Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 67
`Entered: 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.
`____________
`
`Case 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.
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`Tel: 571-272-7822
`
`
`
`
`Paper 67
`Entered: 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.
`____________
`
`Case 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.
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
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`IPR2015-01093
`Patent 7,056,886 B2
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`I. INTRODUCTION
`
`1
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`2
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`3
`
`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.”).
`Based on these submissions, we instituted trial as to claims 1−27,
`31−40, and 44−45 of the ’886 patent on the following grounds of
`unpatentability asserted by Petitioner:
`Ground
`References
`Drucker ’379,1 Kornfelt,2
`Osterberg3
`Drucker ’379, Kornfelt,
`Osterberg, Munroe4
`Drucker ’379, Kornfelt,
`Osterberg, Holthuis5
`
`1−27, 33−35, 38, 45
`
`Basis
`
`Claims challenged
`
`§ 103(a)
`
`§ 103(a)
`
`31, 32, 44
`
`§ 103(a)
`
`39−40
`
`
`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”).
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`Ground
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`4
`
`References
`Drucker ’547, 6 Kornfelt,
`Osterberg, Holthuis,
`Munroe
`
`Basis
`
`Claims challenged
`
`§ 103(a)
`
`36−37
`
`Decision to Institute (Paper 26, “Dec.”).
`After institution of trial, Patent Owner filed a Patent Owner Response
`(Paper 31, “PO Resp.”), to which Petitioner filed a Reply (Paper 40, “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. 2051;7 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 49. Petitioner filed an opposition (Paper 53), and Patent
`Owner filed a reply (Paper 57).
`Oral argument was conducted on June 23, 2016. A transcript is
`entered as Paper 65 (“Tr.”).
`This Final Written Decision is entered pursuant to 35 U.S.C. § 318(a).
`
`6 Drucker et al., PCT Publication WO 98/03547, published January 29,
`1998. Ex. 1028 (“Drucker ’547”).
`7 We note that throughout the Patent Owner Response, reference is made to
`Ex. 2040, the Exhibit number for Dr. Carpenter’s Declaration in related case
`IPR2015-00990 instead of Ex. 2051. We have interpreted those citations to
`Ex. 2040 to refer to Ex. 2051.
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`We conclude for the reasons that follow that Petitioner has shown by a
`preponderance of the evidence that claims 1−27, 31−40, and 44−45 of the
`’886 patent are unpatentable.
`
`A. Related Proceedings
`Petitioner also filed a different Petition requesting inter partes review
`of claims 46−52 and 61−75 of the ’886 patent (IPR2015-00990). We also
`instituted inter partes review in IPR2015-00990, and issue a final decision
`therein concurrently with this Final Written Decision.
`
`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 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 claim 1 is illustrative of the challenged claims, and is
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`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 2−27, 31−40, and 44−45 depend from claim 1,
`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 (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.
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`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,
`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
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`expectation of success.” In re O’Farrell, 853 F.2d 894, 903–04 (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
`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
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`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
`& 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
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`two glucagon-like peptides, GLP-1 and GLP-2. Id. at 1:17−27.
`
`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.
`at 301. 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 “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 crystalli[z]e 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, 1570−1571, 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 ’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
`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.
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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.
`
`D. Patentability Analysis
`1. Petitioner’s Asserted Grounds of Unpatentability
`a. 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
`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,
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`and Osterberg. Pet. 22−42. In support of its assertion that the challenged
`claims would have been obvious, Petitioner summarizes the 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. In particular, 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 25–26 (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 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
`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-
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`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). Petitioner also points to where the cited references
`disclose the limitations recited in dependent claims 2–27, 33–35, 38, and 45.
`Id. at 22−42, 46−48.
`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. Id. at 46−47 (citing
`Ex. 1028, 2:17−37; Ex. 1001 ¶ 88). Petitioner further contends that Holthuis
`provides a lyophilization process for use with a peptide hormone
`formulation containing mannitol. Id. at 51 (citing Ex.1005 at 5:2–22).
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`Petitioner contends that one would have had a reason to combine the
`teachings of Drucker ’379, Munroe, Holthuis, 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 49 (“[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
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`Cleland,8 8).
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`b. Ground 3: Obviousness of Claims 39−40 over the Combination
`of Drucker ’379, Kornfelt, Osterberg, and Holthuis
`Petitioner contends that dependent claims 39−40 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. Id.
`Claims 39 and 40 are directed to lyophilized formulations comprising
`less than 5% or 2% water by weight. Ex. 1003, 14:10−13. With regard to
`claims 39 and 40, Petitioner contends that Holthuis discloses a lyophilized
`formulation of a peptide hormone that has 2% water or less. Pet. 43 (citing
`Ex. 1005, 7:19−23; Ex. 1001 ¶ 85). Specifically, Holthuis discloses that:
`
`Residual moisture in the PTH preparation was determined by the
`standard Karl-Fischer technique and indicated that the water
`content of all freeze-dried preparations remained below 2% by
`weight, and typically at about 1% by weight, throughout the
`storage period.
`Ex. 1005, 7:19−24.
`Petitioner further relies on the on the declaration of Dr. Palmieri, who
`testifies that “[t]he level of moisture required by claims 38 and 39 were
`standard in the art the time of the invention.” Ex. 1001 ¶ 85 (citing Ex.
`1031, 15459 (“The [freeze-drying] process continues until the product is dry
`
`8 Cleland et al., Formulation and Delivery of Proteins and Peptides,
`American Chemical Society, Washington D.C., Chapter 1 (1994). Ex. 1024.
`9 Remington: The Science and Practice of Pharmacy, Vol. II, 19th edition,
`Mack Publishing Co., Easton, PA. 1995 (Ex. 1031).
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`(usually 1% or less moisture).”)).
`
`2. Discussion
`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, 32–39. For example, Patent Owner argues that
`i) Drucker ‘379 does not suggest any “in vitro 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) neither Holthius nor Munroe
`disclose stabilization of glucagon, GLP-2, or GLP-2 analog formulations.
`Id. at 17–18, 39 (citing Ex. 2051 ¶¶ 144, 147). Patent Owner’s arguments
`here essentially attack the merits of each of Drucker ‘379, Osterberg,
`Kornfelt, Holthius, 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 ’547 for
`the disclosure of lyophilized GLP-2 and GLP-2 analog formulations (Pet. 15
`(citing Ex. 1029, 4:6–7:20, 15:1–35; Ex. 1028, 4:3–10; 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 16–17
`(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) are useful to stabilize glucagon formulations (id. (citing Ex. 1027,
`2:28–38, 2:43–57; 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 27 (citing Ex. 1022, 1573, Table 2)); and v)
`Holthuis for its disclosure that lyophilized formulations of a peptide
`hormone have 2% water or less (id. at 43 (citing Ex. 1005, 7:19−23; Ex.
`1001 at ¶ 85)). 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 1−27, 31−40, and 44−45 was known in the art, as
`evidenced by the teachings of Drucker ’379, Drucker ’574, Kornfelt,
`Osterberg, Holthuis, and Munroe. See e.g., Pet. 28–48 (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., 773 F.3d
`1186, 1193 (Fed. Cir. 2014). In this regard, as noted above, Petitioner
`argues that the cited prior art provides relevant guidance for preparing
`storage stable lyophilized formulations for peptide formulations, and that
`“[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.” Pet. 48–49. For the reasons presented in the Petition (id. at
`49–55), Petitioner persuades us that an ordinary artisan would have had
`reason to combine teachings in the cited references to achieve the claimed
`invention with a reasonable expectation of success.
`In response, Patent Owner presents several arguments as to why
`Petitioner’s proposed combination of references fails to render the
`challenged claims obvious. In particular, Patent Owner argues that i) the
`stabilization of glucagon is not predictive of stabilization of GLP-2; ii) that
`histidine is a “problematic excipient,” and thus its use in drug formulation
`unpredictable; and iii) that protein/peptide stabilization is far from routine or
`predictable. PO Resp. 43–56. Patent Owner further argues objective
`evidence of non-obviousness in the form of unexpected results, commercial
`success, and long-felt need. Id. at 40–43, 56–60. Because we are persuaded
`by Petitioner’s position (as discussed in more detail in the analysis section
`below), we summarize each of Patent Owner’s contentions just below.
`
`a. Patent Owner’s Contentions
`Patent Owner first argues that a person of ordinary skill in the art
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`would not have had a reasonable expectation of success in combining the
`references because the stabilization of glucagon, disclosed in Kornfelt, is not
`predictive of stabilization of GLP-2. PO Resp. 43–48. Patent Owner argues
`that, despite belonging to the same superfamily of proteins, glucagon and
`GLP-2 have vastly different physical characteristics affecting, for example,
`the aggregation rate and stability of the peptides. Id. To support its
`argument, Patent Owner cites evidence showing differences between
`glucagon and GLP-2, including the differences in pI (7 vs. 4, respectively),
`optimal pH (2.8 vs. 5.5, respectively), chemical degradation pathways, and
`primary and secondary structure. Id. (citing Ex. 1003, 5:21–22; Ex. 2051 ¶¶
`153–155, 157–163; Ex. 2047; Ex. 2059, 1; Ex. 2046, 1274). Because of
`these differences, Patent Owner contends that a person of ordinary skill in
`the art would have understood that the formulation science important to the
`stability of the two peptides would have resulted in distinct formulations.
`See e.g., id. at 45 (arguing that Petitioner’s contention that “one of ordinary
`skill would be motivated to stabilize GLP-2 with whatever stabilized
`glucagon . . . is just plain wrong”).
`Patent Owner further argues that a person of ordinary skill in the art
`would not have had a reasonable expectation of success in combining the
`references because histidine is a “problematic excipient.” PO Resp. 48–51
`(citing Ex. 2051 ¶ 165–167). Patent Owner’s arguments are summarized in
`the following excerpt from the Patent Owner’s Response:
`
`Amino acids, in general, have been tested as stabilizers for
`proteins in lyophilized formulations since as early as the mid
`1930’s. Ex. [2051] ¶ 165. Although histidine, despite its
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`problems, may, in some cases, provide some level of protection
`to proteins during freeze-drying and storage in the dried solid, in
`some published examples, the degree of stabilization provided
`by histidine would not be sufficient for a successful
`protein/peptide drug product. Id. at ¶ 166. Also, it has been
`demonstrated that the capacity of histidine, even to provide
`partial stabilization to a given protein/peptide, can be greatly
`influenced by solution conditions (e.g., pH) or lyophilization
`processing conditions (e.g., use of a post-freezing annealing
`step). Id. at ¶ 167. No one of ordinary skill in the art would have
`reasonably predicted the effect L-histidine would have in an
`untested formulation comprising an untried protein.
`Id. at 48.
`Next, Patent Owner argues that “protein/peptide stabilization is far
`from routine or predictable.” Id. at 51–52 (citing 2054; 2062; Ex. 2051 ¶¶
`174–175). Patent Owner lists the “many factors that can cause
`destabilization and degradation,” and also notes that “the number of
`components from which a formulation scientist can choose is voluminous.”
`Id. Patent Owner directs our attention to Cleland (Ex. 1024), and argues that
`Cleland discloses that
`
`Each molecule has its own unique physical and chemical
`properties which determine [in vitro] stability. The formulation
`scientist must also be concerned about the [in vivo] stability of
`the drug. Thus, the development of successful formulations is
`dependent upon the ability to study both the in vitro and i
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