Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 28
`Entered: October 23, 2015
`
`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.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`Tel: 571-272-7822
`
`
`
`
`Paper 28
`Entered: October 23, 2015
`
`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.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`IPR2015-00990
`Patent 7,056,886 B2
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`I. INTRODUCTION
`
`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.”).
`Upon consideration of the above-mentioned Petition and Preliminary
`Response, we conclude that Petitioner has established that there is a
`reasonable likelihood that it will prevail with respect to at least one of the
`challenged claims. We institute an inter partes review as to claims 46−52
`and 61−75 of the ’886 patent.
`
`A. Related Proceedings
`The parties inform us of no related litigation between them involving
`the ’886 patent. Pet. 4; Paper 5. Concurrent with the filing of the present
`Petition, Petitioner also filed a different Petition requesting inter partes
`review of claims 1−45 of the ’886 patent (IPR2015-01093).
`
`B. The ’886 Patent (Ex. 1001)
`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 disclosed 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 further comprise a phosphate
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`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;
`(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.
`
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`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,
`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.
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`D. Asserted Grounds of Unpatentability
`
`Petitioner challenges claims 46−52 and 61−75 of the ’886 patent on
`the following grounds. Pet. 20–57.
`Ground
`References
`
`1
`
`2
`
`3
`
`§ 103(a)
`
`§ 103(a)
`
`4
`
`Petitioner relies also on the Declaration of Dr. Anthony Palmieri III,
`Ph.D., R.Ph., in support of the proposed grounds of unpatentability.
`Ex. 1001 (“Palmieri Declaration” or “Palmieri Decl.”).
`
`§ 103(a)
`
`
`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 Osterberg et al., Physical state of L-histidine after freeze-drying and long-
`term storage, 8 EP. J. OF PHARM. SCI. 301−308 (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 Munroe et al., Prototypic G-protein coupled receptor for the
`intestinotrophic factor glucagon-like peptide 2, 96 PROC. NAT’L ACAD.
`SCI. 1569–1573 (1999). Ex. 1022 (“Munroe”).
`
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`Basis
`Drucker ’379,1 Kornfelt,2 Osterberg3 § 103(a)
`Drucker ’600,4 Kornfelt, Osterberg,
`and Holthuis5
`Drucker ’379, Kornfelt, Osterberg,
`and Munroe6
`Drucker ’600, Kornfelt, Osterberg,
`Holthuis, and Munroe
`
`Claim[s] challenged
`46−50, 52, 69−75
`
`61−67
`
`51, 75
`
`68
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`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); see also Office Patent Trial Practice Guide, 77 Fed. Reg.
`48,756, 48,766 (Aug. 14, 2012); In re Cuozzo Speed Techs., LLC, 793 F.3d
`1268, 1278–79 (Fed. Cir. 2015) (“Congress implicitly approved the broadest
`reasonable interpretation standard in enacting the AIA,”7 and “the standard
`was properly adopted by PTO regulation.”). Under the broadest reasonable
`construction standard, claim terms are 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).
`We determine that no explicit construction of any specific claim term
`is necessary to determine whether to institute a trial in this case. See, e.g.,
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`
`
`7 The Leahy-Smith America Invents Act, Pub. L. No. 112−29, 125 Stat. 284
`(2011) (“AIA”).
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`(“[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)). At this stage of the proceeding, we
`have not made a final determination as to the construction of any claim term.
`
`B. Principles of Law
`An inter partes review may be instituted only if “the information
`presented in the [Petition and Preliminary Response] shows that there is a
`reasonable likelihood that the petitioner would prevail with respect to at least
`1 of the claims challenged in the petition.” 35 U.S.C. § 314(a). 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). A patent
`may not be obtained if the differences between the subject matter sought to
`be patented and the prior art are such that the subject matter as a whole
`would have been obvious at the time the invention was made to a person
`having ordinary skill in the art to which the subject matter pertains. 35
`U.S.C. § 103(a). The question of obviousness is resolved on the basis of
`underlying factual determinations, including: (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
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`nonobviousness, i.e., secondary considerations. See Graham, 383 U.S. at
`17–18.
`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
`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 (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 v. John Deere Co., 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).
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`Such a conclusion, however, requires the finding of a nexus to
`establish that the evidence relied upon traces its basis to a novel element in
`the claim and not to something in the prior art. Institut Pasteur & Universite
`Pierre et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013).
`All types of objective evidence of nonobviousness must be shown to have a
`nexus. In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (nexus
`generally); In re Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011) (unexpected
`results); In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (commercial
`success); Rambus Inc. v. Rea, 731 F.3d 1248, 1256 (Fed. Cir. 2013) (long-
`felt need).
`Objective evidence of nonobviousness also must be reasonably
`commensurate in scope with the claim. In re Kao, 639 F.3d at 1068. This
`does not mean that the proffered evidence must reach every embodiment
`within the scope of the claim, so long as there is an “adequate basis to
`support the conclusion that other embodiments falling within the claim will
`behave in the same manner.” Id.
`We analyze the instituted grounds of unpatentability in accordance
`with the above-stated principles.
`
`C. Asserted Grounds of Unpatentability
`
`1. Scope and Content of the Prior Art
`a. 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
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`GLP-2 analogs have intestinotrophic activity. Id. at 2:20−23, 15:1−35. The
`analog h(Gly2)GLP-2 is disclosed. Id. at 6:52−55.
`Drucker ’379 discloses 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.
`
`b. 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
`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 giving
`an optimum stabilization. Id. at 2:58−60.
`
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`c. 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 stabilizer.” Id. at 301, 307.
`Osterberg discloses that:
`
`Freeze 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 crystallization of L-histidine. The reduced
`tendency for crystallization of L-histidine is very important in
`the formulation design. . . .
`Id. at 304.
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`d. Summary of Munroe (Ex. 1022)
`Munroe discloses an assay for the screening and identification GLP-2
`analogs that uses a cell line that expresses the GLP-2 receptor. Ex. 1022,
`1570−1571, 1573, Table 2.
`
`e. 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 the 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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`f. Summary of Drucker ’600 (Ex. 1028)
`Drucker ’600 discloses a package (or kit) containing GLP-2 or a GLP-
`2 analog in lyophilized form and “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 discloses use of
`the h(Gly2)GLP-2 analog. Id. at 31:5−11.
`
`2. 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
`would have been obvious over 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. Id. at 25 (citing Ex.
`1029, 6:52−55; Ex. 1001 ¶ 67). Petitioner further contends that Drucker
`’379 discloses a pharmaceutical composition comprising a GLP-2 analog
`within the range of “about 0.1 to about 50 mg/ml of a GLP-2 peptide or an
`analog thereof” required by claim 46. Id. at 23−24 (citing Ex. 1029,
`3:23−27, 11:22−26, 13:8−33; Ex.1001 ¶¶ 49−51). Petitioner further relies
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`on Drucker ’379 for the use of phosphate buffered saline to buffer the
`formulation at a physiologically tolerable pH, thus, meeting element (b) of
`claims 46 and 52. Id. at 28−29 (citing Ex. 1029, 13:8−33).
`With regard to independent claim 69, Petitioner contends 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 ¶¶ 110−115). Drucker ’379 further
`discloses GLP-2 formulations administered by injection or infusion. Id. at
`27 (citing Ex. 1029, 9:43−51, 13:8−33; Ex. 1001 ¶¶ 153−154).
`The formulation of Drucker ’379 does not include L-histidine. For
`this claim element, 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). 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 claim 46. Id. at 24−25 (citing Ex. 1027, 2:65−67; Ex.
`1001 at ¶ 63); 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.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
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`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 (citing Ex. 1027, 2:43−57; Ex. 1030,
`301; Ex. 1001 ¶¶ 37, 65). 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 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” (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 GLP-2
`analogs. Id. at 27 (citing Ex. 1022, 1570−73, Table 2; Ex.1001 ¶¶ 76−77).
`In support of its assertion that those claims would have been obvious,
`Petitioner sets forth the foregoing teachings of Drucker ’379, Kornfelt,
`Osterberg, and Munroe and provides a detailed claim chart explaining how
`each claim limitation is disclosed in the combination of references. Pet.
`22−37. Petitioner contends that one would have had a reason to combine the
`teachings of Drucker ’379 and Munroe disclosing GLP-2 analog and
`buffered pharmaceutical formulations, with Osterburg and Kornfelt, because
`Osterburg and Kornfelt disclosed 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, Inc. v. Apotex, Inc., 480 F.3d 1348
`(Fed. Cir. 2007); Ex.1001 ¶ 91); 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.
`
`3. Grounds 2 and 4: Obviousness of Claims 61−68 over the
`Combination of Drucker ’600, Kornfelt, Osterberg,
`Holthuis, and Munroe
`
`In Ground 2, Petitioner contends that claims 46−50, 52, and 69−75
`would have been obvious over the combination of Drucker ’600, Kornfelt,
`Osterberg, and Holthuis. Pet. 37−49.
`Petitioner contends that all limitations of the challenged claims where
`known in the art. Id. With regard to independent claim 61, 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 ¶¶ 161−162). Petitioner contends that Drucker ’600 also discloses
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`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 ¶¶ 164−167). Petitioner contends that the package of Drucker ’600
`includes a label instructing use. Id. at 38−39 (Ex. 1028, 21:15−30; Ex. 1001
`¶ 182). 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. Id. at 38−40 (Ex. 1027, 2:20−50; Ex.
`1030, 307; Ex. 1001 ¶ 169).
`In Ground 4, Petitioner contends that Drucker ’600 discloses a
`lyophilized GLP-2 formulation containing the GLP-2 analog required in
`claim 68. Id. at 40 (citing Ex. 1028, 31:5−11, 30:30−31:1; Ex.1022, 1573,
`Table 2; Ex. 1001 ¶¶ 203−205).
`In support of its assertion that claims 61−68 would have been obvious,
`Petitioner sets forth the foregoing teachings of Drucker ’600, Kornfelt,
`Osterberg, Holthuis, and Munroe and provides a detailed claim chart
`explaining how each claim limitation is disclosed in the cited references.
`Pet. 40−49. 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 Osterburg and
`Kornfelt, because Osterburg 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
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`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;
`Ex.1001 ¶ 91); 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.
`
`4. Patent Owner’s Contentions and Analysis
`a. Petition Fails to Articulate Sufficient Motivation to
`Combine the References or Establish a Reasonable
`Expectation of Success
`
`Patent Owner contends that the Petition does not adequately address
`the differences between glucagon and GLP-2 and, thus, “it would not be
`predictable that each could interact similarly or could be stabilized in
`formulation by L-histidine.” Prelim. Resp. 20−26. For example, Patent
`Owner argues that glucagon (the peptide disclosed in Drucker ’379) and
`GLP-2 “share almost no biochemical properties, are processed differently
`from proglucagon in different tissues, and perform entirely different
`functions.” Id.
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`We note the differences between glucagon and GLP-2 identified by
`Patent Owner (id.), and also note the similarities between GLP-2 and other
`protein drugs identified by Petitioner (Pet. 16−18). At this stage of the case,
`however, we find that Petitioner has offered sufficient evidence to institute
`trial. The information relied upon in the Petition tends to suggest that L-
`histidine has a stabilizing effect on peptide drugs generally, indicating that
`properties of peptides affecting L-histidine association (and, therefore,
`peptide stabilization) are relevant in a manner distinct from properties of
`peptides affecting biological activity of the peptides. Ex. 1027; Ex. 1030;
`Ex. 1001 ¶¶ 37, 48, 55, 83, 93−97.
`Patent Owner also argues that:
`
`Petitioner ignores that peptide stabilization is far from routine
`or predictable. There are many factors that can cause
`destabilization and degradation.
`Prelim. Resp. 23 (citing Ex. 2039). As indicated above, at this stage of the
`case, we find Petitioner has shown sufficiently that a person of ordinary skill
`in the art would have had a reasonable expectation of success in formulating
`GLP-2 in combination with L-histidine and sucrose or mannitol to create a
`lyophilized storage stable formulation in view of the guidance set forth in
`the prior art. Ex. 1027; Ex. 1030; Ex. 1001 ¶¶ 37, 48, 55, 83, 93−97; see In
`re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (stating that a reasonable
`expectation of success does not require absolute predictability). We note
`that at this stage of the proceeding, we have not made a final determination
`as to the patentability of any one of the challenged claims.
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`(1) Secondary Considerations
`Patent Owner contends that secondary considerations support a
`finding of nonobviousness of the claims. Prelim. Resp. 27. Specifically,
`Patent Owner contends that GATTEX®, a commercial formulation of the
`claims, met a long felt need and is a commercial success.
`At this stage of the proceeding, we are not persuaded for the reasons
`discussed below.
`
`i. Long-Felt Need
`Among the secondary considerations that must be considered is the
`existence of a long-felt but unsolved need. Graham, 383 U.S. at 17–18.
`Patent Owner, however, does not present sufficient evidence of long-felt
`need, but instead relies on argument and conclusory contentions, which we
`find insufficient to indicate non-obviousness of the challenged claims.
`Prelim. Resp. 27; Ex. 1001 ¶ 92; Ex. 1024, 2.8 For example, Patent Owner
`does not provide evidence sufficient to permit a determination as to whether
`the long-felt need was met by the discovery of GLP-2 analogs having the
`necessary activity (disclosed in the prior art), or the use of L-histidine and
`mannitol or sucrose in a stabilized GLP-2 analog formulation. As such, the
`record before us does not sufficiently indicate that the claimed subject matter
`itself satisfied a long-felt need. See Texas Instruments v. U.S. Int’l Trade
`Comm’n, 988 F.2d 1165, 1178 (Fed.Cir.1993) (“[L]ong-felt need is analyzed
`as of the date of an articulated identified problem and evidence of efforts to
`
`8 Cleland et al., Formulation and Delivery of Proteins and Peptides,
`AMERICAN CHEMICAL SOCIETY, Washington D.C., Chapter 1 (1994).
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`solve that problem.”); Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d
`1317, 1325 (Fed. Cir. 2004) (“Absent a showing of long-felt need or the
`failure of others, the mere passage of time without the claimed invention is
`not evidence of nonobviousness.”); accord In re Wright, 569 F.2d 1124,
`1127 (CCPA 1977).
`
`ii. Commercial Success
`A showing of nexus between commercial success and claimed subject
`matter involves establishing that novel elements in the claim, not prior art
`elements, account for the objective evidence put forward to show
`nonobviousness. In re Kao, 639 F.3d at 1068.
`Patent Owner states that:
`
`The nexus between the sale of GATTEX® and the challenged
`claims is self-evident. Stabilization of the GLP-2 analog, which
`was difficult, allows GATTEX® to have a sufficient shelf life
`for commercialization.
`Prelim. Resp. 27 (citing Ex. 2039).
`As discussed above, however, GLP-2 formulations buffered with
`phosphate buffered saline were known in the prior art. Pet. 24 (citing Ex.
`1029, 13:27−33; Ex. 1001 ¶ 54). We cannot tell from the record before us if
`the asserted commercial success was due to the sale of a buffered
`formulation comprising GLP-2 generally, as compared to a buffered GLP-2
`formulation comprising L-histidine and mannitol or sucrose, as recited in the
`challenged claims. Thus, there is insufficient information on the current
`record to establish sufficient nexus
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