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.: IPR2017-00807
`
`SECOND DECLARATION OF ROBERT P. SCHLEIMER, Ph.D.
`
`Exhibit 1144
`IPR2017-00807
`ARGENTUM
`
`000001
`
`
`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.: IPR2017-00807
`
`SECOND DECLARATION OF ROBERT P. SCHLEIMER, Ph.D.
`
`Exhibit 1144
`IPR2017-00807
`ARGENTUM
`
`000001
`
`
`
`TABLE OF CONTENTS
`Introduction……………….……………………………………….…..1
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`Background and Qualifications………………………………………1
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`I.
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`II.
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`III. Basis for My Opinions…………………………………………………1
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`IV.
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`V.
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`Summary of My Opinions……………………………………………..2
`
`Person of Ordinary Skill in the Art and Obviousness……………….3
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`VI. The early and late phase reactions of AR were well known and clinically
`relevant prior to June 14, 2002…………………………………..……3
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`VII. The prior art clearly suggests a combined nasal formulation of
`azelastine and fluticasone………………………………………..…….5
`
`VIII. The beneficial effect of the combination of antihistamine with intranasal
`steroid was known in the art……………………………..……………6
`
`IX. The Guidelines reflect clinical practice as of June of 2002 and would
`have encouraged a POSA to develop a single formulation of azelastine
`and fluticasone propionate…………………………………………….28
`
`X. Dr. Carr’s side effects analysis is scientifically unsound; topically
`applied drugs such as azelastine are generally safer than the same drug
`administered orally…………………………………………………….33
`XI. Dymista® shows no unexpected results compared to the closest prior
`art………………………………………………………………………..36
`
`The efficacy of Dymista® in treating AR is essentially the same or
`A.
`worse than the active ingredients co-administered separately……………40
`
`B.
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`Dymista® does not have an unexpectedly faster onset of action….49
`
`XII. There was no long-felt, but unmet need for Dymista®……………….61
`XIII. The discussion of the skepticism by the FDA is unconvincing……….62
`
`XIV. The few instances of industry praise are unpersuasive……………….64
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`XV. Conclusion………………………………………………………………..69
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`I.
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`Introduction
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`1.
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`I am over the age of eighteen (18) and otherwise competent to make
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`this 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 of U.S. Patent No. 8,168,620 (EX
`
`1001). I am being compensated for my time in connection with this IPR at my
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`standard consulting rate, which is $400 per hour for any consulting and $600 per
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`hour for any deposition appearances. I understand that my declaration
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`accompanies a petition for inter partes review involving the above-mentioned U.S.
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`Patent.
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`II. Background and Qualifications
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`3.
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`My background and qualifications remain essentially unchanged from
`
`my first declaration, EX1003. My most recent curriculum vitae is concurrently
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`submitted with this document as EX1163.
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`III. Basis for My Opinions
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`4.
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`In formulating my opinion, I reviewed Dr. Carr’s Second Declaration
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`(CIP2147), his deposition transcript (EX1142), and relied on the documents cited
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`herein.
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`1
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`000003
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`IV. Summary of My Opinions
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`5.
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`It remains my opinion that claims 1, 5-6, 24-26 and 291 would have
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`been obvious to a person of ordinary skill in the art (POSA) in view of the
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`combined teachings of Segal, Hettche and Phillipps for the reasons I gave in my
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`first declaration (EX1003) and the additional reasons I give herein. Segal, as well
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`as Cramer expressly suggested a single nasal spray containing the active
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`ingredients of Dymista®, azelastine hydrochloride (“azelastine”) and fluticasone
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`propionate (“fluticasone”). The clinical art also establishes the use of these drugs
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`together for the treatment of allergic rhinitis. However, it did not mandate the
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`inflexible approach of only treatment by the individual monotherapies. The
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`complementarity of antihistamine/steroid pairing and particularly of
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`azelastine/fluticasone, the anti-inflammatory properties of azelastine when
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`topically applied, and the expected convenience and compliance would also have
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`prompted a POSA to develop a single nasal spray containing these ingredients.
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`1 Dr. Carr’s contention that I agree with him that claims 4 and 42-44 are non-
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`obvious because I did not discuss their obviousness is presumptuous. Counsel did
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`not ask me to consider these claims because it asked a formulation expert to weigh
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`in on them. To be clear, I consider the combination of azelastine and fluticasone in
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`a formulation suitable for nasal administration to be obvious for claims 4 and 42-
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`44 for the same reasons as all the claims discussed herein.
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`2
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`V.
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`Person of Ordinary Skill in the Art and Obviousness
`6.
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`I stand by my previous testimony regarding the POSA described in
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`my first Declaration. EX1003 ¶¶11-12. Dr. Carr suggests that “knowledge of and
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`experience in treatment is more relevant in the context of the ‘620 patent than
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`laboratory experiments.” CIP2147 ¶19. I agree that clinical knowledge is relevant
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`to a POSA in the present context. I disagree to the extent he suggests that
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`knowledge of the cellular basis of allergic rhinitis (AR) is somehow less relevant to
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`the development and use of pharmaceuticals to treat this condition.
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`VI. The early and late phase reactions of AR were well known and clinically
`relevant prior to June 14, 2002
`7.
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`Dr. Carr’s assertion that “several laboratory concepts” upon which I
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`rely “were tested in vivo and were found not to affect patients” (Id. ¶19) is wrong
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`and a mischaracterization of the state of the art prior to June 14, 2002. The early
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`phase reaction (EPR) and late phase reaction (LPR) are not merely laboratory
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`concepts as Dr. Carr would have it, but are established phases of AR (AR) that can
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`in fact be clinically distinguished. EX1041, 455; EX1035, 341; EX1003 ¶¶27-28.
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`For example, if a person with seasonal allergies to ragweed steps outdoors in the
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`morning on the first day of ragweed season, that person can experience immediate
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`sneezing and runny nose (the EPR), while later that evening can experience
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`complete nasal blockage and inability to sleep due to her symptoms (LPR).
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`3
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`000005
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`Another example is when a person allergic to cats visits a friend with cats for a
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`short time; they will likely experience both phases of allergic response.
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`8.
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`In my first declaration, I discussed how the EPR occurs when mast
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`cells in the nose release histamine, tryptase, prostaglandin D2 and other mediators.
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`Antihistamines exert their effects on EPR symptoms primarily by blocking
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`histamine from binding to H1-histamine receptors. By contrast, the LPR is
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`characterized by continued release of cytokines by mast cells and by extensive
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`infiltration of inflammatory cells from the blood to the site of inflammation and
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`also by activation of migrating and resident cells. Corticosteroids work by setting
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`in motion a chain of invents that interrupts the complex cascade of events causing
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`inflammation. EX1003 ¶¶27-28; EX1041, 455; CIP2041, 6-8.
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`9.
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`Even in cases where the phases overlap in time and could be difficult
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`to clinically distinguish due to overlapping symptoms, that does not mean that
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`topical antihistamines were understood to be ineffective or provide no additional
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`benefit over intranasal steroids, as Dr. Carr asserts. CIP2047 ¶45. Because the
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`two phases have different etiologies, a patient suffering from, e.g., severe AR, can
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`still benefit from a combination of antihistamine and intranasal steroids (INS) for
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`the reasons I previously outlined. INS were well known before June 2002 to be
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`effective in treating AR. EX1003 ¶¶53-54. However, while antihistamines have a
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`fast onset of action and work quickly to provide relief from EPR symptoms, topical
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`4
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`000006
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`
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`steroids can take a week or more to inhibit LPR and all symptoms of AR. Id.;
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`EX1024, S231-S232; EX1010, 2; CIP2042, 1567. During that one to two-week
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`period—the same period of time over which Dymista® was later tested—the prior
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`art shows the combination of antihistamine and INS had an additive effect in
`
`relieving symptoms of AR. As I show below, this known concept of
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`complementary mechanisms of action explains the results of all studies, including
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`those which did not find benefit to the combination of antihistamine and INS. By
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`contrast, Dr. Carr simply tries to discount and disparage studies that don’t agree
`
`with his viewpoint.
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`VII. The prior art clearly suggests a combined nasal formulation of
`azelastine and fluticasone
`
`10. My understanding of obviousness is set forth in my first declaration.
`
`EX1003 ¶42-44. I have been further advised by counsel that when a reference
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`discloses a combination of products, even from among many possible
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`combinations, the combination is obvious.
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`11.
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`In my first declaration, I pointed out that Segal (EX1012) discloses
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`pharmaceutical formulations for nasal administration that contain a corticosteroid
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`and an antihistamine. EX1003 ¶¶80, 45, 32-40. Included among those
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`formulations were nasal sprays. Id. ¶¶80, 45, 36. I also pointed out that Segal
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`discloses that the corticosteroid can be fluticasone propionate and the antihistamine
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`can be azelastine. Id. Cramer (EX1011) contains the same disclosures. Id. ¶¶78-
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`5
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`000007
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`
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`79. Dr. Carr does not dispute any of these disclosures and does not mention Segal
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`even once in his 71-page declaration (CIP2147). Hence, his arguments that a
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`POSA would not have selected azelastine (Id. ¶¶86-94) or that my views are driven
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`by hindsight (Id. ¶82) are flat wrong. Segal and Cramer both suggest using
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`azelastine in combination with fluticasone propionate as a single nasal spray.
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`EX1012, 2:22-26, 3:19-20, claims 2 and 4; EX1011, 2:34-35.
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`12. Because Segal discloses the combination of a nasal pharmaceutical
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`formulation of fluticasone propionate and azelastine, it remains my opinion that
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`this combination is obvious. It also remains my opinion that claims 1, 5-6, 24-26,
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`and 29 would have been obvious over Hettche, Phillips and Segal together for the
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`reasons given in my first declaration. Id. ¶¶45-51, 80. Moreover, as discussed in
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`my first declaration, and as I elaborate below, the clinical literature as a whole also
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`supports my contention that the claims of the ‘620 patent would have been
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`obvious.
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`VIII. The beneficial effect of the combination of antihistamine with intranasal
`steroid was known in the art
`
`13. My discussion in my first declaration of clinical knowledge and
`
`practice concerning fluticasone propionate, azelastine and the treatment of AR with
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`the combination of INS and antihistamines showed it to be consistent with Segal
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`(and Cramer). Id. ¶¶52-91. Dr. Carr spends pages and pages of his declaration
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`6
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`000008
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`trying to escape the simple fact that prior to June 14, 2002, antihistamines and INS
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`were routinely combined in normal clinical practice (see EX1019, 505; EX1022,
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`125; EX1024, S230), as they still are today. Dykewicz, e.g., expressly
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`recommends the use of INS with intranasal antihistamines and discusses only
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`azelastine. EX1019, 505. Their combined use then and now reflects the well-
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`formed and durable perceptions of both clinicians and patients that combining
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`these two types of drugs provides greater relief in some cases than using only one
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`or the other. I therefore disagree with Dr. Carr that a POSA would have known the
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`co-administration of antihistamines and steroids provides no meaningful benefit
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`over steroids alone or that treatment guidelines and practices would have
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`discouraged a POSA to pursue a fixed dose combination product.
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`14.
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`In his declaration, Dr. Carr boldly states that complementarity of
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`action “as it applied to the co-administration of antihistamines and steroids was
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`squarely rejected in the art prior to the date of invention.” CIP2147 ¶48. This
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`misleading statement finds little support in the prior art discussed by Dr. Carr and
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`myself in our respective declarations. As shown below, studies focusing on the
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`first 1-2 weeks of combined treatment with antihistamine and INS showed additive
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`effects whereas longer trials showed little to no additive effects. In addition, these
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`additive effects were most apparent in reduced symptoms of sneezing and itchy
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`nose, two of the EPR symptoms that antihistamines are most effective at treating.
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`7
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`000009
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`EX1023, S386; see also EX1035, 341; EX1038. When authors focused solely on
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`mean total nasal symptom score (TNSS), these effects were of course less
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`prominent, being in effect “diluted” by antihistamine’s lack of efficacy against
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`nasal congestion and lower efficacy against nasal discharge. Likewise, studies that
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`focused symptoms at the end of the study period, especially those longer than a
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`couple weeks would miss these effects. Finally, none of the studies considered
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`azelastine.
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`15. For example, the Drouin study (EX1035) was a 7-day study of the
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`combination of intranasal beclomethasone dipropionate (BDP) and loratadine
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`versus intranasal BDP and placebo. It tested whether therapeutic efficacy could be
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`maximized by combining drugs having “complementary effects” on different
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`components of the allergic response, i.e., the EPR and LPR. Id., 341. Data was
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`collected on days 3 and 7 in terms of total nasal score, total ocular score and total
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`symptom score. Id., 343. Table 2 (reproduced below) shows statistically
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`significant reductions in total nasal score (day 3), nasal itching (days 3, 7), and
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`sneezing (day 3). Based on these results, the authors concluded that “[p]atients
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`treated with BDP plus loratadine achieved significantly greater (p<0.05) relief of
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`both nasal and non-nasal symptoms than those treated with BDP plus placebo.”
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`Id., 341 (Abstract). The combination therapy did not raise any safety concerns for
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`8
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`
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`the authors who noted “both groups reported similar incidence and types of
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`adverse effects.” Id., 345.
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`16. Dr. Carr alleges (without showing any calculation) that the TNSS
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`differential between the combination and steroid was approximately 0.4 points and
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`characterizes that difference as clinically meaningless. CIP2147 ¶59. In fact, the
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`9
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`000011
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`
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`difference is 0.5 points,2 and is at least as much if not more than the difference
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`observed by Dr. Carr in his own paper (EX1037) reporting the Dymista® clinical
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`trials. Dr. Carr’s paper utilizes a 24-point rTNSS scale rather than the 12-point
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`scale used in Drouin. When normalized to Dr. Carr’s 24-point scale by
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`multiplying by 2, the difference is 1 full point. In Dr. Carr’s paper, in Table II
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`(reproduced below) he presents a meta-analysis of the three individual trials
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`reported and shows only a 0.8 point difference between the reduction of TNSS for
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`Dymista® versus fluticasone propionate alone.
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`2 Based on the baseline TNSS scores for each arm of the study, I calculated the
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`difference in TNSS scores as follows: (baseline TNSS) x ((% reduction in TNSS
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`in Table 2)/100) = (the number of points reduction in symptoms). For BDP +
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`placebo, the reduction is 8.6 x (0.48)=4.1. For BDP + loratadine, the reduction is
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`8.4 x (0.55)=4.6. The difference between the two arms is 4.6-4.1= 0.5 points.
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`10
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`17. Likewise, his comment that the improvement of 0.4 points is typically
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`less than shown by placebo is also misleading. Large placebo effects are routinely
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`observed in the treatment of AR, as can be seen in Table II of Dr. Carr’s Dymista®
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`paper: the meta-analysis of 3498 patients shows that the net improvement
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`Dymista® produced over placebo is less than the improvement placebo produced
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`over baseline by itself (compare the -3.0 point reduction obtained with placebo
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`versus the -2.3 point reduction that Dymista® shows over placebo).
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`18. Furthermore, Drouin’s 3-day nasal itching and sneezing scores show,
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`respectively, a 1 point and 0.8 point reduction in symptoms (on a 12 point scale).
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`The clinical significance of these and the TNSS results are supported by Drouin’s
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`11
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`000013
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`report that 39% of patients and 34% of physicians whose global evaluation at the
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`endpoint of the study found the combination to be excellent compared to only 19%
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`and 17%, respectively who found BDP plus placebo to be excellent. EX1035, 346
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`(Figs. 2-3).
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`19. Similar trends may be observed in the other short studies or in the
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`early parts of longer studies. Brooks (EX1038), a two-week study of the
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`combination of beclomethasone dipropionate (BDP) and loratadine for treatment of
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`hay fever during ragweed season, is a good example of how complementarity
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`between the two types of drugs works. In fact, this study was prompted by the
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`authors’ observation that “low dose corticosteroid primarily benefitted congestion,
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`drainage, and eye symptoms, whereas antihistamine affected primarily itching and
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`sneezing.” Id., 198. They postulated that the combination would at least treat more
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`symptoms, but found “additive symptom suppression almost across the board.” Id.
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`20.
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`In this study, patients were divided between three groups: (1) BDP + a
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`loratadine placebo, (2) loratadine + a BDP inhaler placebo, and (3) BDP +
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`loratadine. Id., 194. Congestion, runny nose, sneezing and itching were assessed
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`twice a day and the effects examined in 3-day intervals. Id., 195. Pretreatment
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`days (-3 to -1) provided a baseline of symptoms, and the drug effects were
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`examined in segments 1 (treatment days 2-4), 2 (treatment days 5-7) and 3
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`(treatment days 8-10). Id.
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`12
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`21. The combination showed superior control of itching and sneezing as
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`shown in Figures 4 and 5. Figure 5 in particular shows how early on (days 2-4) the
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`combination of antihistamine and steroid was clearly superior to the monotherapies
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`in decreasing sneezing, but that the effect of the steroid alone increases over the
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`next two segments until, in segment 3, it appears to account for the bulk of the
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`response observed for the combination.
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`22. Dr. Carr makes no serious attempt to analyze and rebut these findings,
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`but focuses on the fact that although overall at the end of the study, patients in the
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`monotherapy arms preferred beclomethasone to loratadine, this preference did not
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`13
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`reach statistical significance. According to him, because a POSA would have
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`known that a steroid should be substantially better than antihistamine (based
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`merely on general statements concerning efficacy in EX1019 and EX1024), a
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`POSA would interpret the steroid-arm as somehow not working. Yet the POSA
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`would attribute the improvement observed in the combination-arm to the steroid
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`working properly in the co-administration population. EX2147 ¶60. A POSA
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`would have recognized this statement is not true for all steroids over all time
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`periods, and is sheer speculation by Dr. Carr, unsupported by any other evidence in
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`Brooks. Even a cursory review of Figures 1-5 in Brooks comparing the
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`performance of the steroid arm to the antihistamine arm and the combination
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`indicate that the steroid arm is working properly. The study’s authors conclude
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`that for each symptom examined, “antihistamine produced a relatively modest
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`benefit, almost always less than that produced by the topical corticosteroid.” EX
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`1038, 195.
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`23. The symptoms examined in Figures 1-3 are known to be mitigated by
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`corticosteroids and that is what is observed in the Brooks study. EX1038, 198.
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`For example, Fig. 1 shows that, as expected, BDP alone reduces congestion two to
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`three times better than loratadine, and is not statistically different than the
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`combination treatment. EX1038, 196, 198. Likewise, although the reduction in
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`eye symptoms is modest, again as expected, BDP shows from about 3 to 10 times
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`14
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`better symptom reduction than loratadine. Finally, Fig. 3 shows that the
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`antihistamine had almost no effect on runny nose, but BDP had over 10 times
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`better symptom reduction. Far from being flawed, Brooks just shows that in a
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`small two-week study designed to take advantage of the complementary actions of
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`steroids and antihistamines, where the steroid’s full effects on all symptoms had
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`not yet had time to develop, the clear preference for steroid alone (15) over
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`antihistamine alone (9) did not quite reach statistical significance. That does not
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`mean it was not clinically meaningful.
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`24.
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`In my previous declaration, I also discussed Simpson (EX1036), a 21-
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`day study of the steroid budesonide, the antihistamine terfenadine and a
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`combination of both in the treatment of AR. The primary efficacy data were
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`reported at week 3 for overall effectiveness (Figure 1) and for nasal symptoms
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`(blocked nose, runny nose, itch nose, sneezing) (Figure 2), respectively. Simpson
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`showed a statistically significant improvement in sneezing with the combined
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`therapy versus both monotherapies. EX1003, 86. Figure 3 (reproduced below)
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`shows changes in mean total nasal symptom scores in each treatment group over
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`the first week of treatment. The latter graph shows that between the first and
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`seventh day, the mean nasal scores of all arms of the study decreased, and those of
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`the budesonide arm and the combination arm had almost converged, reflecting the
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`expected increasing effectiveness of the steroid over time.
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`15
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`000017
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`25. While Dr. Carr relies on the authors’ comment that budesonide was
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`shown to be effective alone, and that budesonide is stated to be a highly effective
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`treatment for hay fever (EX2147, 55), the article takes no position on the clinical
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`relevance of the combination. These statements do not negate the fact that the
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`combination controlled one of the four cardinal symptoms of AR better than the
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`steroid alone. Data provided in the lower right panel of Figure 2 (reproduced
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`below) clearly show a statistically significantly higher reduction in sneezing score
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`compared to either monotherapy. Notably, Simpson does not conclude that the
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`combination is less effective than budesonide or that it offers no meaningful
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`benefit over budesonide alone. Indeed, the authors conclude that “[b]udesonide
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`alone or in combination with terfenadine, was perceived by patients as being
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`16
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`significantly more effective in alleviating symptoms than terfenadine alone.”
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`EX1038, 501.
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`26.
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`In my first declaration, I pointed out that Ratner’98 (EX1034), a two-
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`week AR treatment study of fluticasone propionate aqueous nasal spray (FP ANS),
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`loratadine, and the combination of the two, showed a statistically significant
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`difference for patient rated TNSS. EX1003 ¶90. However, the authors of this
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`study also stated that addition of loratadine to FP ANS did not “confer meaningful
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`additional benefit.” This conclusion may be based on the clinician ratings of
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`17
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`000019
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`symptoms, which did not find a statistically significant difference in the ratings
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`between FP ANS and the combination with loratadine. EX1043, 121-122. In
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`revisiting this paper, I note that at the end of the timeframe of the study (two
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`weeks), loratadine alone did no better than placebo in alleviating any symptom of
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`AR, and so it is not surprising that the additive effects observed by clinicians for
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`the combination (shown in Fig. 1) did not reach statistical significance. By
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`contrast, in Simpson, where an additive effect was observed for sneezing at the end
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`of three weeks, the antihistamine did provide a statistically significant reduction in
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`that same symptom compared to placebo.
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`27. Consistent with Drouin, Brooks, and Simpson, the later Ratner 2008
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`(EX1045) study demonstrates nicely how the complementarity of antihistamine
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`and INS works during the period that the steroid has not yet achieved its full anti-
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`inflammatory effects. Azelastine and fluticasone propionate— the combination of
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`ingredients in Dymista®—were tested as the individual monotherapies and as the
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`combination by sequential concurrent administration. Fig. 2 from this paper is a
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`graph showing the effects on TNSS by each monotherapy and the concurrent
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`combination for each day of the study. While the first 11 days showed statistical
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`significance of the combination over fluticasone, the last three days did not, as the
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`improvement in the effects of fluticasone rose. This is the same sort of behavior I
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`pointed out in Brooks, Figure 5 (supra).
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`18
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`28. Dr. Carr, who makes much ado about how clinical practice is more
`
`important to this case than “laboratory experiments,” appears to run away from this
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`position in his criticism of Juniper ’97 (EX1031). The investigators of this study
`
`wanted their study “to be as close to real life as possible and to provide practical
`
`information for clinicians” about how patients can use INS and antihistamines
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`alone and in combination to better control their hay fever. Id., 1129, 1124. This
`
`study measured whether health related quality of life (HRQL) of patients suffering
`
`from AR could be improved by starting with antihistamine (terfenadine) and
`
`adding INS (fluticasone propionate, FP) or by starting with FP and adding
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`terfenadine. Id., 1124. Hence the starting premise was that some patients would
`
`need both medications to properly control their symptoms. It found no difference
`
`19
`
`000021
`
`
`
`in outcomes for the two regimes, but concluded that “at least 50% of patients will
`
`need to take both types of medication [nasal corticosteroids and oral
`
`antihistamines] in combination to adequately control symptoms.” EX1003 ¶89;
`
`EX1031, 1123.
`
`29. Alleging that I took this statement out of context, Dr. Carr argues that
`
`the study does not show a benefit to using both drugs together, and that only a need
`
`for better control was shown. CIP2147 ¶68. This complaint is beside the point.
`
`Juniper ‘97 was not an efficacy study but rather represents clinical practice then
`
`and now. It simply illustrates my contention that before 2002 it was known that
`
`some patients would need a combination of antihistamines and INS to control AR
`
`symptoms and that physicians acted on this knowledge by prescribing such
`
`combinations. The study is consistent with the Guidelines in recommending the
`
`use of the two types of drugs together for difficult cases. Contrary to Dr. Carr’s
`
`rigid interpretation of the Guidelines, the authors of Juniper ‘97 conclude that
`
`treatment should be based on patient preference, convenience and cost. There is no
`
`mandate here requiring the sole use of antihistamines and INS as monotherapies.
`
`Juniper's conclusion that “at least 50% of patients will need to take both types of
`
`medication to adequately control symptoms” emphasizes that it would have been
`
`convenient and obvious to combine these medications.
`
`20
`
`000022
`
`
`
`30. Dr. Carr cites two other clinical studies for the proposition that these
`
`studies found no meaningful additional benefit when adding (oral) antihistamine to
`
`INS, including Juniper ’89 (EX1039) (beclomethasone, astemizole) and Benincasa
`
`(EX1040) (FP, cetirizine). In his analysis, Dr. Carr fails to consider the context of
`
`these studies and the differences from studies that found additive effects for the
`
`combination of INS and antihistamine.
`
`31.
`
`Juniper ’89 was a 6-week prophylactic study of beclomethasone and
`
`astemizole, alone and in combination. The authors explained that “the
`
`pharmacologic profile for nasal steroids suggests that the most effective approach
`
`to treatment is regular prophylactic use.” Id., 627. Hence, medication was begun
`
`one week before hay fever season started and for a week after it ended. EX1039,
`
`629. Benincasa was structured similarly; it was an 8-week trial of fluticasone
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`propionate and cetirizine in which “treatment was commenced before the
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`beginning of the expected hayfever season in the U.K.” EX1040, 227. A POSA
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`would have been aware that these studies were designed to provide a lead-in time
`
`for the steroid to reach its maximal effects by or shortly after the hay fever season
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`has begun. Thus, from the start there were fewer AR symptoms to be controlled
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`and less need either for antihistamines’ generally faster onset of action or ability to
`
`control EPR symptoms such as itching and sneezing. Nevertheless, despite the
`
`lead-in time, Juniper ’89 still showed transiently that the combination performed
`
`21
`
`000023
`
`
`
`better than FP alone in reducing sneezing (Figure 1, where baseline is after 1-week
`
`treatment) and the use of eye drops (Figure 2). As the effects of FP ramped up, the
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`advantage faded. Juniper ’89 and Benincasa stand in contrast to shorter studies
`
`such as Drouin, Brooks and Simpson which found significant additional beneficial
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`effects of the combination as described above. Consideration of the timing or
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`window of complementarity is able to explain the seeming discrepancy between
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`studies which showed advantages to the combination of antihistamine and steroid
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`and those which did not.
`
`32. Dr. Carr’s characterization of several review articles is misleading.
`
`He quotes Howarth (CIP2041) out of context, ignoring a key aspect of Howarth’s
`
`conclusion. The Howarth paper is concerned with assessing whether
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`antihistamines have anti-inflammatory activity apart from their antihistaminic
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`activity and whether they may be used in prophylactic treatment, i.e., long-term
`
`treatment to prevent AR symptoms:
`
`While H1-antihistamines are clearly effective in relieving
`symptoms, particularly those associated with sensory
`neural stimulation, it has been proposed that many drugs
`within this class have more extensive actions, modifying
`the inflammatory process in addition to inhibiting the H1-
`receptor-mediated end-organ effects of histamine. As
`such, H1-antihistamines might be potentially considered
`
`22
`
`000024
`
`
`
`prophylactic
`topical
`to
`therapy
`alternative
`an
`corticosteroids in rhinitis. IP2040, 6, emphasis added.
`
`33. As described by Howarth, “by acting very early in the inflammatory
`
`pathway, corticosteroids can prevent the cascade of events associated with cell
`
`recruitment and activation and, ultimately, clinical disease expression.” Id., 7.
`
`While Howarth mentions the antihistaminic symptom relief of antihistamines, he
`
`makes clear that he is discussing the potential antiallergic activity of
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`antihistamines:
`
`With short-term therapy, H1-antihistamines are most
`effective at reducing the neurally mediated symptoms of
`itch, sneeze, and rhinorrhea. This can be attributed to
`end-organ receptor blockade. There is, however, an
`indication that a number of these agents also have the
`potential for anti-allergic activity that, theoretically, may
`increase their spectrum of clinical effectiveness. Id., 8
`
`34. The hypothesis being considered by Howarth was not complementary
`
`mechanisms of activity with respect to EPR and LPR symptom relief—which was
`
`an important point of emphasis (EX1003, ¶¶53-58)—but the ability of
`
`antihistamines to act like steroids, e.g., to inhibit some portion of the inflammatory
`
`cascade. CIP2041, 9. Specifically, Howarth discusses studies suggesting that
`
`antihistamine may inhibit release of histamine (e.g., via mast cell degranulation)
`
`23
`
`000025
`
`
`
`and to inhibit recruitment of some cells. Id., 8-9. While I also discussed this
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`aspect of antihistamines’ activity and especially of azelastine (EX1003 ¶¶56, 66-
`
`67), that was not my sole point. My discussion focused on why antihistamines
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`offer complementarity of relief from EPR and LPR symptoms during the 1-2 week
`
`window that the full anti-inflammatory effects of an INS have yet to develop. Id.,
`
`53-58. Howarth has nothing to say about this kind of complementarity, and does
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`not cite any in vivo studies involving azelastine itself.
`
`35. With respect to complementary anti-inflammatory effects of
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`antihistamines and INS, Dr. Howarth made clear that his conclusion of no superior
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`effect was based on the limited studies available; his paper did not actually contain
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`citations to any in vivo studies, as references 52 and 53 are missing. CIP2041, 9-
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`10. He did not cite or discuss Brooks, Drouin, or Simpson, none of which relate to
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`the anti-inflammatory activity of antihistamines, but all of which speak to
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`complementarity as I discussed above.
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