`Matthew L. Fedowitz, Esq.
`MERCHANT & GOULD P.C.
`191 Peachtree Street N.E., Suite 4300
`Atlanta, GA 30303
`jblake@merchantgould.com
`mfedowitz@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 IPR2015-01093
`Patent No. 7,056,886
`_____________________
`
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`
`
`
`By:
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`
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`
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`
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`I.
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`INTRODUCTION
`
`The Board instituted this IPR proceeding because Petitioner established a
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`reasonable likelihood in prevailing on its assertions that claims 1-27, 31-40, 44,
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`and 45 are obvious. (Paper 26, pp. 2, 19, 20, 23). Patent Owner (“PO”) does not
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`dispute that the prior art teaches each and every element of claims 1-27, 31-40, 44,
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`and 45.
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`Faced with this reality, PO resorts to baseless arguments about alleged
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`“complexities” in stabilizing peptide formulations, interprets the claims too
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`narrowly, improperly attempts to import stability limitations into the claims, and
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`makes unsupported arguments concerning motivation to combine. None of these
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`efforts can withstand scrutiny when considered in view of the ’886 patent and the
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`prior art. Moreover, the positions now taken by PO in this IPR plainly contradict
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`two publications of PO’s own expert, Dr. Carpenter.
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`For example, Dr. Carpenter’s prior publications discredit PO’s positon that
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`stabilizing peptide formulations is unpredictable based on the number of choices
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`and combinations of components. Dr. Carpenter’s publications explain that one of
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`ordinary skill in the art could use a “rational approach” to prepare stable
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`formulations of GLP-2 or analogs thereof. This is particularly true given that there
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`are a finite number of options from which to choose in view of Kornfelt. The
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`contradictions between Dr. Carpenter’s prior publications and his declaration, as
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`1
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`
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`well as the lack of support for many of his current positions, all point to PO’s and
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`Dr. Carpenter’s positions lacking credibility.
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`Furthermore, PO’s improper attempts to discredit Petitioner’s expert, Dr.
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`Palmieri, are misplaced. This is because PO relies on an unnecessarily elevated
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`level of ordinary skill in the art that ultimately disqualifies PO’s own expert as one
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`of ordinary skill in the art.
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`In addition, PO overlooks the well-known fact that both glucagon and GLP-
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`2 are susceptible to in vitro degradation by the same mechanisms. This knowledge
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`in combination with Kornfelt’s disclosure that histidine reduces in vitro
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`degradation of glucagon provides the motivation to choose histidine and develop a
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`lyophilized GLP-2 formulation with a reasonable expectation of success.
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`Finally, PO’s attempts to demonstrate unexpected results, commercial
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`success, and fulfillment of a long-felt, unresolved need do not pass muster and
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`should be disregarded.
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`Based on those arguments originally offered by Petitioner and the rebuttal
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`arguments herein, Petitioner submits that claims 1-27, 31-40, 44, and 45 of the
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`’886 patent are unpatentable as obvious under 35 U.S.C. § 103.
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`
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`2
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`
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`II. RESPONSE TO PATENT OWNER’S ARGUMENTS
`A. The ’886 patent does not recognize any of the “complexities”
`associated with peptide formulation alleged by PO.
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`PO alleges various “complexities” associated with peptide formulations in
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`an attempt to argue that stabilizing glucagon is not predictive of stabilizing GLP-2.
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`(Resp., 43-48). Dr. Carpenter’s “complexities” include protein or peptide
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`degradation pathways, pH requirements, pI, amino acid sequence, sensitivities to
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`processing stresses, and responses to stabilizing excipients. (Ex. 1041, ¶ 11).
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`The ’886 patent, however, never even recognizes these alleged complexities.
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`This is despite the claims of the ’886 patent covering the wide breadth of GLP-2 or
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`an analog thereof. The failure of the ’886 patent to recognize these alleged
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`complexities suggests that one of ordinary skill in the art could have readily
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`addressed them with what was known in the art using routine optimization.
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`If these complexities resulted in protein/peptide formulation science being so
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`complex and unpredictable (Resp., 4-5), the ’886 patent should have provided at
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`least some guidance regarding these complexities in order for it to meet the
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`requirements of 35 U.S.C. § 112, first paragraph. (Ex. 1041, ¶ 11). Logic would
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`dictate that the ’886 patent should have at least addressed these complexities to
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`enable formulating the breadth of peptides (i.e., GLP-2 or an analog thereof) in the
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`claims. (Ex. 1041, ¶¶ 11, 17). The lack of disclosure in the ’886 patent suggests
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`3
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`the purported complexities are contrived, post hoc arguments designed to save the
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`claims at issue from now being invalidated as obvious. (Ex. 1041, ¶¶ 16, 18, 19).
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`B. The previous publications of PO’s expert, Dr. Carpenter,
`contradict his declaration and support Petitioner’s positions.
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`Dr. Carpenter has two publications directly contradicting arguments made in
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`PO’s response: Avis et al. (ed.), Biotechnology and Biopharmaceutical
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`Manufacturing, Processing, and Preservation, (Carpenter et al.) Chapter 4, 199-263
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`(“Carpenter 1996”; Ex. 1049) and Carpenter et al., Pharmaceutical Research, Vol.
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`14, No. 8, 1997, 969-975 (“Carpenter 1997”; Ex. 1050). Dr. Carpenter’s
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`contradictions in these publications show that the basis on which PO relies to
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`allege the non-obviousness of the claims at issue lacks credibility.
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`PO argues the number of components and combinations are voluminous and
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`lead to infinite possibilities to test. (Resp., 19). In support, Dr. Carpenter claims
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`one of ordinary skill in the art would have no idea where to start. (Ex. 1041, ¶ 22).
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`But, Carpenter 1996 and Carpenter 1997 both describe “rational” choices for
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`excipients in lyophilized protein formulations, describe excipients that should be
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`avoided, and name excipients that have been proven useful in stabilizing
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`lyophilized protein formulations. (Ex. 1041, ¶¶ 23-27; see, e.g., Ex. 1049, p. 225;
`
`Ex. 1050, p. 972; Ex. 1043, p. 219, ll. 9-24 and p. 243, l. 15-p. 244, l. 13). For
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`example, Dr. Carpenter points to using sugars, but not reducing sugars. (Ex. 1049,
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`p. 225; Ex. 1050, p. 972). Dr. Carpenter calls out histidine, mannitol, and sucrose
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`
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`4
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`
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`among known, useful excipients for lyophilizing protein formulations. (Ex. 1041,
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`¶¶ 25-27; see, e.g., Ex. 1049, p. 243; Ex 1050, pp. 970, 971, and 973; Ex. 1043, p.
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`234, ll. 18-p. 235, l. 2, p. 238, l. 23-p. 239, l. 4, and p. 239, ll. 16-25). He states
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`that mannitol is a good tonicity modifier and common bulking agent, histidine is a
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`buffer with minimal pH change upon freezing, and sucrose is a main choice as a
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`non-reducing dissacharide. (Ex. 1049, p. 243; Ex. 1050, pp. 970, 971, and 973).
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`Thus, one of ordinary skill in the art could easily identify and narrow the possible
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`excipients to a finite number. (Ex. 1041, ¶¶ 22, 24).
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`PO also relies on Dr. Carpenter to downplay the importance of maintaining
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`peptide secondary structure by incorrectly arguing that it is not critical to do so for
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`lyophilized formulations of glucagon. (Resp., 45-47, Ex. 1041; ¶ 28, 29). In
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`contrast, Carpenter 1996 and Carpenter 1997 consistently stress maintaining
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`secondary structure in lyophilized protein formulations. (Ex. 1041, ¶ 28; see, e.g.,
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`Ex. 1050, p. 972). Moreover, Carpenter 1996 explains conformational changes in
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`solution are not present in stabilized lyophilized formulations, despite Dr.
`
`Carpenter conflating structure in solution and structure in lyophilized forms. (Ex.
`
`1041, ¶ 29; Ex. 1049, pp. 199 and 200; Ex. 1043, p. 206, l. 16-p. 207, l. 4).
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`Another purported complexity argued by PO is that it is important to
`
`minimize compound degradation. (Resp., 9, 15, 24). In contrast, Carpenter 1997
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`states it is not necessary to minimize degradation—instead, degradation can be
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`5
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`
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`slowed and result in an acceptable formulation. (Ex. 1041, ¶ 30; Ex. 1050, p. 969;
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`Ex. 1043, p. 229, l. 13-p. 230, l. 4 and p. 231, l. 21-p. 232, l. 10).
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`PO additionally goes on to argue that formulation of therapeutic
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`proteins/peptides was a highly unpredictable and complicated field prior to
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`December 30, 1999, again relying on Dr. Carpenter (Resp., 24). Yet, Carpenter
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`1997 suggests that rapid formulation development for protein and peptide
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`lyophilization is possible using a “rational” approach. (Ex. 1041, ¶ 31; Ex. 1050,
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`pp. 972, 974; Ex. 1043, p. 240, ll. 2-19, p. 249, ll. 20-25, and p. 250, l. 9-p. 251, l.
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`6). The “rational” approach implements a means by which to choose excipients.
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`As a result, Dr. Carpenter’s publications are directly in line with Petitioner’s
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`position that there would be a reasonable expectation of success in making a
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`storage stable, lyophilized GLP-2 formulation encompassed by the claims at issue
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`based on the disclosures in the prior art.
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`Finally, PO makes a misplaced argument concerning Dr. Palmieri’s
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`supposed lack of knowledge and takes issue with his position on consulting his
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`colleagues regarding information he may have a question about. (Resp., 5, 23, 27-
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`30). In fact, Dr. Carpenter attacks Dr. Palmieri for his inability to know
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`everything. (Ex. 1041, ¶ 32). However, Dr. Carpenter himself wrote in his
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`publications that one of ordinary skill in the art may identify individuals with
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`whom he or she could work if he or she needed assistance in formulating or
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`6
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`
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`lyophilizing a protein or peptide. (Ex. 1041, ¶¶ 32, 33, Ex. 1050, pp. 970, 972; Ex.
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`1043, p. 235, l. 3-p. 236, l. 18 and p. 241, ll. 12-24). When questioned on this
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`during his cross-examination, Dr. Carpenter even admitted that it would be
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`appropriate to reach out to someone or look up information. (Ex. 1041, ¶ 34; Ex.
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`1043, p. 237, ll. 21-25). Dr. Carpenter’s admissions concede that it is possible to be
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`one of ordinary skill in the art even if it is necessary to look up information or
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`speak to a colleague about a particular question.
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`C. Unnecessary elevation of the level of ordinary skill in the art.
`As explained in the Petition, a person of ordinary skill in the art is a
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`pharmaceutical scientist having an advanced degree (a Master’s or a Ph.D.) or
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`equivalent experience in pharmaceutics, pharmaceutical formulations or the
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`pharmaceutical arts with knowledge of formulating peptide formulations and the
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`clinical application of therapeutics in treating gastrointestinal disorders. (Paper 1,
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`p. 21). PO unnecessarily seeks to elevate the level of ordinary skill in the art in an
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`attempt to discredit Dr. Palmieri’s testimony and tout Dr. Carpenter as a true
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`“expert.” (Resp., 23, 24). Yet, PO’s own elevated level of ordinary skill in the art
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`excludes Dr. Carpenter as one of ordinary skill in the art and makes the claims at
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`issue even more obvious. (Ex. 1041, ¶¶ 37, 42, 43).
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`PO states “[e]xperience…cannot replace or substitute for a formal education
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`in the biological sciences underlying protein and peptide formulation science.”
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`7
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`
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`(Resp., 23, 24). This directly cuts against PO because Dr. Carpenter does not have
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`“a formal education in the biological sciences underlying protein and peptide
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`formulation science.” (Ex. 1041, ¶ 37). Rather. Dr. Carpenter has a B.S. in
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`Zoology, a M.S. in Zoology, and a Ph.D. in Biology. (Ex. 1041, ¶ 38; Ex. 1043, p.
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`1). The coursework and research underlying Dr. Carpenter’s degrees were not
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`related to the principles underlying protein and peptide formulation science. (Ex.
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`1041, ¶ 38; Ex. 1043, p. 17, l. 14-p. 18, l. 20, p. 19, l. 14-p. 20, l. 23, and p. 21, l.
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`22-p. 23, l. 6). He had no courses in formulation or peptide formulation science.
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`(Ex. 1041, ¶ 40; Ex. 1043, p. 84, ll. 16-20 and p. 92, l. 21-p. 93, l. 8). He also did
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`not study in any pharmaceutical programs to earn his degrees. (Ex. 1041, ¶ 41; Ex.
`
`1043, p. 93, l. 9-p. 95, l. 7). Rather, when questioned during his cross-examination
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`Dr. Carpenter said his first experience in this area was when he was “wrapping up
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`things” for his Ph.D. and that he “started collaborating with scientists from Amgen,
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`so I would say it is interaction with those scientists that first let me learn about the
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`actual pharmaceutics industry.” (Ex. 1041, ¶ 39; Ex. 1043, p. 21, l. 22- p. 23, l. 15
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`and p. 84, l. 21-p. 85, l. 5). This does not constitute a formal education in the
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`biological sciences underlying protein and peptide formulation science.
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`PO’s requirement that one of ordinary skill in the art have “post-doctorate
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`experience in designing pharmaceutical formulations of proteins/peptides sufficient
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`for a leadership role in a formulation design team” is also unwarranted. (Resp.,
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`
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`8
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`
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`23). Experienced pharmaceutical formulators would rely on those principles
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`known to them and disclosed in the prior art to develop a lyophilized formulation
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`of GLP-2 or an analog thereof, would work in a team, and could reach out to others
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`with a question or look up any necessary information. (Ex. 1041, ¶ 43).
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`D. PO’s statements are unsupported.
`Another flaw in PO’s Response is that it relies on unsupported statements by
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`Dr. Carpenter in his declaration. For example, Dr. Carpenter’s arguments
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`regarding the state of the art in 1999, histidine being a problematic excipient, and
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`the prior art allegedly teaching away are all unsupported by evidence. (Ex. 1041,
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`¶¶ 46, 47). An example is where Dr. Carpenter discusses interaction between
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`histidine and sodium phosphate. (Ex. 2148, ¶ 170). A similar deficiency is where
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`Dr. Carpenter relies on a reference for allegedly disclosing conformational
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`heterogenicity of glucagon when lyophilized in amorphous, non-crystalline form,
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`but that reference does not provide support for this proposition. (Ex. 2148, ¶ 162;
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`see Section II.H.iv., infra). Rather, the reference examines the conformation of
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`glucagon in a variety of other forms. (Id.). In view of the numerous unsupported
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`statements, the Board should not give much credit to Dr. Carpenter’s declaration.
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`E. The claims at issue cannot be narrowed to argue non-obviousness.
`i. The claims recite a GLP-2 peptide or an analog thereof.
`Despite the claims reciting GLP-2 or an analog thereof, PO highlights the
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`differences between glucagon and GLP-2, and then relies on a single GLP-2 analog
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`
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`9
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`
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`to demonstrate unexpected results. (Resp., 40-48). PO’s focus in this regard
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`inappropriately ignores the breadth of the claims directed to GLP-2 or an analog
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`thereof.
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`Dr. Carpenter admits GLP-2 analogs within the scope of the claims include a
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`“large number” and more specifically thousands of GLP-2 analogs. (Ex. 1041, ¶¶
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`50, 51; Ex. 1043, p. 110, l. 17-p. 111, l. 12 and p. 111, l. 22-p. 112, l. 16). Yet, Dr.
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`Carpenter bases his opinion of non-obviousness only on the differences between
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`glucagon and GLP-2, and he fails to address how the breadth of the claims at issue
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`is non-obvious over the prior art. (Ex. 1041, ¶ 51).
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`In addition, Dr. Carpenter’s arguments demonstrate that he wants to have it
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`both ways. (Ex. 1041, ¶ 52). On the one hand, Dr. Carpenter argues the
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`differences between GLP-2 and glucagon presented a person of ordinary skill in
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`the art with unpredictability and preclude any motivation to combine the prior art
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`references with any reasonable expectation of success. (Id). But, on the other
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`hand, Dr. Carpenter does not and cannot provide any meaningful explanation as to
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`why the same logic would not apply to the differences between GLP-2 and its
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`analogs. (Id.).
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`Dr. Carpenter points to experimental data relating to formulations of h[Gly-
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`2]GLP-2 in an attempt to show the claimed formulations of GLP-2 or an analog
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`thereof are non-obvious. (Ex. 1041, ¶¶ 109, 115, 120, 126). Despite this data
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`10
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`
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`being unexpected, Dr. Carpenter does not explain how the results can be applied to
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`the full scope of GLP-2 or an analog thereof as claimed. (Id.).
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`ii. The challenged claims do not require a particular stability.
`PO asks the Board to prop up the challenged claims by importing particular
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`stability limitations into them. This is demonstrated by Dr. Carpenter stating that
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`formulations of GLP-2 or an analog thereof disclosed in the ’886 patent “are
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`stable, particularly when lyophilized (i.e., six months at ambient temperature, 18
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`months at 4°C with less than about 5% peptide degradation). . . .” (Ex. 1041, ¶
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`53). PO and Dr. Carpenter would like to include these stability limitations as part
`
`of the claims in order to then rely on them as a basis for arguing the claims are
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`non-obvious. This is improper.
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`Dr. Carpenter acknowledges the only claims in the ’886 patent reciting time
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`and percent degradation limitations are claims not at issue in either this proceeding
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`or IPR2015-0990. (Ex. 1041, ¶ 54; Ex. 1043, p. 131, l. 10-p. 132, l. 19).1 Dr.
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`Carpenter admits he imported these stability parameters from the examples of the
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`’886 patent. (Ex. 1041 ¶ 54, Ex. 1043, p. 129, l. 11-p. 130, l. 5).
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`PO and Dr. Carpenter also reference various chemical and physical
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`degradation routes in an attempt to import stability limitations into the claims. But,
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`1 Claims 66 and 67 include stability limitations following reconstitution in
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`terms of time only. (Ex. 1041, ¶ 54; Ex. 1043, p. 132, l. 20-p. 134, l. 18).
`
`
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`11
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`
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`most of those degradation routes are not even mentioned in the specification of the
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`’886 patent, and they certainly are not recited in the challenged claims. (Ex. 1041,
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`¶ 55-58; Ex. 1043, p. 137, l. 12-p. 141, l. 11 and p. 144, l. 11-p. 148, l. 13). PO
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`and Dr. Carpenter thus conflate these potential degradation mechanisms with the
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`claimed subject matter. (Ex. 1041, ¶ 57). Likewise, the discussion of “ideal”
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`stability in Dr. Carpenter’s declaration has no bearing on the claimed formulations.
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`(Ex. 1041, ¶ 59).
`
`F. Kornfelt must be read as a whole.
`i. Kornfelt’s disclosure of histidine in combination with
`mannitol is a preferred combination.
`
`PO’s analysis of the validity of the claims ignores Kornfelt’s disclosure of
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`histidine in combination with mannitol among preferable combinations. PO
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`emphasizes Kornfelt’s disclosure of possible ampholytes and excipients, and
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`argues that there are too many combinations for obviousness. (Ex. 1041, ¶ 61).
`
`However, Kornfelt explicitly discloses lactose or mannitol as being preferable in
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`combination with glycine, glycylglycine, histidine, or a mixture of two of more of
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`these. (Ex. 1003, 3:22-25; Ex. 1041, ¶ 62). PO conveniently turns a blind eye to
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`this specific disclosure of a finite number of preferred combinations in Kornfelt
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`and thus refuses to acknowledge the full scope of Kornfelt’s teaching. (Ex. 1041,
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`¶¶ 62, 63).
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`12
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`
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`ii. Kornfelt’s disclosure of a pH range cannot be ignored.
`PO also ignores Kornfelt’s disclosure of a broad pH range and, instead,
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`focuses on it disclosing a pH of 2.8 providing “a minimum for the rate of
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`decomposition of glucagon” to conclude that Kornfelt teaches away from
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`physiological pH. (Resp., 36-37, Ex. 1027, 3:25-26; Ex. 1041, ¶ 64). PO’s
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`conclusion that Kornfelt teaches away from physiological pH is wrong.
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`Kornfelt undoubtedly discloses a pH range of 1-7. (Ex. 1027, 3:9-11; Ex.
`
`1041, ¶ 65). Thus, it is clear that Kornfelt contemplated that a range of pH values
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`up to and including physiological pH are useful. (Ex. 1041, ¶ 65). By focusing on
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`a pH of 2.8 providing a minimum rate of decomposition of glucagon, Dr.
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`Carpenter again attempts to introduce a particular stability limitation into the
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`claims that does not exist. (Ex. 1041, ¶ 66; section II.E.ii., supra). Dr. Carpenter’s
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`statements in this regard contradict his statements in Carpenter 1997, where he
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`provides that the rate of degradative reactions can be reduced or slowed
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`sufficiently for long-term stability. (Ex. 1041, ¶ 66; Ex. 1050, p. 969; Ex. 1043, p.
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`229, l. 13-p. 230, l. 4 and p. 231, l. 21-p. 232, l. 10).
`
`Moreover, Kornfelt also does not criticize, discredit, or otherwise discourage
`
`using physiological pH. (Ex. 1041, ¶ 67). “The prior art’s mere disclosure of more
`
`than one alternative does not constitute a teaching away from any of these
`
`alternatives because such disclosure does not criticize, discredit, or otherwise
`
`
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`13
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`
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`
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`discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir.
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`2004). For this additional reason, PO’s conclusion that Kornfelt teaches away
`
`from physiological pH is incorrect.
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`G. Known protocols and finite options provide a reasonable
`expectation of success.
`
`Even if developing a peptide formulation presented certain stability
`
`challenges prior to December 30, 1999, a pharmaceutical formulator had
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`established protocols and a finite number of formulation components well within
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`their grasp to work with in view of the prior art. (Ex. 1041, ¶ 68). PO disregards
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`this though in an effort to assert that there would be no reasonable expectation of
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`success. (Resp., 19-20).
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`Regarding known protocols, Carpenter 1996 emphasizes that it is necessary
`
`to satisfy only four criteria to provide a lyophilized protein/peptide formulation
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`with long-term storage stability: (1) minimize acute lyophilization-induced
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`unfolding so that the protein is native; (2) the glass transition temperature must be
`
`higher than the storage temperature; (3) residual moisture must be relatively low;
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`and (4) conditions must be developed to inhibit chemical degradation pathways
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`(Ex. 1041, ¶ 69, Ex. 1049, p. 251; Ex. 1043, p. 224, l. 5-p. 225, l. 3). Also, these
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`protocols were known because even Dr. Carpenter explains that Cleland et al.
`
`provides “a system for formulating therapeutic proteins and peptides.” (Ex. 1041,
`
`¶ 69).
`
`
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`14
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`
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`As discussed above in Section II.B, Carpenter 1996 and Carpenter 1997
`
`would guide one of ordinary skill in the art in choosing excipients for lyophilized
`
`protein formulations. (Ex. 1041, ¶ 70). Indeed, Dr. Carpenter calls out histidine,
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`mannitol, and sucrose as particularly useful in these publications. (Id.).
`
`Additionally, Kornfelt discloses a finite number of preferable combinations (i.e.,
`
`glycine, glycylglycine, histidine, or a mixture of two or more of these with lactose
`
`and mannitol). (Ex. 1027, 3:22-25; Ex. 1041 ¶ 70).
`
`One of ordinary skill in the art would understand that routine optimization is
`
`involved in designing lyophilized formulations of proteins and peptides. (Ex.
`
`1041, ¶ 71). Numerous references to optimization throughout Carpenter 1996
`
`demonstrate this. (Ex. 1041, ¶ 71; Ex. 1049, pp. 205, 206, 212, 214, 216, 250; Ex.
`
`1043, p. 212, l. 14-p. 213, l. 8, p. 214, l. 7-p. 215, l. 6, and p. 224, ll. 5-10)
`
`Dr. Carpenter also acknowledged well before 1999 that a rational approach
`
`“will probably lead to a successful lyophilization formulation” for proteins or
`
`peptides. (Ex. 1041, ¶¶ 72, 73; Ex. 1050, p. 974; Ex. 1043, p. 249, l. 20-p. 250, l.
`
`8). A conclusion of obviousness requires only the reasonable expectation of
`
`success that exists if one practices the rational approach advocated by Dr.
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`Carpenter, not absolute certainty. Par Pharmaceutical, Inc. v. TWi
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`Pharmaceuticals, Inc., 773 F.3d 1186, 1198 (Fed. Cir. 2014) citing In re O'Farrell,
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`853 F.2d 894, 903-04 (Fed. Cir. 1988)
`
`
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`15
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`
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`H. Failure to rebut Petitioner’s motivation to combine with a
`reasonable expectation of success.
`
`In addition to PO disregarding known protocols and a finite number of
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`options to assert that there would be no reasonable expectation of success, PO did
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`not rebut Petitioner’s showing of motivation to combine with a reasonable
`
`expectation of success.
`
`i. There was a need for stable peptide formulations.
`PO does not dispute the need for stable peptide formulations, which clearly
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`provides motivation to combine the prior art references. In his Declaration, Dr.
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`Carpenter acknowledges the need for stable peptide formulations in 1999. (Ex.
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`1041, ¶ 76). Moreover, Dr. Carpenter’s publications prior to 1999 discuss the need
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`for stable peptide formulations. (Ex. 1041, ¶ 76; Ex. 1049, p. 199; Ex. 1050, p.
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`969; Ex. 1043, p. 206, ll. 3-15 and p. 227, l. 24-p. 229, l. 12).
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`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.
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`PO asserts that histidine does not have a stabilizing effect on protein/peptide
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`drugs generally. (Resp., 50, 51). However, Kornfelt recognizes histidine has a
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`stabilizing effect on glucagon. This knowledge, combined with the understanding
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`that glucagon and GLP-2 are susceptible to in vitro degradation by the same
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`mechanisms, provides the motivation to choose histidine for formulating GLP-2,
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`with a reasonable expectation of success in doing so. (Ex. 1041, ¶ 77).
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`16
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`Using reverse-phase high-performance liquid chromatography (RP-HPLC),
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`Kornfelt describes histidine acting as a stabilizing agent and also reducing in vitro
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`degradation of glucagon. (Ex. 1041, ¶¶ 78, 79; Ex. 1027, 3:22-25, 4:10-50, and
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`Figures 1, 4, and 7; Ex. 1043, p. 173, l. 4-p. 174, l. 2). One of ordinary skill in the
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`art would understand glucagon is susceptible to deamidation and oxidation. (Ex.
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`1041, ¶ 80). Because GLP-2 is also susceptible to deamidation and oxidation, a
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`person of ordinary skill in the art would recognize both glucagon and GLP-2 are
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`susceptible to in vitro degradation by the same mechanisms. (Id.) As a result, one
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`of ordinary skill in the art would consider the disclosure of histidine from Kornfelt
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`to reduce degradation of GLP-2 and have a reasonable expectation of success in
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`using histidine. (Ex. 1041, ¶ 81).
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`iii. There is no teaching away from Petitioner’s combinations.
`Although PO alleges there are clear teachings away from Petitioner’s
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`combinations, PO fails to provide any citations in any of the prior art references in
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`Grounds 1-4 that criticize, discredit, or otherwise discourage the subject matter of
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`the claims at issue. (Resp., 51-54; Ex. 1041, ¶ 83). For a reference to teach away,
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`there must be some disclosure criticizing, discrediting, or otherwise discouraging
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`the solution claimed; a disclosure of a number of alternatives is not enough. See In
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`Re Fulton, 391 F.3d at 1201. Therefore, PO does not rebut Petitioner’s position
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`that one of ordinary skill in the art would be motivated to combine the prior art.
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`17
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`iv. Dr. Carpenter’s statements regarding secondary structure
`are disingenuous.
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`Dr. Carpenter argued that maintaining the secondary structure of glucagon is
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`not required for the stability of glucagon in lyophilized formulations. (Resp., 45;
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`Ex. 1041, ¶ 84). Dr. Carpenter’s statements in this regard were an attempt to
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`undermine Petitioner’s rationale that one of ordinary skill in the art would be
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`motivated to stabilize GLP-2 by using the same means for stabilizing glucagon.
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`The basis for Dr. Carpenter’s position though is disingenuous.
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`For example, Dr. Carpenter cites to a reference published in 2012 to support
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`his opinion. Knowledge from 2012, however, cannot be attributed to a person of
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`ordinary skill in the art prior to December 30, 1999. (Ex. 1041, ¶ 85; Ex. 2049).
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`Bristol-Myers Squibb Company v. Teva Pharmaceuticals USA, Inc., 923 F. Supp.
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`2d 602, 661 (D. Del. 2013) (stating articles post-dating the presumed invention
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`date were not available to one of ordinary skill in the art and would not have
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`deterred one of ordinary skill in the art), aff’d, 752 F.3d 967 (Fed. Cir. 2014).
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`In direct contrast to Dr. Carpenter’s opinion, Carpenter 1996 and Carpenter
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`1997 consistently stress the importance of maintaining secondary structure in
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`lyophilized protein formulations. (Ex. 1041, ¶ 86; Ex. 1049, p. 220; Ex. 1050, pp.
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`971-972; Ex. 1043, p. 215, l. 16-p. 216, l. 10 and p. 238, ll. 2-22).
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`Further, Dr. Carpenter refers to conformational heterogenicity of glucagon
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`when formulated in solution to support his opinion. (Ex. 1041, ¶ 87). Yet, Dr.
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`18
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`Carpenter clearly understands that solution causes structural changes that
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`lyophilization seeks to avoid. (Ex. 1041, ¶ 87; Ex. 1049, pp. 199 and 200; Ex.
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`1043, p. 206, l. 16-p. 207, l. 4).
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`Dr. Carpenter refers to the Blundell reference in an attempt to show
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`conformational heterogenicity of glucagon when formulated in solution or
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`lyophilized in amorphous, non-crystalline form. (Ex. 2148, ¶ 162; Ex. 2050).
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`However, Blundell does not examine glucagon in either lyophilized or amorphous,
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`non-crystalline form, and Dr. Carpenter’s statements regarding Blundell should be
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`disregarded. (Ex. 1041, ¶ 88; Ex. 2050).
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`PO also argues that glucagon does not possess the alpha helix Dr. Palmieri
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`described it as having. (Resp., 31, 45; Ex. 2148, ¶ 108). However, Blundell
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`actually supports Dr. Palmieri’s characterization of glucagon possessing an alpha
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`helical structure because it suggests that the native form of glucagon has a helical
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`conformer induced or selected at the receptor from a population of conformers.
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`(Ex. 1041, ¶ 89; Ex. 2050, p. 54).
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`v. No support for PO’s characterization of L-histidine.
`Dr. Carpenter’s attempt to portray L-histidine as a problematic,
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`unpredictable excipient (particularly when combined with additional buffers and
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`mannitol or sucrose) is not supported by the evidence of record. (Ex. 1041, ¶ 90).
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`The evidence establishes that histidine was a well-known component in
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`19
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`protein/peptide formulations prior to December 1999, and conferred advantageous
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`properties. A person of ordinary skill in the art thus would be motivated to employ
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`histidine in a GLP-2 formulation with a reasonable expectation of success. (Ex.
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`1041, ¶¶ 96-100; section II.H.ii., supra)
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`Dr. Carpenter relies on references published after December 30, 1999, in an
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`effort to show histidine does not confer sufficient stabilization for a commercially
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`successful human medicine containing a protein or peptide drug. (Ex. 1041, ¶ 91;
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`Ex. 2060; Ex. 2061). Likewise, Dr. Carpenter cites a post-dated reference to argue
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`that histidine is susceptible to oxidation and promotes oxidation of proteins and
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`peptides. (Ex. 1041, ¶ 92; Ex. 2052). Attempting to inject post-dated references
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`such as these is improper and cannot be used to contradict the knowledge of a
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`person of ordinary skill in the art as of the priority date of the ’886 patent. Bristol-
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`Myers, 923 F. Supp. 2d at 661.
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`I. No evidence of secondary considerations.
`i. PO does not demonstrate unexpected results.
`PO incorrectly labels the data in Figures 2-6 of the ’886 patent as surprising
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`and unexpected results. (Resp., 40-43; Ex. 2148, ¶¶ 148-151). The results in
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`Figures 2-6 are not surprising or unexpected, and they are not commensurate in
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`scope with the claims at issue. (Ex. 1041, ¶¶ 106-126). PO’s arguments rely on a
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`flawed interpretation of Kornfelt, the claims, and the results.
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`20
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`Regarding Figure 2, PO argues histidine stabilizing GLP-2 at physiological
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`pH is unexpected in view of Kornfelt. (Resp., 40, 41). PO incorrectly disregards
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`Kornfelt’s disclosure of a pH of 1-7 and focuses on a pH 2.8 providing a minimum
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`glucagon decomposition rate despite the claims at issue not including any such
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`stability limitation. (Ex. 1041, ¶ 107).
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`Regarding Figure 3, PO argues mannitol- and sucrose-containing
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`formulations having better stability than those containing trehalose, maltose, and
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`lactose is unexpected in view of Kornfelt. (Resp., 41). Regarding Figure 4, PO
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`argues that the histidine/mannitol formulation is superior to the histidine/lactose
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`formulation is unexpected in view of Kornfelt. (Resp., 41, 42). Regarding Figures
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`5 and 6, PO argues that the histidine/mannitol formulation is superior to the
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`histidine/sucrose and lysine/mannitol formulations is unexpected in view of
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`Kornfelt. (Resp., 42-43). For the arguments regarding Figures 3-6, PO