IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`Civil Action No. 14-1453 (LPS)
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`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
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`Plaintiffs,
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`v.
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`APOTEX, INC. and APOTEX CORP.
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`Defendants.
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`
`EXPERT REBUTTAL REPORT OF
`ROBERT P. SCHLEIMER, PH.D.
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`1
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`CIP2012
`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.
`LEGAL STANDARDS ..................................................................................................... 5
`II.
`THE STATE OF THE PRIOR ART ............................................................................... 6
`III.
`A. Azelastine was a preferred antihistamine. .......................................................................... 6
`B. Fluticasone propionate was a preferred steroid. ................................................................. 7
`C. Combinations of azelastine and fluticasone were actually practiced in the prior art. ......... 8
`IV.
`SECONDARY CONSIDERATIONS .............................................................................. 9
`A. The primary need Dymista® meets is for a convenient single-dose spray. ......................... 9
`B. Dymista® does not exhibit unexpectedly superior results................................................. 12
`i. Dymista® does not have superior efficacy over the closest prior art (the
`sequential administration of azelastine and fluticasone). ........................................... 12
`ii. Dymista® does not have a faster onset of action than azelastine, or the
`sequential administration of azelastine and fluticasone. ............................................. 14
`iii. The oral combination studies relied upon by Drs. Kaliner and Carr would not
`have deterred a POSA from combining, or doctors from prescribing together,
`azelastine and fluticasone, and the efficacy of such a combination would not
`have been unexpected. ................................................................................................ 17
`iv. The inventor’s testimony reveals that the results of Dymista® were not
`unexpected. ................................................................................................................. 19
`C. The few instances of industry praise are unpersuasive. .................................................... 20
`CONCLUSION ............................................................................................................... 21
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`V.
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`i
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`2
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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 reserve the right to reply to any expert report
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`submitted by plaintiffs in response to my opening expert report.
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`3.
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`I have been asked in addition to respond to the expert reports of Dr. Warner Carr
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`and Dr. Michael Kaliner, submitted by plaintiffs on June 30, 2016, to the extent they opine that
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`Dymista® met a long felt but unmet need, or had unexpected superior results.
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`4.
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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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`5.
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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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`6.
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`My professional background and the bases for my opinions are set forth in my
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`opening expert report.
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`I.
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`SUMMARY OF OPINIONS
`First, it is my opinion that Dymista®, what Meda says is a commercial
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`7.
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`embodiment of the patents-in-suit, does not meet any long-felt but unmet need in the field of
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`treatments for allergic rhinitis.
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`2
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`3
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`8.
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`I understand from counsel that this “secondary consideration of non-obviousness”
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`looks to whether demand existed for the patented invention, and that others tried but failed to
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`satisfy that demand.
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`9.
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`Here, Dymista® did not satisfy any long-felt and unmet need. As explained in my
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`opening report, combination antihistamine/steroid therapies were known and practiced for the
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`treatment of allergic rhinitis in the art before June 2002. Indeed, doctors prescribed both
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`Astelin® (azelastine hydrochloride) and Flonase® (fluticasone propionate) to the same patient at
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`the same time before that date. Opening Report ¶ 79; Accetta Tr., at 22:16-23:5; 55:16-56:13.
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`Additionally, I have reviewed the expert report of Dr. James Wedner, MD, and note that he, too,
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`prescribed both drugs and observed other doctors doing so. Report of H. James Wedner ¶¶ 12,
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`25, 26.
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`10.
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`Thus, the only “need” Dymista could have satisfied was a desire by doctors or
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`patients to combine the active ingredients of Astelin® and Flonase® into a single formulation for
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`patient convenience. Yet, Drs. Carr and Kaliner have not shown that there was any particular
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`long-felt or unmet need for such convenience.
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`11.
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`I further understand from counsel that there was a so-called “blocking patent,”
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`which would have provided a strong disincentive for a person of ordinary skill in the art (a
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`“POSA”) to develop a combination azelastine hydrochloride and fluticasone propionate product.
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`See Hettche, U.S. Patent No. 5,164,194 (covering “a sterile and stable aqueous solution of
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`azelastine or one or more of its salts which can be used in the form of . . . a spray (preferably a
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`nasal spray)”) (expiring May 2011); see also Phillips, U.S. Patent No. 4,335,121 (covering
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`intranasal corticosteroids) (expiring May 2004). In my opinion, the fact that others did not co-
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`formulate azelastine and fluticasone before June 2002 relates to patent protection and not issues
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`of obviousness.
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`12.
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`Second, it is my opinion that Dymista® does not exhibit any unexpected or
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`surprising results in light of the closest prior art.
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`13.
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`Here, the closest prior art is the sequential administration of an azelastine HCl
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`drug (Astelin®) and a fluticasone propionate drug (Flonase®), which were prescribed together by
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`doctors before June 2002. In my opinion, Dymista® produced the same results as azelastine HCl
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`and fluticasone propionate, delivered together in two separate sprays. In fact, Drs. Kaliner and
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`Carr have discussed no study comparing the results of Dymista® to this closest prior art. The
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`only study comparing this prior art to azelastine monotherapy and fluticasone monotherapy
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`suggests that the magnitude of improvement is at least the same as the magnitude of
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`improvement with Dymista®. Moreover, as also explained, to the extent the monotherapies are
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`the correct prior art comparison, the superiority of Dymista® is not unexpected at all, for the
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`numerous reasons stated in my opening report.
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`14.
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`Thus, and as also explained in my opening report, the only attributes Dymista®
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`provides over the prior art are conveniences resulting from using a single nasal spray. But in my
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`opinion a more convenient dosing form was obvious at the time, such increased convenience
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`does not provide a meaningful advance in clinical care, this convenience did not meet any
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`previously unfilled need of any patient population, and the results of the co-formulation were
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`expected.
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`15.
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`Lastly, as I also explain in my opening report, the handful of studies on
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`combinations of oral antihistamines and a steroid on which Plaintiffs rely would not have
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`deterred a POSA from combining an intranasal azelastine and intranasal fluticasone for a number
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`of reasons—and the superior results from such a combination would be fully expected.
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`II.
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`LEGAL STANDARDS
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`16.
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`I have been informed that the following four factors are considered when
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`determining whether a patent claim is obvious: (a) the level of ordinary skill in the art; (b) the
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`scope and content of the prior art; (c) the differences between the prior art and the claim; and (d)
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`secondary considerations tending to prove obviousness or nonobviousness. These secondary
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`considerations may include: (i) long-felt need, (ii) unexpected results, (iii) skepticism of the
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`invention, (iv) teaching away from the invention, (v) commercial success, (vi) praise by others
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`for the invention, and (vii) copying by other companies. I have also been informed that there
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`must be a nexus (a connection) between the evidence that is the basis for the secondary factor
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`and the scope of the invention claimed in the patent.
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`17.
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`I have also been informed that, to support a finding of unexpected results, a
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`patentee must show that the claimed invention exhibits some superior property or advantage that
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`a person of ordinary skill in the art would have found surprising or unexpected compared to the
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`closest prior art. Further, in order to assert unexpected results, a patentee must present evidence
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`that the results claimed to be unexpected actually occurred. Speculation or unproven hypotheses
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`about what might become an unexpected result are simply not enough. I have also been
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`informed that, to be an unexpected result, the difference between the claimed invention and the
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`prior art must be a difference in kind, and not merely a difference in degree.
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`18.
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`In my opening report, I explained that I have been informed that a patent claim is
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`invalid as obvious if the differences between the subject matter sought to be patented and the
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`prior art are such that the subject matter as a whole would have been obvious at the time that the
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`invention was made to a person of ordinary skill in the art (a “POSA”). I defined a POSA for the
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`clinical aspect of this field as having “an M.D., Ph.D. or Pharm.D. in the field of
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`allergy/immunology and/or pharmacology (or the equivalent), and at least three additional years
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`6
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`of experience in the treatment, or research for treatments, of allergic rhinitis, including with
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`nasally administered steroids and antihistamines.” Opening Report ¶ 27. Drs. Smyth, Kaliner,
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`and Carr, in contrast, opine that the relevant POSA would have an M.D. degree and 2-4 years of
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`experience as a general practitioner. Smyth ¶ 23; Kaliner ¶ 28; Carr ¶ 15. I agree that a POSA
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`could have an M.D., but I disagree that only 2-4 years of general practice would suffice. A
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`POSA would have to have “at least three additional years of experience in the treatment, or
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`research for treatments, of allergic rhinitis, including with nasally administered steroids and
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`antihistamines.” Opening Report ¶ 27. Additionally, such a POSA need not have an M.D., but
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`could also have a Ph.D. or Pharm.D. in the field of allergy/immunology and/or pharmacology (or
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`the equivalent).
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`III. THE STATE OF THE PRIOR ART
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`A.
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`19.
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`Azelastine was a preferred antihistamine.
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`In their expert reports, Drs. Kaliner and Carr list 24 antihistamines under sections
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`titled “treatment options.” Kaliner ¶ 47; Carr ¶ 36. Azelastine is buried in the middle of their
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`lists without explanation. However, Drs. Kaliner and Carr omit or ignore several important
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`distinctions among antihistamines. In the first place, most of these antihistamines were not
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`available for intranasal administration—a critical issue. As I explain in my opening report,
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`intranasal (topical) antihistamines have much more rapid onsets of action than oral
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`antihistamines and a higher concentration can be delivered without adverse effects. Opening
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`Report ¶¶ 74, 83. See also, e.g.¸ ARIA (2001) at S230 (“Topical H1-antihistamines have a rapid
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`onset of action (less than 15 minutes) at low drug dosage, but they act only on the treated
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`organ.”); Nielsen et al. (2001), at 1565 (azelastine has “a faster onset of action than oral
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`antihistamines and act[s] within 15 to 30 minutes.”).
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`20.
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` What’s more, only two of the 24 antihistamines listed in Dr. Kaliner and Dr.
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`Carr’s list were available for intranasal administration—azelastine and levocabastine. Opening
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`Report ¶ 91. Of these, azelastine was known to be both safer and more effective. Id.; see also
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`Falser et al. (2001). Additionally, numerous prior art publications specifically recommended
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`azelastine. See, e.g., Lieberman (2001), at 201 (“Only two classes of medication have received
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`Federal Drug Administration approval for use in chronic rhinitis. Included are first-generation
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`oral antihistamines, topical corticosteroids and the topical second-generation antihistamine
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`azelastine.”).
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`21.
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`Additionally, Drs. Kaliner and Carr make no mention in their reports that
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`azelastine was known to have anti-inflammatory effects that treated the late-phase allergic
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`response as well as the early-phase response, thus making it a unique and preferred
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`antihistamine. See Opening Report ¶¶ 48-52; Fields et al. (1984); Fischer & Schmutzler (1981);
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`Katayama et al. (1987); Church & Gradidge (1980); Lytinas et al. (2002); Kusters et al. at
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`(2002); Hide et al. (1997); Honda et al. (1982); Togias et al. (1989); Ciprandi et al. (1996); Wang
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`et al. (1997); Mosges & Klimek (1998); Jacobi et al. (1999).
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`22.
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`Thus, Drs. Kaliner and Carr overstate the treatment options available for the
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`general AR patient population. To determine whether the claims of the patents-in-suit are
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`obvious—and to determine whether Dymista® meets a previously unmet need—a POSA and/or
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`practitioner would compare the drug to previously available treatments suitable for these same
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`patient populations (thus, for example, one would not compare Dymista® to injectable drugs).
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`Of these treatment options, intranasal azelastine was a preferred antihistamine.
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`B.
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`23.
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`Fluticasone propionate was a preferred steroid.
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`In both of their reports, Drs. Kaliner and Carr list eight steroids as available
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`treatment options. Kaliner ¶ 52; Carr ¶ 48. It is true that many of these steroids would be
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`suitable for nasal administration. Drs. Kaliner and Carr neglect to mention, however, that only
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`two of these steroids—mometasone furoate and fluticasone propionate—featured in best-selling,
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`FDA-approved products (Nasonex® and Flonase®, respectively). Additionally, fluticasone
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`propionate was the most potent of the steroids. Opening Report ¶ 66. Thus, Drs. Kaliner and
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`Carr again overstate the number of treatment options available for Dymista®’s patient
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`population. Only a few of the steroids they list were commercially available, and fluticasone
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`was a preferred steroid.
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`C.
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`Combinations of azelastine and fluticasone were actually practiced in the
`prior art.
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`24.
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`In his report, Dr. Kaliner states: “In short, the clinical POSA would attempt to
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`treat his patient by prescribing the appropriate drug or combination of drugs based on symptoms
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`and severity. Due to significant patient-to-patient variability in response to treatment options,
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`the clinical POSA would likely try one drug or combination and, if that regimen did not work,
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`the POSA would cycle through other drugs until he found the best treatment for his patient.”
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`Kaliner ¶ 73. I agree with this statement to the extent it suggests that clinicians combined
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`various medications with different mechanisms of action because they knew that different drugs
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`targeted different components of the mechanisms that caused AR and that targeting two
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`mechanisms could yield better results than targeting a single mechanism. For example, as
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`explained in my opening report, antihistamines specifically treated the early phase reaction and
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`corticosteroids treated more successfully the late phase reaction. Opening Report ¶¶ 44-47
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`(antihistamines); 54-58 (steroids). It thus would have been obvious to a POSA and a prescriber
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`to combine both an antihistamine and a steroid, and azelastine and fluticasone in particular,
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`which were preferred drugs and available in the FDA-approved products Astelin® and Flonase®.
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`25.
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`Indeed, doctors routinely prescribed both drugs to the same patient at the same
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`time. Opening Report ¶ 79; Accetta Tr., at 22:16-23:5; 55:16-56:13. Additionally, I have
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`reviewed the expert report of Dr. James Wedner, MD, and note that he, too, routinely prescribed
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`both drugs and observed other doctors doing so. Report of Dr. H. James Wedner ¶¶ 12, 25, 26.
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`Indeed, it is telling that Drs. Kaliner and Carr do not dispute that doctors regularly prescribed
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`these drugs together before the priority date of the patents-in-suit.
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`IV.
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`A.
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`SECONDARY CONSIDERATIONS
`The primary need Dymista® meets is for a convenient single-dose spray.
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`26.
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`I disagree with the conclusions of Drs. Kaliner and Carr that Dymista® meets a
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`long-felt but unmet need for an improvement in treatment. Dr. Kaliner opines that “the steady
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`growth in prevalence of allergic rhinitis demonstrates a long-felt need for improved treatment.”
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`Kaliner ¶ 84. Dr. Carr similarly opines that the “steadily growing incidence of allergic rhinitis
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`demonstrates a long-felt need for improved treatment.” Carr ¶ 91. While it is true that the
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`prevalence of allergic rhinitis and some other allergic diseases, such as asthma, has increased
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`over the last several decades, this fact is irrelevant with respect to the choice of medications and
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`the role of any particular drug. Whether the medications at issue (antihistamines and
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`corticosteroids) successfully treat the symptoms of allergic rhinitis will have no impact upon the
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`prevalence of the condition itself. Dymista® has not been demonstrated to, nor is it expected to,
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`have any effect on prevalence of disease. It is not curative in any patients, and it is not used to
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`prevent incidence of disease.
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`27.
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`Dr. Kaliner further opines that patients “were often left with incomplete symptom
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`relief,” noting that “[e]ven intranasal corticosteroids, widely accepted as the best option at the
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`time of invention, took days to reach full effect.” Kaliner ¶ 85. He concludes: “Patients needed
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`immediate and complete relief, and no available drug consistently offered both.” Id. Dr. Carr
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`similarly opines that “[n]ot only was complete symptom relief unavailable at the time of the
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`invention, but relief was too slow.” Carr ¶ 96. He adds, “it is important that . . . patients
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`experience quick relief to ensure that they stay on their prescribed treatment[.]” Id. ¶ 101.
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`28.
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`I agree with both of their assessments that corticosteroids take days to reach full
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`effect and that it was important for patients to experience quick relief. But that is why doctors
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`prescribed antihistamines in combination with steroids before the priority date of the patents-in-
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`suit. And that is why doctors, such as Dr. Accetta, prescribed azelastine and fluticasone in
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`particular—because azelastine was available for intranasal administration and was known to be
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`the most effective and fastest-acting antihistamine. Accetta Tr., at 22:16-23:5; 55:16-56:13.
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`29.
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`Dr. Kaliner also offers the following opinion:
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`Where patients take two or more nasal sprays, the sheer volume of fluid in the
`nasal passage has at least two negative effects: (1) the drug may not appropriately
`deposit on the location needed to provide a benefit; and (2) much of the fluid—
`including some of the active dose—either passes from the nasal passages into the
`stomach or drips out the front of the nose, decreasing the efficacy of the dose.
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`Kaliner ¶ 88. I agree with Dr. Kaliner that, before June 2002, it would have been known that
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`excess volume in the nasal passage may lead to a decrease in effectiveness due to leakage and
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`similar issues. Thus I noted in my Opening Report:
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`[P]roviding a combination of a known antihistamine and a known steroid in a
`single administration ensured that the dosing and administration of each drug was
`optimal. For example, it was known that excessive administration of liquids into
`the nasal cavities might be less effective due to drainage, and this might happen
`with sequential administration. See, e.g., Harris et al. (1986). Thus, a POSA
`would have been motivated to combine active ingredients in a single formulation
`to ensure maximal absorption.
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` See Opening Report ¶ 88. The primary need in the prior art that Dymista® might fill was simply
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`the convenience of one nasal spray. But even with regard to this need, it would have been
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`obvious that combining azelastine and fluticasone in one nasal spray would meet this need.
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`30.
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` Moreover, it is not entirely clear whether a single spray actually solves the alleged
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`problem of excess fluid in the nasal passage due to two sprays, or if such a problem actually
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`existed. As I explain in my opening report, a study comparing the efficacy of administering two
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`separate sprays together showed a magnitude of improvement over both monotherapies
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`comparable to the improvement of Dymista® over these monotherapies. Opening Report ¶¶ 127-
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`28. This confirms my opinion that there was no compelling need for a single combination spray.
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`In my opinion, to the extent the patented combination did incrementally improve AR treatment,
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`it did so only based on readily predictable attributes of the two drugs in combination. In short,
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`my opinion is that neither Dr. Kaliner nor Dr. Carr established that the claimed combination,
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`embodied in Dymista®, satisfied a long-felt but unmet need.
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`31.
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`For this reason, too, the Rajan Declaration referred to in Kaliner (¶ 91) is
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`unpersuasive. Dr. Rajan, a consultant for Cipla, submitted a declaration during the prosecution
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`of the patents-in-suit purporting to describe previously unmet needs met by Dymista®’s
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`counterpart in India, Duonase. In that declaration, he states that shortcomings of previously
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`available treatments included the misuse of decongestants; the slow onset of action for intranasal
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`steroids;
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`and
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`the
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`sedative
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`and
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`other
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`side
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`effects
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`of
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`oral
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`antihistamines.
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`MEDA_DYM_00001436. For all the reasons discussed here and in my opening report, all of
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`these shortcomings would have been resolved by the use of either intranasal azelastine—which
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`Dr. Rajan omits from his discussion—or a combination of intranasal azelastine with an intranasal
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`steroid. I would note in addition that Dr. Rajan, in his deposition, admitted that he did not know
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`whether a combination of intranasal azelastine and an intranasal steroid would have met those
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`needs (it would have). Rajan Dep. 140:7–144:1.
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`32.
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`Finally, Drs. Kaliner and Carr opine that Dymista® has a less bitter taste than
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`Astelin®, stating that only 4% of patients experience bitterness with Dymista® whereas nearly
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`20% of patients experience bitterness with Astelin®. Kaliner ¶ 100; Carr ¶ 84. For this
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`proposition, they cite the Dymista® 2015 label for the 4% figure, and the FDA approval letter for
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`Astelin® from fifteen years earlier for the 20% figure. However, many factors might contribute
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`to how patients experience the bitter taste of azelastine, and one must compare the patient
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`response in a single trial with similar conditions. Indeed, the Dymista® label reports that only
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`5% of patients experienced bitterness (dysgeusia) for azelastine monotherapy—that is only one
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`percent more than those who experienced bitterness with Dymista®:
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`MEDA_APTX02180635. Dymista® does not satisfy any unmet need in this respect.
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`B.
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`Dymista® does not exhibit unexpectedly superior results.
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`i. Dymista® does not have superior efficacy over the closest prior art (the
`sequential administration of azelastine and fluticasone).
`As explained in my opening report, Dymista® does not exhibit unexpectedly
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`33.
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`superior results. The closest prior art is the combined administration of a fluticasone propionate
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`spray and an azelastine hydrochloride spray, and studies showed a magnitude of improvement
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`over either monotherapy for this combined administration similar to that shown for Dymista®.
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`As I explain in my opening report, the Dymista® study in Hampel et al. (2010) showed an
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`improvement over fluticasone propionate of just over 39%, whereas the sequential administration
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`study in Ratner et al. (2008) showed an improvement just under 40%—essentially identical.1
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`Thus, the superiority of Dymista® over the closest prior art has not been demonstrated. Opening
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`Report ¶¶ 126-29.
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`34.
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`Although Drs. Kaliner and Carr do not cite Hampel, they cite Meltzer et al. (2012)
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`which reports a Dymista® study from one year after the Hampel et al. study. Meltzer et al.
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`reported the exact same improvement with Dymista® over fluticasone propionate—39%.
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`Meltzer et al. (2012) at 327 (“As shown in Fig. 2, MP29-02 [Dymista®] provided a 39%
`
`improvement in the rTNSS beyond the contribution of FP [fluticasone propionate].”). Taken as
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`true, therefore, this study does not change my analysis from before.
`
`35.
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`
`
`Finally, Drs. Kaliner and Carr also refer to Carr et al. (2012), which compares the
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`efficacy of Dymista® compared to fluticasone propionate and azelastine hydrochloride using
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`formulations with the exact same excipients as in the Dymista® formulation. This study
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`demonstrates an improvement over fluticasone propionate of only 11.8%.2 This is lower than
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`reported in either Hampel or Meltzer, and is far lower than the improvement reported for
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`sequential administration of fluticasone and azelastine in Ratner (2008). This continues to
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`confirm my opinion that the superior efficacy of Dymista® over the closest prior art of separate
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`administration of the monotherapies has not been demonstrated, even though the drug does
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`contain obvious clinical benefits over either azelastine or fluticasone alone.
`
`1
`I have also refined the calculations using better figures from both Hampel et al. and Ratner et al. The
`improvement over fluticasone for Dymista® was more accurately just over 38%, and the improvement over
`fluticasone for a sequential administration was just over 42%. Previously, I had compared the percentage
`improvements for each monotherapy to the percentage improvement for the combination product or the sequential
`administration. Because the subjective nature of the rTNSS scoring, this will sufficiently approximate differences in
`improvement for the various treatments. If one actually calculates based on the mean rTNSS scores, which are
`available in Figure 1 of Hampel and Figure 1 and Table 2 of Ratner, the improvement differences over fluticasone
`are [(5.31-3.84)/3.84] x 100 = 38.3% for the combined product and [(7.4-5.2)/5.2] x 100 = 42.3% for sequential
`administration of the monotherapies. Because of the subjective nature of the scores, either this or my previous
`figures are sufficient approximations. Using the actual rTNSS scores merely further highlights that Dymista® has
`not been proven to be an improvement over a sequential administration.
`2
`This is calculated from the mean change in rTNSS from the baseline as follows: [(5.7-5.1)/5.1] x 100 =
`11.8%.
`
`
`
`13
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`14
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`

`

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`36.
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`
`
`To my knowledge, there is no evidence available showing the superiority of the
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`combination over the administration of both drugs separately but concurrently. Dymista®’s
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`improved efficacy over those monotherapies would be not at all unexpected for all the reasons
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`laid out in my opening report. Id. ¶ 130.
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`ii. Dymista® does not have a faster onset of action than azelastine, or the
`sequential administration of azelastine and fluticasone.
`Drs. Kaliner and Carr both opine that Dymista® had a fast onset of action (as little
`
`37.
`
`
`
`as 30 minutes) and that this would have been unexpected from the prior art. Dr. Carr states:
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`“Dymista® achieves a statistically superior reduction in symptoms in as little as 30 minutes
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`when compared to placebo. This accelerated onset of action would have been unexpected to a
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`POSA at the time of invention. As I previously explained, corticosteroids have a slow onset of
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`action on the order of days, and azelastine had an onset of three hours. The POSA would not
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`have expected Dymista® to take effect in thirty minutes.” Carr ¶ 87. Dr. Kaliner states
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`similarly: “Dymista® achieves a statistically superior reduction in symptoms in as little as 30
`
`minutes when compared to placebo. This accelerated onset of action would have been
`
`unexpected to a POSA at the time of invention, who would not have expected Dymista® to take
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`effect in thirty minutes. As I previously explained, corticosteroids have a slow onset of action on
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`the order of days, and azelastine had an onset of one to three hours.” Kaliner ¶ 99. Both rely on
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`prescribing information for Astelin® (azelastine hydrochloride) as indicating it takes effect in
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`three hours. Carr ¶ 86; Kaliner ¶ 98.
`
`38.
`
`
`This conclusion is wrong. The Astelin® label on which Kaliner and Carr both rely
`
`states: “In dose-ranging trials, Astelin® Nasal Spray administration resulted in a decrease in
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`symptoms, which reached statistical significant from saline placebo within 3 hours after initial
`
`dosing and persisted over the 12-hour dosing interval.” Astelin® Label [APOTEX_AZFL
`
`
`
`14
`
`15
`
`

`

`
`
`0059088] (emphasis added). The label does not specify that azelastine did not have effect until 3
`
`hours had passed.
`
`39.
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`
`
`Indeed, the opinion that the speed of onset was unexpectedly rapid fails to
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`acknowledge a clear literature showing that azelastine gives measurable benefits within minutes.
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`This literature—which would have been known to a POSA and to many prescribing doctors—
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`taught that azelastine took effect in 15 to 30 minutes. Nielsen et al. (2001), at 1565 (azelastine
`
`has “a faster onset of action than oral antihistamines and act[s] within 15 to 30 minutes.”); ARIA
`
`(2001) at S230 (“Topical H1-antihistamines have a rapid onset of action (less than 15 minutes) at
`
`low drug dosage, but they act only on the treated organ.”).
`
`40.
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`
`
`One of the most powerful studies on rapidity was done by Greiff et al., which
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`evaluated the rapidity of azelastine’s ability to inhibit both sneezing and vascular leak (a
`
`component of nasal secretions) caused by histamine. This study found that azelastine inhibited
`
`both parameters profoundly within one hour of treatment, suggesting an impact within minutes.
`
`Figure 2D, reproduced below, illustrates the effects on α-2 macroglobulin, a measure of blood
`
`vessel leakage, one hour after administration of azelastine. The histamine-induced leak is
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`completely blocked using a low doses of histamine in the challenge (40 µg/ml) and nearly
`
`completely blocked using the higher dose of histamine to cause the response (400 µg/ml):
`
`
`
`15
`
`16
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`

`

`
`
`
`
`
`
`This graph shows that both cetirizine (middle bar) and azelastine (left bar) reduced the presence
`
`of α-2 macroglobulin created by a histamine challenge. Not only did azelastine reduce the
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`presence of α-2 macroglobulin more than did cetirizine, it almost completely eliminated the
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`presence of α-2 macroglobulin within one hour. This demonstrates that azelastine acts within
`
`minutes, not hours. Grieff et al (1997).
`
`41.
`
`
`
`Therefore, the conclusion of Drs. Carr and Kaliner that a POSA would find it to
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`be “unexpected” for Dymista® to act within 30 minutes is simply incorrect. The azelastine in
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`Dymista® is the ingredient that acts within 30 minutes, not the fluticasone. And azelastine was
`
`known to act within 15 to 30 minutes.
`
`
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`16
`
`17
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`

`

`
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`iii. The oral combination studies relied upon by Drs. Kaliner and Carr
`would not have deterred a POSA from combining, or doctors from
`prescribing together, azelastine and fluticas