`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`CIPLA LTD.
`Patent Owner
`
`Patent No. 8,168,620
`Issue Date: May 1, 2012
`Title: COMBINATION OF AZELASTINE AND STEROIDS
`
`Inter Partes Review No.: IPR2017-00803
`
`DECLARATION OF DR. MAUREEN D. DONOVAN, Ph.D.
`
`Exhibit 1004
`IPR2017-00807
`ARGENTUM
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`000001
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
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`TABLE OF CONTENTS
`Introduction ....................................................................................................... 1
`I.
`My Background And Qualifications ................................................................. 1
`I.
`The Basis For My Opinion ............................................................................... 2
`II.
`Summary of Opinions ....................................................................................... 4
`III.
`Person Of Ordinary Skill In The Art ................................................................ 5
`IV.
`V.
`The ‘620 Patent ................................................................................................. 6
`Technical Background ...................................................................................... 7
`VI.
`VII. Prior Art ............................................................................................................ 8
`A. Astelin® Label ....................................................................................... 8
`Hettche .................................................................................................... 9
`B.
`C.
`Flonase® Label .................................................................................... 12
`Phillipps Patent ..................................................................................... 13
`D.
`VIII. The co-formulation of fluticasone propionate and azelastine would have been
`obvious to a skilled formulator in the art ........................................................ 14
`A. Nasal formulation comprising azelastine or a pharmaceutically
`acceptable salt and a pharmaceutically acceptable ester of fluticasone
` .............................................................................................................. 16
`B. Microfine particle size .......................................................................... 16
`C.
`Concentrations of azelastine and fluticasone propionate ..................... 17
`D. Nasal spray ........................................................................................... 19
`E.
`Edetate disodium, benzalkonium chloride, and phenylethyl alcohol .. 21
`Glycerine .............................................................................................. 23
`F.
`G. Microcrystalline cellulose and sodium carboxymethyl cellulose ........ 24
`H.
`Polysorbate 80 ...................................................................................... 25
`Purified water ....................................................................................... 26
`I.
`Reasonable expectation of success ....................................................... 27
`J.
`IX. Cramer Example III is not inoperable ............................................................ 29
`X.
`Conclusion ...................................................................................................... 34
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`I, Maureen Donovan, do declare as follows:
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`
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`I.
`
`Introduction
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`1.
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`I am over the age of eighteen (18) and otherwise competent to make this
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`declaration.
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`2.
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`I have been retained as an expert witness on behalf of Argentum
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`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No.
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`8,168,620 (Ex. 1001). I am being compensated for my time in connection with
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`this IPR at my standard consulting rate, which is $400 per hour for any
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`consulting and $600 per hour for any deposition appearances. I understand that
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`my declaration accompanies a petition for inter partes review involving the
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`above-mentioned U.S. Patent.
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`I.
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`My Background And Qualifications
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`3. My area of expertise is in the field of pharmaceuticals and nasal
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`formulations. At University of Iowa’s College of Pharmacy, I am presently a
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`Professor in the Department of Pharmaceutical Sciences and Experimental
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`Therapeutics within the Division of Pharmaceutics and Translational Therapeutics. I
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`am also the Associate Dean for Undergraduate Education.
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`4. My research areas include the development and evaluation of novel
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`drug delivery systems for mucosal drug delivery especially via the nasal,
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`gastrointestinal and vaginal epithelia. I also study the mechanisms of drug
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`absorption and disposition.
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`5.
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`I obtained a Bachelor of Science in Pharmacy from University of
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`Minnesota in 1983 and a Ph.D. in Pharmaceutics from the University of Michigan in
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`1989.
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`6. My curriculum vitae is attached as Ex. 1052 to this document.
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`7.
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`In view of my experiences and expertise outlined above and provided in
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`my curriculum vitae, I am an expert in the field of pharmaceuticals and nasal
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`formulations.
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`II.
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`The Basis For My Opinion
`
`8.
`
`In formulating my opinion, I considered the following documents:
`
`Exhibit Name
`Ex. #
`1001 U.S. Patent No. 8,168,620 (“’620 patent”)
`1002 Prosecution History of U.S. Patent No. 8,168,620
`1006 UK Patent Application GB 0213739.6
`1007 U.S. Patent No. 5,164,194 (“Hettche”)
`1008 Astelin® Label (rev. 2000)
`1009 U.S. Patent No. 4,335,121 (“Phillipps”)
`1010 Flonase® Label (rev. 1998)
`1011 European Patent Application No. 0780127 (“Cramer”)
`1012 PCT Publication No. WO 98/48839 to Segal (“Segal”)
`1013 British Pharmaceutical Codex (1973)
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`2
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`000004
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`1014 U.S. Patent Publication No. 20040136918 (“Garrett”)
`1027 Ansel, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,
`ch. 7 (6th ed. 1995)
`1033 Wade & Weller, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (1994)
`1046
`IMITREX Prescribing Information (2013)
`
`1048 Rabago, David, et al., “Efficacy of daily hypertonic saline nasal
`irrigation among patients with sinusitis: A randomized controlled trial,”
`The Journal of Family Practice, Vol. 51, No. 12, 1049-1055 (2002)
`1049 Budavari, S., et al. (Ed), “Edetate Disodium,” The Merck Index,
`Eleventh Edition, 550 (1989)
`
`1054
`
`“Avicel® RC-591 Microcrystalline Cellulose and
`Carboxymethylcellulose Sodium, NF, BP,” FMC Corporation (1994)
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`9.
`
`I understand that an obviousness analysis involves comparing a claim to
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`the prior art to determine whether the claimed invention would have been obvious to
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`a person of ordinary skill in the art (POSA) in view of the prior art, and in light of
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`the general knowledge in the art. I also understand that when a POSA would have
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`reached the claimed invention through routine experimentation, the invention may be
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`deemed obvious. I understand that a finding of obviousness for a specific range or
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`ratio in a patent can be overcome if the claimed range or ratio is proven to be critical
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`to the performance or use of the claimed invention.
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`10.
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`I also understand that obviousness can be established by combining or
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`modifying the teachings of the prior art to achieve the claimed invention. It is also
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`my understanding that where there is a reason to modify or combine the prior art to
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`achieve the claimed invention, there must also be a reasonable expectation of success
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`in so doing. I understand that the reason to combine prior art references can come
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`from a variety of sources, not just the prior art itself or the specific problem the
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`patentee was trying to solve. And I understand that the references themselves need
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`not provide a specific hint or suggestion of the alteration needed to arrive at the
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`claimed invention; the analysis may include recourse to logic, judgment, and
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`common sense available to a person of ordinary skill that does not necessarily
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`require explication in any reference.
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`11.
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`I understand that when considering the obviousness of an invention, one
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`should also consider whether there are any secondary considerations that support the
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`nonobviousness of the invention. However, I offer no opinion on secondary
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`considerations as I understand from counsel that another expert has been retained to
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`opine on such matters.
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`III.
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`Summary of Opinions
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`12. Based on my investigation and analysis and for the reasons set forth
`below, it is my opinion that claims 1, 4-6, 24-26, and 29 of the ’620 patent would
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`have been obvious to one of ordinary skill in the art at the time of the alleged
`
`invention in view of the combined teachings of U.S. Patent No. 5,164,194
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`(“Hettche”), U.S. Patent No. 4,335,121 (“Phillipps”), and PCT Publication No. WO
`4
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`98/48839 (“Segal”).
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`13.
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`In addition, it is my opinion that claims 42-44 would have been obvious
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`to one of ordinary skill in the art at the time of the alleged invention in view of
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`Hettche, Phillipps, the Flonase® Label, and Segal.
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`IV.
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`Person Of Ordinary Skill In The Art
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`14.
`
`I understand that as of June 14, 2002, a hypothetical POSA would “be
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`aware of all the pertinent prior art” at the time of the alleged invention. For the
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`purposes of this analysis, a hypothetical POSA would be part of a multidisciplinary
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`team including a clinician/scientist and a formulator.
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`15. The formulator of ordinary skill in the art would have: (i) at least a
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`bachelor’s degree in chemistry, biology, chemical engineering, or pharmaceutics, or
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`in a related field in the biological or chemical sciences, and have at least three to five
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`years of experience in developing nasal dosage forms and the ability to operate
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`independently on formulation activities. A POSA would also have familiarity with
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`pharmaceutical excipients and their uses. Such a person may also have (ii) a
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`Master’s degree in chemistry, biology, chemical engineering, or pharmaceutics, or in
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`a related field in the biological or chemical sciences, and have at least one to three
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`years of experience in formulation development of nasal agents as well as the ability
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`to operate independently on formulation activities. Such a person may also have (iii)
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`a Ph.D. in chemistry, chemical engineering, or pharmaceutical sciences with at least
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`one year of experience in formulation development of sterile dosage forms. These
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`
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`persons would also have familiarity with pharmaceutical excipients and their uses.
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`These descriptions are approximate, and a higher level of education or specific skill
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`might make up for less experience, and vice-versa.
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`V.
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`The ‘620 Patent
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`16.
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`I understand that U.S. Patent No. 8,168,620 (“the ’620 patent”) (Ex.
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`1001) issued from U.S. Patent Application No. 10/518,016 (“the ’016 application”),
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`as the 35 U.S.C. § 371 national stage application of International Application No.
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`PCT/GB03/02557 (“PCT/GB03/02557”) filed on June 13, 2003. PCT/GB03/02557
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`purports on its face to claim priority to UK Patent Application No. 0213739.6 (“GB
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`0213739.6”, Ex. 1006), titled “Pharmaceutical Compositions,” filed on June 14,
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`2002 (the earliest possible effective date).
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`17.
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`I understand that the priority date to which the ’620 patent is entitled
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`may be in dispute. I have been instructed to base my opinion from the perspective of
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`a POSA as of June 14, 2002. However, if I were to use June 13, 2003 as the relevant
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`date, my opinion would be the same.
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`18.
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`Independent claim 1 of the ‘620 patent recites:
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`“A pharmaceutical formulation comprising: azelastine, or a
`pharmaceutically acceptable salt thereof, and a pharmaceutically
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`acceptable ester of fluticasone, wherein said pharmaceutical
`formulation is in a dosage form suitable for nasal administration.”
`
`19. The specification of the ’620 patent states:
`
`It is known to use antihistamines in nasal sprays and eye
`drops to treat allergy-related conditions. Thus, for example, it is
`known to use the antihistamine azelastine (usually as the
`hydrochloride salt) as a nasal spray against seasonal or perennial
`allergic rhinitis, or as eye drops against seasonal and perennial
`allergic conjunctivitis.
`these conditions using a
`treat
`to
`It
`is also known
`corticosteroid, which will suppress nasal and ocular inflammatory
`conditions. Among the corticosteroids known for nasal use are,
`for
`example, beclomethasone, mometasone,
`fluticasone,
`budesonide and cyclosenide [sic].
`
`Ex. 1001, 1:20-30.
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`
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`VI.
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`Technical Background
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`20. Nasal sprays are a common form of topical drug delivery of
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`therapeutically active agents to the mucous membranes of the nose. They have long
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`been used to deliver agents such as antihistamines and corticosteroids for the
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`treatment of allergy symptoms such as runny nose, itching, sneezing, etc. Nasal
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`sprays contain a solution and/or suspension of the active ingredient(s) in a vehicle
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`which may include a mixture of excipients such as preservatives, buffers,
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`emulsifiers, solvents and solubilizing agents, viscosity modifiers, humectants and
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`others. A nasal spray must be formulated so that 1) the spray pump can reliably
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`deliver the same amount of active ingredient(s) with each actuation, 2) the solution
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`or mixture is shelf-stable and avoids bacterial contamination, and 3) is as
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`comfortable as possible for the patient without compromising the therapeutic
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`efficacy and safety of the nasal spray. Formulators routinely balance these
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`objectives by employing well-known excipients having well-known functions to
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`control solubility, settling (for suspensions), pH, viscosity, osmolality, preservation,
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`and user comfort.
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`VII.
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`Prior Art
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`A. Astelin® Label
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`21. The Astelin® Label discloses a nasal spray formulation containing the
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`active ingredient, azelastine hydrochloride. This label shows all of the excipients in
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`the Astelin® formulation, all of which are also described in Hettche, which discloses
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`a formulation with the same excipients and concentration of azelastine hydrochloride
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`as the Astelin® formulation. Most of the excipients are also identical to those
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`claimed and described in the ’620 patent.
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`22. The Astelin® Label discloses an aqueous solution of 0.1% azelastine
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`hydrochloride. Ex. 1008, 3147. This can be approximated to 0.1% w/w.1 In
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`addition, the label discloses that after priming, each metered spray delivers 0.137 mL
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`mean volume containing 137 mcg of azelastine hydrochloride. Id.
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`23.
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`In Astelin®, the vehicle for the formulation is purified water, and the
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`excipients include benzalkonium chloride and edetate disodium,
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`hydroxypropylmethyl cellulose, citric acid and dibasic sodium phosphate, and
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`sodium chloride. Id. Because the formulation is an aqueous solution rather than a
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`suspension, no particle size is disclosed because the formulations does not contain
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`particles. Id.
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`B. Hettche
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`24.
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`Issued in 1992, U.S. Patent No. 5,164,194 (“Hettche”) claims a method
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`of intranasal treatment with azelastine and discloses an intranasal spray formulation
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`that contains the same excipients and concentration of azelastine hydrochloride as
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`the Astelin® formulation. Hettche describes nearly every excipient claimed in the
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`formulations of the ’620 patent.
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`25. Claim 1 of Hettche is as follows: A method for the treatment of
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`irritation or disorders of the nose and eye which comprises applying directly to nasal
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`tissues or to the conjunctival sac of the eyes a medicament which contains a member
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`1 Because the mass of1 mL of water is about 1 g at 25 °C, I have assumed the density
`of the Astelin aqueous formulation is about 1 g/mL. Hence, w/w% is essentially
`equivalent to w/v% in this instance.
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`selected from the group consisting of azelastine and its physiologically acceptable
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`
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`salts.” Other claims define the amounts of azelastine (claims 2-4), the type and
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`amounts of excipients (claims 5-8) used in the method of claim 1. Claim 9 of
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`Hettche calls for the medicament to be applied “by spraying.”
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`26. Hettche also discusses the amounts and concentration of azelastine to be
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`used in the nasal formulation. Ex. 1007, 2:20-23. Hettche discloses that the
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`formulations of the invention contain “0.0005 to 2, preferably 0.001 to 1, in
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`particular 0.003 to 0.5% (weight/weight) of azelastine (related to the free azelastine
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`base). Id., 3:26-32. Where the azelastine is “present as a salt, the amounts should be
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`recalculated as necessary to give the amounts of azelastine itself mentioned above.”
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`Id., 3:31-34. The formulations of azelastine may be solutions or suspensions. Id.,
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`3:26-27.
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`27. Hettche discloses that preservatives should be used in a nasal
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`formulation containing azelastine hydrochloride. Id., 2:46-47 (“solutions or
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`formulations preferably contain preservatives and stabilizers”) (“Ethylene diamine
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`tetra-acetic acid (edetic acid) and their alkali salts (for example dialkali salts such as
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`disodium salt, calcium salt, calcium-sodium salt)” are highlighted as suitable
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`preservatives. Id., 2:47-50. It is understood that edetic acid, edetate, and EDTA
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`refer to the same compound. Ex. 1049, 550 (entry 3481). Hettche also notes that
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`“preferred preservatives among the quaternary ammonium compounds are, however,
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`
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`alkylbenzyl dimethyl ammonium chloride and mixtures thereof, for example the
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`compounds generally known as “benzalkonium chloride.”” Id., 2:68-3:4. Further,
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`“the preservative used is preferably a combination of edetic acid (for example as the
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`disodium salt) and benzalkonium chloride.” Id., 4:4-6.
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`28. Hettche discloses the use of 2-phenylethanol, which is commonly
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`understood as phenylethyl alcohol, and that it may be used in combination with the
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`preservative benzalkonium chloride. Id., 3:19-25.
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`29.
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`Isotonization agents are also disclosed. As a POSA would appreciate,
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`isotonization agents “adjust the osmotic pressure of the formulations to the same
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`osmotic pressure as nasal secretion.” Id., 4:36-38. Hettche discloses that “in the case
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`of dosage forms containing water, it is optionally possible to use additional
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`isotonization agents. Isotonization agents which may, for example, be used are: …
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`glycerine….” Id., 4:33-35. Glycerine is also a preferred solvent for an azelastine
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`nasal spray formulation. Id., 2:39.
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`30. Thickening agents are used by Hettche to “prevent the solution from
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`flowing out of the nose too quickly and to give the solution a viscosity of about 1.5
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`to 3, perferably 2 Mpa.s.” Id., 4:51-54. Hettche discloses that “such thickening
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`agents may, for example, be: cellulose derivatives” and lists carboxymethyl cellulose
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`and hydroxypropylmethylcellulose as suitable thickeners. Id., 4:55-60.
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`31. Finally, Hettche provides a working example of how to prepare an
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`aqueous solution of azelastine hydrochloride for use as a nasal spray, nasal drops or
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`eye drops. Id., 6:7-35. 0.1% Azelastine hydrochloride (10 g in 10.05 kg of water
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`and excipients) is present in this formulation (Id., 6:8-20), just as in Astelin® (Ex.
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`1008, 3147). The excipients in the formulation are identical to those in Astelin® and
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`include edetic acid disodium salt dihydrate, sodium chloride, benzalkonium chloride,
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`citric acid, sodium monohydrogen phosphate hydrate and hydroxypropylmethyl
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`cellulose. Ex. 1007, 6:11-18.
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`C.
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`Flonase® Label
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`32. The Flonase® Label, published in June 2002, discloses a nasal spray
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`formulation containing the active ingredient, fluticasone propionate. It lists the
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`Phillips patent, US Patent No. 4,335,121, on its face, indicating that the Flonase®
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`formulation is protected by Phillipps. Ex. 1010, 8. This label also discloses that the
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`formulation contains many of the same excipients found in the claimed formulations
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`of the ’620 patent.
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`33. The Label describes Flonase® Nasal Spray as an “aqueous suspension
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`of microfine fluticasone propionate for topical administration to the nasal mucosa by
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`means of a metering, atomizing spray pump.” Id., 1. With each actuation, a dose of
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`“50 mcg of fluticasone propionate in 100 mg of formulation” is delivered through
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`the nasal adapter. Id. Fifty micrograms is equivalent to 0.05 milligrams per 100 mg
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`
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`spray. In other words, the weight/weight concentration of fluticasone propionate in
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`Flonase® is 0.05%.2
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`34. The Flonase® Label also discloses the following excipients in the
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`formulation: “microcrystalline cellulose and carboxymethylcellulose sodium,”
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`“0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl
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`alcohol.” Id.
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`35. The combination of microcrystalline cellulose and
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`carboxymethylcellulose sodium disclosed by the Label are often used to “thicken” a
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`formulation and delay the settling of the particles in a suspension. Ex. 1033, 84.
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`This combination is widely available commercially by the brand-name , Avicel®
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`D.
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`Phillipps Patent
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`36. U.S. Patent No. 4,335,121 (“Phillipps”) was issued in 1982 and is listed
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`on the Flonase® Label to indicate that the product is patented. Ex. 1010, 8. Phillips
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`discloses androstane carbothioates, including fluticasone propionate, the active
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`ingredient of Flonase.
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`37. Claim 13 of Phillipps states: “A compound as claimed in claim 1 which
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`2 Percent fluticasone propionate is calculated as follows: (0.05 milligrams of
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`fluticasone propionate)(100%)/(100 milligrams) = 0.05% fluticasone propionate.
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`is S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-
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`
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`propionyloxyandrosta-1,4-diene-17β-carbothioate.” The Flonase® Label shows that
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`this is the chemical name of fluticasone propionate. Ex. 1010, 1.
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`38. Phillipps discloses suitable concentrations for most types of
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`formulations of its disclosed steroids, including preferred ranges “from 0.01 to
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`0.25%,” and, with powders for inhalation or insufflation, “the proportion used will
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`be within the range of from 0.1%-2%.” Ex. 1009, 33:27-33. Phillipps also discloses
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`an aerosol spray containing 0.059% w/w of active ingredient, e.g., fluticasone
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`propionate. Ex. 1009, Example (C), 34:55-62.
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`39. Phillipps also states that its fluticasone propionate formulation must be
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`“micronised,” to have a particle size as defined in BPC 1973 pg. 911 for ultrafine
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`powder. Id., 34:47-49. “BPC 1973” refers to British Pharmaceutical Codex in 1973,
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`which explains that an ultrafine powder is a “powder of which the maximum
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`diameter of 90 per cent of the particles is not greater than 5 µm and of which the
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`diameter of none of the particles is greater than 50 µm.” Ex. 1013, 911.
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`VIII.
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`The co-formulation of fluticasone propionate and azelastine would
`have been obvious to a skilled formulator in the art
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`40. For my analysis, I have been asked by counsel to assume it was obvious
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`to combine azelastine hydrochloride and fluticasone propionate into a single nasal
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`spray based on the cited prior art references, including International PCT Publication
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`WO98/048839 (“Segal”) and the knowledge in the art. I have therefore considered
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`only whether it would have been obvious to co-formulate azelastine hydrochloride
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`and fluticasone propionate as a nasal spray with the excipients claimed in the ’620
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`patent.
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`41.
`
`It is my expert opinion that in view of FDA-approved nasal
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`formulations for both drugs and the disclosures of the corresponding patents, Hettche
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`and Phillipps, there were a limited number of excipients that a formulator would
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`have turned to in order to co-formulate a combination fluticasone propionate and
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`azelastine as a nasal spray. A formulator would have understood that all of the
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`excipients claimed in the ’620 patent were used in Flonase® and/or Astelin® and
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`were described on their labels and/or in their corresponding patents. These
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`excipients were well known in the art as shown, e.g., by the Handbook of
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`Pharmaceutical Excipients (an excerpt of which is Ex. 1033). In view of the
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`widespread knowledge of each of the excipients used in the labels and patents as
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`well as the knowledge and skill in the art and the fact that the Patent Owner relied on
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`routine testing to make the patented invention, a skilled formulator would have had a
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`reasonable expectation of success in co-formulating a combined fluticasone
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`propionate/azelastine hydrochloride nasal spray.
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`A. Nasal formulation comprising azelastine or a pharmaceutically
`acceptable salt and a pharmaceutically acceptable ester of fluticasone
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`42. Claims 1, 24, and 25 cover a pharmaceutical formulation suitable for
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`nasal administration or nasal sprays. All require azelastine or a “pharmaceutically
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`acceptable salt thereof” (cl.1, 25) or the “hydrochloride,” (cl. 24) and a
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`“pharmaceutically acceptable ester of fluticasone” (cl. 1, 25) or “fluticasone
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`propionate (cl. 24), and not much more. Ex. 1001, cls. 1, 24, 25. Claims 1 and 25
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`have few or no non-compositional limitations, while claim 24 requires a
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`pharmaceutically acceptable carrier or excipient therefor.
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`B. Microfine particle size
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`43. Claim 4 of the ’620 patent requires that the formulation of claim 1 has a
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`particle size of less than 10 µm. It is my opinion that both the Flonase Label and
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`Phillips disclose such formulations, and that a formulator would have been
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`motivated to prepare formulations with a particle size of less than 10 µm.
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`44. A POSA would have understood “microfine” in the Flonase® Label to
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`mean 10 microns or less in diameter for several reasons. As noted above, the
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`Flonase Label® discloses that the nasal formulation is “an aqueous suspension of
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`microfine fluticasone propionate.” Ex. 1010, 1. A formulator would have
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`understood that “microfine” is commonly used to describe drug particles that are of a
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`low-micron size range. For example, Ansel discloses that the size of “micronized”
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`particles is under 10 microns (µm). Ex. 1027, 255. A person of ordinary skill in the
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`
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`art would have been motivated to use the definitions that are disclosed in Ansel’s
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`Pharmaceutical Dosage Forms and Drug Delivery Systems to ensure that the particle
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`size complied with industry-wide standards.
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`45. Moreover, the Phillipps patent, which is referenced by the Flonase
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`Label, states that in preparing formulations of the disclosed steroids such as
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`fluticasone propionate, the drugs should be micronized to a particle size defined by
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`the British Pharmaceutical Codex (“BPC”). Ex. 1009, 34:63-64. The BPC specifies
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`a micronized “powder of which the maximum diameter of 90 per cent of the
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`particles is not greater than 5 µm and of which the diameter of none of the particles
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`is greater than 50 µm.” Ex. 1013, 911. From the BPC, a formulator would have
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`understood the expected range of particle sizes in a powder for pharmaceutical use.
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`It is therefore my opinion that a person of ordinary skill would have had a reason to
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`keep drug particles of “fluticasone propionate” “preferably in the range 1 to 10
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`microns.” Ex. 1014, [0001], [0023], [0030].
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`C. Concentrations of azelastine and fluticasone propionate
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`46. The concentrations of azelastine and fluticasone propionate in the ’620
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`patent would have been obvious to a formulator of ordinary skill. As stated above,
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`in the field of pharmaceutics one would have first considered the specific
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`concentrations disclosed in the Flonase® and Astelin® labels as well as their
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`corresponding patents to formulate a combination drug product.
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`
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`47. Claims 5, 6, and 26 of the ’620 patent disclose a range of “0.0357 to
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`1.5% (weight/weight)” of fluticasone ester/fluticasone propionate. Ex. 1001, cls. 5,
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`6, 26. A formulator would have understood that the concentrations disclosed in
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`Phillipps of 0.01 to 0.25%, 0.1% to 2% and 0.059% (Ex. 1009, 33:27-33; 34:55-62)
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`and the concentration on the Flonase® Label of 0.05% w/w (Ex. 1010, 1) would
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`have overlapped or been directly within the range mentioned in claims 5, 6, and 26.
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`It would have been obvious to a person of ordinary skill in the art at the time of the
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`invention to use an amount of fluticasone propionate disclosed in Phillips or on the
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`Flonase® Label. Any further modification to the amount of fluticasone propionate
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`within the claimed range would have been routine optimization to meet the potency
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`required by the application at hand and within the skill of the formulator.
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`48. Similarly, Claim 5 of the ’620 patent discloses a range of azelastine
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`between “0.0005% (weight/weight) to 2% (weight/weight).” Ex. 1001, cl. 5. Claim
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`6 discloses a range of “0.001% (weight/weight) to 1% (weight/weight) of said
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`azelastine,” while claim 26 describes a formulation containing only “0.1%
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`(weight/weight) of azelastine hydrochloride.” Ex. 1001, cls. 6, 26.
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`49. As stated above, Hettche discloses that the formulations of the invention
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`contain “0.0005 to 2, preferably 0.001 to 1, in particular 0.003 to 0.5%
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`(weight/weight) of azelastine (related to the free azelastine base)” as well as a
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`
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`formulation example with 0.1% azelastine hydrochloride. Ex. 1007, 3:26-32, 6:8-9.
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`The ranges and amounts of azelastine concentrations disclosed in Hettche are either
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`identical or fall within the ranges disclosed in Claims 5 and 6 of the ’620 patent.
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`Hettche discloses the range of “0.0005% (weight/weight) to 2% (weight/weight).”
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`Id. Indeed, the range of 0.001 to 1% w/w in Claim 6 is a preferred concentration
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`range disclosed in Hettche. Id. Moreover, like Example 1 in Hettche, the Astelin®
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`Label teaches an amount of 0.1% w/w of azelastine hydrochloride, which is exactly
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`the same concentration described in Claim 26 of the ’620 patent. Ex. 1008, 3147. A
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`person of ordinary skill in the art therefore would have been motivated to use the
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`concentration ranges for azelastine and fluticasone propionate as claimed in the ’620
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`patent.
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`D. Nasal spray
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`50. Claims 24, 25, and 29 require that the formulation be a nasal spray. It
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`would have been obvious for a person of ordinary skill in the art to formulate the
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`combination of fluticasone propionate and azelastine as a nasal spray. Both
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`Flonase® and Astelin® are nasal sprays, and their corresponding patents likewise
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`describe nasal spray formulations. Ex. 1007, 2:12-17; Ex. 1009, 33:12-13. A skilled
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`formulator would have been motivated to rely both on the individual drug labels and
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`Hettche and Phillipps when formulating a combination drug product because they
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`demonstrate that nasal sprays are a common and successful method of delivery for
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`these drugs. Id. As such, it would have been obvious to a person of ordinary skill in
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`the art to retain the same type of dosage form for the combination fluticasone
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`propionate and azelastine product, i.e., a nasal spray.
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`51.
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`Furthermore, other references d