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 REPORT OF MAUREEN D. DONOVAN, PH.D.
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`1
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`CIP2015
`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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`PERSONAL BACKGROUND ........................................................................................... 1
`I.
`LEGAL STANDARDS ...................................................................................................... 3
`II.
`SUMMARY OF OPINIONS .............................................................................................. 6
`III.
`ANALYSIS OF THE PRIOR ART .................................................................................... 8
`IV.
`A. State of the art of nasal drug delivery systems. .................................................................. 8
`B. Azelastine HCl and Astelin® ............................................................................................... 9
`1. Preservatives ............................................................................................................... 12
`2. Suspending and thickening agents .............................................................................. 13
`3. Tonicity-adjusting agents (isotonization agents) ........................................................ 14
`C. Fluticasone propionate and Flonase® ................................................................................ 15
`1. Preservatives ............................................................................................................... 17
`2. Thickening agents ....................................................................................................... 18
`3. Tonicity-adjusting agents (isotonization agents) ........................................................ 18
`4. Surfactants................................................................................................................... 18
`D. Additional Prior Art .......................................................................................................... 19
`1. Handbook of Pharmaceutical Excipients .................................................................... 19
`2. Hettche ........................................................................................................................ 20
`3. Cramer......................................................................................................................... 21
`4. Segal ............................................................................................................................ 24
`5. ADVAIR Diskus® ....................................................................................................... 25
`6. Allen, The Art, Science, and Technology of Pharmaceutical Compounding ............. 26
`FORMULATIONS BASED ON THE PRIOR ART ........................................................ 26
`A. Active ingredients ............................................................................................................. 26
`B. Amounts of active ingredients .......................................................................................... 27
`C. Inactive ingredients ........................................................................................................... 29
`1. Water ........................................................................................................................... 29
`2. Flonase® ingredients ................................................................................................... 30
`3. Surfactant .................................................................................................................... 30
`4. Preservatives ............................................................................................................... 31
`5. Thickening agents ....................................................................................................... 33
`6. Tonicity-adjusting agents (isotonization agents) ........................................................ 35
`7. pH of the formulation.................................................................................................. 36
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`V.
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`8. Particle size ................................................................................................................. 37
`9. Manufacturing process ................................................................................................ 38
`D. Summary ........................................................................................................................... 39
`VI.
`THE ASSERTED PATENTS ........................................................................................... 41
`A. Specification of the patents-in-suit ................................................................................... 43
`B. The Asserted Claims ......................................................................................................... 45
`1. The ’723 Patent (8, 11, 14, 25 and 28)........................................................................ 45
`2. The ’620 Patent (4, 29, 42-44). ................................................................................... 46
`3. The ’428 Patent (10, 11, 13, 15, 16, 18-20, 22-24, 26, 28-30). .................................. 47
`VII. THE ASSERTED CLAIMS WOULD HAVE BEEN OBVIOUS TO A POSA. ............. 50
`A. Combinations of azelastine and fluticasone ...................................................................... 50
`B. Concentrations of azelastine and fluticasone .................................................................... 51
`C. Pharmaceutical excipients ................................................................................................. 52
`D. Concentrations of pharmaceutical excipients ................................................................... 54
`E. Particle size and pH .......................................................................................................... 57
`F. Conclusion ........................................................................................................................ 57
`VIII. ANALYSIS OF ALLEGED UNEXPECTED RESULTS ................................................ 58
`A. No Formulation Difficulties .............................................................................................. 58
`B. Replication of Cramer Example III ................................................................................... 60
`IX.
`CONCLUSION ................................................................................................................. 63
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`1.
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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 have formulated certain opinions about those patents and their asserted claims.
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`My opinions are set forth in this report, and I expect to testify about them at trial if asked to do
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`so.
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`3.
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`The basis for my opinions includes the documents and other materials cited in this
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`report, my education, and my years of experience, teaching, and researching in the relevant field.
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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 Meda Pharmaceuticals and Cipla Ltd., or in connection with
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`additional information that may be made available to me in the future.
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`5.
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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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`6.
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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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`7.
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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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`8.
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`In the past five years, I have been deposed only once, in Sanofi Aventis v. Sandoz
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`et al., but I was not a testifying expert at trial.
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`I.
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`PERSONAL BACKGROUND
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`9.
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`I am a Professor in the Division of Pharmaceutics at the University of Iowa
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`College of Pharmacy. I have more than 25 years of experience working and consulting in the
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`field of pharmaceutics. My curriculum vitae is attached to this report as Exhibit A.
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`10.
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`I am an expert in pharmaceutics. I received my Bachelor of Science in Pharmacy
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`from the University of Minnesota College of Pharmacy in 1983 and my Ph.D. in Pharmaceutics
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`from the University of Michigan in 1989.
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`11. My professional experience includes working as a Staff Pharmacist for Clark
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`Professional Pharmacy from 1986 until 1989 and as a Visiting Scholar for SmithKline Beecham
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`Pharmaceuticals in 1991. From 1989 through the present, I have held various positions at the
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`University of Iowa College of Pharmacy. Specifically, in the Division of Pharmaceutics, I was
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`an Assistant Professor from 1989 until 1996, and an Associate Professor from 1996 until 2008. I
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`was promoted to the position of a Professor in 2008 in the College of Pharmacy, and I currently
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`hold this position. From 2008 until 2013, I was the Division Head for the Division of
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`Pharmaceutics. In 2013, I became the Associate Dean for Undergraduate Programs at the
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`College of Pharmacy, and I currently hold this position.
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`12.
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`I have over 25 years of experience in pharmaceutical research and development
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`including actively teaching drug delivery, pharmaceutical preformulation, and compounding to
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`pharmacy students and graduate students, and directing research programs focused on drug
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`absorption, nasal drug delivery, and alternative routes of drug delivery and delivery systems.
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`13.
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`I have published numerous articles, book chapters, and abstracts in the area of
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`pharmaceutics, drug absorption, drug delivery, and materials characterization. I also belong to
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`several professional societies for pharmaceutical science and technology, including the American
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`Association of Pharmaceutical Scientists and the Controlled Release Society.
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`14.
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`In addition to my knowledge, education, and experience in the field of
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`pharmaceutical formulation, I have reviewed materials in forming the opinions I express in this
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`report. A full list of those materials is attached as Exhibit B.
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`II.
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`LEGAL STANDARDS
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`15.
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`Counsel for Apotex has asked me to offer my opinions on whether or not I think
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`the asserted claims of the patents-in-suit and particular aspects of them are inventive or obvious.
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`16.
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`In order to form my opinions on these questions in the context of this litigation,
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`counsel has explained to me certain legal standards. I include below my understanding of these
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`relevant legal standards, as these make up the framework in which I did my analysis.
`
`A.
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`17.
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`Obviousness
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`I have been informed a patent claim is invalid as obvious if the differences
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`between the subject matter sought to be patented and the prior art are such that the subject matter
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`as a whole would have been obvious at the time that the invention was made to a person of
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`ordinary skill in the art (a “POSA”). For my analysis of obviousness, I have considered and
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`applied the following factors: (a) the scope and content of the prior art; (b) the differences
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`between the prior art and the asserted claims; and (c) the level of ordinary skill in the field of the
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`invention. I also understand that courts may review certain other objective indicators tending to
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`show that patent claims are non-obvious or obvious. I have identified some of my opinions on
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`such indicators in this report. I reserve the right to supplement those opinions based on evidence,
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`arguments or opinions presented by or on behalf of Meda or Cipla.
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`18.
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`I also have been informed and understand that a claimed invention may be
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`obvious if at the time of the alleged invention there was a reason that would have prompted a
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`POSA in the field of the invention to combine the known elements in a way the claimed
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`invention does, taking into account such factors as: (1) whether the claimed invention was
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`merely the predictable result of using prior art elements according to their known functions; (2)
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`whether the claimed invention provides an obvious solution to a known problem in the relevant
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`field; (3) whether the prior art teaches or suggests the desirability of combining elements claimed
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`in the invention; (4) whether the prior art teaches away from combining elements in the claimed
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`invention; (5) whether it would have been obvious to try the combinations of elements, such as
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`when there is a design need or market pressure to solve a problem and there are a finite number
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`of identified, predictable solutions; and (6) whether the change resulted more from design
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`incentives or other market forces.
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`19.
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`I also have been informed that a claimed invention may be obvious to try where at
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`the time of the invention, there was a known problem or need in the art, there was a finite
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`number of identified, predictable potential solutions to that need or problem, and a POSA could
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`have pursued those solutions with a reasonable expectation of success. If this leads to the
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`claimed invention, it is not because of innovation but rather because of ordinary skill and
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`common sense.
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`20.
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`I further understand that the prior art must provide to the POSA a reasonable
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`expectation of successfully making and using the alleged invention.
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`21.
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`I further understand that in determining whether the claimed invention was
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`obvious, one must not use hindsight, and must instead consider only what was known at the time
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`of the invention.
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`B.
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`22.
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`Person of Ordinary Skill in the Art.
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`As mentioned, I evaluated the issues of obviousness from the perspective of a
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`POSA. I was informed that to determine the level of ordinary skill in the subject matter of the
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`asserted patents, I should consider (1) the levels of education and experience of the inventors and
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`other persons actively working in the field; (2) the types of problems encountered in the field; (3)
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`prior art solutions to those problems; (4) rapidity with which innovations are made; and (5) the
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`sophistication of the technology. The subject matter of the asserted patents is generally directed
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`to pharmaceutical compositions and methods of using them for the administration of intranasal
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`steroids and intranasal antihistamines for the treatment of allergic rhinitis and other conditions.
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`The asserted claims are generally directed to particular formulations of the compositions, and
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`their use.
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`23.
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`I understand that for the obviousness analysis I was to conduct my analysis from
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`the perspective of a POSA as of the date of the alleged invention of the asserted claims. I have
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`been asked to assume that the date of invention is June 2002.
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`C.
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`24.
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`Level of Person of Ordinary Skill in the Art.
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`In my opinion, the relevant “art” to which the patents are directed is
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`pharmaceutical formulations of topical agents, specifically nasal suspensions and/or solutions. A
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`person of ordinary skill in this field has at least a bachelor’s degree in chemistry, biology,
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`chemical engineering or pharmaceutical sciences with significant experience, 3-5 years in
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`formulation development of nasal dosage forms, and the ability to operate independently on
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`formulation activities. A person of skill in the art would also have familiarity with
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`pharmaceutical excipients and their uses.
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`25.
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`A person of ordinary skill in the art may also have a Master’s degree in chemistry,
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`biology, chemical engineering, or pharmaceutical sciences with 1-3 years of experience in
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`formulation development of nasal agents as well as the ability to operate independently on
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`formulation activities. Such a person may also have a Ph.D. in chemistry, chemical engineering,
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`or pharmaceutical sciences with at least one year of experience in formulation development of
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`sterile dosage forms. These persons would also have familiarity with pharmaceutical excipients
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`and their uses.
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`26.
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`I have reviewed the report of Robert P. Schleimer, who defines a person of
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`ordinary skill in the art as someone 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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`of experience in the treatment, or research for treatments, of allergic rhinitis, including with
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`nasally administered steroids and antihistamines. I agree with Dr. Schleimer’s opinion regarding
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`a person of ordinary skill in the field of allergic rhinitis research and treatment. My opinion is
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`that a person of ordinary skill in formulation would coordinate with a person of ordinary skill in
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`the field of allergic rhinitis research and treatment.
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`III.
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`SUMMARY OF OPINIONS
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`27.
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`I have analyzed the patents-in-suit, their file histories, and the asserted claims,
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`which I understand are Claims 8, 11, 14, 25 and 28 of the ’723 patent; Claims 4, 29, and 42-44 of
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`the ’620 patent; and Claims 10, 11, 13, 15, 16, 18-20, 22-24, 26, and 28-30 of the ’428 patent. In
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`addition to these items and the other materials I discuss in this report, all of which I have
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`reviewed and am prepared to discuss at trial if asked to do so, I have reviewed the expert report
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`of Dr. Robert Schleimer. He offers certain opinions that it would have been obvious to a POSA
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`at the time of the alleged invention to make and administer a combination nasal spray product
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`having both azelastine hydrochloride (HCl) and fluticasone propionate as active ingredients. I
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`agree with his opinion, especially in light of the actual prescribing practices at the time, that it
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`would have been at least obvious for a POSA to try combining these two active ingredients.
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`28.
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`It is my opinion that each of the asserted claims would have been obvious to a
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`POSA as of the earliest purported priority date of the asserted patents, which I understand is June
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`2002.
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`29.
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`It is my opinion that all of the asserted claims of ’620, ’723, and ’428 patents
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`would have been obvious to a POSA in view of the prior art I discuss in more detail in this
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`report.
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`30.
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`In brief, each of the asserted claims covers the use of a pharmaceutical nasal spray
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`composition containing azelastine HCl and fluticasone propionate in amounts that are effective
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`for the treatment of allergic rhinitis in humans. Dr. Schleimer opines that the concept of this
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`composition would have been obvious to a POSA considering how to treat allergic rhinitis in
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`2002. As explained above, I agree with his opinion. It is my further opinion that it would have
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`been obvious to a POSA at that time how to make such a product. Making this product would
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`have resulted in a formulation with characteristics within the scope of the asserted claims.
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`31.
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`Asserted claims 29 of the ’620 patent, and 10, 11, 13, 15, 16, 18-20, 22-24, 26 and
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`28-30 of the ’428 patent also require certain amounts or ranges of amounts of the active
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`ingredients. It is my opinion that making a formulation meeting those requirements would have
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`been obvious to a POSA at the time of the alleged invention. These claims cover the amounts of
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`the active ingredients that were present in two monotherapies from the prior art—Astelin® and
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`Flonase®. Using the same amounts of active ingredients as two commercially marketed products
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`would have been obvious because, for example, those amounts would already have been known
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`to be safe and effective.
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`32.
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`Asserted claims 25 and 28 of the ’723 patent, claims 42-44 of the ’620 patent, and
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`all of the asserted claims of the ’428 patent contain various limitations that identify specific
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`inactive ingredients, and/or types of inactive ingredients, and/or amounts of inactive ingredients.
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`It is my opinion that a POSA would have found formulations meeting each of those requirements
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`to have been obvious as of 2002. Each of these ingredients was well known to a POSA as a
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`pharmaceutically acceptable excipient. All but one had been used in either or both of the
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`Astelin® or Flonase® products, and each was at least otherwise disclosed as acceptable for use in
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`nasal sprays. Each of those ingredients also has been used in the prior art to perform one or more
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`of the same functions later required by the asserted claims.
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`33.
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`Asserted claims 11 of the ’723 patent and 4 of the ’620 patent require that the
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`claimed composition or formulation have a particle size of less than 10 µm. It is my opinion that
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`making a formulation in which azelastine HCl and fluticasone propionate (and other ingredients
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`that have measurable particle size) were less than 10 µm would have been obvious to a POSA.
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`34.
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`Asserted claims 15 and 28 of the ’428 patent also requires the formulation to be
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`within the pH range of 4.5 to about 6.5. It is my opinion that formulating an azelastine
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`HCl/fluticasone propionate combination product with a pH in that range would have been
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`obvious to a POSA.
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`IV. ANALYSIS OF THE PRIOR ART
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`35.
`
`I began my analysis by considering the following: If a POSA were asked
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`immediately prior to the date of the alleged invention to make a combination nasal spray product
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`using azelastine HCl and fluticasone propionate as active ingredients (consistent with Dr.
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`Schleimer’s report and the actual prescribing practices at the time), what would be the obvious
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`way to proceed? To answer that question, I considered the relevant knowledge of a POSA at that
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`time.
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`A.
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`36.
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`State of the art of nasal drug delivery systems.
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`By 2002, it was well known to a POSA that various drugs could be administered
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`by the nasal route, for example through sprays or drops. One example was Afrin, which contains
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`the active ingredient oxymetazoline, a drug that can cause vasoconstriction and thus reduce nasal
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`congestion and related symptoms. It has been available for decades.
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`37.
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`Nasal sprays typically comprise a bottle or other container that contains the active
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`ingredient in its formulation. A device capable of forming a spray or mist of droplets is attached
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`to an appropriate container (bottle), and by 2002, the most common nasal spray devices used a
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`hand-activated, compression-driven pump system to produce the spray droplets as the
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`formulation exits the spray orifice, typically located at the tip of the actuator. In 2002, nasal
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`spray device systems were readily available from commercial vendors.
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`38.
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`The nasal sprays that were commercially available prior to 2002 and are most
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`relevant to a POSA trying to develop an azelastine/fluticasone combination product were
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`products containing azelastine HCl or fluticasone propionate as the active ingredients.
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`B.
`
`39.
`
`Azelastine HCl and Astelin®
`One such product was called Astelin®, which contained azelastine HCl as the
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`active ingredient. I have reviewed the FDA-approved labeling for Astelin® available in 2000.
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`This label was available at this time to any prescriber, consumer, or researcher purchasing
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`Astelin® and was generally available as the FDA-approved label for the drug product. The label
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`indicates that the product was “indicated for the treatment of the symptoms of seasonal allergic
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`rhinitis….” Astelin® Label, at 3-4.
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`40.
`
`One portion of the label states as follows:
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`Astelin® Label, at 1.
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`
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`41.
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`As can be seen, the label provides much information about the active ingredient
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`itself, including its chemical structure, that it is an antihistamine, that it is sparingly soluble in
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`water and slightly soluble in glycerine, and that the product contains 0.1% azelastine
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`hydrochloride in an aqueous solution at pH 6.8 +/-0.3. Each spray of the drug contains a mean
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`volume of 0.137 mL, and delivers 137 µg of azelastine hydrochloride. That is equivalent to 125
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`µg of azelastine base. Each bottle can deliver 100 metered sprays. Id.
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`42.
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`The fact that azelastine is administered as a “metered-spray solution” means that
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`it is dissolved in a solvent. The product is described as an “aqueous solution,” i.e., water is
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`included in the solvent system. The azelastine hydrochloride is described as “sparingly soluble”
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`in water, which means to a POSA that it requires somewhere between 30-100 parts of water to
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`dissolve one part of azelastine HCl. See, for example, Remington’s (2000) at 209, from which
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`the following chart is reproduced:
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`Descriptive terms
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`Very soluble
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`Freely soluble
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`Soluble
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`Sparingly soluble
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`Parts of
`solvent needed
`for 1 part
`solute
`
`< 1
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`1-10
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`10-30
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`30-100
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`Slightly soluble
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`100-1000
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`Very slightly soluble
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`1000-10,000
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`Practically insoluble or insoluble
`
`> 10,000
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`
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`43.
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`The “pH” of an aqueous solution is used as a description of how acidic or basic it
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`is on a scale of 0 to 14, with 0 being the most acidic and 14 being the most basic. A pH of 7 is
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`defined as neutral.
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`44.
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`The label also provides information about the other ingredients in each spray in
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`addition to azelastine HCl. It contains 125 µg/mL of benzalkonium chloride. This concentration
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`of benzalkonium chloride in Astelin® is 0.0125% weight/volume (w/v), which is also
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`approximately its weight/weight (w/w) concentration.1 The product also contains edetate
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`disodium (sometimes abbreviated “disodium EDTA”); hydroxypropyl methyl cellulose
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`(sometimes abbreviated “HPMC”); citric acid; dibasic sodium phosphate; sodium chloride; and
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`purified water.
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`45.
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`Beyond just naming ingredients, this label teaches a POSA that each of these
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`ingredients was by 2002 a common pharmaceutical excipient, or inactive ingredient, that was
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`suitable for nasal administration since they had all been used in at least one FDA-approved
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`product—Astelin®. None of these ingredients was new in the pharmaceutical field. A POSA
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`formulating any nasal composition would also know that these ingredients include at least one (i)
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`preservative, (ii) suspending or thickening agent, (iii) tonicity-adjusting agent, and (iv) pH
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`modifier or buffer to create a nasal solution for maximum absorption and comfort. Those
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`additional materials are commonly used in nasal spray pharmaceutical products.
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`1.
`
`Preservatives
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`46. Well before 2002 a POSA knew that preservatives were excipients that could help
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`prevent degradation of the drug product and/or prevent and inhibit microbial contamination of
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`the drug product. The prior art Astelin® formulation contains two ingredients that were known to
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`act as preservatives: edetate disodium and benzalkonium chloride. See Wade & Weller,
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`Handbook of Pharmaceutical Excipients (1994), at 27 (benzalkonium chloride); id. at 176
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`(“Edetic acid and edetates possess some antimicrobial activity but are most frequently used in
`
`
`1 As I explain in paragraph 91, Example 1 of Astelin®’s patent, Hettche, discloses the formulation for 0.1%
`azelastine hydrochloride, which includes 1.25 g of benzalkonium chloride. Hettche, at 6:13. The solution is diluted
`to 10.05 kg = 10 Liters, which means there are 1.25 g of benzalkonium chloride per 10,050 g of solution. That is
`equivalent to 0.0124378 g of benzalkonium chloride per 100 g of solution, which is 0.01244 % w/w. A POSA
`would view 0.0124% w/w and 0.0125% w/v as essentially equivalent with regard to its preservative activity.
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`combination with other antimicrobial preservatives due to their synergistic effects.”). Edetate
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`disodium is also a chelating agent and antioxidant, i.e., it also helps preserve by removing ions
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`from solution that can contribute to oxidative degradation of materials in aqueous solution. Id.
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`(describing that edetates have been used to stabilize, among other things, corticosteroids). I
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`discuss further these and other known preservatives below.
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`2.
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`Suspending and thickening agents
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`47.
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`It was also known that thickening agents were useful in drug products for nasal
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`administration. These agents work because following administration, the formulation deposits
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`on the tissue surfaces within the nasal cavity and it resides on the surface so the active ingredient
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`can be absorbed. Formulations that are “thin”/low viscosity may only stay on the nasal tissue
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`surfaces for a relatively short time and, instead, are cleared from the nasal cavity and
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`subsequently swallowed. “Thicker” formulations may be able to stay within the nasal cavity for
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`longer periods of time, and may improve the effectiveness of the drug(s). E.g., U.S. Patent No.
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`5,164,194 (“Hettche”), at 4:51-66 (“[I]t is possible to add thickening agents to the solutions to
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`prevent the solution from flowing out of the nose too quickly….”).
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`48.
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`The thickening agent in Astelin® is HPMC, which was in 2002, and is still today,
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`commonly used as a pharmaceutical excipient. Wade & Weller, Handbook of Pharmaceutical
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`Excipients (1994), at 229 (categorizing hydroxypropyl methylcellulose as a suspending agent
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`and viscosity-increasing agent). Other thickening agents were also known for use in
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`pharmaceutical preparations, specifically nasal sprays. As Hettche disclosed to a POSA in 1992,
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`“Such thickening agents may, for example, be: cellulose derivatives (for example cellulose ether)
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`in which the cellulose-hydroxy groups are partially etherified with lower unsaturated aliphatic
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`alcohols and/or lower unsaturated aliphatic oxyalcohols (for example methyl cellulose,
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`carboxymethyl cellulose, hydroxypropylmethylcellulose), . . .” Hettche at 4:51-66; see also
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`13
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`16
`
`

`

`Pennington et al. (1988); Suzuki & Makino (1999). The combination of microcrystalline
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`cellulose (“MCC”) and carboxymethyl cellulose sodium (“CMC”), commercially sold under the
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`brand name “Avicel,” was a common thickening agent. Wade & Weller, Handbook of
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`Pharmaceutical Excipients (1994), at 86 (describing the combinations of microcrystalline
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`cellulose and carboxymethylcellulose sodium); Dolz et al. (1992), at 96-99 (explaining that these
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`combinations “are extensively used in commercial preparations” as viscosity-increasing agents).
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`I refer to that combination herein as MCC-CMC unless otherwise noted.
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`Tonicity-adjusting agents (isotonization agents)
`3.
`The NaCl, or sodium chloride, in Astelin® and other pharmaceutical formulations
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`49.
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`acts to adjust the tonicity of the formulation. E.g., Hettche, at 4:31-35. An “isotonic” nasal
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`solution drug product is one that has the same osmotic pressure as nasal secretions. E.g., id. at
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`4:35-45. The practical effect of that equality in osmotic pressure is that the cells and tissue in the
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`nasal cavities neither swell by imbibing water from the nasal spray, nor do they shrink due to
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`water loss from the cells. Those types of changes could cause irritation in the nasal cavity.
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`50.
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`Formulators of products for nasal administration thus generally preferred to make
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`isotonic preparations, and they still do so today. E.g., European Patent Application No. 0 780
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`127 (1997) (“Cramer”), at 3 (“Most preferably, the [combination] nasal composition is isotonic,
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`i.e., it has the same osmotic pressure as blood and lacrimal fluid.”); Hettche, at 4:36-38 (“The
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`isotonization agents adjust the osmotic pressure of the formulations to the same osmotic pressure
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`as nasal secretions.”); PCT Publication No. WO 98/48839 (1998) (“Segal”), at 4 (“The
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`[disclosed combination nasal] compositions are preferably isotonic. [Tonicity-adjusting] agents
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`such as sugars and sodium chloride are known in the art and may be included in the subject
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`compositions.”). See also Remington’s (2000), at 246-62. However, making an isotonic
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`formulation was not required. A POSA would have known that non-isotonic nasal fo