UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`LUPIN, LTD. and LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`AMGEN, INC.,
`Patent Owner
`___________________________________
`
`U.S. Patent No. 9,856,287
`Issue Date: January 2, 2018
`Title: REFOLDING PROTEINS USING A
`CHEMICALLY CONTROLLED REDOX STATE
`___________________________________
`
`Inter Partes Review No. 2021-00326
`___________________________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,856,287 UNDER 35 U.S.C. §§ 311-319
`and 37 C.F.R. §§ 42 ET SEQ.
`
`

`

`Table of Contents
`
`
`
`V. 
`VI. 
`
`OVERVIEW .................................................................................................... 1 
`I. 
`II.  MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................... 2 
`A. 
`Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1) ............................ 2 
`B. 
`Related Matters Under 37 C.F.R. § 42.8(b)(2) ..................................... 2 
`C. 
`Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) .................. 4 
`D. 
`Service Information Under 37 C.F.R. § 42.8(b)(4) ............................... 4 
`III.  GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a) ..................... 4 
`IV.  STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22) ................................................. 5 
`THRESHOLD REQUIREMENT FOR IPR .................................................... 5 
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ................. 10 
`A.  The Challenged Claims and Grounds (37 C.F.R. §§ 42.104(b)(1)
`and (2)) ................................................................................................ 11 
`VII.  TECHNOLOGY BACKGROUND ............................................................... 11 
`A. 
`Protein Structure .................................................................................. 12 
`B. 
`Recombinant Protein Synthesis ........................................................... 12 
`1. 
`Unfolding and Refolding of Recombinant Proteins ................. 13 
`2. 
`Optimizing Redox Conditions .................................................. 13 
`THE ’287 PATENT AND ITS PROSECUTION HISTORY ....................... 16 
`A. 
`The ’287 Patent ................................................................................... 17 
`B. 
`The ’287 Patent Prosecution History .................................................. 19 
`C. 
`The Board Invalidated Analogous Claims of the Parent ’138
`Patent ................................................................................................... 21 
`
`II. 
`
`-i-
`
`

`

`
`
`V. 
`
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 21 
`III. 
`IV.  CLAIM CONSTRUCTION (37 C.F.R. § 42.104(B)(3)) .............................. 22 
`A. 
`“thiol-pair ratio” .................................................................................. 22 
`B. 
`“thiol-pair buffer strength” .................................................................. 23 
`C. 
`“wherein the thiol-pair ratio is calculated according to the
`following equation” in claims 8, 14-15, 23, 25, and 30. ..................... 24 
`“complex protein” ............................................................................... 26 
`D. 
`STATEMENT OF THE REASONS FOR THE RELIEF
`REQUESTED (37 C.F.R. §§ 42.104(b)(4) and (5)) ...................................... 26 
`A. 
`The Prior Art ....................................................................................... 26 
`B. 
`Ground 1: Vallejo Anticipates Claims 1-4, 7-19, and 22-30 of
`the ’287 Patent ..................................................................................... 28 
`1. 
`Claims 1, 10, 16, and 26 ........................................................... 28 
`The Preamble .................................................................. 28 
`  Making a mixture of protein and non-redox
`refolding components ..................................................... 29 
`Redox components ......................................................... 32 
`Incubating and proper refolding ..................................... 37 
`Claims 2-3, 11, 13, 17-18, and 27-28 ....................................... 38 
`2. 
`Claims 4, 12, 19, and 29 ........................................................... 38 
`3. 
`Claims 7 and 22 ......................................................................... 40 
`4. 
`Claims 8-9, 14-15, 23-25, and 30 ............................................. 41 
`5. 
`Ground 2: Schlegl Anticipates Claims 1-4, 8-19, and 23-30 of
`the ’287 Patent ..................................................................................... 41 
`1. 
`Claims 1, 10, 16 and 26 ............................................................ 42 
`
`C. 
`
`-ii-
`
` 
`
` 
`
` 
`
`

`

` 
`
` 
`
`F. 
`
` 
`
`
`
`The Preamble .................................................................. 42 
`  Making a mixture of protein and non-redox
`refolding components ..................................................... 43 
`Redox components ......................................................... 45 
`Incubating and proper refolding ..................................... 49 
`Claims 2-3, 11, 13, 17-18, and 27-28 ....................................... 49 
`2. 
`Claims 4, 12, 19, and 29 ........................................................... 50 
`3. 
`Claims 8-9, 14-15, 23-25, and 30 ............................................. 51 
`4. 
`D.  Ground 3: Vallejo Renders Claims 1-30 Obvious Alone or in
`Combination with Hevehan ................................................................. 52 
`1. 
`Claims 1-4, 7-19, and 22-30 ..................................................... 52 
`2. 
`Claims 5-6 and 21-22 ................................................................ 54 
`Ground 4: Schlegl Renders Claims 1-6, 8-21, and 23-30
`Obvious Alone or in Combination with Hevehan. .............................. 56 
`1. 
`Claims 1-4, 8-19, and 23-30 ..................................................... 57 
`2. 
`Claims 5-6 and 21-22 ................................................................ 58 
`Grounds 5: Vallejo Renders Claims 8-9, 14-15, 23-25, and 30
`Obvious Alone or in Combination with Ruddon and/or Schafer ........ 59 
`G.  Ground 6: Schlegl Renders Claims 8-9, 14-15, 23-25, and 30
`Obvious Alone or in Combination with Ruddon and/or Schafer ........ 63 
`1. 
`Claims 8-9, 14-15, 23-25, and 30 ............................................. 63 
`H.  No Secondary Considerations of Non-Obviousness ........................... 65 
`VI.  CONCLUSION .............................................................................................. 65 
`
`E. 
`
`-iii-
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Cases
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte GmbH,
`IPR2019-01469 (Feb. 13, 2020) ........................................................................... 5
`
`Page (s)
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586 (P.T.A.B. Dec. 15, 2017) ........................................................... 6
`
`Fresenius Kabi USA, LLC et al. v. Amgen, Inc.,
`IPR2019-01183 (P.T.A.B. Dec. 10, 2019) ..................................................... 8, 10
`
`General Plastic Indus. Co. v. Canon Kabushiki Kaisha,
`IPR2016-01357 (P.T.A.B. Sept. 6, 2017) ............................................................. 6
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 21
`LG Electronics, Inc. v. Bell Northern Research, LLC,
`IPR2020-00319 (P.T.A.B. June 23, 2020)............................................................ 8
`
`Lowes Cos. Inc., et al. v. Nichia Corp.,
`IPR2017-02011 (P.T.A.B. Mar. 12, 2018) ......................................................... 10
`
`Pfizer Inc. v. Chugai Pharmaceutical Co., Ltd.,
`812 F. App’x 979 (Fed. Cir. 2019) ..................................................................... 10
`
`Valve Corp. v. Elec. Scripting Prods., Inc.,
`IPR2019-00062 (April 2, 2019) ............................................................................ 7
`Statutes
`35 U.S.C. § 314(a) ..................................................................................................... 5
`Other Authorities
`Patent Trial and Appeal Board Consolidated Trial Practice Guide
`November 2019 ..................................................................................................... 2
`
`
`
`-iv-
`
`

`

`
`
`Appendix of Exhibits
`
`(Filed Pursuant to 37 C.F.R. § 42.6)
`
`Lupin
`Exhibit
`Number
`1001 U.S. Patent No. 9,856,287
`
`Description
`
`1002 Declaration of George Georgiou, Ph.D., with Exhibits
`
`1003
`
`European Patent No. 1449848 A1 (“Vallejo”)
`
`1004 U.S. Patent Publication 2007/0238860 Al (“Schlegl”)
`
`1005 Hevehan, D. & Clark, E., Oxidative Renaturation of Lysozyme at High
`Concentrations, 53:3 BIOTECHNOLOGY AND BIOENGINEERING. 221-230
`(May 1997) (“Hevehan”)
`
`1006 WO 95/32216 (“Ruddon”)
`
`1007
`
`Schafer, F. & Buettner, G., Redox Environment of the Cell as
`Viewed Through the Redox State of the Glutathione
`Disulfide/Glutathione Couple, 30:11 FREE RADICAL BIOLOGY &
`MEDICINE 1191-12 (June 2001) (“Schafer”)
`
`1008 Whitford, “Proteins: Structure and Function,” September 1, 2005,
`excerpted.
`
`1009
`
`Builder et al., U.S. Patent No. 5,663,304, “Refolding of Misfolded
`Insulin-Like Growth Factor-1,” issued September 2, 1997.
`
`1010 Vallejo and Rinas, “Strategies for the Recovery of Active Proteins
`Through Refolding of Bacterial Inclusion Body Proteins,” Microbial
`Cell Factories, 1-12 (2004).
`
`1011
`
`Cohen et al., U.S. Patent No. 4,237,224, “Process for Producing
`Biologically Functional Molecular Chimeras,” issued December 2,
`1980.
`
`1012
`
`Cohen et al., U.S. Patent No. 4,468,464, “Biologically Functional
`
`-v-
`
`

`

`
`
`Molecular Chimeras,” issued August 28, 1984.
`
`1013
`
`1014
`
`Cohen et al., U.S. Patent No. 4,740,470, “Biologically Functional
`Molecular Chimeras,” issued April 26, 1988.
`
`Johnson, “Human Insulin from Recombinant DNA Technology,” 219
`Science, Vol. 219, 632–637 (1983).
`
`1015 Neubauer et al., “Protein Inclusion Bodies in Recombinant Bacteria,
`Inclusions in Prokaryotes,” Microbiology Monographs, Edited by J.M.
`Shively, Springer, Berlin, Heidelberg, 237-292 (2006).
`
`1016 Ventura and Villaverde, “Protein Quality in Bacterial Inclusion
`Bodies,” TRENDS in Biotechnology, Vol. 24 No. 4, 179-185 (2006).
`1017 Georgiou and Valax, “Isolating Inclusion Bodies from Bacteria,”
`Methods in Enzymology 309:48-58 (1999)
`1018 De Bernardez Clark et al., “Oxidative Renaturation of Hen Egg-White
`Lysozyme. Folding vs Aggregation,” Biotechnology Progress 14(1):47-
`54 (1998)
`
`1019
`
`1020
`
`1021
`
`1022
`
`Clark, “Protein Refolding for Industrial Processes,” Current Opinion in
`Biotechnology, 12:202-207 (2001).
`
`Palmer and Wingfield, “Preparation and Extraction of Insoluble
`(Inclusion-Body) Proteins from Escherichia coli,” Curr Protoc Protein
`Sci., Chapter: Unit–6.3, 1-25 (2004).
`
`Jungbauer and Kaar, “Current Status of Technical Protein Refolding,”
`Journal of Biotechnology, 128, 587–596 (2007).
`
`Panda, “Bioprocessing of Therapeutic Proteins from the Inclusion
`Bodies of Escherichia coli” Adv Biochem Engin/Biotechnol (2003) 85:
`43–93.
`
`1023 Misawa and Kumagai, “Refolding of Therapeutic Proteins Produced in
`Escherichia coli as Inclusion Bodies,” Biopolymers (Peptide Science),
`Vol. 51, 297–307 (1999).
`
`1024 Graumann and Premstaller, “Manufacturing of Recombinant
`Therapeutic Proteins in Microbial Systems,” Biotech J. 1:164-186
`(2006).
`
`-vi-
`
`

`

`
`
`1025 Andersson et al., “Assignment of Interchain Disulfide Bonds in
`Platelet-Derived Growth Factor (PDGF) and Evidence for Agonist
`Activity of Monomeric PDGF,” The Journal of Biological Chemistry,
`Vol. 267, No. 16, 11260-11266 (1992).
`1026 Daopin et al., “Crystal Structure of Transforming Growth Factor-β2:
`An Unusual Fold for the Superfamily,” Science, Vol. 257, 369-373
`(1992).
`
`1027 Gaspar et al., “Cysteine 116 Participates in Intermolecular Bonding of
`the Human VEGF Homodimer,” Archives of Biochemistry and
`Biophysics, 404, 126-135 (2002).
`
`1028 U.S. Patent No. 9,540,429
`
`1029 Gilbert, “Molecular and Cellular Aspects of Thiol-Disulfide
`Exchange,” ADVANCES IN ENZYMOLOGY AND RELATED
`AREAS OF MOLECULAR BIOLOGY, ed. Alton Meister, Vol. 63, pp.
`69-172 (John Wiley & Sons 1990)
`
`1030 Gilbert, “Thiol/Disulfide Exchange Equilibria and Disulfide Bond
`Stability,” METHODS IN ENZYMOLOGY, ed. Lester Packer, Vol.
`251, pp. 8-28 (Academic Press 1995).
`
`1031 U.S. Patent No. 9,856,287 Prosecution History
`
`1032
`
`Apotex Inc. v. Amgen Inc., IPR2016-01542, Paper 60.
`
`1033 U.S. Patent No. 8,952,138
`
`1034
`
`Apotex Inc. v. Amgen Inc., IPR2016-01542, Paper 67.
`
`-vii-
`
`

`

`
`
`Lupin, Ltd. and Lupin Pharmaceuticals, Inc. (together “Petitioner”) request
`
`inter partes review (“IPR”) under 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42 et seq.
`
`of claims 1-30 of U.S. Patent No. 9,856,287 (“the ’287 Patent”) to Shultz et al.
`
`Ex. 1001. Pursuant to 37 C.F.R. § 42.15, the Petition Fee of $52,750.00 is being
`
`paid concurrently with the filing of this Petition. The undersigned representative
`
`of Petitioner hereby authorizes the Patent Office to charge any additional fees or
`
`credit any overpayment to DA232405.
`
`I.
`
`OVERVIEW
`Under Grounds 1 to 6, Petitioner challenges claims 1-30 of the ’287 Patent.
`
`As explained herein and in the accompanying Declaration of George Georgiou,
`
`Ph.D., Ex. 1002, there is nothing novel or unobvious about the protein refolding
`
`methods disclosed and claimed in the ’287 Patent. The ’287 Patent alleges that
`
`the purported invention allows refolding “complex” proteins at “high
`
`concentrations,” which allegedly could not previously be accomplished “with any
`
`meaningful degree of efficiency.” Yet no claims expressly recite refolding
`
`“complex” proteins at “high concentrations.” Furthermore, the ’287 Patent
`
`describes a trial and error approach that was used to identify optimized protein
`
`refolding conditions for individual proteins. But ultimately, the ’287 Patent
`
`simply discloses and claims protein refolding methods that use routine steps and
`
`refolding components to achieve unremarkable protein yields.
`
`-1-
`
`

`

`
`
`For the reasons described below, the challenged claims of the ’287 Patent
`
`are unpatentable over the prior art cited in this Petition. Because Petitioner is, at a
`
`minimum, reasonably likely to prevail in demonstrating the unpatentability of at
`
`least one claim, this Petition should be granted and trial instituted on all of the
`
`challenged claims.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`A. Real Party-In-Interest Under 37 C.F.R. § 42.8(b)(1)
`Lupin, Ltd., Lupin Pharmaceuticals, Inc., Lupin, Inc., and Nanomi BV are
`
`real parties-in-interest for Petitioner. No other parties exercised or could have
`
`exercised control over this petition; no other parties funded or directed this petition.
`
`See Patent Trial and Appeal Board Consolidated Trial Practice Guide November
`
`2019, 12.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`To Petitioner’s knowledge, the ’287 Patent is not the subject of any pending
`
`district court litigation or post-grant proceedings before Patent Trial and Appeal
`
`Board.
`
`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
`
`Application 14/793,590.
`
`-2-
`
`

`

`
`
`The ’287 Patent was the subject of several district court litigations and post-
`
`grant proceedings that have been dismissed or terminated due to settlement by the
`
`parties:
`
` Amgen Inc. et al. v. Tanvex BioPharma USA, Inc. et al., 19-cv-01374, S.D.
`
`Cal. (the “Tanvex litigation”) was dismissed December 19, 2019.
`
` Amgen Inc. et al. v. Adello Biologics, LLC et al., 18-cv-3347, D.N.J., (the
`
`“Adello litigation”) was dismissed November 25, 2019.
`
` Amgen Inc. et al. v. Accord BioPharma USA, Inc. et al., 18-cv-61828, S.D.
`
`Fl. was dismissed November 15, 2019.
`
` PGR2019-00001, Adello Biologics, LLC et al. v. Amgen Inc. et al. (the
`
`“Adello PGR”) was terminated on December 6, 2019. PGR2019-00001,
`
`Paper 28 (P.T.A.B. Dec. 6, 2019).
`
` IPR2019-00971, Fresenius Kabi USA, LLC et al. v. Amgen, Inc. et al. (the
`
`“2019 Fresenius IPR”), was denied institution under § 314(a) as duplicative
`
`of the then-pending Adello PGR, without evaluation on the merits. See
`
`2019 Fresenius IPR, Paper 13 (P.T.A.B. Oct. 16, 2019).
`
` IPR2020-00314, Fresenius Kabi USA, LLC et al. v. Amgen, Inc. et al. (the
`
`“2020 Fresenius IPR”) was terminated on June 19, 2020. Fresenius IPR,
`
`Paper 17 (P.T.A.B. Jun. 19, 2020).
`
`-3-
`
`

`

`C. Lead and Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`Pursuant to 37 C.F.R. §§ 42.8(b)(3) and 42.10(a), Petitioner designates the
`
`
`
`following counsel:
`
`Lead Counsel
`
`
`Thomas J. Meloro (Reg. No. 33,538)
`Willkie Farr & Gallagher LLP
`787 Seventh Avenue
`New York, New York 10019-6099
`
`Telephone: (212) 728-8428
`Facsimile: (212) 728-8111
`tmeloro@willkie.com
`
`
`Back-Up Counsel
`
`
`Michael W. Johnson (Reg. No. 63,731)
`Willkie Farr & Gallagher LLP
`787 Seventh Avenue
`New York, New York 10019-6099
`
`Telephone: (212) 728-8137
`Facsimile: (212) 728-8111
`mjohnson1@willkie.com
`
`D.
`Service Information Under 37 C.F.R. § 42.8(b)(4)
`Please address all correspondence to lead counsel at the contact information
`
`above. Lupin consents to service by electronic mail at tmeloro@willkie.com and
`
`mjohnson1@willkie.com. A Power of Attorney is being filed concurrently
`
`herewith under 37 C.F.R. § 41.10(b).
`
`III. GROUNDS FOR STANDING UNDER 37 C.F.R. § 42.104(a)
`Petitioner certifies that the ’287 Patent is available for IPR, and that
`
`Petitioner is not barred or estopped from requesting IPR of any claim of the ’287
`
`Patent on the grounds set forth herein.
`
`-4-
`
`

`

`
`
`IV. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22)
`Petitioner requests IPR and cancellation of claims 1-30 of the ’287 Patent
`
`under 35 U.S.C. §§ 102 and 103, as set forth herein. Petitioner’s detailed
`
`statement of the reasons for the relief requested is set forth in Section V below.
`
`V. THRESHOLD REQUIREMENT FOR IPR
`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
`
`for the reasons explained below. 35 U.S.C. § 314(a). The Board’s discretion to
`
`deny institution pursuant to 35 U.S.C. §§ 314(a) and 325(d) should not apply here.
`
`A.
`
`Previous examinations of the ’287 Patent support institution
`
`First, the same or substantially the same art or arguments were not presented
`
`to the Office. Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`
`GmbH, IPR2019-01469, Paper 6 (P.T.A.B. Feb. 13, 2020) (precedential). Vallejo,
`
`Ruddon, and Schafer were not before the examiner during prosecution. While
`
`these references were included in subsequent proceedings against the ’287 Patent,
`
`Patent Owner settled those proceedings before there could be a decision on
`
`patentability. Therefore, these IPRs should have no effect because the two-part
`
`framework in Advanced Bionics “reflects a commitment to defer to previous Office
`
`evaluations of the evidence of record unless material error is shown.” Id., 9
`
`(emphasis added). To the extent Patent Owner suggests that references similar to
`
`-5-
`
`

`

`
`
`Vallejo, Ruddon, or Schafer were considered by the Board, these similar references
`
`were not evaluated during examination and were not the basis for rejection.
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586, Paper 8,
`
`17–18 (P.T.A.B. Dec. 15, 2017) (precedential as to § III.C.5, first paragraph).
`
`Even if the same or similar arguments were considered, the Office erred in a
`
`manner material to the patentability of the claims. While the combination of
`
`Schlegl and Hevehan was considered by the Examiner during prosecution, the
`
`Board did not have the benefit of the Final Written Decision finding claims of
`
`parent U.S. Pat. No. 8,952,138 (“the ’138 Patent”) unpatentable, which rejected the
`
`same arguments made by Patent Owner in its attempt to overcome the combination
`
`of Schlegl and Hevehan. In both the prosecution of the ’287 Patent, and the IPR
`
`invalidating claims of the parent ’138 Patent, Patent Owner argued that redox
`
`chemicals do not play a role in Schlegl’s refolding method. Ex. 1031, 165; Ex.
`
`1032, 19. Additionally, this Petition cites to portions of Schlegl that do not
`
`appear to have been considered by the Examiner, see Ex. 1004, [0082], and
`
`includes new evidence not previously considered in the form of an expert
`
`declaration from Dr. Georgiou.
`
`B.
`
`The previous petitions from unrelated parties weigh against
`denying institution
`Second, the General Plastic factors weigh against denying institution here.
`
`General Plastic Indus. Co. v. Canon Kabushiki Kaisha, IPR2016-01357, Paper 19,
`
`-6-
`
`

`

`
`
`9–10 (P.T.A.B. Sept. 6, 2017) (precedential as to § II.B.4.i) (“the General Plastic
`
`factors”). When applying the General Plastic factors to different petitioners, the
`
`Board considers “any relationship between those petitioners when weighing the
`
`General Plastic factors.” Valve Corp. v. Elec. Scripting Prods., Inc., Case
`
`IPR2019-00062, Paper 11, 9-10 (P.T.A.B. April 2, 2019) (precedential).
`
`Factor 1: The first General Plastic factor looks at “whether the same
`
`petitioner filed a petition directed to the same claims of the same patent.” While
`
`there have been previous petitions against the ’287 Patent, there is no relationship
`
`between Petitioner and the previous petitioners—Fresenius and Adello.1 In fact,
`
`Petitioner is a competitor with Fresenius and Adello, and plans to offer a
`
`competing product. Petitioner was not named as a party-in-interest in any of the
`
`previous IPRs, a Defendant in any of the related district court litigations by Patent
`
`Owner against Fresenius and Adello, or a party to either confidential settlement
`
`agreement. Unlike Fresenius, Petitioner did not participate in Adello’s PGR
`
`deposition, the previous petitions have all been dismissed, and there is no
`
`coordination between Petitioner and Fresenius and Adello. Furthermore, there is
`
`not complete overlap between the challenged claims in this petition and the
`
`
`1 In this Section, Adello refers to all Petitioners in PGR2019-00001, including
`
`Adello Biologics, LLC, Apotex Corp., and Apotex Inc.
`
`-7-
`
`

`

`
`
`Fresenius IPRs, and there is not complete overlap between the grounds in this
`
`petition and either the Adello and Fresenius IPRs. Therefore, the first General
`
`Plastic factor weighs heavily against denying institution. LG Electronics, Inc. v.
`
`Bell Northern Research, LLC, IPR2020-00319, Paper 15, 15 (P.T.A.B. June 23,
`
`2020) (“The fact that this is an unrelated Petitioner presenting some new references
`
`and non-overlapping claims weighs against denying institution under § 314(a)
`
`quite heavily.”).
`
`Factor 2: The second General Plastic factor should be given little weight.
`
`Unlike in Valve, Petitioner has no relationship to the petitioners that filed the
`
`previous IPRs, so Petitioner’s knowledge of the prior art does not help to prove or
`
`disprove diligence. As explained below for the fourth and fifth General Plastic
`
`factors, Petitioner is filing this petition at the appropriate time.
`
`Factor 3: The third General Plastic factor should be given little weight.
`
`The previous proceedings were terminated following settlement. “[T]he potential
`
`for abuse by instituting an arguably follow-on Petition in this case has been
`
`ameliorated by the termination” of the earlier proceedings. Fresenius Kabi USA,
`
`LLC v. Amgen, Inc., IPR2019-01183, Paper 10, 11-12 (P.T.A.B. Dec. 10, 2019)
`
`(granting institution when previous IPR had terminated after institution but before
`
`the Patent Owner Response). The arguments in this Petition have not been
`
`tailored to Patent Owner’s previous preliminary responses or the previous
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`institution decisions. Furthermore, Patent Owner avoided a Final Written
`
`Decision on the patentability of the ’287 Patent in PGR2019-00001 by settling
`
`before it filed its Response. Patent Owner should not be able to use previous
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`settlements to continue to insulate the ’287 Patent from a determination of
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`patentability.
`
`Factors 4 and 5: The fourth and fifth General Plastic factors both weigh
`
`against denying institution. PGR2019-00001 was filed on October 1, 2018,
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`IPR2019-00971 was filed on April 14, 2019, and IPR2020-00314 was filed on
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`December 20, 2019. All other proceedings, including district court proceedings,
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`have been settled and terminated. There has been no allegation that Petitioner
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`infringes the ’287 Patent.
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`Regardless of the disputes Patent Owner has had with competitors of
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`Petitioner, Petitioner is filing this IPR early—before any litigation between Patent
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`Owner and Petitioner regarding the ’287 Patent. Petitioner did not have any
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`reason to believe that such an IPR was necessary when the previous proceedings
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`were filed. Petitioner expects to file an aBLA for a pegfilgrastim biosimilar in
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`FY21. At the time of the filing of the previous proceedings, Petitioner was years
`
`away from a potential regulatory filing. The development of Petitioner’s
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`pegfilgrastim biosimilar is a change in the underlying facts, not underlying law as
`
`seen in Valve, that justifies the filing of the petition now. If Petitioner had filed a
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`petition when PGR2019-00001 was filed, Petitioner would have risked being
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`unable to appeal an unfavorable Final Written Decision. See, e.g., Pfizer Inc. v.
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`Chugai Pharm. Co.., 812 F. App’x 979, 981 (Fed. Cir. 2020).
`
`Petitioner should not be denied access to the more efficient IPR process
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`because it did not file its IPR years before it knew that such an IPR would be
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`necessary. Allowing Patent Owner and Petitioner’s competitors to deny a
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`subsequent competitor access to IPRs by settling would be unfairly prejudicial.
`
`Cf. Lowe’s, Cos. v. Nichia Corp., IPR2017-02011, Paper 13, 19 (P.T.A.B. Mar. 12,
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`2018) (“Denial of the Petition in part would prejudice the Petitioner in this
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`proceeding should the [other] Petitions be resolved by settlement.”).
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`Factors 6 and 7: The sixth and seventh General Plastic factors both
`
`weigh against denying institution. The finite resources of the Board “do not
`
`weigh in favor of denial in this case because there are no longer multiple petitions
`
`challenging the same patent.” Fresenius, IPR2019-01183, Paper 10, 12-13.
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`Similarly, there is no concern about the statutory requirements under 35 U.S.C. §
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`316(a)(11) because there are no other pending proceedings and the present
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`proceeding can be resolved within the statutory timeframe.
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`VI.
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`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`Petitioners request IPR and cancellation of claims 1-30 of the ’287 Patent
`
`under §§ 102 and 103. In support of the proposed grounds for unpatentability,
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`this Petition is accompanied by the Declaration of George Georgiou, Ph.D. (Ex.
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`1002) and the prior art references of the grounds and additional background art.
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`Per 37 C.F.R. § 42.6(c), copies of the references are filed herewith.
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`A. The Challenged Claims and Grounds (37 C.F.R. §§ 42.104(b)(1)
`and (2))
`Pursuant to 37 C.F.R. §§ 42.104(b)(1) and (2), the following grounds are
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`offered as reasons for canceling claims 1-30 of the ’287 Patent:
`
`Ground
`1
`
`Reference(s)
`Vallejo
`
`Statutory Basis
`§ 102(b)
`
`Challenged Claims
`1-4, 7-19, and 22-30
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Schlegl
`
`§ 102(b)
`
`1-4, 8-19, and 23-30
`
`Vallejo and Hevehan
`
`§ 103(a)
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`1-30
`
`Schlegl and Hevehan
`
`§ 103(a)
`
`1-6, 8-21, and 23-30
`
`Vallejo, Schafer, and
`Ruddon
`
`Schlegl, Schafer, and
`Ruddon
`
`§ 103(a)
`
`§ 103(a)
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`8-9, 14-15, 23-25, and
`30
`
`8-9, 14-15, 23-25, and
`30
`
`
`VII. TECHNOLOGY BACKGROUND
`
`The technical summary below describes the knowledge in the art as of the
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`earliest priority date on the face of the ’287 Patent, which is June 22, 2009. See
`
`Ex. 1002, ¶30.
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`A.
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`Protein Structure
`
`The polypeptide chains that make up proteins must fold into their native
`
`three-dimensional shapes in order to be biologically active. Ex. 1002, ¶31; Ex.
`
`1008, 40-67. Chemical bonds known as disulfide bonds can stabilize the native
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`three-dimensional structure of proteins by cross-linking different parts of the
`
`folded polypeptide chains. Ex. 1002, ¶32; Ex. 1009, 2:34-47. If disulfide bonds
`
`form in improper locations, the proteins can misfold, making them potentially
`
`inactive. Ex. 1002; Ex. 1009, 2:8-17.
`
`B. Recombinant Protein Synthesis
`Proteins can be synthesized in the laboratory using recombinant DNA
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`technology, which has been known in the art since the late 1970s. Ex. 1002,
`
`¶¶33-35; Ex. 1011; Ex. 1012; Ex. 1013; Ex. 1014. Recombinant DNA
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`technology was commonly used to express protein in non-mammalian expression
`
`systems, including in the bacterium E. coli. Ex. 1002, ¶36; Ex. 1015, 5.
`
`Recombinant proteins produced in bacterial cells often produces misfolded
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`proteins that aggregate together in inclusion bodies. Ex. 1002, ¶¶36-37; Ex. 1010,
`
`1; Ex. 1015, 5; Ex. 1016, 4; Ex. 1017, 1. Various techniques had been developed
`
`for recovering native, folded proteins in a biologically active and stable form from
`
`inclusion bodies. Ex. 1002, ¶38. The most common techniques followed a
`
`general process in which proteins in inclusion bodies are (1) solubilized causing
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`the proteins to dissociate and unfold; and (2) refolded into their native
`
`conformation. Ex. 1002, ¶38; Ex. 1018, 7; Ex. 1019, 6.
`
`1.
`Unfolding and Refolding of Recombinant Proteins
`Proteins are solubilized in a buffer composed of chemical denaturants that
`
`disrupt the bonds and other forces holding the aggregated proteins together, which
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`causes the proteins to dissociate from the aggregates and unfold into single
`
`polypeptide strands. Ex. 1002, ¶¶39-40; Ex. 1015, 35; Ex. 1019, 6-7; Ex. 1020, 8;
`
`Ex. 1024, 6-7. Solubilized proteins are then placed in a refold buffer, also
`
`commonly referred to as a renaturation buffer under conditions that allow proper
`
`folding into the native protein structure. Ex. 1002, ¶42. The refold buffer can
`
`include denaturants, aggregate suppressors, protein stabilizers, as well as oxidants,
`
`and reductants if the native protein structure includes disulfide bonds, each of
`
`which may be adjusted to optimize the efficiency of refolding. Ex. 1002, ¶¶41-42;
`
`Ex. 1015, 36-39; Ex. 1021, 2-3; Ex. 1022, 36-37. Temperature, pH, timing, and
`
`purification methods can also be optimized to complement the process. Ex. 1002,
`
`¶¶43-44; Ex. 1009, Tables IV-VII; Ex. 1005, 1-2; Ex. 1015, 36-39; Ex.1022, 36-37.
`
`2. Optimizing Redox Conditions
`If the desired protein contains disulfide bonds in its native state, the unfolded
`
`proteins must be placed in appropriate redox conditions that favor the formation of
`
`the correct disulfide bonds. Ex. 1002, ¶45; Ex. 1005, 5. The redox conditions
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`are balanced so that oxidation is favored as thermodynamics drives the protein
`
`chains to fold into their native, most-stable conformation over time, but not so
`
`favored that misformed disulfide bonds can reform, known as reshuffling,. Ex.
`
`1002, ¶45; Ex. 1019, 8-9. Scientists used redox systems consisting of a mixture
`
`of reduced and oxidized thiols, sometimes called a thiol pair. Ex. 1002, ¶45; Ex.
`
`1005, 8-9. Commonly used thiol pairs include GSH/GSSG, cysteine/cysteine,
`
`and cysteamine/cystamine. Ex. 1002, ¶42, 46; Ex. 1019, 9.
`
`It was known that the ratio and total concentration of the thiol pairs in the
`
`redox mixture control the desired equilibrium of reduction and oxidization and thus
`
`are important for proper protein folding. Ex. 1002, ¶46; Ex. 1018, 10 (“When
`
`working with reduced and oxidized glutathione as the thiol/disulfide system, not
`
`only must the ratio of reduced to oxidized glutathione be considered but the total
`
`glutathione concentration as well.”); Ex. 1023, 11.
`
`It was also known that the total thiol concentration is the sum of all the
`
`molecules of the reduced species (e.g., GSH) plus two times the molecules of the
`
`oxidized species (e.g., GSSG) because the oxidized species is