Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 26
`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 IPR2015-01093
`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 26
`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 IPR2015-01093
`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
`
`
`
`
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`IPR2015-01093
`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 1−45 (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 18 (“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 1−27,
`31−40, and 44−45 of the ’886 patent, but deny the Petition as to claims
`28−30 and 41−43.
`
`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 46−52 and 61−75 of the ’886 patent (IPR2015-00990). Id.
`
`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 claim 1 is illustrative of the challenged claims, and is
`reproduced below:
`1. A glucagon-like peptide 2 (GLP-2) formulation comprising:
`(a) a medically useful amount of a naturally occurring
`GLP-2 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; and
`(d) a bulking agent selected from the group consisting of
`mannitol and sucrose.
`
`
`Ex. 1003, 12:9–18.
`
`
`Claims 2−45 depend from claim 1, directly or indirectly.
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`D. Asserted Grounds of Unpatentability
`Petitioner challenges claims 1−45 of the ’886 patent on the following
`ground. Pet. 21–55.
`Ground
`
`Basis
`
`Claims challenged
`
`§ 103(a)
`
`1−27, 33−35, 38, 45
`
`§ 103(a)
`
`31, 32, 44
`
`§ 103(a)
`
`28−30, 39−43
`
`1
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`2
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`3
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`References
`Drucker ’379,1 Kornfelt,2
`Osterberg3
`Drucker ’379, Kornfelt,
`Osterberg, Munroe4
`Drucker ’379, Kornfelt,
`Osterberg, Holthuis5
`Drucker ’547, 6 Kornfelt,
`Osterberg, Holthuis, Munroe
`
`§ 103(a)
`
`36−37
`
`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.”).
`
`
`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 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”).
`5 Holthuis et al., U.S. Patent No. 5,496,801, issued March 5, 1996. Ex. 1005
`(“Holthuis”).
`6 Drucker et al., PCT Publication WO 98/03547, published January 29,
`1998. Ex. 1028 (“Drucker ’547”).
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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
`nonobviousness, i.e., secondary considerations. See Graham, 383 U.S. at
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`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
`(1966). 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).
`Such a conclusion, however, requires the finding of a nexus to
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`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
`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.
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`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.
`
`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
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`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.
`
`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,
`1570−71, 1573, Table 2.
`
`e. Summary of Holthuis (Ex. 1005)
`
`Holthuis relates to freeze-dried “preparations containing parathyroid
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`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.
`
`f. Summary of Drucker ’547 (Ex. 1028)
`
`Drucker ’547 discloses GLP-2 antagonists that are structural analogs
`of the intestinotrophic GLP-2 peptides. Ex.1028, Abstract, 3:29−4:4. The
`GLP-2 antagonists have been mutated so that at least one amino acid is
`substituted with an amino acid which does not naturally occur at that
`position in the reference GLP-2. Id. at 2:25−36. For example, amino acid
`positions of human GLP-2 at Asp15, Phe22, Thr29, Thr32, and Asp33 may be
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`substituted with an amino acid which does not naturally occur at that
`position. Id. In another example, position Ala2 is substituted with any one
`of Leu, Cys, Glu, Arg, Trp, and PO3–Tyr. Id.
`
`2. Grounds 1, 2, and 4: Obviousness of Claims 1−27, 31−38, and
`44−45 over the Combination of Drucker ’379, Kornfelt, Osterberg,
`Munroe, and Drucker ’547
`a. Petitioner’s Contentions
`
`In Ground 1, Petitioner contends that claims 1−27, 33−35, 38, and 45
`would have been obvious over the combination of Drucker ’379, Kornfelt,
`and Osterberg. Pet. 22−42. Petitioner contends that Drucker ’379 discloses
`a pharmaceutical composition comprising a therapeutically effective amount
`of a GLP-2 analog meeting the requirement of claim 1 for “a medically
`useful amount of a naturally occurring GLP-2 or an analog thereof.” Id. at
`28−29 (citing Ex. 1029, 3:23−27, 11:22−26, 13:8−33; Ex.1001 ¶¶ 49−51).
`Drucker ’379 specifically discloses the h(Gly2)GLP-2 analog. Id. at 25
`(citing Ex. 1029, 6:52−55; Ex. 1001 ¶ 67).
`Petitioner further relies on Drucker ’379 for the use of phosphate
`buffered saline to buffer the formulation at a physiologically tolerable pH,
`thus meeting element (b) of claim 1. Id. at 28−29 (citing Ex. 1029,
`13:8−33).
`The formulation of Drucker ’379 does not include L-histidine, as
`required by claim 1. 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
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`protein drugs across a broad range of pH levels (pH 1−7). Pet. 22 (citing
`Ex.1027, 3:9−11; Ex. 1001 ¶ 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 by the claims. Id. at 24 (citing Ex. 1027, 2:65−67;
`Ex. 1001 ¶ 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. Pet. 22
`(citing Ex.1030, 305, 307; Ex. 1001 ¶¶ 55−58, 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 (citing Ex. 1027, 2:43−57; Ex. 1030,
`301; Ex. 1001 ¶¶ 37, 65).
`In Ground 2, Petitioner further relies on Munroe to meet the elements
`of dependent claims 31, 32, and 44. Pet. 27−28, 40−42. Petitioner contends
`that Munroe discloses an assay for the screening and identification GLP-2
`analogs. Id. at 27, 40 (citing Ex. 1022, 1570−73 and Table 2; Ex.1001
`¶¶ 76−77).
`In Ground 4, Petitioner further relies on Drucker ’574 to meet the
`elements of dependent claims 36 and 37. Pet. 15, 46−48. Petitioner
`contends that Drucker ’574 discloses a GLP-2 formulation containing the
`specific GLP-2 antagonists specified in claim 36 and 37. Pet. 46−47 (citing
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`Ex.1028, 2:7−37; Ex, 1001 ¶ 88).
`In support of its assertion that the challenged claims would have been
`obvious, Petitioner sets forth the foregoing teachings of Drucker ’379,
`Kornfelt, Osterberg, Munroe, and Drucker ’574 and provides a detailed
`claim chart explaining how each claim limitation is disclosed in the
`combination of references. Pet. 22−42, 46−48. Petitioner contends that one
`would have had a reason to combine the teachings of Drucker ’379, Munroe,
`and Drucker ’547, disclosing buffered GLP-2 analog 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 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 48−49 (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
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`references cited in this petition for IPR.” Id. at 52−55.
`
`b. Patent Owner’s Contentions and Analysis
`
`(1) 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. 22−28. 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.
`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. 15−16). 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:
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`Petitioner ignores that peptide stabilization is far from routine
`or predictable. There are many factors that can cause
`destabilization and degradation.
`
`Prelim. Resp. 25 (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 claims 1−27, 31−40, and 44−45.
`
`(2) Secondary Considerations
`Patent Owner contends that secondary considerations support a
`finding of nonobviousness of the claims. Prelim. Resp. 28–29. 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
`
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`need, but instead relies on argument and conclusory contentions, which we
`find insufficient to indicate non-obviousness of the challenged claims.
`Prelim. Resp. 28−29; 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 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:
`
`8 Cleland et al., Formulation and Delivery of Proteins and Peptides,
`AMERICAN CHEMICAL SOCIETY, Washington D.C., Chapter 1 (1994).
`
`17
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`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. 29 (citing Ex. 2039).
`As discussed above, however, GLP-2 formulations buffered with
`phosphate buffered saline were known in the prior art. Pet. 28−29 (citing
`Ex. 1029, 13:8−33). 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 between the commercial success of the product
`and any novel element recited in the claims.
`
`(3) Priority of the ’886 Patent
`The ’886 patent claims the priority of its parent GB Application No.
`9930882, filed December 30, 1999. Ex. 1003, 1; Prelim. Resp. 30.
`Osterberg was published in August 1999. Ex. 1030; Pet. 19. According to
`Patent Owner, Petitioner fails to demonstrate that the ’886 patent is not
`entitled to the benefit of its priority application, and therefore Petitioner fails
`to establish that Osterberg qualifies as prior art under § 102(b). Prelim.
`Resp. 29−31. Patent Owner argues that the Petition should be denied on this
`basis because each of Petitioner’s grounds for unpatentability of the
`challenged claims relies on Osterberg. Id.
`
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`Osterberg was published prior to the asserted foreign priority date of
`December 30, 1999, for the ’886 patent, and is therefore available as prior
`art under 35 U.S.C. § 102(a). On the current record, the distinction between
`§ 102(a) and § 102(b) does not impact materially our conclusion that there is
`a reasonable likelihood that Petitioner will prevail with respect to at least
`one of the challenged claims. We decline to deny the Petition on the basis
`that Osterberg is unavailable as prior art under § 102(b) when the record
`before us indicates it is available as prior art under § 102(a).
`
`c. Conclusion
`
`Based on the current record, we are persuaded that a person of
`ordinary skill in the art would have recognized the above-mentioned
`teachings, and would have had a reason to combine these prior art
`disclosures with a reasonable expectation of success in arriving at the
`claimed subject matter. The information set forth in the Petition is sufficient
`to establish that buffered pharmaceutical formulations of GLP-2 analogs
`were known and that Osterburg and Kornfelt suggests that the use of L-
`histidine in combination with an excipient such as mannitol or sucrose in
`protein formulations was a predictable variation within the technical grasp of
`a person of ordinary skill in the art done for the purposes of protein
`stabilization. KSR, 550 U.S. at 416 (“If a person of ordinary skill in the art
`can implement a predictable variation, and would see the benefit of doing so,
`§ 103 likely bars its patentability.”). Accordingly, we conclude that
`Petitioner has established a reasonable likelihood of prevailing on its
`assertion that claims 1−27, 33−35, 38, and 45 are unpatentable as obvious
`
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`over the combination of Drucker ’379, Kornfelt, and Osterberg.
`Additionally, we conclude that Petitioner has established a reasonable
`likelihood of prevailing on its assertion that claims 31, 32, and 44 are
`unpatentable as obvious over the combination Drucker ’379, Kornfelt,
`Osterberg, and Munroe. Finally, we conclude that Petitioner has established
`a reasonable likelihood of prevailing on its assertion that claims 36 and 37
`are unpatentable as obvious over the combination Drucker ’379, Kornfelt,
`Osterberg, and Drucker ’574.
`
`3. Ground 3: Obviousness of Claims 28−30 and 39−43 over the
`Combination of Drucker ’379, Kornfelt, Osterberg, and Holthuis
`Petitioner contends that dependent claims 28−30 and 39−43 would
`have been obvious over the combination of Drucker ’379, Kornfelt,
`Osterberg, and Holthuis. Pet. 42−46. Petitioner relies on Osterberg and
`Holthuis for the elements of those dependent claims. Pet. 42−46.
`
`a. Claims 28−30 and 41−43
`
`Claims 28−30 are directed to lyophilized GLP-2 formulations having
`less than about 5%, 4%, or 2% degradation. Ex. 1003, 13:33−42. Claims
`41−43 are directed to a GLP-2 formulation of claim 1 that is stable at 4° C
`for up to 18 months, as evidenced by a degradation of less than 5%, 4%, or
`2%. Id. at 14:14−22.
`Petitioner contends that “Holthuis discloses conditions of
`lyophilization that result in less than 5%, 4%, and 2% degradation.” Id.
`(citing Ex.1005, 7:6−17; Ex. 1001 ¶ 83). Petitioner contends that Holthuis
`discloses stability of a peptide hormone at 4° C for at least 9 months. Id.
`
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`(citing Ex.1005, 6:50−58, 7:6−17; Ex.1001 ¶ 83). Petitioner further relies on
`Osterberg for its teaching that “samples freeze-dried with a thermal cycle
`(stored at 2–8°C for 2 years) revealed some crystallinity, which decreased as
`the pH decreased (Fig. 7).” Pet. 43 (citing Ex. 1030, 306).
`We note that the formulations and “conditions of lyophilization”
`disclosed in Holthuis are not substantially identical to the formulations and
`conditions disclosed in the ’886 patent and recited in the challenged claims.
`Pet. 34–35. For example, the protein preparation disclosed in Holthuis
`contains a different protein and does not contain L-histidine. See Ex. 1005,
`6:6−10 (“Aqueous PTH preparations were first prepared for subsequent
`freeze-drying by mixing human PTH(1−84), as hormone; mannitol, as
`excipient; and a citrate source, as buffering agent.”). With regard to
`Petitioner’s reliance on Osterberg, we note that Osterberg measures
`crystallinity, and there is insufficient information provided in the Petition to
`establish a link between reduced crystallinity, disclosed in Osterberg, with
`the reduced protein degradation seen in Holthuis. Accordingly, we are not
`per
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