IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`LIQUIDIA TECHNOLOGIES, Inc.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793
`
`
`PATENT OWNER SUR-REPLY
`
`
`
`
`
`
`
`
`U.S. Patent No. 10,716,793 B2
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`LIQUIDIA TECHNOLOGIES, Inc.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793
`
`
`PATENT OWNER SUR-REPLY
`
`
`
`
`
`
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`A.
`
`2.
`
`SUMMARY OF ARGUMENT ................................................................ 1
`PETITIONER’S REPLY DOES NOT CURE THE PETITION’S
`FAILURE TO ESTABLISH THE JESC AND JAHA ABSTRACTS AS
`PRIOR ART .............................................................................................. 2
`Petitioner Has Not Shown that a POSA Exercising
`Reasonable Diligence Could Have Located the Abstracts .................... 3
`There Is No Evidence that the Abstracts Were
`1.
`Publicly Accessible at the Respective Conferences ................... 4
`Petitioner’s Belatedly Submitted “Date-Stamped”
`Copies of the Journal Supplements Do Not Prove
`Public Accessibility, Even If From an “Established
`ublisher” ...................................................................................... 6
`Petitioner’s “Research Aid” Evidence Likewise Does Not
`Establish Public Accessibility ............................................................... 9
`III. GROUND 1: PETITIONER’S CALCULATIONS CANNOT SUPPLY
`THE MISSING 15-90 MICROGRAM DOSE ....................................... 11
`Flawed Assumptions Cannot Supply the Missing Dose ..................... 11
`1.
`A POSA Could Not Infer the Fill Volume In JESC ................. 11
`2.
`A POSA Could Not Infer the Output Rate in JESC ................. 13
`3.
`A POSA Could Not Infer the Nebulizer Efficiency
`In JESC ..................................................................................... 15
`Petitioner Relies on Impermissible Hindsight .......................... 17
`4.
`The POSA Could Not Reliably Calculate A Dose from the
`’212 Patent ........................................................................................... 17
`The References Alone or in Combination Fail To Render
`the Claims Obvious ............................................................................. 19
`
`B.
`
`A.
`
`B.
`
`C.
`
`
`
`i
`
`
`
`1.
`
`2.
`
`3.
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`Petitioner’s Calculations Fail Because They Do Not
`Address Non-Linearity .............................................................. 20
`No Motivation to Combine with A Reasonable
`Expectation of Success ............................................................. 21
`The Prior Art Does Not Disclose a “Therapeutically
`Effective” Single Event Dose According to Dr. Hil ................. 22
`IV. GROUND 2: PETITIONER’S REPLY DOES NOT CURE THE
`DEFECTS IN ITS PETITION ................................................................ 23
`GROUNDS 3-6: PETITIONER’S REPLY FAILS TO ADDRESS
`GHOFRANI OR VOSWINCKEL 2006 ................................................. 25
`SECONDARY CONSIDERATIONS REBUT PETITIONER’S
`GROUNDS .............................................................................................. 25
`VII. CONCLUSION ....................................................................................... 26
`
`
`V.
`
`VI.
`
`
`
`
`
`
`
`
`
`ii
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Cyclobenzaprine Hydrochloride,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 26
`Endo Pharms. Sols., Inc. v. Custopharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) .................................................................... 20, 24
`Intelligent Bio-Systems v. Illumina Cambridge,
`821 F.3d 1359 (Fed. Cir. 2016) ............................................................................ 3
`In re Klopfenstein,
`380 F.3d 1345 (Fed. Cir. 2004) ............................................................................ 4
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`(Fed. Cir. 2021) ................................................................................................... 21
`Statutes
`35 U.S.C. § 102(b) ............................................................................................... 2, 10
`
`
`
`
`
`
`
`
`iii
`
`
`
`Exhibit
`EX2001
`EX2002
`EX2003
`EX2004
`EX2005
`EX2006
`EX2007
`EX2008
`
`EX2009
`EX2010
`
`EX2011
`
`EX2012
`
`EX2013
`
`EX2014
`
`EX2015
`
`EX2016
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`EXHIBIT LIST
`
`Description
`Declaration of Dr. Aaron Waxman
`Dr. Waxman’s curriculum vitae
`Declaration of Dr. Werner Seeger
`Declaration of Dr. Hossein A. Ghofrani
`Declaration of Dr. Frank Reichenberger
`Declaration of Dr. Friedrich Grimminger
`Tyvaso Orange Book listing
`Hill, N., 2005, Therapeutic Options for the Treatment of
`Pulmonary Hypertension, Medscape Pulmonary Medicine 9(2).
`Substantive Submission filed in 12/591,200 (Mar. 9, 2015)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-1 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-11 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-16 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), unnumbered
`docket entry dated 7/30/2020
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-20 (public
`docket) (excerpted)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-29 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-45 (public
`docket)
`
`
`
`iv
`
`
`
`Exhibit
`EX2017
`
`EX2018
`
`EX2019
`
`EX2020
`
`EX2021
`
`EX2022
`
`EX2023
`
`EX2024
`
`EX2025
`
`EX2026
`
`EX2027
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-21 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-41 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-49 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-68 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-71 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-40 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-47 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-75 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-80 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-81 (public
`docket)
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-92 (public
`docket)
`
`
`
`v
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`United Therapeutics Corporation v. Liquidia Technologies, Inc.,
`Case No. 1:20-cv-00755-RGA-JLH (D. Del.), ECF-74 (public
`docket)
`Hess et al., 2007, A guide to aerosol delivery devices for
`respiratory therapists. American Association for Respiratory
`Care
`Dennis JH, 2002, Standardization issues: in vitro assessment of
`nebulizer performance. Respir. Care. 47(12):1455-1458
`Hess et al., 1996, Medication nebulizer performance. Effects of
`diluent volume, nebulizer flow, and nebulizer brand. Chest,
`110(2):498-505
`Rubin BK et al., 2008 Treatment Delivery Systems (in Clinical
`Asthma),
`available
`at
`https://www.sciencedirect.com/topics/medicine-anddentistry/
`nebulizer
`Gardenhire, D.S. et al., 2017, A Guide to Aerosol Delivery
`Devices for Respiratory Therapists (4th Ed.) American
`Association for Respiratory Care
`Tyvaso® Label 2021
`Bourge et al., Cardiovascular Therapeutics, 31:38-44 (2013)
`McLaughlin et al., Efficacy and safety of treprostinil: an
`epoprostenol analog for primary pulmonary hypertension, J.
`Cardiovascular Pharmacology, 41:293-299 (2003)
`Springer website (from fn 13 of Hall-Ellis Decl)
`(Intentionally Left Blank)
`Springer website (from fn 14 of Hall-Ellis Decl)
`University of Wisconsin–Madison Library Catalog Search for
`holdings of Circulation: the journal of the American Heart
`Association
`Declaration of Ms. Pilar Wyman
`Ms. Pilar Wyman’s curriculum vitae
`Deposition Transcript of Sylvia Hall-Ellis, Ph. D.
`
`Exhibit
`EX2028
`
`EX2029
`
`EX2030
`
`EX2031
`
`EX2032
`
`EX2033
`
`EX2034
`EX2035
`EX2036
`
`EX2037
`EX2038
`EX2039
`EX2040
`
`EX2041
`EX2042
`EX2043
`
`
`
`vi
`
`
`
`Exhibit
`EX2044
`EX2045
`EX2046
`EX2047
`EX2048
`EX2049
`
`EX2050
`
`EX2051
`
`EX2052
`EX2053
`EX2054
`EX2055
`EX2056
`
`EX2057
`
`EX2058
`
`EX2059
`EX2060
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`American Heart Association Listing of Circulation Supplements
`Chemical Abstracts Plus Search Results Transcript
`Ovid Search Results for “Voswinckel”
`PubMed Search Results for “Voswinckel”
`Compilation Showing Search Results for Descriptor Terms
`Oxford Academic Listing of European Heart Journal
`Supplements
`Simonneau et al., Updated Clinical Classification of Pulmonary
`Hypertension., J Am. College of Cardiol, 62(25)D34-D42 at
`D34-D35 (2013)
`Sitbon and Noordegraaf, Epoprostenol and pulmonary arterial
`hypertension: 20 years of clinical experience, Eur. Respir Rev.
`26:160055 (2017)
`Second Declaration of Dr. Aaron Waxman
`Declaration of Dr. Jason McConville
`Dr. McConville’s curriculum vitae
`Deposition of Dr. Nicholas Hill (Oct. 17, 2021), IPR2021-00406
`Deposition of Igor Gonda, Ph. D. (Oct. 26, 2021), IPR2021-
`00406
`Vital Signs (Body Temperature, Pulse Rate, Respiration Rate,
`Blood Pressure), Johns Hopkins Medicine, available at
`https://www.hopkinsmedicine.org/health/conditions-and-
`diseases/vital-signs-body-temperature-pulse-rate-respiration-
`rate-blood-pressure
`Pharmacokinetics of Inhaled Drugs, available at
`https://media.lanecc.edu/users/driscolln/RT127/Softchalk/
`Pharmcology_SFTCHLK_Lesson/Pharmacology_lesson10.html
`(Intentionally Left Blank)
`Waxman et al., Inhaled Treprostinil in Pulmonary Hypertension
`Due to Interstitial Lung Disease, N. Eng. J. Med. 384:325-334
`(2021)
`
`
`
`vii
`
`
`
`Exhibit
`EX2061
`
`EX2062
`
`EX2063
`
`EX2064
`
`EX2065
`
`EX2066
`
`EX2067
`
`EX2068
`
`EX2069
`
`EX2070
`
`EX2071
`
`EX2072
`
`EX2073
`
`EX2074
`
`EX2075
`
`EX2076
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`Declaration of Dr. Robert Roscigno (EX2048)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2049)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2050)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01622,
`(EX2051)
`Declaration of Dr. Werner Seeger regarding Application No.
`11/748,205
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Declaration of Dr. Werner Seeger (EX2020)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Hossein A. Ghofrani (EX2026)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Frank Reichenberger (EX2027)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Declaration of Dr. Friedich Grimminger (EX2028)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Declaration of Dr. Werner Seeger (EX2097)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`Second Declaration of Dr. Werner Seeger (EX2098)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`(EX2101)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621
`(EX2102)
`Watson Labs., Inc. v. United Therapeutics Inc., IPR2017-01621/-
`01622 Second Declaration of Dr. Hossein A. Ghofrani (EX2099)
`Le Brun et al., A review of the technical aspects of drug
`nebulization, Pharmacy World & Science, 22(3):75-81 (2000)
`Kendrick, et al., Selecting and Using Nebuliser Equipment,
`Thorax, 52(Suppl 2):S92-S101 (1997)
`
`
`
`viii
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Rau et al., Performance Comparison of Nebulizer Designs:
`Constant-Output, Breath-Enhanced, and Dosimetric,
`Respiratory Care, 49(2):174-179 (2004)
`Rau, The Inhalation of Drugs: Advantages and Problems,
`Respiratory Care, 50(3):367-382 (2005)
`Hess et al., Medication Nebulizer Performance, Laboratory and
`Animal Investigations, 110(2):498-505 (1996)
`FDA Guidance 2002
`Newman et al., Efficient Delivery to the Lungs of Flunisolide
`Aerosol from a New Portable Hand-Held Multidose Nebulizer,
`1996 85(9) J. Pharm Sciences 960 (1996)
`Dubus et al., Aerosol Deposition in Neonatal Ventilation,
`PEDIATRIC RESEARCH, 58(1):10-15 (2005)
`Treprostinil, PubChem, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/Treprostinil
`Roscigno et al., 2020 Pharmacokinetics and tolerability of
`treprostinil.
`LIQ861, a novel dry-powder
`formulation of
`Pulmonary Circulation, 10(4):1-9 (2020)
`Roscigno et al., Comparative bioavailability of inhaled
`treprostinil administered as LIQ861 and Tyvaso® in healthy
`subjects, Vascular Pharmacology 138:106840 (2021)
`Declaration of Dr. Roham T. Zamanian regarding Application
`No. 12/591,200
`Sandifer et al., Potent Effects of aerosol compared with
`intravenous Treprostinil on the pulmonary circulation, J. Appl.
`Physiol. 99:2363-2368 (2005)
`U.S. Patent Publication No. 2012/0177693 (Cipolla et al.)
`Liquidia SEC Form 10-K (2020)
`Preston et al., Safety and efficacy of transition from inhaled
`treprostinil to parenteral treprostinil in selected patients with
`pulmonary arterial hypertension, Pulm Cir. 4(3):456-461 (2014)
`Expert Report of Dr. Igor Gonda (D. Del) (excerpts)
`Biography of Mandy H. Kim
`
`Exhibit
`EX2077
`
`EX2078
`
`EX2079
`
`EX2080
`EX2081
`
`EX2082
`
`EX2083
`
`EX2084
`
`EX2085
`
`EX2086
`
`EX2087
`
`EX2088
`EX2089
`EX2090
`
`EX2091
`EX2092
`
`
`
`ix
`
`
`
`Exhibit
`EX2093
`EX2094
`
`EX2095
`
`EX2096
`
`EX2097
`
`EX2098
`EX2099
`
`EX2100
`
`EX2101
`
`EX2102
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Description
`Declaration of Mandy H. Kim
`Deposition of Dr. Sylvia Hall-Ellis, Ph.D. (March 11, 2022),
`IPR2021-00406, with exhibits:
`Deposition Exhibit 2092: British Library Communication from
`Rupert Lee;
`Deposition Exhibit 2093: McLaughlin et al., Addition of Inhaled
`Treprostinil
`to Oral Therapy
`for Pulmonary Arterial
`Hypertension, JACC 55(18):1915-1922 (2010)
`Deposition of Christopher Butler (March 10, 2022), IPR2021-
`00406
`Deposition of Dr. Nicholas Hill (Jan. 4, 2022), United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case
`No. 1:20-cv-00755-RGA-JLH (D. Del.)
`Deposition of Igor Gonda, Ph.D. (Jan. 7, 2022), United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case
`No. 1:20-cv-00755-RGA-JLH (D. Del.)
`(Intentionally Left Blank)
`Deposition of Igor Gonda, Ph.D. (March 14, 2022), IPR2021-
`00406
`Schill: Multisonic, Inhaling with ultrasonic
`Instructions for Use (2004)
`(Exhibit from March 14, 2022 Deposition of Dr. Gonda,
`referenced as “Tab 6”)
`Schill: Multisonic, Inhaling with ultrasonic
`Instructions for Use
`(Exhibit from March 14, 2022 Deposition of Dr. Gonda,
`referenced as “Tab 5”)
`DeVilbiss, UltraNeb, Ultrasonic Nebulizer manual
`(Exhibit from March 14, 2022 Deposition of Dr. Gonda,
`referenced as “Tab 9”)
`
`infraControl,
`
`infraControl,
`
`
`
`x
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`Exhibit
`EX2103
`
`EX2104
`
`
`Description
`Lieberman, et al., In Vitro Performance of the MyNeb®
`Nebulizer: A New Portable Aerosol Delivery System
`(Exhibit from March 14, 2022 Deposition of Dr. Gonda,
`referenced as “Tab 4”)
`Transcript of Telephonic Hearing (March 1, 2022)
`
`
`
`
`
`xi
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`
`I.
`
`SUMMARY OF ARGUMENT
`Liquidia Technologies, Inc. (“Petitioner”) has failed to meet its burden of
`
`proving claims 1-8 of U.S. Patent No. 10,716,793 (“the ’793 patent”) are
`
`unpatentable for two primary reasons.
`
`First, each of Petitioner’s six unpatentability grounds rely upon references that
`
`Petitioner has failed to establish constitute prior art. Grounds 1, 2, and 4 rely on the
`
`JESC and JAHA abstracts, but Petitioner has not set forth sufficient evidence to
`
`show that either abstract was publicly accessible as of the priority date of the claimed
`
`inventions. Petitioner improperly adds new exhibits in its Reply attempting to cure
`
`this failure of proof, but the belated exhibits (even if admissible) fail to establish a
`
`date of indexing required for public accessibility. Petitioner’s untimely evidence
`
`likewise fails to show that either abstract was in widespread circulation, cited by
`
`others who did not have a connection to the inventors, or presented to anyone at the
`
`meetings. Grounds 3-6 rely on Ghofrani and/or Voswinckel 2006, but Petitioner has
`
`not set forth sufficient evidence to show that either is antedating or “by others.”
`
`These fundamental failures are fatal to Petitioner’s case.
`
`Second, Petitioner’s unpatentability grounds based on the combination of the
`
`’212 patent, JESC, and/or JAHA are constructed with impermissible hindsight.
`
`None of these references, alone or in combination, discloses the administration of
`
`the claimed single event dose from 15 to 90 micrograms to a human, let alone
`
`
`
`1
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`delivery of that dose in 1-3 breaths. Petitioner relies on unsupported assumptions
`
`and unreliable calculations, while
`
`ignoring uncontroverted evidence of
`
`unpredictability, in order to argue that the prior art teaches the claimed dose. The
`
`POSA, however, would not perform these calculations and, even if performed, the
`
`calculations are unreliable and yield speculative doses that fall outside the claimed
`
`range.
`
`II.
`
`PETITIONER’S REPLY DOES NOT CURE THE PETITION’S
`FAILURE TO ESTABLISH THE JESC AND JAHA ABSTRACTS AS
`PRIOR ART
`The Petition fails to establish that Voswinckel JESC (EX1007) (“JESC”) and
`
`Voswinckel JAHA (EX1008) (“JAHA”) (collectively, the “Abstracts”) are prior art
`
`under Section 102(b) because they were not publicly accessible to a person of
`
`ordinary skill in the art more than one year before the priority date. The Petition,
`
`citing the Gonda and Hall-Ellis declarations, asserted that the Abstracts are prior art
`
`because they were “presented” at conferences in 2004. Pet., 22, 24 (citing EX1004
`
`(Gonda), ¶¶55, 58; EX1036 (Hall-Ellis), ¶¶59-75). Dr. Gonda, however, merely
`
`parrots the Petition’s claim that the Abstracts “correspond” to presentations at the
`
`conferences and provided no evidence that he attended or of what was actually
`
`presented at either conference. Dr. Hall-Ellis relied on MARC records for
`
`Circulation and European Heart Journal in arguing that the special supplements
`
`containing the Abstracts were received by libraries in late 2004. Yet Dr. Hall-Ellis
`
`
`
`2
`
`
`
`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`provided no evidence that the supplements—not searchable or indexed in any
`
`meaningful way—were, in fact, publicly accessible. The Petition thus failed to
`
`prove that the Abstracts qualify as prior art. See POR, 11-18.
`
`Realizing the Petition’s shortcomings, the Reply barely discusses the Petition
`
`evidence, focusing instead on new arguments and evidence. Petitioner earlier sought
`
`unsuccessfully to file supplemental information. The Board found that Petitioner
`
`failed to show that it could not have presented such evidence earlier. Paper 30.
`
`Undeterred, Petitioner instead filed new evidence and arguments with its Reply, to
`
`which Patent Owner timely objected. Reply, 1-9; Paper 47. Petitioner’s late
`
`arguments and evidence should not be considered for at least the same reasons that
`
`submitting supplemental information was not permitted. Intelligent Bio-Systems v.
`
`Illumina Cambridge, 821 F.3d 1359, 1369 (Fed. Cir. 2016); Trial Practice Guide,
`
`74. Permitting Petitioner to introduce new evidence and argument at this late stage
`
`prejudices Patent Owner, who is barred from presenting any rebuttal evidence with
`
`its sur-reply beyond that associated with the cross-examination of Petitioner’s
`
`declarants (see Paper 50). Even if considered, however, Petitioner’s new evidence
`
`still fails to establish the Abstracts are prior art.
`
`A.
`Petitioner Has Not Shown that a POSA Exercising Reasonable
`Diligence Could Have Located the Abstracts
`Petitioner has failed to meet its burden—to be satisfied in the Petition—of
`
`proving that the Abstracts are prior art. Petitioner provides no evidence establishing
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`3
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`whether or how the Abstracts were “presented” at their respective conferences. The
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`supplements containing the Abstracts lack meaningful indexing and do not remedy
`
`this fatal deficiency. Ms. Wyman—an expert in indexing—testified that a POSA in
`
`the 2004-2005 timeframe seeking these abstracts would have been searching for a
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`needle in a haystack—without even knowing that a needle was present. EX2041,
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`¶¶6-38.
`
`1.
`There Is No Evidence that the Abstracts Were Publicly
`Accessible at the Respective Conferences
` Petitioner’s argument that the “presentation” of the abstracts at their
`
`respective conferences make them prior art (Reply, 2-3, 6-7) fails because Petitioner
`
`has not proved that the Abstracts were, in fact, presented in any meaningful way. In
`
`re Klopfenstein, 380 F.3d 1345, 1350 (Fed. Cir. 2004). Petitioner cannot satisfy its
`
`burden by simply claiming that a POSA would have attended the conferences.
`
`Reply, 2-3, 7.1 Nor is Petitioner’s burden satisfied by vague assertions that
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`
`
`1 For example, Petitioner’s expert admits that the presentations may have occurred
`
`in any number of formats but has no idea what was actually said or presented or to
`
`whom. EX2094, 37:5–39:3, 42:21–44:17. Petitioner also failed to adduce any
`
`evidence from the ’793 patent inventors, JESC/JAHA authors, or conference
`
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`4
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`U.S. Patent No. 10,716,793 B2
`conference programs or abstract books were allegedly available or given to attendees
`
`(id.), given the lack of actual evidence of those hypothetical programs and books,
`
`their content, or testimony from conference organizers or attendees regarding
`
`whether and how the Abstracts were presented. This lack of evidence is astounding
`
`given Petitioner’s claims that the ESC conference had more than 25,000 attendees
`
`(Reply, 2) and the AHA conference was even larger (see EX1106, ¶22 n.3).
`
`This lack of evidence also moots Petitioner’s argument (Reply, 3, 7) that
`
`POSAs at the conference would have sought out these presentations by searching
`
`for the authors or subject matter, since no record evidence establishes how a POSA
`
`knew the presentations would occur. The lack of evidence also distinguishes the
`
`three cases cited by Petitioner where conference proceedings established public
`
`accessibility because those cases relied on evidence establishing what was presented
`
`at the conference and confirming the number and type of attendees. Reply, 2. Here,
`
`there is no such evidence.
`
`
`
`attendees to establish what information in the abstracts was actually presented at
`
`either conference.
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`5
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`U.S. Patent No. 10,716,793 B2
`2.
`Petitioner’s Belatedly Submitted “Date-Stamped” Copies of
`the Journal Supplements Do Not Prove Public Accessibility, Even
`If From an “Established Publisher”
`Petitioner’s Reply argues for the first time that the Board should presume
`
`public accessibility because the supplements are from an “established publisher.”
`
`Reply, 2, 6. As support, Petitioner submits date-stamped copies of the Supplements
`
`from the European Heart Journal (for JESC) and Circulation (for JAHA) (see
`
`EX1089-EX1096) along with an unsworn statement from a librarian alleging that
`
`the Circulation Supplement was “available for public use” (EX1116). Even if this
`
`belated argument/evidence is considered, it still does not establish that the Abstracts
`
`were publicly accessible during the relevant timeframe because none of it shows that
`
`a POSA exercising reasonable diligence could have located the Abstracts.
`
`Two critical facts separate this case from the typical analysis regarding run-
`
`of-the-mill journal articles. First, before the 2006 priority date, neither of these
`
`Abstracts were indexed in any online database or index outside of the printed
`
`supplement issues themselves. POR, 6. Petitioner’s expert identified the online
`
`databases that a POSA would have used for such a search (see EX2043, 41:1-42:4;
`
`242:11-243:18), and the abstracts do not appear in any of them (see EX2041, ¶¶5,
`
`16-17, 37). While Dr. Hall-Ellis belatedly asserts that the Circulation Supplement
`
`can be found in PubMed (EX1112, ¶60), she fails to present any evidence that
`
`PubMed includes the abstracts themselves (or the indexes), as opposed to just a
`
`
`
`6
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`U.S. Patent No. 10,716,793 B2
`citation to the supplement. EX2094, 12:9–14:8; 50:11–56:22. Dr. Hall-Ellis also
`
`now claims that JESC can be found on the “Web of Science” (id., ¶87), but fails to
`
`assert (let alone prove) that this listing was available in 2004-2005.2
`
`Compounding the difficulty a POSA would encounter if trying to locate the
`
`Abstracts, Petitioner’s newly-submitted evidence confirms that the indexes for the
`
`JAHA Abstract supplement appear only within that issue:
`
`
`
`EX1095, 12 (highlighting added).
`
`Second, a POSA could not access the only available indexes within the
`
`supplements to find the Abstracts—even if received by a library as Petitioner
`
`claims—because the supplemental issues of Circulation and EHJ were not made
`
`available to patrons in their entirety. Therefore, because the only indexes identifying
`
`the Abstracts are within the supplement issues themselves, a POSA could not access
`
`
`
`2 Patent Owner was not allowed to present rebuttal evidence on these points, but Dr.
`
`Hall-Ellis admitted that she did not use the Internet Archive to try to show that either
`
`of these results existed in 2006. EX2094, 25:4-26:6.
`
`
`
`7
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`U.S. Patent No. 10,716,793 B2
`those indexes to even attempt to find Abstracts without the entire issue.3 While Dr.
`
`Hall-Ellis relies on an unsworn, conclusory statement from a librarian at the British
`
`Library that the JAHA Supplement was “available for public use” (EX1112, ¶50
`
`(citing EX1116)), another librarian at the British Library explained that the
`
`supplements could not be requested or checked out in their entirety. See EX2094,
`
`63-65. Instead, they were only available to the extent a patron provided a specific
`
`citation for the desired abstract(s) and asked to have them copied. Id., 64 (¶2). Thus,
`
`even if the supplements were from an “established publisher” and various libraries
`
`had them, the Abstracts themselves were not available unless patrons somehow had
`
`the specific citations.
`
`These two crucial facts taken together show why Petitioner’s new evidence
`
`(even if admitted and considered) fails to establish public accessibility. A POSA
`
`could not have reasonably located the citations for either Abstract because they were
`
`not indexed anywhere other than within the printed supplemental volumes
`
`themselves. Those printed indices were not available to patrons because the libraries
`
`
`
`3 Patent Owner does not concede that the Table of Contents (JESC), subject matter
`
`index (JESC), or author index (JAHA) were sufficient for a POSA to locate the
`
`Abstracts using reasonable diligence, but was not permitted to submit rebuttal
`
`evidence from its indexing expert on these newly raised points by Petitioner.
`
`
`
`8
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`U.S. Patent No. 10,716,793 B2
`did not make the whole supplements available (EX2094, 64). The fact that Dr. Hall-
`
`Ellis was able to retrieve copies of the Abstracts by providing exact citations
`
`(EX2094, 6:6–9:3, 39:5 41:16) does not establish a POSA interested in pulmonary
`
`hypertension treatments—who would not have known the citations to ask for,
`
`whether the Abstracts existed, where they were located, or how to obtain/review the
`
`indexes within the supplemental issues—could find the Abstracts through the
`
`exercise of reasonable diligence.
`
`B.
`Petitioner’s “Research Aid” Evidence Likewise Does Not Establish
`Public Accessibility
`Another of Petitioner’s new arguments—that the Abstracts are prior art by
`
`virtue of being cited in two later publications—is also unavailing. Petitioner
`
`contends that Ghofrani (EX1121) and Sulica (EX1104) are “research aids” that
`
`would have allowed a POSA to find the Abstracts. Reply, 3-4, 7-8. This belated
`
`argument establishes, at best, that a POSA may have been able to find the Abstract
`
`as of the date the alleged “research aids” became available. Ghofrani bears a July
`
`2005 date-stamp (EX1121, 1), while Sulica shows only the year 2005 (EX1104, 1).4
`
`
`
`4 Petitioner references a “March 2005” publication date (Reply, 7 (citing EX1104)),
`
`but Sulica only identifies 2005, not any month of publication. Patent Owner also
`
`
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`9
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`U.S. Patent No. 10,716,793 B2
`However, if the Abstracts only became publicly accessible (via these alleged
`
`“research aids”) after May 15, 2005, they do not qualify as prior art under 35 U.S.C.
`
`§ 102(b). And if the Abstracts are not Section 102(b) prior art, they are not prior art
`
`at all because they are not “by another” under Section 102(a), given Patent Owner’s
`
`prior showing that the subject matter of both Abstracts is the inventors’ own work.
`
`See EX2071, ¶¶6-8 (referencing the Abstracts as Watson Exhibits 1003 (JAHA) and
`
`1046 (JESC)); EX2003, ¶27; EX2061, ¶¶12-13.
`
`Finally, although Petitioner’s expert argued that the citations in Ghofrani and
`
`Sulica showed a POSA could find the Abstracts (EX1112, ¶¶62, 89), she admitted
`
`that she did not consider the close affiliations among the authors and how that might
`
`explain how the Abstracts came to be cited in Ghofrani and Sulica (see EX2094,
`
`30:19–36:16). Ghofrani’s authors include both Voswinckel and Seeger, who of-
`
`course knew about their own JESC Abstract and would not have needed to search
`
`for it like a POSA. Similarly, Sulica was a principal investigator in the TRIUMPH
`
`study group that participated in the clinical trial reported in the Voswinckel
`
`publications. See, e.g., EX2094, 75-76 (listing both Sulica and Seeger as principal
`
`investigators in the TRIUMPH study group); EX2061, ¶¶5-8; EX2066, ¶¶5-12
`
`
`
`objected to Exhibit 1104 on hearsay grounds (Paper 46, 4-5), but Petitioner did not
`
`serve any supplemental evidence for this exhibit.
`
`
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`10
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`IPR2021-00406
`U.S. Patent No. 10,716,793 B2
`(confirming TRIUMPH study relates to Ghofrani, JESC, and JAHA). Therefore,
`
`neither Ghofrani nor Sulica constitute evidence that a POSA found the Abstracts
`
`using reasonable diligence.
`
`III. GROUND 1: PETITIONER’S CALCULATIONS CANNOT SUPPLY
`THE MISSING 15-90 MICROGRAM DOSE
`A.
`Flawed Assumptions Cannot Supply the Missing Dose
`Petitioner cannot dispute that JESC, JAHA, and the ’212 patent lack any
`
`express disclosure of the claimed dose. The Reply continues attempting to fill this
`
`gap in new (and belated) ways by relying on flawed assumptions driven by hindsight.
`
`1.
`A POSA Could Not Infer the Fill Volume In JESC
`Petitioner’s first attempt at calculating the claimed dosage simply assumes a
`
`fill volume while ignoring contrary evidence. A POSA could not reliably determine
`
`the fill volume used, or the volume actually delivered, to JESC’s patients because:
`
` Drs. Waxman and Hill’s experience with 1 mL “or more” fi
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