniques,
`
`shown below:
`
`.!;;,,
`
`C.
`
`
`_fi§i.f‘rx.*~$rsar;>é‘cm2 amtmids
`
`.-2:2
`
`azetazsms
`
`§ cs.r-so
`3 gamsmsarnzasass
`E 3.e:,\:*.;‘
`§ §?‘s=‘i>§fit‘i
`Ir15a‘ds'<>:x§-2:«:»:<g:~,:§ rmthz_:I;:sl§n;1mw g UIQSF
`§
`ethytenmizgmineletrsssetse e~:;\:S §
`E:-3'~‘.3¥,‘YET.i‘\:. as-ténrti.
`E
`i1§’$.E§§3€3 water
`§ cm. tcwsxi.
`
`4§
`
`(see page 6, Example Ill).
`
`
`
`9
`
`1
`
`
`
`
`
`Ascertainment of the difference between the prior art and the claims (MPEP
`
`2141.02)
`
`Cramer et al. do not teach the instantly claimed formulation comprising
`
`azelastine and fluticasone with a particle size of less than 10pm. This deficiency
`
`is cured by the teachings of Fassberg et al.
`
`Fassberg et al. teach aerosol formulations for nasal administration
`
`comprising 1,1,1,2 tetrafluoroethane and a medicament (see the abstract and
`
`column 3 lines 2-7). Examples of the medicaments include antihistamines and
`
`M ED_DYM_0O000587
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 13 of 63 PageID #: 409
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 13 of 63 PagelD #: 409
`
`Application/Control Number: 10/518,016
`
`Page 11
`
`Art Unit: 1616
`
`steroids (see column 5 lines 61-66). The particle size of the active compound
`
`ranges from 0.1—25pm (see column 6 lines 11-15). The formulation may
`
`optionally contain an excipient or surfactant (see the abstract).
`
`Finding of prima facie obviousness Rational and Motivation
`
`(MPEP 2142-2143)
`
`One of ordinary skill in the art would have been motivated to make a
`
`composition comprising azelastine and fluticasone with a particle size of less
`
`than 10pm because Fassberg et al. nasal compositions comprising
`
`antihistamines (e.g. azelastine) or steroids (e.g. fluticasone) can be prepared
`
`with a particle size ranging from 0.1-25pm, which overlaps with the instantly
`
`claimed particle size of less than 10pm.
`
`Thus, it would have been obvious to one of ordinary skill in the art at the
`
`time the claimed invention was made to make a composition with the instantly
`
`claimed particle size range because it is an obvious variation of particle sizes that
`
`can be used in the preparation of nasal formulations.
`
`Therefore, 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.
`
`9.
`
`Claims 1, 25, 28-29 are rejected under U.S.C. 103(a) as being
`
`unpatentable over Cramer (EP 0780127) in view of Alfonso et al. (US 6,017,963).
`
`M ED_DYM_0O000588
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`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 14 of 63 PageID #: 410
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 14 of 63 PagelD #: 410
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`Application/Control Number: 10/518,016
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`Page 12
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`Art Unit: 1616
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`Applicant claims a pharmaceutical formulation which comprises
`
`azelastine, or a pharmaceutically acceptable salt, solvate or physiologically
`
`functional derivative thereof and fluticasone, or a pharmaceutically acceptable
`
`ester thereof, wherein fluticasone or a pharmaceutically acceptable ester thereof
`
`in an amount from about 50micrograms/ml to about 5mg/ml of the formulation.
`
`Determination of the scope and content of the prior art (MPEP 2141.01)
`
`Cramer teaches a nasal spray composition comprising about 0.001 to
`
`about 0.2% concentration of a glucocorticosteroid (i.e. beclomethasone,
`
`flunisolide, triamcinolone, fluticasone, mometasone, bedusonide and
`
`pharmaceutically acceptable salts), 0.01 to about 4% concentration of an
`
`antihistamine (i.e. azelastine or pharmaceutically acceptable salt thereof, and an
`
`intranasal carrier (see the abstract and page 2 lines 36-45). The composition
`
`may contain isotonic agents such as citric acid, boric acid, propylene glycol, etc.,
`
`thickening agents such as xanthan gum, microcrystalline cellulose,
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`carboxymethyl cellulose, hydroxypropyl cellulose, etc., humectants such as
`
`sorbitol, propylene glycol, polyethylene glycol, etc. and preservatives such as
`
`benzyl alcohol, phenylethyl alcohol, and quaternary ammoniums such as
`
`benzalkonium chloride (see page 4 lines 50-58 and page 5 lines 1-22). The pH of
`
`the composition is from about 4.5 to about 9 (see page 2 lines 57-58). The
`
`composition may be formulated into a nasal solution (for use as drops or a
`
`spray), a nasal suspension, ointment, or gel (see page 3 lines 43-47). Typically
`
`M ED_DYM_0O000589
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 15 of 63 PageID #: 411
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 15 of 63 PagelD #: 411
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`Application/Control Number: 10/518,016
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`Page 13
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`Art Unit: 1616
`
`the dosage units may be prepared to deliver O.5mcg to about 100mcg of the
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`glucocorticoid and 5mcg to about 1000mcg of the antihistamine spray (see page
`
`3 lines 58 and page 4 lines 1-2).
`
`Example Ill discloses an intranasal pharmaceutical composition prepared by
`
`combining the following components utilizing conventional mixing techniques,
`
`shown below:
`
`
`
`I
`
`(see page 6, Example Ill).
`
`..
`
`.
`
`km‘
`
`‘L}.f_i~'\."
`
`t
`§
`
`EE
`
`§
`
`§
`
`am=tmi'z:§a
`
`
`
`.~.aa+:-h.3:a:2m.
`
`§:¢¥a‘{.-':éi..‘-é‘3.>.£:E'::‘d:
`,
`_.
`=
`g giwaenfi
`F“i*,«I’4i$'~?.$9£f;*§T.i*!Q:‘i5‘,~*§ rn.a:.'h~_.rIs »-::‘al§:.~sI<;\e‘ws
`
`ethyésnecimnimlezlmazesw
`rszsm-zeskzmiursa. csrsfixlfiss
`c1%'e:§§aec1 crease;
`
`Ascertainment of the difference between the prior art and the claims (MPEP
`
`Cramer does not teach the instant formulation in the form of an insufflation
`
`2141.02)
`
`powder. This deficiency is cured by the teachings of Alfonso et al.
`
`Alfonso et al. teaches intranasal and/or inhalation administration of
`
`pharmaceutical agents (see the abstract). The dosage form suitable for
`
`intranasal and/or inhalation administration can be in the form of a liquid solution
`
`suspension, insufflation powder, etc. for administration as a nasal spray, drop or
`
`inhaled fine particles (i.e. insuflation) (see column 3 lines 1-65, column 5 lines
`
`36-45, and column 7 lines 1-26).
`
`M ED_DYM_0O000590
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 16 of 63 PageID #: 412
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 16 of 63 PagelD #: 412
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`Application/Control Number: 10/518,016
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`Page 14
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`Art Unit: 1616
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`Finding of prima facie obviousness Rational and Motivation (MPEP
`
`2142-2143)
`
`One of ordinary skill in the art would have been motivated to make the
`
`instant composition in the form of an insufflation powder because Alfonso et al.
`
`suggest the nasal compositions in the form of a spray, droplet, insufflation
`
`powder, etc.
`
`Thus, it would have been obvious to one of ordinary skill in the art at the
`
`time the claimed invention was made to make the instant composition in the form
`
`of an insufflation powder because it is an obvious variation of ways to administer
`
`a nasal composition, as suggested Alfonso et al.
`
`Therefore, 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.
`
`Response to Arguments
`
`Applicant's arguments filed August 7, 2009 have been fully considered but
`
`they are not persuasive.
`
`Applicant argues that Cramer is not fairly suggestive of the instantly
`
`claimed combination and that the particular combination instantly claimed is not
`
`explicitly mentioned.
`
`This argument is not persuasive. Cramer specifically teaches a nasal
`
`spray comprising the combination of a glucocorticoid (i.e. fluticasone) and an
`
`antihistamine (i.e. azelastine). There are a limited number of glucocorticoids (six)
`
`M ED_DYM_0O000591
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 17 of 63 PageID #: 413
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 17 of 63 PagelD #: 413
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`Application/Control Number: 10/518,016
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`Page 15
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`Art Unit: 1616
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`and antihistamines (three) recited. It is well within the means for one of ordinary
`
`skill in the art to try the instant combination as there are a small number of
`
`actives to choose from. Furthermore, disclosed examples and preferred
`
`embodiments do not constitute a teaching away from a broader disclosure or
`
`nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA
`
`1971).
`
`Next, Applicant argues that the combination of azelastine and fluticasone
`
`display unexpected beneficial results. Applicant provides a 1.132 declaration,
`
`submitted on July 23, 2009, as evidence of the superior combination.
`
`1.132 Declaration
`
`The declaration provided by Applicant provides a table (Table I) that
`
`discloses five compositions, i.e. budesonide alone, azelastine alone, azelastine
`
`and budesonide, fluticasone alone, and azelastine and fluticasone. The table
`
`also lists the ingredients or excipients added to each composition.
`
`Table II compares the stability of each composition by disclosing the total
`
`impurity level of the composition, at the beginning of testing, after one month,
`
`and after three months of storage. The impurity level for the composition
`
`comprising azelastine and fluticasone appears to remain low and consistently
`
`stable throughout the testing period when compared to the composition
`
`comprising azelastine and budesonide.
`
`M ED_DYM_0O000592
`
`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 18 of 63 PageID #: 414
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 18 of 63 PagelD #: 414
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`Application/Control Number: 10/518,016
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`Page 16
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`Art Unit: 1616
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`However, this data is not persuasive. First, Applicant has not described
`
`what testing method was used, what assay was utilized, and how the impurity
`
`level was calculated.
`
`Second, Applicant has not described what the impurity is. It is unclear if
`
`the impurity arises from the active, excipients, formulations, etc.
`
`Third, Applicant did not test against the closest prior art examples,
`
`described in Cramer (see Example 3). Example 3 in Cramer discloses a
`
`composition comprising azelastine and triamcinolone.
`
`Last, it should be noted in Table I, that the instant composition comprising
`
`azelastine and fluticasone contains phenylethyl alcohol (a preservative]
`
`antibacterial), whereas the composition comprising azelastine and budesonide
`
`does not. It is well known in the art that a preservative is added to composition to
`
`prevent decomposition of a substance and to destroy or inhibit multiplication of
`
`microorganisms, which also causes decomposition (as evidence by Dorland’s
`
`Medical Dictionary, Mosby’s Medical Dictionary, and American Heritage Medical
`
`Dictionary, see 892 form). It is further known that a preservative increases the
`
`shelf life of compositions (as evidenced by Cramer page 5 lines 16-18).
`
`Applicant is predicating its unexpected results of the instant formulation by
`
`measuring the level of impurity in the formulations when compared compositions
`
`with similar actives. However, an extremely critical element is missing from the
`
`comparative composition. It is neither unexpected nor surprising that a
`
`composition comprising an additional preservative would be capable of keeping
`
`M ED_DYM_0O000593
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`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 19 of 63 PageID #: 415
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 19 of 63 PagelD #: 415
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`Application/Control Number: 10/518,016
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`Page 17
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`Art Unit: 1616
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`impurity levels lower and increasing shelf life when compared to a composition
`
`that does not contain the preservative or a lesser amount of preservative.
`
`Applicant also provided a compilation of statements from 6 medical
`
`practitioners that attest to the various advantages and superior results associated
`
`with the use of the instant invention. Applicant further argues that there is a long
`
`felt need for an improved nasal formulation and that the instant composition,
`
`known as DUONASE, is a commercial success.
`
`However, given the deficiencies in the data provided by Applicant, one of
`
`ordinary skill in the art cannot accurately ascertain whether any unexpected
`
`results have occurred.
`
`Therefore, Applicant's arguments and evidence of nonobviousness are not
`
`persuasive.
`
`Conclusion
`
`10.
`
`Applicant's amendment necessitated the new ground(s) of rejection
`
`presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL.
`
`See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as
`
`set forth in 37 CFR1.136(a).
`
`A shortened statutory period for reply to this final action is set to expire
`
`THREE MONTHS from the mailing date of this action.
`
`In the event a first reply is
`
`filed within TWO MONTHS of the mailing date of this final action and the advisory
`
`action is not mailed until after the end of the THREE-MONTH shortened statutory
`
`M ED_DYM_0O000594
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`

`
`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15 Page 20 of 63 PageID #: 416
`Case 1:14—cv—01453—LPS Document 43-6 Filed 10/22/15 Page 20 of 63 PagelD #: 416
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`Application/Control Number: 10/518016
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`Page 18
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`Art Unit: 1616
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`period, then the shortened statutory period will expire on the date the advisory
`
`action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be
`
`calculated from the mailing date of the advisory action.
`
`In no event, however, will
`
`the statutory period for reply expire later than SIX MONTHS from the date of this
`
`final action.
`
`Any inquiry concerning this communication or earlier communications from
`
`the examiner should be directed to KRISTIE L. BROOKS whose telephone
`
`number is (571)272-9072. The examiner can normally be reached on M-F
`
`8:30am-6:00pm Est..
`
`If attempts to reach the examiner by telephone are unsuccessful, the
`
`examiner’s supervisor, Johann R. Richter can be reached on (571) 272-0646.
`
`The fax phone number for the organization where this application or proceeding
`
`is assigned is 571-273-8300.
`
`M ED_DYM_0O000595
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`

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`Case 1:14-cv-01453-LPS Document 43-6 Filed 10/22/15