UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`COALITION FOR AFFORDABLE DRUGS II LLC
`Petitioner
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`v.
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`NPS PHARMACEUTICALS, INC.
`Patent Owner
`____________
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`Case IPR2015-01093
`Patent 7,056,886
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`____________
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`DECLARATION OF JOHN F. CARPENTER, PH.D.
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`IN SUPPORT OF PATENT OWNER’S RESPONSE
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION .......................................................................................... 1
`I.
`SUMMARY OF QUALIFICATIONS ........................................................... 1
`II.
`III. MATERIALS CONSIDERED ....................................................................... 4
`IV. UNDERSTANDING OF THIS PROCEEDING ........................................... 4
`V.
`LEGAL PRINCIPLES APPLIED AND LEVEL OF SKILL ........................ 6
`VI. THE ‘886 PATENT AND THE CHALLENGED CLAIMS ......................... 7
`VII. TECHNICAL BACKGROUND AND STATE OF THE ART IN 1999 ..... 11
`VIII. THE COMMERCIAL EMBODIMENT OF THE ‘886 PATENT .............. 18
`IX. THE PETITIONER’S CHALLENGES - OBVIOUSNESS ........................ 23
`X.
`SUMMARY OF NON-OBVIOUSNESS OF EACH CHALLENGED
`CLAIM.......................................................................................................... 28
`XI. THE FIELD OF THE INVENTION AND LEVEL OF ORDINARY
`SKILL IN THIS ART ................................................................................... 34
`XII. THE PRIOR ART ......................................................................................... 36
`A. Drucker ‘379 ....................................................................................... 36
`B. Drucker ‘600 ....................................................................................... 37
`C. Osterberg ............................................................................................ 38
`D. Kornfelt............................................................................................... 39
`E.
`Holthiuis ............................................................................................. 42
`F. Munroe ............................................................................................... 43
`XIII. SURPRISING AND UNEXPECTED RESULTS OF THE ‘886
`PATENT INVENTION ................................................................................ 43
`XIV. STABILIZATION OF GLUCAGON IS NOT PREDICTIVE OF
`STABILIZATION OF GLP-2 ...................................................................... 46
`XV. HISTIDINE IS A PROBLEMATIC EXCIPIENT ....................................... 51
`XVI. THERE IS NO MOTIVATION TO COMBINE, AND THERE ARE
`CLEAR TEACHINGS AWAY FROM PETITIONER’S
`COMBINATIONS ........................................................................................ 54
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`I.
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`INTRODUCTION
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`1.
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`2.
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`I, John Frank Carpenter, Ph.D., hereby declare as follows:
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`I have been retained by counsel for Patent Owner NPS
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`Pharmaceuticals, Inc. as an expert in formulation science to address topics relevant
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`to the subject matter of this inter partes review proceeding involving certain claims
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`of U.S. Patent No. 7,056,886 (Ex. 1003; the “ʼ886 patent”). I am being
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`compensated at the rate of $690 per hour. My compensation is in no way
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`dependent on the outcome of this case.
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`II.
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`SUMMARY OF QUALIFICATIONS
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`3. My curriculum vitae is Ex. 2043.
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`4.
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`I am a tenured Professor of Pharmaceutical Sciences and the Co-
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`Director of the Center for Pharmaceutical Biotechnology at the University of
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`Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
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`5.
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`I received a Bachelor of Science degree in Zoology from Duke
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`University, a Masters of Science from Oregon State University, and a Ph.D. in
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`Biology from the University of Louisiana, Lafayette in 1978, 1981, and 1985,
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`respectively.
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`6.
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`I was a Visiting Lecturer at the University of California, Davis from
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`1987-1988 and also a Postdoctoral Research Associate in Biophysics during that
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`time at UC Davis.
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`7.
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`8.
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`I was a Senior Scientist at CryoLife, Inc. from 1988-1992.
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`I was an Assistant Professor of Pharmaceutical Biotechnology at the
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`University of Colorado from 1993 to 1998; from 1998-2004, I was a tenured
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`Associate Professor of Pharmaceutical Biotechnology at the University of
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`Colorado Health Sciences Center; and from 2004 until present I have been a
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`tenured Professor of Pharmaceutical Sciences at the University of Colorado Health
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`Sciences Center.
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`9.
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`Since 1993 I have been Graduate Faculty at University of Colorado
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`Health Sciences Center.
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`10. Since 1997 I have been the Co-Founder and Co-Director of the Center
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`for Pharmaceutical Biotechnology at University of Colorado.
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`11. Since 1997 I have also been Graduate Faculty as the University of
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`Colorado, Boulder.
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`12. From 2000 to 2003, I was Associate Director of the Pharmaceutical
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`Sciences Graduate Training Program in the Department of Pharmaceutical
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`Sciences, University of Colorado.
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`13. From 2004 to 2008, I was Director of the Pharmaceutical Sciences
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`Graduate Training Program in the Department of Pharmaceutical Sciences,
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`University of Colorado.
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`14. From 2001 to 2010, I was Co-Director, NIH Training Grant,
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`Leadership Training in Pharmaceutical Biotechnology, University of Colorado.
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`15. Since 2012, I have been Director of Business Development,
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`University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
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`16.
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`I have published more that 250 peer-reviewed publications in the field
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`of protein/peptide formulation, consulted for dozens of pharmaceutical companies
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`internationally, and have been an invited lecturer at conferences, pharmaceutical
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`companies and universities around the world.
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`17.
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`I was elected a Fellow of the American Association for the
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`Advancement of Science in 2009. I was awarded a Research Achievement Award
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`in Biotechnology, American Association of Pharmaceutical Scientists in 2007. I
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`was awarded the Ebert Prize, AphA, Journal of Pharmaceutical Sciences, in 2007.
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`My other scientific honors and awards are listed in my curriculum vitae, which
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`also includes a list of my publications, patents, grant activity, presentations, and
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`teaching activity.
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`18. Over the course of my career, I have more than three decades of
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`experience in studies including protein/peptide formulation development;
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`protein/peptide degradation and stabilization during processing storage and
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`administration to patients; rational development of stable lyophilized formulations;
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`mechanisms by which excipients provide stabilization or fail to stabilize
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`proteins/peptide during freezing, drying and storage in the dried solid; and
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`development and testing of advanced analytical methods.
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`III. MATERIALS CONSIDERED
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`19.
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`In reaching the conclusions set forth below, I have relied on my close
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`to three decades of experience in pharmaceutical studies and have specifically
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`considered the '886 patent, relevant portions of the Coalition For Affordable Drugs
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`II LLC’s (“Petitioner”) Petition for inter partes review (“IPR”) (Paper 1; the
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`“Petition”) and exhibits thereto, Patent Owner’s Preliminary Response (Paper 18),
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`the declaration of Dr. Anthony Palmieri (the “Palmieri Declaration”; Exh. 1001),
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`the transcript of the deposition of Dr. Anthony Palmieri on December 10, 2015 (the
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`“Palmieri Dep; Exh. 2042) and the other materials cited below.
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`IV. UNDERSTANDING OF THIS PROCEEDING
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`20.
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`I understand that this is an inter partes review (“IPR”) proceeding
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`conducted before the Patent Trial and Appeal Board (“Board”) of the U.S. Patent
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`and Trademark Office (“PTO”) to determine if claims 1-45 of the '886 patent (the
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`challenged claims) should be cancelled as unpatentable. I understand that
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`Petitioner requested institution of this proceeding through a Petition dated April
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`23, 2015, and that the Petition asserted that the challenged claims of the '832 patent
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`are invalid as obvious over combinations of references. Pet. at 7-9. The Petition
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`was accompanied by a declaration of Dr. Anthony Palmieri.
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`21.
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`I understand that on August 7, 2015 Patent Owner submitted a
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`Preliminary Response in opposition to Petitioner’s Petition.
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`22.
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`I understand that the Board, in a decision on October 23, 2015,
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`decided to institute an IPR.
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`23.
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`I understand that the Board has not made any determination that the
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`challenged claims are in fact obvious; the Board has only determined that, on the
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`record then before it, the Petition satisfied the threshold standard for instituting this
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`proceeding, by showing a “reasonable likelihood that Petitioner would prevail in
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`establishing the unpatentability” of the challenged claims.
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`24.
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`I am not an attorney. However, I have been advised of the following
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`legal principles, and they have helped to form my conclusions in this report.
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`25. An invention that is patentable in the United States must not be, inter
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`alia, obvious. 35 U.S.C. § 103.
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`26. Obviousness is a question of law based upon (1) the scope and content
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`of the prior art, (2) the claims at issue, (3) the level of ordinary skill in the art, and
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`(4) objective evidence of secondary considerations. Routine experimentation does
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`not render an otherwise obvious claim valid. Obviousness only calls for a
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`reasonable expectation of success, not a guarantee.
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`27. To establish obviousness in view of a combination of references,
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`Petitioner must set forth sufficiently articulated reasoning with rational
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`underpinnings of why one skilled in the art would have been motivated to combine
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`the teachings of those references to derive the claimed subject matter and would
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`have had a reasonable expectation of success in doing so. Bumble Bee Foods, LLC
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`v. Kowalski, IPR2014-00224, Paper 18, 25-26 (PTAB June 20, 2014).
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`Furthermore, “[a] reference may be said to teach away when a person of ordinary
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`skill, upon reading the reference would be discouraged from following the path set
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`out in the reference or would be led in a direction divergent form the path taken by
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`the applicant.” Ricoh Corp. v. Quanta Computer Inc., 550 F.3d 1325, ____
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`(Fed.Cir. 2008).
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`V. LEGAL PRINCIPLES APPLIED AND LEVEL OF SKILL
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`28.
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`I understand that the ʼ886 patent must be read from the perspective of
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`a person of ordinary skill in the relevant art at the time the invention was made,
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`which here is approximately 1999—the earliest filing date listed on the face of the
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`patent is December 30, 1999. I understand the person of ordinary skill in the art is
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`a hypothetical person who is presumed to know the relevant art at the time of the
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`invention.
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`29. The subject to which the challenged claims of the '866 patent are
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`directed are formulations of GLP-2 or an analog that are stabilized, particularly
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`when lyophilized (i.e., six months at ambient temperature, 18 months at 4oC with
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`less than about 5% peptide degradation) at a pharmaceutically tolerable or
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`acceptable pH (i.e., a pH that can be administered without patient reactions that
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`preclude further administration) by a combination of L-histidine, phosphate buffer,
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`and mannitol (18-24) or mannitol or sucrose (1-17 and 25-45). This invention
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`resulted in a successfully marketed GLP-2 analog product and an approved drug
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`treatment for short bowel syndrome - GATTEX®. Therefore, the person(s) of
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`ordinary skill to whom the patent is directed would need to have a good
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`understanding of at least: i) peptide formulations; ii) peptide formulation
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`development; iii) and peptide degradation pathways.
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`30.
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`In my opinion, the person(s) of ordinary skill in the art to whom the
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`'886 patent is directed would have been a pharmaceutical protein or peptide
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`formulation scientist with a Ph.D. in pharmaceutical sciences or one of the
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`biological sciences, including molecular biology, biochemistry, and protein
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`chemistry, and would have had relevant post-doctorate experience in designing
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`pharmaceutical formulations of proteins or peptides sufficient to lead, or be an
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`integral part of, a development team.
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`VI. THE ‘886 PATENT AND THE CHALLENGED CLAIMS
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`31. The ’886 patent discloses GLP-2/GLP-2 analog formulations
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`“exhibiting superior stability following storage and/or exposure to elevated
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`temperatures.” Ex. 1003, Abstract. These formulations are at a pH that can be
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`administered without patient reactions that preclude further administration (i.e.,
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`pharmaceutically/physiologically tolerable/acceptable) and are stable, particularly
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`when lyophilized (i.e., six months at ambient temperature, 18 months at 4oC with
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`less than about 5% peptide degradation). Ex. 1003, 11:29-67.
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`32.
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`Independent ‘886 patent claim 1 is directed to a GLP-2 formulation of
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`(a) a medically useful amount of GLP-2 or analog, (b) a phosphate buffer in an
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`amount sufficient to adjust the formulation’s pH to a physiologically level, (c) L-
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`histidine, and (d) mannitol or sucrose. Claim 2 (dependent from claim 1) specifies
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`that specifies that the pH of the formulation is greater than about 6.0. Claim 3
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`(dependent form claim 2) specifies that the GLP-2 analog is h(Gly2)GLP-2 which
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`is human GLP-2 in which amino acid residue 2 has been substituted with a glycine
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`residue. Claim 4 (dependent from claim 2) specifies that the pH of the formulation
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`is from about 6.9 to about 7.9.
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`33. Claim 5 (dependent from claim 4) specifies that the GLP-2 analog is
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`h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
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`substituted with a glycine residue. Claim 6 (dependent from claim 4) specifies that
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`the pH of the formulation is from about 7.3 to about 7.4. Claim 7 (dependent from
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`claim 6) specifies that the GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2
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`in which amino acid residue 2 has been substituted with a glycine residue. Claim 8
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`(dependent from claim 1) specifies that the concentration of the GLP-2 or analog is
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`about 0.1 to bout 50 mg/mL. Claim 9 (dependent from claim 8) specifies that the
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`GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2 in which amino acid
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`residue 2 has been substituted with a glycine residue.
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`34. Claim 10 (dependent from claim 8) specifies that the concentration of
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`the GLP-2 or analog is about 5 to about 40 mg/mL. Claim 11 (dependent from
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`claim 10) specifies that the GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2
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`in which amino acid residue 2 has been substituted with a glycine residue. Claim
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`12 (dependent from claim 10) specifies that the concentration of the GLP-2 or
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`analog is about 7 to about 30 mg/mL. Claim 13 (dependent from claim 12)
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`specifies that the GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2 in which
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`amino acid residue 2 has been substituted with a glycine residue. Claim 14
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`(dependent from claim 12) specifies that the concentration of the GLP-2 or analog
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`is about 10 to about 20 mg/mL.
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`35. Claim 15 (dependent from claim 14) specifies that the GLP-2 analog
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`is h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
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`substituted with a glycine residue. Claim 16 (dependent from claim 14) specifies
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`that the amount of L-histidine is about 0.5 to about 1%. Claim 17 (dependent from
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`claim 16) specifies that the GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2
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`in which amino acid residue 2 has been substituted with a glycine residue. Claim
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`18 (dependent from claim 16) specifies that the bulking agent is mannitol. Claim
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`19 (dependent from claim 18) specifies that the GLP-2 analog is h(Gly2)GLP-2
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`which is human GLP-2 in which amino acid residue 2 has been substituted with a
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`glycine residue.
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`36. Claim 20 (dependent from claim 18) specifies that the concentration
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`of mannitol is about 2 to about 5%. Claim 21 (dependent from claim 20) specifies
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`that the GLP-2 analog is h(Gly2)GLP-2 which is human GLP-2 in which amino
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`acid residue 2 has been substituted with a glycine residue. Claim 22 (dependent
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`from claim 20) specifies that the concentration of mannitol is about 2.5 to about
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`3.5%. Claim 23 (dependent from claim 22) specifies that the GLP-2 analog is
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`h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
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`substituted with a glycine residue. Claim 24 (dependent from claim 1) specifies
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`that the GLP-2 peptide is a mammalian, vertebrate, or human GLP-2 peptide.
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`37. Claim 25 (dependent from claim 24) specifies that the GLP-2 analog
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`is h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
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`substituted with a glycine residue. Claim 26 (dependent from claim 24) specifies
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`that the GLP-2 peptide has the sequence of a primate, rat, mouse, porcine, species,
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`oxine species, bovine species, degu hamster, guinea pig, fish, chicken, or human
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`GLP-2 species. Claim 27 (dependent from claim 26) specifies that the GLP-2
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`analog is h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has
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`been substituted with a glycine residue. Claim 28 (dependent from claim 27)
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`provides that the formulation is stable at ambient temperature for up to 6 months,
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`and that this stability is evidenced by degradation of the peptide of less than about
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`5% during that time. Claim 29 (dependent from claim 28) provides that less than
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`about 4% peptide degradation is observed after the formulation is stored during the
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`time period of claim 28.
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`38. Claim 30 (dependent from claim 29) provides that less than about 2%
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`peptide degradation is observed after the formulation is stored during the time
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`period of claim 28.
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`39. Claim 31 (dependent from claim 1) provides that the GLP-2 analog is
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`identified by a specific process. That process includes screening peptides against
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`cells that have been genetically engineered to produce the GLP-2 receptor, and
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`identifying peptides that bind to the receptor. These are the peptides that are
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`identified as useful in the formulations of claim 1.
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`40. Claim 32 (dependent from claim 1) specifies that the GLP-2 peptide is
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`an analog having one or more amino acid substitutions, additions, deletions, or
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`modifications and has GLP-2 receptor binding activity.
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`41. Claim 33 (dependent from claim 1) provides that the GLP-2 peptide is
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`an analog that was altered to confer resistance to endogenous enzymes.
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`42. Claim 34 (dependent from claim 33) specifies that the alteration
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`includes a substitution at Ala2.
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`43. Claim 35 (dependent from claim 34) specifies that Ala2 is substituted
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`with Gly or Ser.
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`44. Claim 36 (dependent from claim 1) specifies that the GLP-2 analaog
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`is a GLP-2 receptor antagonist.
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`45. Claim 37 (dependent from claim 36) specifies that the antagonist has a
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`substitution (using mammalian GLP-2 numbering) at (i) Asp15, Phe22, Thr29,
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`Thr32, Aps33 or a combination of these or (ii) at Ala2 by Leu, Cys, Glu, Arg, Trp,
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`or PO3—Tyr.
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`46. Claim 38 (dependent from claim 1) specifies that formulation is
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`lyophilized.
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`47. Claim 39 (dependent from claim 38) specifies that the lyophilized
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`formulation has less than 5% water by weight.
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`48. Claim 40 (dependent from claim 39) specifies that the lyophilized
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`formulation has 2% or less water by weight. Claim
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`49.
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`41 (dependent from claim 1) provides that the formulation is stable at
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`about 4oC for up to 18 months, and that this stability is evidenced by degradation
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`of the peptide of less than about 5% during that time.
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`50. Claim 42 (dependent from claim 41) provides that provides that less
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`than about 4% peptide degradation is observed after the formulation is stored
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`during the time period of claim 41.
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`51. Claim 43 (dependent from claim 42) provides that provides that less
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`than about 2% peptide degradation is observed after the formulation is stored
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`during the time period of claim 41.
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`52. Claim 44 (dependent from claim 1) specifies that the GLP-2 analog
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`has one or more amino acid substitutions, additions, deletions, or modifications
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`and has GLP-2 receptor binding activity.
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`53. Claim 45 (dependent from claim 1) specifies that the GLP-2 analog is
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`h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
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`substituted with a glycine residue...
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`VII. TECHNICAL BACKGROUND AND STATE OF THE ART IN 1999
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`54. The formulation of therapeutic proteins and peptides was, before
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`December 30, 1999, and continues to be, a highly unpredictable, complicated and
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`specialized art.
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`55. Protein and peptide therapeutics must be stable during processing
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`steps (e.g., filling of vials or syringes; freeze-drying), immediately after
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`manufacture as well throughout their designated shelf lives to ensure product
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`safety and efficacy. There are numerous physical and chemical factors that can
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`affect the quality and stability of protein and peptide biopharmaceutical products.
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`This is particularly true during long-term storage in a container–closure system
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`likely to be subject to variations in temperature, light, and agitation with shipping
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`and handling. Compared with traditional chemical or small molecule
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`pharmaceuticals, proteins are considerably larger molecular entities with inherent
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`physio-chemical complexities.
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`56. Peptides and proteins differ from conventional chemical entities such
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`as small molecules in their sensitivity to different degradation pathways and
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`stresses. Also, unlike small molecule drugs, which are often administered orally,
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`therapeutic peptides and proteins are administered parenterally; i.e., by injection
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`and infusion. With parenteral administration there are additional product quality
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`and safety requirements including sterility and specifications (e.g., USP 788) levels
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`of subvisible particles. Proteins and peptides are typically more sensitive to slight
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`changes in solution chemistry. They usually remain stable only within a relatively
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`narrow range of pH, are subjected to a variety of chemical and physical
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`degradation processes. The challenges in formulating a protein or peptide are often
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`more difficult than those in formulating a small molecule.
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`57. Formulation scientists typically refer to two broad categories of
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`protein or peptide degradation- physical and chemical. Chemical degradation refers
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`to the formation or destruction of covalent bonds within a protein or peptide.
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`Chemical modifications of protein include hydrolysis, oxidation, disulfide bond
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`scrambling, deamidation, Malliard reaction, succinimide formation,
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`diketopiperazine formation, deglycosylation and desialylation, and enzymatic
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`proteolysis due to proteases. Unfolding, dissociation, denaturation, aggregation,
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`particle formation, fragmentation, adsorption to interfaces, fibril formation,
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`gelation and precipitation are among modifications known as physical degradation
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`of peptides and proteins. Different protein and peptide degradation pathways can
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`promote each other for a given protein or peptide and a given formulation. A
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`chemical event may trigger a physical event, such as when oxidation is followed
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`by aggregation. And unfolding may foster chemical degradation such oxidation of
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`an interior methionine residue that is exposed to solvent in a fully- or partially-
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`unfolded protein molecules.
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`58. Even small levels of degradation can compromise a therapeutic
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`protein or peptide product. For example, even a few percent or less of protein or
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`peptide aggregation or precipitation (i.e., examples of many types of physical
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`degradation) can render a product medically unacceptable.
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`59. One reason that a protein or peptide medicine can often be
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`pharmaceutically unacceptable is if visible particles are observed in the solution,
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`for example, after reconstitution of a lyophilized product. The mass percent of the
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`protein or peptide in these visible particles can be quite low and even less than 1%.
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`Development of a formulation for a given protein or peptide that gives enough
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`stabilization to prevent this is extremely challenging.
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`60. Traces of physical degradation of even a few percent or less of the
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`protein or peptide to soluble aggregates or subvisible particles may result in
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`adverse, unwanted immunogenicity in patients (resulting in loss of drug efficacy),
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`as well as dangerous infusion reactions.
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`61. The foregoing reasons are examples of showing why a relative
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`decrease in degradation of a given protein or peptide during processing and storage
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`is not of value. One must provide quantitative reduction in degradation that keeps
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`degradation to an absolute minimum.
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`62. Chemical degradation of a protein or peptide in a pharmaceutical
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`formulation can result in similar problems, including adverse immunogenicity and
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`reduced potency of the medicine. Chemical degradation may also make the protein
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`or peptide more sensitive to physical degradation.
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`63. This is why every key route of degradation for a given protein or
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`peptide, not just selected ones, should be characterized and inhibited as much as
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`possible for a successful, commercial protein- or peptide-based formulation. The
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`success of a protein or peptide drug often depends upon the delivery of the
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`biologically active form of the protein or peptide to the site of action, as well as
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`minimizing key degradation pathways (which are unique for each product). Failure
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`to develop an adequately stabilized product can result directly in failure to gain
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`approval by regulatory agencies, halting of clinical trials due inadequate product
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`stability, as well as development-halting adverse events during clinical trials. Thus,
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`the medical and commercial success of a therapeutic peptide or protein product is
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`absolutely dependent of meeting the great challenge of developing a properly
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`stabile formulation.
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`64. Each protein and peptide is unique in that it has its own physico-
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`chemical properties, degradation routes, sensitivities to processing stresses (e.g.,
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`the freezing and drying steps of the lyophilization process) and responses to
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`stabilizing excipients. Proteins or peptides with similar sequences may have
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`widely different degradation pathways. They may also have widely different
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`condition requirements for optimal stability and optimal response to stabilizing
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`excipients. For example, typically when formulating a given protein or peptide, the
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`formulation scientist empirically determines the optimal pH in order to minimize
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`physical and chemical degradation pathways. With respect to GLP-2 and glucagon,
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`it has been determined that GLP-2 precipitates to insoluble aggregates at acidic
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`pH’s, whereas glucagon is soluble and resistant to aggregation at very acid
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`conditions of pH 2.8 and lower.
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`65. Formulation science is unpredictable. Protein or peptide formulation
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`development requires extensive and often complicated experimentation. Many
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`excipients that are available to stabilize proteins or peptides during processing
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`(such as during lyophilization) and storage may not yield sufficient stability to a
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`particular protein or peptide because of that protein’s or peptide’s unique critical
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`degradation pathways its unique responses to a specific excipient. In additional,
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`degradation products effects on safety and efficacy are different for each protein or
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`peptide. One illustrative, but non-limiting, example is that oxidation of a
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`methionine residue in one peptide may render it biologically inactive, but oxidation
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`of methionine in a different peptide methionine oxidation may not alter activity at
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`all. There is no way reasonably to predict whether a particular excipient will
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`provide a pharmaceutically necessary degree of stability in a given protein or
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`peptide product.
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`66. Dr. Jeffery L. Cleland from Genentech, Inc. and Dr. Robert Langer
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`from Massachusetts Institute of Technology are prominent protein/peptide
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`formulation scientists. They stated that “[e]ach molecule has its own unique
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`physical and chemical properties which determine in vitro stability. The
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`formulation scientist must also be concerned about the in vivo stability of the drug.
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`Thus, the development of successful formulations is dependent upon the ability to
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`study both the in vitro and in vivo characteristics of the drug as well as its intended
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`application.” Ex. 1024, 2. I agree, and these considerations still apply today.
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`Accordingly, a formulation scientist should consider the clinical indication,
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`pharmacokinetics, toxicity, and physicochemical stability of the protein or peptide
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`drug.
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`67.
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`Individual analysis and balancing of the rates of individual
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`degradation pathways of a protein or peptide are necessary and must be undertaken
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`to achieve the most stabile formulation possible. Additionally, formulation
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`components must be considered and balanced in terms, for example, of protein or
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`peptide stability and administration route.
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`68. Although a formulation scientist’s approach to formulation
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`development may be systematic, it is not like a cookbook and is not formulaic.
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`69. Cleland, Figure 2 illustrates one example of a system for formulating
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`therapeutic proteins and peptides. This is only one system; there are many others.
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`This process, like most other protein or peptide formulation development systems,
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`list first variables and then other variables within the first ones that are to narrow
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`the possible substituents.
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`70. These processes are undertaken in light of an individual formulation
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`scientist’s artfulness, experience, and inventiveness. This is not a simple recipe for
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`success, as the possible solutions are virtually endless, even in light of Cleland’s
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`process diagram. For example, Cleland lists at least three first variables -
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`individual protein or peptide physicochemical properties, in vivo parameters, and
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`degradation pathways. Ex. 1020, 1-6. Each first variable has several secondary
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`variables (and there are even more known to those of ordinary skill in the art. Id.
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`There are three or more for physicochemical properties, four for in vivo
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`information, and five for degradation pathways, which amounts to over 17,000 (3!
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`x 3! x 4! x 5!) combinations of variables. Id. You can multiply this by thousands
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`more to address the combinations of constituents for each second variable. This
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`holds true even if some of these variables are eliminated through analysis of a
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`given protein or peptide.
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`71.
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`It is my opinion that understanding and implementing this type of
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`discovery process and finding the right combination of components that yield a
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`successful formulation is inventive. Furthermore, what is claimed in the ‘886
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`patent is a good example of such an invention.
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`VIII. THE COMMERCIAL EMBODIMENT OF THE ‘886 PATENT
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`72.