UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`COALITION FOR AFFORDABLE DRUGS II LLC
`Petitioner
`
`v.
`
`NPS PHARMACEUTICALS, INC.
`Patent Owner
`____________
`
`Case IPR2015-00990
`Patent 7,056,886
`
`
`____________
`
`DECLARATION OF JOHN F. CARPENTER, PH.D.
`
`IN SUPPORT OF PATENT OWNER’S RESPONSE
`
`
`
`
`
`Active 27864656v1 242019.000529
`
`Page 1
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`TABLE OF CONTENTS
`
`
`Page
`
`
`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
`
`Active 27864656v1 242019.000529
`
`
`
`-i-
`
`
`
`Page 2
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`2.
`
`I, John Frank Carpenter, Ph.D., hereby declare as follows:
`
`I have been retained by counsel for Patent Owner NPS
`
`Pharmaceuticals, Inc. as an expert in formulation science to address topics relevant
`
`to the subject matter of this inter partes review proceeding involving certain claims
`
`of U.S. Patent No. 7,056,886 (Ex. 1003; the “ʼ886 patent”). I am being
`
`compensated at the rate of $690 per hour. My compensation is in no way
`
`dependent on the outcome of this case.
`
`II.
`
`SUMMARY OF QUALIFICATIONS
`
`3. My curriculum vitae is Ex. 2043.
`
`4.
`
`I am a tenured Professor of Pharmaceutical Sciences and the Co-
`
`Director of the Center for Pharmaceutical Biotechnology at the University of
`
`Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
`
`5.
`
`I received a Bachelor of Science degree in Zoology from Duke
`
`University, a Masters of Science from Oregon State University, and a Ph.D. in
`
`Biology from the University of Louisiana, Lafayette in 1978, 1981, and 1985,
`
`respectively.
`
`6.
`
`I was a Visiting Lecturer at the University of California, Davis from
`
`1987-1988 and also a Postdoctoral Research Associate in Biophysics during that
`
`time at UC Davis.
`
`Active 27864656v1 242019.000529
`
`Page 3
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`7.
`
`8.
`
`I was a Senior Scientist at CryoLife, Inc. from 1988-1992.
`
`I was an Assistant Professor of Pharmaceutical Biotechnology at the
`
`University of Colorado from 1993 to 1998; from 1998-2004, I was a tenured
`
`Associate Professor of Pharmaceutical Biotechnology at the University of
`
`Colorado Health Sciences Center; and from 2004 until present I have been a
`
`tenured Professor of Pharmaceutical Sciences at the University of Colorado Health
`
`Sciences Center.
`
`9.
`
`Since 1993 I have been Graduate Faculty at University of Colorado
`
`Health Sciences Center.
`
`10. Since 1997 I have been the Co-Founder and Co-Director of the Center
`
`for Pharmaceutical Biotechnology at University of Colorado.
`
`11. Since 1997 I have also been Graduate Faculty as the University of
`
`Colorado, Boulder.
`
`12. From 2000 to 2003, I was Associate Director of the Pharmaceutical
`
`Sciences Graduate Training Program in the Department of Pharmaceutical
`
`Sciences, University of Colorado.
`
`13. From 2004 to 2008, I was Director of the Pharmaceutical Sciences
`
`Graduate Training Program in the Department of Pharmaceutical Sciences,
`
`University of Colorado.
`
`14. From 2001 to 2010, I was Co-Director, NIH Training Grant,
`
`Active 27864656v1 242019.000529
`
`Page 4
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`Leadership Training in Pharmaceutical Biotechnology, University of Colorado.
`
`15. Since 2012, I have been Director of Business Development,
`
`University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.
`
`16.
`
`I have published more that 250 peer-reviewed publications in the field
`
`of protein/peptide formulation, consulted for dozens of pharmaceutical companies
`
`internationally, and have been an invited lecturer at conferences, pharmaceutical
`
`companies and universities around the world.
`
`17.
`
`I was elected a Fellow of the American Association for the
`
`Advancement of Science in 2009. I was awarded a Research Achievement Award
`
`in Biotechnology, American Association of Pharmaceutical Scientists in 2007. I
`
`was awarded the Ebert Prize, AphA, Journal of Pharmaceutical Sciences, in 2007.
`
`My other scientific honors and awards are listed in my curriculum vitae, which
`
`also includes a list of my publications, patents, grant activity, presentations, and
`
`teaching activity.
`
`18. Over the course of my career, I have more than three decades of
`
`experience in studies including protein/peptide formulation development;
`
`protein/peptide degradation and stabilization during processing storage and
`
`administration to patients; rational development of stable lyophilized formulations;
`
`mechanisms by which excipients provide stabilization or fail to stabilize
`
`proteins/peptide during freezing, drying and storage in the dried solid; and
`
`Active 27864656v1 242019.000529
`
`Page 5
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`development and testing of advanced analytical methods.
`
`III. MATERIALS CONSIDERED
`
`19.
`
`In reaching the conclusions set forth below, I have relied on my close
`
`to three decades of experience in pharmaceutical studies and have specifically
`
`considered the '886 patent, relevant portions of the Coalition For Affordable Drugs
`
`II LLC’s (“Petitioner”) Petition for inter partes review (“IPR”) (Paper 1; the
`
`“Petition”) and exhibits thereto, Patent Owner’s Preliminary Response (Paper 19),
`
`the declaration of Dr. Anthony Palmieri (the “Palmieri Declaration”; Exh. 1001),
`
`the transcript of the deposition of Dr. Anthony Palmieri on December 10, 2015 (the
`
`“Palmieri Dep; Exh. 2042) and the other materials cited below.
`
`IV. UNDERSTANDING OF THIS PROCEEDING
`
`20.
`
`I understand that this is an inter partes review (“IPR”) proceeding
`
`conducted before the Patent Trial and Appeal Board (“Board”) of the U.S. Patent
`
`and Trademark Office (“PTO”) to determine if claims 46-52 and 61-75 of the '886
`
`patent (the challenged claims) should be cancelled as unpatentable. I understand
`
`that Petitioner requested institution of this proceeding through a Petition dated
`
`April 1, 2015, and that the Petition asserted that the challenged claims of the '832
`
`patent are invalid as obvious over combinations of references. Pet. at 8. The
`
`Petition was accompanied by a declaration of Dr. Anthony Palmieri.
`
`21.
`
`I understand that on July 24, 2015 Patent Owner submitted a
`
`Active 27864656v1 242019.000529
`
`Page 6
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`Preliminary Response in opposition to Petitioner’s Petition.
`
`22.
`
`I understand that the Board, in a decision on October 23, 2015,
`
`decided to institute an IPR.
`
`23.
`
`I understand that the Board has not made any determination that the
`
`challenged claims are in fact obvious; the Board has only determined that, on the
`
`record then before it, the Petition satisfied the threshold standard for instituting this
`
`proceeding, by showing a “reasonable likelihood that Petitioner would prevail in
`
`establishing the unpatentability” of the challenged claims.
`
`24.
`
`I am not an attorney. However, I have been advised of the following
`
`legal principles, and they have helped to form my conclusions in this report.
`
`25. An invention that is patentable in the United States must not be, inter
`
`alia, obvious. 35 U.S.C. § 103.
`
`26. Obviousness is a question of law based upon (1) the scope and content
`
`of the prior art, (2) the claims at issue, (3) the level of ordinary skill in the art, and
`
`(4) objective evidence of secondary considerations. Routine experimentation does
`
`not render an otherwise obvious claim valid. Obviousness only calls for a
`
`reasonable expectation of success, not a guarantee.
`
`27. To establish obviousness in view of a combination of references,
`
`Petitioner must set forth sufficiently articulated reasoning with rational
`
`underpinnings of why one skilled in the art would have been motivated to combine
`
`Active 27864656v1 242019.000529
`
`Page 7
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`the teachings of those references to derive the claimed subject matter and would
`
`have had a reasonable expectation of success in doing so. Bumble Bee Foods, LLC
`
`v. Kowalski, IPR2014-00224, Paper 18, 25-26 (PTAB June 20, 2014).
`
`Furthermore, “[a] reference may be said to teach away when a person of ordinary
`
`skill, upon reading the reference would be discouraged from following the path set
`
`out in the reference or would be led in a direction divergent form the path taken by
`
`the applicant.” Ricoh Corp. v. Quanta Computer Inc., 550 F.3d 1325, ____
`
`(Fed.Cir. 2008).
`
`V. LEGAL PRINCIPLES APPLIED AND LEVEL OF SKILL
`
`28.
`
`I understand that the ʼ886 patent must be read from the perspective of
`
`a person of ordinary skill in the relevant art at the time the invention was made,
`
`which here is approximately 1999—the earliest filing date listed on the face of the
`
`patent is December 30, 1999. I understand the person of ordinary skill in the art is
`
`a hypothetical person who is presumed to know the relevant art at the time of the
`
`invention.
`
`29. The subject to which the challenged claims of the '866 patent are
`
`directed are formulations of GLP-2 or an analog that are stabilized at a
`
`pharmaceutically tolerable or acceptable pH by a combination of L-histidine,
`
`phosphate buffer, and mannitol (46-51) or mannitol or sucrose (52), kits containing
`
`the latter formulations (61-68), and methods of using the latter formulations to treat
`
`Active 27864656v1 242019.000529
`
`Page 8
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`serious intestinal diseases (69-75). These formulations are at a pH that can be
`
`administered without patient reactions that preclude further administration (i.e.,
`
`pharmaceutically tolerable/acceptable) and are stable, particularly when
`
`lyophilized (i.e., six months at ambient temperature, 18 months at 4oC with less
`
`than about 5% peptide degradation). This invention resulted in a successfully
`
`marketed GLP-2 analog product and an approved drug treatment for short bowel
`
`syndrome - GATTEX®. Therefore, the person(s) of ordinary skill to whom the
`
`patent is directed would need to have a good understanding of at least: i) peptide
`
`formulations; ii) peptide formulation development; iii) and peptide degradation
`
`pathways.
`
`30.
`
`In my opinion, the person(s) of ordinary skill in the art to whom the
`
`'886 patent is directed would have been a pharmaceutical protein or peptide
`
`formulation scientist with a Ph.D. in pharmaceutical sciences or one of the
`
`biological sciences, including molecular biology, biochemistry, and protein
`
`chemistry, and would have had relevant post-doctorate experience in designing
`
`pharmaceutical formulations of proteins or peptides sufficient to lead, or be an
`
`integral part of, a development team.
`
`VI. THE ‘886 PATENT AND THE CHALLENGED CLAIMS
`
`31. The ’886 patent discloses GLP-2/GLP-2 analog formulations
`
`“exhibiting superior stability following storage and/or exposure to elevated
`
`Active 27864656v1 242019.000529
`
`Page 9
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`temperatures.” Ex. 1003, Abstract. These formulations are at a pH that can be
`
`administered without patient reactions that preclude further administration (i.e.,
`
`pharmaceutically/physiologically tolerable/acceptable) and are stable, particularly
`
`when lyophilized (i.e., six months at ambient temperature, 18 months at 4oC with
`
`less than about 5% peptide degradation). Ex. 1003, 11:29-67.
`
`32.
`
`Independent ‘886 patent claim 46 is directed to formulations of a
`
`specified amount of GLP-2 or an analog, a specified amount of L-histidine, an
`
`amount of phosphate buffer sufficient to adjust the pH of the formulation to a
`
`pharmaceutically tolerable level, and a specified amount of mannitol.
`
`33. Claim 47 (dependent from claim 46) specifies that the GLP-2 analog
`
`is h(Gly2)GLP-2 which is human GLP-2 in which amino acid residue 2 has been
`
`substituted with a glycine residue.
`
`34. Claim 48 (dependent from claim 47 specifies that the formulation is
`
`lyophilized (i.e., freeze-dried).
`
`35. Claim 49 (dependent from claim 47) specifies that the pH of the
`
`formulation is greater than about 6.0 or from about 6.9 to about 7.9.
`
`36. Claim 50 (dependent from claim 49) specifies that the pH of the
`
`formulation is from about 7.3 to about 7.4.
`
`37. Claim 51 (dependent from claim 46, specifies that the GLP-2 analog
`
`has one or more amino acid substitutions, additions, deletions, or modifications
`
`Active 27864656v1 242019.000529
`
`Page 10
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`and that it has GLP-2 receptor binding activity.
`
`38.
`
`Independent claim 52 is directed to formulations of a medically useful
`
`amount of a natural GLP-2 peptide or an analog, an amount of phosphate buffer
`
`sufficient to adjust the pH of the formulation to a physiologically tolerable level,
`
`an amount of L-histidine sufficient to stabilize the formulation, and mannitol or
`
`sucrose.
`
`39.
`
`Independent claim 61 is directed to a kit that includes a lyophilized
`
`formulation of a GLP-2 or an analog, an amount of phosphate buffer sufficient to
`
`adjust the pH of the formulation to a pharmaceutically acceptable level, L-
`
`histidine, and mannitol or sucrose. The kit also includes a vial of sterile water for
`
`injection and instructions directing how to perform reconstitution.
`
`40. Claim 62 (dependent from claim 61) specifies that the pH of the
`
`formulation is greater than about 6.0 or from about 6.9 to about 7.9.
`
`41. Claim 63 (dependent from claim 62) specifies that the pH of the
`
`formulation is from about 7.3 to about 7.4.
`
`42. Claim 64 (dependent from claim 63) specifies that the GLP-2 analog
`
`is h(Gly2)GLP-2.
`
`43. Claim 65 (dependent from claim 61) adds an injection device to the
`
`kit.
`
`44. Claim 66 (dependent from claim 61) specifies that following
`
`Active 27864656v1 242019.000529
`
`Page 11
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`reconstitution the formulation in the kit is stable for at least about 12 hours.
`
`45. Claim 67 (dependent from claim 61) specifies that the formulation in
`
`the kit is stable for up to about 24 hours.
`
`46. Claim 68 (dependent from claim 61) specifies that the GLP-2 analog
`
`in the formulation in the kit has one or more amino acid substitutions, additions,
`
`deletions, or modifications and that it has GLP-2 receptor binding activity.
`
`47.
`
`Independent claim 69 is directed to a method of treating humans or
`
`animals with a GI disorder, disease, or condition for which GLP-2 treatment is
`
`indicated. The method includes administering a therapeutically effective amount
`
`of a GLP-2 formulation. The formulation includes a GLP-2 or an analog, an
`
`amount of phosphate buffer sufficient to adjust the pH of the formulation to a
`
`pharmaceutically tolerable level, L-histidine, and mannitol or sucrose. The
`
`treatment enhances, maintains, or promotes the growth or function of the GI tract.
`
`48. Claim 70 (dependent from claim 69) specifies that the pH of the
`
`formulation used in the method of treatment is greater than about 6.0 or from about
`
`6.9 to about 7.9.
`
`49. Claim 71 (dependent from claim 70) specifies that the pH of the
`
`formulation used in the method of treatment is from about 7.3 to about 7.4.
`
`50. Claim 72 (dependent from claim 70) specifies that the GLP-2 analog
`
`in the formulation used in the method of treatment is h(Gly2)GLP-2.
`
`Active 27864656v1 242019.000529
`
`Page 12
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`51. Claim73 (dependent from claim 69) specifies that the administration
`
`is by injection.
`
`52. Claim74 (dependent from claim 69) specifies that the administration
`
`is by infusion.
`
`53. Claim 75 (dependent from claim 69) specifies that the GLP-2 analog
`
`in the formulation used in the method of treatment has one or more amino acid
`
`substitutions, additions, deletions, or modifications and that it has GLP-2 receptor
`
`binding activity.
`
`VII. TECHNICAL BACKGROUND AND STATE OF THE ART IN 1999
`
`54. The formulation of therapeutic proteins and peptides was, before
`
`December 30, 1999, and continues to be, a highly unpredictable, complicated and
`
`specialized art.
`
`55. Protein and peptide therapeutics must be stable during processing
`
`steps (e.g., filling of vials or syringes; freeze-drying), immediately after
`
`manufacture as well throughout their designated shelf lives to ensure product
`
`safety and efficacy. There are numerous physical and chemical factors that can
`
`affect the quality and stability of protein and peptide biopharmaceutical products.
`
`This is particularly true during long-term storage in a container–closure system
`
`likely to be subject to variations in temperature, light, and agitation with shipping
`
`and handling. Compared with traditional chemical or small molecule
`
`Active 27864656v1 242019.000529
`
`Page 13
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`pharmaceuticals, proteins are considerably larger molecular entities with inherent
`
`physio-chemical complexities.
`
`56. Peptides and proteins differ from conventional chemical entities such
`
`as small molecules in their sensitivity to different degradation pathways and
`
`stresses. Also, unlike small molecule drugs, which are often administered orally,
`
`therapeutic peptides and proteins are administered parenterally; i.e., by injection
`
`and infusion. With parenteral administration there are additional product quality
`
`and safety requirements including sterility and specifications (e.g., USP 788) levels
`
`of subvisible particles. Proteins and peptides are typically more sensitive to slight
`
`changes in solution chemistry. They usually remain stable only within a relatively
`
`narrow range of pH, are subjected to a variety of chemical and physical
`
`degradation processes. The challenges in formulating a protein or peptide are often
`
`more difficult than those in formulating a small molecule.
`
`57. Formulation scientists typically refer to two broad categories of
`
`protein or peptide degradation- physical and chemical. Chemical degradation refers
`
`to the formation or destruction of covalent bonds within a protein or peptide.
`
`Chemical modifications of protein include hydrolysis, oxidation, disulfide bond
`
`scrambling, deamidation, Malliard reaction, succinimide formation,
`
`diketopiperazine formation, deglycosylation and desialylation, and enzymatic
`
`proteolysis due to proteases. Unfolding, dissociation, denaturation, aggregation,
`
`Active 27864656v1 242019.000529
`
`Page 14
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`particle formation, fragmentation, adsorption to interfaces, fibril formation,
`
`gelation and precipitation are among modifications known as physical degradation
`
`of peptides and proteins. Different protein and peptide degradation pathways can
`
`promote each other for a given protein or peptide and a given formulation. A
`
`chemical event may trigger a physical event, such as when oxidation is followed
`
`by aggregation. And unfolding may foster chemical degradation such oxidation of
`
`an interior methionine residue that is exposed to solvent in a fully- or partially-
`
`unfolded protein molecules.
`
`58. Even small levels of degradation can compromise a therapeutic
`
`protein or peptide product. For example, even a few percent or less of protein or
`
`peptide aggregation or precipitation (i.e., examples of many types of physical
`
`degradation) can render a product medically unacceptable.
`
`59. One reason that a protein or peptide medicine can often be
`
`pharmaceutically unacceptable is if visible particles are observed in the solution,
`
`for example, after reconstitution of a lyophilized product. The mass percent of the
`
`protein or peptide in these visible particles can be quite low and even less than 1%.
`
`Development of a formulation for a given protein or peptide that gives enough
`
`stabilization to prevent this is extremely challenging.
`
`60. Traces of physical degradation of even a few percent or less of the
`
`protein or peptide to soluble aggregates or subvisible particles may result in
`
`Active 27864656v1 242019.000529
`
`Page 15
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`adverse, unwanted immunogenicity in patients (resulting in loss of drug efficacy),
`
`as well as dangerous infusion reactions.
`
`61. The foregoing reasons are examples of showing why a relative
`
`decrease in degradation of a given protein or peptide during processing and storage
`
`is not of value. One must provide quantitative reduction in degradation that keeps
`
`degradation to an absolute minimum.
`
`62. Chemical degradation of a protein or peptide in a pharmaceutical
`
`formulation can result in similar problems, including adverse immunogenicity and
`
`reduced potency of the medicine. Chemical degradation may also make the protein
`
`or peptide more sensitive to physical degradation.
`
`63. This is why every key route of degradation for a given protein or
`
`peptide, not just selected ones, should be characterized and inhibited as much as
`
`possible for a successful, commercial protein- or peptide-based formulation. The
`
`success of a protein or peptide drug often depends upon the delivery of the
`
`biologically active form of the protein or peptide to the site of action, as well as
`
`minimizing key degradation pathways (which are unique for each product). Failure
`
`to develop an adequately stabilized product can result directly in failure to gain
`
`approval by regulatory agencies, halting of clinical trials due inadequate product
`
`stability, as well as development-halting adverse events during clinical trials. Thus,
`
`the medical and commercial success of a therapeutic peptide or protein product is
`
`Active 27864656v1 242019.000529
`
`Page 16
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`absolutely dependent of meeting the great challenge of developing a properly
`
`stabile formulation.
`
`64. Each protein and peptide is unique in that it has its own physico-
`
`chemical properties, degradation routes, sensitivities to processing stresses (e.g.,
`
`the freezing and drying steps of the lyophilization process) and responses to
`
`stabilizing excipients. Proteins or peptides with similar sequences may have
`
`widely different degradation pathways. They may also have widely different
`
`condition requirements for optimal stability and optimal response to stabilizing
`
`excipients. For example, typically when formulating a given protein or peptide, the
`
`formulation scientist empirically determines the optimal pH in order to minimize
`
`physical and chemical degradation pathways. With respect to GLP-2 and glucagon,
`
`it has been determined that GLP-2 precipitates to insoluble aggregates at acidic
`
`pH’s, whereas glucagon is soluble and resistant to aggregation at very acid
`
`conditions of pH 2.8 and lower.
`
`65. Formulation science is unpredictable. Protein or peptide formulation
`
`development requires extensive and often complicated experimentation. Many
`
`excipients that are available to stabilize proteins or peptides during processing
`
`(such as during lyophilization) and storage may not yield sufficient stability to a
`
`particular protein or peptide because of that protein’s or peptide’s unique critical
`
`degradation pathways its unique responses to a specific excipient. In additional,
`
`Active 27864656v1 242019.000529
`
`Page 17
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`degradation products effects on safety and efficacy are different for each protein or
`
`peptide. One illustrative, but non-limiting, example is that oxidation of a
`
`methionine residue in one peptide may render it biologically inactive, but oxidation
`
`of methionine in a different peptide methionine oxidation may not alter activity at
`
`all. There is no way reasonably to predict whether a particular excipient will
`
`provide a pharmaceutically necessary degree of stability in a given protein or
`
`peptide product.
`
`66. Dr. Jeffery L. Cleland from Genentech, Inc. and Dr. Robert Langer
`
`from Massachusetts Institute of Technology are prominent protein/peptide
`
`formulation scientists. They stated that “[e]ach molecule has its own unique
`
`physical and chemical properties which determine in vitro stability. The
`
`formulation scientist must also be concerned about the in vivo stability of the drug.
`
`Thus, the development of successful formulations is dependent upon the ability to
`
`study both the in vitro and in vivo characteristics of the drug as well as its intended
`
`application.” Ex. 1024, 2. I agree, and these considerations still apply today.
`
`Accordingly, a formulation scientist should consider the clinical indication,
`
`pharmacokinetics, toxicity, and physicochemical stability of the protein or peptide
`
`drug.
`
`67.
`
`Individual analysis and balancing of the rates of individual
`
`degradation pathways of a protein or peptide are necessary and must be undertaken
`
`Active 27864656v1 242019.000529
`
`Page 18
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`to achieve the most stabile formulation possible. Additionally, formulation
`
`components must be considered and balanced in terms, for example, of protein or
`
`peptide stability and administration route.
`
`68. Although a formulation scientist’s approach to formulation
`
`development may be systematic, it is not like a cookbook and is not formulaic.
`
`69. Cleland, Figure 2 illustrates one example of a system for formulating
`
`therapeutic proteins and peptides. This is only one system; there are many others.
`
`This process, like most other protein or peptide formulation development systems,
`
`list first variables and then other variables within the first ones that are to narrow
`
`the possible substituents.
`
`70. These processes are undertaken in light of an individual formulation
`
`scientist’s artfulness, experience, and inventiveness. This is not a simple recipe for
`
`success, as the possible solutions are virtually endless, even in light of Cleland’s
`
`process diagram. For example, Cleland lists at least three first variables -
`
`individual protein or peptide physicochemical properties, in vivo parameters, and
`
`degradation pathways. Ex. 1020, 1-6. Each first variable has several secondary
`
`variables (and there are even more known to those of ordinary skill in the art. Id.
`
`There are three or more for physicochemical properties, four for in vivo
`
`information, and five for degradation pathways, which amounts to over 17,000 (3!
`
`x 3! x 4! x 5!) combinations of variables. Id. You can multiply this by thousands
`
`Active 27864656v1 242019.000529
`
`Page 19
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`more to address the combinations of constituents for each second variable. This
`
`holds true even if some of these variables are eliminated through analysis of a
`
`given protein or peptide.
`
`71.
`
`It is my opinion that understanding and implementing this type of
`
`discovery process and finding the right combination of components that yield a
`
`successful formulation is inventive. Furthermore, what is claimed in the ‘886
`
`patent is a good example of such an invention.
`
`VIII. THE COMMERCIAL EMBODIMENT OF THE ‘886 PATENT
`
`72.
`
`I have been advised that commercial embodiment of the ’886 patent
`
`invention is the product marketed as GATTEX®. I understand from the label for
`
`GATTEX (Ex. 2027), that GATTEX is a formulation of the GLP-2 analog
`
`[Glyn2]GLP-2 (which is also called teduglutide) that is stabilized at a
`
`pharmaceutically tolerable or acceptable pH by a combination of L-histidine,
`
`phosphate buffer, and mannitol. Each single-use vial of GATTEX contains 5 mg
`
`of teduglutide, 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium
`
`phosphate monohydrate, and 3.434 mg dibasic sodium phosphate heptahydrate as a
`
`white lyophilized powder for solution for subcutaneous injection. Based on my
`
`review of the Gattex product label (Ex. 2027), I have calculated the concentration
`
`of certain components in the Gattex formulation to determine whether Gattex is
`
`covered by the claims of the ‘886 patent. Those concentrations are provided in the
`
`Active 27864656v1 242019.000529
`
`Page 20
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`chart below.
`
`Component 
`Teduglutide 
`L-His 
`Mannitol 
`NaH2PO4·H2O 
`Na2HPO4·7H2O 
`Total phosphate buffer 
`
`
`
`
`Amount, mg/mL
`10 
`7.76 
`30 
`6.868 
`1.288
`8.156
`
`Amount, %1 or [conc]
`1 %2 
`0.776 % 
`3 % 
`25.62 mM3 
`9.33 mM 
`34.95 mM
`
`
`1 % are given as weight/volume percentages of formulated product prior to
`
`lyophilization in gms/mL (x100).
`
`2 Because wt % values are based on g/100 ml, convert mg/ml into g/100ml:
`
`divide mg/ml by 1000 mg/g = g/ml. Then multiple g/ml by 100 (actually
`
`100/100) = g/100 ml. For example, 10 mg/ml / 1000 mg/g = 0.01 g/ml; 0.01 g/ml
`
`x 100/100 = 1g/100ml = 1 wt %.
`
`3 The concentrations of the buffers are calculated by first converting mg/ml to g/l
`
`and then dividing the amount by the molecular weight of the buffering salt. E.g.,
`
`[NaH2PO4·H2O] = 6.868 mg/mL = 6.868 g/l; 6.868 g/l / 268.1 g/mol = 0.02562
`
`mol/l = 0.02562 M = 25.62 mM.
`
`Active 27864656v1 242019.000529
`
`Page 21
`
`PROTECTIVE ORDER MATERIAL
`
`

`
`IPR2015-00990
`
`73. The following table illustrates that GATTEX is a product as claimed
`
`in the challenged ‘886 patent claims and its use is a method as claimed in the
`
`challenged ‘886 patent claims.
`
`‘886 Patent Claim Language
`46. A GLP-2 formulation comprising:
`
`(a) about 0.1 to about 50 mg/ml of a
`GLP-2 peptide or an analog thereof;
`
`(b) a phosphate buffer in an amount
`sufficient to adjust the pH of the
`formulation to a pharmaceutically
`tolerable level;
`
`(c) about 0.5 to about 1% L-histidine;
`and
`(d) about 2 to about 5% mannitol.
`
`47. The GLP-2 formulation of claim 46,
`wherein the GLP-2 is h(Gly2)GLP-2.
`48. The GLP-2 formulation of claim 47,
`wherein the formulation is lyophilized.
`49. The GLP-2 formulation of claim 47,
`wherein the pH of the formulation is
`selected from the group consisting of
`greater then about 6.0, and from about
`6.9 to about 7.9.
`50. The GLP-2 formulation of claim 49,
`wherein the pH of the formulation is
`from about 7.3 to about 7.4.
`51. The GLP-2 formulation of claim 46,
`wherein said GLP-2 analog has one or
`more amino acid substitutions,
`additions, deletions, or modifications
`
`Active 27864656v1 242019.000529
`
`GATTEX®
`GATTE