UNITED STATES PATENT AND TRADEMARK OFFICE
`
`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
`
`000001
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`

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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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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
`
`
`
`
`
`I, Maureen Donovan, do declare as follows:
`
`
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Argentum
`
`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No.
`
`8,168,620 (Ex. 1001). I am being compensated for my time in connection with
`
`this IPR at my standard consulting rate, which is $400 per hour for any
`
`consulting and $600 per hour for any deposition appearances. I understand that
`
`my declaration accompanies a petition for inter partes review involving the
`
`above-mentioned U.S. Patent.
`
`I.
`
`My Background And Qualifications
`
`3. My area of expertise is in the field of pharmaceuticals and nasal
`
`formulations. At University of Iowa’s College of Pharmacy, I am presently a
`
`Professor in the Department of Pharmaceutical Sciences and Experimental
`
`Therapeutics within the Division of Pharmaceutics and Translational Therapeutics. I
`
`am also the Associate Dean for Undergraduate Education.
`
`4. My research areas include the development and evaluation of novel
`
`drug delivery systems for mucosal drug delivery especially via the nasal,
`
`1
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`Patent No. 8,168,620
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`gastrointestinal and vaginal epithelia. I also study the mechanisms of drug
`
`
`
`absorption and disposition.
`
`5.
`
`I obtained a Bachelor of Science in Pharmacy from University of
`
`Minnesota in 1983 and a Ph.D. in Pharmaceutics from the University of Michigan in
`
`1989.
`
`6. My curriculum vitae is attached as Ex. 1052 to this document.
`
`7.
`
`In view of my experiences and expertise outlined above and provided in
`
`my curriculum vitae, I am an expert in the field of pharmaceuticals and nasal
`
`formulations.
`
`II.
`
`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)
`
`2
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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
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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)
`
`9.
`
`I understand that an obviousness analysis involves comparing a claim to
`
`the prior art to determine whether the claimed invention would have been obvious to
`
`a person of ordinary skill in the art (POSA) in view of the prior art, and in light of
`
`the general knowledge in the art. I also understand that when a POSA would have
`
`reached the claimed invention through routine experimentation, the invention may be
`
`deemed obvious. I understand that a finding of obviousness for a specific range or
`
`ratio in a patent can be overcome if the claimed range or ratio is proven to be critical
`
`to the performance or use of the claimed invention.
`
`10.
`
`I also understand that obviousness can be established by combining or
`
`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
`
`achieve the claimed invention, there must also be a reasonable expectation of success
`
`in so doing. I understand that the reason to combine prior art references can come
`
`from a variety of sources, not just the prior art itself or the specific problem the
`
`patentee was trying to solve. And I understand that the references themselves need
`
`not provide a specific hint or suggestion of the alteration needed to arrive at the
`
`claimed invention; the analysis may include recourse to logic, judgment, and
`
`common sense available to a person of ordinary skill that does not necessarily
`
`require explication in any reference.
`
`11.
`
`I understand that when considering the obviousness of an invention, one
`
`should also consider whether there are any secondary considerations that support the
`
`nonobviousness of the invention. However, I offer no opinion on secondary
`
`considerations as I understand from counsel that another expert has been retained to
`
`opine on such matters.
`
`III.
`
`Summary of Opinions
`
`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
`
`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
`
`(“Hettche”), U.S. Patent No. 4,335,121 (“Phillipps”), and PCT Publication No. WO
`4
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`98/48839 (“Segal”).
`
`
`
`13.
`
`In addition, it is my opinion that claims 42-44 would have been obvious
`
`to one of ordinary skill in the art at the time of the alleged invention in view of
`
`Hettche, Phillipps, the Flonase® Label, and Segal.
`
`IV.
`
`Person Of Ordinary Skill In The Art
`
`14.
`
`I understand that as of June 14, 2002, a hypothetical POSA would “be
`
`aware of all the pertinent prior art” at the time of the alleged invention. For the
`
`purposes of this analysis, a hypothetical POSA would be part of a multidisciplinary
`
`team including a clinician/scientist and a formulator.
`
`15. The formulator of ordinary skill in the art would have: (i) at least a
`
`bachelor’s degree in chemistry, biology, chemical engineering, or pharmaceutics, or
`
`in a related field in the biological or chemical sciences, and have at least three to five
`
`years of experience in developing nasal dosage forms and the ability to operate
`
`independently on formulation activities. A POSA would also have familiarity with
`
`pharmaceutical excipients and their uses. Such a person may also have (ii) a
`
`Master’s degree in chemistry, biology, chemical engineering, or pharmaceutics, or in
`
`a related field in the biological or chemical sciences, and have at least one to three
`
`years of experience in formulation development of nasal agents as well as the ability
`
`to operate independently on formulation activities. Such a person may also have (iii)
`
`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
`
`
`
`persons would also have familiarity with pharmaceutical excipients and their uses.
`
`These descriptions are approximate, and a higher level of education or specific skill
`
`might make up for less experience, and vice-versa.
`
`V.
`
`The ‘620 Patent
`
`16.
`
`I understand that U.S. Patent No. 8,168,620 (“the ’620 patent”) (Ex.
`
`1001) issued from U.S. Patent Application No. 10/518,016 (“the ’016 application”),
`
`as the 35 U.S.C. § 371 national stage application of International Application No.
`
`PCT/GB03/02557 (“PCT/GB03/02557”) filed on June 13, 2003. PCT/GB03/02557
`
`purports on its face to claim priority to UK Patent Application No. 0213739.6 (“GB
`
`0213739.6”, Ex. 1006), titled “Pharmaceutical Compositions,” filed on June 14,
`
`2002 (the earliest possible effective date).
`
`17.
`
`I understand that the priority date to which the ’620 patent is entitled
`
`may be in dispute. I have been instructed to base my opinion from the perspective of
`
`a POSA as of June 14, 2002. However, if I were to use June 13, 2003 as the relevant
`
`date, my opinion would be the same.
`
`18.
`
`Independent claim 1 of the ‘620 patent recites:
`
`“A pharmaceutical formulation comprising: azelastine, or a
`pharmaceutically acceptable salt thereof, and a pharmaceutically
`
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`
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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.
`
`
`
`VI.
`
`Technical Background
`
`20. Nasal sprays are a common form of topical drug delivery of
`
`therapeutically active agents to the mucous membranes of the nose. They have long
`
`been used to deliver agents such as antihistamines and corticosteroids for the
`
`treatment of allergy symptoms such as runny nose, itching, sneezing, etc. Nasal
`
`sprays contain a solution and/or suspension of the active ingredient(s) in a vehicle
`
`which may include a mixture of excipients such as preservatives, buffers,
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`emulsifiers, solvents and solubilizing agents, viscosity modifiers, humectants and
`
`
`
`others. A nasal spray must be formulated so that 1) the spray pump can reliably
`
`deliver the same amount of active ingredient(s) with each actuation, 2) the solution
`
`or mixture is shelf-stable and avoids bacterial contamination, and 3) is as
`
`comfortable as possible for the patient without compromising the therapeutic
`
`efficacy and safety of the nasal spray. Formulators routinely balance these
`
`objectives by employing well-known excipients having well-known functions to
`
`control solubility, settling (for suspensions), pH, viscosity, osmolality, preservation,
`
`and user comfort.
`
`VII.
`
`Prior Art
`
`A. Astelin® Label
`
`21. The Astelin® Label discloses a nasal spray formulation containing the
`
`active ingredient, azelastine hydrochloride. This label shows all of the excipients in
`
`the Astelin® formulation, all of which are also described in Hettche, which discloses
`
`a formulation with the same excipients and concentration of azelastine hydrochloride
`
`as the Astelin® formulation. Most of the excipients are also identical to those
`
`claimed and described in the ’620 patent.
`
`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
`
`addition, the label discloses that after priming, each metered spray delivers 0.137 mL
`
`mean volume containing 137 mcg of azelastine hydrochloride. Id.
`
`23.
`
`In Astelin®, the vehicle for the formulation is purified water, and the
`
`excipients include benzalkonium chloride and edetate disodium,
`
`hydroxypropylmethyl cellulose, citric acid and dibasic sodium phosphate, and
`
`sodium chloride. Id. Because the formulation is an aqueous solution rather than a
`
`suspension, no particle size is disclosed because the formulations does not contain
`
`particles. Id.
`
`B. Hettche
`
`24.
`
`Issued in 1992, U.S. Patent No. 5,164,194 (“Hettche”) claims a method
`
`of intranasal treatment with azelastine and discloses an intranasal spray formulation
`
`that contains the same excipients and concentration of azelastine hydrochloride as
`
`the Astelin® formulation. Hettche describes nearly every excipient claimed in the
`
`formulations of the ’620 patent.
`
`25. Claim 1 of Hettche is as follows: A method for the treatment of
`
`irritation or disorders of the nose and eye which comprises applying directly to nasal
`
`tissues or to the conjunctival sac of the eyes a medicament which contains a member
`
`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
`
`
`
`salts.” Other claims define the amounts of azelastine (claims 2-4), the type and
`
`amounts of excipients (claims 5-8) used in the method of claim 1. Claim 9 of
`
`Hettche calls for the medicament to be applied “by spraying.”
`
`26. Hettche also discusses the amounts and concentration of azelastine to be
`
`used in the nasal formulation. Ex. 1007, 2:20-23. Hettche discloses that the
`
`formulations of the invention contain “0.0005 to 2, preferably 0.001 to 1, in
`
`particular 0.003 to 0.5% (weight/weight) of azelastine (related to the free azelastine
`
`base). Id., 3:26-32. Where the azelastine is “present as a salt, the amounts should be
`
`recalculated as necessary to give the amounts of azelastine itself mentioned above.”
`
`Id., 3:31-34. The formulations of azelastine may be solutions or suspensions. Id.,
`
`3:26-27.
`
`27. Hettche discloses that preservatives should be used in a nasal
`
`formulation containing azelastine hydrochloride. Id., 2:46-47 (“solutions or
`
`formulations preferably contain preservatives and stabilizers”) (“Ethylene diamine
`
`tetra-acetic acid (edetic acid) and their alkali salts (for example dialkali salts such as
`
`disodium salt, calcium salt, calcium-sodium salt)” are highlighted as suitable
`
`preservatives. Id., 2:47-50. It is understood that edetic acid, edetate, and EDTA
`
`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,
`
`
`
`alkylbenzyl dimethyl ammonium chloride and mixtures thereof, for example the
`
`compounds generally known as “benzalkonium chloride.”” Id., 2:68-3:4. Further,
`
`“the preservative used is preferably a combination of edetic acid (for example as the
`
`disodium salt) and benzalkonium chloride.” Id., 4:4-6.
`
`28. Hettche discloses the use of 2-phenylethanol, which is commonly
`
`understood as phenylethyl alcohol, and that it may be used in combination with the
`
`preservative benzalkonium chloride. Id., 3:19-25.
`
`29.
`
`Isotonization agents are also disclosed. As a POSA would appreciate,
`
`isotonization agents “adjust the osmotic pressure of the formulations to the same
`
`osmotic pressure as nasal secretion.” Id., 4:36-38. Hettche discloses that “in the case
`
`of dosage forms containing water, it is optionally possible to use additional
`
`isotonization agents. Isotonization agents which may, for example, be used are: …
`
`glycerine….” Id., 4:33-35. Glycerine is also a preferred solvent for an azelastine
`
`nasal spray formulation. Id., 2:39.
`
`30. Thickening agents are used by Hettche to “prevent the solution from
`
`flowing out of the nose too quickly and to give the solution a viscosity of about 1.5
`
`to 3, perferably 2 Mpa.s.” Id., 4:51-54. Hettche discloses that “such thickening
`
`agents may, for example, be: cellulose derivatives” and lists carboxymethyl cellulose
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`and hydroxypropylmethylcellulose as suitable thickeners. Id., 4:55-60.
`
`
`
`31. Finally, Hettche provides a working example of how to prepare an
`
`aqueous solution of azelastine hydrochloride for use as a nasal spray, nasal drops or
`
`eye drops. Id., 6:7-35. 0.1% Azelastine hydrochloride (10 g in 10.05 kg of water
`
`and excipients) is present in this formulation (Id., 6:8-20), just as in Astelin® (Ex.
`
`1008, 3147). The excipients in the formulation are identical to those in Astelin® and
`
`include edetic acid disodium salt dihydrate, sodium chloride, benzalkonium chloride,
`
`citric acid, sodium monohydrogen phosphate hydrate and hydroxypropylmethyl
`
`cellulose. Ex. 1007, 6:11-18.
`
`C.
`
`Flonase® Label
`
`32. The Flonase® Label, published in June 2002, discloses a nasal spray
`
`formulation containing the active ingredient, fluticasone propionate. It lists the
`
`Phillips patent, US Patent No. 4,335,121, on its face, indicating that the Flonase®
`
`formulation is protected by Phillipps. Ex. 1010, 8. This label also discloses that the
`
`formulation contains many of the same excipients found in the claimed formulations
`
`of the ’620 patent.
`
`33. The Label describes Flonase® Nasal Spray as an “aqueous suspension
`
`of microfine fluticasone propionate for topical administration to the nasal mucosa by
`
`means of a metering, atomizing spray pump.” Id., 1. With each actuation, a dose of
`
`“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
`
`
`
`spray. In other words, the weight/weight concentration of fluticasone propionate in
`
`Flonase® is 0.05%.2
`
`34. The Flonase® Label also discloses the following excipients in the
`
`formulation: “microcrystalline cellulose and carboxymethylcellulose sodium,”
`
`“0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl
`
`alcohol.” Id.
`
`35. The combination of microcrystalline cellulose and
`
`carboxymethylcellulose sodium disclosed by the Label are often used to “thicken” a
`
`formulation and delay the settling of the particles in a suspension. Ex. 1033, 84.
`
`This combination is widely available commercially by the brand-name , Avicel®
`
`D.
`
`Phillipps Patent
`
`36. U.S. Patent No. 4,335,121 (“Phillipps”) was issued in 1982 and is listed
`
`on the Flonase® Label to indicate that the product is patented. Ex. 1010, 8. Phillips
`
`discloses androstane carbothioates, including fluticasone propionate, the active
`
`ingredient of Flonase.
`
`37. Claim 13 of Phillipps states: “A compound as claimed in claim 1 which
`
`
`2 Percent fluticasone propionate is calculated as follows: (0.05 milligrams of
`
`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-
`
`
`
`propionyloxyandrosta-1,4-diene-17β-carbothioate.” The Flonase® Label shows that
`
`this is the chemical name of fluticasone propionate. Ex. 1010, 1.
`
`38. Phillipps discloses suitable concentrations for most types of
`
`formulations of its disclosed steroids, including preferred ranges “from 0.01 to
`
`0.25%,” and, with powders for inhalation or insufflation, “the proportion used will
`
`be within the range of from 0.1%-2%.” Ex. 1009, 33:27-33. Phillipps also discloses
`
`an aerosol spray containing 0.059% w/w of active ingredient, e.g., fluticasone
`
`propionate. Ex. 1009, Example (C), 34:55-62.
`
`39. Phillipps also states that its fluticasone propionate formulation must be
`
`“micronised,” to have a particle size as defined in BPC 1973 pg. 911 for ultrafine
`
`powder. Id., 34:47-49. “BPC 1973” refers to British Pharmaceutical Codex in 1973,
`
`which explains that an ultrafine powder is a “powder of which the maximum
`
`diameter of 90 per cent of the particles is not greater than 5 µm and of which the
`
`diameter of none of the particles is greater than 50 µm.” Ex. 1013, 911.
`
`VIII.
`
`The co-formulation of fluticasone propionate and azelastine would
`have been obvious to a skilled formulator in the art
`
`40. For my analysis, I have been asked by counsel to assume it was obvious
`
`to combine azelastine hydrochloride and fluticasone propionate into a single nasal
`
`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
`
`
`
`only whether it would have been obvious to co-formulate azelastine hydrochloride
`
`and fluticasone propionate as a nasal spray with the excipients claimed in the ’620
`
`patent.
`
`41.
`
`It is my expert opinion that in view of FDA-approved nasal
`
`formulations for both drugs and the disclosures of the corresponding patents, Hettche
`
`and Phillipps, there were a limited number of excipients that a formulator would
`
`have turned to in order to co-formulate a combination fluticasone propionate and
`
`azelastine as a nasal spray. A formulator would have understood that all of the
`
`excipients claimed in the ’620 patent were used in Flonase® and/or Astelin® and
`
`were described on their labels and/or in their corresponding patents. These
`
`excipients were well known in the art as shown, e.g., by the Handbook of
`
`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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`Patent No. 8,168,620
`Declaration in Support of Inter Partes Review
`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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`Patent No. 8,168,620
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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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`Patent No. 8,168,620
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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.
`
`51.
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`Furthermore, other references d