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`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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`Defendants.
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`EXPERT REPLY REPORT OF MAUREEN D. DONOVAN, PH.D.
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`
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`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
`
`
`Plaintiffs,
`
`
`v.
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`APOTEX, INC. and APOTEX CORP.
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`
`1
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`CIP2016
`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.
`III. ANALYSIS ........................................................................................................................ 5
`A. A POSA would not need to choose between a solution and a suspension, because
`every suspension is already a combination of dissolved materials in solution and
`undissolved materials in suspension. .................................................................................. 5
`B. The core issue is whether any ingredient necessary for the dissolution of
`azelastine hydrochloride would be expected to be incompatible with the
`ingredients necessary for the suspension of fluticasone propionate—Dr. Smyth
`gives no example or reason to think that any such an incompatibility exists or was
`thought to exist. ................................................................................................................... 9
`C. As of June 2002, it would have been obvious to a POSA formulator how to
`formulate an azelastine hydrochloride-fluticasone propionate product and a POSA
`would have had an expectation of success. ....................................................................... 11
`D. It would have been obvious to a POSA which excipients to try for a successful
`formulation. ....................................................................................................................... 13
`E. Dr. Herpin’s studies were conducted with impermissible hindsight and do not
`prove that Cramer III is not enabled. ................................................................................ 18
`i. Dr. Herpin did not act as a formulator POSA as of 2002. .......................................... 18
`ii. Dr. Herpin does not prove that Cramer is inoperable. ................................................ 19
`IV. CONCLUSION ............................................................................................................... 23
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`1
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`2
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`1.
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`
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`I, Maureen Donovan, have been retained by Defendants Apotex, Inc., and Apotex
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`Corp. as an expert to analyze certain aspects of U.S. Patent Nos. 8,163,723 (“the ’723 patent”);
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`8,168,620 (“the ’620 patent”); and 9,259,428 (“the ’428 patent”), in connection with 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, and
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`I incorporate both reports by reference. I have been asked to respond to the report of Hugh
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`David Charles Smyth, Ph.D., submitted by plaintiffs on July 29, 2016, in rebuttal to my opening
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`report. I reserve the right to amend or supplement my opinions in light of evidence presented by
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`or on behalf of Meda Pharmaceuticals and Cipla Ltd., or in connection with additional
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`information that may be made available to me in the future.
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`3.
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`In addition to the information, materials and opinions discussed in this report, I
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`may use demonstrative exhibits at trial to the extent useful for explaining and understanding the
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`opinions I set forth in this report.
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`4.
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`I may testify at trial about background scientific concepts related to my opinions
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`to the extent that is useful for understanding my opinions.
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`5.
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`I am being compensated for my time on this matter at a rate of $250/hour for
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`general document and background review, $400/hour for preparing reports, and $600/hour for
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`testifying at trial or depositions. Those are my standard consulting rates. My compensation is in
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`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 opinion are set forth in my
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`opening expert report.
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`I.
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`SUMMARY OF OPINIONS
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`7.
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`Dr. Smyth’s rebuttal report rests on two fundamental misconceptions. First, he
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`opines that one cannot merely assume that a formulator would have sought to combine azelastine
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`3
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`hydrochloride and fluticasone propionate and then proceed to determine how to go about
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`formulating the two active ingredients. This, he claims, would “be nothing more than hindsight:
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`starting at the end of the process by considering the obvious way a formulator POSA would
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`proceed if she were to make a combination nasal spray that uses azelastine hydrochloride and
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`fluticasone propionate.” Smyth ¶ 2. Rather, Dr. Smyth claims, “a formulator first would
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`consider formulation issues when selecting an active ingredient,” and by doing so “would be
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`counseled away from trying an intranasal antihistamine and steroid combination.” ¶ 3. A
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`formulator would be counseled away, he argues, because “given the formulation challenges of a
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`solution-suspension system, such a combination would not have been obvious to try, and in June
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`2002, a formulator POSA would not have had a reasonable expectation of success in combining
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`those systems into a new type of nasal dosage form.” ¶ 5.
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`8.
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`Dr. Smyth’s hindsight argument, however, assumes the conclusion that a co-
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`formulation would in fact have been difficult to achieve. My opinion, as I explained in my
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`opening report, is that there would be no readily apparent difficulties in such a formulation, and
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`hence it would be obvious for a formulator to combine the two ingredients if that is what was
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`desired. Assuming that such a combination is desired, as Dr. Schleimer opines without the use
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`of hindsight, only then determining how to formulate it is not hindsight on my part or the part of
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`any other expert whose report I have read on behalf of Apotex. Dr. Smyth, on the other hand,
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`relies entirely on hindsight to dig through the literature finding what he says are reasons the
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`claimed combination formula may not have worked. That inquiry makes no sense and is not
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`how scientists work. A formulator tasked with making the combination product would have
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`known that it was fully possible and would have had a reasonable expectation of success—even
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`if not guaranteed success—based on the teachings of the prior art.
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`9.
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`Second, Dr. Smyth’s entire report is based on his opinion that formulating
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`azelastine hydrochloride and fluticasone propionate would be difficult because it would require
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`creating “a new dosage form: a solution/suspension” (¶ 61)—or as he puts it elsewhere, a
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`“dosage form that is both a solution and suspension” (¶ 50). See also, e.g., ¶¶ 1, 4, 5, 23, 37, 59,
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`68, 69, 74–78, 84, 88, 104, 105, 107 (making similar statements). This is incorrect. Every
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`suspension is a “dosage form that is both a solution and suspension.” ¶ 50. That is because
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`every suspension includes materials that are in solution as well as materials that are undissolved.
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`Flonase®, for example, is actually ~99.95% fluid vehicle with dissolved materials and less than
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`0.05% undissolved particles in suspension. Opening Report ¶ 93. Hence Dymista® is actually
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`properly categorized—as Dr. Smyth notes in paragraph 55—as an “aqueous suspension” and not
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`as some hybrid, “new” dosage form.
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`10.
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`The question for a POSA as of June 2002—just as it would be for a POSA today
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`when making any formulation with similar goals—is whether adding azelastine hydrochloride to
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`the Flonase® formulation would be expected to be incompatible with fluticasone propionate or
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`any of the excipients in Flonase®. That is the question that would have determined, as of June
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`2002, whether formulating a combined azelastine hydrochloride-fluticasone propionate product
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`would have been obvious to a POSA. Dr. Smyth does not give a single example of such an
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`incompatibility. His report fails to show that a POSA would foresee any difficulty in
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`formulating a suspension of fluticasone propionate
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`that
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`includes dissolved azelastine
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`hydrochloride.
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`11.
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`As I explained in my opening report, a POSA would have expected none. It was
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`known how to formulate azelastine hydrochloride from the Astelin® product, it was known how
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`to formulate fluticasone propionate from the Flonase® product, and a POSA would have
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`5
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`expected no obvious incompatibility by combining the products, and if any unexpected
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`incompatibility did arise, adjusting with known excipients and optimization techniques would
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`have been a matter of routine experimentation.
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`II.
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`LEGAL STANDARDS
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`12.
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`I note that throughout his report, Dr. Smyth appears to assume that the legal
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`standard for obviousness is that a POSA must have expected success to a complete certainty. He
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`states that a formulator must have a “reasonable expectation of success,” but claims that there
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`would be no such expectation because “a formulator POSA attempting to combine fluticasone
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`propionate and azelastine hydrochloride would be unable to predict how the two actives interact
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`with each other.” ¶ 80. The factual premise of his conclusion is incorrect, as I have explained in
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`detail elsewhere. A POSA would have no reason to expect that there would be any material,
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`negative interaction between the two active ingredients, and indeed there is no material, negative
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`interaction between them. But Dr. Smyth appears to conflate the actual standard—a reasonable
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`expectation of success—with the proposition that a POSA must be able to predict every
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`interaction in its entirety and to a certainty in order for something to be obvious. I do not believe
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`that proposition is consistent with the standard. As I explained in my opening report and as I
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`explain again below, much was and is known about each ingredient and excipient in Astelin® and
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`in Flonase® and a POSA would fully have expected a satisfactory formulation containing
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`azelastine hydrochloride and fluticasone propionate and no incompatibilities—even if she were
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`unable to know in advance to an absolute certainty.
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`III. ANALYSIS
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`A.
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`13.
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`A POSA would not need to choose between a solution and a suspension,
`because every suspension is already a combination of dissolved materials in
`solution and undissolved materials in suspension.
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`As summarized above, Dr. Smyth’s entire opinion that it would not be obvious to
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`5
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`6
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`formulate a combination product with azelastine hydrochloride (which is FDA-approved in
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`dissolved form and sold as the nasal spray Astelin®) and fluticasone propionate (which is FDA-
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`approved as a suspension dosage form and sold as the nasal spray Flonase®) is based on a
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`misconception—that a POSA would not be led to combine a solution and suspension because
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`such a combination would be novel. He writes: “[T]he formulator POSA would have understood
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`that nasal solutions and nasal suspensions referred to two separate dosage forms and therefore
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`would have selected one or the other. To combine the two dosage forms would have required a
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`leap in the state of the art, as I am not aware of any art the describes a successful
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`solution/suspension nasal spray that combines two actives in a single dosage form available as of
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`June 2002.” ¶ 23.
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`14.
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`Elsewhere he opines: “A formulator POSA seeking to develop a new drug product
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`would use one of the existing dosage forms available, especially because literature and guidance
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`were available only for existing dosage forms.” ¶ 37. Thus, “a formulator POSA would not
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`have had a reasonable expectation of success in developing a dosage form that is both a solution
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`and a suspension.” ¶ 59. He subsequently reiterates: “Combining azelastine hydrochloride and
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`fluticasone propionate [in] a single nasal spray in 2002 would require developing a new dosage
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`form: a solution/suspension in which the azelastine hydrochloride is in solution, while the
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`fluticasone propionate remains in suspension.” ¶ 61.
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`15.
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`He adds that a POSA would have looked to several resources on existing dosage
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`forms, but no such guidance was available “at that time for a formulation that would be both a
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`nasal solution and a nasal suspension.” ¶ 68. “A formulator POSA, therefore, would have little
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`to no information on the challenges, problems, or potential ways to formulate a nasal
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`solution/suspension combination product.” Id. It would not have been obvious to formulate
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`6
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`“such a product given the lack of any working examples or literature describing how to
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`formulate such a product.” ¶ 69. For example, he claims, “Cramer does not provide useful
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`guidance to a formulator POSA trying to develop a combination nasal solution/suspension
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`product.” ¶ 74. Similarly, “[t]he Segal reference provides no guidance at all on how to
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`formulate a combination nasal solution/suspension product.” ¶ 75.
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`16.
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`Dr. Smyth repeats similar statements in paragraphs 5, 50, 60, 78, 88, 104, 105,
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`107, and elsewhere in his opinion, which depends on this proposition. Dr. Smyth concludes: “In
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`my opinion, the technical knowledge necessary to create a new dosage form goes well beyond
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`ordinary creativity to create a new dosage form.” ¶ 76. “In my opinion, discovering a
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`formulation that would lead to a stable and useful nasal spray that combined a solution and a
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`suspension could not have been done by routine optimization as of June 2002.” ¶ 77. “It is my
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`opinion that the asserted claims of the patents-in-suit are not obvious, for at least the reason that
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`the invention required combining two different and incompatible dosage forms.” ¶ 1. “Solutions
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`and suspensions are two different dosage forms, and the literature did not set forth ways to make
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`a combination of these two distinct dosage forms.” ¶ 4.
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`17.
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`Each of these statements and the opinions they support in paragraphs 1, 4, 5, 23,
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`37, 59, 61, 68, 69, 74–78, 84, 88, 104, 105, 107, and elsewhere in the report rest on the
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`misconception that combining an active ingredient in solution with an active ingredient in
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`suspension would be a “new dosage form.” This is incorrect. Every suspension is in fact already
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`a combination of solution and suspension. That is because many suspensions have numerous
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`ingredients —indeed, most ingredients—in solution. Only a small fraction of the total weight is
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`undissolved particles. Flonase®, for example, which is a “suspension” because the active
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`ingredient fluticasone propionate is suspended, is in fact ~99.95% fluid vehicle with dissolved
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`materials and less than 0.05% undissolved materials in suspension. Opening Report ¶ 93.
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`Indeed, even some of the fluticasone propionate is dissolved in solution. It thus “combines a
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`solution and suspension.” There is no such thing as the “new” dosage form that supposedly
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`would be required before azelastine hydrochloride and fluticasone propionate could be
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`combined. That is why Dymista®—the very combination of azelastine hydrochloride and
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`fluticasone propionate that is the embodiment of the patents-in-suit—is categorized as a
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`suspension, as Dr. Smyth himself notes in his report. ¶ 55.
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`18.
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`Indeed, the key pharmaceutical textbook, Remington’s (2000), defines a
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`suspension as follows (p. 743, emphasis supplied): “The physical chemist defines the word
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`‘suspension’ as a two-phase system consisting of a finely divided solid dispersed in a solid,
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`liquid, or gas. The pharmacist accepts this definition and can show that a variety of dosage
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`forms fall within the scope of the preceding statement. There is, however, a reluctance to be all-
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`inclusive, and it is for this reason that the main emphasis is placed on solids dispersed in
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`liquids.” In other words, any POSA would understand that a suspension by definition is a “two-
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`phase system,” typically containing a solid phase dispersed in a liquid phase.1
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`19.
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`It is telling that Dr. Smyth makes the following observation in support of his
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`opinion: “The textbooks that Dr. Donovan relies upon support my opinion because each
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`discusses solutions and suspensions in different sections. I would expect that if the formulation
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`considerations were related they would have been discussed together.” ¶ 60. However, a single
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`chapter in Remington’s (Chapter 39: “Solutions, Emulsions, Suspensions, and Extracts”)
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`discusses both solutions and suspensions. But what is more, Remington’s discusses the science
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`1 Some amount of the solid phase is dissolved in the liquid phase where it reaches a concentration equal to the
`equilibrium solubility in the system. Any excess material remains in the solid form. Other materials, alone or in
`combination, can be added to the suspension to improve its performance or organoleptic characteristics, including its
`taste or color, its resistance to bacterial or fungal growth, or its ability to slow the settling of the particles due to
`gravity, for example.
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`8
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`of tonicity in Chapter 18, of rheology in Chapter 23, and of drug absorption in Chapter 57.
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`These are not discussed with either the section on solutions in Chapter 39 or the section on
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`suspensions in that same chapter, but knowledge of all these subjects would have been crucial for
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`a POSA in order to formulate either a solution or a suspension—and a POSA would have known
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`to consider them. The section in Chapter 39 on suspensions also explains (p. 744) that the
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`principles outlined in Chapters 20 and 22 govern the formulation of suspensions—yet these are
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`in separate parts of the textbook. Dr. Smyth’s main observation in support of his claim that a
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`solution/suspension would be a new dosage form is nothing but a non-sequitur.
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`B.
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`The core issue is whether any ingredient necessary for the dissolution of
`azelastine hydrochloride would be expected to be incompatible with the
`ingredients necessary for the suspension of fluticasone propionate—Dr.
`Smyth gives no example or reason to think that any such an incompatibility
`exists or was thought to exist.
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`20.
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`An important question for a POSA as of June 2002 in determining how to proceed
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`with formulating any suspension or solution is whether any of the ingredients is expected to be
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`incompatible with any of the others. Dr. Smyth says that when a formulator seeks to enhance the
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`solubility of a particle, she will normally look to different ingredients than if she were looking to
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`enhance the suspendability of a particle. But Dr. Smyth seems to assume that these opposing
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`objectives are sought for the same particle. Yet different active ingredients can have vastly
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`different properties, including vastly different solubilities. There was no reason to think that
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`azelastine hydrochloride even needed the assistance of a solubility-enhancing excipient (because
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`Astelin® had no such excipient), and if it did that such an excipient would have any meaningful
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`impact on the suspendability of fluticasone propionate. A POSA would select excipients to
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`accomplish the desired endpoints—and would certainly evaluate whether such excipients might
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`hinder or change the properties of the other drug—but there is a reasonable expectation that a
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`POSA would be able to find excipients that are perfectly compatible with both objectives.
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`21.
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`For example, Dr. Smyth states that “[t]o prevent dissolution” of suspended
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`particles, “a formulator must select the appropriate vehicle and avoid excipients that may
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`promote partial dissolution of the active ingredient” and that “[s]uspensions generally require
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`additional excipients to ensure a uniform and stable dispersion of the suspended particles, unlike
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`what occurs with a solution.” ¶ 62. He then states that to ensure the dissolution of an active
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`ingredient in solution, “a formulator may select excipients that promote solubility, including
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`solubilizing excipients, co-solvents, among others,” and that “[a] formulator may promote
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`solubility by modifying the pH of the solution, for example.” ¶ 63.2
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`22.
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`But, crucially, Dr. Smyth does not give a single example or reason to think that
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`any of the ingredients known from the Astelin® formulation (indeed, Astelin® does not have any
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`solubility enhancing excipients at all) would be incompatible with any of the ingredients known
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`from the Flonase® formulation to be useful for the suspension of fluticasone propionate. That is
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`the core issue, and it is one on which Dr. Smyth offers nothing but a vague generality: “a
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`formulator POSA would recognize that techniques used to promote solubility of an active
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`ingredient in a formulation could potentially adversely affect the acceptability of a suspended
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`active ingredient in the same formulation.” ¶ 64 (emphasis added). What Dr. Smyth does not
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`acknowledge is that those “techniques used to promote solubility” to which he refers were
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`already known from the Astelin® formulation (and in fact, no solubility enhancers are necessary),
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`and the techniques used to promote the suspension of fluticasone were already known from the
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`Flonase® formulation, and a POSA would have no reason to believe any of these were
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`incompatible with each other. Thus, a POSA would have had a reasonable expectation of
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`2 Indeed, Dr. Smyth’s observation here fully supports the argument in my rebuttal report that MedPointe did not
`make a serious attempt at formulation—because it did not undertake any of these obvious steps to enhance the
`solubility of azelastine, even assuming that azelastine was not dissolved in the supernatant.
`10
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`11
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`success in attempting to combine azelastine hydrochloride and fluticasone propionate in a single
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`suspension product.
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`C.
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`As of June 2002, it would have been obvious to a POSA formulator how to
`formulate an azelastine hydrochloride-fluticasone propionate product and a
`POSA would have had an expectation of success.
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`23.
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`Not only does Dr. Smyth offer no reason to expect that any of the considerations
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`
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`for formulating azelastine hydrochloride in solution would be incompatible with any of the
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`considerations for formulating fluticasone propionate in suspension, but as explained in my
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`opening report a POSA would expect no such incompatibilities. The reason a POSA would
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`expect no significant incompatibilities or barriers to formulation is because it was already known
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`how to formulate azelastine hydrochloride in a successful formulation (Astelin®) and it was
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`already known how to formulate fluticasone propionate in a successful formulation (Flonase®).
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`A formulator would have begun with Flonase® because suspensions are generally more difficult
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`to formulate, and then added azelastine hydrochloride. Because Astelin® had no solubility-
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`enhancing ingredients, a POSA would not have been concerned about the opposing
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`considerations to which Dr. Smyth refers. If there were unanticipated incompatibilities, they
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`could be accommodated with routine optimization or by selecting alternative known excipients
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`with similar functions.
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`24.
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`Thus, paragraphs 24-52 & 66-67 of Dr. Smyth’s report detailing the many steps in
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`formulating various dosage forms such as tablets, powders, and emulsions—suggesting that a
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`POSA would have to wade through all of these possibilities—is beside the point, because as of
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`June 2002 a formulator already knew how successfully to formulate azelastine hydrochloride and
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`how successfully to formulate fluticasone propionate as nasal sprays for local treatment of
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`allergy.
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`25.
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`Indeed, as the patents at issue here state, “It would be highly desirable . . . to
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`provide a treatment that combines the effects of anti-histamine treatments and steroid
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`treatments . . . .” ’620 Patent at 1:34-36. Thus, a POSA would have started with the known
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`treatments, including Astelin® and Flonase®. Moreover, a POSA would not have looked to
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`formulate a tablet because, as Dr. Kaliner recognizes in his rebuttal report, “the use of
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`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.” Kaliner
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`Rebuttal Report ¶ 36; see also Kaliner Opening Report ¶ 52 (“At the time of invention, intranasal
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`corticosteroids were generally recognized as the best treatment option for allergic rhinitis.”). A
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`POSA, in other words, would know to start with an intranasal steroid. If she were looking to
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`formulate a combination product, she would look to intranasal antihistamines, which can be
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`combined with the intranasal steroid.
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`26.
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`Dr. Smyth argues, however, that starting with Flonase® “would not lead to a
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`workable product” because, as he previously described, “formulating a solution requires vastly
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`different considerations than formulating a suspension” and “at several critical points, those
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`considerations directly compete with each other.” ¶ 96. But as before, Dr. Smyth has given no
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`example that the known requirements for dissolving azelastine in solution were incompatible
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`with the known requirements for suspending fluticasone—and a POSA would have expected
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`none.
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`27.
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`
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`Dr. Smyth next relies on MedPointe’s purported failure to formulate a
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`combination product in 2006. ¶¶ 97-101. But as explained in my rebuttal report to Dr. Smyth’s
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`opening report, MedPointe’s short-lived experiment—terminated within a few days once
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`MedPointe discovered Cipla’s intellectual property—cannot be considered a serious attempt to
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`formulate a combination product. I incorporate my rebuttal report into this reply.
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`28.
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`Dr. Smyth claims that even if MedPointe “could have determined how to
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`successfully dissolve azelastine in a suspension system, it would have needed to conduct
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`numerous additional tests to verify a successful formulation” (¶ 100) and “would have then
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`needed to analyze whether the formulation was a suitable nasal spray (¶ 101). Any POSA would
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`have to run tests and analyses if she were trying to develop a product for commercialization
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`following FDA approval. Dr. Smyth’s implication that such tests would somehow render a
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`formulation attempt nonobvious merely goes to show that MedPointe’s formulation attempt in
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`2006—in which they conducted not a single test, and in fact likely did successfully dissolve
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`azelastine—was not a serious one.
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`29.
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`Regardless, MedPointe’s “failure” to formulate in 2006, even if it was a failure, is
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`merely hindsight on the part of Dr. Smyth, and would not factor into a POSA’s expectation of
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`success in 2002.
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`30.
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`
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`Dr. Smyth’s only remaining argument that formulating a combination product
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`would have been nonobvious is that “effects of small changes in a formulation are
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`unpredictable.” ¶¶ 79-94. That does not affect a POSA formulator’s expectation whether
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`combining known elements would be successful. A POSA would have fully expected success in
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`attempting to co-formulate azelastine hydrochloride and fluticasone propionate, expected that
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`some unanticipated problems might arise, and expected that, should any such problem arise, they
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`could be resolved with known optimization and excipient-selection techniques.
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`D.
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`It would have been obvious to a POSA which excipients to try for a
`successful formulation.
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`31.
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`
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`Dr. Smyth specifically claims that it would not have been obvious how to account
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`
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`for the pH of a combined formulation, or for the preservatives, tonicity agent, suspending agent,
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`or the concentrations of the active ingredients in a co-formulated product. He is wrong on each
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`count.
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`32.
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` With respect to pH, he writes: “Astelin® uses a buffer system to ensure that the
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`pH of the formulation is stable and compatible with the nasal mucosa. Flonase®, on the other
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`hand, does not use a buffer system because fluticasone propionate is stable with the
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`formulation’s pH range.” ¶ 82. Nothing in this paragraph suggests a POSA would expect any
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`problem with respect to pH. A POSA would combine the active ingredients and then determine
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`whether the pH needed to be adjusted or controlled as in Astelin®, or not, as in Flonase®. If
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`adjustment were necessary, a POSA would have no difficulty finding a buffer compatible with
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`both of these active ingredients. In particular, a POSA would start with the buffer used in
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`Astelin®. Further, a POSA would anticipate no incompatibility between fluticasone propionate
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`and any known buffer used in nasal spray formulations. As with adjusting tonicity, adding
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`buffers to solutions or suspensions is not novel—it is what formulators do every day and what
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`their education and experience train them to do.
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`33.
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`
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`As for preservatives, Dr. Smyth writes: “There would be many choices of
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`preservatives that could have been used for nasal products in 2002 . . . .” ¶ 83. But a POSA
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`would have initially selected the preservatives in Astelin® and Flonase®—both included
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`benzalkonium chloride, a very common preservative. Two other routinely used preservatives
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`were phenylethyl alcohol and edetate disodium—the former of which was present in Flonase®
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`and the latter of which was present in Astelin®. A POSA would not have expected any
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`challenges in terms of creating an adequate preservative system.
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`34.
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`
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`Next, Dr. Smyth opines that glycerin would not have been an obvious choice. He
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`writes: “I see no particular reason why using glycerine or the claimed range of glycerine would
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`have been obvious or routine to a POSA seeking to formulate a combination azelastine
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`hydrochloride and fluticasone propionate product. Glycerine was not used in either Astelin® or
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`Flonase®.” ¶ 85. Here, Dr. Smyth undermines the rest of his argument—he acknowledges that
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`if glycerin had been used in either Astelin® or Flonase®, that would have been a reason why
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`using it would be obvious. But every other excipient claimed by the asserted claims in this case
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`was in either Astelin® or Flonase®. Thus, Dr. Smyth effectively concedes that the inclusion of
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`those other ingredients would have been obvious.
`
`35.
`
`
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`As for glycerin itself, Dr. Smyth ultimately opines that “a formulator had no
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`information on how glycerine interacts with fluticasone propionate.” ¶ 86. But that would not
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`have deterred a POSA from using glycerin. A POSA would have had any number of known
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`tonicity-adjusting agents to choose from and would have no reason to expect that any of them
`
`would have any kind of negative interaction with fluticasone propionate. To the extent that any
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`tonicity-adjusting agent did have a negative interaction with another ingredient, it would have
`
`taken routine experimentation to choose another agent that had no such interaction. I understand
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`from counsel that routine experimentation does not amount to nonobviousness.
`
`36.
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`
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`For this same reason, Dr. Smyth’s argument that using microcrystalline cellulose
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`and carboxymethylcellulose (“MCC-CMC”) would not have been obvious—a “POSA had no
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`experience with how any excipients would interact with the selected ingredients,” ¶ 87—gets it
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`exactly backward. MCC-CMC was known to be perfectly acceptable in the Flonase®
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`formulation, and there was no reason for a POSA to think the inclusion of azelastine
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`hydrochloride would be incompatible. Dr. Smyth offers no reason why a POSA would not have
`
`expected success by the inclusion of the obvious choice of MCC-CMC, already in the Flonase®
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`formulation, except for his refrain that you never know for sure until you try.
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`37.
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`
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`Each of the above points fails to demonstrate that formulating a combination
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`product would not be obvious. As I explained in my opening report, developing formulations
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`with suitable preservatives, tonicity, and a suitable pH is something formulators do every day
`
`using common and known ingredients. What is more, Dr. Smyth’s opinion appears to assume
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`that a formulator would have known vir