Trials@uspto.gov
`571.272.7822
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`Paper No. 68
`Filed: October 21, 2016
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`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.
`____________
`
`Cases IPR2015-00990
`Patent 7,056,886 B2
`_______________
`
`Before LORA M. GREEN, JACQUELINE WRIGHT BONILLA, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`571.272.7822
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`
`
`
`
`Paper No. 68
`Filed: October 21, 2016
`
`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.
`____________
`
`Cases IPR2015-00990
`Patent 7,056,886 B2
`_______________
`
`Before LORA M. GREEN, JACQUELINE WRIGHT BONILLA, and
`SHERIDAN K. SNEDDEN, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
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`IPR2015-00990
`Patent 7,056,886 B2
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`I. INTRODUCTION
`
`1
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`2
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`3
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`§ 103(a)
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`61−67
`
`§ 103(a)
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`51, 75
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`1 Drucker et al., U.S. Patent No. 5,789,379, issued August 4, 1998 (Ex.
`1029) (“Drucker ’379”).
`2 Kornfelt et al., U.S. Patent No. 5,652,216, issued July 29, 1997 (Ex. 1027)
`(“Kornfelt”).
`3 Thomas Osterberg & Tommy Wadsten, Physical state of L-histidine after
`freeze-drying and long-term storage, 8 EP. J. OF PHARM. SCI. 301−08
`(1999) (Ex. 1030) (“Osterberg”).
`4 Drucker et al., PCT Publication WO 98/52600, published November 26,
`1988 (Ex. 1028) (“Drucker ’600”).
`5 Holthuis et al., U.S. Patent No. 5,496,801, issued March 5, 1996 (Ex. 1005)
`(“Holthuis”).
`6 Donald G. Munroe et al., Prototypic G-protein coupled receptor for the
`intestinotrophic factor glucagon-like peptide 2, 96 PROC. NAT’L ACAD.
`SCI. USA 1569–73 (1999) (Ex. 1022) (“Munroe”).
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`Coalition for Affordable Drugs II LLC (“Petitioner”) filed a Petition
`to institute an inter partes review of claims 46−52 and 61−75 (Paper 1,
`“Pet.”) of U.S. Patent No. 7,056,886 B2 (Ex. 1003, “the ’886 patent”). NPS
`Pharmaceuticals, Inc. (“Patent Owner”) filed a Patent Owner Preliminary
`Response. Paper 19 (“Prelim. Resp.”).
`Based on these submissions, we instituted trial on the following
`grounds of unpatentability asserted by Petitioner:
`Ground
`References
`Drucker ’379,1 Kornfelt,2
`Osterberg3
`Drucker ’600,4 Kornfelt,
`Osterberg, and Holthuis5
`Drucker ’379, Kornfelt,
`Osterberg, and Munroe6
`
`46−50, 52, 69−75
`
`Basis Claim[s] challenged
`
`§ 103(a)
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`Ground
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`4
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`References
`Drucker ’600, Kornfelt,
`Osterberg, Holthuis, and
`Munroe
`
`Basis Claim[s] challenged
`
`§ 103(a)
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`68
`
`Decision to Institute (Paper 28, “Dec.”).
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 33, “PO Resp.”), to which Petitioner filed a Reply (Paper 42, “Pet.
`Reply”).
`Petitioner relies on the Declarations of Anthony Palmieri III, Ph.D.,
`R.Ph. (Exs. 1001, 1041) and Ivan T. Hoffmann (Ex. 1042) in support of the
`proposed grounds of unpatentability.
`Patent Owner relies on the Declarations of John F. Carpenter, Ph.D.
`(Ex. 2040; redacted version Ex. 2148) and Gordon Rausser, Ph.D. (Ex.
`2041; redacted version Ex. 2149).
`Patent Owner filed a motion to exclude certain of Petitioner’s
`evidence. Paper 51. Petitioner filed an opposition (Paper 55), and Patent
`Owner filed a reply (Paper 59).
`Oral argument was conducted on June 23, 2016. A transcript is
`entered as Paper 67 (“Tr.”).
`This Final Written Decision is entered pursuant to 35 U.S.C. § 318(a).
`We conclude for the reasons that follow that Petitioner has shown by a
`preponderance of the evidence that claims 46−52 and 61−75 of the ’886
`patent are unpatentable.
`
`A. Related Proceedings
`Petitioner also filed a different Petition requesting inter partes review
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`of claims 1−45 of the ’886 patent (IPR2015-01093). We also instituted inter
`partes review in IPR2015-01093, and issue a final decision therein
`concurrently with this Final Written Decision.
`
`B. The ’886 Patent (Ex. 1003)
`The ’886 patent discloses L-histidine stabilized drug formulations of
`glucagon-like peptide-2 (“GLP-2”) and GLP-2 analogs. Ex. 1003, Abstract.
`The ’886 patent discloses that the GLP-2/GLP-2 analog formulations of the
`invention exhibit “superior stability following storage and/or exposure to
`elevated temperatures.” Id. The formulations comprise a phosphate buffer,
`L-histidine (as a stabilizing amino acid), and mannitol or sucrose (as a
`bulking agent). Id. at 2:7−27.
`The GLP-2 analogs may be agonists or antagonists. Id. at 4:19−31.
`“[A]ntagonists of GLP-2 analogs include any mutation or variation of the
`naturally occurring GLP-2 peptide which results in the inhibition of
`intestinotrophic activity of naturally occurring GLP-2 or GLP-2 analogs
`which exhibit agonist acitivity [sic].” Id. at 4:61−67. The GLP-2 analog
`known as “h[Gly2]GLP-2” is specifically disclosed. Id. at 5:21−32.
`
`C. Illustrative Claims
`Independent claims 46, 52, 61, and 69 are representative of the
`challenged claims, and are reproduced below:
`46. A GLP-2 formulation comprising:
`(a) about 0.1 to about 50 mg/ml of a GLP-2 peptide or an
`analog thereof;
`(b) a phosphate buffer in an amount sufficient to adjust the
`pH of the formulation to a pharmaceutically tolerable level;
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`(c) about 0.5 to about 1% L-histidine; and
`(d) about 2 to about 5% mannitol.
`
`52. A GLP-2 formulation comprising:
`(a) a medically useful amount of a naturally occurring
`GLP-2 peptide or an analog thereof;
`(b) a phosphate buffer in an amount sufficient to adjust the
`pH of the formulation to a physiologically tolerable level;
`(c) L-histidine in an amount sufficient to stabilize the
`formulation; and
`(d) a bulking agent selected from the group consisting of
`mannitol and sucrose.
`
`61. A kit comprising:
`(a) a lyophilized GLP-2 formulation comprising:
`(i) a GLP-2 peptide or an analog thereof;
`(ii) a phosphate buffer in an amount sufficient to adjust
`the pH of the formulation to a pharmaceutically
`acceptable level;
`(iii) L-histidine; and
`(iv) a bulking agent selected from the group consisting
`of mannitol and sucrose;
`(b) a vial of sterile water for reconstitution; and
`(c) instructions directing reconstitution.
`
`69. A method for treating a human or animal having a
`gastrointestinal disorder, disease or condition for which
`treatment with GLP-2 is indicated, the method comprising the
`step of administering a therapeutically effective amount of a
`GLP-2 formulation comprising:
`(a) a GLP-2 peptide or an analog thereof;
`(b) a phosphate buffer in an amount sufficient to adjust the
`pH of the formulation to a pharmaceutically tolerable level;
`(c) L-histidine; and
`(d) a bulking agent selected from the group consisting of
`mannitol and sucrose,
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`thereby enhancing, maintaining, or promoting the growth
`or functioning of the gastrointestinal tract.
`
`Claims 47−51 depend from claim 46, directly or indirectly. Claims
`62−68 depend from claim 61, directly or indirectly. Claims 70−75 depend
`from claim 69, directly or indirectly.
`
`II. ANALYSIS
`A. Claim Interpretation
`We interpret claims using the “broadest reasonable construction in
`light of the specification of the patent in which [they] appear[].” 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142–46
`(2016). Under the broadest reasonable construction standard, claim terms
`are generally given their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art at the time of the invention. In
`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent
`claim language carrying a narrow meaning, the PTO should only limit the
`claim based on the specification . . . when [it] expressly disclaim[s] the
`broader definition.” In re Bigio, 381 F.3d 1320, 1325 (Fed Cir. 2004).
`“Although an inventor is indeed free to define the specific terms used to
`describe his or her invention, this must be done with reasonable clarity,
`deliberateness, and precision.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`1994).
`Based upon the facts presented, we determine that the explicit
`construction of any specific claim term is unnecessary to reach our decision
`in this case. See, e.g., Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355,
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`1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the extent
`necessary to resolve the controversy.’”) (quoting Vivid Techs., Inc. v. Am.
`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`
`B. Principles of Law
`To prevail in its challenges to the patentability of the claims, a
`petitioner must establish facts supporting its challenges by a preponderance
`of the evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`Obviousness is a question of law based on underlying determinations
`of fact. Graham v. John Deere Co., 383 U.S. 1, 17 (1966); Richardson-
`Vicks, Inc. v. Upjohn Co., 122 F.3d. 1476, 1479 (Fed. Cir. 1997). The
`underlying factual determinations include: (1) the scope and content of the
`prior art; (2) any differences between the claimed subject matter and the
`prior art; (3) the level of skill in the art; and (4) objective evidence of
`nonobviousness, i.e., secondary considerations. See Graham, 383 U.S. at
`17–18. Subsumed within the Graham factors are the requirements that all
`claim limitations be found in the prior art references and that the skilled
`artisan would have had a reasonable expectation of success in combining the
`prior art references to achieve the claimed invention. Pfizer, Inc. v. Apotex,
`Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007). “Obviousness does not require
`absolute predictability of success . . . all that is required is a reasonable
`expectation of success.” In re O’Farrell, 853 F.2d 894, 903–4 (Fed. Cir.
`1988).
`In KSR Int’l Co. v. Teleflex Inc., the Supreme Court stated that an
`invention may be found obvious if trying a course of conduct would have
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`been obvious to a person having ordinary skill:
`
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`550 U.S. 398, 421 (2007). “KSR affirmed the logical inverse of this
`statement by stating that § 103 bars patentability unless ‘the improvement is
`more than the predictable use of prior art elements according to their
`established functions.’” In re Kubin, 561 F.3d 1351, 1359–60 (Fed. Cir.
`2009) (citing KSR, 550 U.S. at 417).
`The factual inquiries for an obviousness determination also include
`secondary considerations based on evaluation and crediting of objective
`evidence of nonobviousness. Graham, 383 U.S. at 17. Notwithstanding
`what the teachings of the prior art would have suggested to one with
`ordinary skill in the art at the time of the invention, the totality of the
`evidence submitted, including objective evidence of nonobviousness, may
`lead to a conclusion that the claimed invention would not have been obvious
`to one with ordinary skill in the art. In re Piasecki, 745 F.2d 1468, 1471–72
`(Fed. Cir. 1984). We acknowledge also that “there is a presumption of
`nexus for objective considerations when the patentee shows that the asserted
`objective evidence is tied to a specific product and that product ‘is the
`invention disclosed and claimed in the patent.” WBIP, LLC v. Kohler Co.,
`829 F.3d 1317, 1329 (Fed. Cir. 2016) (quoting J.T. Eaton & Co. v. Atl. Paste
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`& Glue Co., 106 F.3d 1563, 1571 (Fed.Cir.1997)). That presumption may
`be rebutted, however, if there is evidence “that shows that the proffered
`objective evidence was ‘due to extraneous features other than the patented
`invention.’” Id. (quoting Demaco Corp/ v. F. Von Langsdorff Licensing
`Ltd., 821 F.2d 1387, 1393 (Fed. Cir. 1988).
`We analyze the instituted grounds of unpatentability in accordance
`with the above-stated principles.
`
`C. Scope and Content of the Prior Art
`
`1. Summary of Drucker ’379 (Ex. 1029)
`
`Drucker ’379 discloses pharmaceutical compositions comprising a
`therapeutically effective amount of a GLP-2 analog. Ex. 1029, 3:23–27.
`The GLP-2 analogs have intestinotrophic activity. Id. at 2:20−23, 15:1−35.
`The analog (Gly2)hGLP-2 is disclosed. Id. at 6:52−55.
`Drucker ’379 discloses GLP-2 formulations for injection buffered to
`physiologically tolerable pH. Id. at 9:35−56. Phosphate buffered saline is
`disclosed as a suitable buffer. Id. at 13:8–33. The GLP-2 formulations may
`be provided in lyophilized form. Id. at 10:25−33.
`Drucker ’379 further discloses that the glucagon gene “yields a tissue-
`determined variety of peptide products that are processed from the 160
`residue proglucagon product,” which include glucagon, glicentin, and the
`two glucagon-like peptides, GLP-1 and GLP-2. Id. at 1:17−27.
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`2. Summary of Osterberg (Ex. 1030)
`Osterberg discloses that “[p]rotein drugs are generally chemically and
`physically unstable in solution and freeze-drying is frequently used to
`obtain an acceptable shelf life.” Ex. 1030, 301. Osterberg further discloses
`that the “selection of buffer for a protein formulation is very important.” Id.
`at 303. In this context, Osterberg discloses that “[s]ugars and amino acids
`protect the protein by preferential exclusion during freezing and by glass
`formation and/ or by functioning as a water substitute in the dried state.” Id.
`Osterberg teaches that amino acids may act as both a stabilizer and buffer,
`and highlights L-histidine as one such “multifunctional protein stabili[z]er.”
`Id. at 301, 307.
`Osterberg discloses that “[f]reeze drying of L-histidine from solutions
`having a pH in the range 4–8 showed that L-histidine has a rather low
`tendency to crystallize during freeze drying.” Id. at 305.
`Osterberg further discloses that:
`
`Another important observation was that the addition of sucrose
`abolished the crystalli[z]ation of L-histidine. The reduced
`tendency for crystalli[z]ation of L-histidine is very important in
`the formulation design.
`Id. at 304.
`
`3. Summary of Kornfelt (Ex. 1027)
`Kornfelt discloses stabilized pharmaceutical compositions comprising
`glucagon and a stabilizing amount of a pharmaceutically acceptable
`ampholyte, such as histidine. Ex. 1027, 2:21−44. The histidine may be
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`present in an amount from 0.01 to 50 micromoles per mg glucagon in order
`to obtain the desired stabilization. Id. at 2:20−53 and 2:65−67.
`The pharmaceutical compositions may also include an “excipient, e.g.
`for facilitating the lyophilization and rapid and complete redissolution
`thereof when reconstituting the preparation before use.” Id. at 2:45–53.
`Such excipients include mannitol and sucrose. Id. The excipient may be
`present in an amount of from 10 to 600 micromoles per mg glucagon to give
`an optimum stabilization. Id. at 2:58−60.
`
`4. Summary of Munroe (Ex. 1022)
`Munroe discloses an assay for the screening and identification of
`GLP-2 analogs, wherein the assay uses a cell line that expresses the GLP-2
`receptor. Ex. 1022, 1570−71, 1573, Table 2. Munroe discloses that [Gly-
`2]Glp-2 binds to the GLP-2 receptor and has intestinotrophic activity. Id. at
`1573 (Table 2); Ex. 1001 ¶ 36.
`
`5. Summary of Drucker ’600 (Ex. 1028)
`Drucker ’600 discloses a package (or kit) containing GLP-2 or a GLP-
`2 analog in lyophilized form that is “suitable for reconstitution in a suitable
`carrier, such as phosphate-buffered saline.” Ex. 1028, 21:26−30, 19:25−36,
`21:26−30, 45:35−46:13. The package provides a label instructing use. Id. at
`21:15−30.
`Drucker ’600 discloses that lyophilized GLP-2 formulations can be
`administered by injection. Id. at 19:25−33. Drucker ’600 also discloses the
`use of the h(Gly2)GLP-2 analog. Id. at 31:5−11.
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`6. Summary of Holthuis (Ex. 1005)
`Holthuis relates to freeze-dried “preparations containing parathyroid
`hormone that has been stabilized with an excipient and buffering agent.”
`Ex. 1005, Abstract, 6:6−58. “Preferred preparations incorporate human
`PTH(1−84), mannitol as excipient and citrate as buffering agent, and are
`incorporated in vials as a freeze-dried powder for reconstitution to treat
`osteoporosis.” Id. at Abstract. Holthuis discloses that the reconstituted PTH
`preparations according to its invention are stable. Specifically, Holthuis
`discloses as follows:
`
`reconstituted PTH
`the
`analysis of
`SDS-PAGE
`preparations, performed in the conventional manner, similarly
`revealed no significant decrease of purity during storage at either
`pH, temperature and storage temperatures examined, as shown
`in FIG. 2. Some decrease in purity was revealed by RP-HPLC
`analysis of the reconstituted formulation, but only at the higher
`37° C. storage temperature (0.7% decrease in purity per month
`of storage), with 4° C. storage showing no significant purity
`decrease by reversed phase-HPLC analysis. The stability of the
`intact PTH was also revealed by immunoassay (Allegro) to be
`constant throughout the storage period at all concentrations, pHs
`and temperatures evaluated.
`Id. at 7:6−18.
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`D. Patentability Analysis
`
`1. Petitioner’s Asserted Grounds of Unpatentability
`
`a. Grounds 1 and 3: Obviousness of Claims 46−52, and
`69−75 over the Combination of Drucker ’379,
`Kornfelt, Osterberg, and Munroe
`
`In Ground 1, Petitioner contends that claims 46−50, 52, and 69−75
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`would have been obvious over the combination of Drucker ’379, Kornfelt,
`and Osterberg. Pet. 22−37. In support of its assertion that those claims
`would have been obvious, Petitioner provides a detailed discussion and
`claim chart explaining how each claim limitation is disclosed by the
`combination of Drucker ’379, Kornfelt, and Osterberg. Pet. 22−37.
`With regard to independent claims 46 and 52, Petitioner contends that
`Drucker ’379 discloses the recited GLP-2 peptide analogs. Pet. 22−23
`(citing Ex. 1029, 3:23−27, 9:43−47, 13:8−33; Ex. 1001 ¶¶ 50, 52, 57−59,
`78−88). In particular, Petitioner contends that Drucker ’379 specifically
`discloses the h(Gly2)GLP-2 analog, as recited in dependent claims 47–50
`and 72 (and dependent claims 64, discussed ahead in relation to Grounds 2
`and 4). Id. at 25 (citing Ex. 1029, 6:52−55). Petitioner further contends that
`Drucker ’379 discloses a pharmaceutical composition comprising a GLP-2
`analog within the recited range of “about 0.1 to about 50 mg/ml of a GLP-2
`peptide or an analog thereof,” as required by element (a) of claim 46. Id. at
`23−24 (citing Ex. 1029, 3:23−27, 11:22−26, 13:8−33; Ex. 1001 ¶¶ 49−51).
`Petitioner contends that Drucker ’379 describes GLP-2 analogs in
`lyophilized form, as required in dependent claim 48 (and claim 61, discussed
`ahead in relation to Grounds 2 and 4). Id. at 25, 31 (citing Ex. 1029, 10:25–
`33; Ex. 1001 ¶ 146). Petitioner further relies on Drucker ’379 as disclosing
`the use of phosphate buffered saline to generate from powder an injectable
`formulation at a physiologically tolerable pH, alleging that this disclosure
`meets element (b) of claims 46 and 52. Id. at 28−29 (citing Ex. 1029,
`13:8−33).
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`With regard to independent claim 69, Petitioner contends that Drucker
`’379 discloses administering a GLP-2 formulation with a therapeutically
`effective amount of GLP-2 analog to treat gastrointestinal disease. Id. at 26
`(citing Ex. 1029 at 3:33−39; Ex. 1001 ¶¶ 110−15). According to Petitioner,
`Drucker ’379 further discloses GLP-2 formulations administered by
`injection or infusion, as required in dependent claims 73 and 74 (and claim
`65, discussed ahead in relation to Grounds 2 and 4). Id. at 27 (citing Ex.
`1029, 9:43−51, 13:8−33; Ex. 1001 ¶¶ 153−54).
`Drucker ’379 does not disclose a formulation including L-histidine,
`mannitol, or sucrose. For these claim elements, Petitioner relies on the
`teachings of Kornfelt and Osterberg. Petitioner contends that Kornfelt
`teaches L-histidine as a stabilizing amino acid useful in the formulation of
`protein drugs across a broad range of pH levels (pH 1−7). Id. at 23 (citing
`Ex.1027, 3:9−11; Ex. 1001 ¶¶ 73, 101). Further, with regard to claims 49,
`50, 70 and 71, Petitioner contends that Drucker ’379 teaches the pH of the
`GLP-2 formulation as “slightly acidic or physiological pH.” Id. at 31 (citing
`Ex. 1029 at 9:43–51).
`Petitioner further contends that Kornfelt discloses an amount of L-
`histidine per mg of peptide (i.e., glucagon) that is within the range specified
`in element (c) of claim 46. Id. at 24−25 (citing Ex. 1027, 2:65−67; Ex. 1001
`¶¶ 62–64); see Ex. 1003, claim 16 (“about 0.5 to about 1% [L-histidine]”).
`Additionally, Petitioner contends that Osterberg further supports a finding
`that L-histidine was well known as a buffer and a stabilizing agent useful in
`lyophilized pharmaceutical formulations of peptides. Id. at 23 (citing Ex.
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`1030, 305, 307; Ex. 1001 ¶¶ 73, 101).
`With regard to the use of mannitol or sucrose as a bulking agent,
`Petitioner contends that “sucrose and mannitol were both well known as
`conventional bulking agents or excipients in the art of pharmaceutical
`formulations prior to the effective filing date of the ’886 patent as described
`in Osterberg and Kornfelt.” Pet. 17–18 (citing Ex. 1027, 2:43−57; Ex. 1030,
`301; Ex. 1001 ¶¶ 37–38). Petitioner contends that Kornfelt discloses that
`“[t]he excipient is preferably present in an amount of from 10 to 600
`micromoles per mg glucagon giving an optimum stabilization,” which falls
`within the range of 2% to about 5% mannitol required by element (d) of
`claim 46. Id. at 25 (citing Ex. 1027, 2:58−60; Ex. 1001 ¶ 65). Osterberg
`discloses that sucrose abolishes the crystallization of L-histidine, which
`Osterberg notes is “very important in the formulation design.” Id. at 33
`(citing Ex. 1030, 304).
`In Ground 3, Petitioner further relies on Munroe to meet the elements
`of dependent claims 51 and 75. Pet. 27−28. Petitioner contends that
`Munroe discloses an assay for the screening and identification of GLP-2
`analogs. Id. at 27 (citing Ex. 1022, 1570−73, Table 2; Ex.1001 ¶ 151).
`Petitioner contends that one would have had a reason to combine the
`teachings of Drucker ’379 and Munroe disclosing GLP-2 analogs and
`buffered pharmaceutical formulations, with Osterberg and Kornfelt, because
`Osterberg and Kornfelt disclose the use of L-histidine in combination with
`an excipient such as mannitol or sucrose in protein formulations for the
`purposes of protein stabilization. Id. at 49−52. In particular, Petitioner
`
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`contends that because all the elements of the invention are described in the
`combined references, and because the prior art provides guidance for
`preparing storage stable lyophilized formulations for peptide formulations,
`“[t]he claimed GLP-2 formulation . . . [is] nothing more than a combination
`of known ingredients for a predictable result of stability as confirmed by
`routine testing.” Id. at 49 (citing Pfizer, 480 F.3d 1348); see also id. at 50
`(“[O]ne of ordinary skill in the art would certainly recognize that the same
`storage stable formulation can be applied to molecules structurally similar to
`glucagon like GLP-2.”). Petitioner also argues that one of ordinary skill in
`the art would have had a reasonable expectation of success in “formulating
`GLP-2 in combination with L-histidine and sucrose or mannitol to create a
`lyophilized storage stable formulation in view of the combination of
`references cited in this petition for IPR.” Id. at 52−55.
`Petitioner further argues that “[a] design need for formulating a stable
`GLP-2 formulation for therapeutic use would be recognized by a person of
`ordinary skill in the art based on FDA requirements.” Id. at 49 (citing
`Cleland7 8).
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`b. Grounds 2 and 4: Obviousness of Claims 61−68 over
`the Combination of Drucker ’600, Kornfelt,
`Osterberg, Holthuis, and Munroe
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`In Ground 2, Petitioner contends that claims 61−67 would have been
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`7 Jeffrey L. Cleland & Robert Langer, Formulation and Delivery of Proteins
`and Peptides, ACS Symposium Series; Am. Chem. Society, 1–19 (1994)
`(Chapter 1) (Washington, D.C.) (Ex. 1024) (“Cleland”).
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`obvious over the combination of Drucker ’600, Kornfelt, Osterberg, and
`Holthuis. Pet. 37−49. In support of its assertion that claims 61−67 would
`have been obvious, Petitioner provides a detailed discussion and claim chart
`explaining how each claim limitation is disclosed by the combination of
`Drucker ’600, Kornfelt, Osterberg, and Holthuis. Pet. 40−49.
`With regard to independent claims 61–67, Petitioner contends that
`Drucker ’600 discloses a package (or kit) containing GLP-2 or a GLP-2
`analog in lyophilized form. Id. at 37 (citing Ex. 1028, 21:26−30; Ex. 1001
`¶¶ 161−62). Petitioner contends that Drucker ’600 also discloses a
`lyophilized GLP-2 formulation having the phosphate buffer according to the
`claims. Id. at 38 (citing Ex. 1028, 19:25−36, 21:26−30, 45:35−46:13;
`Ex. 1001 ¶¶ 164−67). Petitioner contends that the package of Drucker ’600
`includes a label instructing use. Id. at 38−39 (citing Ex. 1028, 21:15−30;
`Ex. 1001 ¶ 182). Regarding dependent claims 62 and 63, Petitioner
`contends that Drucker ’600 teaches the pH of the GLP-2 formulation as
`“slightly acidic or physiological pH.” Id. at 45 (citing Ex. 1028 at 19:25–
`33). As with Grounds 1 and 3, discussed above, Petitioner relies on
`Osterberg and Kornfelt for the disclosure of L-histidine, sucrose, and
`mannitol in protein drug formulations to provide stability to the formulation,
`as required in dependent claims 66 and 67. Id. at 38−40, 46–47 (citing Ex.
`1027, 2:20−50; Ex. 1030, 307; Ex. 1001 ¶ 169).
`In Ground 4, Petitioner contends that claim 68 would have been
`obvious over the combination of Drucker ’600, Kornfelt, Osterberg, and
`Holthuis, and Munroe. Pet. 37–49. Petitioner contends that Drucker ’600
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`discloses a lyophilized GLP-2 formulation containing the GLP-2 analog
`required in claim 68. Id. at 40, 48–49 (citing Ex. 1028, 31:5−11,
`30:30−31:1; Ex.1022, 1573, Table 2; Ex. 1001 ¶¶ 203−5). Petitioner further
`relies on Drucker ’600 for its disclosure of “a kit including a lyophilized
`formulation of GLP-2 or GLP-2 analog and a desired carrier, as well as a
`label with instructions for use.” Id. at 52 (citing Ex. 1028, 21:15–30; Ex.
`1001 ¶¶166–173, 188–191). Petitioner relies on Munroe to establish that the
`[Gly-2]Glp-2 analog binds to the GLP-2 receptor and has the desired
`biological activity. Id. at 49 (citing Ex. 1022 at 1573, Table 2).
`
`2. Petitioner contends that one would have had a reason to
`combine the teachings of Drucker ’600 and Munroe
`disclosing GLP-2 analog and buffered pharmaceutical
`formulations, with Osterberg and Kornfelt, because
`Osterberg and Kornfelt disclose the use of L-histidine in
`combination with an excipient such as mannitol or sucrose
`in protein formulations for the purposes of protein
`stabilization. Id. at 49−52. In particular, Petitioner
`contends that because all the elements of the invention are
`described in the combined references, and because the prior
`art provides guidance for preparing storage stable
`lyophilized formulations for peptide formulations, “[t]he
`claimed GLP-2 formulation . . . [is] nothing more than a
`combination of known ingredients for a predictable result of
`stability as confirmed by routine testing.” Id. at 49 (citing
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007);
`see also id. at 50 (“[O]ne of ordinary skill in the art would
`certainly recognize that the same storage stable formulation
`can be applied to molecules structurally similar to glucagon
`like GLP-2.”). Petitioner also argues that one of ordinary
`skill in the art would have had a reasonable expectation of
`success in “formulating GLP-2 in combination with L-
`histidine and sucrose or mannitol to create a [lyophilized]
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`storage stable formulation in view of the combination of
`references cited in this petition for IPR.” Id. at
`52−55.Discussion
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`Patent Owner does not argue that the combination of references fails
`to disclose each limitation of the challenged claims. Rather, Patent Owner
`provides a detailed discussion noting the deficiencies in each of the cited
`references as compared to the subject matter encompassed by the challenged
`claims. PO Resp. 17–23, 32–40. For example, Patent Owner argues that
`i) Drucker ‘379 does not suggest any “in vitro protein/peptide stabilization
`other than simple lyophilization;” ii) “Osterberg does not disclose any
`protein/peptide formulations;” iii) “Kornfelt does not disclose degradation
`pathways of glucagon or GLP-2 or their inhibition;” and iv) “Munroe does
`not disclose stabilization of glucagon, GLP-2, or GLP-2 analog
`formulations.” Id. at 17–18, 33, 40 (citing Ex. 2040 ¶ 114). Patent Owner’s
`arguments here essentially attack the merits of each of Drucker ‘379,
`Osterberg, Kornfelt, and Munroe in isolation.
`Such arguments, however, do not persuade us that the subject matter
`of the challenged claims is nonobvious in view of Petitioner’s proposed
`combination of references, because the asserted obviousness ground is
`predicated on a combination of the teachings of these references. See In re
`Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non-obviousness
`cannot be established by attacking references individually where the
`[obviousness ground] is based upon the teachings of a combination of
`references. . . . [The reference] must be read, not in isolation, but for what it
`fairly teaches in combination with the prior art as a whole”).
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`We note that Petitioner relies on i) Drucker ’379 and Drucker ’600 for
`the disclosure of lyophilized GLP-2 and GLP-2 analog formulations (Pet. 16
`(citing Ex. 1029, 4:6–7:20, 15:1–35; Ex. 1028, 2:25–32; Ex. 1001 ¶ 35));
`ii) Osterberg for the disclosure that histidine and sugars (such as sucrose)
`may be used to stabilize lyophilized peptide formulations (id. at 17 (citing
`Ex. 1030, 301; Ex. 1001 ¶ 37); iii) Kornfelt for the disclosure that histidine
`and conventional bulking agents or excipients (such as lactose and mannitol)
`is useful to stabilize glucagon formulations (id. (citing Ex. 1027, 1:23–30;
`Ex. 1001 ¶ 37)); iv) Munroe for its disclosure of GLP-2 analogs and
`screening methods to identify analogs having the desired biological activity
`(id. at 37 (citing Ex. 1022, 1573 (Table 2))); and v) Holthuis for its
`disclosure of kits including formulations of peptides prepared for injection,
`which include a vial of water and an injection device (id. at 18 (citing Ex.
`1005, 5:28–36; Ex. 1001 ¶ 185)). Patent Owner does not dispute
`persuasively that each of Drucker ’379, Osterberg, Kornfelt, Holthuis, and
`Munroe presents the above-mentioned disclosures, as Petitioner contends.
`Accordingly, we are persuaded that Petitioner has established that
`each limitation of claims 46−50, 52, and 69−75 was known in the art, as
`evidenced by the teachings of Drucker ’379, Drucker ’600, Kornfelt,
`Osterberg, Holthuis, and Munroe. See e.g., Pet. 28–37, 40–49 (providing
`detailed charts indicating where each limitation of the challenged claims is
`disclosed or discussed in each of the references relied upon by Petitioner).
`A patent, however, “is not proved obvious merely by demonstrating
`that each of its elements was, independently, known in the prior art.” KSR,
`550 U.S. at 418. Petitioner must also show that there was a reason to
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`combine those elements to achieve the claimed invention with a reasonable
`expectation of success. PAR Pharm., Inc. v. TWI Pharm., Inc., 7
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