UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BAUSCH HEALTH IRELAND LIMITED,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2022-01102 - Patent No. 9,610,321
`Case No. IPR2022-01103 - Patent No. 9,616,097
`Case No. IPR2022-01104 - Patent No. 9,919,024
`Case No. IPR2022-01105 - Patent No. 9,925,231
`
`_____________________________
`
`DECLARATION OF UWE CHRISTIANS, M.D., PH.D.
`
`MYLAN - EXHIBIT 1004
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`

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`
`
`TABLE OF CONTENTS
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` Page
`QUALIFICATIONS............................................................................................... 1
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`SCOPE OF WORK ............................................................................................... 5
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`I.
`
`II.
`
`III. LEGAL PRINCIPLES ............................................................................................ 7
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`IV. OVERVIEW OF THE CHALLENGED PATENTS .................................................... 10
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` Claims of the ’231 and ’097 Patents ........................................................ 11
`
` Claims of the ’024 and ’321 Patents ........................................................ 12
`
`V.
`
`THE LEVEL OF ORDINARY SKILL IN THE ART .................................................. 14
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`VI. CLAIM TERMS ................................................................................................. 16
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`VII. THE STATE OF THE ART .................................................................................. 16
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`VIII. ASSERTED REFERENCES DISCLOSE OR SUGGEST CLAIMED
`FEATURES ....................................................................................................... 20
`
` The ’024 and ’321 Patents ........................................................................ 22
`
`1. Ground 1: Each of Claims 1-6, 8-9, and 11-16 Was
`Obvious over Shailubhai, Camilleri, Remington, and
`Mihranyan ........................................................................................... 22
`
`2. Ground 2: Each of Claims 7 and 10 Was Obvious over
`Shailubhai, Camilleri, Remington, Mihranyan, and Currie ................ 42
`
`3. Ground 3: Each of Claims 1-4 and 11-16 Was Obvious
`over the 2009 Abstract and Doelker .................................................... 44
`
`4. Ground 4: Each of Claims 5-10 Was Obvious over the
`2009 Abstract, Doelker, and Currie .................................................... 56
`
` The ’231 and ’097 Patents ........................................................................ 62
`
`1. Ground 1: Each of Claims 1-2, and 4-12 Was Obvious
`over Shailubhai, Remington, and Mihranyan ..................................... 62
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`2. Ground 2: Claim 3 Was Obvious over Shailubhai,
`Remington, Mihranyan, and Aulton .................................................... 71
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`3. Ground 3: Each of Claims 1-2, 4-6, and 8-12 Was
`Obvious over the 2009 Abstract and Doelker ..................................... 72
`
`4. Ground 4: Claim 3 Was Obvious over the 2009 Abstract,
`Doelker, and Aulton ............................................................................ 79
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`5. Ground 5: Claim 7 Was Obvious over the 2009 Abstract,
`Doelker, and Zimmer .......................................................................... 80
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`IX. SECONDARY CONSIDERATIONS ....................................................................... 80
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`X.
`
`CONCLUDING STATEMENTS ............................................................................ 85
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`XI. APPENDIX – LIST OF EXHIBITS ....................................................................... 86
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`I, Uwe Christians, declare as follows:
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`I. QUALIFICATIONS
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`
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` I am a Professor with tenure at the University of Colorado School of
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`Medicine at the Anschutz Medical Campus, a position I have held since 2005.
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`Since 1999 I have also served as a Professor of Clinical and Experimental
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`Pharmacology and Toxicity at the Institut für Pharmakologie at Medizinische
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`Hochschule Hannover in Hannover, Germany.
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`
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`I received my M.D. with highest honors from Medizinische
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`Hochschule Hannover in Hannover, Germany in 1988. I became board-certified in
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`pharmacology and toxicology in 1992, and board-certified in clinical
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`pharmacology in 1996. I received my Ph.D. in experimental and clinical
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`pharmacology and toxicology in 1995 from Medizinische Hochschule Hannover. I
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`completed post-doctoral studies at the School of Medicine at Stanford University
`
`from 1996-1999, focusing on cardiothoracic surgery and transplant immunology. I
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`similarly completed post-doctoral studies at the School of Pharmacy at the
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`University of California in San Francisco, focusing on Biopharmaceutical Sciences
`
`from 1996-2000. I received a board certification from the American Board of
`
`Clinical Pharmacology for my work in Clinical Pharmacology at the University of
`
`Colorado, Denver, in 2005. I also earned a Master in Research Quality Assurance
`
`in 2007 from the British Association of Research Quality Assurance.
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`From 1988-1995 I also served as the Head of the Laboratory of
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`Therapeutic Drug Monitoring and Drug Metabolism at the Institut für Allgemeine
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`Pharmakologie at the Medizinische Hochschule Hannover in Hannover, Germany.
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`During this time I also served as an Instructor in Pharmacology and Toxicology as
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`well as Instrumental Analytics. From 1995-1999 I served as an Assistant Professor
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`at the Medizinische Hochschule in Hannover, Germany. From 1997-2001 I also
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`served as a Visiting Assistant Professor in the Department of Biopharmaceutical
`
`Sciences at the University of California, San Francisco. I began my current
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`position of Professor of Clinical and Experimental Pharmacology and Toxicology
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`at the Medizinische Hochschule in Hannover, Germany in 1999. From 2001-2004,
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`I served as an Associate Professor in the Department of Anesthesiology at the
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`University of Colorado Health Sciences Center, Denver, Colorado, where I also
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`held a joint appointment in Pharmaceutical Sciences. In 2006, I began an
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`appointment in Biomolecular Structure. From 2002-2010 I served as the Director
`
`of the Mass Spectrometry Core of the Clinical Nutrition Research Unit. From
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`2005-2008 I was the Director of Pharmacology at Bionovo Inc. From 2007-2008, I
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`also served as the General Manager and President of Eurofins/Medinet Colorado.
`
`
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`I have been a member of the German Society of Experimental and
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`Clinical Pharmacology and Toxicology since 1991 and the International Society of
`
`the Study of Xenobiotics since 1992. I have also been a member of the German
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`Society of Clinical Chemistry since 1995 and was a member of the American
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`Association of Clinical Chemistry from 1995-2001. In 1995, I began my
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`membership in the International Association of Therapeutic Drug Monitoring and
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`Clinical Toxicology. I also served as a member of the American Association of
`
`Pharmaceutical Scientists from 1998-2000. In 2004, 2005, and 2007, I began my
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`membership in the American Society of Transplantation, the American Society of
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`Clinical Pharmacology and Therapeutics, and the American Association of
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`Pharmaceutical Sciences (AAPS), respectively.
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`
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`During my time in the Department of Pharmacology at the
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`Medizinische Hochschule Hannover, from 1990-1995, I collaborated with the
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`Niedersächsisches Institut für Peptidforschung GmbH (Prof. W. Forssmann), the
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`research of which was mostly focused on soluble guanylin and derivatives such as
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`uroguanylin.
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` My research has been funded by such organizations and companies as
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`Sandoz AG, Fujisawa GmbH, Deutsche Forschungsgemeinschaft1, the German
`
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`1 The Deutsche Forschungsgemeinschaft is the Research Foundation of the
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`German government and corresponds to the United States National Institutes of
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`Health (NIH).
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`Cancer Society, the Freunde der Medizinischen Hochschule Foundation, Bristol-
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`Myers Squibb, Novartis Pharma AG, the NIH, the Department of Defense, and the
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`Food and Drug Administration (FDA).
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`
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`I have served as a reviewer on almost 40 peer-reviewed journals,
`
`including Pharmacology, the European Journal of Clinical Pharmacology, the
`
`Journal of Clinical Pharmacology, Proceedings of the National Academy of
`
`Sciences, Analytical Chemistry, and the Journal of Medicinal Chemistry. I serve on
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`the Editorial Board of Therapeutic Drug Monitoring, the European Journal of
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`Clinical Pharmacology, and Drug Metabolism and Disposition. I am also Editor-
`
`in-Chief of Therapeutic Drug Monitoring and Associate Editor of Transplantation.
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`
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`I have received numerous awards and honors. In 1988 I won the
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`Award of the “Freunde der Medizinischen Hochschule” Foundation for best thesis.
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`In 1995 I won the Young Investigator Award from the International Society of
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`Therapeutic Drug Monitoring and Clinical Toxicology. That same year I received
`
`the “Heisenberg” grant from Deutsche Forschungsgemeinschaft. In 1997 my work
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`was named as Best Paper in Drug Metabolism and Disposition by the American
`
`Society of Pharmacology and Experimental Therapeutics. In 2008 I was named
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`Top Referee of the Journal of Chromatography B. From 2009-2010 I was named
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`Vice-Chair of the Therapeutic Drug Monitoring and Toxicology Section of the
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`American Association of Clinical Pharmacology and Therapeutics. From 2010-
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`2011 I was named Chair of the Biomarker and Imagining Section of the American
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`Association of Clinical Pharmacology and Therapeutics. In 2015 I earned the C.E.
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`Pippenger Award for Outstanding Contributions to Therapeutic Drug Monitoring
`
`from the International Association of Therapeutic Drug Monitoring and Clinical
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`Toxicology.
`
`
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`As exemplified by my education and varied experiences discussed
`
`briefly above and further detailed in my curriculum vitae (EX1033), which
`
`provides further details regarding my education, honors and awards, publications,
`
`work, and research history, I am an expert in clinical pharmacology. During the
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`course of my career, I have had substantial experience developing and
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`administering both animal studies and human clinical trials. My experiences range
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`from, among many other things, formulating compounds for use in those studies,
`
`conducting dose ranging studies, and analyzing and reporting results. Moreover,
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`as noted above, I spent approximately five years of my career conducting research
`
`on soluble guanylin and guanylin derivatives such as uroguanylin. Accordingly, I
`
`am well qualified to provide opinions on the very basic subject matter covered by
`
`the challenged patents.
`
`II. SCOPE OF WORK
`
`
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`I understand that, in conjunction with this declaration, petitions for
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`Inter Partes Review of each of U.S. Patent Nos. 9,919,024 (“the ’024 patent,”
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`IPR2022-01104), 9,610,321 (“the ’321 patent,” IPR2022-01102), 9,925,231 (“the
`
`’231 patent,” IPR2022-01105), and 9,616,097 (“the ’097 patent,” IPR2022-01103)
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`(collectively, “the challenged patents”) are being filed at the United States Patent
`
`and Trademark Office on the behalf of Mylan Pharmaceuticals Inc. (“Mylan”). I
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`have been retained as a technical expert by Mylan in all four Inter Partes Review
`
`proceedings to provide opinions regarding the challenged patents. I have not
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`previously served as an expert witness for Mylan.
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`
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`In particular, I have been asked to review each of the challenged
`
`patents, along with their prosecution histories, to provide my expert opinions on
`
`the validity of the challenged patent claims (claims 1-16 of the ’321 patent, claims
`
`1-16 of the ’024 patent, claims 1-12 of the ’097 patent, and claims 1-12 of the ’231
`
`patent). In the course of forming my opinions, I have also considered other
`
`documents, which are listed in Section XI at the end of this declaration.
`
`
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`It is my understanding that this declaration is being submitted in all
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`four proceedings. Because the disclosures across the challenged patents are
`
`substantially identical, I may cite to just one patent, e.g., the ’231 patent, for a
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`representational patent disclosure, rather than providing four separate citations for
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`the same disclosure in each of the challenged patents.
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`I am being compensated $575/hour for my services in connection with
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`these proceedings, and this compensation is in no way dependent upon the
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`opinions that I have provided or the outcome of these proceedings.
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`
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`I also understand that Bausch Health Ireland Limited (“Bausch”)
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`currently holds the assignments for the challenged patents. While I understand that
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`the challenged patents originally issued to a different entity, for simplicity I
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`collectively refer to the current assignee as well as its predecessors as “Bausch” in
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`this declaration. I do not have any affiliations—past or present—with Bausch.
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`III. LEGAL PRINCIPLES
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`
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`I have been advised that the burden in this proceeding is on the
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`petitioner (Mylan) to demonstrate the unpatentability of the challenged claims.
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`
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`I have been advised that a claimed invention is not patentable under
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`35 U.S.C. §102 (anticipation) if every element of the claim is disclosed, either
`
`expressly or inherently, as arranged in the claim in a single prior-art reference.
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`
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`I have also been advised that a claimed invention is not patentable
`
`under 35 U.S.C. §103 (obviousness) if the differences between the claimed
`
`invention and the prior art are such that the subject matter as a whole would have
`
`been obvious at the time the claimed invention was made to the person of ordinary
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`skill in the art (“POSA”) to which the subject matter pertains.
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`I understand that a determination of obviousness requires inquiries
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`into: (i) the scope and content of the art when the claimed invention was made;
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`(ii) the differences between the art and the claims at issue; (iii) the level of ordinary
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`skill in the pertinent art when the claimed invention was made; and, to the extent
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`any exist, (iv) secondary considerations indicating non-obviousness.
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`
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`I understand that hindsight must not be used when comparing the
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`prior art to the claimed invention for obviousness. Thus, a conclusion of
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`obviousness must be firmly based on the knowledge and skill of the POSA at the
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`time the claimed invention was made, without the use of post-filing knowledge.
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`I understand that for a claimed invention to be considered obvious,
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`there must be some rational underpinning for combining cited references as
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`proposed.
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`
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`I further understand that obviousness may also be shown by
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`demonstrating that it would have been obvious to modify what is taught in a single
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`piece of prior art to create the claimed invention. Obviousness may be shown by
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`demonstrating that the POSA would have considered it obvious to combine the
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`teachings of more than one element disclosed by prior art. I understand that the
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`following examples are approaches and rationales that may be considered in
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`determining whether a piece of prior art could have been combined with other prior
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`art or with other information within a POSA’s knowledge:
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`(a)
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`(b)
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`(c)
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`(d)
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`(e)
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`(f)
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`(g)
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`combining prior-art elements according to known methods to yield
`predictable results;
`substituting one known element for another to obtain predictable
`results;
`using a known technique to improve similar devices (methods, or
`products) in the same way;
`applying a known technique to a known device (method, or product)
`that was ready for improvement to yield predictable results;
`applying a technique or approach that would have been “obvious to
`try” (i.e., choosing something from a finite number of identified,
`predictable solutions, with a reasonable expectation of success);
`applying variations based on known work in one field of endeavor for
`use in either the same field or a different one, based on design
`incentives or other market forces, if the variations would have been
`predictable to one of ordinary skill in the art; or
`acting upon some teaching, suggestion, or motivation in the prior art
`to modify the prior-art reference or to combine prior-art reference
`teachings thereby arriving at the claimed invention.
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`
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`I have been instructed that secondary considerations, when in
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`evidence, may include: (i) commercial success of a product due to the merits of the
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`claimed invention; (ii) a long-felt, but unsatisfied need for the claimed invention;
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`(iii) failure of others to find the solution provided by the claimed invention;
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`(iv) deliberate copying of the claimed invention by others; (v) unexpected results
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`achieved by the claimed invention; (vi) praise of the claimed invention by others
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`skilled in the art; (vii) lack of independent simultaneous invention within a
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`comparatively short span of time; and (viii) teaching away from the claimed
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`invention in the prior art. I am informed that secondary considerations are relevant
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`where there is a nexus between the evidence and the claimed invention.
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`I am informed that Bausch bears the burden to establish any
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`secondary considerations indicating non-obviousness. I am further informed that
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`for anticipation secondary considerations are not relevant and that for obviousness
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`they must be clearly linked to a claimed feature or features not already known in
`
`the prior art.
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`IV. OVERVIEW OF THE CHALLENGED PATENTS
`
` The four challenged patents are all directed towards formulations of a
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`peptide known as plecanatide, along with an inert low moisture carrier and a
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`lubricant. Two of the patents recite particular dosage amounts, and two recite
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`administering the formulation to treat conditions including irritable bowel
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`syndrome (“IBS”) and chronic constipation, as well as symptoms associated with
`
`these conditions, such as constipation and abdominal pain.
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` The peptide of interest, plecanatide, was known before the challenged
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`patents—a fact that the patents themselves admit. EX1001 (’231 Patent), 3:59-65,
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`21:62-22:4, 25:58-66, 27:18-23; see also id., 27:26-28:40, 29:7-10, 29:7-30:62
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`(noting methods of preparing this peptide were also known). The challenged
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`patents also acknowledge that the mechanism of action of guanylate cyclase-c
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`(“GCC”) peptides and biology involved in conditions such as chronic constipation
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`and IBS were known. Id., 2:40-42. Notably, the challenged patents do not purport
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`to elucidate any additional information regarding the “precise causes of IBS and
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`inflammatory bowel diseases.” Id., 2:44-45.
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` The challenged patents further assert that the “invention is also based
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`in part on the discovery that very low doses of the GCC agonist peptides described
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`herein are effective for the treatment of diseases and disorders in humans.”
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`EX1001 (’231 patent), 7:30-33. I note, however, that two of the four patents (the
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`’231 and ’024 Patents) do not recite dosage amounts and two of the four patents
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`(the ’231 and ’097 Patents) do not recite the treatment of a particular disease or
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`disorder. Nevertheless, the challenged patents assert that the “dosage range found
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`to be effective was not predicted based on animal studies.” Id.
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` Claims of the ’231 and ’097 Patents
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` The ’231 and ’097 patents each include 12 claims. Both patents have
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`only one independent claim. I understand that the remaining 11 claims depend
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`either directly or indirectly from independent claim one, and that these dependent
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`claims include all of the limitations of the claim from which they depend.
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`I understand the only difference between the two sets of claims is that
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`the ’097 patent includes an additional limitation with regard to dosage amounts.
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`Otherwise, both sets of patent claims recite an oral dosage formulation of
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`plecanatide (“a Guanylate Cyclase-C (GCC) agonist peptide consisting of SEQ ID
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`NO:1, wherein said peptide is a (4,12; 7,15) bicycle,” that “has a chromatographic
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`purity of no less than 91% after storage for at least three months”), an “inert low
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`moisture carrier,” and “a lubricant.” Claim 1 of the ’097 patent further specifies
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`that plecanatide is present as a per unit dose of 3.0 mg or 6.0 mg.
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` For both patents, dependent claims 2-6 and 8-12 depend directly from
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`claim 1. Claim 7 depends from claim 6.
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` Dependent claims 2, 3, and 5 each recite limitations relating to purity
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`or stability of plecanatide. Similarly, for both the ’231 and ’097 patents, dependent
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`claims 4 and 6 recite that the oral dosage formulation is a particular form, such as a
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`capsule or tablet. Dependent claim 7 recites that the capsule or tablet is in a blister
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`pack or strip. For both patents, dependent claims 8 and 9 recite that the lubricant is
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`magnesium stearate and present at an amount of 0.25% w/w. Claims 10-12 recite
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`that the inert carrier is microcrystalline cellulose, is present at an amount of at least
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`96% w/w, and has a particle size of between 50-900 microns.
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` Claims of the ’024 and ’321 Patents
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` The ’024 and ’321 patents each include 16 claims. Both patents have
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`two independent claims—claims 1 and 3.
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`I understand the only difference between the two sets of claims is that
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`the ’321 patent includes an additional limitation with regard to dosage amounts.
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`Otherwise, both sets of patent claims recite methods of treatment involving the
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`administration of the same oral dosage formulation recited in the ’231 and ’097
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`patents.
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` For both the ’024 and the ’321 patents, independent claim 1 recites a
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`method for treating chronic constipation in a human subject comprising orally
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`administering to the human subject the composition recited in the ’231 and ’097
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`patents. Independent claim 3 of the ’024 and ’321 patents recites a method of
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`treating or alleviating a symptom associated with chronic constipation or irritable
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`bowel syndrome in a human subject comprising orally administering to the human
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`subject the same composition recited in the ’231 and ’097 patents. Like claim 1 of
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`the ’097 patent, claims 1 and 3 of the ’321 patent further specify that plecanatide is
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`present as a per unit dose of 3.0 mg or 6.0 mg.
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` Dependent claim 2 of the ’024 and ’321 patents depends from
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`independent claim 1 and recites that the constipation is associated with irritable
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`bowel syndrome or chronic idiopathic constipation. Dependent claim 4 depends
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`from independent claim 3 and recites that the symptom is constipation or
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`abdominal pain.
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` Dependent claims 5-10 of the ’024 and ’321 patents each recite
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`limitations regarding the co-administration of additional therapeutic agents. For
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`example, dependent claims 5 and 8 depend from independent claims 1 and 3,
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`respectively, and recite further administration of an effective dose of an inhibitor of
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`cGMP-dependent phosphodiesterase. Dependent claims 6 and 9 depend from
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`claims 5 and 8, respectively, and recite that the inhibitor is sulindac sulfone,
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`zaprinast, or motapizone. Dependent claims 7 and 10 depend from independent
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`claims 1 and 3, respectively, and recite further administration of an effective dose
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`of a laxative.
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` Dependent claims 11-16 of the ’024 and ’321 patents each recite
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`limitations regarding the formulation. For example, claims 11 and 14 depend from
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`independent claims 1 and 3, respectively, and recite that the inert low moisture
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`carrier is microcrystalline cellulose. Dependent claims 12 and 15 depend from
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`independent claims 1 and 3, respectively, and recite that the lubricant is
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`magnesium stearate. Dependent claims 13 and 16 depend from independent claims
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`1 and 3, respectively, and recite that the inert low moisture carrier is
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`microcrystalline cellulose and that the lubricant is magnesium stearate.
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`V. THE LEVEL OF ORDINARY SKILL IN THE ART
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`I have been advised that the POSA is a hypothetical person who is
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`presumed to have known the relevant art at the time of the claimed invention. I
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`understand that the POSA is also regarded as a person of ordinary creativity, as
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`well as someone to whom one could assign a routine task with reasonable
`
`confidence that the task would be successfully completed.
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`I understand that a POSA may work in consultation with other
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`specialists, and that the definition of the POSA may depend on whether the
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`challenged patent is primarily claiming a formulation or a method of treatment.
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`Thus, for the ’321 and ’024 patents, which recite methods of treatment, a POSA
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`would include an M.D. with experience in treating constipation and related
`
`disorders. This individual may have worked with other specialists including, e.g.,
`
`an individual with a graduate degree in pharmaceutics or a related field, along with
`
`knowledge and experience formulating active pharmaceutical ingredients into oral-
`
`dosage formulations, a clinical pharmacologist, and a medicinal chemist. By virtue
`
`of my own education, experience, and training, I am familiar with the level of skill
`
`in the art of these challenged patents. In my opinion, this level of skill is consistent
`
`with that which is presumed by each of these challenged patents.
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` For the ’097 and ’231 patents, which recite formulations, the lead
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`investigator would instead be an individual with a graduate degree in
`
`pharmaceutics or a related field, along with knowledge and experience formulating
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`active pharmaceutical ingredients into oral-dosage formulations. This individual
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`may again have worked in consultation with other specialists including, e.g., an
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`M.D. with experience in treating constipation and related disorders, as well as the
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`other specialists I noted above for the ’321 and ’024 patents. Again, I am familiar
`
`with this level of skill and, again, in my opinion, this level of skill is consistent
`
`with that which is presumed by each of these challenged patents.
`
`
`
`I have also been advised that the relevant timeframe for my analysis is
`
`the time period prior to September 15, 2011. Therefore, the opinions that I have
`
`expressed in this declaration with regard to the POSA apply to a POSA as of
`
`September 15, 2011. I note though, that the opinions that I have expressed in this
`
`declaration would not be affected if the relevant timeframe is determined to be
`
`September 15, 2010, based off of the earliest-filed provisional application to which
`
`the challenged patents claim priority.
`
`VI. CLAIM TERMS
`
`
`
`I have been advised that, for purposes of my testimony in the present
`
`proceedings, the challenged patent claims are to be given their plain and ordinary
`
`meaning (i.e., the meaning that the terms would have to the person of ordinary skill
`
`in the art at the time of the invention).
`
`VII. THE STATE OF THE ART
`
` Plecanatide is a peptide consisting of sixteen amino acid residues.
`
`Also referred to as SP304, Guanilib, and Glu3-uroguanylin, plecanatide has the
`
`following sequence:
`
`
`
`
`
`-16-
`
`

`

`
`
`
`Asn1-Asp2-Glu3-Cys4-Glu5-Leu6-Cys7-Val8-Asn9-Val10-Ala11-Cys12-Thr13-Gly14-Cys15-Leu16
`
`EX1005 (Shailubhai2), 5:4-16, 10:40-64, 15:56-58.
`
` Shailubhai teaches that plecanatide operates by increasing potassium-
`
`and calcium-ion influx and water transport into the gastrointestinal tract. EX1005
`
`(Shailubhai), 6:13-32; see also id., 15:25-17:5 (noting plecanatide as the “most
`
`potent peptide for enhancing cGMP); id., [57], 2:57-61, 4:55-61 (teaching the
`
`administration of plecanatide for the treatment of gastrointestinal inflammatory
`
`disorders).
`
` Well before the challenged patents, plecanatide was known as a
`
`“guanylyl cyclase receptor agonist with both anti-inflammatory and
`
`antiproliferative effects.” EX1028 (Peyrin-Biroulet3), 78. POSAs thus understood
`
`plecanatide to have utility in the treatment of gastrointestinal disorders such as
`
`inflammatory bowel disease. Id., 73, 78.
`
`
`2 K. Shailubhai et al., Guanylate Cyclase Receptor Agonists for the Treatment
`
`of Tissue Inflammation and Carcinogenesis, U.S. Patent No. 7,041,786 (2006)
`
`(“Shailubhai,” EX1005).
`
`3 L. Peyrin-Biroulet et al., Crohn’s disease: beyond antagonists of tumour
`
`necrosis factor, LANCET, 372, 67-81 (2008) (“Peyrin-Biroulet,” EX1028).
`
`-17-
`
`
`
`
`
`

`

`
`
`
`
` POSAs also knew that plecanatide “can be given orally, and is not
`
`systemically absorbed (i.e., taken up in the blood and distributed throughout the
`
`body) which means that the compound is likely to be very safe in clinical use.”
`
`EX1017 (Callisto Website4), 1. Moreover, “[s]ince the GC-C receptors are found
`
`on the inside of the gastrointestinal lining, systemic absorption is not needed” for
`
`plecanatide to exert therapeutic effects. Id.
`
` By 2008, POSAs had identified that GCC agonists had utility in
`
`treating both chronic constipation and irritable bowel syndrome (IBS). EX1031
`
`(Camilleri5), 1879 (Table 2). As explained by Camilleri, this therapeutic utility was
`
`likely due to GCC agonists’ mechanism of increasing intestinal water and
`
`electrolyte secretion. Id., 1879 (Table 2). POSAs also understood that plecanatide
`
`
`4 Callisto Pharmaceuticals, SP-304 Science,
`
`https://web.archive.org/web/20081106172937/https://www.callistopharma.com/co
`
`ntent/pipeline/guanilib/science.jsp, captured by the WayBack Machine on
`
`November 6, 2008 (“Callisto Website,” EX1017).
`
`5 M. Camilleri et al., Challenges to the Therapeutic Pipeline for Irritable Bowel
`
`Syndrome: End Points and Regulatory Hurdles, GASTROENTEROL., 135, 1877-1891
`
`(2008) (“Camilleri,” EX1031).
`
`-18-
`
`
`
`
`
`

`

`
`
`
`(also sometimes referred to as Guanilib) is a guanylate cyclase-C agonist that, via
`
`this mechanism, increases intestinal water and electrolyte secretion. Id., 1878
`
`(Table 1); see also EX1005 (Shailubhai), [57], 2:57-61, 4:55-61, 6:13-32, 15:25-
`
`17:5. Thus, by 2008, POSAs understood that plecanatide was in development for
`
`the treatment of irritable bowel syndrome with associated constipation (“IBS-C”).
`
`EX1031 (Camilleri), 1878 (Table 1).
`
` By 2009, POSAs had already evaluated the use of plecanatide, at
`
`doses as low as 0.1 mg, for the treatment of chronic constipation, IBS with
`
`constipation, and other gastrointestinal diseases. EX1009 (2009 Abstract6), A-641.
`
`For example, the 2009 Abstract teaches the oral administration of 0.1-48.6 mg of
`
`plecanatide in healthy individuals, and notes that even in healthy volunteers
`
`plecanatide appeared to decrease the time to first bowel movement and elicited an
`
`increase in the post-dose BSFS [(Bristol Stool Form Scale)] versus placebo.” Id.
`
`
`6 K. Shailubhai et al., SP-304 to Treat GI Disorders – Effects of a Single, Oral-
`
`Dose of SP-304 on Safety, Tolerability, Pharmacokinetics and Pharmacodynamics
`
`in Healthy Volunteers, GASTROENTEROL., 136(5), A641, Abstract W1041 (2009)
`
`(“2009 Abstract,” EX1009).
`
`-19-
`
`
`
`
`
`

`

`
`
`
`The 2009 Abstract also reported that plecanatide was “well-tolerated at all dose
`
`levels with no unexpected side effects reported.” Id.
`
` Well before the challenged patents, POSAs also understood that GCC
`
`receptor agonists administered for the treatment of IBS and constipation could be
`
`co-administered with other therapeutic agents, such as laxatives and cGMP
`
`phosphodiesterase inhibitors such as motapizone, zaprinast, and suldinac sulfone.
`
`EX1032 (Currie7), ¶0011.
`
`VIII. ASSERTED REFERENCES DISCLOSE OR SUGGEST CLAIMED FEATURES
`
` Below I present my analysis regarding the obviousness of various
`
`aspects of the claims of the challenged patents. While my analysis focuses on the
`
`clinical or medical aspects of the claims, including methods of treatment and
`
`dosage amounts, I also note here that the formulation elements of the claim—i.e.,
`
`formulating plecanatide, which was known to be orally administrable, with an inert
`
`low moisture carrier and a lubricant—hardly seem inventive or non-obvious.
`
`
`7 M. Currie et al., Methods and Compositions for the Treatment of
`
`Gastrointestinal Disorders, U.S. Patent Publication No. 2005/0020811 (2005)
`
`(“Currie,” EX1032).
`
`
`
`
`
`-20-
`
`

`

`
`
`
`
` Rather, the recited formulations appear to state nothing more than a
`
`simple, routinely prepared type of composition. See, e.g., EX1005 (Shailubhai),
`
`13:18-52 (teaching formulation of plecanatide could be done using conventional
`
`methods); EX1006 (Remington8), 889-902 (teaching carriers and lubricants for
`
`oral dosage forms); EX1029 (Aulton9), 114