`
`
` Preliminary Response in IPR2015-01517
`
`U.S. Patent No. 8,916,158
`
`Filed on behalf of: AbbVie Biotechnology Ltd.
`
`
`
`
`
`
`
`Entered: October 19, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`AMGEN INC.
`Petitioner
`
`v.
`
`ABBVIE BIOTECHNOLOGY LTD.
`Patent Owner
`_______________________
`
`Case IPR2015-01517
`U.S. Patent No. 8,916,158
`_______________________
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`TABLE OF CONTENTS
`
`I.
`
`
`Introduction ...................................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Petitioner’s Analysis Is Tainted by Hindsight, Overreliance on
`“Routine” Experimentation, and Conclusory Assertions ...................... 1
`The Petition Is Particularly Deficient with Respect to at Least
`Dependent Claims 3, 15, 24, and 26 ..................................................... 3
`Petitioner’s Arguments Were Overcome by the Patentee During
`Prosecution, and the Petition Adds Nothing More ............................... 5
`The Petition’s Violation of PTAB Rules Supports Denial of
`Institution ............................................................................................... 6
`
`II.
`
`
`Level of Ordinary Skill in the Art and Claim Construction ............................ 6
`
`A.
`B.
`
`Level of Ordinary Skill in the Art ......................................................... 6
`Claim Construction ............................................................................... 7
`1.
`“stable” ........................................................................................ 7
`2.
`“a human IgG1 anti-human Tumor Necrosis Factor alpha
`(TNFα) antibody, or an antigen-binding portion
`thereof, . . . wherein the antibody comprises the light
`chain variable region and the heavy chain variable region
`of D2E7” ..................................................................................... 9
`
`
`
` The Petition’s Violation of PTAB Rules Supports Denial of Institution ...... 11 III.
`
`A.
`
`B.
`
`C.
`
`D.
`
`The Petition Fails to Identify the Specific Printed Publications
`and Patents upon Which It Relies ....................................................... 11
`The Petition Fails to Provide a Detailed Explanation of the
`Significance of the References upon Which It Relies ......................... 12
`The Petition Improperly Incorporates by Reference Large
`Portions of the Randolph Declaration ................................................. 13
`The Petition Circumvents the 60-Page Limit ...................................... 14
`
`IV.
`
` The Petition Fails to Demonstrate a Reasonable Likelihood that Any
`Challenged Claim is Unpatentable ................................................................ 15
`
`A.
`
`Background and State of the Art ......................................................... 16
`1.
`Despite a long-felt need, no commercial stable high
`concentration liquid antibody formulations had been
`successfully developed before HUMIRA ................................. 16
`
`i
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`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`2.
`
`3.
`
`4.
`
`2.
`
`3.
`
`4.
`
`The art at the time taught away from liquid formulations
`and toward lyophilized formulations ........................................ 19
`Formulating proteins, particularly antibodies, was (and
`remains) complicated and unpredictable .................................. 21
`AbbVie invented a stable, high concentration liquid
`antibody formulation ................................................................. 28
`Petitioner Relies on Impermissible Hindsight to Arrive at the
`Claimed Invention ............................................................................... 29
`The Challenged Claims Would Not Have Been Obvious over
`Lam and Barrera (Ground 1) ............................................................... 31
`1.
`Petitioner fails to establish a reasonable expectation of
`success in applying a formulation of Lam to the D2E7
`antibody of Barrera (or vice versa) ........................................... 32
`Petitioner fails to identify a lead or reference composition
`to be modified in Lam ............................................................... 37
`Petitioner’s recourse to “routine experimentation” cannot
`support its obviousness argument ............................................. 39
`The dependent claims are nonobvious over Lam and
`Barrera ....................................................................................... 40
`The Challenged Claims Would Not Have Been Obvious over
`Salfeld and Heavner (Ground 2) ......................................................... 46
`1.
`The combination of Salfeld and Heavner fails to disclose
`all the claimed elements ............................................................ 46
`Petitioner fails to identify a lead or reference formulation
`to be modified, or any motivation to combine Salfeld
`with Heavner ............................................................................. 49
`No reasonable expectation of success exists in combining
`Salfeld with Heavner ................................................................. 51
`The dependent claims are nonobvious over Salfeld and
`Heavner ..................................................................................... 53
`Secondary Considerations Support the Nonobviousness of the
`Challenged Claims .............................................................................. 54
`Petitioner’s Art and Arguments Were Previously Considered
`During Prosecution .............................................................................. 56
`
`2.
`
`3.
`
`4.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`V.
`
`
`
`Conclusion ..................................................................................................... 59
`
`
`
`ii
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`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`TABLE OF AUTHORITIES
`
`Pages(s)
`
`CASES
`
`Apotex Inc. v. Wyeth LLC,
`No. IPR2015-00873 (P.T.A.B. Sept. 16, 2015) .................................................... 30
`
`Apple Inc. v. ContentGuard Holdings, Inc.,
`No. IPR2015-00454 (P.T.A.B. July 13, 2015) ..................................................... 14
`
`BioDelivery Scis. Int’l, Inc. v. MonoSol Rx, LLC,
`No. IPR2015-00167 (P.T.A.B. May 20, 2015) .............................................. 50, 52
`
`Boehringer Ingelheim Int’l GmbH v. Biogen Inc.,
`No. IPR2015-00418 (P.T.A.B. July 13, 2015) .............................................. 12, 13
`
`Cadence Pharm., Inc. v. Paddock Labs. Inc.,
`886 F. Supp. 2d 445 (D. Del. 2012) ........................................................................ 9
`
`Cisco Sys., Inc. v. C-Cation Techs., LLC,
`No. IPR2014-00454 (P.T.A.B. Aug. 29, 2014) .................................................... 14
`
`Endo Pharm. Inc. v. Depomed, Inc.,
`No. IPR2014-00654 (P.T.A.B. Sept. 21, 2015) .................................................... 21
`
`Excelsior Med. Corp. v. Lake,
`No. IPR2013-00494 (P.T.A.B. Feb. 6, 2014) ....................................................... 59
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .................................................................................................. 55
`
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................. 30
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ............................................................................... 7
`
`In re Glatt Air Techniques, Inc.,
`630 F.3d 1026 (Fed. Cir. 2011) ............................................................................. 55
`
`iii
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`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ............................................................................. 55
`
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) ............................................................................. 37
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ............................................................................... 32
`
`Integrated Global Concepts, Inc. v. Advanced Messaging Techs., Inc.,
`No. IPR2014-01028 (P.T.A.B. Dec. 22 2014) ............................................... 58, 59
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................. 32
`
`Merial Ltd. v. Virbac,
`No. IPR2014-01279 (P.T.A.B. Jan. 22, 2015) ...................................................... 59
`
`Microboards Tech., LLC v. Stratasys Inc.,
`No. IPR2015-00288 (P.T.A.B. May 28, 2015) ..................................................... 59
`
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) ...................................................................... 35, 54
`
`Mylan Pharm., Inc. v. Gilead Scis., Inc.,
`No. IPR2014-00886 (P.T.A.B. Dec. 17, 2014) ..................................................... 35
`
`Novartis Pharm. Corp. v. Watson Labs., Inc.,
`611 F. App’x 988 (Fed. Cir. 2015) ................................................................ 48, 50
`
`Oxford Nanopore Techs. Ltd. v. Univ. of Wash.,
`No. IPR2014-00512 (P.T.A.B. Sept. 15, 2014) .................................................... 38
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................... 33
`
`Rambus Inc. v. Rea,
`731 F.3d 1248 (Fed. Cir. 2013) ............................................................................. 55
`
`S.S. Steiner, Inc. v. John I. Haas, Inc.,
`No. IPR2014-01490 (P.T.A.B. Mar. 16, 2015) .................................................... 15
`
`iv
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`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ...................................................................... 37, 50
`
`STATUTES
`
`35 U.S.C. § 314(a) ................................................................................................... 15
`
`35 U.S.C. § 325(d) ............................................................................................ 56, 59
`
`RULES
`
`37 C.F.R. § 42.104(b)(2) ............................................................................... 6, 11, 12
`
`37 C.F.R. § 42.22(a)(2) ................................................................................. 6, 11, 12
`
`37 C.F.R. § 42.24(a)(1)(i) ............................................................................. 6, 11, 14
`
`37 C.F.R. § 42.51(b)(1)(iii) ........................................................................................ 2
`
`37 C.F.R. § 42.6(a)(3) ................................................................................... 6, 11, 14
`
`77 Fed. Reg. 48,756 (Aug. 14, 2012) ...................................................................... 12
`
`
`
`
`
`
`
`v
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`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`PATENT OWNER’S EXHIBIT LIST
`
`2002
`
`2003
`
`2004
`
`2005
`
`EXHIBIT DESCRIPTION
`2001
`Simon King, The Best Selling Drugs of All Time; Humira Joins The
`Elite, FORBES (Jan. 28, 2013, 9:58 AM),
`http://www.forbes.com/sites/simonking/2013/01/28/the-best-selling-
`drugs-of-all-time-humira-joins-the-elite/print/
`Abbott Laboratories 2003 Annual Report, Abbott Laboratories
`(2004)
`Luke Timmerman, Abbott’s Humira, the 3rd-in-Class Drug That
`Toppled Lipitor as No. 1, XCONOMY (Apr. 16, 2012),
`http://www.xconomy.com/national/2012/04/16/abbotts-humira-the-
`3rd-in-class-drug-that-toppled-lipitor-as-no-1/
`Marco van de Weert & Theodore W. Randolph, Chapter 6: Physical
`Instability of Peptides and Proteins, in PHARMACEUTICAL
`FORMULATION DEVELOPMENT OF PEPTIDES AND PROTEINS 107 (2012)
`Theodore W. Randolph & John F. Carpenter, Engineering
`Challenges of Protein Formulations, 53 AM. INST. CHEM. ENG. J.
`1902 (2007)
`Branden A. Salinas, et al., Understanding and Modulating
`Opalescence and Viscosity in a Monoclonal Antibody Formulation,
`99 J. PHARM. SCIS. 82 (2010)
`U.S. Serial No. 13/521,999 (U.S. Pat. No. 8,883,151) (Amgen), Dec.
`3, 2013 Office Action Response
`Sampathkumar Krishnan, et al., (Amgen) Chapter 16: Development
`of Formulations for Therapeutic Monoclonal Antibodies and Fc
`Fusion Proteins,” in FORMULATION AND PROCESS DEVELOPMENT
`STRATEGIES FOR MANUFACTURING BIOPHARMACEUTICALS 383 (2010)
`U.S. Serial No. 14/091,938 (U.S. Pat. No. 8,795,670), Jan. 29, 2014
`Office Action
`U.S. Serial No. 14/091,661 (U.S. Pat. No. 8,802,100), Jan. 27, 2014
`Office Action
`U.S. Serial No. 14/091,888 (U.S. Pat. No. 8,802,101), Apr. 16, 2014
`Office Action Response
`U.S. Serial No. 14/147,287 (U.S. Pat. No. 8,802,102), Apr. 16, 2014
`Office Action Response
`U.S. Serial No. 14/322,565 (U.S. Pat. No. 8,940,305), Sept. 26, 2014
`Office Action Response
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`2006
`
`2007
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`2008
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`2009
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`2010
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`2011
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`2012
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`vi
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2015
`
`EXHIBIT DESCRIPTION
`2014
`U.S. Serial No. 13/401,496 (U.S. Pat. No. 8,828,947)
`(Immunex/Amgen), Apr. 21, 2014 Office Action Response
`U.S. Serial No. 11/784,538 (U.S. Pat. No. 7,648,702) (Amgen), July
`24, 2009 Office Action Response
`U.S. Serial No. 11/437,602 (U.S. Pat. No. 8,858,935) (Amgen), June
`25, 2009 Office Action Response
`John F. Carpenter, et al., Chapter 7: Freezing- and Drying-Induced
`Perturbations of Protein Structure and Mechanisms of Protein
`Protection by Stabilizing Additives, in FREEZE-
`DRYING/LYOPHILIZATION OF PHARMACEUTICAL AND BIOLOGICAL
`PRODUCTS 167 (2d ed. 2004)
`Eva Y. Chi, et al., Physical Stability of Proteins in Aqueous Solution:
`Mechanism and Driving Forces in Nonnative Protein Aggregation,
`20 PHARM. RES. 1325 (2003)
`U.S. Serial No. 11/437,602 (U.S. Pat. No. 8,858,935) (Amgen), June
`25, 2009 Declaration by Dr. Grace C. Chu
`Emily Ha, et al., Peroxide Formation in Polysorbate 80 and Protein
`Stability, 91 J. PHARM. SCIS. 2252 (2002)
`Masako Ohnishi & Hiromichi Sagitani, The Effect of Nonionic
`Surfactant Structure on Hemolysis, 70 J. AM. OIL CHEMISTS’ SOC’Y
`679 (1993)
`“ORTHOCLONE OKT®3 Sterile Solution”, PHYSICIANS’ DESK
`REFERENCE, 2498-2502 (56th ed. 2002)
`“RITUXAN®”, PHYSICIANS’ DESK REFERENCE, 1428-1430, 1750-
`1752 (56th ed. 2002)
`“CAMPATH®”, PHYSICIANS’ DESK REFERENCE, 992-995 (56th ed.
`2002)
`“REOPRO®”, PHYSICIANS’ DESK REFERENCE, 1958-1962 (56th ed.
`2002)
`“WINRHO SDF™”, PHYSICIANS’ DESK REFERENCE, 2297-2299
`(56th ed. 2002)
`Douglas D. Banks, et al., (Amgen) Native-State Solubility and
`Transfer Free Energy as Predictive Tools for Selecting Excipients to
`Include in Protein Formulation Development Studies, 101 J. PHARM.
`SCIS. 2720 (2012)
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`2023
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`2024
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`2025
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`2029
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`PHARMALIVE (Aug. 12, 2015), http://www.pharmalive.com/special-
`report-top-200-medicines/
`John F. Carpenter, et al., Inhibition of Stress-Induced Aggregation of
`Protein Therapeutics, 309 METHODS IN ENZYMOLOGY 236 (1999)
`Christine C. Lee, et al., Toward aggregation-resistant antibodies by
`design, 31 TRENDS IN BIOTECH. 612 (2013)
`Robert G. Hamilton, THE HUMAN IGG SUBCLASSES (2001)
`Rajesh Krishnamurthy & Mark C. Manning, The Stability Factor:
`Importance in Formulation Development, 3 CURRENT PHARM.
`BIOTECH. 361 (2002)
`Romain Rouet, et al., Stability engineering of the human antibody
`repertoire, 588 FEBS LETTERS 269 (2014)
`Michio Nishida, et al., Characterization of novel murine anti-CD20
`monoclonal antibodies and their comparison to 2B8 and c2B8
`(rituximab), 31 INT’L. J. ONCOLOGY 29 (2007)
`U.S. Serial No. 14/091,938 (U.S. Pat. No. 8,795,670), Apr. 16, 2014
`Office Action Response
`U.S. Serial No. 14/091,661 (U.S. Pat. No. 8,802,100), Apr. 16, 2014
`Office Action Response
`U.S. Serial No. 14/091,888 (U.S. Pat. No. 8,802,101), Jan. 28, 2014
`Office Action
`U.S. Serial No. 14/147,287 (U.S. Pat. No. 8,802,102), Feb. 7, 2014
`Office Action
`U.S. Serial No. 14/322,565 (U.S. Pat. No. 8,940,305), Sept. 17, 2014
`Office Action
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`the Conformational Heterogeneity and Bonding Network that
`Influence Solution Properties, 113 J. PHYS. CHEM. B 6109 (2009)
`“NUTROPIN AQ®”, PHYSICIANS’ DESK REFERENCE, 1420-1423
`(56th ed. 2002)
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`2041
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`viii
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`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`
`I.
`
`INTRODUCTION
`
`In
`
`two petitions (IPR2015-01514 & IPR2015-01517), Amgen (the
`
`“Petitioner”) seeks inter partes review of two AbbVie patents1 directed to stable
`
`liquid aqueous antibody formulations (U.S. Pat. Nos. 8,916,157 (“the ’157 patent”)
`
`and 8,916,158 (“the ’158 patent”)), alleging that all challenged claims of each are
`
`rendered obvious by the same two combinations of prior art. Because the petitions
`
`are both substantively and legally defective, they should be denied.
`
`A.
`
`Petitioner’s Analysis Is Tainted by Hindsight, Overreliance on
`“Routine” Experimentation, and Conclusory Assertions
`First, Petitioner’s obviousness arguments depend on
`
`impermissible
`
`hindsight, as evidenced by the prior art, as well as numerous prior inconsistent
`
`statements made by both Petitioner and its Declarant, Dr. Theodore Randolph.
`
`Specifically, the Petition depends upon two false premises: (i) that the antibody
`
`formulation art in 2002 was routine and predictable, and (ii) that once a stable
`
`formulation was discovered for one antibody, a skilled artisan would expect the
`
`1
`The ’157 and ’158 patents are members of the same patent family and share
`
`identical disclosures. Petitioner filed a separate petition on the ’157 patent based on
`
`identical prior art combinations and a near-identical Declaration. AbbVie’s
`
`Response to the ’158 Petition differs from that of the ’157 Petition chiefly in its
`
`treatment of the ’158 patent’s dependent claims 27-30, which recite buffers.
`
`1
`
`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`same formulation to stabilize other, completely different antibodies. But these
`
`premises are contrary to both the scientific literature and numerous representations
`
`that Petitioner made before this Office. As described in Section IV.A.3, prior to
`
`filing its petition, Petitioner emphasized that antibody formulation is not routine
`
`and that one of skill in the art would not expect different antibodies to be similarly
`
`stable in the same formulation. Likewise, Dr. Randolph repeatedly explained in the
`
`scientific literature the complexities of preparing such formulations, and stated that
`
`developing stable formulations was simply “not possible” for some proteins. In
`
`fact, due to the unpredictability and difficulties associated with inventing stable
`
`liquid formulations, Dr. Randolph’s publications at the time of AbbVie’s invention
`
`taught away from the preparation of stable liquid antibody formulations, and
`
`instead toward lyophilized (freeze-dried) formulations.
`
`The contemporaneous scientific literature—as well as Petitioner’s prior
`
`representations to this Office and Dr. Randolph’s to the scientific community—
`
`demonstrate that the Petition’s false premises do not reflect the views of a person
`
`of ordinary skill in the art (“POSA”) at the time of the invention in 2002.2 At best,
`
`the Petition is grounded in hindsight, using the successful teaching of the ’158
`
`2
`Petitioner failed to serve evidence of its numerous prior inconsistent
`
`positions as required by PTAB rules. See 37 C.F.R. § 42.51(b)(1)(iii).
`
`2
`
`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`patent as a roadmap through the prior art.
`
`Second, Petitioner does not conduct a proper obviousness analysis for a
`
`formulation patent because it: (i) fails to identify a lead or reference composition;
`
`and (ii) fails to establish any motivation to combine the cited prior art references
`
`with a reasonable expectation of success. Petitioner argues extensively that the
`
`claimed elements are found in the prior art (which is true for nearly all inventions),
`
`yet fails to establish why a POSA at the time of the invention would have selected
`
`the proposed combinations or expected them to result in stable liquid formulations
`
`as claimed in the ’158 patent.
`
`Third, while purporting to rely on only two pairs of references, Petitioner
`
`attempts to fill gaps in its prior art combinations by citing broadly to dozens of
`
`additional references. But conclusory statements about “routine experimentation”
`
`and non-specific allusions to numerous prior art references cannot overcome
`
`deficiencies in the primary combination. In short, Petitioner fails to establish the
`
`core aspects of the obviousness inquiry.
`
`B.
`
`The Petition Is Particularly Deficient with Respect to at Least
`Dependent Claims 3, 15, 24, and 26
`
`The Petition is particularly deficient with regard to at least two sets of
`
`dependent claims. First, claims 3 and 26 recite a stable liquid formulation of a
`
`3
`
`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`D2E73 antibody with a concentration of 50 mg/ml, but Petitioner fails to carry its
`
`burden to establish any teaching or suggestion in the art that would cause the
`
`skilled artisan to reasonably expect to successfully arrive at a concentration as high
`
`as 50 mg/ml merely by applying an existing formulation for a different antibody to
`
`D2E7. The Lam reference and other art cited by Petitioner actually teach away
`
`from such a high concentration. While Lam included an example of a single
`
`antibody (not D2E7) formulated at 40 mg/ml, it also expressly advised that a lower
`
`concentration might be needed to reduce protein aggregation. And Dr. Randolph’s
`
`own table of then-existing commercial antibody formulations illustrates why a
`
`skilled artisan would not have expected success in applying that Lam formulation
`
`to other antibodies, much less at a still higher concentration: All of the commercial
`
`liquid antibody formulations available at the time had a concentration between 1
`
`and 10 mg/ml, i.e., between 1/5 and 1/50 of the claimed concentrations. Simply
`
`put, there was no teaching or suggestion in the art to quintuple (or more) these
`
`commercial antibody concentrations to 50 mg/ml in a liquid formulation for a
`
`D2E7 antibody, nor was there any reasonable expectation of successfully doing so.
`
`Second, dependent claims 15 and 24 recite a pH between 4.8 and 5.5.
`
`3
`As used in this paper, D2E7 refers to a human IgG1 anti-TNFα antibody
`
`with the VL and VH regions of D2E7.
`
`4
`
`

`

`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`Although Petitioner tries to establish that prior art antibody formulations had a pH
`
`within the range of the independent claims (i.e., 4.0 to 8.0), that same evidence
`
`reveals that those formulations were well above the 4.8 to 5.5 pH range recited by
`
`claims 15 and 24. Here again, while the Lam reference exemplified formulations of
`
`certain antibodies at pH 5.0, Petitioner’s own evidence teaches away from any
`
`expectation that such a pH would work for a different antibody. All the
`
`commercially available antibodies instead pointed toward the need for higher pH.
`
`Thus, Petitioner fails to present meaningful evidence that addresses the specific
`
`limitations found in dependent claims 3, 15, 24, and 26.
`
`C.
`
`Petitioner’s Arguments Were Overcome by the Patentee During
`Prosecution, and the Petition Adds Nothing More
`
`All four of the references relied upon in Grounds 1 and 2 were already
`
`considered during prosecution of the ’158 and its parent patents. All four are listed
`
`on the face of the ’158 patent, and the Examiner considered virtually the same
`
`arguments involving the same references during prosecution of parent and grand-
`
`parent patents. In fact, the only new material this Petition adds is the Declaration of
`
`Dr. Randolph—which deserves no weight because it contradicts numerous prior
`
`statements by Petitioner and Dr. Randolph and advances arguments and references
`
`not properly set forth in the Petition.
`
`5
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`D. The Petition’s Violation of PTAB Rules Supports Denial of
`Institution
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`Amgen’s petition should be denied for violating any of four separate
`
`provisions: 37 C.F.R. §§ 42.104(b)(2), 42.22(a)(2), 42.6(a)(3) and 42.24(a)(1)(i).
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`In particular, the Petition violates the Board’s requirement to (i) identify specific
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`references relied upon for each ground (37 C.F.R. § 42.104(b)(2)); and (ii) include
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`a full statement of the reasons for the relief requested, including a detailed
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`explanation of the significance of the evidence (37 C.F.R. § 42.22(a)(2)).
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`Attempting to fill gaps left by the four references enumerated in Grounds 1 and 2,
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`the Petition makes numerous conclusory statements, citing large portions of
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`Dr. Randolph’s 150-page Declaration—which refers through convoluted internal
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`cross-referencing and nested arguments to dozens of additional references. This
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`extensive reliance on Dr. Randolph’s Declaration and its many cited references
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`also amounts to an improper incorporation by reference (37 C.F.R. § 42.6(a)(3))
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`and a violation of the Board’s strict 60-page limit (37 C.F.R. § 42.24(a)(1)(i)).
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`Petitioner’s violations of these rules alone mandate denial of institution.
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` LEVEL OF ORDINARY SKILL IN THE ART AND CLAIM
`II.
`CONSTRUCTION
`A. Level of Ordinary Skill in the Art
`For the limited purpose of this Preliminary Response, Patent Owner deems it
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`unnecessary to contest at this time the level of ordinary skill in the art. Pet. at 7-8.
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`B. Claim Construction
`Petitioner’s claim construction positions are unreasonably broad even under
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`the “broadest reasonable interpretation” standard applicable to these proceedings,
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`(see In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1279 (Fed. Cir. 2015)),
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`leading to an improper and unrealistic assessment of obviousness. To the extent
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`Dr. Randolph’s opinions and Petitioner’s arguments are grounded in these
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`constructions, they are further flawed.
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`“stable”
`
`1.
`The term “stable” is explicitly defined in the specification of the ’158 patent:
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`A “stable” formulation is one in which the antibody therein essentially
`retains its physical stability and/or chemical stability and/or biological
`activity upon storage.
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`Ex. 1001 (’158 patent) at 7:23-25. Given the practical realities of therapeutic
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`antibodies, a POSA would have understood that a formulation would need to be
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`stable for storage and use, and, as Dr. Randolph concedes, that “formulations
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`intended as commercial products needed to be robust enough to withstand shipping
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`stress and long term storage.” Ex. 1002 at ¶ 47. For example, the ’158 patent
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`describes the “invention” as “a liquid aqueous pharmaceutical formulation …
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`having a shelf life of at least 18 months” (Ex. 1001 at 3:18-22) or “with an
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`extended shelf life.” Id. at 3:10-11; see also id. at Abstract. “Stable” is properly
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`read in the context of the “pharmaceutical formulation” to which it applies. As
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
`
`explained in the ’158 patent, “the term ‘pharmaceutical formulation’ refers to
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`preparations which are in such form as to permit the biological activity of the
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`active ingredients to be unequivocally effective, and which contain no additional
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`components which are significantly toxic to [] subjects . . . .” Id. at 7:14-18.
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`Nonetheless, Petitioner proposes an illogical construction of a “stable”
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`formulation as one “that retains its physical stability and/or chemical stability
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`and/or biological stability upon storage” and “for any period of time, no matter
`
`how short.” Pet. at 11 (emphasis added).4 In other words, Petitioner attempts to
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`define “stable” to encompass formulations stable either chemically or physically or
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`biologically, and then only for a fraction of a second—which is to say, not stable at
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`all. This not only contradicts arguments Petitioner made in the Petition, (see Pet. at
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`21 (arguing that a POSA would have been motivated to make a “stable
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`formulation” for long term storage)), but is, even under a “broadest reasonable
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`interpretation” standard, virtually the complete opposite of what a POSA would
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`understand the term to mean in the context of the invention, particularly in view of
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`the “pharmaceutical formulation” claim language and the extensive guidance
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`provided in the specification. See Ex. 1001 at 7:23-64.
`
`
`4
`In this paper, all emphases are added unless otherwise indicated.
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
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`2.
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`“a human IgG1 anti-human Tumor Necrosis Factor alpha
`(TNFα) antibody, or an antigen-binding portion thereof, . . .
`wherein the antibody comprises the light chain variable
`region and the heavy chain variable region of D2E7”
`
`Petitioner tries to pull itself up by its bootstraps, pressing an unreasonably
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`broad construction that encompasses many antibodies, while arguing that such a
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`construction undermines the contention that different antibodies require different
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`formulations. See Pet. at 9-13. In fact, the individual words of this phrase are
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`interrelated and should be construed together to convey their proper meaning—not
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`in isolation as Petitioner has done. See, e.g., Cadence Pharm., Inc. v. Paddock
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`Labs. Inc., 886 F. Supp. 2d 445, 455 (D. Del. 2012). The correct construction is: A
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`human anti-human TNFα antibody of the IgG1 subclass, or an antibody fragment
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`thereof, that retains binding activity against human TNFα and includes the
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`complete light chain variable (VL) region and the heavy chain variable (VH) region
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`of the antibody D2E7. While the claim language encompasses antibody fragments
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`that retain binding to TNFα, the claim also specifically recites that the complete VL
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`and VH regions of D2E7 are present.
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`Petitioner’s constructions ignore the patent specification and settled antibody
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`science. First, Petitioner’s construction of “IgG1…antibody”
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`to mean
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`“immunoglobulin molecules comprised of four polypeptide chains, two heavy (H)
`
`chains and two light (L) chains interconnected by disulfide bonds,” (Pet. at 9)
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`Preliminary Response in IPR2015-01517
`U.S. Patent No. 8,916,158
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`completely reads out the recitation of “IgG1.” IgG1 is a particular antibody
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`subclass distinct in sequence, physical, and chemical properties from other IgG
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`subclasses and other immunoglobulin classes, and cannot simply be omitted. See
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`Ex. 2031 at 7-9.
`
`Next, Petitioner’s construction of “antigen-binding portion” to mean “one or
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`more fragments of an antibody that retain the ability to specifically bind to an
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`antigen (e.g., hTNFα)” similarly reads out the requirement that the VL and VH
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`regions of D2E7 are present. As a result, Petitioner incorrectly construes this claim
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`to read on “an antibody fragment that can be as small as one CDR (5 to 17 amino
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`acids).” Pet. at 12.
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`Finally, Petitioner’s construction of “wherein the antibody comprises the
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`light chain variable region and the heavy chain variable region of D2E7” as “any
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`antibody that includes one heavy and one light chain variable region that retain the
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`CDR3 sequences of a D2E7 antibody disclosed in the Salfeld patent (Ex. 1005)”
`
`(Pet. at 10) again reads out the complete VL and VH region sequences of D2E7
`
`recited in the claims. Petitioner appears to rely on a flatly incorrect statement by
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`Dr. Randolph (Ex. 1002 at ¶ 44) that the Salfeld patent only discloses the CDR3
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`sequence of D2E7. However, Salfeld discloses the entire VL and VH region
`
`sequences, e.g., in SEQ ID Nos. 1 and 2, and in Figs. 1, 2, 7, and 8. Thus,
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`Petitioner’s constructions are improper and should be rejected.
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`10
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