Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of 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 B2
`
`
`REPLY DECLARATION OF IGOR GONDA, Ph.D.
`
`
`
`Liquidia's Exhibit 1107
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`B.
`
`C.
`
`D.
`
`INTRODUCTION AND QUALIFICATIONS .............................................. 1 
`B. Materials Considered ............................................................................ 2 
`PERSON OF ORDINARY SKILL IN THE ART ......................................... 4 
`II.
`III. STATEMENT OF LEGAL PRINCIPLES ..................................................... 5 
`IV. THE ’793 PATENT IS OBVIOUS ................................................................ 5 
`A. A POSA Reading the ’793 Patent Would Understand that the
`Claimed “Dose” Refers to the Amount Delivered to the
`Mouthpiece and Inhaled by the Patient ................................................ 5 
`POSAs in May 2006 Would Have Readily Estimated the Dose
`Delivered to the Mouthpiece in Voswinckel JESC .............................. 7 
`Professor McConville Exaggerates the Amount of Information
`a POSA Would Need to Reliably Estimate the Doses Delivered
`in Voswinckel JESC ........................................................................... 20 
`Professor McConville Exaggerates the Effect Variations in the
`OptiNeb Nebulizer Would Have on Delivered Dose and
`Nebulizer Output ................................................................................ 39 
`POSAs in May 2006 Would Have Been Very Familiar with
`Pulsed Nebulizers Like That Disclosed in Voswinckel JAHA .......... 42 
`Titration of Prostacyclin Dose to Achieve Efficacy and Safety
`Was Known in May 2006 ................................................................... 43 
`CONCLUSION ............................................................................................. 48 
`
`E.
`
`F.
`
`II.
`
`- i -
`
`Liquidia's Exhibit 1107
`Page i
`
`

`

`
`
`I, Igor Gonda, Ph.D. declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`1.
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained by counsel for the Petitioner to offer technical
`
`opinions with respect to U.S. Patent No. 10,716,793 (“the ’793 Patent”) and prior art
`
`references cited in inter partes review proceedings for the ’793 Patent.
`
`3.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate, which is $850 per hour, plus reasonable expenses. My
`
`compensation is not dependent on the outcome of, or the content of my testimony
`
`in, the present IPR.
`
`4.
`
`I understand that the Patent Trial and Appeal Board (“the Board”) has
`
`instituted inter partes review of the ’793 Patent based on the petition submitted by
`
`Liquidia Technologies, Inc. (“Liquidia”). Since IPR institution, I understand that
`
`United Therapeutics Corporation (“UTC”) has filed a Patent Owner Response as
`
`well as declarations from Ms. Pilar Wyman, Dr. Aaron Waxman, and Dr. Jason
`
`McConville in support thereof.
`
`5.
`
`This declaration presents my additional expert opinions, considering
`
`the Institution Decision rendered by the Board, as well as UTC’s Patent Owner
`
`Response and Supporting Declarations of Drs. Aaron Waxman and Jason
`
`
`
`
`
`
`
`Liquidia's Exhibit 1107
`Page 1
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`McConville, that Claims 1-8 of the ’793 Patent would have been obvious to a person
`
`of ordinary skill in the art before May 15, 2006.
`
`6. My background, qualifications, and experience relevant to the issues
`
`raised in this proceeding are summarized in Section I.A of my original declaration.
`
`Ex. 1004 at ¶¶ 1-7. A full description of my background and qualifications is set
`
`forth in my curriculum vitae. Ex. 1005.
`
`B. Materials Considered
`7.
`In addition to the materials that I considered in connection with my
`
`prior declaration (Ex. 1004), in forming the opinions in this declaration, I have
`
`reviewed the Institution Decision, Patent Owner Response, the supporting
`
`declaration of Professor Jason McConville and exhibits, the supporting declaration
`
`of Dr. Aaron Waxman, the deposition testimony of Professor McConville, and the
`
`deposition testimony of Dr. Waxman. In arriving at my opinions, I have also
`
`reviewed and considered additional documents that are cited in this declaration. I
`
`have listed the additional documents below. To the extent I am provided additional
`
`documents or information, including additional expert declarations in this
`
`proceeding, I may offer further opinions.
`
`Exhibit
`No.
`1087
`
`Butler Affidavit
`
`Description of Document
`
`2
`
`Liquidia's Exhibit 1107
`Page 2
`
`

`

`Exhibit
`No.
`1089
`1090
`1091
`1093
`1094
`1095
`1096
`1097
`
`1098
`
`1099
`
`1100
`1101
`
`1102
`
`1103
`
`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Description of Document
`Voswinckel JESC, UWash
`Voswinckel JESC, UWisc
`Voswinckel JESC, British Library
`Voswinckel JAHA, British Library
`Voswinckel JAHA, Library of Congress
`Voswinckel JAHA, Stanford
`Voswinckel JAHA, UC Davis
`Rhind, G.B. et al., “Effect of Spirometry of Distilled Water and
`Cromoglycate Solutions Nebulised by a Small Portable
`Ultrasonic Nebuliser,” Respiration, 51:86-90 (1987) (“Rhind
`1987”)
`Hager, J., et al., “Measurement of Particle and Mass
`Distribution of Pentamidine Aerosol by Ultrasonic and Air Jet
`Nebulizers,” Journal of Aerosol Medicine, Vol. 5, No. 2 (1992)
`(“Hager 1992”)
`Leigh, T.R., et al., “Performance characteristics of the
`DeVilbiss Ultraneb 99 ultrasonic nebuliser with reference to
`use in sputum induction,” International Journal of
`Pharmaceutics, 67 (1991) 275-282 (“Leigh 1991”)
`Ventavis EU Summary of Product Characteristics
`Denyer, J., et al., “Adaptive Aerosol Delivery (AAD®)
`technology,” Expert Opinion on Drug Delivery, 1:1, 165-176
`(“Denyer 2004”)
`Byrne, N.M., et al., “Comparison of lung deposition of
`colomycin using the HaloLite and the Pari LC Plus nebulisers
`in patients with cystic fibrosis,” Arch Dis Child 2003;88:715–
`718 (“Byrne 2003”)
`Leung, K., et al., “Comparison of Breath-Enhanced to Breath-
`Actuated Nebulizers for Rate, Consistency, and Efficiency,”
`CHEST 2004; 126:1619–1627 (“Leung 2004”)
`
`3
`
`Liquidia's Exhibit 1107
`Page 3
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`Exhibit
`No.
`1106
`1108
`
`1109
`
`Description of Document
`Reply Declaration of Nicholas Hill, M.D.
`Transcript from the January 8, 2022 Deposition of Aaron
`Waxman, M.D., Ph.D., Liquida Technologies, Inc. v. United
`Therapeutics Corp., IPR2021-00406
`Transcript from the January 11, 2022 Deposition of Jason
`McConville, Liquida Technologies, Inc. v. United Therapeutics
`Corp., IPR2021-00406
`1131 Michael Mellon et al., Comparable Efficacy of Administration
`with Face Mask or Mouthpiece of Nebulized Budesonide
`Inhalation Suspension for Infants and Young Children with
`Persistent Asthma, 162 AM. J. RESPIR. CARE MED. 593 (2000)
`(“Mellon 2000”)
`
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`8.
`I provided my understanding of a person of ordinary skill in the art
`
`(“POSA” or “skilled artisan”) as of May 2006 in paragraphs 9-12 of my opening
`
`declaration. In my opinion, a POSA with respect to inhaled formulations used in a
`
`method of treating pulmonary hypertension would be 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).
`
`9.
`
`I understand that Dr. Waxman has defined the POSA as of May 15,
`
`2006 as follows:
`
`[T]he person having ordinary skill in the art (“POSA”) would have an
`M.D. or a graduate degree (Masters or Ph.D.) in a field relating to drug
`
`4
`
`Liquidia's Exhibit 1107
`Page 4
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`development and at least two years of practical experience in either (i)
`the investigation or treatment of pulmonary hypertension or (ii) the
`development of potential drug candidates, specifically in the delivery
`of drugs by inhalation.
`Ex. 2052 (Waxman Declaration) at ¶ 15; see also Ex. 2053 (McConville Declaration)
`
`at ¶¶ 29-31. My opinions expressed in my opening declaration (Ex. 1004) and this
`
`declaration would not change if the Board were to adopt Dr. Waxman’s definition
`
`of a POSA.
`
`10. As reflected in my qualifications set forth in Section I.A of my opening
`
`declaration (Ex. 1004) and in my curriculum vitae (Ex. 1005), I qualified as a POSA
`
`with respect to inhaled formulations at the time of the alleged invention (before May
`
`2006) under both my and Dr. Waxman’s definitions of a POSA.
`
`III. STATEMENT OF LEGAL PRINCIPLES
`11. My understanding of the relevant legal principles is provided in
`
`Section III of my opening declaration. Ex. 1004 at ¶¶ 13-18.
`
`IV. THE ’793 PATENT IS OBVIOUS
`A. A POSA Reading the ’793 Patent Would Understand that the
`Claimed “Dose” Refers to the Amount Delivered to the Mouthpiece
`and Inhaled by the Patient
`12. A POSA reading the ’793 Patent would understand that the “dose” in
`
`claim 1 refers to the dose inhaled by the patient. Ex. 1001 (’793 Patent), claim 1.
`
`Professor McConville in some instances appears to refer to the claimed “dose” as
`
`5
`
`Liquidia's Exhibit 1107
`Page 5
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`the amount deposited in the lung. Ex. 2053 (McConville Declaration) at ¶¶ 55-65.
`
`To the extent Professor McConville contends that “dose” refers to the amount
`
`deposited in the lung, that interpretation is contrary to the plain meaning of “dose
`
`. . . delivered in 1 to 3 breaths” in claim 1 as of May 2006 and the usage of “dose”
`
`in the ’793 Patent.
`
`13. A POSA in May 2006 in the field of inhaled formulations would
`
`understand that a “dose” that is “delivered” as used in the ’793 Patent to mean the
`
`dose delivered to the mouthpiece and inhaled by a patient. A POSA would
`
`understand that this is different from the amount of drug deposited in the patient’s
`
`lungs. Ventavis® (iloprost), is another inhaled prostacyclin analog product for the
`
`treatment of pulmonary arterial hypertension and that label similarly refers to the
`
`dose “delivered at the mouthpiece” when describing dose and administration of the
`
`drug. Ex. 1029 (Ventavis® Label 2004) at 9.
`
`14. Nowhere does the ’793 Patent describe a “dose” as the amount
`
`deposited in the lung. Nor does the ’793 Patent describe methods of determining the
`
`amount deposited in the lung. Instead, the ’793 Patent refers only to “dose” as the
`
`amount inhaled in 1-3 breaths. For the clinical study described in Example 1, for
`
`example, the ’793 Patent explains that “[t]he aerosol volume delivered by one cycle
`
`from the SMI was 15 µl.” Ex. 1001 (’793 Patent) at 10:22-23 (emphasis added).
`
`6
`
`Liquidia's Exhibit 1107
`Page 6
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`The ’793 Patent explains that “[t]he different doses were applied as 2 puffs 1000
`
`µg/ml (30 µg), 3 puffs 1000 µg/ml (45 µg) and 2 puffs 2000 µg/ml (60 µg).” Id. at
`
`10:28-30; see also id. at 10:25-27 (“The SMI was either filled with a concentration
`
`of 1000 µg/ml treprostinil sodium (one aerosol puff=15 µg TRE) or with 2000 µg/ml
`
`(one puff=30 µg TRE).”). A POSA would recognize that the doses were calculated
`
`from the volume delivered multiplied by the concentration of treprostinil and by the
`
`number of puffs, i.e., as doses delivered to the patient but not as lung doses. A POSA
`
`would understand from this that doses in claim 1 of the ’793 Patent are referring
`
`simply to the amount delivered to the mouthpiece and inhaled by the patient (i.e.,
`
`delivered in 1-3 breaths), with no detail as to what proportion of that dose delivered
`
`to the mouth of the patient reaches the lung.
`
`15. For at least these reasons, a POSA would understand the claimed
`
`“dose” of the ’793 Patent as the amount delivered to the mouthpiece and inhaled by
`
`the patient.
`
`B.
`
`POSAs in May 2006 Would Have Readily Estimated the Dose
`Delivered to the Mouthpiece in Voswinckel JESC1
`16. A POSA would have readily determined that the doses delivered to the
`
`
`1 Patent Owner argues that no copy of Voswinckel JESC was ever publicly
`disseminated. POR at 1. This is directly contradicted. Firstly, a POSA interested
`in the development of inhaled treprostinil for pulmonary hypertension would have
`
`
`7
`
`Liquidia's Exhibit 1107
`Page 7
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`mouthpiece and inhaled by the patient in Voswinckel JESC in May 2006 were within
`
`15 to 90 µg treprostinil, the very broad dose range claimed by the ’793 Patent.
`
`Professor McConville makes several unsupported arguments that a POSA in May
`
`2006 could not estimate a delivered dose of treprostinil in the range of 15 to 90 µg
`
`based on Voswinckel JESC. See generally Ex. 2053 (McConville Declaration)
`
`Section VI.A.1.c. It was common practice in May 2006, however, to reliably
`
`estimate ranges of delivered doses of drugs inhaled by patients from disclosures such
`
`as Voswinckel JESC. Indeed, well before May 2006, my colleagues and I at
`
`Aradigm Corporation used such intuitive and simple methods of extrapolating doses
`
`delivered by nebulizers to humans based on the concentrations and volumes
`
`administered to estimate the equivalent doses administered in a small number of
`
`breaths using Aradigm’s soft mist inhaler AERx.
`
`
`keenly followed the major conferences on this topic and possibly even attended them
`and, in the process, acquired a copy of Voswinckel JESC. Moreover, I was provided
`date-stamped copies of Ex. 1007 (Voswinckel JESC), stamped on November 16,
`2004 by the University of Washington Health Sciences Libraries (Ex. 1089
`(Voswinckel JESC, UWash)), stamped on October 15, 2004 by Ebling Library at the
`University of Wisconsin (Ex. 1090 (Voswinckel JESC, UWisc.)), and stamped on
`September 27, 2004 by the British Library (Ex. 1091 (Voswinckel JESC, British
`Library)). These date stamped copies, in my opinion, further establish that
`Voswinckel JESC was publicly disseminated prior to May 2006. For ease of
`reference, I cite Ex. 1007 (Voswinckel JESC) throughout this declaration, but my
`opinions remain the same for all versions of Voswinckel JESC cited here and in my
`opening declaration.
`
`8
`
`Liquidia's Exhibit 1107
`Page 8
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`
`17. Professor McConville’s criticisms of Dr. Hill’s dose calculations suffer
`
`from multiple flaws. First, Professor McConville ignores the express teachings of
`
`Voswinckel JESC which indicates that patients inhaled 16, 32, 48, and 64 µg/mL
`
`solutions for 6 minutes via an “OptiNeb ultrasound” nebulizer, which resulted in
`
`significant, long-lasting pulmonary vasodilation. Ex. 1007 (Voswinckel JESC) at
`
`Methods. Second, Professor McConville ignores the fact that a POSA who wished
`
`to estimate the range of delivered doses from Voswinckel JESC would have assumed
`
`and applied the average values for ultrasound nebulizers working in continuous
`
`mode available at the time as there is nothing in the reference to dissuade a POSA
`
`otherwise (e.g., in contrast to Ex. 1008 (Voswinckel JAHA)2 in which the pulsed
`
`
`2 Patent Owner argues that no copy of Voswinckel JAHA was ever publicly
`disseminated. POR at 1. This is directly contradicted. Firstly, a POSA interested
`in the development of inhaled treprostinil for pulmonary hypertension would have
`keenly followed the major conferences on this topic and possibly even attended them
`and, in the process, acquired a copy of Voswinckel JESC. Moreover, I was provided
`date-stamped copies of Ex. 1008 (Voswinckel JAHA), stamped on November 19,
`2004 by the British Library (Ex. 1093 (Voswinckel JAHA, British Library)),
`stamped in October 2004 by the Library of Congress (Ex. 1094 (Voswinckel JAHA,
`Library of Congress)), stamped on November 11, 2004 by the Lane Medical Library
`at Stanford University (Ex. 1095 (Voswinckel JAHA, Stanford), and stamped on
`November 26, 2004 by the University of California Davis Health Sciences Library
`(Ex. 1096 (Voswinckel JAHA, UC Davis)). These date stamped copies, in my
`opinion, further establish that Voswinckel JAHA was publicly disseminated prior to
`May 2006. For ease of reference, I cite Ex. 1008 (Voswinckel JAHA) throughout
`this report, but my opinions remain the same for all versions of Voswinckel JAHA
`cited here and in my opening declaration.
`
`9
`
`Liquidia's Exhibit 1107
`Page 9
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`mode of the ultrasound OptiNeb nebulizer is emphasized). Instead, as discussed
`
`below, Professor McConville relies on extremes and outliers within the inhalation
`
`field in an attempt to inject more uncertainty and variability than what actually would
`
`concern a POSA at the time. Third, Professor McConville points to some variables
`
`that do not have a significant impact on the dose delivered to the mouthpiece and
`
`inhaled by the patient, again in an attempt to inject a level of uncertainty and
`
`variability that is not relevant, especially bearing in mind the broad range of doses
`
`delivered in claim 1 of the ’793 Patent. Professor McConville also gives examples
`
`of inhaler configurations that would be inconsistent with the text in Voswinckel
`
`JESC or Voswinckel JAHA (Ex. 2053 (McConville Declaration) at ¶ 55), such as
`
`the use of face masks (used mainly in children) or connecting tubing used for
`
`ventilators typically in intensive care units. Ex. 1131 (Mellon 2000) at 594 (“As
`
`expected, most of the younger patients used face masks during nebulization. The
`
`mean age of face mask users was 36.4 mo[nths] . . . .”); Ex. 1037 (OPTINEB-ir
`
`Translation) at 11 (showing tubing used with ventilators).
`
`18.
`
`I agree with Dr. Hill’s calculation that a POSA in May 2006 would have
`
`reasonably assumed that at least 1 mL of volume was delivered during the 6 minutes
`
`disclosed in Voswinckel JESC for each of the concentrations administered, resulting
`
`in a delivered dose of 16, 32, 48, and 64 µg. Ex. 1002 (Hill Declaration) at ¶ 65.
`
`10
`
`Liquidia's Exhibit 1107
`Page 10
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`This is consistent with the actual disclosure of Voswinckel JESC, which states that
`
`“patients inhaled . . . treprostinil for 6 min (OptiNeb ultrasound nebulizer, Nebu-
`
`tec, Germany). . . .” Ex. 1007 (Voswinckel JESC) at Conclusion (“With the applied
`
`technology, at a concentration of 16 µg/ml, near maximal pulmonary vasodilation is
`
`achieved without adverse effects.”). A POSA would understand that “inhaled” doses
`
`provided in Voswinckel JESC means the actual dose inhaled by the patient.
`
`Professor McConville further confirmed that he would not expect the concentration
`
`of API to change during nebulization of a solution. Ex. 1109 (McConville Dep. Tr.)
`
`at 224:1-227:22. I agree with Professor McConville that nebulization in an
`
`ultrasonic nebulizer would not result in a change in concentration of the API that
`
`would impact the delivered dose.
`
`19. A volume of 1 to 5 mL conventionally delivered by nebulizers is also
`
`consistent with my decades of experience in the inhalation field. See Section IV.C
`
`below; see also Ex. 1004 at ¶ 56. As I mentioned in my opening declaration,
`
`inhalation therapies approved by the FDA before May 2006, including iloprost, were
`
`delivered using a nebulizer in 1 to 5 mL volumes. Ex. 1004 at ¶ 56 & n.4. This
`
`volume refers to the amount of drug solution actually employed in these nebulizers
`
`and not the theoretical possible fill volumes for these devices. Even with 1 mL
`
`delivered via the nebulizer for 6 minutes, a POSA in 2006 could reasonably calculate
`
`11
`
`Liquidia's Exhibit 1107
`Page 11
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`from Voswinckel JESC inhaled treprostinil delivered doses of 16, 32, 48, and 64 µg
`
`for the 16, 32, 48, and 64 µg/mL concentrations, respectively. I understand that the
`
`Board adopted this position in its Institution Decision here.
`
`20. Professor McConville’s reference, Ex. 2076 (Kendrick 1997), states in
`
`a footnote to Table 2 and consistent with Table 6 of that reference, that typical
`
`volumes of solutions to be delivered by continuous nebulizers (such as the OptiNeb
`
`nebulizer in Voswinckel JESC) were 2-2.5 mL. Ex. 2076 (Kendrick 1997) at S94
`
`(“Whilst the residual and maximum fill volumes are accurate, the percentage of
`
`solution nebulised at 5 and 10 minutes is the best figure obtainable. This has been
`
`obtained for a fill volume of 2-2.5 ml and is generally taken from data obtained with
`
`its retail compressor.”), S96 (showing 9/10 nebulizers with 2-2.5 fill volumes). The
`
`assumption that 1 mL is actually inhaled in Voswinkel JESC is fully consistent with
`
`an average fill volume of 2-2.5 mL fill volumes. For example, a 1 mL inhaled
`
`volume allows for 50-60% loss of the drug solution loaded in the nebulizer, which
`
`in my opinion is reasonable given loss of aerosol during expiration and potential loss
`
`of solution in the device. Kendrick therefore supports my position that nebulizers
`
`conventionally deliver between 1 and 5 mL solution and it was reasonable to assume
`
`at least 1 mL of solution was inhaled in Voswinckel JESC.
`
`21. A POSA would have known, just as stated in Ex. 2076 (Kendrick 1997),
`
`12
`
`Liquidia's Exhibit 1107
`Page 12
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`that the selection of ranges of volumes for nebulized solutions is such that the patient
`
`can conveniently inhale them in 5-10 minutes using common nebulizers available in
`
`May 2006. Ex. 2076 (Kendrick 1997) at S95 (“The optimum time for nebulisation
`
`is 5-10 minutes. Patients will generally not accept long delivery times (fig 4),
`
`especially if the treatment is required several times per day.”). Voswinckel JESC
`
`discloses a nebulization time of 6 minutes, which is within the recognized optimum
`
`range of nebulization time, especially when patients need to take the treatment
`
`several times a day as is the case with inhaled treprostinil. Ex. 1007 (Voswinckel
`
`JESC). This is consistent with my position that 1-5 mL of nebulized solutions were
`
`typical and is also consistent with the rate of delivery of common nebulizers used
`
`for therapeutic purposes. 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.
`
`(Indeed, Voswinckel JESC discloses that the nebulization time was 6 min, i.e., in the
`
`range of 5-10 min disclosed by Kendrick.) See, e.g., Ex. 2053 (McConville
`
`Declaration) at ¶¶ 58 (citing 9-90% nebulizer efficiencies), 71 (citing 15 µL and 0.5
`
`mL minimal fill volumes and 38 mL maximal fill volumes). Voswinckel JESC and
`
`Dr. Hill’s calculations of dose based on this reference are completely consistent with
`
`13
`
`Liquidia's Exhibit 1107
`Page 13
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`these reasonable expectations by a POSA of typical volumes being in the range 1-5
`
`mL.
`
`22. Professor McConville also relies on several references to support his
`
`position that “devices can have a wide variety of efficiencies, varying by about 10x
`
`(i.e., about 9 to 90%).” Ex. 2053 at ¶ 58 (citing Ex. 2077 (Rau 2004), Ex. 1066
`
`(AccuNeb® Label), Ex. 1083 (Ventavis® Label), Ex. 1062 (Gessler), Ex. 2078 (Rau
`
`2005)). Unlike the ultrasonic nebulizer used in Voswinckel JESC and Voswinckel
`
`JAHA, the nebulizers described in Ex. 2077 (Rau 2004), Ex. 1066 (AccuNeb®
`
`Label), and Ex. 2078 (Rau 2005) are all jet nebulizers, which Professor McConville
`
`confirmed. Ex. 1109 (McConville Dep. Tr.) at 132:18-136:14, 160:3-20, In fact,
`
`the only ultrasonic nebulizer cited by Professor McConville had an efficiency of
`
`86%. Ex. 1062 (Gessler) at 16. Professor McConville confirmed that jet nebulizers
`
`are “different devices” that generate aerosol in a different way than ultrasonic
`
`nebulizers. Ex. 1109 (McConville Dep. Tr.) at 129:2-131:8. Before May 2006,
`
`Ex. 1062 (Gessler) compared jet and ultrasonic nebulizers for inhaled iloprost 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.” Ex. 1062 (Gessler) at 19. As such, Professor
`
`14
`
`Liquidia's Exhibit 1107
`Page 14
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`McConville’s reliance on references disclosing jet nebulizers are not relevant to the
`
`delivery of inhaled treprostinil using an ultrasonic nebulizer disclosed in Voswinckel
`
`JESC and Voswinckel JAHA.
`
`23.
`
`In fact, the reference by Gessler is co-authored by several persons from
`
`the University of Giessen who co-authored Voswinckel JESC and JAHA and are
`
`also co-inventors of the ’793 Patent, showing that they were pursuing in their earlier
`
`research faster and more efficient delivery of inhaled treprostinil. Based on this
`
`information, a POSA would assume that the ultrasonic nebulizers used in
`
`Voswinckel JESC and Voswinckel JAHA were more efficient and had higher output
`
`rates than the jet nebulizers presented by Professor McConville. See Ex. 1062
`
`(Gessler) at 19 (comparing jet and ultrasonic nebulizers for inhaled iloprost and
`
`concluding “[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.”).
`
`24.
`
`I agree with Dr. Hill that the estimated 16-64 µg dose inhaled in
`
`Voswinckel JESC could have been further confirmed by the known nebulization rate
`
`of 0.6 mL/min of the OptiNeb device in May 2006. Ex. 1002 (Hill Declaration) at
`
`¶ 67; Ex. 1037 (OPTINEB-ir Translation) at 28; Ex. 1087 (Butler Affidavit) at 27.
`
`15
`
`Liquidia's Exhibit 1107
`Page 15
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`Using the 6 min administration time and the concentration of the treprostinil
`
`solutions in Voswinckel JESC, a POSA would understand that 57.6 µg was delivered
`
`for the 16 µg/mL dose (i.e., 16 µg/mL * 0.6 mL/min * 6 min). Even assuming that
`
`50% of the output may be lost to expiration this still produces an inhaled dose of
`
`28.8 µg. The use of the output rate provided in the OptiNeb manual takes into
`
`account all material that is lost before reaching the mouthpiece which makes
`
`Professor McConville’s argument that “the emitted dose (or ‘delivered dose’) will
`
`be less than the nominal or metered dose, as drug can be lost along the way”
`
`irrelevant (Ex. 2053 (McConville Declaration) at ¶ 40) as the output is the amount
`
`arriving at the mouthpiece after all the losses inside the nebulizer and connecting
`
`equipment occurred. The point being that both of these approaches (using typical
`
`fill volumes or output rates), applying the knowledge of a POSA, produce reasonable
`
`estimates of the doses inhaled in Voswinckel JESC that overlap with the broad dose
`
`range of the ’793 Patent.
`
`25.
`
`I understand that Professor McConville and UTC’s experts have
`
`disputed the public availability and, by implication, nebulization rate of the OptiNeb
`
`device (~0.6 mL/min). Ex. 2053 (McConville Declaration) at Section VI.A.1.e. The
`
`OptiNeb device manual only confirms my opinion, based on the express disclosure
`
`of Voswinckel JESC and my own experience. Further, in my opinion, a POSA
`
`16
`
`Liquidia's Exhibit 1107
`Page 16
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`would have reasonably assumed the OptiNeb device was employed in Voswinckel
`
`JESC. However, even without knowledge of the OptiNeb device, a POSA would
`
`have assumed that the average output of the ultrasound nebulizer used in continuous
`
`mode in Voswinckel JESC (“OptiNeb ultrasound nebulizer”) was approximately
`
`0.6 mL/min for continuous nebulization based on rates available for ultrasonic
`
`(ultrasound) nebulizers used for inhalation of solutions of therapeutic drugs at the
`
`time. Ex. 1097 (Rhind 1987) at 87 (reporting 0.33 mL/min nebulizer output from
`
`De Vilbiss Pulmosonic ultrasonic nebulizer); Ex. 1098 (Hager 1992) at 71-73
`
`(reporting 0.22-0.68 mL/min nebulization rate for De Vilbiss ultrasonic nebulizer);
`
`Ex. 1099 (Leigh 1991) at 280 (reporting 0.67-1.14 mL/min nebulizer flow rate for
`
`De Vilbiss Ultraneb 99 ultrasonic nebulizer). Therefore, taking these available
`
`examples from the literature of several ultrasonic nebulizers, using a wide variety of
`
`drug solutions and excipients, the average output is approximately 0.6 mL/min,
`
`identical to the value for the output provided in the OptiNeb-ir manual.
`
`26.
`
`In several instances, Professor McConville mentions factors allegedly
`
`absent from Voswinckel JESC that “could affect the nebulizer’s output.” Ex. 2053
`
`(McConville Declaration) at ¶¶ 55-56. Specifically, Professor McConville reports
`
`that Voswinckel JESC is missing information on the formulation, including the
`
`solvent and excipients. Id. at ¶ 55. The evidence presented in my previous paragraph
`
`17
`
`Liquidia's Exhibit 1107
`Page 17
`
`

`

`Reply Declaration of Igor Gonda in Support of
`Petition for Inter Partes Review
`of U.S. Patent No. 10,716,793 B2
`
`also negates these arguments by Professor McConville on a variety of factors that
`
`might impact the output of ultrasonic nebulizers such as the nature of the solution.
`
`None of those would have changed significantly the typical value for output of this
`
`class of nebulizers and aqueous solutions of drugs in the literature prior to May 2006
`
`(Rhind 1987 (Ex. 1097); Hager 1992 (Ex. 1098); Leigh 1991 (Ex. 1099)) as they
`
`cover a number of ultrasonic nebulizers and a range of drugs, their concentrations
`
`and excipients. Since the concentrations of treprostinil in the aqueous solutions in
`
`Voswinckel JESC (and JAHA) are very low, a POSA would have known that it is
`
`extremely unlikely that the properties of those solutions would be markedly different
`
`from water in terms of, e.g., viscosity that might in principle impact the rate of
`
`nebulization using ultrasonic nebulizers. In other words, a POSA would have
`
`assumed that the values in the literature are applicable to estimate the range of doses
`
`delivered in Voswinckel JESC.
`
`27. Additionally, both Drs. Hill and Waxman provided deposition
`
`testimonies concerning Voswinckel JESC and Voswinckel JAHA and the group of
`
`investigators named as authors on this reference (commonly referred to as the
`
`“Giessen group”). More specifically, the investigators listed as authors on
`
`Voswinckel JESC and Voswinckel JAHA were well-known by POSAs as they were
`
`also responsible for developing iloprost, which as noted above is another inhaled
`
`18
`
`Liquidia's Exhibit 1107
`Page 18
`
`

`

`Reply Declaration of Igor