Patent Owner’s
`Demonstratives
`
`United Therapeutics Corporation v. Liquidia Technologies, Inc.
`IPR2021-00406 – U.S. Patent No. 10,716,793
`
`May 13, 2022
`
`IPR2021-00406
`United Therapeutics EX2109
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`Demonstratives
`
`United Therapeutics Corporation v. Liquidia Technologies, Inc.
`IPR2021-00406 – U.S. Patent No. 10,716,793
`
`May 13, 2022
`
`IPR2021-00406
`United Therapeutics EX2109
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`1
`
`
`
`1. A method of treating pulmonary hypertension comprising administering by inhalation to a human
`suffering from pulmonary hypertension a therapeutically effective single event dose of a formulation
`comprising treprostinil or a pharmaceutically acceptable salt thereof with an inhalation device, wherein
`the therapeutically effective single event dose comprises from 15 micrograms to 90 micrograms of
`treprostinil or a pharmaceutically acceptable salt thereof delivered in 1 to 3 breaths.
`2. The method of claim 1, wherein the inhalation device is a soft mist inhaler.
`3. The method of claim 1, wherein the inhalation device is a pulsed ultrasonic nebulizer.
`4. The method of claim 1, wherein the inhalation device is a dry powder inhaler.
`5. The method of claim 1, wherein the inhalation device is a pressurized metered dose inhaler.
`6. The method of claim 4, wherein the formulation is a powder.
`7. The method of claim 6, wherein the powder comprises particles less than 5 micrometers in diameter.
`8. The method of claim 1, wherein the formulation contains no metacresol.
`No prior art disclosure of the claimed therapeutically effective dose delivered in 1-3 breaths
`
`Source: Paper No. 2 (Petition), 3-4.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`
`
`Ground
`
`Basis
`
`1
`2
`3
`4
`
`5
`6
`
`§103
`§103
`§102
`§103
`
`§102
`§103
`
`'793
`Claims
`
`1-8
`1-8
`1
`1, 3, 8
`
`1, 3
`2, 4-8
`
`’212
`Patent
`(EX1006)
`X
`X
`
`X
`
`JESC
`(EX1007)
`
`JAHA
`(EX1008)
`
`Ghofrani
`(EX1010)
`
`Vos. 2006
`(EX1009)
`
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`Source: Paper No. 2, 3-4.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`
`
`Institution Decision
`Grounds 1 (’212 + JAHA + JESC) and 2
`(’212 + JESC)
` Petition’s 1st calculation found to show
`a dose within 15-90 μg (ID 27-29)
` Petition’s 2nd calculation did not yield a
`dose within 15-90 μg (ID 29-30)
`Grounds 3-6
` Board agreed Ghofrani and Voswinckel
`2006 were not “by others”
` Only instituted pursuant to SAS
`Institute Inc. v. Iancu, 138 S. Ct. 1348,
`1355–56 (2018)
`
`Liquidia’s initial calculation:
`• Based on faulty hindsight assumptions
`• Alleged “confirm[ation]” reference
`does not corroborate POSA general
`knowledge
`
`Liquidia’s shifting sands calculations
`are belated and still have major flaws
`
`Liquidia waived depositions and failed
`to develop further evidence
`
`Source: Paper No. 18 (Institution Decision or "ID"), 27-30, 37-43.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`
`
`Ground
`
`Basis
`
`1
`2
`3
`4
`
`5
`6
`
`§103
`§103
`§102
`§103
`
`§102
`§103
`
`'793
`Claims
`1-8
`1-8
`1
`1, 3, 8
`
`1, 3
`2, 4-8
`
`’212 Patent
`(EX1006)
`X
`X
`
`JESC
`(EX1007)
`X
`X
`
`JAHA
`(EX1008)
`X
`
`Ghofrani
`(EX1010)
`
`Vos. 2006
`(EX1009)
`
`X
`X
`
`X
`
`X
`X
`
`X
`
`Source: Paper No. 2, 3-4.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`
`
`Ground
`
`1
`2
`3
`4
`
`5
`6
`
`Basis
`
`'793
`’212 Patent
`JESC
`Claims
`(EX1006)
`(EX1007)
`1-8
`§103
`X
`X
`1-8
`§103
`X
`X
`1
`§102
`JESC and JAHA are not prior art
`§103
`1, 3, 8
`Absence of evidence in Petition
`Untimely new evidence
`§102
`1, 3
`§103
`2, 4-8
`X
`
`Ghofrani
`(EX1010)
`
`Vos. 2006
`(EX1009)
`
`JAHA
`(EX1008)
`X
`
`X
`X
`
`X
`
`X
`X
`
`Sources: Paper No. 2, 3-4; Paper No. 29 (Patent Owner Response), 12-18; Paper No. 55 (Patent Owner Sur-Reply), 2-3.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`6
`
`
`
`’212 Patent
`(EX1006)
`X
`X
`
`JESC
`(EX1007)
`X
`X
`
`JAHA
`(EX1008)
`X
`
`Basis
`
`Ground
`
`1
`2
`3
`4
`
`5
`6
`
`'793
`Claims
`1-8
`§103
`1-8
`§103
`1
`§102
`No dose
`X
`1, 3, 8
`§103
`Dr. Hill: no teaching of “therapeutically effective”
`No reasonable expectation of success
`§102
`1, 3
`§103
`2, 4-8
`X
`
`Ghofrani
`(EX1010)
`
`Vos. 2006
`(EX1009)
`
`X
`X
`
`X
`X
`
`Sources: Paper No. 2, 3-4; Paper No. 29, 18-24; Paper No. 55, 11-19.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`
`
`Ghofrani & Voswinckel 2006
`Are Not Prior Art “By Others”
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`
`
`Less than 1 year before
`priority date
`No evidence of “by others”
`Inventors’ own work
`Liquidia’s failed burden
`
`Sources: Paper No. 29, 44-54; Paper No. 55, 25; EX1009; EX2003; EX2004; EX2005; EX2006.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`
`
`Dr. Seeger’s declaration is unrebutted
`Ghofrani:
` “Initial trials in Giessen” section is the inventors’ work
` Non-inventors did not contribute to the section Liquidia
`relies upon as alleged prior art
` Non-inventor Ghofrani wrote different sections
`(introduction and sections on phosphodiesterase
`inhibitors, vasoactive therapy, treatment of pulmonary
`hypertension, and compiled cited literature)
` Non-inventors Reichenberger and Grimminger wrote
`different section on endothelin A receptor agonists
`
`Seeger Decl.
`
`Sources: Paper No. 29, 44-54; Paper No. 55, 25; EX2003, 2-4, 6-8.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`10
`
`
`
`Dr. Seeger’s declaration is unrebutted
`Voswinckel 2006:
` Describes inventors’ own work
` Non-inventors did not contribute to the described work
` Non-inventors Ghofrani and Grimminger did not
`participate in design of clinical studies, dosing regimen,
`or analysis of patient results
` Ghofrani and Grimminger performed support work and
`named as co-authors consistent with Giessen group’s
`practice to acknowledge all individuals that assist with
`clinical trials
`
`Seeger Decl.
`
`Sources Paper No. 29, 44-54; Paper No. 55, 25; EX2003, 8-11.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`
`
`Three non-inventor author declarations
`corroborate Seeger Declaration
`
`As Board observed:
` “[A]ffidavits from the other authors
`disclaiming the invention are
`particularly strong evidence that the
`reference is not ‘by others.’”
`Paper No. 18 (Inst. Dec.) at 39 (citing In re Katz, 687 F.2d 450, 455-56 (CCPA 1982))
`
`Ghofrani Decl.
`
`Reichenberger
`Decl.
`
`Grimminger
`Decl.
`
`Sources: EX2004, EX2005, EX2006; Paper No. 18, 39.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`
`
`Source: Paper No. 18, 39, 42-43.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`
`
`Liquidia waived opportunity to
`depose Dr. Seeger
`Liquidia’s Reply: no evidence on
`prior art status
`Liquidia’s Reply: no argument on
`prior art status
`
`Sources: Paper No. 44 (Petitioner Reply), 1-9; Paper No. 55, 2-9.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`
`
`POSA
`
`DEMONSTRATIVE EXHIBIT — NOT EVIDENCE
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`
`
` Source: PTX-450, ¶ ¶ 53–57
`PATENT OWNER
`A person having ordinary skill in the art (“POSA”)
`would have a graduate degree in medicine or a field
`relating to drug development, such as an M.D. or a
`Ph.D., with at least two years practical experience in
`either (i) the investigation or treatment of pulmonary
`hypertension or (ii) in the development of potential
`drug candidates, specifically in the delivery of drugs
`by inhalation.
`
`PETITIONER
`With respect to a method of treating pulmonary
`hypertension as of May 15, 2006, a POSA would have a
`medical degree with a specialty in pulmonology or
`cardiology, plus at least two years of experience treating
`patients with pulmonary hypertension as an attending,
`including with inhaled therapies, or equivalent degree or
`experience.
`With respect to inhaled formulations used in the method
`to treat pulmonary hypertension as of May 15, 2006, a
`POSA would have a Ph.D. in pharmaceutical science or a
`related discipline like chemistry or medicinal chemistry,
`plus two years of experience in pharmaceutical
`formulations, including inhaled products, or equivalent
`(e.g., an M.S. in the same fields, plus 5 years of
`experience.
`
`Sources: Paper No. 2, 13-14; Paper No. 29, 7-8; EX1002, ¶¶17-19; EX1004, ¶¶9-11; EX2052, ¶¶13-16; EX2053, ¶¶28-31.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`
`
`“The petition must set forth: … (3) How the challenged
`claim is to be construed.”
`
`- 37 C.F.R. §42.1-4(b)(3)
`
`Source: Paper No. 2, 12-13.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`
`
`Grounds 1 & 2:
`JESC & JAHA Are Not Prior Art
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`18
`
`
`
`“‘[P]ublic accessibility’ has been called the touchstone in determining
`whether a reference constitutes a ‘printed publication’ …. A reference is
`publicly accessible ‘upon a satisfactory showing that such document has
`been disseminated or otherwise made available to the extent that
`persons interested and ordinarily skilled in the subject matter or
`art exercising reasonable diligence, can locate it.’”
`Kyocera Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d 1340, 1350
`(Fed. Cir. 2008) (internal citations omitted)
`
`“[I]ndexing plays a significant role in evaluating whether a
`reference in a library is publicly accessible.”
`
`Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1348 (Fed. Cir. 2016)
`
`Source: Paper 29 at 12.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`19
`
`
`
`The Petition argues that the JESC and JAHA Abstracts were “published” in
`supplements to their respective journals more than one year before priority
`date (citing Dr. Gonda and Dr. Hall-Ellis)
`o Dr. Gonda merely says that POSAs would have attended the conferences, and that to
`his recollection the journals are published in PubMed (EX1004, ¶¶55, 58)
`o But…
`• No evidence of what was presented at the conferences
`• No evidence that the journals/supplements/abstracts were published in PubMed
`(and in fact, these were not)
`
`Sources: Paper No. 2, 22, 24; Paper No. 29, 10, 14, 17; Paper No. 55, 2-4, 6-9; EX1036, ¶¶ 60-67, 69-75.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`
`
`For the Petition, Dr. Hall-Ellis submits only unstamped copies of the
`Abstracts, and MARC records for the underlying journals (EX1036)
`o Inexplicably concludes that the Abstracts were publicly available because the MARC
`records were available (¶¶61, 65, 70, 74)
`o References two catalog descriptor terms “cardiology” and “heart diseases” (¶¶61, 70)
`o But…
`•
`NO date-stamped copies of the Supplements/Abstracts
`
`•
`
`•
`
`•
`
`NO showing that the Supplements were available to a patron
`
`NO evidence of indexing of either the Abstracts or the Supplements
`
`NO indication of how a POSA would reasonably find the Abstracts based on descriptors
`
`Source: Paper No. 2, 22, 24; Paper No. 29, 10, 12-18, 17; Paper No. 55, 2-4, 6-9; EX1036, ¶¶ 60-67, 69-75.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`21
`
`
`
`Petition/experts fail to show public accessibility because:
`o No proof that either Abstract was received and publicly available at
`a library or elsewhere before the priority date
`o No evidence showing how an interested POSA could locate either
`Abstract with reasonable diligence
`
`• No evidence that the Supplements or the individual Abstracts were
`indexed or could otherwise be located through any kind of search
`
`•
`
`Petitioner’s expert only obtained copies by providing the exact
`citations to the libraries
`
`Sources: Paper No. 29, 10, 12-18; Paper No. 55, 2-3, 8-9; EX2041, ¶¶9-38; EX2043, 105:25-106:9.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`
`
`POR pointed out the deficiencies in the Petition evidence
`In Reply (Paper 44), Petitioner attempted to submit NEW evidence and
`arguments alleging that:
` Abstracts were “publicly presented” at their respective conferences
` Each Abstract cited in another journal article (“research aids”)
` Supplements were by an “established publisher”/alleged on-line
`availability of the Supplements/Abstracts
` Date-stamped copies of each Supplement, now with reference to
`alleged indexes within the Supplements
`
`Sources: Paper No. 29, 10, 12-18; Paper No. 44 (Pet. Reply), 2-9; Paper No. 46 (PO Obj. To Reply Evidence).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`
`
`Petitioner’s Reply arguments and evidence are improper (Sur-Reply at 3):
` Intelligent Bio-Systems v. Illumina Cambridge, 821 F.3d 1359, 1369 (Fed. Cir. 2016) (“It is of the
`utmost importance that petitioners in the IPR proceedings adhere to the requirement that the
`initial petition identify ‘with particularity’ the ‘evidence that supports the grounds for the
`challenge to each claim.’ 35 U.S.C. § 312(a)(3).”)
` Trial Practice Guide, 74 (“It is also improper for a reply to present new evidence (including new
`expert testimony) that could have been presented in a prior filing.”)
`Petitioner’s attempt to submit date-stamped copies as Supplemental Information
`denied for failure to show it could not have been presented earlier (Paper 30, 3-5)
`o Petitioner did not even attempt to justify late filing in its Reply
`Patent Owner sought permission to file evidence responsive to Petitioner’s Reply
`evidence, but was prevented from doing so (Paper 50)
`
`Sources: Paper Nos. 30 (Order Deny Pet. Req. Submit Suppl. Info.); 47 (PO Id. Non-Responsive Evid.); 50 (Order); 55, 3.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`24
`
`
`
`Even if considered, petitioner’s reply evidence fails
`Petitioner presented no evidence from the JESC or JAHA
`conferences
` NO testimony from anyone who attended the conferences
` NO evidence that the Abstracts were displayed or recited
` NO evidence that the Abstracts were distributed (e.g., no evidence of
`“Abstract books”)
`
`Source: Paper No. 55, 3-5.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`
`
`Even if considered, the “research aids” both fail to establish public
`accessibility
` As pure research aide, Ghofrani and Sulica not shown to have published
`before May 15, 2005—public accessibility after this date allows for their
`disqualification as not “by another”
` Also, no evidence that these authors were able to independently find the
`Abstracts, because the authors of both Ghofrani and Sulica were connected to
`the Giessen inventor group:
`• Ghofrani: Authors included Voswinckel and Seeger
`• Sulica: Principal Investigator in TRIUMPH study group that participated in the
`clinical trial reported in the Voswinckel publications
`
`Sources: Paper No. 55, 9-11; EX2003, ¶27; EX2061, ¶¶12-13; EX2071, ¶¶6-8; EX2094, 30:19-31:19, 75-76.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`26
`
`
`
`AHA Archive listing of Circulation Supplements:
`
`Patent Owner’s Expert, Ms. Wyman:
`NO listing for Volume 110, Issue 17
`Supplement (Oct. 2004)
`Keyword searches also do not retrieve
`the JAHA Supplement
`No copy of the Supplement could be
`found on-line
`
`EX2041,¶¶ 12-15
`
`EX2044, 5
`
`Sources: Paper No. 29, 16; EX2041, ¶¶12, 15; EX2044, 5.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`27
`
`
`
`NO evidence that either Abstract, or the
`Supplements as a whole, were indexed or
`available on-line:
` EX1114: Wayback machine archive of
`Circulation (i.e., JAHA Abstract) does
`not include the JAHA Supplement or
`the abstracts within
` Hall-Ellis admits she did not locate
`the JAHA Abstract via this website
`(EX2094, 50:11-56:22)
`
`Sources: Paper No. 55, 6-7; Paper No. 66 (Motion to Exclude), 10-12; EX1112, ¶39 (citing EX1014); EX1114; EX2094, 50:11-56:22.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`
`
`Same lack of evidence as to this page:
` No evidence that this Abstract Viewer
`encompassed the JAHA Abstract
` Dr. Hall-Ellis admits she did not
`locate the JAHA Abstract via this
`website (EX2094, 50:11-51:10)
` Patent Owner precluded from
`introducing sur-reply evidence to
`affirmatively prove that the JAHA
`abstract was not so accessible
`
`Sources: Paper No. 50; Paper No. 55, 6-7; Paper No. 66, 10-13; EX1112 ¶39 (citing EX1014); EX2094, 50:11-51:10.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`29
`
`
`
`EX1017 at 17 (PubMed “search results”)
`
`EX1020 at 5 (Web of Science “search results”)
`
`NO evidence that either
`Abstract, or the Supplements
`as a whole, were available on-
`line:
` NEITHER result shows that the
`actual Abstracts were
`available
` NEITHER result shows search
`results as of 2006 or before
`
`See EX2094 at 24:10-26:6, 27:11-28:9, 41:18-42:20
`
`Sources: Paper No. 55, 6-7; Paper No. 66, 13-14.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`30
`
`
`
`Both Abstracts are obscure – not indexed on standard databases like Ovid, PubMed,
`MEDLINE, Index Medicus, and Chemical Abstracts (EX2041, ¶¶5, 16-17, 37)
` These are the indexes Dr. Hall-Ellis said a POSA would turn to in 2004-2005 (EX2043, 41:1-42:4;
`242:11-243:18)
` Consistent with what the JAHA Supplement says about indexing:
`
`EX1095 at 12
`Without being indexed outside of the Supplements themselves, a POSA would never
`know what abstracts exist or what citations to ask for from a library
`
`Sources: Paper 29, 16; Paper 55 at 7-10; EX2071, ¶¶6-8; EX2003, ¶27; EX2061, ¶¶12-13.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`
`
`Hall-Ellis relies on British Librarian statement (EX1116) to claim that the JAHA
`Supplement was “available for public use”
`BUT Patent Owner’s impeachment exhibit (a different British Librarian statement)
`indicates that it wasn’t available as a whole:
`
`EX2094, 64 (emphasis added)
`The only possible “indexes” were within the Supplements themselves, but evidence
`suggests that the entire Supplements couldn’t be checked out
`
`Sources: Paper No. 44, 8-9; Paper No. 55, 6-8; EX1116; Depo. Ex. 2092 of Hall-Ellis 2nd Deposition (EX2094, 64).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`
`
`Petition does not establish any meaningful indexing of the Supplements, or of
`the Abstracts themselves, or any date of public accessibility for either
`Although not in the Petition, even if the Supplements were received by libraries
`before priority date, no evidence that the Supplements were available in their
`entirety to POSAs
`Without the entire JESC and JAHA Supplements, no way for a POSA to locate
`the individual Abstracts
` Petitioner fails to prove that the Abstracts were “made available to the
`extent that persons interested and ordinarily skilled in the subject
`matter or art exercising reasonable diligence[] can locate it”
`Kyocera Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d 1340, 1350 (Fed. Cir. 2008) (citations omitted).
`
`Sources: Paper No. 29, 12, 16; Paper No. 55, 6-11.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`
`
`Grounds 1 & 2:
`No Reference Discloses
`The Claimed Dose
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`34
`
`
`
`Source: EX1001, claim 1.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`
`
`Proper obviousness inquiry:
`do references disclose or
`teach 15-90 μg dose?
`Answer: no
`
`Only disclosure of 15-90 μg
`dose is the ‘793 patent
`
`Sources: Paper No. 13 (PO Preliminary Response), 43; Paper No. 29, 18-22.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`36
`
`
`
`Dr. Hill:
`
`Q. So about a year ago when you started your analysis, you had the '793
`patent in your hands, correct?
`A. Yes.
`Q. And you had materials that you had received from counsel, correct?
`A. That is correct.
`Q. So you knew when you started your analysis on the claims of the '793
`patent – what they said, correct?
`A. Correct.
`
`Source: EX2055, 35:25-36:10.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`
`
`Dr. Gonda:
`Q. And is it fair to say that to analyze
`obviousness, you first reviewed the 793 patent
`and then compared that to the prior art.
`A. Yes. The process as far as I recall was to look
`at the 793 and then compare that patent to
`the prior art.
`
`Source: EX2097, 26:4-6, 8-10.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`38
`
`
`
`’212 patent does not teach the claimed dose:
`Chemically induced PH
`Sheep, not humans
`Rates, not doses
`30-90 minutes, not 1-3 breaths
`Liquidia’s cited range: PVD, not PH
`Board agreed it does not teach claimed
`dose (ID, 26-27)
`
`Sources: Paper No. 55, 17-19; EX1006; EX2052, ¶¶ 58, 62.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`
`
`JESC does not teach the claimed dose:
`Concentrations of 16, 32, 48, 64
`μg/mL
`Pre-aerosolized concentration of
`solution put into device
`Continuous inhalation for 6
`minutes, not 1-3 breaths
`No disclosure of μg of
`treprostinil delivered to patient
`
`Sources: Paper No. 29, 20-21; EX1007; EX2052, ¶¶ 65-67.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`40
`
`
`
`JAHA does not teach the
`claimed dose:
`Concentration of 600
`μg/mL
`Pre-aerosolized
`concentration
`No disclosure of μg of
`treprostinil delivered
`to patient
`
`Sources: Paper No. 29, 22; EX1008; EX2052, ¶72, et seq.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`41
`
`
`
`Institution Decision recognized two calculations:
`1. [JESC concentrations] * [assumed volumes]
`“[C]onfirmation” of volumes from [OptiNeb manual rate] * [time]
`•
`2. [Remodulin IV dosing] * [alleged ‘212 patent 10-50% conversion rate], as
`“confirmation”
`Petition Footnote 13 asserts PVD doses are “equally possible” (?):
`3. [’212 patent PVD daily range 2.5 μg-125 mg]
`
`Sources: Paper No. 2, 39-40; Paper No. 18, 28-30; Paper No. 44, 12-14.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`
`
`Reply added new and revised arguments
`
`Institution Decision recognized two calculations:
`1. [JESC concentrations] * [assumed volumes] * efficiency
`“[C]onfirmation” of volumes from [OptiNeb manual rate and additional
`•
`references] * [time]
`2. [Remodulin IV dosing] * [alleged ‘212 patent 10-50% conversion rate], as
`“confirmation”
`• Heavier patients, new formulas, up-titrated dose rates, divides by 4
`Petition Footnote 13 asserts PVD doses are “equally possible” (?):
`3. [’212 patent PVD daily range 2.5 μg-125 mg] divided by 4
`
`Sources: Paper No. 2, 39-40; Paper No. 18, 28-30; Paper No. 44, 12-14.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`43
`
`
`
`Flawed Calculation #1 - JESC
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`44
`
`
`
`Dr. Waxman
`
`Dr. Hill
`
`Dr. Gonda
`
`Sources: EX2052, ¶65, n.8; EX1106, ¶39; EX1107, ¶13.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`45
`
`
`
`POSA could
`not calculate dose
`because too many
`variables
`
`POSA would not
`rely on JESC to
`calculate a dose
`
`Sources: EX2052, ¶¶ 65, n.7, 66.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`46
`
`
`
`Unknowns:
`Formulation
` Solvent
` Excipients
`Device
` Model Number
` No
`characterization data –
`only know it was
`ultrasonic
`
`Nebulizer use
` Fill volume
` Residual volume
` Frequency
` MMAD
` Output rate
` Efficiency
`Patient Factors
` Number breaths
` Breath rate
` Breath depth
`
`POSA could not
`calculate dose because
`there are too many
`variables
`
`Sources: Paper No. 29, 21, 23-37; EX2053, ¶¶55-57.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`47
`
`
`
`Hill’s First Calculation
`
`Alleged “Confirmation”
`
`
`
`Volume (mL)Volume (mL)
`
`
`Concentration Concentration
`
`(μg/mL)(μg/mL)
`
`
`
`Rate (mL/min)Rate (mL/min)
`
`
`
`Time (min)Time (min)
`
`
`Concentration Concentration
`
`(μg/mL)(μg/mL)
`
`Sources: Paper No. 2; EX1002; EX1106.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`48
`
`
`
`
`
`VolumeVolume
`
`
`
`ConcentrationConcentration
`
`Efficiency
`
`References do not
`disclose volume
`References do not
`disclose rate
`Petition omitted
`efficiency
`References do not
`disclose efficiency
`
`RateRate
`
`
`
`TimeTime
`
`
`
`ConcentrationConcentration
`
`Efficiency
`
`Sources: Paper No. 2; EX1002; EX1106.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`49
`
`
`
`1
`
`2
`
`3
`
`Volume Flaws
`Rate Flaws
`Efficiency Flaws
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`50
`
`
`
`Dr. Hill cites:
`Unspecified experience (with other drugs)
`Gonda Decl. (EX1004, ¶56), which relies on three
`drug labels for alleged 1-5 mL range
`“[C]onfirm[ation]” from OptiNeb Manual, EX1037
` UTC objected to EX1037
` Calculation: [0.6 mL/min rate] * [6 min] = 3.6 mL
`
`All flawed
`
`Sources: Paper No. 29, 25; EX1002, ¶65, 67; EX1004, ¶56; EX1037.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`51
`
`
`
`Dr. Waxman:
`
`Dr. Hill:
`Q. What products did you prescribe for use in
`nebulizers before 2006 in volumes of at least 1
`milliliter, if you recall?
`A. Well, certainly bronchodilators for treatment of
`asthma of COPD, inhaled corticosteroids,
`anticholinergics such as Ipratropium. I think that
`would be the main things I would have
`nebulized.
`
`• Not treprostinil
`• Not pulmonary hypertension
`
`Sources: Paper No. 29, 23-27; Paper No. 64 (UTC Observ. on Dep. of Dr. Hill), 1; EX2052, ¶69; EX2055, 146:16-23.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`52
`
`
`
`Dr. Hill:
`
`“[A]t least” 1 mL has no
`upper bound: unhelpful to
`calculate actual delivered
`dose
`Dr. Hill conflates fill volume
`and delivered volume
`
`Sources: Paper No. 18, 28; Paper No. 29, 25-26; EX1002, ¶65; EX2055 (Hill Dep.), 146:16-23.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`53
`
`
`
`Source: Koninklijke Philips N.V. v. Google LLC, 948 F.3d 1330 (Fed. Cir. 2020) (cited in Paper 18 (ID), 24-25).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`54
`
`
`
`Do not address treprostinil
`• EX1066: AccuNeb label (albuterol sulfate -
`relieve bronchospasm)
`• EX1029: Ventavis label (iloprost – pulmonary
`hypertension)
`• EX1050: Pulmozyme label (rhDNase – improve
`pulmonary function for cystic fibrosis patients)
`
`Sources: Paper No. 18, 24; EX1029, 1; EX1050, 1; EX1066, 1; EX2001, ¶41.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`55
`
`
`
`Liquidia
`says:
`
`Label
`actually
`says:
`
`Sources: Paper No. 44, 11-12; Paper No. 55, 13; EX1004, 33 n.4; EX1050; see also EX2056, 127:25-128:4.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`56
`
`
`
`EX1029, EX1050, EX1066 at most disclose fill volume
`Delivered volume depends on nebulized volume, which
`depends on fill and residual volume
`Liquidia’s EX1037 (OptiNeb Manual) states that residual
`volume may vary from 0.5 ml – 1.5 ml
`(EX1037, 22; see also EX2076 (citing residual volumes 0.5-2.3 mL))
`
`Sources: Paper No. 55, 12-13; EX1029; EX1050; EX1066; EX1037; EX2076.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`57
`
`
`
`No basis to assume any given volume was used in JESC
`
`mL
`40
`
`30
`
`20
`
`10
`
`0
`
`Liquidia’s
`positions
`
`Gonda Decl.
`Gonda’s Refs.
`Hill
`
`Volumes
`known to
`POSA
`
`0.5 – 38 mL
`(McConville)
`
`Sources: Paper No. 55, 11-13; EX1004, ¶56, ¶56, n.4; EX2053, ¶71.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`58
`
`
`
`UNKNOWNS
`Fill volume in JESC
`Residual volume
`Whatever the fill volume, whether it was
`used for one or multiple administrations
`Which nebulizer was used
`Patient factors – size, breathing pattern,
`breath depth
`Volume actually delivered
`
`FLAWS
`Gonda did not survey all available
`nebulizers to assess alleged “typical” fill
`or delivered volumes
`Unsupported assumption that JESC used
`treprostinil from ampules
`Failure to account for device losses
`(inefficiency)
`
`Sources: Paper No. 29, 21-22, 28, 30-32, 44; Paper No. 55, 11-13; EX2053, 30, 32, 36-37; EX2097, 160:12-17.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`59
`
`
`
`1
`
`2
`
`3
`
`Volume Flaws
`Rate Flaws
`Efficiency Flaws
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCEDEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`60
`
`
`
`Brun 2000
`
`Sources: EX2075, 77, 79, 80; see also EX2053, ¶¶52, 55.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`61
`
`
`
`Sources: Paper No. 55, 13-16; EX2053, ¶¶ 52, 55-56, 58; EX2079, 4.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`62
`
`
`
`Sources: EX1066; EX2053, ¶¶ 60-61; EX2079, 7-8.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`63
`
`
`
`McConville:
`
`Source: EX2053, ¶55.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`64
`
`
`
`Liquidia asserts that volume can be calculated from rates
` e.g., 0.6 mL/min x 6 min = volume
`Liquidia’s overly simplistic math fails:
` No basis to rely on 0.6 mL/min rate for treprostinil at the
`mouthpiece (from EX1037 or otherwise)
` Rates are affected by numerous factors
`Liquidia’s unsupported rate reduction
` Hill asserts 0.5 and 0.6 in Reply, without basis
`POSA would not infer a dose from unreliable rates
`
`Sources: Paper No. 2, 23-24; Paper No. 29, 26, 28-29; EX1002, ¶¶ 67, 99-100; EX1006, ¶¶ 61, 909-100.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`65
`
`
`
`Hill Reply Decl.
`
`Hill Deposition
`(Apr. 13, 2022)
`
`Q. So in paragraph – excuse me, paragraph 61, the
`evidence you cite for the 0.6 rate is the exhibit 1037
`English translation OptiNeb user manual 2005?
`A. Yes, and including my clinical experience.
`Q. And you don't cite there in paragraph 61 a
`separate document that specifically discloses a
`nebulizing rate of 0.5 milliliters per minute?
`I don't believe so, no.
`
`A.
`
`Sources: Paper No. 64, 1; EX1106, ¶¶ 61, 90; EX2108 23:1-11.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`66
`
`
`
`English only
`
`Sources: Ex1037; Paper No. 2, 23; EX1002, ¶67; Paper No. 29, 26-27.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`67
`
`
`
`No copy of document that was
`allegedly translated
`No basis for public accessibility before
`priority date
`
`Sources: Paper No. 29, 27; Paper No. 55, 11-12, n.5; Paper No. 66, 4-5; EX1037.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`68
`
`
`
`Hill and Gonda’s 0.6 mL/min rate
` Measured or just a target?
` What solution?
` Continuous/intermittent?
` Real life: would not output 0.6 mL/min
`Unknowns Gonda admits affect output
` Frequency
` Baffle plates
` Connection to patient
` Program used
`
`Sources: Paper No. 29, 28-29; Paper No. 55, 13-15; EX2053, ¶52; EX2056, 81:17-89:18, 93:16-25.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`69
`
`
`
`JESC abstract w/callout of
`optineb nebulizer (no
`model #)
`
`Sources: EX1007, 7; EX2055, 61:14-23, 81:16-22, 93:7-10.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`70
`
`
`
`Sources: EX1007, 7; EX2056, 83:12-24.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`71
`
`
`
`EX1037: 6 different programs
`Different programs can give
`different outputs
` McConville: “Especially because the
`programs affect whether the
`nebulizer would run continuously or
`intermittently, and for how long, the
`POSA would understand that the
`programs would affect nebulizer
`output.”
`JESC does not describe which
`program was used
`
`Sources: Paper No. 29, 28-29; EX1007, 7; EX1037, 18-20; EX2053, ¶79, see also ¶78.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`72
`
`
`
`Document
`
`English
`
`EX1037
`
`EX1086
`
`EX1087
`
`?
`
`German
`
`?
`
`Rate
`
`0.6 mL/min
`
`<0.6 mL/min
`
`<0.6 mL/min
`
`Sources: EX1037, 28; EX1086 (provided as exhibit to EX2108), 31, 50; EX1087, 27.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`73
`
`
`
`Even if EX1037 is not excluded, Petitioner
`has not shown it to be publicly available
`EX1087 does not prove availability
` No evidence that web pages for
`Optineb manual existed on the same
`date as the manual
`EX1087, Ex. D
` Multiple potential links to manuals
` No evidence identifying which the POSA
`would allegedly use
` Unclear which, if any, leads to EX1087,
`Ex. E
`
`Sources: Paper No. 29, 26-27; EX1087; Paper No. 72, 1-2, 5.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`74
`
`
`
`EX1087:
`Butler Decl.
`
`Ex. D – URLs,
`screenshots
`
`Ex. E – OptiNeb-ir
`manual - German
`
`Ex. F - HTML
`
`Source: EX1087, 27.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`75
`
`
`
`Source: EX1086, 31 (English), 50 (German).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`76
`
`
`
`Liquidia asserted EX1037 was from 2005
`Liquidia’s declarant in EX1087 states the manual is from 2004
`Rates in EX1037 and EX1087 don’t match
`<0.6 mL/min teaches away from Liquidia’s JESC calculation
`
`EX1037
`
`EX1087 (German)
`
`EX1086 (English)
`
`Sources: Paper No. 55, 11-12; Paper No. 64, ¶4; EX1037, 28; EX1086, 31; EX1087, 27.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`77
`
`
`
`Q. Exhibit 1086 does not describe the
`nebulizer output as 0.6 milliliters per
`minute. It actually describes it as less
`than 0.6; correct?
`A. That’s what it says, yes.
`Q. And then just numerically, 0.5
`milliliters per minute as a rate is less
`than .6; correct?
`A. Yes, it is.
`Q. 0.3 milliliters per minute is also less
`than 0.6; correct?
`A. Yes, it is.
`Q. 0.1 milliliters per minute is also less
`than 0.6; correct?
`A. Yes.
`
`Sources: Paper No. 64, ¶4; EX1086; EX1087; EX2108, 29:3-16.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`78
`
`
`
`On September 8, 2021:
`Liquidia provided EX1086, EX1087
`
`On February 10, 2022:
`Liquidia relied on 0.6 mL/min
`rate (e.g., Reply at 12)
`Dr. Hill relied on 0.6 mL/min
`rate (e.g., EX1106, ¶61)
`Dr. Gonda relied on 0.6
`mL/min rate (e.g., EX1107, ¶53)
`
`Liquidia continued relying upon 0.6 mL/min
`
`Sources: Paper No. 44, 12, 15; EX1086; EX1087; Paper No. 64, 2; EX1106, ¶61; EX1107, ¶53.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`79
`
`
`
`Dr. Gonda asserts an “average” rate
`of 0.6 mL/min
`But:
` He ignores true variation in
`measured rate of 0.22-1.14
`mL/min
` One manufacturer, limited
`number of devices
` He did not search for and review
`data for all ultrasonic nebulizers,
`or all nebulizers available at the
`time
`
`Dr. Gonda’s references, if
`anything, show variation
`EX1097
` 1987, not 2006
` 0.33 mL/min
`EX1098
` 1992
` 0.22-0.68 mL/min
`EX1099
` 1990
` 0.67-1.14 mL/min
`
`Sources: Paper No. 55, 13-14; EX1097; EX1098; EX1099; EX1107, ¶¶ 25, 33; EX2097, 160:12-17.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`80
`
`
`
`Manual Rates
`
`Tested Rate
`
`Nebuliser performance: approx. 0.5 ml/min
`
`Nebuliser performance: approx. 0.6 ml/min
`
`=0.163 mL/min
`
`POSA would not rely on manual rates
`Manual output rates do not “account for” all variables as Liquidia asserts
`
`Sources: Paper No. 55, 14-15; EX1062; EX2100; EX2101; EX2099, 173:19-24.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`81
`
`
`
`Dr. Gonda:
`Q. Would you understand that as describing the nebulizer
`output for the Multisonic Infracontrol as 0.5 milliliters of
`drug solution per minute?
`A. I would have probably asked the manufacturer how
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