By:
`
`
`
`Jeffrey D. Blake, Esq.
`Matthew L. Fedowitz, Esq.
`MERCHANT & GOULD P.C.
`191 Peachtree Street N.E., Suite 4300
`Atlanta, GA 30303
`jblake@merchantgould.com
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`
`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 No. IPR2015-01093
`Patent 7,056,886
`__________________
`
`REPLY DECLARATION OF
`ANTHONY PALMIERI III, Ph.D., R.Ph.
`
`CFAD Exhibit 1041
`CFAD v. NPS
`IPR2015-01093
`
`

`
`
`
`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
`
`TABLE OF CONTENTS
`
`I. 
`
`INTRODUCTION................................................................................................................ 1 
`
`II.  QUALIFICATIONS ............................................................................................................ 2 
`
`III.  SUMMARY OF OPINION ................................................................................................. 3 
`
`IV.  ANALYSIS OF PATENT OWNER’S OPPOSITION ..................................................... 6 
`
`A.  The ‘886 patent does not recognize any of the “complexities” associated with
`
`peptide formulation that Dr. Carpenter discusses ............................................................ 6 
`
`B.  Dr. Carpenter’s previous publications contradict his declaration and support
`
`Petitioner’s positions .......................................................................................................... 11 
`
`C.   Dr. Carpenter unnecessarily elevates the level of ordinary skill in the art ........... 20 
`
`D.   Dr. Carpenter’s Declaration contains statements unsupported by any evidence 23 
`
`E.   Dr. Carpenter improperly and unnecessarily narrows the claims to support his
`
`arguments ........................................................................................................................... 24 
`
`i.  The claims recite a GLP-2 peptide or an analog thereof ............................. 24 
`
`ii.  Dr. Carpenter improperly characterizes the claims as requiring a
`
`particular stability ................................................................................................. 27 
`
`F.  Dr. Carpenter does not read Kornfelt as a whole and improperly concludes
`
`Kornfelt provides a teaching away ................................................................................... 31 
`
`i.  Dr. Carpenter ignores Kornfelt’s disclosure of histidine in combination
`
`with mannitol among preferable combinations .................................................. 31 
`
`ii.  Dr. Carpenter ignores Kornfelt’s broad pH range ..................................... 32 
`i
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`G.   Dr. Carpenter disregards known protocols and a finite number of options to
`
`assert that there would be no reasonable expectation of success................................... 34 
`
`H.   Dr. Carpenter fails to rebut the motivation to combine with a reasonable
`
`expectation of success ........................................................................................................ 39 
`
`i.  There was a need for stable peptide formulations ....................................... 39 
`
`ii.  RP-HPLC shows histidine reduces in vitro degradation of glucagon, and
`
`both glucagon and GLP-2 are susceptible to in vitro degradation by the same
`
`mechanisms ............................................................................................................. 39 
`
`iii.  Dr. Carpenter does not point to any teaching away from Petitioner’s
`
`combinations ........................................................................................................... 42 
`
`iv.  Dr. Carpenter’s statements regarding lack of importance of secondary
`
`structure are disingenuous .................................................................................... 42 
`
`v.  Dr. Carpenter’s characterization of histidine is unsupported ................... 45 
`
`I.  Dr. Carpenter does not demonstrate unexpected results ....................................... 49 
`
`i.  Legal standards regarding unexpected results ............................................ 49 
`
`ii.  The results in Figure 2 are not surprising and unexpected, and are not
`
`commensurate in scope with the claims ....................................................... 50 
`
`iii.  The results in Figure 3 are not surprising and unexpected, and are not
`
`commensurate in scope with the claims ....................................................... 53 
`
`iv.  The results in Figure 4 are not surprising and unexpected, and are not
`
`commensurate in scope with the claims ....................................................... 56 
`
`ii
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`v.  The results in Figures 5 and 6 are not surprising and unexpected, and are
`
`not commensurate in scope with the claims ................................................. 58 
`
`J.  A formulation of Gattex® did not address a long-felt, unresolved need ................ 62 
`
`V.  CONCLUSION .................................................................................................................. 62 
`
`
`
`iii
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
`
`I, Dr. Anthony Palmieri III, hereby declare and state as follows:
`
`INTRODUCTION
`
`I previously submitted a Declaration in IPR2015-00990 (Ex. 1001) setting
`
`
`
`I.
`
`1.
`
`forth my background and credentials. My curriculum vitae (Ex. 1002) sets forth
`
`my education and experience in further detail.
`
`2.
`
`In forming the opinions set forth herein, I have considered the documents
`
`and exhibits referenced by Patent Owner and those referenced by Dr. Carpenter in
`
`his Declaration (Ex. 2148). I have also relied on my own experience, knowledge,
`
`and considered the documents referenced in my initial Declaration (Ex. 1001).
`
`Furthermore, I considered the documents discussed herein that are responsive to
`
`the arguments and positions taken by Dr. Carpenter.
`
`3.
`
`I understand that the Board found that the Petitioner established that there is
`
`a reasonable likelihood that it will prevail with respect to at least one of the
`
`challenged claims in U.S. Patent No. 7,056,886 and, thus, instituted an inter partes
`
`review on the following grounds in IPR2015-01093:
`
`Ground 1 - Claims 1-27, 33-35, 38, and 45 as obvious over the combination
`
`of Drucker ’379, Kornfelt, and Osterberg;
`
`Ground 2 - Claims 31, 32, and 44 as obvious over the combination of
`
`Drucker ’379, Kornfelt, Osterberg, and Munroe;
`
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`1
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`Ground 3 - Claims 39-40 as obvious over the combination of Drucker ’379,
`
`
`
`Kornfelt, Osterberg, and Holthius; and
`
`
`
`Ground 4 - Claims 36 and 37 as obvious over the combination of Drucker
`
`’379, Kornfelt, Osterberg, and Drucker ’547. See Paper 26: Decision.
`
`4.
`
`This declaration is based on information currently available to me. I further
`
`reserve the right to expand or otherwise modify my opinions and conclusions and
`
`to supplement my opinions and conclusions in response to any additional
`
`information that becomes available to me.
`
`II. QUALIFICATIONS
`
`5.
`
`I previously provided my qualifications in my initial Declaration (Ex. 1001).
`
`In an effort to provide a brief summary again here, it is important to note that I
`
`received my Ph.D. in Pharmaceutics from the University of Georgia and my M.S.
`
`and B.S. in Pharmacy from the University of Rhode Island. I am the author of over
`
`80 publications and presentations on pharmaceutics, intellectual property, dosage
`
`forms, dissolutions, pharmacy education, and the history of pharmacy.
`
`6.
`
`Despite recently retiring from my position as a member of the faculty of the
`
`College of Pharmacy at the University of Florida in the Department of
`
`Pharmaceutics, I still remain an adjunct professor of pharmaceutics and participate
`
`in a research committee advising five Ph.D. candidates. It is also important to be
`
`
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`2
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`

`
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`aware that I taught and/or worked in the field of pharmacy and the pharmaceutical
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`sciences for over 35 years. During this time, my teaching responsibilities included
`
`clinical biochemistry, dose form design, and sustained release and dissolution. (Ex.
`
`1002, pp. 1-3). I am well versed in the area of protein/peptide formulation.
`
`7.
`
`In addition to this, I remain on the Editorial Advisory Board of the Journal
`
`of Chemical and Pharmaceutical Sciences and the Research Journal of
`
`Pharmaceutical Biological and Chemical Sciences. I was on the Steering
`
`Committee for the second through fifth editions of the American Pharmacists
`
`Association’s Handbook of Pharmaceutical Excipients. I was also the Steering
`
`Committee chairman for the second edition. I have reviewed and written
`
`monographs for all editions. I am a Fellow of the Academy of Pharmaceutical
`
`Research and Sciences and the past president of that organization.
`
`III. SUMMARY OF OPINION
`
`8.
`
`After submission of my Declaration (Ex. 1001) accompanying the Petition
`
`for Inter Partes Review of U.S. Patent No. 7,056,886 (Claims 1-45), the Patent
`
`Trial and Appeal Board issued a Decision instituting inter partes review as to
`
`claims 1-27, 31-40, 44, and 45 based on Grounds 1-4. (Paper 26). The statements,
`
`arguments, and evidence presented in Patent Owner’s Response (Paper 31) and the
`
`Declaration of John F. Carpenter, Ph.D. in Support of Patent Owner’s Response
`
`
`
`3
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`

`
`
`(Ex. 2148) do not convince me that claims 1-27, 31-40, 44, and 45 are non-obvious
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`to a person of ordinary skill in the art. My opinion that claims 1-27, 31-40, 44, and
`
`45 are obvious are grounded in the reasons I set forth in my initial Declaration (Ex.
`
`1001) and also confirmed through my opinions in this Reply Declaration that are
`
`responsive to opinions raised in Dr. Carpenter’s Declaration.
`
`9.
`
`I am still of the opinion that claims 1-27, 33-35, 38, and 45 are obvious in
`
`view of the combination of Drucker ‘379, Kornfelt, and Osterberg (Ground 1);
`
`claims 31, 32, and 44 are obvious in view of Drucker ‘379, Kornfelt, Osterberg,
`
`and Munroe (Ground 2); claims 39 and 40 are obvious in view of Drucker ‘379,
`
`Kornfelt, Osterberg, and Holthuis (Ground 3); and claims 36 and 37 are obvious in
`
`view of Drucker ‘379, Kornfelt, Osterberg, and Drucker ‘547 (Ground 4).
`
`10.
`
`In summary, the statements, arguments, and evidence presented in Patent
`
`Owner’s Response and Dr. Carpenter’s Declaration do not convince me that claims
`
`1-27, 31-40, 44, and 45 are non-obvious to one of ordinary skill in the art for the
`
`following reasons:
`
` The inventor of the ‘886 patent did not consider the characteristics of GLP-2
`
`or analogs thereof that Dr. Carpenter discusses at length as complexities in
`
`formulating proteins/peptides, despite the claims encompassing a large
`
`number (i.e., thousands) of GLP-2 analogs; therefore, they shouldn’t be
`
`considered complexities now just because Dr. Carpenter says so;
`
`
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`4
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` Dr. Carpenter repeatedly contradicts two of his previous publications
`
`published in 1996 and 1997, respectively;
`
` Dr. Carpenter does not have an appropriate perspective as to a person of
`
`ordinary skill in the art;
`
` Dr. Carpenter makes many statements and assertions unsupported by any
`
`evidence;
`
` Dr. Carpenter’s opinions are based on an interpretation of the claims at issue
`
`having particular stability limitations, which they do not;
`
` Dr. Carpenter picks and chooses portions of Kornfelt that suit his viewpoint,
`
`and does not read Kornfelt as a whole for all that it teaches;
`
` Dr. Carpenter disregards known protocols and disclosures of optimization
`
`set forth in his own previous publications published in 1996 and 1997,
`
`respectively;
`
` Based on the knowledge in the art, a person of ordinary skill in the art would
`
`identify a finite number of excipients to work with to formulate GLP-2;
`
` Dr. Carpenter’s own previous publications published in 1996 and 1997,
`
`respectively, illustrate a rational approach would generally assure rapid
`
`development of a protein/peptide formulation;
`
`5
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` Dr. Carpenter acknowledges the need for stable peptide formulations as
`
`motivation to prepare stable GLP-2 formulations both in his Declaration and
`
`in his previous publications;
`
` The susceptibility of both glucagon and GLP-2 to the same chemical
`
`degradation pathways provide motivation to identify histidine as a stabilizer
`
`from Kornfelt to reduce the in vitro degradation of GLP-2 with a reasonable
`
`expectation of success of increased stability;
`
` Dr. Carpenter does not point to any teaching away in the prior art from
`
`Petitioner’s combinations;
`
` Dr. Carpenter’s statements disingenuously downplay the importance of
`
`secondary structure in peptides;
`
` Dr. Carpenter’s characterization of histidine is unsupported by the evidence;
`
`and
`
` The results in Figures 2-6 of the ‘886 patent are not surprising and
`
`unexpected, and are not commensurate in scope with the claims at issue.
`
`IV. ANALYSIS OF PATENT OWNER’S OPPOSITION
`
`A. The ‘886 patent does not recognize any of the “complexities”
`associated with peptide formulation that Dr. Carpenter discusses
`
`
`11. Throughout his Declaration, Dr. Carpenter makes an effort to identify a
`
`variety of “complexities” associated with formulating proteins and peptides. Dr.
`6
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`
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`Carpenter’s “complexities” include characteristics associated with protein or
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`peptide degradation pathways, pH requirements, pI, amino acid sequences,
`
`sensitivities to processing stresses, and responses to stabilizing excipients. (Ex.
`
`2148, Section VII. Technical Background and State of the Art in 1999 and Section
`
`X. Summary of Non-Obviousness of Each Challenged Claim, ¶¶ 55, 56, 64, and
`
`87). However, from my review of the ‘886 patent specification, I do not see that
`
`these issues were ever emphasized by the inventor in order to provide a sufficient
`
`disclosure necessary to practice the invention. Indeed, the inventor of the ‘886
`
`patent, Indu Isaacs, does not even discuss or describe within the patent itself the
`
`issues that Dr. Carpenter makes as a centerpiece to his declaration. I have been
`
`informed that, for a patent to issue, the breadth of its claims must be enabled by the
`
`specification. To this end, if these differences made formulating peptides so
`
`complex, unpredictable, and non-routine as Dr. Carpenter insists, the ’886 patent
`
`should have provided at least some guidance with regard to these differences. Yet,
`
`a discussion of such differences and their impact on formulation methodology is
`
`notably absent. It is my opinion that the likely reason for this is due to the fact that
`
`one of ordinary skill in the art could use what was already well known in the art to
`
`address any of these issues quickly and efficiently. Thus, it would be unnecessary
`
`to include them in the specification.
`
`
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`7
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`

`
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`12. For example, even though the ‘886 patent, in a limited manner, states that
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`GLP-2 is potentially susceptible to the chemical degradation pathways of oxidation
`
`and deamidation, it does not list any chemical degradation pathways for GLP-2
`
`analogs much less those that Dr. Carpenter focuses on. (Ex. 1003, col. 1, ll. 45-48;
`
`Ex. 1043, p. 121, ll. 17-24).
`
`13. There is also no discussion of any “complexities” with regard to pI, pH
`
`requirements, sensitivities to processing stresses, and responses to stabilizing
`
`excipients between GLP-2 and its analogs in the ‘886 patent. Indeed, as Dr.
`
`Carpenter admits, the experimentation in the ‘886 patent focuses on just one GLP-
`
`2 analog, h[Gly2]GLP-2. (Ex. 1003, col. 7-col. 11, Ex. 1044; Ex. 1043, p. 123, ll.
`
`3-5). Perhaps this is because these complexities were not complexities at all when
`
`the ‘886 patent was originally filed. Rather, one of ordinary skill in the art could
`
`easily address them using what was already known in the art.
`
`14. This includes the “complexities” Dr. Carpenter describes such as hydrolysis,
`
`oxidation, disulfide bond scrambling, deamidation, Malliard reactions, succinimide
`
`formation, diketopiperazine formation, deglycosylation and desialylation, and
`
`enzymatic proteolysis due to proteases. (Ex. 2148, Section VII. Technical
`
`Background and State of the Art in 1999, ¶ 57). Support for the fact that these
`
`alleged complexities were not complexities at all is demonstrated by Dr. Carpenter
`
`not being able find where the ‘886 patent describes any of these chemical
`
`
`
`8
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`

`
`
`degradation mechanisms other than oxidation and deamidation when asked during
`
`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`his cross-examination. (Ex. 1044; Ex. 1043, p. 137, l. 12-p. 141, l. 11 and p. 144,
`
`l. 11-p. 148, l. 13). In fact, Dr. Carpenter admitted that “not every protein or
`
`peptide has all these degradations and not for everyone do they matter.” (Id., p.
`
`140, l. 25-p. 141, l. 3).
`
`15. Based on this, the only conclusion I can draw is that as of the December 30,
`
`1999 filing date, the “complexities” that Dr. Carpenter points to were not
`
`complexities at all. Rather, they were issues that one of ordinary skill in the art
`
`could address through routine optimization and application of common sense based
`
`on what was known by those of ordinary skill in the art. In fact, Dr. Carpenter’s
`
`own publications point this out very clearly. (Ex. 1049, pp. 201, 205, 206, and
`
`250; Ex. 1050, p. 972). And, from my review of the deposition transcript of Dr.
`
`Carpenter, it is clear that he concedes that one of ordinary skill in the art could
`
`overcome any of the obstacles he describes based on a rational approach to
`
`obtaining a stabilized lyophilized protein or peptide compound. (Ex. 1050, pp. 972
`
`and 974; Ex. 1043, p. 240, ll. 2-19, p. 249, ll. 20-25, and p. 250, l. 9-p. 251, l. 6).
`
`This is clearly set forth by Dr. Carpenter’s admission that degradative reactions can
`
`instead be “slowed sufficiently, such that the protein product remains stable for
`
`months or years at ambient temperature.” (Ex. 1050, p. 969; Ex. 1043, p. 229, l.
`
`13-p. 230, l. 4).
`
`
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`9
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`

`
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`16. Thus, it is my opinion that the “complexities” provided by Dr. Carpenter are
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`a contrived effort to save the claims at issue from being deemed unpatentable in
`
`view of the prior art and the grounds I discuss in my initial declaration. Dr.
`
`Carpenter’s concessions during his cross-examination support my position
`
`regarding the claims at issue and so do his prior art publications which I discuss in
`
`detail below.
`
`17. Furthermore and even in view of his attempts to contrive a multitude of
`
`“complexities,” Dr. Carpenter then argues that the stabilization of glucagon is not
`
`predictive of stabilization of GLP-2 based on the differences between the two.
`
`(Ex. 2148, Section XIV. Stabilization of Glucagon is Not Predictive of
`
`Stabilization of GLP-2, ¶¶ 152-164). Dr. Carpenter’s argument discounts the
`
`important fact that the ‘886 patent does not address any of the differences between
`
`GLP-2 and any “analogs thereof” as claimed. Given the breadth of the claims
`
`being directed to “GLP-2 or an analog thereof” logic would dictate that to the
`
`extent there would allegedly be such wide variation between “glucagon like
`
`peptide-2” and glucagon, then the requisite disclosure necessary to practice the
`
`breadth of the claims would have been provided in the specification of the ‘886
`
`patent. The inventor apparently did not believe this to be necessary at the time of
`
`filing the ‘886 patent. In fact, during his cross-examination, Dr. Carpenter
`
`admitted there is no discussion of potential effects of differences in amino acid
`
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`10
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`

`
`
`sequence between GLP-2 and its analogs. (Ex. 1044; Ex. 1043, p. 119, l. 24-p.
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`120, l. 10).
`
`18. Thus, it is questionable why Dr. Carpenter believes this is an issue now.
`
`After all, the name GLP-2 comes from the phrase “glucagon like peptide-2.” It
`
`only makes sense that the physio-chemical properties of glucagon known prior to
`
`the filing of ‘886 patent would provide guidance for formulating a storage stable
`
`“glucagon like peptide-2” or GLP-2 as well as “an analog thereof.”
`
`19.
`
`In view of this, it is my opinion that the “complexities” associated with the
`
`protein or peptide to be formulated and the differences between glucagon and
`
`GLP-2 that Dr. Carpenter points to are merely post hoc arguments designed to save
`
`the claims at issue from being deemed obvious in view of the prior art.
`
`B. Dr. Carpenter’s previous publications contradict his declaration
`and support Petitioner’s positions
`
`
`20. Throughout his Declaration, Dr. Carpenter contradicts his own written work
`
`he authored prior to 1999. In an effort to rebut Dr. Carpenter, I point out that these
`
`two prominent prior art publications are identified as:
`
` Avis et al. (ed.), Biotechnology and Biopharmaceutical Manufacturing,
`
`Processing, and Preservation, (Carpenter et al.) Chapter 4, 199-263
`
`(“Carpenter 1996”) (Ex. 1049).; and
`
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`11
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` Carpenter et al., Pharmaceutical Research, Vol. 14, No. 8, 1997, 969-975
`
`(“Carpenter 1997”). (Ex. 1050).
`
`21. Carpenter 1996 is a chapter in a book entitled “Lyophilization of Protein
`
`Pharmaceuticals.” (Ex. 1049). Carpenter 1997 is a review article entitled
`
`“Rational Design of Stable Lyophilized Protein Formulations: Some Practical
`
`Advice.” (Ex. 1050).
`
`22.
`
`In his Declaration, Dr. Carpenter argues that one of ordinary skill in the art
`
`would have had an enormous number of formulation components from which to
`
`choose, and would have had no idea where to start. (Ex. 2148, Section X.
`
`Summary of Non-Obviousness of Each Challenged Claim and Section XVI. There
`
`is No Motivation to Combine, and There Are Clear Teachings Away from
`
`Petitioner’s Combinations, ¶¶ 88 and 175). It is my opinion that many references
`
`in the prior art, including those cited in Grounds 1-4 as well as those authored by
`
`Dr. Carpenter, contradict this assertion. These prior art references all point to an
`
`easily recognized, finite number choices of components for formulating peptide
`
`and protein compositions.
`
`23.
`
`In both Carpenter 1996 and Carpenter 1997, Dr. Carpenter discusses
`
`“rational” choices for excipients in lyophilized protein formulations. (Ex. 1049,
`
`pp. 201-202; Ex. 1050, pp. 972 and 974; Ex. 1043, p. 240, ll. 2-19, p. 249, ll. 20-
`
`25, and p. 250, l. 9-p. 251, l. 6). Indeed, Dr. Carpenter even outlines a four step
`
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`12
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`process for stabilizing proteins during the lyophilization process which he
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`describes as “relatively straight forward if the underlying physical principles are
`
`understood and a rational approach is taken.” (Ex. 1049, pp. 201-202).
`
`24.
`
`It is clear from these publications that certain excipients should be avoided
`
`and certain excipients have proven useful in stabilizing lyophilized protein
`
`formulations in the past, and one of ordinary skill in the art would be guided by
`
`this knowledge to narrow the choice of excipients to a finite number.
`
`25. As to choosing excipients that are useful for stabilizing lyophilized proteins,
`
`Dr. Carpenter admits in his publications that prior to the December 1999 filing
`
`date of the ‘886 patent:
`
` sugars providing protection during drying and preventing drying-induced
`
`denaturation of the protein were known (Ex. 1049, p. 225; Ex. 1043, p. 219,
`
`ll. 9-24);
`
` reducing sugars (e.g., glucose, lactose, maltose, and maltodextrins) should
`
`be avoided (Ex. 1049, p. 222; Ex. 1050, p. 972; Ex. 1043, p. 243, l. 15-p.
`
`244, l. 23);
`
` the earliest use of sucrose to stabilize proteins was more than 80 years ago in
`
`1935 (Ex. 1049, p. 221; Ex. 1043, p. 218, l. 16-p. 219, l. 8); and
`
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`13
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` stabilizers for stabilizing proteins were available and their use could be
`
`optimized (Ex. 1049, p. 201; Ex. 1050, p. 972; Ex. 1043 p. 207, l. 24-p. 208,
`
`l. 15 and p. 240, l. 20-p. 241, l. 11).
`
`Furthermore, one of ordinary skill in the art would look to certain excipients, like
`
`sucrose, which are used in products already approved by the Food and Drug
`
`Administration (Ex. 1049, p. 222; Ex. 1050, p. 973; Ex. 1043, p. 246, ll. 18-22 and
`
`p. 248, ll. 3-10).
`
`26. Notably, Carpenter 1996 and Carpenter 1997 show that mannitol and
`
`histidine were known to be useful excipients for lyophilized protein formulations
`
`prior to 1999. Dr. Carpenter provides:
`
` mannitol is a good choice as a tonicity modifier and can also serve as a
`
`bulking agent1 for lyophilizing proteins (Ex. 1050, p. 970; Ex. 1043, p. 234,
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`ll. 18-p. 235, l. 2 and p. 248, l. 11-p. 249, l. 19);
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` mannitol is a common bulking agent and moderately effective as a stabilizer
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`(Ex. 1049, p. 243); and
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`1 I further note mannitol is a very common bulking agent and was known to be
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`such prior to 1999.
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` histidine exhibits minimal pH change upon freezing and is a good choice as
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`a buffer (Ex. 1050, p. 971; Ex. 1043, p. 238, l. 23-p. 239, l. 4 and p. 239, ll.
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`16-25).
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`27. Of the non-reducing sugars, Carpenter 1996 and Carpenter 1997 show that
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`sucrose is desirable for use in lyophilized protein formulations for a variety of
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`reasons:
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` sucrose is a main choice as a non-reducing disaccharide to protect proteins
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`during freezing and to inhibit unfolding (Ex. 1050, p. 973; p. 244, l. 24-p.
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`245, l. 18);
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` sucrose is a common excipient that protects the protein during the
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`dehydration step (Ex. 1049, p. 206; Ex. 1043, p. 213, l. 9-p. 214, l. 6);
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` sucrose minimizes crystallization of excipients (Ex. 1049, pp. 211 and 212;
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`Ex. 1043, p. 214, ll. 7-16);
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` sucrose protects proteins during both freezing and dehydration (Ex. 1049, p.
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`220; Ex. 1043, p. 216, l. 11-p. 217, l. 14); and
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` sucrose has been known to protect proteins during dehydration/rehydration
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`since at least 1935 (Ex. 1049, p. 221; Ex. 1043, p. 218, l. 16-p. 219, l. 8).
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`28.
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`In his Declaration, Dr. Carpenter downplays the importance of secondary
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`structure to stability of lyophilized formulations. (Ex. 2148, Section XIV.
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`Stabilization of Glucagon Is Not Predictive of Stabilization of GLP-2, ¶¶ 161-163).
`15
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`However, in his previous publications, Dr. Carpenter consistently stressed the
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`importance of maintaining secondary structure in lyophilized protein formulations.
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`Dr. Carpenter provides:
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` “the success of the formulation can be judged immediately by examining the
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`protein secondary structure in the dried solid with infrared spectroscopy”
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`(Ex. 1050, p. 972);
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` infrared spectroscopy has shown that stabilizers prevent unfolding (Ex.
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`1049, p. 220; Ex. 1043, p. 215, l. 16-p. 216, l. 10); and
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` immobilizing the native protein in a chemically inert solid matrix having
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`both high Tg and low residual moisture is important (Ex. 1050, p. 971; Ex.
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`1043, p. 238, ll. 2-22).
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`29.
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`In particular, Dr. Carpenter addresses the importance of secondary structure
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`in lyophilized formulations of glucagon by referring to conformational
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`heterogenicity of glucagon in solution. (Ex. 2148, Section XIV. Stabilization of
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`Glucagon is Not Predictive of Stabilization of GLP-2, ¶ 162). But, Dr. Carpenter
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`has written about the problems associated with proteins in solution and the answer
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`to those problems:
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` solution fosters conformational changes of proteins and degradation of
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`proteins (Ex. 1049, pp. 199 and 200); and
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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` “[t]he practical solution to the protein stability dilemma is to remove the
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`damaging component—water. Lyophilization (freeze-drying) is the method
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`most commonly used to prepare dehydrated proteins” (Ex. 1049, p. 200; Ex.
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`1043, p. 206, l. 16-p. 207, l. 4).
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`Dr. Carpenter clearly understands conformational changes are not present in a
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`stabilized lyophilized formulation, where secondary structure is of the utmost
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`importance as evidenced by his statements in Carpenter 1996 and Carpenter 1997,
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`yet he conflates structure in solution and structure in lyophilized form.
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`30.
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`In his Declaration, Dr. Carpenter stresses the importance of minimizing
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`degradation. (Ex. 2148, Section VII. Technical Background and State of the Art in
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`1999, ¶¶ 61, 63, and 64). However, Dr. Carpenter has conceded in his very own
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`publication that is prior art to the ‘886 patent that:
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` degradative reactions can instead be “slowed sufficiently, such that the
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`protein product remains stable for months or years at ambient temperature”
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`(Ex. 1050, p. 969; Ex. 1043, p. 229, l. 13-p. 230, l. 4); and
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` “reduced reaction rates in a dried product can allow for long-term stability”
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`(Ex. 1050, p. 969; Ex. 1043, p. 231, l. 21-p. 232, l. 10).
`
`31. Finally, the tenor of Dr. Carpenter’s Declaration with regard to formulating
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`proteins and peptides is unnecessarily pessimistic and not in keeping with his own
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`prior publications. Despite identifying certain specific stabilizers and bulking
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`agents in his publications, he contrarily maintains in his testimony that protein and
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`peptide formulation is generally difficult and unpredictable. (Ex. 2148, e.g.,
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`Section VII. Technical Background and State of the Art in 1999, ¶¶ 54 and 65). In
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`fact, Dr. Carpenter’s previous publication suggests rapid formulation development
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`for protein and peptide lyophilization using a “rational approach” by stating that:
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` “with a rational approach to formulation design, most formulation problems
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`are resolved quickly” (Ex. 1050, pp. 972; Ex. 1043, p. 240, ll. 2-19); and
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` “[c]ombining a detailed knowledge of the protein properties with the
`
`rational choice of excipients should allow rapid development of a stable
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`lyophilized formulation.” (Ex. 1050, pp. 974; Ex. 1043, p. 249, ll. 20-25
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`and p. 250, l. 9-p. 251, l. 6).
`
`32.
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`In his Declaration, Dr. Carpenter faults me for not knowing everything
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`regarding proteins/peptides and lyophilization. (Ex. 2148, Section XI. The Field of
`
`the Invention and Level of Ordinary Skill in This Art, ¶ 108). This is directly
`
`contrary to statements Dr. Carpenter made in his previous 1997 publication and
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`during his cross-examination where he agrees that it is appropriate for a person of
`
`ordinary skill in the art to work in a team with individuals to lyophilize proteins
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`and peptides.
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`33.
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`In this regard, Dr. Carpenter agrees with my position on working in a team
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`as he identifies several individuals who one of ordinary skill in the art could look
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`to in the event that they needed assistance in formulating or lyophilizing a protein
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`Declaration of Anthony Palmieri III, Ph.D.
`IPR2015-01093
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`or peptide. For example, he states that:
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` “the pharmaceutical scientist should work closely with the process
`
`engineers, who will be designing lyophilization cycles” (Ex. 1050, p. 970;
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`Ex. 1043, p. 235, l. 3-p. 236, l. 6);
`
` “input from a researcher knowledgeable in the physics of freeze-drying will
`
`help prevent the formulation scientists from arbitrarily rejecting useful
`
`formulations” (Ex. 1050, p. 970; Ex. 1043, p. 236, ll. 7-18); and
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` formulation scientists should consult those responsible for bulk drug
`
`purification and pharmaceutical preformulation before attempting to design
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`a lyophilized formulation (Ex. 1050, p. 972; Ex. 1043 p. 241, ll. 12-24).
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`34. Dr. Carpenter also agreed with me when he said if he did not know
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`something, he would reach out to someone for an answer or look