Filed: January 20, 2016
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`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 IPR2015-00990
`Patent 7,056,886
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`____________
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`PATENT OWNER’S RESPONSE
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`IPR2013-00482
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`TABLE OF CONTENTS
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`I.
`II.
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`III.
`IV.
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`B.
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`C.
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`D.
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`Introduction ........................................................................................................................ 1
`The Claimed Invention – Stable, Pharmaceutically Acceptable pH GLP-2
`Formulations and Their Use to Treat Serious Diseases ..................................................... 7
`The Petitioner’s Challenges - Obviousness ..................................................................... 12
`Summary of Non-Obviousness of Each Challenged Claim ............................................. 16
`A.
`Ground 1 - Claims 46-50, 52, and 69-75 Are Not Obvious over Drucker
`’379 in view of Kornfelt and Osterberg ............................................................... 17
`Ground 2 - Claims 61-67 Are Not Obvious over Drucker ’600 in view of
`Kornfelt, Osterberg, and Holthius ........................................................................ 21
`Ground 3 - Claims 51 and 75 Are Not Obvious over Drucker ’379 in view
`of Kornfelt, Osterberg, and Munroe .................................................................... 22
`Ground 4 - Claim 68 Is Not Obvious over Drucker ’600 in view of
`Kornfelt, Osterberg, Holthius, and Munroe ......................................................... 23
`State of the Art ................................................................................................................. 23
`A.
`The Field of the Invention and Level of Ordinary Skill in this Art ..................... 23
`B.
`The State of the Art Was Unpredictable and Complex ........................................ 24
`C.
`Dr. Palmieri’s Testimony Is Unreliable; He Is Neither an Expert Nor One
`of Ordinary Skill in the Art .................................................................................. 27
`Petitioner Misconstrued the Disclosures of the Prior Art ................................................ 32
`A.
`Drucker ‘379 ........................................................................................................ 32
`B.
`Drucker ‘600 ........................................................................................................ 33
`C.
`Osterberg .............................................................................................................. 33
`D.
`Kornfelt ................................................................................................................ 35
`E.
`Holthius ................................................................................................................ 39
`F.
`Munroe ................................................................................................................. 39
`VII. Surprising and Unexpected Results of the ‘886 Patent Invention ................................... 40
`VIII. Stabilization of Glucagon Is not Predictive of Stabilization of GLP-2 ........................... 43
`IX.
`Histidine Is a Problematic Excipient ................................................................................ 48
`X.
`There Is No Motivation to Combine the References to Arrive at the Claimed
`Invention with a Reasonable Expectation of Success; Rather, There Are Clear
`Teachings Away from Petitioner’s Combinations ........................................................... 51
`Petitioner’s Obviousness Analysis Was Plagued by Hindsight ....................................... 54
`XI.
`XII. Secondary Considerations Support a Finding of Non-Obviousness ................................ 56
`A. ‘886 Patent Solved a Long-Felt Need ........................................................................ 57
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`V.
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`VI.
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`IPR2015-00990
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`TABLE OF CONTENTS
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`Page
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`B.
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`GATTEX - The Commercial Embodiment of the ‘886 Patent Is a
`Significant Commercial Success.......................................................................... 57
`XIII. The Nexus Between the Secondary Considerations and the Invention ........................... 59
`XIV. Conclusion ....................................................................................................................... 60
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`The Patent Trial and Appeal Board (“PTAB”), on October 23, 2015,
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`implemented this Inter Partes Review (“IPR”) of certain claims of U.S. Patent No.
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`7,056,886 (“the ’886 patent”). Pursuant to 35 U.S.C. §§ 314 and 316((a)(8) and 37
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`C.F.R. §42.120, Patent Owner NPS Pharmaceuticals, Inc. submits this Patent
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`Owner’s Response and requests issuance of a final written decision under 35
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`U.S.C. § 318 (a) and issuance and publication of a certificate under 35 U.S.C. §
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`318 (b) confirming the patentability of the challenged claims.
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`I.
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`Introduction
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`The’886 patent inventor discovered 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. The challenged claims (46-52 and 61-75) are
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`directed to 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 acceptable pH (i.e.,
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`a pH that can be administered without patient reactions that preclude further
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`administration) by a combination of L-histidine, phosphate buffer, and mannitol
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`(46-51) or mannitol or sucrose (52), kits containing the latter formulations (61-68),
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`and methods of use to treat serious intestinal diseases (69-75). This invention
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`resulted in the first successfully marketed GLP-2 analog product approved for
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`treating short bowel syndrome - GATTEX®.
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`The PTAB instituted this IPR because:
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`[t]he information relied upon in the Petition tend[ed] to suggest that
`L-histidine has a stabilizing effect on peptide drugs generally,
`indicating that properties of L-histidine peptides affecting peptide
`association (and, therefore, peptide stabilization) are relevant in a
`manner distinct from properties of L-histidine affecting biological
`activity of the peptides.
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`* * * * *
`[the Petitioner showed] sufficiently that a person of ordinary skill in
`the art would have had a reasonable expectation of success in
`formulating GLP-2 in combination with L-histidine and sucrose or
`mannitol to create a lyophilized storage stable formulation in view of
`the guidance set forth in the prior art.
`* * * * *
`[t]he information set forth in the Petition [was] sufficient to establish
`that buffered pharmaceutical formulations of GLP-2 analogs were
`known and that Osterberg and Kornfelt suggests that the use of L-
`histidine in combination with an excipient such as mannitol or sucrose
`in protein formulations was a predictable variation within the
`technical grasp of a person of ordinary skill in the art done for the
`purposes of protein stabilization.
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`Paper 28, 19, 22-23. These conclusions are incorrect and arise from incomplete and
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`unreliable expert testimony. The PTAB relied upon Petitioner’s alleged expert Dr.
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`Anthony Palmieri, who provided an uninformed and less than expert explanation
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`of the prior art, particularly Kornfelt et al., U.S. Patent No. 5,652,216 (“Kornfelt”)
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`(Ex. 1027) and Osterberg et al., “Physical State of L-histidine after Freeze Drying
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`and Long Term Storage.” E. J. Pharm. Sci. 8(1999) 301-308 (“Osterberg”) (Ex.
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`1030); misstated the level of ordinary skill in the art; incorrectly described and
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`erroneously compared glucagon and GLP-2; misapplied and trivialized the
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`difficulties and unpredictability of formulation science, particularly with regard to
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`protein/peptide degradation and formulation; and found motivation to combine
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`references to make a pH-acceptable stabilized peptide when there was not any and
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`when any result was unpredictable. Furthermore, Petitioner’s and Dr. Palmieri’s
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`obviousness analyses were plagued by hindsight. This was highlighted by cross-
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`examination of Dr. Palmieri (see e.g., Ex. 2042, 194:9-21 (“Q. Did you consider
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`the degradation pathway of a GLP-2 analog in forming your opinion of the
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`obviousness of the claims of the ‘886 patent? [… A.] I did not think it was relevant
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`to this – these opinions in my expert report. I knew I could make – I knew a person
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`of skill in the art looking at the patent and scientific literature prior to the
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`application date would know how to make it.”). Additionally, the PTAB
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`discounted secondary considerations as the record was not fully developed. The
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`PTAB’s initial obviousness impressions were based on hand-waiving and non-
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`credible and simply incorrect information provided by Petitioner and Dr. Palmieri.
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`The record is corrected and completed by this Response and the concurrently
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`submitted declarations of John F. Carpenter, Ph.D. and Gordon Rausser, Ph.D. Dr.
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`Carpenter is a Professor of Pharmaceutical Sciences, the Co-Director of the Center
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`for Pharmaceutical Biotechnology at the University of Colorado Skaggs School of
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`Pharmacy and Pharmaceutical Sciences, and a true expert formulation scientist
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`with more than three decades of experience in studies including protein/peptide
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`formulation development; protein/peptide degradation and stabilization during
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`processing storage and administration to patients; rational development of stable
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`lyophilized formulations; mechanisms by which excipients provide stabilization or
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`fail to stabilize proteins/peptide during freezing, drying and storage in the dried
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`solid; and development and testing of advanced analytical methods. He has
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`published more that 250 peer-reviewed publications in the field, has consulted for
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`dozens of pharmaceutical companies internationally, and has been an invited
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`lecturer at conferences, pharmaceutical companies and universities around the
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`world. Dr. Carpenter explains:
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`the complexity and unpredictability of
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`protein/peptide formulation science; what Kornfelt and Osterberg actually disclose
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`(or more pertinently, fail to disclose) to one of ordinary skill in the art at the time
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`of the invention; why Petitioner’s and Dr. Palmieri’s understanding of glucagon
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`and GLP-2, their properties, and their structures is wrong; and why their
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`application of formulation science, and in particular the formulation science of
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`therapeutic proteins/peptides, and the prior art are incorrect, simplistic, and
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`impermissibly retrospective. Formulation scientists working on
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`therapeutic
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`protein/peptide products would not have followed Petitioner’s and Dr. Palmieri’s
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`speculative path to obviousness and would not have proceeded from an evident
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`lack of understanding of the science of stabilizing therapeutic peptides or proteins.
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`They would not have reached Petitioner’s conclusory results, nor arrived at the
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`‘886 invention.
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`Unlike Dr. Palmieri, formulation scientists would have evaluated and
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`compared the physical and chemical degradation pathways and solubilities of
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`glucagon (formulated in the cited prior art) with those of GLP-2 (not yet
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`formulated successfully) and found that they were entirely different. The artisan
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`would have understood that what stabilized glucagon could not be expected to
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`stabilize GLP-2 with any reasonable expectation of success. The PTAB’s basic
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`understanding, coming as it did from Dr. Palmieri’s misguided assertions and lack
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`of pertinent knowledge, is scientifically incorrect. There is no information
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`suggesting to one skilled in the art that L-histidine has a stabilizing effect on
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`peptide drugs generally. There was not a reasonable expectation of success in
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`formulating GLP-2 with L-histidine and sucrose or mannitol to create a lyophilized
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`storage stable formulation in view of the prior art. The prior art does not suggest
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`that L-histidine in combination with mannitol or sucrose (and particularly
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`mannitol) in protein formulations was a predictable variation within the technical
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`grasp of a person of ordinary skill in the art done for protein stabilization.
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`Because the degradation pathways of glucagon and GLP-2 are so different,
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`no conclusions could be drawn about GLP-2 stabilization from prior art glucagon
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`stabilization. Those skilled in the art would have also known that there is a nearly
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`infinite number of stabilizer, buffer, and bulking agent combinations that could be
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`suggested by the prior art, but the prior art does not make any of them reasonably
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`expected to be successful without undue, and more than routine, experimentation.
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`Those skilled in the art would additionally have been aware of the many problems
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`associated with histidine in peptide formulations, particularly when combined with
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`additional buffers and mannitol or sucrose.
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`Dr. Palmieri never considered any of this; he did not need to because,
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`according to him, it was all irrelevant. He simply looked at the present invention,
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`then looked at the prior art, and made a retrospective reconstruction using the ‘886
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`patent as a blueprint. Those skilled in the art would have seen glaring deficiencies
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`in Petitioner’s and Dr. Palmieri’s readings of Kornfelt and Osterberg. They would
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`have rejected Dr. Palmieri’s unique misunderstandings of glucagon, GLP-2,
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`histidine, mannitol, and sucrose and would have concluded that the ‘886 patent
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`presents surprising and unexpected results when compared with combinations that
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`include other amino acids and other sugars which the prior art alleged were
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`equivalent. Those skilled in the art would never have entertained the notion that
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`what is good for glucagon was also good for GLP-2. Nor would they have found
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`sufficient teaching, motivation, or suggestion to combine the prior art into a
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`successfully stabilized GLP-2 formulation at acceptable pH.
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`Dr. Rausser is the Robert Gordon Sproul Distinguished Professor at the
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`University of California, Berkeley. He has studied the evidence of long-felt need
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`and commercial success of the present invention, including the required nexus. He
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`found that the use of the traditional treatment for short bowel syndrome (“SBS”)
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`(i.e., parenteral nutrition (“PN”)) is a significant burden for patients. He found that
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`there was a strong need for better SBS treatments and that the commercial
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`embodiment of the ‘886 patent invention (i.e., GATTEX) met this need by
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`reducing dependence on PN, reducing treatment and other economic costs of SBS,
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`increasing patient life expectancy, and enhancing patient quality of life. He also
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`found GATTEX to be a commercial success by steadily capturing SBS patient
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`share, commanding a reasonable price, having high sales with rapid sales growth,
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`exceeding pre-launch sales expectations, quadrupling NPS’s share price before
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`Shire’s acquisition of the company, and being a key value driver in that
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`acquisition. Dr. Rausser shows that this commercial success is attributable to
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`GATTEX’s therapeutic benefits and the long-felt need for a drug with its clinical
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`properties, none of which would have been possible without the ability to stabilize
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`the peptide in Gattex – teduglutide – as provided by the ‘886 patent.
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`II. The Claimed Invention – Stable, Pharmaceutically Acceptable pH
`GLP-2 Formulations and Their Use to Treat Serious Diseases
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`The challenged claims encompass GLP-2/analog formulations stabilized at
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`pharmaceutically/physiologically tolerable/acceptable pH by a combination of L-
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`histidine, phosphate buffer, and mannitol or sucrose, preferably mannitol (claims
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`46-52), kits with the mannitol formulations (claims 61-68), and methods of treating
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`serious intestinal diseases with these formulations (claims 69-75).
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`A
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`therapeutic protein/peptide product’s safety and efficacy can be
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`compromised by even small levels of degradation. Ex. 2040, ¶ 55. For example,
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`even a few percent of protein/peptide aggregation or precipitation (i.e., physical
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`degradation) can render a product medically unacceptable. Id. at ¶ 58. A
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`protein/peptide medicine is usually rendered pharmaceutically unacceptable upon
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`visibility of particles in the solution. Id. at ¶ 59. The mass percent of the
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`protein/peptide in these visible particles can be less than 1%. Id. It is challenging to
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`develop a formulation for a given protein/peptide that provides sufficient
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`stabilization to prevent this. Additionally, even traces of physical degradation (e.g.,
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`a few percent or less) of the protein/peptide to soluble aggregates or subvisible
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`particles can cause adverse, unwanted immunogenicity in patients (resulting in loss
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`of drug efficacy), as well as dangerous infusion reactions. Id. at ¶ 60. Thus, simply
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`showing a relative decrease in degradation of a protein/peptide during processing
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`and storage is not valuable. Id. at ¶ 61. There must be a quantitative reduction in
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`degradation such that it is kept to an absolute minimum. Id.
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`Similar concerns apply to chemical degradation, such as oxidation or
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`deamidation. Id. at ¶ 62. These alterations in the protein/peptide can contribute to
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`adverse immunogenicity and can reduce the potency of the medicine. Id. Also,
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`chemical degradation may foster greater sensitivity of the protein/peptide to
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`physical degradation. Id. Accordingly, all key routes of degradation for a given
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`protein/peptide, not just selected routes, should be characterized and inhibited to
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`the greatest degree possible for a successful, commercial protein- or peptide-based
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`formulation. Id. at ¶ 63. Failure to develop an adequately stabilized product can
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`result directly in non-approval by regulatory agencies, halting of clinical trials, and
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`development-halting adverse clinical events. The success of a therapeutic
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`protein/peptide product depends on meeting the great challenge of developing a
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`properly stable formulation.
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`Furthermore, each protein/peptide has unique physicochemical properties,
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`degradation routes, sensitivities to processing stresses (e.g., freezing and drying
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`steps of the lyophilization process), and responses to stabilizing excipients. Id. at ¶
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`64. Even those with similar sequences may have vastly different degradation routes
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`and different specific condition requirements for optimal stability and response to
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`stabilizing excipients. Id. For example, typically during formulation development
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`for a given protein/peptide, scientists must empirically determine the optimal pH to
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`minimize physical/chemical degradation pathways. Id. Particularly here, GLP-2
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`precipitates to insoluble aggregates at acidic pHs, whereas glucagon is soluble and
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`resistant to aggregation at very acid conditions of pH 2.8 and lower). Id.
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`Formulation science is unpredictable. Many excipients that may be used to
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`stabilize proteins/peptides during processing (e.g., lyophilization) and storage may
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`not provide sufficient stability to a given protein/peptide because of unique critical
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`degradation pathways of each protein/peptide and their unique responses to a given
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`excipient. Id. at ¶ 65. The effects of degradation products on safety and efficacy
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`also differ for each protein/peptide. Id. For example, oxidation of a methionine
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`residue in one peptide may render it biologically inactive, whereas in a different
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`one, methionine oxidation may not alter activity. Id. There is no way reasonably to
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`predict whether a particular excipient will provide a pharmaceutically necessary
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`degree of stability in a given protein/peptide product, as does the ‘886 patent. Id.
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`Finally, proteins/peptides are subject
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`to many different degradation
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`pathways, stresses, and formulation issues than are small molecules. Id. at ¶ 56.
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`Also, unlike small molecule drugs, which are often administered orally, therapeutic
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`peptides and proteins are administered parenterally which raises additional product
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`quality and safety requirements. See generally Ex. 2053. The challenges in
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`formulating a protein/peptide are often more difficult than those in formulating a
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`small molecule. Id.
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`The commercial embodiment of the ’886 patent invention, GATTEX, is a
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`formulation of the GLP-2 analog [Gly2]GLP-2 (i.e., teduglutide) that is stabilized
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`at a pharmaceutically acceptable pH by a combination of L-histidine, phosphate
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`buffer, and mannitol. Id. at ¶ 72-73. Each vial of GATTEX contains 5 mg of
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`teduglutide, 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium
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`phosphate monohydrate, and 3.434 mg dibasic sodium phosphate heptahydrate as a
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`white lyophilized powder for solution for subcutaneous injection. Ex. 2027, 5.
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`GATTEX is the first drug product for treating adult patients with SBS who are
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`dependent on parenteral support. Ex. 2041, ¶ 41-47. It was approved by the U.S.
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`Food and Drug Administration (“FDA”) on December 21, 2012, as an orphan drug
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`and has been sold by NPS (now a part of Shire PLC) since February 2013. The
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`’886 patent is listed in the FDA’s Approved Drug Products with Therapeutic
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`Equivalence Evaluations (the “Orange Book”) for GATTEX. Ex. 2058.
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`SBS is a highly disabling condition. It has life-threatening complications,
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`can severely impair quality of life, and is associated with intestinal failure and the
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`inability to absorb sufficient nutrients and fluids through the GI tract. Ex. 2041, ¶
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`17. SBS typically arises after extensive bowel resection bowel due to Crohn’s
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`disease, ischemia, or trauma. Id. at ¶ 19. SBS patients are highly prone to
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`malnutrition, diarrhea, dehydration, and inability to maintain weight due to reduced
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`intestinal capacity to absorb macronutrients, water, and electrolytes. Id. at ¶ 33.
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`Consequently, many SBS patients require chronic parenteral nutrition
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`(“PN”) and intravenous (“IV”) fluids for nutritional supplementation and
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`hydration. Id. at ¶¶ 19-20. PN/IV fluids bypass the digestive tract and are delivered
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`directly into the bloodstream through a central venous catheter. Id. at ¶ 22.
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`However, PN/IV fluids do not improve the ability to absorb nutrients, and their
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`long-term use can shorten life span and can cause life-threatening complications
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`such as blood clots and liver damage. Id. at ¶ 23-24, 29, 34. Development of PN-
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`associated liver disease predisposes patients to an increased incidence of sepsis,
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`increased mortality rates, and potentially irreversible liver damage. Id. Patients on
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`parenteral support often experience poor quality of life including difficulty
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`sleeping, frequent urination and bowel movements, need for and problems with
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`ostomy bags, and loss of independence. Id. at ¶ 35. There are an estimated 10,000
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`to 15,000 PN/IV fluids-dependent SBS patients in the U.S. Id. at ¶ 27.
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`GATTEX improves intestinal rehabilitation by promoting mucosal growth,
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`inhibiting gastric acid secretion and emptying, increasing intestinal barrier
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`function, and enhancing nutrient and fluid absorption. Ex. 2041, ¶ 31, 45-46.
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`GATTEX treatment is associated with enhancement/restoration of the remaining
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`intestine’s structural and functional integrity, thereby improving absorption and
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`reducing PN needs. Id. GATTEX allows patients more independence and self
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`esteem and the ability to lead rewarding personal, social, and working lives. Id
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`III. The Petitioner’s Challenges - Obviousness
`The Petition divides the challenged claims into four groups and then alleges
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`one ground of obviousness for each grouping. Ground 1 alleges formulation claims
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`46-50, and 52, and treatment claim 69-75 are obvious over Drucker, U.S. Patent
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`No. 5,789,379 (“Drucker ’379”) (Ex. 1029), in view of Kornfelt (Ex. 1027), and
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`Osterberg (Ex. 1030). Pet., 20. Ground 2 alleges kit claims 61-67 are obvious over
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`Drucker, PCT patent publication no. WO98/52600 (“Drucker ’600”) (Ex. 1028) in
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`view of Kornfelt, Osterberg, and Holthius, U.S. Patent No. 5,469,801 (“Holthius”)
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`(Ex. 1005). Pet., 20-21. Ground 3 alleges formulation claim 51 and treatment claim
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`75 are obvious over Drucker ’379 in view of Kornfelt, Osterberg, and Munroe et
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`al., “Prototypic G protein-coupled receptor for the intestinotrophic factor
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`glucagon-like peptide 2,” Pro. Natl. Acad. Sci. USA, Vol. 96, pp. 1569-1573 (Fe.
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`1999) (“Munroe”) (Ex. 1022). Pet., 21. Ground 4 alleges claim kit 68 is obvious
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`over Drucker ’600 in view of Kornfelt, Osterberg, Holthius, and Munroe. Pet., 21.
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`Petitioner argues obviousness by assembling disparate “facts” that are
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`overstated, do not apply to GLP-2, or both.1.
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`1 See Pet., 22 (Drucker ‘379 discloses GLP-2 peptide formulations); 22, 23, 37-40,
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`51 (Osterberg and Kornfelt disclose L-histidine stabilization of glucagon); 37-40
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`(Drucker ‘600 discloses a lyophilized GLP-2 kit); 38-39 (Holthius discloses a
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`parathyroid hormone kit with water); 49-52 (motivation to combine because of
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`Petitioner then hedges its bet and submits that “[a]t the very least, the L-
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`histidine stabilized formulation taught by Kornfelt would be obvious to try with
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`GLP-2 or an analog thereof [because] Kornfelt and Osterberg teach that preparing
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`stable formulations do not involve numerous parameters.” Id., 54. According to
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`Petitioner, “Kornfelt provides specific guidance as to a small number of known
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`options, such as L-histidine and sucrose or mannitol, for preparing a storage stable
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`formulation of glucagon” and “provides a detailed methodology for preparing
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`formulations of glucagon [not GLP-2 or GLP-2 analogs] with L-histidine as a
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`stabilizing amino acid and an excipient like lactose or mannitol.” Id., 54-55.
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`Petitioner ignores what really matters to formulation scientists, in favor of
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`exaggerated generalities and unfounded extrapolations. This is a mistake the
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`artisan (lacking hindsight and Petitioner’s motives) would not have made.
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`Petitioner ignores, as explained in more detail below, that Drucker ‘379 does not
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`disclose a stabilized GLP-2/analog formulation at pharmaceutically tolerable pH
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`containing L-histidine, phosphate buffer, and mannitol or sucrose.
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`Crucially, glucagon and GLP-2 degrade differently and do not have similar
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`FDA, structural similarity between glucagon and GLP-2), 53-54 (expectation of
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`success).
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`physico-chemical profiles, which means that a skilled artisan would not believe
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`that what stabilizes glucagon would stabilize GLP-2. Glucagon is not the alpha
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`helix Dr. Palmieri claims it is. (That glucagon is an alpha helix is essential to his
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`obviousness opinions.) Further, the primary structures of glucagon and GLP-2 are
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`different. Also, glucagon has a pI (i.e., isoelectric point) of around 7.0, where the
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`pI of GLP-2 is about 4.0. These are vastly different physical characteristics and are
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`vitally important in formulation science because the optimal pH for minimizing
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`aggregation and precipitation of a peptide is one that is not near the peptide’s pI.
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`Therefore, Petitioner’s and Dr. Palmieri’s theory - “what is good for glucagon is
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`good for GLP-2” - is baseless and not all reflective of what has been learned in the
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`decades of
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`the challenging work of developing stable formulations for
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`proteins/peptides. Rather, the opposite is true, and the dissimilarities between the
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`two molecules teach away from Petitioner’s hindsight hypothesis.
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`Osterberg does not describe any protein/peptide formulations. It only
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`describes tests of solutions of L-histidine and sucrose or mannitol and nothing else.
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`No conclusions about protein/peptide stability, solubility, or proper pH can be
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`inferred. Whether solutions or lyophilized forms of L-histidine and sucrose, absent
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`the particular protein/peptide to be studied, are storage stable from pH 4-8
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`discloses nothing about their ability to stabilize GLP-2 or its analogs.
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`Kornfelt does not help. Kornfelt did not formulate glucagon with L-
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`histidine at any pH other than 2.8. It does not disclose that storage stable glucagon
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`formulations have a pH range of 1-7; Kornfelt formulated glucagon at pH 2.8.
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`Kornfelt discloses millions of millions of possible combinations of excipients for
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`glucagon and nothing about GLP-2.
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`Of course the FDA requires all drugs to be stable. This identifies a problem,
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`but does not motivate any particular solution generally, nor does it indicate any
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`specific “how to” for GLP-2. Relying on that as motivation to combine references
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`is like saying that wishing makes world peace a reality.
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`Neither Munroe, nor Holthius discuss amino acid, buffer, bulking agent
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`stabilization. Holthius is directed to parathyroid hormone, which is not even a
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`member of the glucagon super family that uses to relate prior art glucagon to GLP-
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`2.
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`Furthermore, L-histidine is a problematic formulation component; the ‘886
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`patent demonstrates surprising and unexpected results of the combination of L-
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`histidine, phosphate buffer and mannitol/sucrose; there was a long-felt need for the
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`‘886 patent invention; and the invention is a great commercial success.
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`Unaided by hindsight, the combinations relied upon by the Petitioner are no
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`more than an invitation to experiment with no reasonable expectation of success.
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`IV. Summary of Non-Obviousness of Each Challenged Claim
`All of the terms of the challenged claims should be construed by their
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`ordinary meanings unless otherwise discussed herein.
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`A. Ground 1 - Claims 46-50, 52, and 69-75 Are Not Obvious over
`Drucker ’379 in view of Kornfelt and Osterberg
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`‘886 patent independent claim 46 claims a GLP-2 formulation of (a) a GLP-
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`2 peptide or analog, (b) a phosphate buffer in an amount sufficient to adjust the
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`formulation’s pH to a pharmaceutically tolerable level, (c) L- histidine, and (d)
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`mannitol. Drucker ‘379 does not disclose any form of GLP-2 stabilization other
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`than amino acid substitutions or using terminal blocking groups, which are
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`intended to reduce in vivo degradation by proteases; does not disclose any in vitro
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`stabilization other than simple lyophilization; and only exemplifies injectable GLP-
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`2 analog formulations with either phosphate buffered saline or gelatin, sterile
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`water, and sodium hydroxide to adjust the pH.
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`Osterberg does not disclose any protein/peptide
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`formulations;
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`the
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`degradation pathways of glucagon or GLP-2; or any information about mannitol,
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`let alone its superior effects in the ‘886 patent invention. The ‘886 patent
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`formulations use a different buffer than histidine. Furthermore, histidine is a
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`problematic excipient. It may not provide sufficient stabilization for a
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`commercially successful human medicine containing a protein/peptide drug. Its
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`usefulness in lyophilized formulations is largely dependent upon the solution
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`conditions (e.g., pH) or lyophilization processing conditions (e.g., use of a post-
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`freezing annealing step). Although histidine should remain amorphous during
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`lyophilization, numerous factors affect the crystallization of histidine (and other
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`excipients that can crystallize) during freeze-drying including the initial solution
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`pH, the presence and amounts of other excipients, the amount of protein/peptide in
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`the formulation and the freeze-drying processing conditions. Accordingly, one
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`cannot reasonably predict whether or the degree to whi