Petitioner Liquidia
`Technologies, Inc.
`
`Oral Argument
`Demonstratives
`
`May 13, 2022
`Liquidia Technologies, Inc. v.
`United Therapeutics Corp.,
`IPR2021-00406
`
`U.S. Patent No. 10,716,793
`
`attorney advertisement
`Copyright © Cooley LLP, 3175 Hanover Street, Palo Alto, CA 94304. The content of this packet is an introduction to Cooley LLP’s
`capabilities and is not intended, by itself, to provide legal advice or create an attorney-client relationship. Prior results do not
`guarantee future outcome.
`
`Petitioner’s Ex. 1134 – IPR2021-00406
`
`
`Technologies, Inc.
`
`Oral Argument
`Demonstratives
`
`May 13, 2022
`Liquidia Technologies, Inc. v.
`United Therapeutics Corp.,
`IPR2021-00406
`
`U.S. Patent No. 10,716,793
`
`attorney advertisement
`Copyright © Cooley LLP, 3175 Hanover Street, Palo Alto, CA 94304. The content of this packet is an introduction to Cooley LLP’s
`capabilities and is not intended, by itself, to provide legal advice or create an attorney-client relationship. Prior results do not
`guarantee future outcome.
`
`Petitioner’s Ex. 1134 – IPR2021-00406
`
`
`
`Person of Ordinary
`Skill in the Art
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Person of Ordinary Skill in the Art:
`“a second computer system distinct
`No Dispute that Dr. Hill, Dr. Gonda, Dr. Waxman, and Dr. McConville are POSAs
`from the first computer system”
`
`Liquidia
`Proposed Definition
`
`Method of treating pulmonary hypertension:
`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.
`
`Inhaled formulations used in the method to treat pulmonary
`hypertension:
`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).
`
`UTC
`Proposed Definition
`
`M.D. or a graduate degree
`(Masters or Ph.D.) in a field
`relating to drug development and
`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.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 13-14; POR 7-8
`3
`
`
`
`Grounds and Claims
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`Grounds for Consideration
`from the first computer system”
`• Ground 1 (Claims 1-8): ’212 Patent, Voswinckel JESC, Voswinckel JAHA
`•
`’212 Patent = treatment of pulmonary hypertension with inhaled treprostinil, inhalation devices,
`solution and powder formulations
`• Voswinckel JESC = therapeutically effective single event dose of 15-90µg
`• Voswinckel JAHA = 3 breaths
`• Ground 2 (Claims 1-8): ’212 Patent, Voswinckel JESC
`•
`’212 Patent = treatment of pulmonary hypertension with inhaled treprostinil, inhalation devices,
`solution and powder formulations
`• Voswinckel JESC = therapeutically effective single event dose of 15-90µg and routine optimization to
`achieve 3 breaths
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`All are UTC publications.
`Pet. 30-50; Reply 1-23; EX1006; EX1007, 7; EX1008
`5
`
`
`
`“a second computer system distinct
`’212 Patent (EX1006)
`from the first computer system”
`• Assigned to UTC
`• Method of Treatment:
`• Sheep experiments comparing treprostinil sodium (UT-15 or Remodulin®)
`delivery via inhalation versus intravascularly
`• Claims directed to treating humans with pulmonary hypertension (Claim 5)
`• Dosage:
`•
`Inhalation delivery is more potent: teaches delivering “only a fraction (10–
`50%) of the dosage delivered intravascularly”
`•
`“Titration to effect may be used to determine proper dosage”
`• Peripheral Vascular Disease daily dosage of 25 μg to 250 mg
`• Formulation:
`• Discloses liquid and powder formulations for inhalation
`• Powder particles would be “preferably, less than 5 micrometers in diameter”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 19-20; Inst. Dec. 21-22; EX1006
`6
`
`
`
`“a second computer system distinct
`Voswinckel JESC (EX1007)
`from the first computer system”
`• Abstract presented in 2004 European Society of Cardiology (ESC)
`Congress and published in European Heart Journal
`• Method of Treatment:
`• Study to evaluate “hemodynamic response to inhaled treprostinil” in humans
`• Sponsored by UTC
`• Dosage:
`• 29 patients; non-placebo patients were administered 16, 32, 48, or 64 μg/mL
`solutions of treprostinil as a single event dose
`• Delivered over 6 minutes with OptiNeb nebulizer
`• Results:
`•
`“Treprostinil inhalation results in a significant long-lasting pulmonary
`vasodilatation”
`• No adverse effects for 16 μg/mL dose
`•
`“Mild and transient” side effects at 32, 48, and 64 μg/mL doses
`Pet. 22-24; Inst. Dec. 22; EX1007
`7
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`Voswinckel JAHA (EX1008)
`from the first computer system”
`• Abstract presented in 2004 Scientific Sessions in Louisiana and published in
`the Circulation, the Journal of the American Heart Association (JAHA)
`• Method of Treatment:
`•
`Inhaled treprostinil to 17 patients with “severe pulmonary hypertension”
`•
`Sponsored by UTC
`• Dosage:
`•
`Single Event Dose given to all 17 patients:
`•
`“ 3 single breaths”
`•
`“pulsed OptiNeb® ultrasound nebulizer”
`•
`“600 μg/mL” treprostinil solution
`• 2 patients received 4 inhalations per day for 3 months
`• Results:
`•
`“strong pulmonary selective vasodilatory efficacy with a long duration of effect
`following single acute dosing”
`“Tolerability is excellent even at high drug concentrations and short inhalation
`times (3 breaths)”
`Pet. 24-25; Inst. Dec. 22-23; EX1008
`8
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`Independent Claim 1: Only Dispute is 15-90µg Dose
`from the first computer system”
`Claim Limitation
`Disputed By UTC?
`Disclosed
`A method of treating pulmonary hypertension
`EX1006, Abstract, 2:16-18, 2:66-
`comprising administering by inhalation to a
`3:5, 4:10-13, 4:41-54, 7:18-24;
`human suffering from pulmonary hypertension a
`EX1007; EX1008;
`therapeutically effective single event dose of a
`EX1108 (Waxman), 68:3-70:4,
`formulation comprising treprostinil or a
`71:13-72:6 (’212), 79:18-22, 82:10-
`pharmaceutically acceptable salt thereof
`16 (JAHA), 93:16-94:16 (JESC)
`with an inhalation device,
`EX1006, 5:30-32;
`EX1007; EX1008
`
`No
`
`No
`
`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.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Yes
`
`No for Ground 1;
`Yes for Ground 2
`
`EX1008; EX1108 (Waxman), 84:4-9
`
`Pet. 35-46; POR 11-18
`9
`
`
`
`UTC’s Expert Dr. Waxman Agrees That Voswinckel JESC Discloses a
`“a second computer system distinct
`“Therapeutically Effective Single Event Dose”
`from the first computer system”
`
`UTC Expert
`Dr. Waxman
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1007; EX1108, 94:10-16
`10
`
`
`
`UTC’s Expert Dr. Waxman Agrees That Voswinckel JAHA Discloses a
`“a second computer system distinct
`“Therapeutically Effective Single Event Dose”
`from the first computer system”
`
`UTC Expert
`Dr. Waxman
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`. . .
`
`EX1008; EX1108, 82:10-86:14
`11
`
`
`
`“a second computer system distinct
`Dependent Claims 2-8 Fall with Claim 1
`from the first computer system”
`Claim Limitation
`Disputed?
`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.
`
`Disclosed
`EX1006, 5:30-32; EX1002, ¶¶106-
`110; EX1004, ¶¶66-71
`
`EX1006, 5:33-36; EX1007; EX1008
`
`EX1006, 5:30-32, 5:37-39; EX1002,
`¶¶116-117; EX1004, ¶¶77-80
`EX1006, 5:30-32, EX1006, 5:30-32;
`EX1002, ¶119; EX1004, ¶¶82-85
`EX1006, 5:37-39
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 41-46; POR 38-40
`12
`
`EX1006, 5:39-41, claim 9
`
`EX1006, 5:25-29, 8:39-44
`
`
`
`Single Event Dose of
`15-90µg is Obvious
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`A POSA Would Expect the Single Event Dosage Given in
`“a second computer system distinct
`Voswinckel JESC to be 15-90µg
`from the first computer system”
`
`A POSA would have understood at least 1mL of solution was delivered over six minutes
`1mL of 16-64µg/mL = 16-64µg delivered.
`Pet. 22-24, 38; Inst. Dec. 28-29; Reply 10-13; EX1007, 7
`14
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Both Parties’ Clinical Experts Agree that Typical Nebulizers
`“a second computer system distinct
`Deliver at Least 1ml to a Patient
`from the first computer system”
`
`UTC Expert
`Dr. Waxman
`
`Liquidia
`Expert Dr. Hill
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1108 (Waxman), 153:7-22; EX2055 (Hill), 145:22-146:12
`15
`
`
`
`A POSA Would Have Expected the Ultrasound Nebulizer Used in JESC to
`“a second computer system distinct
`Efficiently Deliver the Treprostinil Solution
`from the first computer system”
`
`“A volume of 1 to 5 mL conventionally delivered by nebulizers is also consistent with my decades
`of experience in the inhalation field.”
`
`“In my opinion, a POSA seeking to estimate doses for nebulized therapies would have assumed
`use of these average fill volumes (1-5 mLs) consistent with the average nebulization times (5-10
`min) rather than apply or rely on extremes in fill volume or nebulization output as Professor
`McConville suggests.”
`
`Liquidia Expert
`Dr. Gonda
`
`“[T]he only ultrasonic nebulizer cited by Professor McConville had an efficiency of 86%. Ex. 1062
`(Gessler) at 16.”
`
`A POSA would also have knowledge of the typical ultrasonic nebulizer output rates, all of which
`support delivery of at least 1mL of solution over 6 minutes. (See EX1107, ¶25 (citing EX1097, 87
`(0.33 mL/min delivery rate)); EX1098, 71-73 (0.22-0.68 mL/min); EX1099, 280 (0.67-1.14
`mL/min)); EX1037, 28 (0.6mL/min); see also EX1107, ¶¶18-21, 47-50.)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1107, ¶¶ 19-23
`16
`
`
`
`1ml at the Concentrations Disclosed in Voswinckel JESC Results
`“a second computer system distinct
`from the first computer system”
`in Delivering Single Event Dosages Of 15-90µg
`
`1mL x 16µg/mL = 16 µg POSA’s Understanding of Single Event Dose given in JAHA to 6 patients
`
`1mL x 32µg/mL = 32 µg POSA’s Understanding of Single Event Dose given in JAHA to 6 patients
`
`1mL x 48µg/mL = 48 µg POSA’s Understanding of Single Event Dose given in JAHA to 6 patients
`
`1mL x 64 µg/mL = 64 µg POSA’s Understanding of Single Event Dose given in JAHA to 3 patients
`
`Even assuming a conservative 50% efficiency loss between fill and delivered volumes,
`at 3-5mL fill volumes, a POSA would still expect >1mL delivered volume
`of treprostinil in Voswinckel JESC.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 22-24, 38; Inst. Dec. 28-29; Reply 10-13; EX1007, 7; EX1010, 298; EX1106, ¶41; EX1107, ¶20
`17
`
`
`
`POSA Would Have Expected the JESC Authors,
`“a second computer system distinct
`Who Were Well-Known and Experienced with Inhaled Prostayclins,
`from the first computer system”
`to Properly Use an Efficient Nebulizer
`• Giessen group was well-known, particularly for developing the only FDA-approved inhalation therapy
`for PH at the time (iloprost) and publishing a large clinical trial on that work in the New England
`Journal of Medicine pre-2006.
`• Both parties’ experts agree that these authors were well-known in a small-field of pulmonary
`hypertension.
`
`Liquidia
`Expert Dr. Hill
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1107, ¶¶22-27; EX2055 (Hill), 154:6-155:10; EX1106, ¶27;
`EX1065; EX1108 (Waxman), 79:5-17, 124:18-125:5
`
`18
`
`
`
`POSA Would Have Expected the JESC Authors,
`“a second computer system distinct
`Who Were Well-Known and Experienced with Inhaled Prostayclins,
`from the first computer system”
`to Properly Use an Efficient Nebulizer
`• Giessen group was well-known, particularly for developing the only FDA-approved inhalation therapy
`for PH at the time (iloprost) and publishing a large clinical trial on that work in the New England
`Journal of Medicine pre-2006.
`• Both parties’ experts agree that these authors were well-known in a small-field of pulmonary
`hypertension.
`“[A] POSA would have understood that these authors, based on their experience, would have
`instructed patients on the proper use of the nebulization device . . . .”
`
`“Given that the Giessen group was well-known in the field, a POSA would have understood that the
`Giessen group was using nebulizers with high output and efficiency.”
`
`Liquidia Expert
`Dr. Gonda
`
`“[T]he Giessen group compared jet and ultrasonic nebulizers for inhaled iloprost, as described in
`Gessler, and reported ‘[m]arkedly higher efficiency and output of the currently investigated
`ultrasonic device, in comparison to a standard jet aerosolization technique, avoids wastage of drug
`and allows shortening of the inhalation time to ~30%, with comparable haemodynamic effects.’”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1107, ¶¶22-27; EX2055 (Hill), 154:6-155:10; EX1106, ¶27;
`EX1065; EX1108 (Waxman), 79:5-17, 124:18-125:5
`
`19
`
`
`
`POSA Would Have Expected the JESC Authors,
`“a second computer system distinct
`Who Were Well-Known and Experienced with Inhaled Prostayclins,
`from the first computer system”
`to Properly Use an Efficient Nebulizer
`• Giessen group was well-known, particularly for developing the only FDA-approved inhalation therapy
`for PH at the time (iloprost) and publishing a large clinical trial on that work in the New England
`Journal of Medicine pre-2006.
`• Both parties’ experts agree that these authors were well-known in a small-field of pulmonary
`hypertension.
`
`UTC Expert
`Dr. Waxman
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1107, ¶¶22-27; EX2055 (Hill), 154:6-155:10; EX1106, ¶27;
`EX1065; EX1108 (Waxman), 79:5-17, 124:18-125:5
`20
`
`
`
`“a second computer system distinct
`Dosage Confirmed by Ghofrani (EX1010)
`from the first computer system”
`
`• Ghofrani was published in 2005 and
`would have been part of a POSA’s
`general knowledge by 2006
`
`• Discloses a dosage of
`• “15mcg/inhalation”
`• “up to 90mcg (absolute inhaled
`dose per inhalation exercise)”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 33; EX1010, 298
`21
`
`
`
`FDA-Approved IV Dosing of Remodulin®, Adjusted for Inhalation with the
`“a second computer system distinct
`’212 Patent’s Disclosure, Confirms Obviousness of 15-90µg Inhaled Dosage
`from the first computer system”
`’212 Patent
`2004 Remodulin® (treprostinil) Label
`• Only 10-50% of intravascular dose needs
`FDA-approved for continuous infusion 1440 minutes/day
`1.2ng/kg/min infusion rate, increased weekly up to 40ng/kg/min
`to be delivered via inhaled dose
`
`•
`•
`
`Voswinckel JAHA
`Either 1 dose or 4 doses per day
`
`•
`
`•
`
`Administration in 60-75 kg patients
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 38-39; EX1002, ¶100; EX 1018, 4, 9, 10-11; EX1006, 8:8-12; EX1008, 3;
`Inst. Dec. 29-30; Reply 15-18; EX1106, ¶¶47, 49, 52-56
`
`22
`
`
`
`FDA-Approved IV Dosing of Remodulin®, Adjusted for Inhalation with the
`“a second computer system distinct
`’212 Patent’s Disclosure, Confirms Obviousness of 15-90µg Inhaled Dosage
`from the first computer system”
`• 1.25ng x 65kg x (24x60)min x 50% = 58.5 µg Single Event Dose in JAHA, in Petition
`• 1.25ng x 65kg x (24x60)min x 50%/4 = 14.63 µg Single Event Dose given in JAHA for 4
`doses/day
`
`But Remodulin label also teaches:
`
`• Titrating up: The “infusion rate should be increased in increments of no
`more than 1.25 ng/kg min per week for the first four weeks”
`
`• Administration in patients with weights >65 kg (including 70 and 75 kg)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 38-39; EX1002, ¶100; Reply 16-17; EX1106, ¶¶53-55; EX2036, 295
`23
`
`
`
`FDA-Approved IV Dosing of Remodulin®, Adjusted for Inhalation with the
`“a second computer system distinct
`’212 Patent’s Disclosure, Confirms Obviousness of 15-90µg Inhaled Dosage
`from the first computer system”
`Even assuming dividing into 4 doses per day:
`•
`2.5ng x 65kg x (24x60)min x 50% /4 = 29.25 µg Single Event Dose for week 2, which is
`titrated up by 1.25 ng per Remodulin label
`1.25ng x 75kg x (24x60)min x 50% /4 = 16.88 µg Single Event Dose for 75 kg patient
`(with Remodulin label starting dose)
`
`•
`
`All calculations result in patients going through the inhaled
`single event dosage range of 15-90µg.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 38-39; EX1002, ¶100; Reply 16-17; EX1106, ¶¶53-55; EX2036, 295
`24
`
`
`
`Motivation to Combine
`’212 Patent, Voswinckel JESC, and
`Voswinckel JAHA with a
`Reasonable Expectation of Success
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`A POSA Would Have Been Motivated to Combine the ’212 Patent,
`“a second computer system distinct
`Voswinckel JESC, and Voswinckel JAHA . . .
`from the first computer system”
`’212 Patent (UTC) teaches and claims use of inhaled treprostinil sodium for the treatment of pulmonary hypertension
`at 10-50% of the dose needed for intravascular delivery in sheep and humans. Sheep are used as a model for
`pulmonary hypertension in humans.
`POSA would look further for human studies
`
`•
`
`•
`
`•
`
`Voswinckel JESC (UTC) is a human study, demonstrating with single event dose “significant long-lasting pulmonary
`vasodilatation . . . without adverse effects.” (EX1007, 7.) Administration time was 6 minutes.
`POSA would have been motivated to reduce administration
`time to increase patient convenience and compliance
`
`Voswinckel JAHA (UTC) teaches administering treprostinil in three breaths using a high concentration of treprostinil in
`the aerosolized solution. (Ex. 1008, 3.)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 30-34; Inst. Dec. 32-34
`26
`
`
`
`“a second computer system distinct
`. . . With a Reasonable Expectation of Success
`from the first computer system”
`POSA had evidence of success by May 15, 2006.
`• Voswinckel JESC (UTC)’s results showed that “[t]reprostinil inhalation results in
`significant long-lasting pulmonary vasodilatation” and that “near maximal pulmonary
`vasodilatation is achieved without adverse effects.”
`• Voswinckel JAHA (UTC) taught that “[t]olerability is excellent” for its short-duration,
`high-concentration treprostinil inhalation therapy, with “strong pulmonary selective
`vasodilatory efficacy with a long duration of effect following single acute dosing.”
`• Confirmed by Ghofrani (EX1010) and Geller (EX1034) administering in 3 breaths.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 30-34; Inst. Dec. 32-34
`27
`
`
`
`“a second computer system distinct
`Patent Owner Confirms Motivation to Combine
`from the first computer system”
`• The existing treatments for pulmonary hypertension had known problems:
`• Eproprostenol:
`• Half-life of only a few minutes, requiring administration by continuous intravenous infusion
`• A permanent catheter was required, but came with risks of infection, occlusion, and sepsis
`• Short interruption in infusion could increase risk hemodynamic collapse and even death
`• Required patient to carry cold pack, which decreased patient compliance
`Iloprost was inhaled, but had a short half-life, requiring dosing as frequently as every 2 hours, including
`during the night (resulting in patients being under-medicated if they didn’t wake up at regular intervals
`to take another dose)
`• Remodulin, or intravenous treprostinil was better in terms of room temperature stability and longer
`half-life, but still had the drawbacks of IV delivery, such as severe site pain and system side effects
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR 2-4; EX1108 (Waxman), 141:6-146:22
`28
`
`
`
`Patent Owner’s Argument that a POSA Would Expect Delivering Higher
`“a second computer system distinct
`Concentrations in Fewer Breaths to Have Side-Effects is Unfounded
`from the first computer system”
`• JESC teaches that “at a concentration of 16μ.g/ml, near maximal
`pulmonary vasodilatation is achieved without adverse effects.”
`• JESC teaches that “side effects may occur” at higher dosages but were
`“mild and transient,” with the exception of one headache that resolved
`after one hour.
`• Both parties’ clinical experts agree that such mild side effects would not have
`deterred a POSA. (EX1106, ¶¶74-77; EX1108 (Waxman), 97:13-16, 101:16-102:10.)
`• JAHA teaches that “[t]olerability is excellent even at high drug
`concentrations and short inhalation times (3 breaths).”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 48; Inst. Dec. 35-37; Reply 19-23; EX1007; EX1008
`29
`
`
`
`A POSA Would Have Had a Reasonable Expectation of Success from Prior
`“a second computer system distinct
`Art that Delivered Both Treprostinil and Other Drugs in 1-3 Breaths
`from the first computer system”
`•
`’212 patent’s breath-actuated dry powder inhalers (EX1006, claim 9; EX1039, 81)
`• Ghofrani (EX1010) (known to a POSA by 2006, even if not “by another” under
`§102(a)) successful inhaled treprostinil delivery in 1-2 breaths
`
`• Voswinckel 2006 (EX1009) (known to a POSA by 2006, even if not “by another” under
`§102(a)) successful inhaled treprostinil delivery in 3 breaths
`
`• Geller (EX1034) reduced administration time to 3 breaths for cystic fibrosis inhaled
`drug for efficiency
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 48; Inst. Dec. 35-37; Reply 19-23
`30
`
`
`
`Ground 2: ’212 Patent and
`Voswinckel JESC
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`Ground 2: Claims 1-8 are Obvious Over ’212 Patent and Voswinckel JESC
`from the first computer system”
`
`• ’212 Patent:
`• Treatment of pulmonary hypertension with inhaled treprostinil
`• Inhalation devices
`• Solution and powder formulations
`• Voswinckel JESC:
`• Therapeutically effective single event dose of 15-90µg
`• Routine optimization to achieve 3 breaths
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 46-50; Reply 21-23; EX1006; EX1007, 7
`32
`
`
`
`“a second computer system distinct
`POSA Would Have Been Motivated to Optimize Delivery in 1-3 Breaths . . .
`from the first computer system”
`• Known problem with patient convenience and compliance with the continuous dosing
`taught in JESC
`• Breath-actuated dry powder inhalers disclosed by the ’212 patent address this
`problem
`• Ex. 1006, 14:19–21 (claiming delivery of treprostinil as an inhaled dry powder)
`• Ex. 1039, 81 (teaching that dry powder inhalers “are breath-actuated”)
`• Hill, Ex. 1002, ¶131: (inhaled dry powder delivery requires use of dry-powder inhaler)
`’212 patent teaches modifying dosage for each patient
`• Varying “[t]he precise amount” of treprostinil administered “depend[ing] upon the
`specific circumstances of the patient being treated and the magnitude of effect
`desired by the patient’s doctor. Titration to effect may be used to determine proper
`dosage.” (Ex. 1006, 6:56–7:3.)
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet. 48-49; Inst. Dec. 35-37; Reply 21-23
`33
`
`
`
`•
`
`“a second computer system distinct
`. . . With a Reasonable Expectation of Success
`from the first computer system”
`Increasing doses and reducing administration time was standard for clinicians and in
`the art. E.g.:
`• The ’212 patent teaches varying “[t]he precise amount” of treprostinil administered “depend[ing]
`upon the specific circumstances of the patient being treated and the magnitude of effect desired by
`the patient’s doctor.” (Ex. 1006, 6:56–7:3.)
`• Ghofrani and Voswinckel 2006 (known to a POSA by 2006, even if not “by another” under §102(a))
`successful inhaled treprostinil delivery in 3 breaths.
`• Geller (EX1034) reduced administration time to 3 breaths for cystic fibrosis inhaled drug for
`efficiency.
`• FDA-approved Remodulin (EX1018) and Ventavis (EX1029) taught increasing dosage weekly
`
`• Devices able to deliver high dosages in 3 breaths known in the same art, as well as
`’212 patent and Voswinckel JAHA. (See, e.g., supra, slide 30.)
`Pet. 48; Inst. Dec. 35-37; Reply 19-23
`34
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Secondary Considerations Do
`Not Support Non-Obviousness
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`No Nexus between Tyvaso® and the ’793 Patent Claims
`from the first computer system”
`• Tyvaso® Not Commensurate in Scope with Claims: Delivered with nebulizer as
`solution, not with SMI, pMDI, DPI, or as a powder (EX1043, 1)
`• Target dose is 9 to 12 breaths, not 1-3 breaths (EX1043, 1, 2)
`
`• Has side effects including headache, cough, nausea, pharyngolaryngeal pain
`which Petitioner has argued are the types of “dose limiting adverse side effects”
`the ’793 patent overcame (EX1106, 75; EX1043, 1, 5; POR 56)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR 56; Reply 23
`36
`
`
`
`No Unexpected Results: UTC Did Not Compare Claim to Closest Prior Art
`
`Closest prior art is Voswinckel JESC and Voswinckel JAHA.
`• Closest prior art did NOT teach that high doses of treprostinil had limiting adverse
`side effects (EX1106, ¶104)
`• Voswinckel JESC teaches “near maximal pulmonary vasodilatation is achieved without adverse effects” and
`side effects at higher doses were “mild and transient.” (EX1106, ¶104; EX1007, at Results, Conclusion.)
`• Voswinckel JAHA discloses no side effects in patients treated long-term. (EX1106, ¶104; EX1008, Results.)
`• Closest prior art taught high concentrations in 1-3 breaths
`• Voswinckel JAHA discloses “TRE inhalation by use of the pulsed OptiNeb® ultrasound nebulizer (3 single
`breaths, TRE solution 600 μg/ml).” (EX1008, Methods.)
`• McLaughlin (EX2036) & Ventavis® (EX1029) are not the closest prior art. Regardless:
`•
`Inhaled administration (local) would avoid side effects of intravenous administration (systemic).
`•
`Inhaled iloprost approved at doses > 15 mcg, a dose which most patients tolerated. (EX1106, ¶¶ 104-105.)
`Reply 24
`37
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`No Long-Felt, Unmet Need or Evidence of Copying
`from the first computer system”
`• Invention of the ’793 Patent does not satisfy a long-felt unmet need
`•
`’793 Patent issued over 10 years after Tyvaso® was approved. (EX1106, ¶102.)
`• Tyvaso® is an add-on therapy, not first-line therapy. (EX1106, ¶98.)
`• Tyvaso® not used or approved to treat a “broader range” of PH patients in May 2006. The drug was
`not approved for PH-ILD until 2021. (EX1106, ¶100.)
`
`• LIQ861 does not copy Tyvaso®
`• LIQ861 is a dry-powder delivered using a DPI. Tyvaso® is a solution delivered using a nebulizer.
`(EX1088, 1; EX2084, 1-2.)
`• Mere overlap between the two is not evidence of copying. Wyers v. Master Lock Co., 616 F.3d
`1231, 1246 (Fed. Cir. 2010).
`• Bioavailability comparisons of LIQ861 and Tyvaso® are irrelevant – the claims do not recite
`bioavailability.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply 25-27; POR 57-61
`38
`
`
`
`Voswinckel JESC was publicly
`Available by May 15, 2006
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`A Reference is Considered Publicly Accessible if
`“a second computer system distinct
`Disseminated or Publicly Presented
`from the first computer system”
`A reference is considered publicly accessible only if it was “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)
`
`A reference can qualify as a “printed publication” if publicly presented, independent of
`whether that presentation was further distributed, or meaningfully indexed.
`In re Klopfenstein, 380 F.3d 1345, 1350-52 (Fed. Cir. 2004); MPEP §2128.01(IV).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply 2, 4-6; POR 12
`40
`
`
`
`Petition Contained Sufficient Evidence of
`“a second computer system distinct
`Voswinckel JESC’s Public Availability
`from the first computer system”
`
`Abstract presented at the European Society of Cardiology Congress in 2004 in Munich, Germany
`
`• Undisputed the conference was widely attended by POSAs. (EX1106, ¶28; EX1108, 116:4-117:13; EX1105, 19)
`•
`Both parties’ experts agree that a POSA would have received a copy of the abstract book prior to or at the conference. Thus
`“disseminated” to a POSA. See Kyocera Wireless Corp. v. Int’l Trade Comm’n, 545 F.3d 1340, 1350 (Fed. Cir. 2008). (See EX1106, ¶28;
`EX1108, 105:20-108:1.)
`Both experts agree that a POSA would have been interested in treatments for pulmonary arterial hypertension, and would have
`been interested in the session in which JESC was presented. (See EX1106, ¶29; EX1108, 104:10-20.)
`
`•
`
`Apparent from face of EX1007 that it was published in the European Heart Journal in 2004, and that the University of Iowa had a copy.
`
`•
`
`•
`
`•
`
`Dr. Hall-Ellis cited to University of Madison-Wisconsin copy with receipt date stamp of October 15, 2004.
`UTC did not challenge Voswinckel JESC’s prior art status in its POPR, despite doing so for other exhibits (e.g. Ghofrani)
`Pet. 22; EX1036, ¶¶ 68-76 & n.22; EX1004, ¶55; EX1007, 1, 2, 7
`41
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Patent Owner is Incorrect: JESC Supplement Containing Abstract was
`“a second computer system distinct
`Published and Disseminated Globally Well Before 2006
`from the first computer system”
`Three different libraries date-stamped a copy of the JESC supplement as received in 2004
`
`•
`
`•
`
`Published by well-established publisher (est. 1880)
`
`• MARC records show that supplements were included in library subscriptions (Reply, 5 (citing EX1112,
`¶¶70-78))
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply 2, 4-6; EX1036, ¶¶68-75; EX1089, 1; EX1090, 1; EX1091, 1;
`EX1112, ¶¶65, 78-86, 88; EX1106, ¶31; EX1110 (Wyman), 58:13-17
`
`42
`
`
`
`Patent Owner Is Incorrect: POSA Would Have Been Easily Able to Find
`“a second computer system distinct
`Abstract 218 within the JESC Supplement
`from the first computer system”
`• Supplement has Short (5-page) table of contents
`• Abstract 218 is one of 5 abstracts under subject “Epidemiology and treatment of pulmonary arterial
`hypertension”
`• Supplement has short (9-page) topic index
`• One of 2 lines of abstracts listed under the subject “Therapy (Pulmonary circulation)”
`• No dispute that a POSA would have been interested in these topics, and thus looked for,
`and easily found the Voswinckel JESC abstract within the supplement.
`• Patent Owner’s expert, Dr. Waxman, testified that a POSA would have been able to find the JESC abstract within
`the supplement in which it appears. (EX1108 (Waxman), 104:22-105:15.)
`• Giessen group was well-known, particularly for developing the only FDA-approved inhalation therapy for PH at
`the time (iloprost)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply 3-4; EX1108 (Waxman), 104:22-105:15; EX1007, 2, 7; EX1036, ¶76; EX1092, 2-10;
`EX1110 (Wyman), 156:3-6; EX1106, ¶¶27, 29, 32-34; EX1112, ¶¶87, 90, 92
`
`43
`
`
`
`Patent Owner is Incorrect: POSA Would Have Had the Full Citation to the
`“a second computer system distinct
`Abstract When Searching for It
`from the first computer system”
`• Cited in June 2005 Ghofrani article (EX1010, 298, 301)
`
`• UTC’s witness Dr. Wyman agreed that a POSA with this citation “would know where to go and look for
`[the abstract].” (EX1110 (Wyman), 169:21-170:17.)
`• No dispute that Ghofrani was publicly available to a POSA by May 2006
`• A POSA reading Ghofrani would be directed to Voswinckel JESC as a cutting-edge trial:
`Initial trials in Giessen have shown proof of efficacy of inhaled treprostinil for the effective reduction of the pulmonary vascular
`resistance (PVR) [6]. In this first study, 17 patients with severe pre-capillary pulmonary hypertension were administered inhaled
`treprostinil (15 mcg/inhalation). This led to a major reduction in pulmonary selective pressure and resistance with an overall duration of
`action of > 180 min. In direct comparison with inhaled iloprost, inhaled treprostinil showed a stronger pulmonary selectivity, so that it is
`possible to increase the dosage to up to 90 mcg (absolute inhaled dose per inhalation exercise) without adverse effects occurring [6].
`
`Bruckelmyer v. Ground Heaters, Inc., 445 F.3d 1374, 1379 (Fed. Cir. 2006);
`Blue Calypso LLC v. Groupon, Inc., 815 F.3d 1331, 1350 (Fed. Cir. 2016) (citation to article can establish public accessibility)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply 3-4; EX1010, 298, 301
`44
`
`
`
`Voswinckel JAHA was publicly
`Available by May 15, 2006
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Petition Contained Sufficient Evidence of
`“a second computer system distinct
`Voswinckel JAHA’s Public Availability
`from the first computer system”
`
`Cited by Patent Office as prior art during prosecution (Pet. 9; EX1016, 40; Reply 6)
`Abstract presented at the November 2004 Scientific Sessions of the American Heart Association in Louisiana
`
`• Undisputed the conference was widely attended by POSAs. (EX1106, ¶¶ 21-23; EX1108 (Waxman), 116:4-21; EX1112, ¶¶ 36, 63)
`•
`Both parties’ experts agree that a POSA would have
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