IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
`
`
`Plaintiffs,
`
`
`v.
`
`APOTEX, INC. and APOTEX CORP.
`
`
`Defendants.
`
`EXPERT REPLY REPORT OF ROBERT P. SCHLEIMER, PH.D.
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`
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`
`
`Civil Action No. 14-1453 (LPS)
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`1
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`CIP2013
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`

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`TABLE OF CONTENTS
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`Page
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`SUMMARY OF OPINIONS ............................................................................................ 2
`I.
`PERSON OF ORDINARY SKILL IN THE ART ......................................................... 5
`II.
`III. ANALYSIS ........................................................................................................................ 6
`A. Dr. Kaliner’s main arguments are unconvincing. ............................................................... 6
`i. Combining an intranasal antihistamine and intranasal steroid would have been
`an obvious choice, and combining intranasal azelastine and intranasal
`fluticasone would have been obvious in particular. ...................................................... 6
`ii. The combination studies of oral antihistamines and intranasal steroids relied
`upon by Dr. Kaliner would not have deterred a POSA from combining, and
`did not deter doctors from prescribing together, azelastine and fluticasone. .............. 14
`iii. The need to reduce drug exposure to patients needing less exposure is not
`relevant to the question whether a combination would be effective for patients
`needing more serious treatment. ................................................................................. 20
`B. Dr. Kaliner’s other arguments are equally unconvincing. ................................................ 21
`i. Dr. Kaliner’s discussion of failure of others and FDA skepticism is
`unconvincing. .............................................................................................................. 21
`ii. Dr. Kaliner misreads the prior art references and reads them in isolation. ................. 23
`iii. Ratner 2008 demonstrates that a sequential administration of Astelin® and
`Flonase® had similar results to a combination product, and thus plaintiffs have
`not met their burden to produce evidence showing that Dymista® was superior
`to this closest prior art. ................................................................................................ 24
`C. The patents are not sufficiently described or enabled if the plaintiffs are right
`about obviousness. ............................................................................................................ 25
`IV. CONCLUSION ............................................................................................................... 27
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`i
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`1.
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`
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`I, Robert P. Schleimer, have been retained by Defendants Apotex, Inc., and
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`Apotex Corp. as an expert to analyze certain claims of U.S. Patent Nos. 8,163,723 (“the ’723
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`patent”); 8,168,620 (“the ’620 patent”); and 9,259,428 (“the ’428 patent”), in connection with
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`this lawsuit.
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`2.
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`I submitted an opening expert report on June 30, 2016, opining that the asserted
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`claims of the patents-in-suit are obvious. I also submitted a rebuttal report on July 29, 2016. I
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`have been asked to respond to the report of Dr. Michael Kaliner submitted by plaintiffs on July
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`29, 2016, in rebuttal to my opening report. I do so below, and incorporate the contents of my
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`previous reports here, as if set forth verbatim.
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`3.
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`I reserve the right to amend or supplement my opinions in light of evidence
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`presented by or on behalf of the plaintiffs, or in connection with additional information that may
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`later be made available to me. At trial, I may use demonstrative exhibits if useful for explaining
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`and understanding the opinions in this report, and I may testify about background scientific
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`concepts related to pharmacology to explain as necessary the context of the claims.
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`4.
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`I am being compensated for my time on this matter at a rate of $400/hour for
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`consulting and $600/hour for testimony. Those are my standard consulting rates. My
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`compensation is in no way dependent on the outcome of this case.
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`5.
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`My professional background and the bases for my opinions are set forth in my
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`previous reports.
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`I.
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`SUMMARY OF OPINIONS
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`6.
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`
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`In paragraph 31 of his report, Dr. Kaliner succinctly states the basis for his
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`disagreements with my opinion that it would have been obvious to a POSA to combine intranasal
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`azelastine and intranasal fluticasone. He offers six grounds for disagreement. He alleges: (1)
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`there were dozens of available allergic rhinitis treatments, yielding hundreds of possible two-
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`drug pairings; (2) many of these drugs had activity in both the early and late phases of the
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`allergic response, and thus a POSA would not have sought to combine an early-phase drug with
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`a late-phase drug; (3) studies of antihistamine/steroid pairings showed no benefit over steroids
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`alone; (4) experts at the time concluded from these studies that there is no benefit to combining
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`an antihistamine and a steroid; (5) a clinician would have been discouraged from combining the
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`two drugs to minimize patients’ drug exposure; and (6) a POSA would have been discouraged by
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`FDA’s combination rule requiring superior results over either monotherapy, in light of the
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`antihistamine/steroid studies suggesting no improvement over steroids. Points (3), (4), and (6)
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`all generally rely on the combination studies to which Dr. Kaliner refers and may be treated
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`together. None of these points are correct or cause me to change my opinions.
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`7.
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`To the first point, it is not true that a POSA would have had to wade through
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`hundreds of possible pairings in 2002 in coming to an obvious decision about what drugs to
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`combine into a single product. As explained in my opening report, my rebuttal report, and in the
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`rebuttal report of Dr. James Wedner, there were only a handful of treatments that doctors
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`routinely used for the treatment of allergic rhinitis. Dr. Kaliner himself admits that intranasal
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`steroids were the most common treatment. Of these, fluticasone propionate was one of only five
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`FDA-approved steroids in 2002 and was a best-selling drug product (known as Flonase®).
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`Antihistamines were the other most common treatment, and although oral antihistamines were
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`and continue to be prescribed, intranasal antihistamines were nonetheless a widely used option
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`and were known to be more effective than oral antihistamines. At the time, there were only two
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`available intranasal antihistamines—azelastine and levocabastine. Of these, azelastine was
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`shown to be more safe and effective and it was far more commonly prescribed (as Astelin®) than
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`levocabastine. What’s more, doctors routinely prescribed both Flonase® and Astelin® to patients
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`who did not respond sufficiently to Flonase® (and occasionally Astelin®) alone.
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`8.
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`Addressing the second point, it is true that some drugs have effects on both the
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`early-phase allergic response as well as the late phase. I stated no differently in my report.
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`Intranasal steroids have an impact on all symptoms, but they have their strongest, and more
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`importantly most timely, impact on the late phase. Intranasal azelastine, moreover, was known to
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`be effective in part because it also had an effect on late-phase inflammation. But like other
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`antihistamines, its predominant effect was on the early-phase response. It would have been
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`obvious to combine the two, as doctors routinely did by prescribing both Flonase® and Astelin®,
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`for patients with cases of more severe or persistent allergic rhinitis. The fact that they have some
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`overlapping effects does not make it inventive to combine the two, particularly when there is no
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`dispute that they achieve those effects through different mechanisms of action.
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`9.
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`To the third, fourth, and sixth points, Dr. Kaliner interprets selected studies
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`showing that oral antihistamines combined with intranasal corticosteroids are no better than
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`corticosteroids alone as indicating that any combination of these drugs would have no benefit
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`above that of the steroid monotherapy. I strongly disagree with this interpretation. Even if these
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`studies would be interpreted as Dr. Kaliner says (a proposition with which I disagree), they are of
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`relatively little importance to a POSA’s decision in 2002 whether to combine intranasal
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`azelastine and intranasal fluticasone. As discussed in some detail in my opening report, in my
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`rebuttal report, and in the rebuttal report of Dr. McCulloch, these studies were all of oral
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`antihistamines combined with intranasal steroids—none studied a combination of an intranasal
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`antihistamine with an intranasal steroid. As explained repeatedly, intranasal antihistamines were
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`known to be significantly more effective than oral antihistamines. Additionally, all but one of
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`these studies reported results only after at least a week of treatment—a time point at which the
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`delayed effects of the corticosteroids would have taken effect, masking any immediate benefit of
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`the antihistamines in the first days of treatment. As also discussed in these earlier reports, the
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`true value of adding the topical antihistamine to the intranasal steroid is primarily realized during
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`that first week while the steroid effects are not yet fully apparent. But moreover, these
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`combination studies did show improved results for a combination treatment for two symptoms
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`that are critical to allergic rhinitis patients—itching and sneezing.
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`10.
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`Finally, as to the fifth point that addresses Dr. Kaliner’s concerns about
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`minimizing drug exposure, a combination product would not impact the clinician’s consideration
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`at all. The clinician would know that a combination product was suitable for the more severe
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`and persistence cases of allergic rhinitis—for those patients for whom Flonase® (or Astelin®)
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`was insufficiently effective on its own. But once a patient’s symptoms were under control,
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`reverting to a monotherapy prescription would still be an option. Thus, a POSA would not be
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`discouraged by the desire to minimize drug exposure. Such a desire is always present and does
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`not discourage the development of more effective drugs. And to the extent a POSA would have
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`viewed this concern as a material one, it is not addressed by the claimed invention or Dymista®.
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`11.
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`I discuss these views in more detail below and in my earlier reports. If I do not
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`directly respond to any particular statement of Dr. Kaliner’s, I do not intend to convey that I
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`agree with that statement.
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`II.
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`PERSON OF ORDINARY SKILL IN THE ART
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`12.
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`Dr. Kaliner challenges my definition of a person of ordinary skill in the art (a
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`“POSA”). He disagrees that a POSA would have a Ph.D. or a Pharm.D., “because these
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`individuals are not qualified to diagnose patients, treat patients, or prescribe drugs to patients.”
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`¶ 17. “Critically,” Dr. Kaliner writes, “the majority of the asserted claims are directed to
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`methods of using claimed compositions to treat allergic rhinitis.” Id. But doctors are usually not
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`involved in the discovery of new drug products. Rather, although some researchers are clinicians
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`and some clinicians are researchers, it is typically researchers who are the ones that develop,
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`discover, and invent new drugs that practicing clinicians can then use.
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`13.
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`Dr. Kaliner’s own opinion demonstrates why merely being a clinician—without
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`any experience researching the science behind allergic rhinitis treatments—is insufficient. He
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`explains “that the POSA clinician in 2002 would have focused on actually treating patients’
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`symptoms; he would not have been concerned with the underlying mechanisms.” ¶ 57.
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`However, all inventors have to have some understanding of how something works in order to
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`make progress in the field. That is particularly true here. Dr. Kaliner’s POSA would have no
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`such knowledge, and would know nothing about the vast literature describing the mechanisms of
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`allergic rhinitis drugs that would have been known to a clinician researcher or to a Ph.D. or
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`Pharm.D. This definition excuses Dr. Kaliner’s POSA from being aware of the well-developed
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`literature showing that intranasal azelastine, and some other intranasal antihistamines, have anti-
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`inflammatory properties that are not shared by the oral versions of the same drugs or by oral
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`antihistamines as a class. This literature was widely available to and diffused across the relevant
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`academic and industry communities. A POSA actually involved in the research and
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`development of new drugs or drug formulations would undoubtedly have been aware of it.
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`III. ANALYSIS
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`A.
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`Dr. Kaliner’s main arguments are unconvincing.
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`i. Combining an intranasal antihistamine and intranasal steroid would
`have been an obvious choice, and combining intranasal azelastine and
`intranasal fluticasone would have been obvious in particular.
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`14.
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`Dr. Kaliner opines that it would not have been obvious to combine intranasal
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`azelastine and intranasal fluticasone because of the “many available possible treatments
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`documented in the art” (¶ 67), including “twenty-four antihistamines, nine decongestants, four
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`anticholinergics, three leukotriene receptor antagonists, two mast cell stabilizers, and eight
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`corticosteroids” (¶ 72). See also ¶¶ 73, 75, 76.
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`15.
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`Dr. Kaliner’s point is not persuasive. First, as he explains in his report, “the use
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`of corticosteroids supplanted antihistamines as the most effective treatment option for allergic
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`rhinitis; by 2002, corticosteroids were recognized as the most potent treatment option.” ¶ 36. He
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`thus agrees that a POSA would have looked to a corticosteroid above all else—and further agrees
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`that potency was one of the most important concerns. As I stated in my opening report,
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`fluticasone propionate is among the most potent of the steroids—meaning a smaller
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`concentration achieves the same efficacy as other steroids with higher concentrations. Opening
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`Report ¶ 66; see also Stellato et al. (1999) (showing fluticasone propionate is more potent in
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`vitro than mometasone furoate, budesonide, and beclomethasone dipropionate). That may help
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`explain why Flonase® was one of the best-selling drugs prior to 2002 and continues to be a best-
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`selling drug today.
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`16.
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`Dr. Kaliner’s point that intranasal steroids are largely indistinguishable in clinical
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`effect is irrelevant. ¶ 83. Dr. Kaliner, or a general practitioner that he refers to as a POSA, may
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`be unfamiliar with the difference between efficacy and potency, but a POSA as I have defined
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`them, i.e. a researcher developing drugs, would know the difference.
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`17.
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`Dr. Kaliner also opines that fluticasone “was associated with a strange smell and
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`taste that many patients found undesirable,” and thus other options “were far preferable to
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`fluticasone.” ¶ 83. The sales and marketing numbers, however, belie this claim. As reported in
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`the report of plaintiffs’ commercial success expert, fluticasone propionate had 42 million
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`prescriptions in 2015—far outstripping all other nasal spray treatments (branded Nasonex was
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`second with about 4.6 million prescriptions). See Jarosz Opening Report Tab 3.
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`18.
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`Patients do not, and did not prior to June 2002, have a problem with the odor and
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`taste of fluticasone. Dr. Kaliner’s source for the claim that “many patients found undesirable”
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`the taste and smell of fluticasone—Blaiss 2001—reports the results of two studies of an
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`experimental design intended to test the sensory attributes of the various intranasal
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`corticosteroids, in which only 94 and 95 patients participated respectively. A POSA would not
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`draw firm conclusions from such an isolated study of so few patients. Besides the very modest
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`effect, the data do not indicate that the patients actually reported disliking the odor or taste of
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`fluticasone; rather, they reported liking the taste and odor of triamcinolone more:
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`Blaiss 2001, at S8. Regardless, the author explains in the conclusion: “Now, the challenge is to
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`develop a reliable, consistent instrument and method of assessment for these patient preference
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`studies, which will allow us to include patient preference as a standard assessment tool in all of
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`our intranasal steroid clinical studies.” Id. at S10. In short, the studies reported in Blaiss 2001
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`were isolated, experimental, admittedly unreliable, included extremely small sample sizes, and
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`do not even stand for the proposition that Dr. Kaliner claims they do. Considering this, as well
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`as the tens of millions of patients taking this drug, there is simply no convincing evidence that
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`fluticasone propionate is or ever has been offensive to patients. There is simply no evidence that
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`any patient has ever refused to use fluticasone because of its smell or taste.
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`19.
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`Next, although Dr. Kaliner writes that there were 24 “available” antihistamines,
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`he stated in his opening report that there were 24 “known” antihistamines (Kaliner Opening
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`Report ¶ 47)—only five of which were commercially available or FDA-approved in oral form in
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`2002, and only two of which were available for intranasal administration. Wedner Opening
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`Report ¶¶ 19, 24; Schleimer Opening Report ¶ 91. As I explain in my opening report, intranasal
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`(topical) antihistamines have much more rapid onsets of action than oral antihistamines and a
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`higher concentration can be delivered without adverse effects. Because of these high local
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`concentrations, they have anti-inflammatory effects that oral versions of the same drugs do not
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`have. These facts would have motivated a POSA toward the antihistamines that had strong
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`intranasal activity and that exerted these anti-inflammatory effects locally in the nose. That was
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`an obvious thing to do. Opening Report ¶¶ 74, 83. Only azelastine and levocabastine were
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`available for intranasal use, and azelastine was by far the more commonly prescribed. Oddly,
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`Dr. Kaliner cites the fact that there were only two available intranasal antihistamines as evidence
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`that a POSA would not have sought to combine an intranasal antihistamine with a steroid. ¶ 77.
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`But that is exactly why a POSA would have been led to azelastine—because it was the only
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`available best-selling intranasal antihistamine and was known to be more effective than oral
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`antihistamines.
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`20.
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`Dr. Kaliner adds that I ignored the intranasal antihistamine “antazoline although it
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`was known to be associated with ‘almost no side effects.’” ¶ 82 (citing ARIA at S253). This is
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`misleading. The ARIA guidelines actually state: “The use of intranasal antihistamines like
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`levocabastine, azelastine and antazoline has the benefit of almost no side effects.” ARIA at
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`S253. That is, all of these antihistamines have no side effects, not merely antazoline. More
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`importantly, as already explained, only levocabastine and azelastine were FDA-approved as of
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`June 2002, and only azelastine was widely used (in the form of Astelin®). There is no
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`compelling reason a POSA would have thought the use of antazoline was a more obvious choice
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`than azelastine for a useful, nasally administered antihistamine.
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`21.
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`Thus, Dr. Kaliner overstates the number of treatment options available for the
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`great majority of allergic rhinitis patients.
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`22.
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`Dr. Kaliner claims that my citing Falser as evidence that azelastine would be
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`viewed by a POSA as being clinically superior to levocabastine is incorrect, and that I have
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`misread the key study by Falser comparing these drugs (specifically stating that the error bars in
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`the study showed overlap). Dr. Kaliner also states that Falser acknowledged the frequently
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`reported bitter taste of azelastine. As far as bitter taste is concerned, Falser states: “Surprisingly
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`enough not a single case of taste disturbance was reported...,” i.e., of the 90 patients receiving
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`azelastine, not one complained about bitter taste. Falser at 392. Regarding the more important
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`point about efficacy of the two drugs, a POSA, even as narrowly defined by Dr. Kaliner, would
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`not have misunderstood the findings and conclusions of Falser et al. In the abstract summarizing
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`the entire study they finish with the statement: “Azelastine, however, was statistically superior in
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`efficacy as well as in safety....” Id. at 387. The basis for this strong conclusion is that this study
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`of 180 patients demonstrated that the superiority of azelastine to levocabastine spanned three of
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`the five criteria evaluated, including evening total symptom score, evening nasal symptom score
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`and, importantly, global judgment of efficacy by the investigator. Even the patients themselves
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`judged azelastine effects to be “very good” or “good” 92% of the time while levocabastine
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`received a “very good” or “good” score only 76% of the time. In all of these cases, the
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`superiority of azelastine was statistically significant. Thus, azelastine was determined to be
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`superior by patients, by the clinicians carrying out the study, by the statisticians analyzing the
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`data, and by the investigators performing and writing up the study.
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`23.
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`But moreover, a POSA would not have had to wade through hundreds of possible
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`combinations because doctors already routinely prescribed both Astelin® and Flonase® to the
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`same patient at the same time. Opening Report ¶ 79; Schleimer Rebuttal Report ¶ 25; Accetta
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`Tr., at 22:16-23:5; 55:16-56:13; Wedner Rebuttal Report ¶¶ 12, 25, 26. This combination was
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`known—and it was known to be effective.
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`24.
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`Dr. Kaliner challenges the probative value of Dr. Accetta’s testimony, arguing
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`that “[t]he small number of records over the course of thousands of patients shows that the use of
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`azelastine and fluticasone together was not obvious” and that “Dr. Accetta’s stepwise
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`prescriptions teach away from the combination of the two drugs in a single formulation.” ¶ 68.
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`This is beside the point, however, because no one disputes that a combination of azelastine and
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`fluticasone is only appropriate for patients with persistent and severe allergic rhinitis. Dr.
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`Accetta’s stepwise prescription method is fully consistent with the relevant guidelines, as Dr.
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`Kaliner himself recognizes. ¶¶ 19, 57. And it is also completely consistent with prescribing
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`azelastine and fluticasone together—or to combine them in one drug—to those patients at the
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`more severe end of the stepwise treatment paradigm. Such a combination for these patients was
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`obvious to and used by Dr. Accetta, Dr. Wedner, and other clinicians and researchers well before
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`June 2002.
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`25.
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`Part of the reason this combination was expected to be effective, as explained,
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`was that the different drugs targeted different components of the mechanisms that caused AR and
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`that targeting two mechanisms could yield better results than targeting a single mechanism. For
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`example, as explained in my opening report, antihistamines specifically treated the early phase
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`reaction and corticosteroids treated more successfully the late phase reaction. Opening Report
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`¶¶ 44-47 (antihistamines); 54-58 (steroids). Moreover, azelastine was particularly effective
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`because it also treated the late-phase response through its anti-inflammatory properties. See
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`Opening Report ¶¶ 48-52; Fields et al. (1984); Fischer & Schmutzler (1981); Katayama et al.
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`(1987); Church & Gradidge (1980); Lytinas et al. (2002); Kusters et al. at (2002); Hide et al.
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`(1997); Honda et al. (1982); Togias et al. (1989); Ciprandi et al. (1996); Wang et al. (1997);
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`Mosges & Klimek (1998); Jacobi et al. (1999).
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`26.
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`
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`Dr. Kaliner argues, however, that a POSA would not have sought to combine an
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`early-phase drug with a late-phase drug because many AR drugs affect both phases (¶¶ 50-55,
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`85, 88, 119), and because “[t]he POSA clinician at the time of invention did not have a complete
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`understanding of the mechanisms of allergic rhinitis, and as such, would not have relied on the
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`early- and late-phase dichotomy to treat his patients” (¶ 70). These arguments are wrong. First,
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`as explained above, antihistamines were known to treat predominantly the early-phase response,
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`and corticosteroids were known to treat predominantly the late-phase response. Thus,
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`antihistamines would have been obvious to combine with corticosteroids—and doctors regularly
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`did combine them. But moreover, and as repeatedly explained, a POSA would have been
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`particularly motivated to combine intranasal azelastine with a corticosteroid because of its
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`additional beneficial effect in the late-phase response as well. Indeed, Dr. Kaliner recognizes in
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`his statement respecting my research that intranasal corticosteroids have some effects in in the
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`early-phase response as well as the late-phase response, whereas research shows systemic (oral)
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`corticosteroids have no effect on the early phase. ¶ 53.
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`27.
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`Indeed, it is noteworthy that in the introduction of Falser et al., which was
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`published in 2001, the investigators state: “Azelastine (CAS 58581-89-8) being an antiallergic
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`agent has potent activity at a number of sites associated with the allergic reaction: these include
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`potent and selective H1 receptor antagonism (ref 1), blockade of histamine release from mast
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`cells (ref 2) and antagonism of leukotriene and platelet activating factor (ref 3).” It is my opinion
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`that even a POSA defined by Dr. Kaliner’s weak terms, i.e. a clinician seeing patients in this
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`field and not involved in drug discovery, would have been aware of this study and therefore
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`informed about the non-canonical anti-inflammatory effects that distinguish intranasal azelastine
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`from oral antihistamines, including inhibition of mast cells and suppression of leukotrienes. That
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`is, even Dr. Kaliner’s POSA should have been aware that intranasal azelastine was a particularly
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`effective antihistamine because of its effect in both phases.
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`28.
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`Thus, I do not and have never disputed that some drugs have effects in both
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`phases. Azelastine was a particularly obvious choice for treatment because it was known to
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`rapidly relieve symptoms otherwise controlled too slowly by the steroid component as well as to
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`have effects in both phases. The contention that these drugs may have effects in both phases is in
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`no way contrary to my opinions.
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`29.
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`As for Dr. Kaliner’s point that the mechanisms of allergic rhinitis were not
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`completely understood, his argument is partly overstated and partly irrelevant. To be sure, if Dr.
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`Kaliner’s clinician POSA did not understand the mechanisms of allergic rhinitis very well, it
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`would support very well my contention that a POSA interested in creating new drugs would be a
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`researcher in industry or in the academy steeped in the widely available literature on such
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`mechanisms and who actually has experience developing new drug products. Regardless, that
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`the mechanisms of allergic rhinitis were not fully understood—and still are not fully
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`understood—does not undermine the fact that a POSA would have had significant knowledge of
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`these mechanisms that can well inform the development process.
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`ii. The combination studies of oral antihistamines and intranasal steroids
`relied upon by Dr. Kaliner would not have deterred a POSA from
`combining, and did not deter doctors from prescribing together,
`azelastine and fluticasone.
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`30.
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`Dr. Kaliner’s third, fourth, and sixth argument are really the same argument: a
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`POSA would not have had an expectation of success because the four studies Dr. Kaliner cites
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`allegedly show no improvement with a combination of antihistamine and corticosteroid. For
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`example, he writes that a POSA would have been discouraged from combining intranasal
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`azelastine and intranasal fluticasone because of FDA’s combination rule requiring superiority
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`over each monotherapy, because “[a]s I said, it was widely accepted in the art at the time of
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`invention that the co-administration of an antihistamine and a corticosteroid conferred no benefit
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`over the corticosteroid alone.” ¶¶ 62-64. See also, e.g., ¶¶ 34-49, 86-87, 89. He summarizes
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`with the conclusions of Akerlund 2005 that adding an oral antihistamine to a corticosteroid “is
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`not supported by clinical trials.” ¶ 46.1
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`31.
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`But Akerlund’s conclusion—which was written in 2005 and would not have been
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`available to a POSA—is only as good as the literature on which he and Dr. Kaliner rely: Juniper
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`(1989), Benincasa (1994), Simpson (1994), and Ratner (1998). See Akerlund (2005) at S476.
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`The same is true of the other summary review articles such as Howarth and Nielsen. ¶¶ 45-49.
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`1 He also notes Barnes 2006 concluded that such a combination is “inappropriate” (¶ 47), but Barnes did not base his
`conclusion on any pre-2002 knowledge and must be discounted because it is not prior art.
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`And as explained in my opening report (¶¶ 80-83) and my rebuttal report (¶¶ 42-47), the
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`literature to which Dr. Kaliner refers studied only oral antihistamines with corticosteroids. There
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`was already a well-developed literature, not discussed by Dr. Kaliner, showing that topical
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`azelastine provided anti-inflammatory effects not observed with oral antihistamines. Thus, a
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`POSA and any clinician would still have been motivated to combine or prescribe an intranasal
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`antihistamine with an intranasal steroid, knowing that localized application permitted higher
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`concentrations with better, faster, and safer effects. Opening Report ¶ 83; Nielsen et al. (2001),
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`at 1565 (azelastine has “a faster onset of action than oral antihistamines and act[s] within 15 to
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`30 minutes.”); ARIA (2001) at S230 (“Topical H1-antihistamines have a rapid onset of action
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`(less than 15 minutes) at low drug dosage, but they act only on the treated organ.”); see also
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`Fields et al. (1984); Fischer & Schmutzler (1981); Katayama et al. (1987); Church & Gradidge
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`(1980); Lytinas et al. (2002); Kusters et al. at (2002); Hide et al. (1997); Honda et al. (1982);
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`Togias et al. (1989); Ciprandi et al. (1996); Wang et al. (1997); Mosges & Klimek (1998); Jacobi
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`et al. (1999).
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`32.
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`Additionally, as I explain in my opening report, the four combination studies
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`involving oral antihistamines would not have deterred a POSA from combining azelastine and
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`fluticasone—and they would not (and did not) deter a doctor from prescribing them together—
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`because all but one of these studies report the effects of the steroid or the steroid combined with
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`oral antihistamine after a number of weeks of administration. Thus, by the time the data were
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`collected, the steroids would be at their full effect. See Juniper (1989) (reporting after week
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`one); Benincasa (1994) (reporting only after week three); Ratner (1998) (reporting after week
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`one). However, patients outside of clinical trials routinely failed to adhere to intranasal steroid
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`treatment for this long because of its delayed onset of action. See Opening Report ¶¶ 59-62, 65,
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`81; Spector (1999) at S387; Nielsen (2001) at 1567; Flonase® Label at 2, ll. 44-47. Thus, doctors
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`knew to prescribe a fast-acting antihistamine in addition to the slower-acting steroid to increase
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`effectiveness. More critically, by the end of the first week the steroids would be in full effect
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`and thus mask the additional benefit of the antihistamines that had been apparent in the early
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`days of treatment.
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`33.
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`As explained in my rebuttal report, Simpson (1994), the only of the above studies
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`to report daily results, shows that with an oral antihistamine there was more improvement on day
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`one for patients taking the antihistamine or combination than those taking the steroid alone.
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`Simpson (1994) at 500. This confirms the benefit of prescribing both a steroid and an
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`antihistamine that would be fully expected from the literature: antihistamines provide fast-acting
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`relief, especially of acute phase symptoms, whereas steroids prov