UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`FRESENIUS KABI USA, LLC and FRESENIUS KABI SWISSBIOSIM GmbH
`Petitioners,
`v.
`AMGEN, INC. and AMGEN MANUFACTURING LIMITED
`Patent Owner.
`
`
`IPR2020-00314
`Patent No. 9,856,287
`Title: REFOLDING PROTEINS USING A CHEMICALLY CONTROLLED
`REDOX STATE
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,856,287 B1
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION ........................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................. 3
`
`Real Parties In Interest (§ 42.8(b)(1)) ................................................... 3
`
`Related Matters (§ 42.8(b)(2)) .............................................................. 3
`
`Identification of Counsel (§ 42.8(b)(3)) and Service
`Information (§ 42.8(b)(4)) ..................................................................... 4
`III. THE BOARD SHOULD INSTITUTE REVIEW ........................................... 5
`IV. TECHNOLOGY BACKGROUND ............................................................... 11
`
`The Basic Science of Proteins ............................................................. 11
`1.
`Protein Structure ....................................................................... 11
`2.
`Protein Synthesis in and out of the Lab .................................... 11
`Recovery and Refolding of Expressed Protein ................................... 12
`1.
`Unfolding and Refolding of Recombinant Proteins ................. 12
`2.
`Optimizing Redox Conditions .................................................. 13
` Additional Considerations in Commercial Production of
`Recombinant Proteins ......................................................................... 15
`THE ’287 PATENT, PROSECUTION HISTORY, AND RELATED
`PROCEEDINGS ............................................................................................ 16
`
`The ’287 Patent ................................................................................... 16
`1.
`The Known Problem in the Art and the Alleged
`Innovative Solution ................................................................... 16
`The Scope of the Challenged Claims ........................................ 19
`2.
`Prosecution History ............................................................................. 21
`The Adello PGR .................................................................................. 22
`The Board’s Invalidation of Analogous Claims of the ’138
`Patent ................................................................................................... 23
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................ 23
`VII. CLAIM CONSTRUCTION .......................................................................... 24
`
`V.
`
`
`
`
`
`
`
`
`
`- i -
`
`

`

`
`
`
`
`IX.
`
`TABLE OF CONTENTS
`(Continued)
`
`Page
`“Preparation” ....................................................................................... 25
`
`“Is Calculated” .................................................................................... 25
`
`“Maintains Solubility” ......................................................................... 25
`
` Defined Claim Terms In Specification ............................................... 26
`IDENTIFICATION OF CHALLENGE AND RELIEF REQUESTED ....... 26
` Ground 1: Claims 1, 4, 8-10, 12, 14-16, 19, 23-26, 29-30 are
`anticipated by Vallejo (Ex. 1031) ....................................................... 27
`1.
`Claims 1, 10, 16, and 26 ........................................................... 28
`2.
`Claims 4, 12, 19 and 29 ............................................................ 36
`3.
`Claims 8, 9, 14, 15, 23, 24, 25 and 30 ...................................... 37
`4.
`Claim Chart ............................................................................... 38
` Ground 2: Claims 16, 19-21, 23-26 and 29-30 are anticipated
`by Ruddon (Ex. 1025) ......................................................................... 42
`1.
`Claims 16, and 26 are Anticipated by Ruddon ......................... 42
`2.
`Claims 19 and 29 Are Anticipated by Ruddon ......................... 46
`3.
`Claims 23, 24, 25 and 30 Are Anticipated By Ruddon ............ 46
`4.
`Claim Chart ............................................................................... 48
` Ground 3: Claims 1, 4-6, 8-10, 12, 14-16, 19-21, 23-26, 29-30
`are obvious over Ruddon in view of Clark 1998 in light of
`Schafer or Gilbert ................................................................................ 51
`1.
`Scope and Content of the Prior Art and Differences
`Between the Prior Art and the Challenged Claims ................... 51
`2. Motivation To Combine and Expectation of Success .............. 57
`3.
`Obviousness of the Independent Claims ................................... 59
`4.
`Obviousness of Claims 4, 12, 19 and 29 ................................... 62
`5.
`Obviousness of Claims 5, 6, 20, and 21 .................................... 63
`6.
`Obviousness of Claims 8, 9, 14, 15, 23, 24, 25 and 30 ............ 64
` Ground 4: Claims 8, 9, 14, 15, 23, 24, 25 and 30 Would Have
`Been Obvious From Vallejo In Combination With Ruddon and
`Clark 1998, In Light Of Schafer or Gilbert ......................................... 65
`
`
`
`ii
`
`

`

`TABLE OF CONTENTS
`(Continued)
`
`Page
`Secondary Considerations ................................................................... 66
`
`CONCLUSION .............................................................................................. 67
`
`
`
`
`
`D.
`
`
`
`
`iii
`
`

`

`
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Amgen Inc. et al. v. Tanvex BioPharma USA, Inc. et al.,
`19-cv-01374 .......................................................................................................... 3
`Apotex Inc. v. Amgen Inc.,
`IPR2016-01542, Paper 60 (PTAB Feb. 15, 2018) (Ex. 1038) ............................. 2
`Choirock Contents Factory Co., Ltd., v. Spin Master Ltd.,
`IPR2019-00897, Paper 17 (PTAB Sept. 26, 2019) ............................................... 8
`Cook Inc. et al., v. Medtronic, Inc.,
`IPR2019-00123, Paper 11 (PTAB June 11, 2019) ............................................... 8
`Corning Optical Comm. RF, LLC, v. PPC Broadband, Inc.,
`IPR2014-00440, IPR2014-00441 ......................................................................... 8
`Foundation Medicine, Inc. v. Guardant Health, Inc.,
`IPR2019-00652, Paper 12 (PTAB Aug. 19, 2019) ............................................... 8
`Fresenius Kabi USA, LLC et al. v. Amgen, Inc. et al.,
`IPR2019-00971, Paper 13 (PTAB Oct. 16, 2019) ........................................ 3, 4, 7
`Fresenius Kabi USA, LLC et al. v. Amgen, Inc.,
`IPR2019-01183, Paper 10 (PTAB Dec. 10, 2019) ......................................... 6, 11
`General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (PTAB Sept. 6, 2017) ............................................. 7, 9
`King Pharm., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 38
`Lowes Cos. Inc., et al. v. Nichia Corp.,
`IPR2017-02011, Paper 13 (PTAB Mar. 12, 2018) ............................................... 6
`PayPal, Inc. v. IOENGINE, LLC,
`IPR2019-00884, Paper 22 (PTAB Oct. 3, 2019) .................................................. 8
`
`
`
`- iv -
`
`

`

`
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 24
`Valve Corp. v. Electronic Scripting Products, Inc.,
`IPR2019-00062, Paper 11 (PTAB Apr. 2, 2019) ............................................. 7, 8
`Statutes
`35 U.S.C. § 102 .................................................................................. 5, 27, 43, 51, 52
`35 U.S.C. § 112 .............................................................................................. 5, 22, 25
`35 U.S.C. § 314(a) ................................................................................................. 4, 5
`35 U.S.C. § 325(d) ..................................................................................................... 5
`35 U.S.C. § 311(c) .................................................................................................... 10
`Other Authorities
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 3
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 3
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 4
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 4
`37 C.F.R. § 42.15(a) ................................................................................................... 3
`37 C.F.R. § 42.100(b) .............................................................................................. 24
`37 C.F.R. § 42.103 ..................................................................................................... 3
`37 C.F.R. § 42.104(a) ................................................................................................. 3
`
`
`
`v
`
`

`

`
`
`LIST OF EXHIBITS
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`United States Patent No. 9,856,287
`
`Declaration of Professor Paul A. Dalby, Ph.D.
`
`United States Patent No. 4,237,224
`
`United States Patent No. 4,468,464
`
`United States Patent No. 4,740,470
`
`Curriculum Vitae of Professor Paul A. Dalby, Ph.D.
`De Bernardez Clark, E. et al., “Oxidative Renaturation of Hen
`Egg-White Lysozyme. Folding vs Aggregation,” Biotechnology
`Progress 14(1):47-54 (1998)
`De Bernardez Clark, E., “Protein refolding for industrial
`processes,” Current Opinion in Biotechnology 12(2):202-07
`(April 2001)
`Ejima, D. et al., “High Yield Refolding and Purification Process
`for Recombinant Human Interleukin-6 Expressed in Escherichia
`coli,” Biotechnology and Bioengineering, 62(3):301-10
`(February 1999)
`Excerpts of United States Patent No. 9,856,287 File History
`Ferrer-Miralles, N. et al., “Microbial factories for recombinant
`pharmaceuticals,” Microbial Cell Factories 8:17 (2009)
`Georgiou, G. & Valax, P., “Isolating Inclusion Bodies from
`Bacteria,” Methods in Enzymology 309:48-58 (1999)
`Gilbert, H., “Molecular and Cellular Aspects of Thiol-Disulfide
`Exchange,” in Advances in Enzymology and Related Areas of
`Molecular Biology, ed. Alton Meister, Vol. 63, pp. 69-172 (John
`Wiley & Sons 1990)
`Gilbert, H., “Thiol/Disulfide Exchange Equilibria and Disulfide
`Bond Stability,” in Methods in Enzymology, ed. Lester Packer,
`Vol. 251, pp. 8-28 (Academic Press 1995)
`
`
`
`- vi -
`
`

`

`
`
`EXHIBIT NO.
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`
`
`DESCRIPTION
`Graumann, K. & Premstaller, A., “Manufacturing of
`recombinant therapeutic proteins in microbial systems,”
`Biotechnology Journal 1:164-86 (2006)
`Hevehan, D, & Clark, E., “Oxidative Renaturation of Lysozyme
`at High Concentrations,” Biotechnology and Bioengineering,
`54(3):221-30 (May 1997)
`Horton, R. et al., Principles of Biochemistry ( Pearson
`Education, 4th ed., 2006)
`Jungbauer, A. & Kaar, W., “Current status of technical protein
`refolding,” Journal of Biotechnology 128:587-96 (2007)
`Keire, D. et al., “Kinetics and Equilibria of Thiol/Disulfide
`Interchange Reactions of Selected Biological Thiols and Related
`Molecules with Oxidized Glutathione,” J. Org. Chem. 57(1):123-
`27 (1992)
`Neubauer, P. et al., “Protein Inclusion Bodies in Recombinant
`Bacteria,” in Inclusions in Prokaryotes, ed. J.M. Shively, pp.
`237-92 (Springer-Verlag Berlin Heidelberg 2006)
`Palmer, I. & Wingfield, P., “Preparation and Extraction of
`Insoluble (Inclusion-Body) Proteins from Escherichia coli, Curr
`Protoc Protein Sci. Chapter: Unit-6.3 (November 2004)
`Panda, A., “Bioprocessing of Therapeutic Proteins from the
`Inclusion Bodies of Escherichia coli,” Adv Biochem
`Engin/Biotechnol 85:43-93 (2003)
`Patra, A. et al., “Optimization of Inclusion Body Solubilization
`and Renaturation of Recombinant Human Growth Hormone
`from Escherichia coli,” Protein Expression and Purification
`18:182-92 (2000)
`Profacgen, “Inclusion body purification & protein refolding,”
`accessed at https://www.profacgen.com/inclusion-body-
`purification-protein-refolding.htm
`International Publication No. WO 95/32216
`Ryan, R. et al., “Structure-Function Relationships of
`Gonadotropins,” in Recent Progress in Hormone Research, Vol.
`43, pp. 383-429 (Academic Press 1987)
`Schafer, F. & Buettner, G., “Redox Environment of the Cell as
`Viewed Through the Redox State of the Glutathione
`
`vii
`
`

`

`
`
`EXHIBIT NO.
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`
`
`DESCRIPTION
`Disulfide/Glutathione Couple,” Free Radical Biology &
`Medicine 30(11):1191-12 (June 2001)
`United States Patent Application Publication No. 2007/0238860
`Singh, S. & Panda, A., “Solubilization and Refolding of
`Bacterial Inclusion Body Proteins,” Journal of Bioscience and
`Bioengineering 99(4):303-10 (2005)
`Vallejo, L. & Rinas, U., “Strategies for the recovery of active
`proteins through refolding of bacterial inclusion body proteins,”
`Microbial Cell Factories 3:11 (2004)
`European Patent Application No. 1 449 848 A1, Method for the
`production of cystine-knot proteins (2004)
`Ventura, S. & Villaverde, A., “Protein quality in bacterial
`inclusion bodies,” Trends in Biotechnology 24(4):179-85 (April
`2006)
`Wetlaufer, D. et al., “The oxidative folding of proteins by
`disulfide plus thiol does not correlate with redox potential,”
`Protein Engineering 1(2):141-46 (1987)
`Whitford, D., Proteins: Structure and Function (John Wiley &
`Sons 2005)
`Peptides Guide, “What are Proteins?” accessed at
`http://www.peptidesguide.com/proteins.html
`Xie, Y. et al., “Recombinant Human Retinol-Binding Protein
`Refolding, Native Disulfide Formation, and Characterization,”
`Protein Expression and Purification 14:31-37 (1998)
`Patent Owner’s Preliminary Response Under 37 C.F.R. § 42.207,
`dated January 23, 2019
`Final Written Decision in IPR2016-01542, Patent 8,952,138,
`dated February 15, 2018
`Archer, D. et al., “Hen Egg White Lysozyme Expressed In, and
`Secreted from, Aspergillus Niger is Correctly Processed and
`Folded,” Bio/Technology 8:741-45 (August 1990)
`United States Patent No. 5,663,304
`
`United States Patent No. 8,952,138
`De Bernardez Clark, E., “Refolding of recombinant proteins,”
`Current Opinion in Biotechnology 9:157-63 (1998)
`
`viii
`
`

`

`
`
`EXHIBIT NO.
`
`DESCRIPTION
`
`Atassi, M.Z., “Chemical Strategy for Studying the Antigenic
`Structures of Disulfide-Containing Proteins: Hen Egg-White
`Lysozyme as a Model,” in Protein Crosslinking, ed. M.
`Friedman, Vol. 6, pp. 89-137 (Plenum Press 1977)
`Table of categorized claims for United States Patent No.
`9,856,287
`“Glutathione” in The Merck Index, 12th Ed., pp. 4483-84 (Merck
`Research Laboratories 1996)
`Middleberg, A., “Preparative protein folding,” TRENDS in
`Biotechnology 20(10):437-43 (October 2002)
`Redline Petition IPR2019-00917/Petition IPR2020-000314
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`
`
`
`ix
`
`

`

`
`
`I.
`
`INTRODUCTION
`Fresenius Kabi USA, LLC and Fresenius Kabi SwissBioSim GmbH, pursuant
`
`to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, et seq.,1 petition for Inter Partes Review
`
`(“IPR”) of claims 1, 4-6, 8-10, 12, 14-16, 19-21, 23-26, 29-30 of U.S. Patent No.
`
`9,856,287 (“the ’287 patent,” Ex. 1001). Petitioners’ request is supported by the
`
`Expert Declaration of Paul Dalby, Ph.D. (Ex. 1002) and the other exhibits submitted
`
`herewith.
`
`The challenged claims of the ’287 patent are generally directed to methods of
`
`refolding proteins expressed in non-mammalian cells. Unfolded proteins are
`
`incubated in a buffer containing, among other ingredients, amounts of an oxidant
`
`and a reductant that permit the proteins to refold into their native three-dimensional
`
`structure. This basic “redox” refolding method was in common use as of June 22,
`
`2009, the earliest possible filing date of the patent, and scientists routinely tailored
`
`the compositions of their redox buffers to optimize the yield of properly refolded
`
`proteins. In particular, it was understood that for a given protein, the yield could be
`
`optimized in part by varying the ratio and strength of the oxidant and reductant (i.e.,
`
`thiol pair) to determine which combinations produced the highest yield at a given
`
`
`1 Unless otherwise stated, all statutory and regulatory citations herein are to 35
`
`U.S.C. or 37 C.F.R.
`
`
`
`- 1 -
`
`

`

`
`
`protein concentration. As explained by Dr. Dalby, this optimization was routine and
`
`well within the scope of ordinary skill in 2009.
`
`While the ’287 patent purports to disclose novel mathematical equations to
`
`calculate thiol pair ratio and buffer strength, it cannot be disputed that the specific
`
`ranges of thiol pair ratio and buffer strength that appear in the claims encompass
`
`ratios and strengths described in the prior art. Moreover, the equations themselves
`
`are not novel. They express basic redox chemistry principles and were expressly
`
`disclosed and used in the prior art. Even if the equations had not been written down
`
`in the prior art, a mathematical equation does not make a claim patentable where its
`
`“only contribution was to quantify into a previously unwritten equation relationships
`
`that were discernible to one of ordinary skill in the art from the prior art.” Apotex
`
`Inc. v. Amgen Inc., IPR2016-01542, Paper 60 at 29 (PTAB Feb. 15, 2018) (Ex.
`
`1038).
`
`As described below, each of the challenged claims is anticipated by the prior
`
`art. To the extent a single reference does not disclose every element of every claim,
`
`every element was disclosed in the prior art and there was a motivation to combine
`
`these elements, rendering the claimed subject matter obvious from that art as a
`
`whole. Petitioners are not aware of any relevant secondary evidence of non-
`
`obviousness.
`
`
`
`2
`
`

`

`
`
`The required fee set forth in § 42.15(a) is paid pursuant to § 42.103, and the
`
`Commissioner is hereby authorized to charge all fees due in connection with this
`
`matter to Attorney Deposit Account 506989.
`
`Pursuant to § 42.104(a), Petitioners certify that the ’287 patent is available for
`
`IPR and that Petitioners are not barred or estopped from requesting IPR on the
`
`grounds raised in this petition.
`
`II. MANDATORY NOTICES
` Real Parties In Interest (§ 42.8(b)(1))
`The real parties in interest are Fresenius Kabi USA, LLC, Fresenius Kabi
`
`SwissBioSim GmbH, Fresenius Kabi AG, Fresenius Kabi Pharmaceuticals Holding,
`
`Inc., Fresenius Kabi Deutschland GmbH, Fresenius SE & Co. KGaA, Dr. Reddy’s
`
`Laboratories, Ltd., Dr. Reddy’s Laboratories, S.A., and Dr. Reddy Laboratories Inc.
`
` Related Matters (§ 42.8(b)(2))
`The ’287 patent is currently the subject of Amgen Inc. et al. v. Tanvex
`
`BioPharma USA, Inc. et al., 19-cv-01374, S.D. Cal., but the parties recently filed a
`
`joint motion to dismiss that case. In addition, U.S. Patent Application 15/889,559 is
`
`pending and claims priority to the ’287 patent. The ’287 patent is a continuation of
`
`pending U.S. Patent Applications 14/611,037 and 14/793,590.
`
`There are no currently pending Patent Trial and Appeal Board (“PTAB”)
`
`proceedings that address the validity of the ’287 patent. The Board instituted
`
`PGR2019-00001, Adello Biologics, LLC v. Amgen Inc. et al. (“the Adello PGR”),
`
`
`
`3
`
`

`

`
`
`which challenged the ’287 patent, on April 19, 2019, and subsequently terminated
`
`the proceeding on December 6, 2019 due to settlement between the parties.
`
`PGR2019-00001, Paper 28 (PTAB Dec. 6, 2019). Before the Adello PGR was
`
`instituted, Petitioners filed a previous IPR petition challenging the ’287 patent, but
`
`the Board found that the petition was duplicative of the then-pending but now-
`
`terminated Adello PGR, and used its discretion to deny institution under § 314(a)
`
`without evaluating the merits of the petition. Fresenius Kabi USA, LLC et al. v.
`
`Amgen, Inc. et al., IPR2019-00971, Paper 13 (PTAB Oct. 16, 2019).
`
`
`
`Identification of Counsel (§ 42.8(b)(3)) and Service Information
`(§ 42.8(b)(4))
`Lead Counsel
`Huiya Wu
`(Reg. No. 44,411)
`Goodwin Procter LLP,
`620 Eighth Avenue,
`New York, NY 10018,
`T: (212) 813-7295
`Fax: (212) 355-3333
`hwu@goodwinlaw.com,
`DG-
`FK287@goodwinlaw.com
`
`
`Back-Up Counsel
`Robert V. Cerwinski
`(to seek pro hac vice
`admission)
`Goodwin Procter LLP,
`620 Eighth Avenue,
`New York, NY 10018,
`T: (212) 813-8800
`Fax: (212) 355-3333
`rcerwinski@goodwinlaw.
`com
`
`Back-Up Counsel
`Linnea Cipriano
`(Reg. No. 67,729)
`Goodwin Procter LLP,
`620 Eighth Avenue,
`New York, NY 10018,
`T: (212) 813-7295
`Fax: (212) 355-3333
`lcipriano@goodwinlaw.com
`
`Please direct all correspondence to lead counsel and back-up counsel at the
`
`contact information above. Petitioners consent to electronic mail service at the
`
`following addresses: hwu@goodwinlaw.com, DG-FK287@goodwinlaw.com;
`
`rcerwinski@goodwinlaw.com; lcipriano@goodwinlaw.com;
`
`Hanna.Yoon@fresenius-kabi.com.
`
`
`
`4
`
`

`

`
`
`III. THE BOARD SHOULD INSTITUTE REVIEW
`The Board should institute review because there is at least a reasonable
`
`likelihood that Petitioners will prevail with respect to at least one challenged claim.
`
`§ 314(a).
`
`There are no grounds for denying institution under § 314(a) or § 325(d).
`
`There are no pending Patent Trial and Appeal Board (“PTAB”) proceedings
`
`challenging the ’287 patent, and there have been no PTAB proceedings that have
`
`adjudicated the merits of a challenge under 35 U.S.C. §§ 102 or 103 against any
`
`claims of the ’287 patent, either in an institution or final decision. Although the
`
`Board instituted the now-terminated Adello PGR, that decision was founded on the
`
`merits of Adello’s challenge under 35 U.S.C. § 112, which cannot be raised in an
`
`IPR. And while the Board issued a decision declining to institute Petitioners’ earlier-
`
`filed IPR2019-000971 challenging the same claims, the Board did not consider the
`
`merits of the petition. Rather, the Board used its discretion to deny institution solely
`
`because on the pendency of the now-terminated Adello PGR, which the Board
`
`believed contained duplicative challenges under §§ 102 and 103.2
`
`
`2 The Board’s decision denying institution of IPR2019-000971 incorrectly indicated
`
`that there was “complete overlap” between Petitioners’ arguments and those
`
`presented in the Adello PGR. Petitioners relied on prior art not cited or made of
`
`
`
`5
`
`

`

`
`
`The discretionary denial of Petitioners’ prior petition should not weigh against
`
`institution here. The Board recently terminated the Adello PGR after the parties
`
`there entered into a confidential settlement agreement. PGR2019-00001, Paper 28
`
`(PTAB Dec. 6, 2019). As the Board recently confirmed, termination of an earlier-
`
`filed petition ameliorates the potential for abuse arising from later-filed challenges
`
`to the same patent. Fresenius Kabi USA, LLC et al. v. Amgen, Inc., IPR2019-01183,
`
`Paper 10 at 11-12 (PTAB Dec. 10, 2019) (explaining that “the potential for abuse by
`
`instituting an arguably follow-on Petition in this case has been ameliorated by the
`
`termination”).
`
`Further, denial of this Petition as a “follow-on” petition after Adello and
`
`Patent Owner (“PO”) acted in concert to terminate the earlier-filed petition would
`
`unjustly prejudice Petitioners, barring them from a fair opportunity to have the
`
`merits of their challenge adjudicated. See Lowes Cos. Inc., et al. v. Nichia Corp.,
`
`IPR2017-02011, Paper 13 at 19 (PTAB Mar. 12, 2018) (“Denial of the Petition in
`
`part would prejudice the Petitioner in this proceeding should the [other] Petitions be
`
`
`record in the Adello PGR, specifically Clark 1998 (Ex. 1007), Schafer (Ex. 1027),
`
`and Gilbert (Ex. 1014). Petitioners’ grounds also included arguments that claims are
`
`invalid as anticipated by Ruddon (Ex. 1025), an argument not raised in the Adello
`
`PGR.
`
`
`
`6
`
`

`

`
`
`resolved by settlement.”). This Petition does not run afoul of the factors articulated
`
`in General Plastic Indus. Co. v. Canon Kabushiki Kaisha, IPR2016-01357, Paper
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`19 at 9–10 (PTAB Sept. 6, 2017) (precedential as to § II.B.4.i). Regarding factor 1,
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`Petitioners and Adello are unrelated competitors with different pegfilgrastim
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`biosimilar products, namely Adello’s TPI-120 and Petitioners’ MSB11455.
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`Petitioners and Adello certainly do not have the kind of “significant relationship” at
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`issue in Valve Corp. v. Electronic Scripting Products, Inc., IPR2019-00062, Paper
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`11 (PTAB Apr. 2, 2019) (precedential), that justified treating two petitioners as a
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`single actor under the General Plastic factors. Petitioners were not involved in the
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`preparation or filing of Adello’s PGR petition and have not reaped any benefits from
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`their settlement. Petitioners and Adello are not co-defendants in a related litigation,
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`they do not share an interest in the Adello filgrastim product that gave rise to the
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`district court litigation between Adello and PO, and there is no business or licensing
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`relationship between them.3 Notably, Petitioners were never listed as a real party-
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`3 The Board acknowledged as much in its denial of Petitioners’ IPR2019-00971,
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`finding that “there is no evidence of any business relationship” between Adello and
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`Petitioners. IPR2019-00971, Paper 13 at 7 (PTAB Oct. 16, 2019). Respectfully, it
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`mistakenly implied a relationship based on Petitioners’ suggestion that they would
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`attempt to coordinate the schedule of the IPR with the PGR if both were instituted,
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`7
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`in-interest (“RPI”) in the Adello PGR, nor did PO ever assert that they should have
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`been.4 As PO is aware, neither the settlement negotiations nor the agreement
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`between PO and Adello included Petitioners. Denying institution of this Petition as
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`an improper follow-on petition would essentially enable a patent owner to insulate
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`and Petitioners’ counsel’s attendance at a publicly-noticed deposition in the Adello
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`PGR. These efforts to coordinate two co-pending proceedings for efficiency are not
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`evidence that Adello and Petitioners had the kind of “significant” pre-filing
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`relationship found in Valve and other cases that merited discretionary denial of
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`institution. E.g., PayPal, Inc. v. IOENGINE, LLC, IPR2019-00884, Paper 22 at 8-
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`11 (PTAB Oct. 3, 2019); cf. Foundation Medicine, Inc. v. Guardant Health, Inc.,
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`IPR2019-00652, Paper 12 at 30 (PTAB Aug. 19, 2019); Cook Inc. et al., v.
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`Medtronic, Inc., IPR2019-00123, Paper 11 at 39 (PTAB June 11, 2019), and
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`Choirock Contents Factory Co., Ltd., v. Spin Master Ltd., IPR2019-00897, Paper 17
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`at 12-13 (PTAB Sept. 26, 2019).
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`4 If PO believed that Adello and Petitioners were working together in these
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`proceedings, they could have challenged the identification of RPIs. Corning Optical
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`Comm. RF, LLC, v. PPC Broadband, Inc., IPR2014-00440, IPR2014-00441, and
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`IPR2014-00736, Paper 68 at 23-25, (PTAB Aug. 18, 2015).
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`8
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`its patent from challenge by settling with the first challenger, inviting future
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`gamesmanship.
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`Moreover, the fact that this Petition challenges fewer claims than the Adello
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`PGR is further evidence that their interests are not co-extensive. While both
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`proceedings concern some of the same patent claims, the mere fact that two parties
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`have challenged the same claims is insufficient to treat them as joint actors. See
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`Foundation Medicine, Inc., Paper 12 at 29–30 (PTAB Aug. 19, 2019).
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`The remaining General Plastic factors also favor institution. Factors 2 and
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`3: As explained, Petitioners had no interest in, or control over, the Adello PGR when
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`it was filed, thus the question of when Petitioners became aware of the prior art in
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`this Petition and whether it could have been asserted in Adello’s PGR is irrelevant.
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`There is no evidence suggesting that Petitioners could have influenced the arguments
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`in that PGR. Petitioners are also not using multiple petitions to “game” the system.
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`While Petitioners’ IPR2019-00971 was filed after PO filed its preliminary response
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`in the Adello PGR, it was filed before the Board issued its institution decision. Here,
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`Petitioners are asserting identical grounds of invalidity as presented in IPR2019-
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`00971.5 Petitioners have not gained any benefit from either the institution decision
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`5 The only changes made to the substantive arguments are revisions for brevity and
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`typographical and citation corrections, as shown in Exhibit 1047.
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`9
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`in the now-terminated Adello PGR or PO’s preliminary response in Petitioners’
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`IPR2019-00971 and simply ask that their previously-presented arguments be
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`considered on their merits.
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`Factors 4 and 5: The timing of the Petition similarly does not signal
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`gamesmanship. This Petition is being filed two weeks after the Board granted PO
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`and Adello’s request to terminate the Adello PGR, rendering the Board’s reasons for
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`denying institution of IPR2019-00971 moot. While Petitioners did not bring a PGR
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`within the 9-month statutory window, this does not weigh against institution of the
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`present petition. Petitioners developed an interest in challenging the ’287 patent
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`after the nine-month window to file a PGR had expired, and Petitioners have a
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`statutory right to bring this IPR now that Adello’s PGR has been terminated.
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`§ 311(c).
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` Factors 6 and 7: This Petition does not unduly burden the Board’s limited
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`resources or impact the statutory one year deadline for the Board to issue a final
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`determination since there is no other pending petition concerning the ’287 patent.
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`As the Board stated, “the finite resources of the Board . . . do not weigh in favor of
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`denial in this case because there are no longer multiple petitions challenging the
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`same patent.” IPR2019-01183, Paper 10 at 12-13. Therefore, when assessing all
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`relevant circumstances in the case, the Board should institute this Petition.
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`10
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`IV. TECHNOLOGY BACKGROUND
` The Basic Science of Proteins
`1.
`Protein Structure
`Protein molecules must fold into precise three-dimensional shapes in order to
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`be biologically active. Ex. 1002 ¶ 42. The biologically-active form of a protein is
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`known as the “native” form. Id. Usually the native form is the most
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`thermodynamically stable way of folding the particular sequence of amino acids that
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`make up the protein. Id. Thus, under appropriate conditions, proteins will
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`automatically fold into their native forms. Id.
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`For many proteins, their native three-dimensional structure is stabilized by
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`“disulfide” bonds that cross-link different parts of the folded polypeptide chain.
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`Disulfide bonds form between particular amino acids called “cysteines” when they
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`come into close proximity during refolding and help lock the protein into its native
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`shape. Ex. 1002 ¶ 43; Ex. 1034 at 32-33. However, if disulfide bonds form in
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`improper locations, the proteins can misfold. Misfolded proteins can be inactive.
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`2.
`Protein Synthesis in and out of the Lab
`Recombinant DNA technology can be used with both mammalian and non-
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`mammalian cell cultures (often referred to as “expression systems”), but scientists
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`have generally turned to high-yield bacterial expression systems to express
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`recombinant proteins at a lower cost. Ex. 1017 at 719-23; Ex. 1002 ¶ 44-47. One
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`11
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`well-established bacterial expression system is Escherichia coli, (“E. coli.”)
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`Ex. 1002 ¶ 48.
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` Recovery and Refolding of Expressed Protein
`A bacterial host cell expressing recombinant proteins often produces
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`misfolded proteins that aggregate together into “inclusion bodies.” In particular,
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`rec