`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`ADELLO BIOLOGICS, LLC,
`APOTEX INC. and APOTEX CORP.,
`Petitioners
`
`v.
`
`AMGEN INC. and AMGEN MANUFACTURING, LIMITED,
`Patent Owners.
`______________________
`
`Case PGR2019-00001
`Patent 9,856,287 B2
`______________________
`
`
`
`PATENT OWNERS’ RESPONSE
`UNDER 37 C.F.R. § 42.220
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`EX2026
`EX2027
`EX2028
`
`EX2029
`
`EX2030
`
`EX2031
`
`EX2032
`EX2033
`
`EX2034
`
`EX2035
`EX2036
`
`EX2037
`
`EX2038
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`LIST OF EXHIBITS
`
`
`Description
`Expert Declaration of Richard C. Page, Ph.D.
`Deposition of Anne S. Robinson (Jul 10, 2019)
`Joint Claim Construction and Prehearing Statement, Amgen Inc., et
`al. v. Kashiv Biosciences LLC, et al., No. 2:18-cv-03347 (CCC-
`MF), DE 101 (March 22, 2019)
`Gohda, S., et al., “The Superreactive Disulfide Bonds in α-
`Lactalbumin and Lysozyme,” Journal of Protein Chem., 14(8):
`731-737 (1995)
`Excerpt of Declaration of Anne S. Robinson, Ph.D. in Support of
`Defendants’ Opening Claim Construction Brief, Amgen Inc., et al.
`v. Apotex Inc., et al., No. 15-cv-61631-CV-COHN, DE 76-4 (Dec.
`11, 2015).
`Excerpt of Declaration of Anne S. Robinson, Ph.D. in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,940,878,
`Kashiv Biosciences, LLC v. Amgen Inc., IPR2019-00791 (EX1002)
`(March 7, 2019)
`Declaration of Sayem Osman
`Pereira, D.A., Williams, J.A., “Origin and Evolution of High
`Throughput Screening,” Br. Journal of Pharmacology, 152(1): 53-
`61 (Sep. 2007)
`Oganesyan, N., et al., “On-Column Protein Refolding for
`Crystallization,” J. Structural & Functional Genomics, 6:177-182
`(2005)
`Intentionally Omitted
`Palandra, J., et al., “Flexible Automated Approach for Quantitative
`Liquid Handling of Complex Biological Samples,” Anal. Chem.,
`79, 9010-9015 (2007)
`Cohen, S. et al., “Fully Automated Screening Systems,” Methods
`Mol. Biol., 190:213-228 (2002)
`Tsumoto, K., et al., “Highly Efficient Recovery of Functional
`Single-Chain Fv Fragments from Inclusion Bodies Overexpressed
`in Escherichia Coli by Controlled Induction of Oxidizing
`Reagent—Application to a Human Single Chain Fv Fragment,”
`Journal of Immunological Methods, 219:119-129 (1998)
`
`i
`
`

`

`
`
`Exhibit
`EX2039
`
`EX2040
`
`EX2041
`
`EX2042
`
`EX2043
`
`EX2044
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`Description
`Lutz, M.W., et al., “Experimental Design for High-Throughput
`Screening,” Drug Discovery Today, 1(7): 277-286 (July 1996)
`Tye, H., “Application of Statistical ‘Design of Experiments’
`Methods in Drug Discovery,” Drug Discovery Today, 9(11): 485-
`491 (June 2004)
`Gerami et al., “Co-Solute Assistance in Refolding of Recombinant
`Proteins,” African Journal of Biotechnology, 10(53): 10811-10816
`(Sep. 2011)
`Sethuraman, A. et al., “Protein Structural Perturbation and
`Aggregation on Homogeneous Surfaces,” Biophysical Journal,
`Vol. 88: 1322-1333 (Feb. 2005)
`“Explain the four levels of protein structure, indicating the
`significance of each level,” available at http://www.old-
`ib.bioninja.com.au/higher-level/topic-7-nucleic-acids-and/75-
`proteins.html
`U.S. Patent No. 5,428,130
`
`
`
`
`
`
`
`ii
`
`

`

`
`
`I.
`II.
`
`B.
`
`C.
`
`B.
`
`V.
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`The Challenged Claims Of The ’287 And The Level Of Skill In The
`Art .................................................................................................................... 6
`III. Claim Construction ........................................................................................ 10
`A.
`“At Least About 25%” Should Not Be Construed To Require
`Exactly 25% To 100% Refolding (Claims 1-9 and 16-25) ................. 10
`The Claimed Yields (Refolding Percentages) Relate To The
`Yield Of Target Protein Not All Protein ............................................. 13
`“Wherein The Thiol-Pair Buffer Strength Maintains The
`Solubility Of The Preparation” And “Wherein The Thiol-Pair
`Buffer Strength Maintains The Solubility Of The Solution” .............. 14
`“Is Calculated” (Dependent Claims 8, 9, 14, 15, 23, 24, And 25) ...... 19
`D.
`IV. Petitioners Failed To Establish That The ’287 Is A Post-AIA Patent ........... 20
`A.
`Petitioners Have Not Established That Claims 1-9 And 16-25
`Were Not Fully Disclosed In The ’287’s Priority Applications
`Before March 16, 2013 ........................................................................ 21
`1.
`Petitioners Failed to Demonstrate That The Priority
`Applications Lack Written Description Support for “At
`Least About 25% Of The Proteins Are Properly Folded” ........ 24
`Petitioners Failed To Demonstrate That Claims 1-9 And 16-25
`Were Not Fully Enabled By The ’287’s Priority Applications ........... 33
`Petitioners Failed To Establish Lack Of Written Description Or
`Enablement For Ground 1 And 2 .................................................................. 42
`VI. The Challenged Claims Are Not Anticipated By Or Obvious Over
`Any Prior Art ................................................................................................. 46
`A.
`Claims 1-4, 7-19, And 22-30 Are Not Anticipated By Vallejo
`(Ground 3), Nor Are Claims 5, 6, 20, And 21 Obvious Over
`Vallejo In View Of Hevehan (Ground 7) ............................................ 46
`1.
`Claims 1-4, 7-19, And 22-30 Are Not Anticipated By
`Vallejo (Ground 3) .................................................................... 46
`Petitioners Have Not Established That Claims 5, 6, 20,
`And 21 Are Obvious Over Vallejo In View Of Hevehan
`(Ground 7) ................................................................................. 58
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`2.
`
`iii
`
`

`

`
`
`B.
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`Petitioners Failed To Establish That Claims 1-4, 8-19, And 23-
`30 Are Anticipated By Schlegl (Ground 4), And That Claims 7
`And 22 Are Obvious Over Schlegl In View Of Vallejo (Ground
`5) .......................................................................................................... 61
`1.
`Petitioners Have Not Established That Claims 1-4, 8-19,
`And 23-30 Are Anticipated By Schlegl (Ground 4) ................. 61
`Petitioners Have Not Established That Claims 7 And 22
`Are Unpatentable Over Schlegl In View Of Vallejo
`(Ground 5) ................................................................................. 69
`Petitioners Have Not Established That Claims 1-4, 7-19, And
`22-30 Are Obvious Over Ruddon In View Of Vallejo (Ground
`6) .......................................................................................................... 71
`1.
`Ruddon Does Not Teach Refolding Protein Expressed In
`A Non-Mammalian System Into Properly Refolded
`Biologically Active Protein ....................................................... 71
`Petitioners Failed To Show How Or Why Ruddon And
`Vallejo Would Be Combined To Arrive At The Claimed
`Invention ................................................................................... 73
`POSITA Would Not Reasonably Expect That The
`Teachings Of Ruddon And Vallejo Could be
`Successfully Combined ............................................................. 74
`Neither Ruddon Nor Vallejo Teach The Limitations
`“Thiol-Pair Buffer Strength Maintains The Solubility Of
`The Preparation” Or “Thiol-Pair Buffer Strength
`Maintains The Solubility Of The Solution” .............................. 76
`Neither Ruddon Nor Vallejo Teach “Is Calculated”
`Under The Correct Construction (Claims 8, 9, 14, 15, 23,
`24, 25, 30) ................................................................................. 77
`VII. Petitioners Failed To Establish That Claims 1-15 Are Indefinite
`(Ground 8) .................................................................................................... 77
`VIII. Petitioners’ Expert Is Not Credible Or Reliable ............................................ 82
`IX. Conclusion ..................................................................................................... 86
`
`
`
`2.
`
`C.
`
`2.
`
`3.
`
`4.
`
`5.
`
`iv
`
`

`

`
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`
`CASES
`In re Abbott Diabetes Care Inc.,
`696 F.3d 1142 (Fed. Cir. 2012) .......................................................................... 10
`Alcon Research Ltd. v. Barr Labs., Inc.,
`745 F.3d 1180 (Fed. Cir. 2014) .............................................................. 22, 39, 40
`All Dental Prodx LLC v. Advantage Dental Prods., Inc.,
`309 F.3d 774 (Fed. Cir. 2002) ............................................................................ 22
`Amgen, Inc. v. Chugai Pharm. Co.,
`927 F.2d 1200 (Fed. Cir. 1991) .......................................................................... 59
`Andersen Corp. v. Fiber Composites, LLC,
`474 F.3d 1361 (Fed. Cir. 2007) .................................................................... 12, 33
`In re Angstadt,
`537 F.2d 498 (C.C.P.A. 1976) ............................................................................ 40
`Ariad Pharm., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) .................................................... 22, 44
`Arris Int’l PLC v. Sony Corp.,
`IPR2016-00828, Pap. 10 (Oct. 7, 2016) ............................................................. 73
`Atlas Powder Co. v. E.I. du Pont De Nemours & Co.,
`750 F.2d 1569 (Fed. Cir. 1984) .......................................................................... 41
`Ex Parte Baxter Int’l, Inc.,
`Appeal 2009-006493 (BPAI Mar. 18, 2010) ...................................................... 43
`Ex Parte Cai,
`Appeal 2011-005302 (BPAI Dec. 9, 2011) ....................................................... 37
`Capon v. Eshhar,
`418 F.3d 1349 (Fed. Cir. 2005) .......................................................................... 22
`
`
`
`v
`
`

`

`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`
`
`
`TABLE OF AUTHORITIES (CONTINUED)
`Costco Wholesale Corp. v. Robert Bosch LLC,
`IPR2016-00035, Pap. 23 (Aug. 12, 2016) .......................................................... 65
`Crown Operations Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .................................................................... 25, 34
`CVI/Beta Ventures, Inc. v. Tura LP,
`112 F.3d 1146 (Fed. Cir. 1997) .......................................................................... 13
`Falko-Gunter Falkner v. Inglis,
`448 F.3d 1357 (Fed. Cir. 2006) .......................................................................... 22
`Fox Factory, Inc. v. SRAM, LLC,
`PGR2016-00043, Pap. 9 (Apr. 3, 2017) ............................................................. 34
`Fujian Sanan Grp. Co. v. Epistar Corp.,
`IPR2018-00971, Pap. 9 (Nov. 20, 2018) ............................................................ 53
`Google Inc. v. Unwired Planet, LLC,
`CBM2014-00006, Pap. 51 (Aug. 13, 2018) ....................................................... 42
`Hybritech Inc. v. Abbott Labs.,
`849 F.2d 1446 (Fed. Cir. 1988) .......................................................................... 11
`Hybritech, Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) .......................................................................... 35
`Hyundai Motor Co. v. Blitzsafe Texas, LLC,
`IPR2016-01477, Pap. 13 (Jan. 27, 2017) ............................................................ 55
`I.M.L. SLU v. WAG Acquisition, LLC,
`IPR2016-01658, Pap. 46 (Feb. 27, 2018) ........................................................... 43
`Inphi Corp. v. Netlist, Inc.,
`805 F.3d 1350 (Fed. Cir. 2015) .......................................................................... 23
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ................................................................ 3, 59, 72
`
`vi
`
`

`

`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`
`
`TABLE OF AUTHORITIES (CONTINUED)
`Johnson Matthey Inc. v. BASF Corp.,
`IPR2015-01267, Pap. 35 (Nov. 30, 2016) .......................................................... 59
`Kingston Tech. Co. v. Spex Techs., Inc.,
`IPR2017-01021, Pap. 39 (Oct. 1, 2018) ............................................................. 69
`Ex Parte Liu,
`Appeal 2009-015302 (BPAI Sept. 17, 2010) ..................................................... 37
`Microsoft Corp. v. Biscotti, Inc.,
`878 F.3d 1052 (Fed. Cir. 2017) .......................................................................... 49
`Microsoft Corp. v. Biscotti Inc.,
`IPR2014-01459, Pap. 49 (March 17, 2016),
`aff’d 878 F.3d 1052 (Fed. Cir. 2017) .................................................................. 53
`Mobile Tech, Inc. v. InVue Sec. Prods. Inc.,
`PGR2018-00004, Pap. 15 (May 3, 2018) ........................................................... 21
`Nat’l Recovery Techs., Inc. v. Magnetic Separation Sys., Inc.,
`166 F.3d 1190 (Fed. Cir. 1999) .......................................................................... 35
`Nautilus, Inc. v. Biosig. Instruments, Inc.,
`572 U.S. 898 (2014) ............................................................................................ 77
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 49
`Nintendo Co. v. Genuine Enabling Tech., LLC,
`IPR2018-00543, Pap. 7 (Aug. 6, 2018) .............................................................. 75
`In re NuVasive, Inc.,
`841 F.3d 966 (Fed. Cir. 2016) .............................................................................. 3
`Perkinelmer Health Scis., Inc. v. Agilent Techs., Inc.,
`962 F. Supp. 2d 304 (D. Mass. 2013) ................................................................. 12
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .................................................... 14, 44
`Rexnord Corp. v. Laitram Corp., 274 F.3d 1336 (Fed. Cir. 2001) .......................... 17
`
`vii
`
`

`

`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`
`
`TABLE OF AUTHORITIES (CONTINUED)
`RF Del., Inc. v. Pac. Keystone Techs., Inc.,
`326 F.3d 1255 (Fed. Cir. 2003) .......................................................................... 15
`Rimfrost AS v. Aker BioMarine Antarctic AS,
`PGR2018-00033, Pap. 9 (Aug. 29, 2018) ........................................................... 33
`Rohm & Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .............................................................. 35, 40, 55
`Scripps Clinic & Research Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) .......................................................................... 12
`SecureNet Techs., LLC v. Icontrol Networks, Inc.
`IPR2016-01919, Pap. 9 (Mar. 30, 2017) ............................................................ 53
`St. Jude Med., LLC v. Snyders Heart Valve LLC,
`IPR2018-00105, Pap. 59 (May 2, 2019) ............................................................. 73
`Streck, Inc. v. Research & Diagnostic Sys., Inc.,
`665 F.3d 1269 (Fed. Cir. 2012) .................................................................... 23, 44
`Sumitomo Dainippon Pharma Co. v. Emcure Pharm. Ltd.,
`887 F.3d 1153 (Fed. Cir. 2018) .......................................................................... 15
`Symantec Corp. v. RPost Commc’ns Ltd.,
`IPR2014-00357, Pap. 14 (July 15, 2014) ........................................................... 49
`SynQor, Inc. v. Artesyn Techs., Inc.,
`709 F.3d 1365 (Fed. Cir. 2013) .......................................................................... 48
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) ...................................................................... 18, 19
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .......................................................... 35, 37, 42, 45
`Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc.,
`853 F.3d 1272 (Fed. Cir. 2017) ............................................................................ 3
`In re Wertheim,
`541 F.2d 257 (C.C.P.A. 1976) ............................................................................ 32
`
`viii
`
`

`

`
`
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`TABLE OF AUTHORITIES (CONTINUED)
`
`STATUTES
`35 U.S.C § 312(a)(3) ................................................................................................ 73
`35 U.S.C. § 326(e) ................................................................................................... 21
`REGULATIONS
`37 C.F.R. § 42.65(a) ..................................................................................... 34, 40, 55
`37 C.F.R. § 42.108(c) ................................................................................................. 1
`37 C.F.R. § 42.200(b) .............................................................................................. 10
`77 Fed.Reg. at 48,767 (Aug. 14, 2012) ...................................................................... 3
`83 Fed.Reg. at 51340 (Oct. 11, 2018) ...................................................................... 10
`Fed. R. Evid. 104(b)(3) .............................................................................................. 3
`AIA § 3(n)(1) ........................................................................................................... 21
`AIA § 6(f)(2)(A) ...................................................................................................... 21
`
`
`
`
`ix
`
`

`

`
`I.
`
`Introduction
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`U.S. Patent No. 9,856,287’s (“’287”) invention addressed the difficulty of
`
`identifying acceptable protein refolding conditions by controlling the
`
`concentrations of the reductant and oxidant present in the refolding buffer in a
`
`particular manner, and presented a novel and efficient protein refolding method
`
`based on control of redox conditions with reductant and oxidant (“redox”)
`
`reagents. Patent Owners1 now address the Petition’s numerous errors and
`
`omissions, supported by Dr. Page’s expert testimony (EX2026), and free of
`
`§42.108(c)’s institution-only constraints.2
`
`First, as demonstrated below, the ’287 is not eligible for PGR since it issued
`
`from a transition application that properly claims priority to applications filed well
`
`before the March 16, 2003 statutory cut-off for PGRs. Petitioners attempt to break
`
`
`
` 1
`
` Petitioners listed both Amgen Inc. and Amgen Manufacturing, Limited in the
`
`caption as “Patent Owner.” Amgen Manufacturing, Limited is an exclusive
`
`licensee. Nevertheless, consistent with the caption, this Response refers
`
`collectively to both parties, collectively, as “Patent Owners” or “Amgen.”
`
`2 All emphasis/annotations added unless noted; statutory/regulatory citations are to
`
`35 U.S.C. or 37 C.F.R., as context indicates.
`
`1
`
`

`

`
`the priority chain to establish PGR eligibility, but their written description and
`
`
`
`PGR2019-00001
`U.S. Patent 9,856,287
`
`enablement arguments are incomplete and without merit. The 25% yield number
`
`in the claims for which Petitioners challenge written description is supported by
`
`the specification and figures in the priority application, as found during
`
`prosecution. And, with respect to enablement, POSITA could achieve close to
`
`100% refolding in 2009, and this invention made it easier for POSITA to identify
`
`optimal refolding conditions. Thus, POSITA would certainly have been able to
`
`achieve close to 100% refolding without undue experimentation using the
`
`teachings of the patent in 2009.
`
`Second, even if Petitioners were to succeed in breaking the priority chain,
`
`Grounds 1 (written description) and 2 (enablement) fail because their analyses are
`
`based in the wrong decade. For these Grounds, Petitioners assert that the ’287
`
`application, which was filed in 2017, does not provide sufficient written
`
`description or enablement support. However, Petitioners’ analyses are based
`
`solely on the state of the art and POSITA’s knowledge as of 2009—the date of the
`
`first priority application. Petitioners merely incorporate their same PGR eligibility
`
`arguments without bothering to update their analysis to account for the state of the
`
`art in 2017. And their expert analyzed the state of the art only as of 2009.
`
`Accordingly, these Grounds fail for a lack of proof, and, even if the Board were to
`
`2
`
`

`

`
`consider Petitioners’ 2009-based arguments, the ’287 specification provides
`
`
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`PGR2019-00001
`U.S. Patent 9,856,287
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`sufficient support for the claims.3
`
`
`
` 3
`
` Petitioners have made no arguments for any of their grounds (including, inter
`
`alia, enablement, written description, novelty, obviousness, or indefiniteness)
`
`based on the state of the art in 2017. Thus, Amgen has no arguments from
`
`Petitioner as of the alleged 2017 priority date that Amgen can respond to and rebut
`
`with evidence and argument of its own. This failure of proof violated the basic
`
`rules for the contents of a petition, see, e g., Rule 104(b)(3), and Petitioners should
`
`not be able to remedy this deficiency on Reply (which, inter alia, would deprive
`
`Amgen of a meaningful opportunity to respond). See Wasica Fin. GmbH v. Cont’l
`
`Auto. Sys., Inc., 853 F.3d 1272, 1286 (Fed. Cir. 2017) (rejecting reply brief
`
`attempting to cure deficiencies in petition and noting the “obligation for petitioners
`
`to make their case in their petition”); In re NuVasive, Inc., 841 F.3d 966, 972-73
`
`(Fed. Cir. 2016) (vacating final written decision when Board relied on factual
`
`assertion by petitioner not asserted until after patent owner’s Response because
`
`patent owner was not given fair notice and opportunity to respond); Intelligent Bio-
`
`Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367–68 (Fed. Cir. 2016);
`
`Trial Practice Guide,77 Fed.Reg. at 48,767 (Aug. 14, 2012) (“[A] reply that raises
`
`3
`
`

`

`Third, with respect to Grounds 3-7, which present Petitioners various
`
`
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`PGR2019-00001
`U.S. Patent 9,856,287
`
`
`
`anticipation and obviousness analyses, Petitioners have not met their burden for at
`
`least the following reasons:
`
`•
`
`Petitioners failed to present any analysis for any Ground under the proper
`
`constructions of the “maintains the solubility” terms.
`
`• With respect to Vallejo, Petitioners’ thiol-pair buffer pair ratio calculation is
`
`incorrect, Petitioners improperly mix and match embodiments, and
`
`Petitioners provide no proof that the yield described in Vallejo is calculated
`
`in the same way as the yield in the claims.
`
`• With respect to Schlegl, inter alia, Petitioners offered no proof that the
`
`bovine α-lactalbumin protein Petitioners rely on in Schlegl was produced in
`
`a non-mammalian expression system; Petitioners mixed and matched
`
`Schlegl’s “renaturation buffer” and “refold buffer” (which are different) in
`
`mapping both the “preparation” and “solution” in the claims; Petitioners
`
`performed the wrong math in calculating the thiol-pair ratio; and Petitioners
`
`
`
` a
`
` new issue or belatedly presents evidence will not be considered and may be
`
`returned.”).
`
`4
`
`

`

`
`
`•
`
`•
`
`
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`PGR2019-00001
`U.S. Patent 9,856,287
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`provided no proof that the yield described in Schlegl is calculated in the
`
`same way as the yield described in the claims.
`
`Ruddon does not teach refolding recombinantly produced protein into
`
`properly refolded biologically active protein as required by the claims.
`
`Petitioners failed to present any argument regarding the dependent claims
`
`requiring thiol-pair ratio and thiol-pair buffer strength to be “calculated”
`
`(claims 8, 9, 14, 15, 23, 24, 25, and 30) when that term is properly
`
`construed.
`
`•
`
`Petitioners’ obviousness arguments are legally insufficient. With respect to
`
`Ruddon and Vallejo, for example, Petitioners failed to show how the
`
`references could be combined to arrive at the claimed invention, why
`
`POSITA would have been motivated to combine the teachings of the
`
`references, and why POSITA have a reasonable expectation of success in
`
`doing so.
`
`Fourth, with respect to Ground 8, which alleges that the term “maintains the
`
`solubility of the preparation” is indefinite, this Ground fails because the plain
`
`meaning of that term is clear from the claims, as further confirmed by the
`
`admissions of Petitioners’ expert, Dr. Anne S. Robinson, in a related case. Indeed,
`
`Petitioners admit the plain meaning of “maintains the solubility of the preparation”
`
`indicates that the solubility of the preparation does not refer to the solubility of the
`
`5
`
`

`

`
`proteins, which undercuts and eliminates one supposed source of ambiguity
`
`
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`PGR2019-00001
`U.S. Patent 9,856,287
`
`asserted by the Petitioners. And Dr. Robison admitted in previous testimony that
`
`the “preparation” does not itself include protein.
`
`Fifth, because Dr. Robinson’s testimony is contradictory, inconsistent, and
`
`self-serving, her statements are not credible and should not be given any weight.
`
`Petitioners’ evidence fails to establish unpatentability for any instituted
`
`Ground, and every claim should be confirmed.
`
`II. The Challenged Claims Of The ’287 And The Level Of Skill In The Art
`The ’287 is directed to a novel and efficient protein refolding method based
`
`on control of reduction-oxidation (“redox”) conditions with reductant and oxidant
`
`reagents. EX1001, 2:62-3:5; EX2026, ¶47. The goal of protein refolding is to
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`increase and maximize the yield of properly refolded proteins. EX1001, 1:32-38;
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`EX2026, ¶47. Desired proteins are recombinantly expressed in non-mammalian
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`culture systems (e.g., bacteria). EX1001, 3:37-38; EX2026, ¶¶47, 49. But, these
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`expressed proteins misfold and precipitate in intracellular limited-solubility
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`precipitates known as inclusion bodies. EX1001, 1:25-30; EX2026, ¶¶47, 49.
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`These inclusion bodies are formed because the bacterial host cell is unable to fold
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`recombinant proteins properly. EX1001, 1:29-31; EX2026, ¶¶47, 49. These host
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`cells are collected and lysed, and then the released inclusion bodies are solubilized
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`in a denaturing solution to linearize the proteins into individual protein chains.
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`EX1001, 1:43-50; EX2026, ¶¶47, 49.
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`Prior to the ’287, POSITA were able to achieve high yields (including over
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`80%, and even close to 100%) of properly refolded protein. EX2026, ¶45;
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`EX2027, 22:8-20 (Robinson); EX2038 (Tsumoto) (reporting refolding human
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`single-chain Fv fragment from inclusion bodies with a total yield of 95%). 4 To
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`achieve these high yields, those skilled in the art manipulated relevant variables to
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`achieve high yields of properly refolded proteins. EX1001, 4:27-30, 8:47-65;
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`EX2026, ¶45. Further, robots were available in 2009 to help with choosing among
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`and determining those variables. EX2026, ¶46; EX2033 (Pereira & Williams
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`reference on the high-throughput screening and the use of robotics for automation);
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`EX2034 (Oganesyan reference discussing methods enabling high-throughput or
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`automated screening); EX2039 (describing how to design full factorial or
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`fractional factorial screens); EX2027, 7:8-12:5 (Robinson); EX2036 (Paladra);
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` 4
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` And although Schlegl’s percentage “yields” are inapplicable for reasons
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`discussed infra, §VI.B.E, Schlegl itself reports “the yield of refolded protein is
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`90%” in 2007—although Petitioners pointedly ignore this higher percentage while
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`pointing to other, low refolding results. EX1007, [0082].
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`EX2037 (Cohen); EX1002, ¶¶54-55.5 For instance, robots were available to assist
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`with otherwise tedious, repetitive functions, providing greater speed, accuracy, and
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`reproducibility. EX2026, ¶46; EX2036; EX2037; EX2033; EX2027, 7:8-12:5
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`(Robinson); EX2010, 197:3-198:25 (Robinson). In addition to standard liquid
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`handling duties, EX2027, 11:6-12:5, the use of robotics to assay and assess failure
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`or success of an experiment was well-known and regularly performed. See. e.g.,
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`EX2026, ¶46; EX2033; EX2024; EX2039; EX2027, 7:8-12:5 (Robinson). With
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`the aid of robotics, even if a large number of assays and tests were required, it
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`would not have represented undue experimentation, and many tests could be run at
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`once and in succession and in little time. EX2026, ¶46; EX2036.
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`The inventors of the ’287 made it easier to identify optimized refolding
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`conditions by controlling the concentrations of the reductant and oxidant present in
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`the refolding buffer in a particular manner (e.g., using the interrelationship of thiol-
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` EX2029 (published in 1995), EX2033 (published in 2007), EX2034 (published in
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`2005), EX2036 (published in 2007), EX2037 (published in 2002), EX2038
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`(published in 1998), EX2039 (published in 1996), and EX2040 (published in
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`2004), and EX2042 (Sethuraman) were all published in regularly published
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`journals and thus also publicly available as of those dates. EX2026, ¶15.
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`[𝑜𝑜𝑜𝑜𝑜𝑜𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟] ) and thiol-pair buffer strength (2[𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜]+
`pair ratio (i.e., [𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟]2
`[𝑟𝑟𝑟𝑟𝑜𝑜𝑟𝑟𝑟𝑟𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜])) for the purpose of properly refolding a recombinantly expressed
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`protein. EX1001, 4:18-5:10, 6:50-55, 6:63-67; EX2026, ¶¶48-55. The method
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`disclosed in the ’287 therefore also made it easier to efficiently refold large
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`quantities of protein on a commercial scale. EX1001, 13:44-46.
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`A POSITA would have had a Ph.D. in biochemistry, biochemical
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`engineering, molecular biology, or a related biological/chemical/ engineering
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`discipline, or a master’s degree in such disciplines and several years of industrial
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`experience producing proteins in non-mammalian expression systems, as of the
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`’287 Patent priority date of June 22, 2009. EX2026, ¶30. Indeed, those in the art
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`of refolding therapeutic biologics (the audience for the ’287 invention), would
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`have had a Ph.D. or at least a masters in such disciplines and several years of
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`industrial experience producing proteins in non-mammalian expression systems.
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`However, the analysis below would not change if Petitioners’ POSITA definition
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`were applied. See EX2026, ¶32.
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`As discussed below, Petitioners have only provided analysis of their
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`Grounds as of 2009. However, for any claims the Board has found to give rise to
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`PGR standing, the Petition’s Grounds, for purposes of this proceeding only, must
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`be analyzed as of the May 25, 2017 filing date of the ’287 application itself.
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`Petitioners have provided no such evidence, and to the extent Petitioners are
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`allowed to supplement the record (they should not be (see n.3)), Amgen reserves
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`its right to submit evidence and argument as of 2017.
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`III. Claim Construction
`For purposes of post-grant review for a petition filed before November 13,
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`2018, “[a] claim in an unexpired patent . . . shall be given its broadest reasonable
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`construction in light of the specification of the patent in which it appears.”
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`§42.200(b); Final Rule, 83 Fed.Reg. at 51340 (Oct. 11, 2018) (“This rule [change
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`from broadest reasonable construction] is effective on November 13, 2018 and
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`applies to all IPR, PGR and CBM petitions filed on or after the effective date.”).
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`However, even under the broadest reasonable interpretation, the Board’s
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`construction must “be consistent with the specification, and that claim language
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`should be read in light of the specification as it would be interpreted by one of
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`ordinary skill in the art.” In re Abbott Diabetes Care Inc., 696 F.3d 1142, 1149
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`(Fed. Cir. 2012).
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`A.
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` “At Least About 25%” Should Not Be Construed To Require
`Exactly 25% To 100% Refolding (Claims 1-9 and 16-25)
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`While Petitioners never offer any claim construction analysis, the Petitioners
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`implicitly construe “at least about 25%” to require that “at least about 25%” mean
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`exactly “25% to 100%.” Pet., 28 (“The specification does not provide support for
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`‘at least about 25% of the proteins are properly refolded,’ i.e., 25%-100%.”).
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`In view of the claims’ “