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`Paper No. __
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LASSEN THERAPEUTICS 1, INC.,
`Petitioner,
`
`v.
`
`SINGAPORE HEALTH SERVICES PTE LTD., AND NATIONAL
`UNIVERSITY OF SINGAPORE,
`Patent Owners.
`_____________
`
`Case No. PGR2019-00053
`Patent No. 10,106,603
`_____________
`
`PATENT OWNERS’ PRELIMINARY RESPONSE
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`

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`
`I.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ............................................................................................. 1
`
`A. The Prior Art Grounds Fail .......................................................................... 2
`
`B. The § 112 Grounds Fail ............................................................................... 3
`
`II. THE ‘603 PATENT ........................................................................................... 7
`
`A. The Inventors Discovered That IL-11 Produces Fibrosis ........................... 7
`
`B. The Inventors Discovered That Fibrosis Could Be Treated Using
`Known Antibodies That Inhibited IL-11 Mediated Signaling .................... 9
`
`C. The Claims Are Narrowly Directed to a Preferred Embodiment of
`Treating Fibrosis in Humans Using Known Antibodies That Inhibit
`IL-11 Mediated Signaling in a Specific Way ............................................12
`
`III. EDWARDS DISCLOSES SUITABLE ANTIBODIES AND IS
`INCORPORATED IN THE ’603 PATENT ....................................................13
`
`A. Edwards Discloses the Structures of 8E2, 8D10, 8E4 and Sixty-One
`Other Antibodies That Are Described as Binding Human IL-11Rα
`and Inhibiting IL-11 Mediated Signaling. .................................................13
`
`B. The Petition Admits Edwards Discloses Antibodies Suitable for
`Practicing the Claimed Invention ..............................................................16
`
`C. Edwards Is Incorporated by Reference in the ’603 Patent ........................16
`
`IV. CLAIM CONSTRUCTION AND POSA DEFINITION ................................17
`
`A. Claim 1 Is Limited to Administering an Antibody That Is
`Therapeutically Effective in a Human .......................................................17
`
`B. Petitioner’s POSA Definition Can Be Adopted ........................................19
`
`V. WRITTEN DESCRIPTION ............................................................................20
`
`A. The Claims Are Directed to a Method of Treatment ................................20
`
`B. The Petition Misapplies the Law on What Is Required to Provide
`Written Description for a Claim to a Method of Use of a Known
`Genus .........................................................................................................21
`
`1. The Specification Need Only Provide Written Description for
`the Claimed Method of Treatment ......................................................21
`
`2. Rochester Is Inapposite .......................................................................24
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`3. The Petition Improperly Alleges That the Specification Needed
`to Describe Antibodies That Could Not Be Used to Practice the
`Claimed Method ..................................................................................26
`
`C. The Petition Improperly Ignores Antibodies Suitable for Use in the
`Claimed Method ........................................................................................27
`
`1. The Petition Fails to Establish a Prima Facie Case of
`Unpatentability Because It Ignores Disclosure in the
`Specification ........................................................................................28
`
`2. The Petition Fails to Establish a Prima Facie Case of
`Unpatentability Because It Ignores What Was Known to a
`POSA ...................................................................................................29
`
`3. Representative Number of Species .....................................................30
`
`a. The Specification Discloses Clones 8E2 and 8E4 ...................... 31
`
`b. The Specification Discloses Sixty-Two Additional
`Suitable Antibodies ..................................................................... 33
`
`c. Edwards’ Disclosure Must Be Considered Even If It Were
`Not Incorporated by Reference ................................................... 33
`
`d. The Petition’s Failure to Even Allege That Edwards’
`Species Are Not Representative Ends the Inquiry on the
`Written Description Ground........................................................ 34
`
`4. Structural Features Common to the Members ....................................35
`
`D. Petitioner’s Working Example Arguments Fail ........................................37
`
`1. Numerous Working Examples Are Disclosed ....................................38
`
`2. Example 6 Describes the “Enabling Attributes” .................................40
`
`3. Petitioner’s Attacks on Example 6 Are Legally Flawed .....................41
`
`4. Petitioner’s Attacks on Other Examples Are Equally Flawed ............42
`
`E. Petitioner’s § 112 Expert Is Not Credible .................................................43
`
`VI. ENABLEMENT ..............................................................................................44
`
`A. The Specification Need Not Disclose What Was Known .........................44
`
`B. The Petition Misstates the Breadth of the Claims (Wands Factor 8) ........45
`
`C. The Petition Misstates the Nature of the Invention (Wands Factor 4) ......46
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`D. State of the Art, Skill of Those in the Art, and Predictability of the
`Art (Wands Factors 5-7) ............................................................................47
`
`E. The Enablement Ground’s Ignoring of Edwards Is Fatal .........................51
`
`F. The Petition Misstates the Direction, Guidance and Working
`Examples in the Specification (Wands Factors 2-3) .................................51
`
`1. The Enablement Ground Ignores 8E2 and 8E4...................................52
`
`2. The Enablement Ground Ignores Sixty-Two Additional
`Suitable Antibodies .............................................................................52
`
`3. The Enablement Ground Fails Because It Depends on an
`Alleged Absence of Even a Single Working Example .......................53
`
`G. Quantity of Experimentation Required (Wands Factor 1) ........................54
`
`VII. PRIOR ART GROUNDS ................................................................................55
`
`A. Petitioner Fails to Demonstrate That Edwards Inherently
`Anticipates .................................................................................................60
`
`1. The Burden of Establishing Inherency Is High ...................................60
`
`2. Petitioner Does Not Attempt to Establish That Chegini
`Supports Inherent Anticipation ...........................................................60
`
`3. Petitioner Fails to Establish That Wynn Evidences Inherent
`Anticipation .........................................................................................61
`
`a. Petitioner Fails To Prove That Treating Inflammation
`Necessarily Treats Fibrosis ......................................................... 61
`
`b. Petitioner’s Argument That Edwards Treats Heart and
`Kidney Disease, Which Necessarily Treats Fibrosis of
`Those Organs, Fails ..................................................................... 65
`
`(1) Wynn Does Not Teach That All Cardiac or Kidney
`Diseases Are Fibroproliferative .......................................... 65
`
`(2) Edwards Does Not Treat Heart or Kidney Disease ............ 66
`
`c. Edwards Does Not Teach Administering a Therapeutically
`Effective Amount for Treating Fibrosis ...................................... 68
`
`B. Petitioner Fails to Demonstrate That Any Challenged Claim Would
`Have Been Obvious over Edwards Alone .................................................69
`
`1. Petitioner’s Recycled Inherency Arguments Fail Again .....................71
`
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`2. Petitioner’s Assertion That a POSA Would Have Sought to
`Treat Fibrosis of the Claimed Organs by Inhibiting IL-11
`Mediated Signaling Fails .....................................................................71
`
`a. Petitioner Ignores the State of the Art ......................................... 71
`
`b. Petitioner Fails to Establish That a POSA Would Have
`Sought to Inhibit IL-11 to Treat Fibrosis of Any of the
`Organs Recited in Claim 1 .......................................................... 74
`
`(1) Petitioner Fails to Establish That a POSA Would
`Have Understood That IL-11 Caused Fibrosis of Any
`Organ Recited in Claim 1 ................................................... 75
`
`(2) Petitioner’s Rehashed Wynn Arguments Fail Again .......... 78
`
`(3) Petitioner’s Argument That Treating Asthma Renders
`Obvious Treating Fibrosis of Any Other Organ Fails ........ 80
`
`C. The Petition Fails to Demonstrate That Any Challenged Claim
`Would Have Been Obvious over Edwards in View of Wynn and
`Chegini .......................................................................................................83
`
`1. The Petition Fails to Demonstrate That Claim 1 Would Have
`Been Obvious over Edwards in View of Wynn ..................................83
`
`2. The Petition Fails to Demonstrate That Claim 1 Would Have
`Been Obvious over Edwards in View of Chegini ...............................84
`
`a. Chegini Does Not Teach That Fibrosis of the Claimed
`Organs Is Caused by IL-11 ......................................................... 84
`
`b. Petitioner’s Assertion That It Would Have Been Obvious
`to Treat Fibrosis of the Eye Fails ................................................ 87
`
`c. Petitioner’s Rehashed Arguments About Edward’s
`Teachings of Treating Cachexia Fail Again ............................... 87
`
`VIII. THE PETITION’S DEFECTS ARE FATAL ..................................................88
`
`IX. DISCRETIONARY DENIAL UNDER 35 U.S.C. § 325 ...............................89
`
`
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`iv
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`

`
`
`CASES
`
`TABLE OF AUTHORITIES
`
`
`Ajinomoto v. Int’l Trade Comm’n,
`932 F.3d 1342 (Fed. Cir. 2019) ............................................................. 22, 29, 34
`
`Allergan v. Apotex,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................60
`
`Alnylam Pharm. v. Silence Therapeutics,
`PGR2018-00059, Paper 9 (PTAB Oct. 10, 2018) ..............................................28
`
`Amgen v. Hoechst Marion Roussel,
`314 F.3d 1313 (Fed. Cir. 2003) ..........................................................................23
`
`Ariad Pharm. v. Eli Lilly,
`598 F.3d 1336 (Fed. Cir. 2010) ............................................................. 21, 27, 30
`
`Becton Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017) ...............................................89
`
`Benson Hill Biosystems v. Broad Institute,
`PGR2018-00072, Paper 11 (PTAB Jan. 22, 2019) ................................ 20, 27, 46
`
`Bicon v. Straumann,
`441 F.3d 945 (Fed. Cir. 2006) ............................................................................17
`
`Capon v. Eshhar,
`418 F.3d 1349 (Fed. Cir. 2005) ............................................................. 21, 29, 30
`
`Coalition for Affordable Drugs V v. Hoffman-LaRoche,
`IPR2015-01792, Paper 14 (PTAB Mar. 11, 2016) ............................................... 3
`
`Continental Can Co. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991 ) ........................................................................60
`
`CSL Behring v. Bioverativ Therapeutics,
`IPR2018-01313, Paper 10 (PTAB Jan. 9, 2019) ........................................ passim
`
`Eli Lilly v. Actavis Elizabeth,
`435 F. App’x 917 (Fed. Cir. 2011) .....................................................................55
`
`
`
`v
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`

`

`
`
`Erfindergemeinschaft UroPep v. Eli Lilly,
`276 F. Supp. 3d 629 (E.D. Tex. 2017) ................................................... 22, 33, 50
`
`Ex Parte Douglas D. Taylor,
`No. APPEAL 2014-005092, 2016 WL 3454060 (PTAB June 22,
`2016) ...................................................................................................................23
`
`Ex Parte Jayakrishna Ambati,
`No. APPEAL 2017-011580, 2019 WL 645869 (PTAB Jan. 25,
`2019) ............................................................................................................ 22, 36
`
`Falko-Gunter Falkner v. Inglis,
`448 F.3d 1357 (Fed. Cir. 2006) .................................................................. passim
`
`Finisar v. DirecTV Grp.,
`523 F.3d 1323 (Fed. Cir. 2008) ................................................................... 18, 19
`
`Grünenthal GMBH v. Antecip Bioventures II LLC,
`PGR2018-00062, Paper 32 (PTAB Oct. 29, 2019) ..................................... 46, 51
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) ..........................................................................44
`
`I-MAK v. Gilead Pharmasset,
`IPR2018-00119, Paper 7 (PTAB May 4, 2018) .................................................28
`
`Impax Labs. v. Lannett Holdings,
`893 F.3d 1372 (Fed. Cir. 2018) ..........................................................................73
`
`In re Magnum Oil Tools Int’l,
`829 F.3d 1364 (Fed. Cir. 2016) ................................................................... 35, 54
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ............................................................................60
`
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .................................................................... passim
`
`In re Wright,
`866 F.2d 422 (Fed. Cir. 1989) ............................................................................28
`
`Lifescan Global v. Ikeda Food Research,
`PGR-2019-00031, Paper 7 (PTAB Aug. 15, 2019) ..................................... 30, 34
`
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`vi
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`
`Medichem v. Rolabo,
`437 F.3d 1157 (Fed. Cir. 2006) ..........................................................................86
`
`Nidec Motor v. Zhongshan Broad Ocean Motor,
`868 F.3d 1013 (Fed. Cir. 2017) ..........................................................................19
`
`Paice v. Ford Motor,
`881 F.3d 894 (Fed. Cir. 2018) ............................................................................17
`
`Pause Tech. v. TiVo,
`419 F.3d 1326 (Fed. Cir. 2005) ..........................................................................18
`
`Perricone v. Medicis Pharm,
`432 F.3d 1368 (Fed. Cir. 2005) ................................................................... 63, 65
`
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) ............................................................. 59, 60, 64
`
`Rimfrost v. Aker Biomarine Antartic,
`PGR2018-00033, Paper 9 (PTAB Aug. 29, 2018) .............................................28
`
`Smith & Nephew v. Arthrex,
`IPR2016-00918, Paper 42 (PTAB Oct. 16, 2017) ..............................................66
`
`Streck v. Research & Diagnostic Sys.,
`665 F.3d 1269 (Fed. Cir. 2012) ..........................................................................29
`
`TIP Sys. v. Phillips & Brooks/Gladwin,
`529 F.3d 1364 (Fed. Cir. 2008) ..........................................................................17
`
`Univ. of Rochester v. G.D. Searle,
`358 F.3d 916 (Fed. Cir. 2004) .................................................................... passim
`
`STATUTES
`
`35 U.S.C. § 112 ................................................................................................ passim
`
`35 U.S.C. § 312(a)(3) ...............................................................................................73
`
`35 U.S.C. § 324(a) ...................................................................................................89
`
`35 U.S.C. § 325 ........................................................................................................89
`
`35 U.S.C. § 325(d) ...................................................................................................90
`
`
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`vii
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`35 U.S.C. § 326(e) ............................................................................................ 35, 54
`
`REGULATIONS
`
`37 C.F.R. § 42.65(a) .................................................................................................66
`
`OTHER AUTHORITIES
`
`MPEP § 2164.05 ......................................................................................................50
`
`
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`viii
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`
`
`LISTING OF EXHIBITS
`
`
`Exhibit Description
`
`2005
`
`2007
`
`Full file history of U.S. Patent No. 10,106,603
`2001
`2002 King, K., A scar-y movie, starring IL-11, SCIENCE TRANSLATIONAL
`MED., Vol. 9, No. 418, eaar2443 (Nov. 2017)
`2003 Obana et al., “Therapeutic activation of signal transducer and activator
`of transcription 3 by interleukin-11 ameliorates cardiac fibrosis after
`myocardial infarction,” Circulation, 2010 Feb. 9;121(5):684-91
`(“Obana-2010”)
`2004 Obana et al., “Therapeutic administration of IL-11 exhibits the
`postconditioning effects against ischemia-reperfusion injury via
`STAT3 in the heart,” Am. J. Physiol. Heart Circ. Physiol., 2012 Sep.
`1;303(5):H569-77 (“Obana-2012”)
`Stangou et al., “Effect of IL-11 on glomerular expression of TGF-beta
`and extracellular matrix in nephrotoxic nephritis in Wistar Kyoto rats,”
`J. Nephrol., 2011 Jan.-Feb.;24(1):106-11 (“Stangou”)
`2006 Ham et al., “Critical role of interleukin-11 in isoflurane-mediated
`protection against ischemic acute kidney injury in mice,”
`Anesthesiology, 2013 Dec.;119(6):1389-401 (“Ham”)
`Zhu et al., “IL-11 Attenuates Liver Ischemia/Reperfusion Injury (IRI)
`through STAT3 Signaling Pathway in Mice,” PLoS One, 2015 May
`6;10(5):e0126296 (“Zhu”)
`Fersht, A., The most influential journals: Impact Factor and
`Eigenfactor, PNAS, Vol. 106, No. 17, 6883-6884 (2009).
`Pflanz, S. et al, A fusion protein of interleukin-11 and soluble
`interleukin-11 receptor acts as a superagonist on cells expressing
`gp130, FEBS LETT, 450(1-2):117-22
`Schleinkofer, K. et al, Identification of the domain in the human
`interleukin-11 receptor that mediates ligand binding, J MOL BIOL,
`306(2):263-274
`2011 WO2015/184009
`2012 WO2017/070170
`2013
`“What You Need to Know About Pulmonary Fibrosis and Asthma,”
`PulmonaryFibrosisNow.org, available at
`https://pulmonaryfibrosisnow.org/2018/09/16/can-asthma-cause-
`pulmonary-fibrosis/, retrieved Nov. 14, 2019
`
`2008
`
`2009
`
`2010
`
`
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`

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`
`I.
`
`INTRODUCTION
`
`The ’603 patent claims a method of treating fibrosis in humans. Fibrosis is
`
`the formation of excess fibrous connective tissue in a tissue or organ. Ex. 1001
`
`(“’603-patent”), 33:25-44. The claimed method treats fibrosis by administering an
`
`Interleukin 11 receptor α (“IL-11Rα”) antibody capable of inhibiting signaling
`
`mediated by the protein Interleukin 11 (“IL-11”). ’603-patent, claim 1. Such an
`
`antibody binds to the α component of a cell’s receptor for IL-11 and inhibits IL-11
`
`from signaling via that receptor. ’603-patent, 17:27-35. The ’603 patent’s
`
`inventors discovered that this would inhibit formation of excess fibrous connective
`
`tissue. ’603-patent, 2:29-39, 19:8-16.
`
`The inventors did not purport to have invented the genus of IL-11Rα
`
`antibodies that inhibit signaling. Far from it. The specification explicitly
`
`acknowledges that such antibodies were “known,” and lists examples of known
`
`antibodies that could be used to practice the invention, including examples
`
`“described in US 2014/0219919.” ’603-patent, 18:41-46. US 2014/0219919 is
`
`Edwards (Ex. 1008), the primary reference in Petitioner’s prior art grounds.
`
`The ’603 patent’s invention involved the discovery that antibodies known to
`
`inhibit IL-11 mediated signaling could treat human fibrosis. As the specification
`
`explains at length, prior to the ’603 patent’s filing, there was no understanding in
`
`the art that IL-11 caused fibrosis. In fact, numerous prior-art studies taught the
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`
`
`1
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`

`

`
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`exact opposite—that IL-11 was beneficial in preventing fibrosis. ’603-patent, 2:1-
`
`25; see § II.A below. The ’603 patent’s inventors undertook and disclosed
`
`revolutionary studies that overturned this established understanding by
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`demonstrating for the first time that IL-11 actually causes increased fibrosis. They
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`went further and developed an inventive treatment that used known IL-11Rα
`
`antibodies to treat fibrosis in a way the conventional wisdom did not recognize.
`
`The inventors’ ground-breaking work was contemporaneously recognized. The
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`prestigious peer-reviewed journal Nature published an article describing the
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`claimed method for treating fibrosis (Ex. 1066), and that article was selected as an
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`“editor’s choice” in a later journal praising the inventors for having “discovered a
`
`surprising role for interleukin-11 (IL-11)” in treating fibrosis (Ex. 2002). See
`
`§ II.B below. The Petition improperly ignores all of this.
`
`A. The Prior Art Grounds Fail
`
`Petitioner relies primarily on the Edwards reference the specification itself
`
`presented as disclosing the known antibodies but not the claimed treatment
`
`method. Petitioner admits that Edwards does not teach using the disclosed
`
`antibodies to treat fibrosis (Petition, 39), but alleges that Edwards nevertheless
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`inherently anticipates. The Petitioner does not remotely meet the high burden to
`
`show inherency.
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`2
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`

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`The Petition alternatively alleges it would have been obvious to use
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`Edwards’ antibodies to treat fibrosis; but no other reference provides any
`
`suggestion to do so. The Petition’s assertions to the contrary are rife with
`
`mischaracterizations and fatal factual inaccuracies. The Petition improperly
`
`ignored the wealth of prior art cited in the ’603 patent that taught away from the
`
`claimed invention. See §§ II.A and VII.B.2.a below. Petitioner’s hindsight
`
`contentions are refuted by the contemporaneous praise for the invention (Exs.
`
`2002, 1066), which is objective evidence that the invention was not obvious. See
`
`Coalition for Affordable Drugs V v. Hoffman-LaRoche, IPR2015-01792, Paper 14
`
`at 17-19 (Mar. 11, 2016) (denying institution when objective evidence supports
`
`nonobviousness).
`
`B.
`
`The § 112 Grounds Fail
`
`The Petition’s attacks on written description and enablement fare no better.
`
`The Petition’s “State of the Art” section (Petition, 13-21) discusses nothing but
`
`how to identify and characterize antibodies. The ’603 patent does not purport to
`
`have invented a new genus of antibodies, nor a new way to make antibodies.
`
`Contrary to the Petition’s mischaracterization, the claimed invention is not a
`
`“genus of anti-IL-11Rα antibodies” (Petition, 22); it is a method of treating
`
`fibrosis using known IL-11Rα antibodies by administering a therapeutically
`
`effective amount for a human. Thus, the Petition’s citation to the legal
`
`
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`3
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`

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`requirements to satisfy written description and enablement for an inventor who
`
`claims to have invented a new genus are inapposite. The Petition entirely ignores
`
`the correct law relating to requirements for supporting a claim directed to a method
`
`of treatment using a known genus.
`
`IL-11Rα antibodies suitable for the claimed use were already identified and
`
`characterized in the art. ’603-patent, 18:41-44; Edwards ¶¶ 489, 492. The
`
`Petition’s lengthy discussion of difficulties in identifying and characterizing
`
`antibodies is irrelevant, because that work had already been done by Edwards and
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`a POSA could have practiced the claimed method by using any of the examples
`
`known in the art, including the examples cited in Edwards and specifically
`
`identified in the ’603 patent’s specification. Falko-Gunter Falkner v. Inglis, 448
`
`F.3d 1357, 1365 (Fed. Cir. 2006) (finding written description and enablement
`
`satisfied by prior-art references establishing what was already known in the art).
`
`Indeed, the Petition’s § 112 attacks are contradicted by its own prior art
`
`grounds. The Petition alleges that claim 1 is anticipated by Edwards’ disclosure of
`
`the IL-11Rα antibody genus used in the method of claim 1. Compare Petition, 39
`
`(“Edwards teaches anti-IL-11Rα antibodies capable of binding to IL-11Rα and
`
`neutralizing IL-11 signaling”) with ’603-patent, claim 1 (reciting use of a
`
`therapeutically effective amount of “(IL-11Rα) capable of inhibiting Interleukin 11
`
`(IL-11) mediated signaling”). While Petitioner did not inform the Board of it,
`
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`4
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`Edwards is incorporated by reference in the ’603 patent’s specification. ’603-
`
`patent, 18:41-46, 40:51-52; see § III.A below. Thus, the Petition’s prior art
`
`grounds lay bare fatal flaws in its § 112 grounds. Perhaps that is why Petitioner
`
`chose different experts to testify about the § 112 attacks and the prior art grounds.
`
`No single expert could have credibly testified in support of all grounds because
`
`their arguments are irreconcilably inconsistent. Indeed, the Petition’s § 112 attacks
`
`are supported only by an expert who knows nothing about fibrosis, and his
`
`testimony in material respects is directly contradicted by the testimony of
`
`Petitioner’s other expert who does have a background with fibrosis but supports
`
`only Petitioner’s prior art grounds.
`
`The Petition’s written description and enablement attacks are also based on
`
`the factually erroneous assertion that the ’603 patent’s specification describes only
`
`a desired function for the IL-11Rα antibody used in the method of claim 1 without
`
`providing any examples, so that a POSA would have had to “design and screen an
`
`enormous number of antibodies to determine which bind to IL-11Rα, and inhibit
`
`IL-11 mediated signaling” to practice the claimed invention. Petition, 31. This
`
`assertion is manifestly false. Edwards had already done that work, and the
`
`specification explicitly states that “[e]xamples of known anti-IL-11R antibodies
`
`include… clones 8E2 and 8E4 described in [Edwards].” ’603-patent, 18:41-46.
`
`Clones 8E2 and 8E4 are just two of sixty-four suitable antibody species disclosed
`
`
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`5
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`

`

`
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`in Edwards as binding to human IL-11Rα and inhibiting IL-11 mediated signaling.
`
`See § III.A below. Because Edwards is incorporated by reference in the ’603
`
`patent, the ’603 patent’s specification identifies not only clones 8E2 and 8E4, but
`
`all sixty-four of the antibody species Edwards discloses as binding to IL-11Rα and
`
`inhibiting IL-11 mediated signaling. ’603-patent, 40:51-52. Given the inventors’
`
`recognition that such antibodies can be used to treat fibrosis, and the
`
`specification’s reference to Edwards’ extensive disclosure of such antibodies, a
`
`POSA would not have needed to design or screen a single antibody to practice
`
`claim 1, and could have simply used any of Edwards’ numerous examples.
`
`Given that the Petition’s § 112 attacks are based entirely on the erroneous
`
`factual predicate that the specification does not disclose even a single antibody
`
`species suitable for practicing the claimed invention, these grounds fail on their
`
`face. See § V.C.2 below (discussing cases denying institution where § 112
`
`analysis failed to consider portions of challenged patent’s disclosure).
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`The Petition’s ignoring of Edwards’ sixty-four suitable species in its § 112
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`analysis is also fatal even if those species are somehow considered to not be
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`disclosed in the ’603 patent’s specification. The state of the art must be considered
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`in determining written description and enablement, and the specification need not
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`describe what is known to a POSA to fulfill either requirement. See § V.B.1
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`below. The Petition was required to demonstrate how the specification was alleged
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`6
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`to be deficient under § 112 in view of the prior art to establish a prima facie case
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`of unpatentability. The Petition’s failure to address the state of the art, including
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`Edwards’ disclosure of numerous antibodies suitable for practicing claim 1
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`because they bind to IL-11Rα and inhibit IL-11 mediated signaling, is fatal. The
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`§ 112 grounds fail for this additional reason.
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`Patent Owner identifies in more detail below the numerous legal and factual
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`deficiencies in each of the Petition’s grounds. The Petition must be denied.
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`II. THE ‘603 PATENT
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`A. The Inventors Discovered That IL-11 Produces Fibrosis
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`The ’603 patent relates to “Treatment of Fibrosis.” ’603-patent, Title.
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`Fibrosis occurs normally in response to tissue injury, with myofibroblasts
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`producing a collagen-rich extracellular matrix to aid in closing a wound. ’603-
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`patent, 33:25-58. In this normal case, fibrosis is an essential process, critical for
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`wound healing. ’603-patent, 1:20-21. However, in other pathological cases,
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`myofibroblasts can become overactive and fibrosis can become excessive and
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`associated with disease that may need treatment. ’603-patent, 1:21-31, 33:58-34:9.
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`The ’603 patent addresses “an unmet medical need” for “therapeutic and diagnostic
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`approaches to fibrosis.” ’603-patent, 1:15-16, 29-31.
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`7
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`Specifically, the inventors identified IL-11 as a signaling molecule necessary
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`for excess fibrosis, and developed a method of treating fibrosis by administering an
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`agent that neutralizes IL-11’s pro-fibrotic activity. ’603-patent, 2:29-35.
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`Prior to the invention, the role of IL-11 in the formation of excess fibrous
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`connective tissue was not understood. ’603-patent, 1:31-36. IL-11 was “thought
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`to be important for fibrosis and inflammation in the lung,” but precisely how it was
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`affecting lung fibrosis was “not clear.” ’603-patent, 1:51-67 (citing studies
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`including Minshall (Ex. 1069)); see also Minshall, 237 (“Whether IL-11 exerts
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`predominantly proinflammatory or anti-inflammatory actions within the airways
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`remains to be elucidated.”).1 In other organs, including those treated in the ’603
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`patent’s claims, multiple prior art studies taught that IL-11 inhibited fibrosis.
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`’603-patent, 2:1-25. For example, prior studies taught that: (a) IL-11 “ameliorates
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`cardiac fibrosis” (’603-patent, 2:2-5 (citing Obana-2010 (Ex. 2003, also in file
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`history (Ex. 2001) at 1501-23 with additional supplemental material)) and Obana-
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`2012 (Ex. 2004, also in file history (Ex. 2001) at 1430-38))); (b) IL-11 inhibits
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`“extracellular matrix” deposition in the kidney (’603-patent, 2:10-13 (citing
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`Stangou (Ex. 2005, also in file history (Ex. 2001) at 1541-46))) and provides
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`“protection against” a kidney disease (’603-patent, 2:13-16, (citing Ham (Ex. 2006,
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`also in file history (Ex. 2001) at 1446-58)); see also Ham, 1398 (“prolonged and
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`1 All emphases are added unless otherwise indicated.
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`8
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`high-dose IL-11 therapy does not induce tissue fibrosis”)); and (c) IL-11
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`“[a]ttenuates” a liver disease (’603-patent, 2:20-25 (citing Zhu (Ex. 2007, also in
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`file history (Ex. 2001) at 1579-93)); see also Zhu, 12 (“IL-11 treatment attenuates
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`injury and fibrosis”)).
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`Thus, from at least 2010 until the ’603 patent’s filing in 2015, the prior art
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`taught that IL-11 was, if anything, protective against fibrosis, and proposed the
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`polar opposite treatment of the claimed invention. That is, the prior art taught
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`deliberately administering IL-11, as opposed to administering something to inhibit
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`it, to treat fibrosis. E.g., Obana-2010, 689 (“These findings suggest that IL-11
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`treatment is a promising strategy”); Stangou, 110 (“possible new applications of
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`IL-11 and also novel treatment strategies”). The inventors discovered and
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`demonstrated that these prior art teachings were wrong because the prior studies
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`had tested human IL-11 in rodents and arrived at misleading results. ’603-patent,
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`45:1-13. The inventors conducted experiments definitively establishing that
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`human IL-11 is actually pro-fibrotic in humans. ’603-patent, 41:5-50:38,
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`Examples 1-8).
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`B.
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`The Inventors Discovered That Fibrosis Could Be Treated
`Using Known Antibodies That Inhibited IL-11 Mediated
`Signaling
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`Having established, for the first time and contrary to numerous prior-art
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`studies (see § II.A above), that “inhibition of IL-11 activity leads to a reduction in
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`9
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`the molecular basis for fibrosis,” the inventors developed a new and unexpected
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`treatment for fibrosis by “administering to a subject in need of treatment a
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`therapeutically effective amount of an agent capable of inhibiting the action of
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`Interleukin 11