`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`Civil Action No. 1:14-cv-01453-LPS
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`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
`
`
`Plaintiffs,
`
`
`v.
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`APOTEX, INC. and APOTEX CORP.
`
`
`Defendants.
`
`
`EXPERT REPORT OF ROBERT P. SCHLEIMER, PH.D.
`
`CIP2011
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`1
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`

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`TABLE OF CONTENTS
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`Page
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`I. PROFESSIONAL BACKGROUND .........................................................................................1
`II. LEGAL STANDARDS .............................................................................................................4
`III. SUMMARY OF OPINIONS .....................................................................................................8
`IV. ANALYSIS ..............................................................................................................................11
`A. The etiology of allergic rhinitis: early-phase and late-phase reactions..............................12
`B. Prior art treatment of allergic rhinitis.................................................................................13
`1. Antihistamines were known to treat primarily the early-phase response. ...................13
`i. Azelastine HCl .......................................................................................................14
`2. Steroids were known to treat the late-phase response. ................................................18
`i. Steroids were known to have delayed onsets of action compared to
`antihistamines. .......................................................................................................19
`ii. Fluticasone propionate was a nasally administered steroid approved for the
`treatment of AR......................................................................................................21
`C. Combination antihistamine/steroid therapies were well known in the prior art. ...............22
`1. The medical literature recommended combining antihistamine and steroids. .............22
`i. Prior art at the time would not have discouraged a POSA from seeking a
`combination therapy with an expectation of success. ............................................26
`2. Antihistamines and steroids were taught to be administered together as a
`single product. ..............................................................................................................27
`3. A POSA would have known azelastine HCl and fluticasone propionate were
`appropriate choices for combined administration. .......................................................28
`V. THE ASSERTED PATENTS ..................................................................................................30
`A. Specification ......................................................................................................................31
`B. Asserted Claims .................................................................................................................31
`1. The ’723 Patent (8, 11, 14, 25 and 28).........................................................................31
`2. The ’620 Patent (4, 29, 42-44). ....................................................................................32
`3. The ’428 Patent (10, 11, 13, 15, 16, 18-20, 22-24, 26, 28-30) ....................................34
`VI. THE ASSERTED CLAIMS ARE OBVIOUS IN VIEW OF THE PRIOR ART. ..................36
`A. The use of an azelastine HCl and fluticasone propionate combination. ............................37
`B. The use of certain amounts of azelastine HCl and fluticasone propionate. .......................39
`VII. OTHER EVIDENCE CONFIRMS MY CONCLUSION THAT THE ASSERTED
`CLAIMS ARE OBVIOUS. ............................................................................................................42
`VIII. THERE ARE NO UNEXPECTEDLY SUPERIOR RESULTS FROM
`COMBINING AZELASTINE AND FLUTICASONE IN A SINGLE NASAL SPRAY. ...........43
`
`i
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`2
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`A. The closest prior art to a single product combining azelastine and fluticasone for
`nasal administration is the simultaneous or sequential intranasal administration of
`azelastine and fluticasone. .................................................................................................44
`B. If the monotherapies are the closest prior art, then the results are not unexpected. ..........45
`IX. ALTERNATIVE OPINIONS ..................................................................................................45
`X. CONCLUSION ........................................................................................................................48
`
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`ii
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`3
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`1.
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`I, Robert P. Schleimer, have been retained by Defendants Apotex, Inc., and
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`Apotex Corp. as an expert to analyze certain claims of U.S. Patent Nos. 8,163,723 (“the ’723
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`patent”); 8,168,620 (“the ’620 patent”); and 9,259,428 (“the ’428 patent”), in connection with
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`this lawsuit.
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`2.
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`I have developed certain opinions about those patents and their asserted claims,
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`which I set forth in this report. I expect to testify about them at trial if asked to do so. To form
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`my opinions, I relied on documents and other materials cited in this report, my education, and
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`my years of experience, teaching, and performing research in this field.
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`3.
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`I reserve the right to amend or supplement my opinions in light of evidence
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`presented by or on behalf of the plaintiffs, or in connection with additional information that may
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`later be made available to me. At trial, I may use demonstrative exhibits if useful for explaining
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`and understanding the opinions in this report, and I may testify about background scientific
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`concepts related to pharmacology to explain as necessary the context of the claims.
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`4.
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`I am being compensated for my time on this matter at a rate of $400/hour for
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`consulting and $600/hour for testimony. Those are my standard consulting rates. My
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`compensation is in no way dependent on the outcome of this case.
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`5.
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`I have not given testimony or written an expert report in connection with litigation
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`in the last five years.
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`I.
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`PROFESSIONAL BACKGROUND
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`6.
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`I am the Roy and Elaine Patterson Professor of Medicine and the Chief, Division
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`of Medicine-Allergy-Immunology, at
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`the Feinberg School of Medicine, Northwestern
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`University.
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`7.
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`I received my B.A. from the University of California at San Diego and my Ph.D.
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`from the University of California at Davis. My Ph.D. is in Pharmacology-Toxicology and I have
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`received training as an Immuno-pharmacologist. My postdoctoral fellowship was at the Johns
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`Hopkins University School of Medicine where I studied mechanisms of allergic diseases using
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`both in vitro and in vivo approaches. The in vivo challenge models of human disease included
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`nasal challenge of human subjects with allergen to assess allergic rhinitis mechanisms, bronchial
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`challenges of human subjects with allergen to assess asthma mechanisms, and studies of the skin
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`and sinuses. Between 1982 and 2004 I was on the faculty at Johns Hopkins, and since 2004 I
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`have been on the faculty at Northwestern. During my time at Johns Hopkins and subsequently at
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`Northwestern, allergic rhinitis has been one of the major allergic diseases I have studied.
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`8.
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`I have published widely on the use of steroids and antihistamines. A Pubmed
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`search of my publications reveals 61 papers for the search term “steroid” and 64 papers for the
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`search term “histamine.” These are listed in my curriculum vitae, attached hereto as Exhibit A
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`(current as of December 2015). I am recognized as an international expert in the study of the
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`mechanisms of anti-inflammatory steroid actions in allergic disease.
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`9.
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`I have taught Pharmacology and/or Allergy-Immunology at Northwestern
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`Feinberg School of Medicine, Johns Hopkins School of Medicine, California State University at
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`Chico, and the University of California at Davis. I have trained dozens of scientific investigators
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`holding either the Ph.D. or M.D. degree, and many of my former trainees are now recognized as
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`international experts in the mechanisms of allergic disease.
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`10.
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`I also have significant experience outside of the academic setting. For instance, I
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`have served as a full time member on three standing National Institutes of Health grant review
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`committees—Lung Biology and Pathology (LBPA), Lung Cell and Molecular Immunology
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`(LCMI), and the Specialized Center of Clinically Oriented Research (SCCOR). I have also
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`served as a member and served as the Chairman for two NIH study sections (Lung Cell and
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`Molecular Immunology (LCMI) and Severe Asthma Research Program (SARP)). I have served
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`on numerous other National Institutes of Health committees, including Strategic Planning,
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`Asthma Outcomes, Immunological Aspects, Outstanding New Environmental Scientist (ONES)
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`review, the NIAID Biomarkers committee, Scientific Counselors, and others. These study
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`sections reviewed dozens of multimillion dollar grants in the area of molecular and cellular
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`mechanisms of allergic disease and the effects of drugs on these diseases. I have been on
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`numerous committees at Northwestern University and at Johns Hopkins during my tenure at each
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`institution.
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`11.
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`I serve or have served on editorial boards for many major biomedical journals.
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`This includes service as an Associate Editor on the Journal of Allergy and Clinical Immunology,
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`the worldwide leading journal in the field of allergy. This journal publishes the best research in
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`the field relevant to the actions of antihistamines and glucocorticoids (a class of steroids) in
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`allergic disease.
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`12.
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`I am presently serving as an advisor or advisory board member for several
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`pharmaceutical companies (AstraZeneca, Genentech, GlaxoSmithKline, Intersect ENT, Merck,
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`Regeneron, Sanofi). I am also a founder of a startup company, Allakos. Allakos is developing
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`drugs to treat severe allergic diseases.
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`13. My additional qualifications, including a complete list of papers I have published
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`and book chapters I have co-authored, can be found on my curriculum vitae. Also included in
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`my CV is my record of NIH funding (continuous funding for the past 33 years), a record of
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`international and domestic invited lectures, honors and awards that I have received (including
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`named lectures), a list of invited visits with pharmaceutical companies over the years (from
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`which my advisory service can be inferred), and patents issued in my name.
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`14.
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`In light of all of this experience, I consider myself to be an expert at least in the
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`areas of allergic rhinitis, its pathophysiology, and its treatment with antihistamines and steroids
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`through any route of administration.
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`15.
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`In addition to my knowledge, education, and experience in the fields of allergy,
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`immunology, and pharmacology, I have reviewed certain materials in forming the opinions I
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`express in this report and I have attached a full list of those materials as Exhibit B.
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`II.
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`LEGAL STANDARDS
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`16.
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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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`whether or not certain of the asserted claims have satisfied the written description requirement of
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`the patent law; and whether or not certain of the asserted claims have satisfied the enablement
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`requirement of the patent law.
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`17.
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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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`18.
`
`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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`19.
`
`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 known elements in a way the claimed invention
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`does, taking into account such factors as: (1) whether the claimed invention was merely the
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`predictable result of using prior art elements according to their known functions; (2) whether the
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`claimed invention provides an obvious solution to a known problem in the relevant field; (3)
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`whether the prior art teaches or suggests the desirability of combining elements claimed in the
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`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 from the prior art resulted more
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`from design incentives or other market forces.
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`20.
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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 number
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`of identified, predictable potential solutions to that need or problem, and a POSA could have
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`pursued those solutions with a reasonable expectation of success. If this leads to the claimed
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`invention, it is not because of innovation but because of ordinary skill and common sense.
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`21.
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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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`22.
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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. Written Description and Enablement
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`23.
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`I have also been informed and understand that a patent claim is invalid for lack of
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`written description if the patent specification fails to provide an adequate written description of
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`the full scope of the claimed invention. I understand that the written description requirement is
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`satisfied if a POSA reading the patent application as originally filed, would recognize that the
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`patent application described the full scope of the invention as claimed. The written description is
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`adequate if it shows that the inventors were in possession of the full scope of the claimed
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`invention at the time the application for the patent was filed. It is not necessary that each and
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`every aspect of the claim be explicitly discussed in the specification, so long as the patent
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`application when and as originally filed still reflects that the named inventors possessed the full
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`scope of the claimed invention.
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`24.
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`Likewise, I have been informed and understand that a patent claim is invalid for
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`lack of enablement if the specification of the patent as of its earliest claimed filing date does not
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`enable a POSA to make and use the claimed invention without undue experimentation. I
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`understand that whether practicing a claim requires undue experimentation requires weighing a
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`number of factual considerations. They include: (1) the quantity of experimentation necessary;
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`(2) the amount of direction or guidance presented; (3) the presence or absence of working
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`examples; (4) the nature of the invention; (5) the state of the prior art; (6) the relative skill of
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`those in the art; (7) the predictability or unpredictability of the art; and (8) the breadth of the
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`claims.
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`C.
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`25.
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`
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`Person of Ordinary Skill in the Art
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`I evaluated the questions of obviousness and the written description and
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`enablement requirements from the perspective of a POSA. I was informed that to determine the
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`level of ordinary skill in the subject matter of the asserted patents, I should consider: (1) the
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`levels of education and experience of the inventor(s) and other persons actively working in the
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`field; (2) the types of problems encountered in the field; (3) prior art solutions to those problems;
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`(4) rapidity with which innovations are made; and (5) the sophistication of the technology. The
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`subject matter of the asserted patents is generally directed to pharmaceutical compositions
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`comprising an intranasal steroid and intranasal antihistamine, and methods of using such
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`compositions, for the treatment of allergic rhinitis and other conditions.
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`26.
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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. For my
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`analysis of written description and enablement, I understand that the evaluation is conducted
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`from the perspective of a POSA as of the earliest claimed filing date of the asserted patents. I
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`have been asked to assume that the date of invention is June 2002, and the earliest claimed patent
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`application filing date is June 13, 2003. My opinions are the same regardless of which date is
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`correct for the analysis.
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`27.
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`Based on those factors, it is my opinion that a POSA in the field of the asserted
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`patents would have an M.D., Ph.D. or Pharm.D. in the field of allergy/immunology and/or
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`pharmacology (or the equivalent), and at least three additional years of experience in the
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`treatment, or research for treatments, of allergic rhinitis, including with nasally administered
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`steroids and antihistamines. I have also reviewed the report of Dr. Maureen Donovan, and she
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`defines the qualifications of a person of ordinary skill in the field of pharmaceutical formulations
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`as follows:
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`In my opinion, the relevant “art” to which the patents are directed is
`pharmaceutical formulations of topical agents, specifically nasal suspensions
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`and/or solutions. A person of ordinary skill in this field has at least a bachelor’s
`degree in chemistry, biology, chemical engineering or pharmaceutical sciences
`with significant experience, 3-5 years in formulation development of nasal dosage
`forms and the ability to operate independently on formulation activities. A person
`of skill in the art would also have familiarity with pharmaceutical excipients and
`their uses.
`
` A
`
` person of ordinary skill in the art may also have a Master’s degree in
`chemistry, biology, chemical engineering, or pharmaceutical sciences with 1-3
`years in formulation development of nasal agents as well as the ability to operate
`independently on formulation activities. Such a person may also have a Ph.D. in
`chemistry, chemical engineering, or pharmaceutical sciences with at least one
`year of experience in formulation development of sterile dosage forms. These
`persons would also have familiarity with pharmaceutical excipients and their uses.
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`I agree with the above definition. I also agree with her opinion that a person of
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`28.
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`ordinary skill in the field of research for and treatment of allergic rhinitis would collaborate with
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`a person of ordinary skill in pharmaceutical formulations.
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`III.
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`SUMMARY OF OPINIONS
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`29.
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`I have analyzed the patents-in-suit and their file histories, and offer the following
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`opinions concerning the asserted claims, which I understand are Claims 8, 11, 14, 25 and 28 of
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`the ’723 patent; Claims 4, 29, and 42-44 of the ’620 patent; and Claims 10, 11, 13, 15, 16, 18-20,
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`22-24, 26, and 28-30 of the ’428 patent.
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`30.
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`First, each of the asserted claims covers, among other things, pharmaceutical
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`compositions containing, or methods of using, a combination of azelastine hydrochloride (HCl)
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`and fluticasone propionate for the treatment of allergic rhinitis via a single nasal spray. It is my
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`opinion that these aspects of each of the asserted claims would have been obvious to a POSA.
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`31.
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`It was well known at the time of the alleged invention that there was a dual
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`etiology underlying allergic rhinitis. An early-phase allergic response characterized by sneezing,
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`itching, and rhinorrhea (i.e., runny nose) was due largely to activity of histamine at histamine
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`(H1) receptor sites. A late-phase response characterized by congestion and nasal blockage was
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`the result of an inflammatory reaction. It was also well known at the time of the alleged
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`invention that antihistamines such as azelastine antagonize the H1-receptor site and treat
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`primarily the early-phase response, and that intranasal steroids such as fluticasone primarily treat
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`late-phase inflammation.
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`32.
`
`Because of these different mechanisms and methods of action, a POSA would
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`have had a motivation to combine antihistamine and steroid therapies for additive clinical effects.
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`Therapies combining antihistamines and steroids were well known in the prior art to be effective
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`for the treatment of allergic rhinitis. The prior art disclosed both the dual intranasal use of an
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`antihistamine product and a steroid product, and even disclosed the simultaneous intranasal
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`administration of azelastine and fluticasone specifically in a single pharmaceutical composition,
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`for the treatment of allergic rhinitis. There was thus a motivation to combine and a reasonable
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`expectation that combining azelastine and fluticasone into a single nasal spray for the treatment
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`of allergic rhinitis would have led to a treatment at least as successful as azelastine or fluticasone
`
`alone, and likely with additive clinical effects.
`
`33.
`
`Prior art combination therapies using azelastine and fluticasone were also known
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`to overcome certain shortcomings of their individual use. For instance, steroids like fluticasone
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`were known to have a delayed onset of action relative to antihistamines, sometimes requiring
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`several days of use before effective symptom relief would be achieved. The prior art taught that
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`administering the drugs together would help increase compliance rates with the steroid, because
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`the antihistamine would give some initial relief to patients during the pre-onset phase of the
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`steroid treatment. Doctors in fact already practiced this teaching by prescribing both Astelin®
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`(intranasal azelastine hydrochloride) and Flonase® (intranasal fluticasone propionate) to
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`individual patients.
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`34.
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`Second, Claim 8 of the ’723 patent encompasses a method for the prophylaxis or
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`treatment in a mammal of allergic rhinitis, comprising intranasal administration of a
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`therapeutically effective amount of a pharmaceutical composition comprising azelastine HCl and
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`fluticasone propionate. That subject matter would have been obvious to a POSA for the same
`
`reasons I discussed above, and in further detail below.
`
`35.
`
`Third, asserted claims 29 of the ’620 patent, and 10, 11, 13, 15, 16, 18-20, 22-24,
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`26 and 28-30 of the ’428 patent, cover specific amounts or ranges of amounts of azelastine HCl
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`and fluticasone propionate to be used as part of the claimed composition or method of treatment.
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`It is my opinion that those specific amounts and/or ranges of amounts would have been obvious
`
`to a POSA for use in a combination product like that encompassed by all of the claims. Among
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`the strongest reasons supporting that opinion is that those exact amounts, or amounts squarely
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`within the claimed ranges, had been used and were commercially available in individual
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`azelastine and fluticasone treatments in the prior art. Claim 14 of the ’723 patent covers specific
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`ranges of amounts of azelastine HCl and of fluticasone propionate or fluticasone valerate, and is
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`obvious for the same reasons.
`
`36.
`
`Fourth, in addition to the subject matter I just described, many of the asserted
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`claims contain limitations about excipient ingredients, amounts of those ingredients, and other
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`properties of the combination azelastine/fluticasone product(s) covered by the claims. My
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`opinion is that it would have been obvious to a POSA to try to make and use the combination
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`product that, as stated above, I opine would have been obvious to a POSA. That is evidenced, in
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`part, by the fact that both azelastine HCl and fluticasone propionate had been formulated into
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`FDA-approved, commercialized nasal spray products by the time of the alleged invention. I do
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`not mean to suggest that FDA approval and commercialization would have been necessary to
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`make these concepts obvious, but it is certainly relevant.
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`37.
`
`I also understand that Apotex has retained Dr. Maureen Donovan to offer
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`opinions concerning
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`the ways a POSA would have
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`formulated a combination
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`azelastine/fluticasone nasal spray at the time of the alleged invention. I have read her report and
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`agree with her conclusions.
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`38.
`
`Fifth, it is my opinion that the plaintiffs’ evidence of unexpectedly superior
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`results, in the form of the clinical studies reported in Joachim Maus’s declaration to the patent
`
`examiner, does not actually show unexpected or superior results compared to the closest prior
`
`art. The superiority of the combination product compared to either azelastine alone or
`
`fluticasone alone would not have been surprising or unexpected to a POSA for the same reasons
`
`the asserted claims are obvious: because antihistamines and steroids were known to have
`
`different mechanisms of action, additive results would not have been surprising when combining
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`the two into a single therapy. Moreover, the results of the studies were not actually superior to
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`the closest prior art—the simultaneous or sequential administration of an antihistamine and a
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`steroid, and the simultaneous or sequential use of Astelin® (azelastine hydrochloride) and
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`Flonase® (fluticasone propionate) in particular. Studies comparing a co-administration of
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`azelastine hydrochloride and fluticasone propionate in separate sprays showed a magnitude of
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`superiority over the administration of either alone that was similar to the superiority of the
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`combination product in the clinical trials reported in Dr. Maus’s declaration. Thus, there is no
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`evidence that the effectiveness of the combination is superior to the effectiveness of
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`simultaneous use of both drugs given separately.
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`IV. ANALYSIS
`
`39.
`
`To formulate my opinions on whether or not the subject matter of the asserted
`
`claims would or would not have been obvious to a POSA, I first put myself in the mindset of a
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`14
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`POSA prior to June 2002 to assess the scope of the art at that time in the field of treatments of
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`allergic rhinitis.
`
`A.
`
`40.
`
`The etiology of allergic rhinitis: early-phase and late-phase reactions.
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`Allergic rhinitis (“AR”), commonly called “Hay Fever,” is caused when a person
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`becomes sensitized to ordinarily innocuous allergens in the air such as pollen grains, animal
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`dander, or material from insects such as house dust mites or cockroaches.
`
`41.
`
`Exposure of a sensitized person to these allergens quickly causes their histamine-
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`containing mast cells and basophils to release histamine and other pharmacologically active
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`mediators that cause blood vessels to swell and leak, cause smooth muscle in the nose and throat
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`to constrict, and stimulate nerves that cause sneezing, wheezing, and coughing. This is referred
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`to as the early-phase AR response. As one author explains: “Prolonged exposure to indoor
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`allergens results in production of IgE antibodies that bind to mucosal mast cells and circulating
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`basophils. Thus sensitised, the patient develops acute nasal and ocular symptoms following
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`further exposure. This response, which can occur within minutes of exposure and is termed the
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`early-phase allergic response, is caused primarily by the release of mast cell mediators. These
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`include histamine, tryptase, prostaglandin D2 and the cysteinyl leukotrienes (LT) C4, D4 and
`
`E4.” Galant & Wilkinson (2001), at 455. It was thus known well before the alleged date of
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`invention that histamine was one cause of the early-phase AR response.
`
`42.
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`As I noted above, however, there is also a late-phase AR response. “A late-phase
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`response that occurs 4 to 8 hours after allergen exposure in 50% of patients is thought to be due
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`to cytokine release by mast cells and thymic-derived helper T cells called TH2 cells. The late-
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`phase response is characterized by profound infiltration and activation of migrating and resident
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`cells. This inflammatory response is thought to be responsible for the persistent, chronic signs
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`and symptoms of AR, particularly nasal obstruction and increased sensitivity of the nasal mucosa
`12
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`15
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`to allergens and irritants.” Galant & Wilkinson (2001), at 455. It was thus known well before
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`the alleged date of invention that the late-phase AR response was primarily inflammatory in
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`nature.
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`43.
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`Other sources also reflect the established knowledge that AR generally comes in
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`two phases. Drouin (1995), for example, explains: “The nasal response to allergen challenge can
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`be divided into an early reaction (occurring within minutes of allergen exposure) and a late-phase
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`reaction (occurring 4 to 10 hours after allergen challenge in about half of patients).” Drouin
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`(1995), at 341.
`
`B.
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`Prior art treatment of allergic rhinitis.
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`1.
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`Antihistamines were known to treat primarily the early-phase
`response.
`
`44.
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`Antihistamines are a class of drugs that, as the name suggests, block the activity
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`of histamine in the body. As noted above, histamine has long been known to play a role in the
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`early-phase response of AR. It causes, among other things, dilation of blood vessels
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`(vasodilation), which can lead to runny nose, watery eyes and, ultimately, congestion. It can also
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`stimulate mucus-secreting glands, which also contributes to these symptoms. Histamine in AR
`
`can also stimulate receptors in the nose that cause sneezing and coughing.
`
`45.
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`It was also known long before the alleged date of invention that antihistamines are
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`useful in stopping or reducing these reactions. The usefulness of antihistamines in treating AR
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`was first discovered in the first half of the twentieth century. Feinberg & Friedlaender (1945).
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`46.
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`The first generation of antihistamines was shown to inhibit the early phase of AR,
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`but have little or no effect on the late phase. Grönneberg et al. (1981). However, a second
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`generation of antihistamines was shown before the alleged date of invention to inhibit the
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`responses of not only mast cells, but also other inflammatory cells at high concentrations,
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`thereby providing some (not complete) relief for the late-phase response of AR and adding to
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`their efficacy.
`
`47.
`
`The prior art succinctly summarizes what would have been well known to a
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`POSA about the role of histamine and antihistamines in AR before 2002. As Galant &
`
`Wilkinson reported, “First- and second-generation antihistamines are very effective in the
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`treatment of AR because they alleviate both nasal and ocular symptoms. Antihistamines
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`antagonise histamine directly, but reversibly, at the H1 receptor, thereby blocking the
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`physiological effects of histamine on blood vessels, mucous-secreting glands, and sensory nerve
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`endings in the nose. In addition, several antihistamines, including the second-generation agents
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`fexofenadine hydrochloride and loratadine, also appear to block release of histamine and other
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`inflammatory mediators from mast cells and basophils in vivo. The second-generation
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`antihistamine cetirizine inhibits LTC4 and D4 production in nasal secretions and inhibits
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`recruitment of eosinophils in the cutaneous late-phase model.” Galant & Wilkinson (2001), at
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`456. Drouin (1995) similarly taught that “H1-rece