Declaration of Nicholas Hill 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
`
`
`
`
`U.S. Patent No. 10,716,793 B2
`
`
`DECLARATION OF NICHOLAS HILL, M.D.
`
`
`
`Liquidia's Exhibit 1002
`Page 1
`
`

`

`TABLE OF CONTENTS
`
`
`Page
`
`
`INTRODUCTION .......................................................................................... 1
`I.
`II. QUALIFICATIONS ....................................................................................... 2
`A. Qualifications and Experience ............................................................. 2
`B. Materials Considered ............................................................................ 4
`III. PERSON OF ORDINARY SKILL IN THE ART ......................................... 7
`IV. STATEMENT OF LEGAL PRINCIPLES ..................................................... 8
`V.
`RELEVANT TECHNICAL BACKGROUND ............................................ 11
`A. Overview of Pulmonary Hypertension ............................................... 11
`B. Well Known Advantages of Inhalation Therapy and Inhalers ........... 12
`C.
`Considerations for Inhalation Therapy ............................................... 13
`D.
`Treprostinil ......................................................................................... 15
`VI. THE ’793 PATENT ...................................................................................... 17
`VII. APPLICATION OF THE PRIOR ART TO THE CLAIMS ........................ 19
`A.
`Brief Summary of Prior Art ............................................................... 20
`
`’212 Patent [Ex. 1006] ............................................................. 20
`
`Voswinckel JESC [Ex. 1007] .................................................. 23
`
`Voswinckel JAHA [Ex. 1008] ................................................. 26
`
`Ghofrani [Ex. 1010] ................................................................. 26
`
`Voswinckel 2006 [Ex. 1009] ................................................... 27
`B. Ground 1: Claims 1–8 are Obvious over ’212 Patent in View of
`Voswinckel JAHA and Voswinckel JESC ......................................... 28
` Motivation to Combine the ’212 Patent with Voswinckel
`JAHA and Voswinckel JESC with a Reasonable
`Expectation of Success ............................................................ 28
`Independent Claim 1 ................................................................ 32
`
`
`
`- i -
`
`Liquidia's Exhibit 1002
`Page 2
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`

`

`(a)
`
`(b)
`(c)
`
`“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” (Claim
`1[a]) ................................................................................ 33
`“with an inhalation device,” (Claim 1[b]) ..................... 35
`“wherein the therapeutically effective single event
`dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a pharmaceutically
`acceptable salt thereof” (Claim 1[c]) ............................. 36
`“delivered in 1 to 3 breaths.” (Claim 1[d]) .................... 39
`(d)
`Dependent Claim 2 .................................................................. 41
`
`Dependent Claim 3 .................................................................. 42
`
`Dependent Claim 4 .................................................................. 43
`
`Dependent Claim 5 .................................................................. 44
`
`Dependent Claims 6, 7, and 8 .................................................. 44
`
`C. Ground 2: Claims 1–8 are Obvious over ’212 Patent in View of
`Voswinckel JESC ............................................................................... 46
` Motivation to Combine the ’212 Patent with Voswinckel
`JESC With a Reasonable Expectation of Success ................... 46
`Independent Claim 1 ................................................................ 47
`(a)
`“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” (Claim
`1[a][b][c]) ...................................................................... 47
`“delivered in 1 to 3 breaths.” (Claim 1[d]) .................... 47
`
`
`
`(b)
`
`- ii -
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`Liquidia's Exhibit 1002
`Page 3
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`

`

`(b)
`(c)
`
`E.
`
`Dependent Claims 2-8 .............................................................. 49
`
`D. Ground 3: Claim 1 is anticipated by Ghofrani ................................... 50
`
`Independent Claim 1 ................................................................ 50
`(a)
`“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” (Claim
`1[a]) ................................................................................ 50
`“with an inhalation device,” (Claim 1[b]) ..................... 51
`“wherein the therapeutically effective single event
`dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a pharmaceutically
`acceptable salt thereof” (Claim 1[c]) ............................. 52
`“delivered in 1 to 3 breaths.” (Claim 1[d]) .................... 52
`(d)
`Ground 4: Claims 1, 3, and 8 are Obvious over Voswinckel
`JAHA and Ghofrani ........................................................................... 53
` Motivation to Combine Voswinckel JAHA and Ghofrani
`With a Reasonable Expectation of Success ............................. 53
`Independent Claim 1 ................................................................ 55
`(a)
`“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” (Claim
`1[a]) ................................................................................ 55
`“with an inhalation device,” (Claim 1[b]) ..................... 56
`“wherein the therapeutically effective single event
`dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a pharmaceutically
`acceptable salt thereof” (Claim 1[c]) ............................. 57
`“delivered in 1 to 3 breaths.” (Claim 1[d]) .................... 58
`(d)
`Dependent Claim 3 .................................................................. 58
`
`(b)
`(c)
`
`
`
`
`
`- iii -
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`Liquidia's Exhibit 1002
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`

`

`F.
`
`(c)
`(d)
`
`Dependent Claim 8 .................................................................. 58
`
`Ground 5: Claims 1 and 3 are Anticipated by Voswinckel 2006 ...... 59
`
`Independent Claim 1 ................................................................ 59
`(b)
`“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” (Claim
`1[a]) ................................................................................ 59
`“with an inhalation device,” (Claim 1[b]) ..................... 60
`“wherein the therapeutically effective single event
`dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a pharmaceutically
`acceptable salt thereof” (Claim 1[c]) ............................. 60
`“delivered in 1 to 3 breaths.” (Claim 1[d]) .................... 60
`(e)
`Dependent Claim 3 .................................................................. 61
`
`G. Ground 6: Claims 2 and 4–8 are Obvious over Voswinckel
`2006 and the ’212 Patent .................................................................... 61
` Motivation to Combine Voswinckel 2006 and the ’212
`Patent with a Reasonable Expectation of Success ................... 61
`Dependent Claim 2 .................................................................. 63
`
`Dependent Claim 4 .................................................................. 63
`
`Dependent Claim 5 .................................................................. 64
`
`Dependent Claim 6, 7, and 8 .................................................... 64
`
`VIII. NO SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ...... 66
`IX. CONCLUSION ............................................................................................. 67
`
`- iv -
`
`Liquidia's Exhibit 1002
`Page 5
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`

`

`I, Nicholas Hill, M.D., declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`Counsel for Liquidia Technologies, Inc. (“the Petitioner”) retained me to
`
`offer technical opinions with respect to U.S. Patent No. 10,716,793 (“the ’793 Patent”)
`
`and the prior art references cited in the inter partes review (IPR) proceedings for the
`
`’793 Patent, Ex. 1001.
`
`3.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate of $550 per hour. My compensation does not depend on the
`
`outcome of, or the content of my testimony in, the current IPR.
`
`4.
`
`I have assessed the ’793 Patent. In doing so, I have considered the
`
`teachings of the scientific literature before May 15, 2006, in light of general
`
`knowledge in the art before that date.
`
`5.
`
`In this declaration, I set forth my opinion that the claims of the ’793
`
`Patent would have been obvious to a person of ordinary skill in the art before May 15,
`
`
`
`
`
` 1
`
`
`
`2006.
`
`
`
`
`
`
`
`Liquidia's Exhibit 1002
`Page 6
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`

`

`II. QUALIFICATIONS
`A. Qualifications and Experience
`6.
`Below, I summarize my background, qualifications, and experience
`
`relevant to the issues raised in the present IPR. A copy of my curriculum vitae, which
`
`includes a full description of my background and qualifications is attached to this
`
`declaration as Exhibit 1003.
`
`7.
`
`I am a Doctor of Medicine with more than 41 years of experience treating
`
`pulmonary diseases. I practiced at Tufts Medical Center from 1982 through 1987,
`
`spent 15 years in Pulmonary and Critical Care Medicine at Rhode Island Hospital,
`
`Brown University, and returned to Tufts in 2002 to occupy my current position as
`
`Chief of the Division of Pulmonary, Critical Care, and Sleep. As a physician, I
`
`specialize
`
`in pulmonary hypertension, mechanical ventilation, noninvasive
`
`ventilation, and general pulmonology. I am also a Professor of Medicine at Tufts
`
`University School of Medicine where I research pulmonary vascular biology, disease,
`
`and treatment.
`
`8.
`
`In 1975, I earned my medical degree from Dartmouth Medical School. I
`
`then trained as a resident at the New England Medical Center, Tufts University School
`
`of Medicine, from 1975-1977, and at the Boston Veterans Admin. Medical Center
`
`from 1977-1978. From 1978 to 1979, I served as a fellow in cardiovascular medicine
`
`at University of Massachusetts Medical Center. From 1979-1982, I completed a
`
`fellowship in pulmonary medicine at Boston University School of Medicine.
`
` 2
`
`
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`Liquidia's Exhibit 1002
`Page 7
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`

`

`9.
`
`I am licensed to practice in Massachusetts and Rhode Island and hold
`
`certifications in Internal Medicine, Pulmonary Diseases, and Critical Care Medicine
`
`from the American Board of Internal Medicine. In addition to my position at Tufts
`
`Medical Center, I have held several clinical positions at pulmonary clinics in New
`
`England. From 2002-2012, I held a clinical position at the Rhode Island Hospital
`
`Pulmonary Hypertension Clinic. Since 2017, I have held a clinical position at the
`
`University of Massachusetts Medical Center Pulmonary Hypertension Clinic.
`
`10.
`
`I have treated many hundreds of patients with pulmonary hypertension,
`
`and have prescribed inhaled prostacyclin, including treprostinil and iloprost, to many
`
`dozens of these patients. I regularly prescribe the use of inhalers to my patients
`
`including soft mist inhalers, dry powder inhalers, pressurized metered dose inhalers,
`
`and nebulizers.
`
`11. As a supervising physician, I have conducted or helped conduct over
`
`fifteen clinical trials evaluating treatments for pulmonary hypertension, including
`
`treatments with inhaled therapies. Of particular relevance, in 2006, I participated in
`
`a multi-center trial on the effects on pulmonary hypertension of the addition of inhaled
`
`treprostinil to sildenafil or bosentan. Ex. 1003, at 10. In 2007, I participated in the
`
`extension of the multicenter study to examine the long-term effects of inhaled
`
`treprostinil on patients. Id.
`
` 3
`
`
`
`Liquidia's Exhibit 1002
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`

`

`12. Since 1974, I have published over 176 original articles in peer-reviewed
`
`journals, including at least 70 on pulmonary hypertension. Several of these articles
`
`concern treatments for pulmonary hypertension, including treatments using inhaled
`
`therapies. For example, in 2015, I published a review article titled “Inhaled Therapies
`
`for Pulmonary Hypertension” in the journal Respiratory Care. Ex. 1079 (Hill 2015).
`
`The article reviews FDA-approved inhaled therapies for pulmonary hypertension over
`
`the last 20 years, including inhaled treprostinil, and describes the advantages and
`
`disadvantages of inhaled therapies. Id.
`
`13. During my time as a Professor of Medicine, I have supervised over fifty
`
`students and postdoctoral fellows who completed original research on pulmonary
`
`hypertension and treatments for pulmonary diseases.
`
`14. Accordingly, I consider myself an expert in the field of pulmonary
`
`medicine, and I have been an expert in this field since before May 15, 2006.
`
`B. Materials Considered
`15. The analysis that I provide in this Declaration is based on my education,
`
`research, and experience, as well as my investigation and study of relevant materials,
`
`including the ’793 Patent. I have further reviewed the declaration in support of
`
`Petitioner from Dr. Igor Gonda. Ex. 1004. In addition to these materials, I may
`
`consider additional documents and information in forming any supplemental
`
`opinions. To the extent I am provided additional documents or information, I may
`
` 4
`
`
`
`offer further opinions.
`
`Liquidia's Exhibit 1002
`Page 9
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`

`

`16.
`
`I have reviewed and cited to the following documents in my analysis
`
`below:
`
`Exhibit
`No.
`
`Description of Document
`
`1001 U.S. Patent No. 10,716,793 B2 to Olschewski, et al. (“’793 patent”)
`1003 Curriculum Vitae of Dr. Nicholas Hill
`1004 Declaration of Dr. Igor Gonda (“Gonda Decl.”)
`1006 U.S. Patent No. 6,521,212 B1 to Cloutier, et al. (“’212 patent”)
`1007 Voswinckel, R., et al., Abstract 218: “Inhaled treprostinil is a potent
`pulmonary vasodilator in severe pulmonary hypertension,” European
`Heart Journal 25:22 (2004) (“Voswinckel JESC”)
`1008 Robert Voswinckel, Beate Enke, Andre Kreckel, Frank
`Reichenberger, Stefanie Krick, Henning Gall, Tobias Gessier,
`Thomas Schmehl, Markus G. Kohstall, Friedrich Grimminger,
`Hossein A. Ghofrani, Werner Seeger, and Horst Olschewski,
`Abstract 1414: “Inhaled Treprostinil Sodium (TRE) For the
`Treatment of Pulmonary Hypertension,” Abstracts from the 2004
`Scientific Sessions of the American Heart Association, Circulation,
`110(17 Suppl.):III-295 (October 26, 2004) (“Voswinckel JAHA”)
`1009 Robert Voswinckel, Hossein A. Ghofrani, Friedrich Grimminger,
`and Werner Seeger, “Clinical Observations” on “Inhaled Treprostinil
`for Treatment of Chronic Pulmonary Arterial Hypertension,”
`“Letters” Section of the Annals of Internal Medicine, 144(2):149-50
`(January 2006) (“Voswinckel 2006”)
`1010 Hossein Ardeschir Ghofrani, Robert Voswinckel, et al., Neue
`Therapieoptionen in der Behandlung der pulmonalarteriellen
`Hypertonie, 30(4) HERZ, 30(4):296–302 (June 2005) (“Ghofrani”)
`(Foreign article and English translation attached)
`1018 Remodulin® 2004 Label
`1019
`Stein, S.W., et al., “The History of Therapeutic Aerosols: A
`Chronological Review,” Journal of Aerosol Medicine and
`Pulmonary Drug Delivery, 30(1):20-41 (2017) (“Stein”)
`
` 5
`
`
`
`Liquidia's Exhibit 1002
`Page 10
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`

`

`1020 Clark, A.R., “Medical Aerosol Inhalers: Past, Present, and Future,”
`Aerosol Science and Technology, 22:374-91 (1995) (“Clark”)
`1022 Walmrath, D., et al., “Direct Comparison of Inhaled Nitric Oxide and
`Aerosolized Prostacyclin in Acute Respiratory Distress Syndrome,”
`American Journal of Respiratory Critical Care Medicine, 153:991-
`96 (1996) (“Walmrath 1996”)
`1023 Olschewski, H., et al., “Inhaled Prostacyclin and Iloprost in Severe
`Pulmonary Hypertension Secondary to Lung Fibrosis,” American
`Journal of Respiratory Critical Care Medicine, 160:600-07 (1999)
`(“Olschewski 1999”)
`1025 De Wet, C.J., et al., “Inhaled prostacyclin is safe, effective, and
`affordable in patients with pulmonary hypertension, right heart
`dysfunction, and refractory hypoxemia after cardiothoracic surgery,”
`Journal of Thoracic and Cardiovascular Surgery, 127:1058-67
`(2004) (“De Wet”)
`1028 U.S. Patent Application Publication No. US 2004/0265238 A1 to
`Chaudry (“Chaudry”)
`1029 Ventavis® Label 2004
`1030 Newman, S.P., “Aerosols”, Chapter from Encyclopedia of
`Respiratory Medicine pp. 58-64 (2006) (“Newman”)
`1031 Geller, D.E., “Comparing Clinical Features of the Nebulizer,
`Metered-Dose Inhaler, and Dry Powder Inhaler,” Respiratory Care,
`50(10):1313-21 (2005) (“Geller 2005”)
`1032 Bender, B., et al., “Nonadherence in asthmatic patients: is there a
`solution to the problem?” Annals of Allergy, Asthma & Immunology,
`79:177-86 (1997) (“Bender 1997”)
`1034 Geller, D., et al., “Bolus Inhalation of rhDNase with the AERx
`System in Subjects with Cystic Fibrosis,” Journal of Aerosol
`Medicine, 16(2):175-82 (2003) (“Geller 2003”)
`1035 Chattaraj, S.C., “Treprostinil sodium Pharmacia,” Current Opinion
`in Investigational Drugs, 3(4):582-86 (Apr. 2002), available at
`https://pubmed.ncbi.nlm.nih.gov/12090728/ (“Chattaraj”)
`1037
`English translation of OptiNeb® User Manual 2005
`1046 U.S. Patent No. 9,358,240 to Olschewski, et al. (“’240 Patent”)
`
` 6
`
`
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`Liquidia's Exhibit 1002
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`1047 Hoeper, M.M., et al., “Long-Term Treatment of Primary Pulmonary
`Hypertension with Aerosolized Iloprost, a Prostacyclin Analogue,” N
`Engl J Med, 342:1866-70 (2000) (“Hoeper”)
`1048 Walmrath, D., et al., “Aerosolised prostacyclin in adult respiratory
`distress syndrome,” Lancet, 342:961-62 (1993) (“Walmrath 1993”)
`1059 Nauser, T.D., “Pulmonary Hypertension: New Perspectives,” CHF,
`9:155-62 (2003) (“Nauser 2003”)
`1065 Olschewski, H., et al., “Inhaled Iloprost for Several Pulmonary
`Hypertension,” N Engl J Med, 347(5):322-29 (2002) (“Olschewski
`2002”)
`1068 Vachiéry, J.-L., et al., “Transitioning From IV Epoprostenol to
`Subcutaneous Treprostinil in Pulmonary Arterial Hypertension,”
`CHEST, 121:1561-65 (2002) (“Vachiéry 2002”)
`1077 Boyle, M.P., “So Many Drugs, So Little Time. The Future Challenge
`of Cystic Fibrosis Care,” CHEST, 123(1):3-5 (2003) (“Boyle 2003”)
`1078 Azmacort® Label 2003
`1079 Hill, N.S., et al., “Inhaled Therapies for Pulmonary Hypertension,”
`Respiratory Care, 60(6):794-805 (2015) (“Hill 2015”)
`
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`17.
`I understand that an assessment of the claims of the ’793 Patent should
`
`be undertaken from the perspective of a person of ordinary skill in the art (“POSA”
`
`or “skilled artisan”) as of the earliest claimed priority date, which I have been
`
`informed is May 15, 2006. I have been advised by counsel for Liquidia that to
`
`determine the appropriate level of a person having ordinary skill in the art, the
`
`following factors may be considered: (1) the types of problems encountered by those
`
`working in the field and prior art solutions thereto; (2) the sophistication of the
`
`technology in question, and the rapidity with which innovations occur in the field; (3)
`
` 7
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`the educational level of active workers in the field; and (4) the educational level of
`
`the inventor.
`
`18.
`
`I have assessed the level of ordinary skill in the art based upon my review
`
`of the prior art, the patent, and my over 41 years of working in the field of pulmonary
`
`medicine.
`
`19. A POSA for a method of treating pulmonary hypertension as of May 15,
`
`2006 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.
`
`Accordingly, I qualify as a POSA: I am Chief of the Division of Pulmonary, Critical
`
`Care, and Sleep at Tufts Medical Center. Ex. 1003. By 2006, I had treated patients
`
`with pulmonary hypertension for more than several decades including prescribing
`
`inhaled prostacyclin receptor agonists. See id.
`
`IV. STATEMENT OF LEGAL PRINCIPLES
`A. Claim Construction
`20.
`I have been informed by counsel that claim terms are generally given
`
`their ordinary and customary meaning, which is the meaning that the term would have
`
`to a POSA in question at the time of the invention, i.e., as of the effective filing date
`
`of the patent application. I further understand that a POSA is deemed to read the claim
`
`term not only in the context of the particular claim in which a claim term appears, but
`
`in the context of the entire patent, including the specification and prosecution history.
`
` 8
`
`
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`21.
`
`I have reviewed the claims of the ’793 Patent and believe a POSA would
`
`understand each of the claim terms to have their plain and ordinary meaning.
`
`B. Anticipation
`22.
`I understand from counsel that the law recognizes a concept called
`
`“anticipation.” I understand that a patent is invalid when the invention claimed is
`
`anticipated (i.e. not novel) over a prior art reference. I have been advised by counsel
`
`that a patent claim is anticipated only if the prior art reference teaches every element
`
`of the claim.
`
`C. Obviousness
`23. Counsel has advised me that a patent claim may be found invalid as
`
`obvious if, at the time when the invention was made, the subject matter of the claim,
`
`considered as a whole, would have been obvious to a person having ordinary skill in
`
`the field of the technology (the “art”) to which the claimed subject matter belongs.
`
`24.
`
`I understand that the following factors should be considered in analyzing
`
`obviousness: (1) the scope and content of the prior art; (2) the differences between the
`
`prior art and the claims; and (3) the level of ordinary skill in the pertinent art.
`
`25.
`
`I also understand that certain other factors known as “secondary
`
`considerations” such as commercial success, unexpected results, long felt but unmet
`
`need, industry acclaim, simultaneous invention, copying by others, skepticism by
`
`experts in the field, and failure of others may be utilized as indicia of nonobviousness.
`
` 9
`
`
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`Liquidia's Exhibit 1002
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`

`

`I understand, however, that secondary considerations should be connected, or have a
`
`“nexus,” with the invention claimed in the patent at issue.
`
`26.
`
`I understand that a POSA is assumed to have knowledge of all prior art.
`
`I understand that a POSA can combine various prior art references based on the
`
`teachings of those references, the general knowledge present in the art, or common
`
`sense. I understand that a motivation to combine references may be implicit in the
`
`prior art, and there is no requirement that there be an actual or explicit teaching to
`
`combine two references. Thus, one may take into account the inferences and creative
`
`steps that a person of ordinary skill in the art would employ to combine the known
`
`elements in the prior art in the manner claimed by the patent at issue. I understand
`
`that one should avoid “hindsight bias” and ex post reasoning in performing an
`
`obviousness analysis, but that this does not mean that a POSA does not have recourse
`
`to common sense for purposes of the obviousness inquiry.
`
`27.
`
`I have been advised by counsel that obviousness may be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. Obviousness may also be shown
`
`by demonstrating that it would have been obvious to combine the teachings of more
`
`than one item of prior art.
`
`28.
`
`I have been advised by counsel that a claimed invention may be obvious
`
`if some teaching, suggestion, or motivation exists that would have led a person of
`
`
`10
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`Liquidia's Exhibit 1002
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`

`

`ordinary skill in the art to combine the invalidating references and to do so with a
`
`reasonable expectation of success. Counsel has also advised me that this suggestion
`
`or motivation may come from the knowledge of a person having ordinary skill in the
`
`art, or from sources such as explicit statements in the prior art. Alternatively, any
`
`need or problem known in the field at the time and addressed by the patent may
`
`provide a reason for combining elements of the prior art. I have been further advised
`
`by counsel that if a patent claims a combination of familiar elements according to
`
`known methods, the combination is likely to be obvious when a POSA has a
`
`reasonable expectation of success in combining the elements. Absolute certainty of
`
`success is not required.
`
`V. RELEVANT TECHNICAL BACKGROUND
`A. Overview of Pulmonary Hypertension
`29. Pulmonary hypertension
`is a chronic disease characterized by
`
`abnormally elevated pressure in the pulmonary arteries, the arteries that carry blood
`
`from the right heart to the lungs. Patients with pulmonary hypertension suffer from
`
`persistent and progressive exertional shortness of breath, fatigue, and dizziness. In
`
`my experience, advanced stages of the disease are fatal, and without therapy, patients
`
`may die on average in two to three years. Ex. 1059 (Nauser 2003) at 158.
`
`30. Therapies for respiratory diseases, including pulmonary hypertension,
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`were used extensively by 2006. Exs. 1034 (Geller 2003); 1065 (Olschewski 2002);
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`1023 (Olschewski 1999); 1022 (Walmrath 1996). These therapies could be
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`administered to a patient through a variety of routes, including intravenous,
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`subcutaneous, and inhalation delivery. Id. Because the ’793 Patent concerns delivery
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`of therapies via inhalation, I focus here on the state of inhalation therapy in 2006.
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`B. Well Known Advantages of Inhalation Therapy and Inhalers
`31. Several advantages of inhalation therapy were well-known by 2006.
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`Compared to intravenous or subcutaneous therapies, inhalation was relatively non-
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`invasive. A patient needed to only breathe in the drug. Such ease of administration
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`meant that, unlike continuous intravenous therapy, patients did not need to receive
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`treatment at “specialized centers familiar with the [intravenous] technique,
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`equipment, and dose ranging.” Ex. 1028 (Chaudry 2004) at [0011].
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`32.
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`Inhalation therapies were also known to provide pulmonary selectivity
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`because they were delivered to the organ of interest—the lung. Direct delivery to the
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`lung could eliminate or reduce the side effects associated with intravenous delivery.
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`As Chaudry 2004 explains, with intravenous therapies, larger doses were often
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`required as only a small fraction of the dose delivered actually reached the lungs. Id.
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`Inhalation therapy was also known to reduce systemic toxicity (i.e. toxicity at multiple
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`sites or throughout the body) and intravenous catheter infection. Ex. 1065
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`(Olschewski 2002) at 322.
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`33. By 2006, inhalation therapies could easily be administered with inhalers.
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`As early as the 1950s, clinicians and patients recognized inhalers were convenient and
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`portable. Ex. 1019 (Stein) at 27. In 1956, for example, the metered dose inhaler for
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`treating asthma was introduced. As the first “truly convenient and portable”
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`inhalation device, it quickly became the dominant system for delivering asthma
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`medication. Id.; see also Ex. 1020 (Clark) at 375.
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`34. Several other inhalers and inhalation devices were also well-known and
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`used by me, along with many other clinicians, for treatment of pulmonary disease
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`before 2006. By 2006, I was regularly prescribing these devices to patients with
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`airways diseases. Older forms of medical nebulizers had been used since at least the
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`1950s, Ex. 1020 (Clark) at 375, and by the early 2000s, clinicians and researchers
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`used pulsed ultrasonic and jet nebulizers, including the OptiNeb® Ex. 1037
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`(OptiNeb® 2005 manual) and HaloLite. Exs. 1065 (Olschewski 2002) at 323; 1067
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`(Anderson 2005) at 1144. Dry powder inhalers were invented in 1852, and like the
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`nebulizer and metered dose inhaler, were widely available by the 1990s. See generally
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`Ex. 1020 (Clark). Compared to the nebulizer, dry powder inhalers were easier and
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`quicker to use. Ex. 1031 (Geller 2005) at 1315. And unlike nebulizers or most
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`metered dose inhalers, dry powder inhalers provided breath actuation. Exs. 1030
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`(Newman) at 62; 1031 (Geller 2005) at 1316.
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`C. Considerations for Inhalation Therapy
`35.
`Inhalation therapy was not without its technical difficulties. By the early
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`1990s, it was well known that large drug particles were ineffective when used in
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`inhalation therapy. Clark reported that “to avoid inertial impaction in the
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`oropharyngeal cavity and reach the lung” aerosol particles needed to be 7 micrometers
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`or less. Ex. 1020 (Clark) at 374. To reach the peripheral lung, furthermore, the
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`particles needed to be 2 to 3 micrometers. Id.
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`36. Many inhalation therapies required administration times of tens of
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`minutes or longer. For example, iloprost, which has been on the market since the
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`early 2000s, was prescribed at four to ten minutes per dose. Ex. 1029 (Ventavis Label
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`2004) at 17. Long inhalation times meant patients did not reliably adhere to a
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`treatment regime.
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`37. By the early 2000s, numerous groups had worked and were working to
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`improve upon inhalation therapy. Notably, while inhalation therapy provided
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`advantages over intravenous therapy, adherence rates were still not 100 percent. Ex.
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`1032 (Bender 1997) at Abstract, 179-80. My own experience in the early 2000s
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`echoes this finding. I regularly treated patients with asthma chronic obstructive
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`pulmonary disease (COPD), and pulmonary vascular disease using inhaled therapies,
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`including iloprost. Patients receiving iloprost required six doses per day at ten
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`minutes per dose. Due to the time required to administer the therapies and frequency
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`of dosing, a sizable percentage of patients did not adhere to their treatment regimen.
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`38. Clinicians and researchers recognized adherence rates might improve if
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`drug delivery time and number of breaths required for inhalation therapy were
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`reduced. Geller, et. al. noted “more efficient delivery methods are required to reduce
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`the time burden of taking multiple inhaled drugs” for patients with cystic fibrosis. Ex.
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`1034 (Geller 2003) at 176. Olschewski, et al. explained that while their study
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`delivered iloprost to patients over a ten minute inhalation period, other techniques
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`could be used to considerably shorten the duration. Ex. 1065 (Olcheswki 2002) at
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`328. A patent from Chaudry et al. in 2004 describing an inhalable formulation for
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`pulmonary hypertension explained “[r]educing the amount of time to complete the
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`treatment means individuals will be more likely to comply with the prescribed dosing
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`regimen and achieve optimal benefit from the medication prescribed.” Ex. 1028
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`(Chaudry 2004) at [0063].
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`39. Several of these groups were successful in demonstrating that inhalation
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`t