UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________________
`
`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED,
`Petitioner,
`
`v.
`
`BIOVIE, INC.,
`Patent Owner.
`________________________________
`
`Case IPR2018-00974
`Patent 9,655,945
`
`________________________________
`
`DECLARATION OF PAUL GOW UNDER 37 C.F.R. §1.68
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,655,945
`
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`Page 1 of 90
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`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 7
`
`II.
`
`Background Qualifications .............................................................................. 9
`
`III. Understanding of U.S. Patent Law ................................................................ 11
`
`IV. Level of Ordinary Skill in the Pertinent Art .................................................. 13
`
`V.
`
`The ‘945 Patent .............................................................................................. 15
`
`A.
`
`The Prosecution History ...................................................................... 15
`
`VI. The State of the Art Relevant to the ‘945 Patent ........................................... 16
`
`A.
`
`The Field of the ‘945 Patent ................................................................ 16
`
`VII. Detailed Invalidity Analysis .......................................................................... 23
`
`VIII. Background on the Prior Art References ....................................................... 24
`
`A.
`
`Background of Robertson .................................................................... 25
`
`B.
`
`C.
`
`Background of Angeli ......................................................................... 26
`
`Background of Fimiani ........................................................................ 28
`
`IX. The Challenged Claims are Invalid ............................................................... 30
`
`A.
`
`Claims 1-3 and 5 are anticipated under 35 U.S.C. § 102 by
`
`Robertson. ............................................................................................ 30
`
`B.
`
`Claims 7-8, and 10 are rendered obvious under 35 U.S.C. § 103
`
`by Robertson. ....................................................................................... 35
`
`C.
`
`Claims 1, 2, 6, and 12 are rendered obvious under 35 U.S.C. §
`
`103 by Angeli. ..................................................................................... 39
`
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`D.
`
`Claims 1-14 are rendered obvious under 35 U.S.C. § 103 by
`
`Fimiani in view of Robertson. ............................................................. 47
`
`E.
`
`Claims 1-14 are rendered obvious under 35 U.S.C. § 103 by
`
`Fimiani in view of Angeli. .................................................................. 69
`
`X.
`
`Conclusion ..................................................................................................... 89
`
`
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`LIST OF EXHIBITS
`
`
`
`Exhibit 1001 U.S. Patent No. 9,655,945 (“the ‘945 patent”)
`
`Exhibit 1002 Expert Declaration of Dr. Paul Gow
`
`Exhibit 1003 Dr. Paul Gow’s curriculum vitae
`
`Exhibit 1004
`
`Robertson, et al., Continuous Outpatient Terlipressin Infusion for
`Hepatorenal Syndrome
`as
`a Bridge
`to Successful Liver
`Transplantation, Hepatology, December 2014, pp. 2125–2126
`(“Robertson”)
`
`Exhibit 1005
`
`Angeli, Terlipressin for the Treatment of Hepatorenal Syndrome in
`Patients with Cirrhosis, Expert Opinion on Orphan Drugs, 1:3, 241-
`248, published online February 8, 2013 (“Angeli”)
`
`Exhibit 1006
`
`Fimiani, et al., The Use of Terlipressin in Cirrhotic Patients with
`Refractory and Normal Renal Function: A Multicentric Study,
`European Journal of Internal Medicine, 22 (6), 587-590, December
`2011 (“Fimiani”)
`
`Exhibit 1007
`
`PharmaIN Press Release, FDA Grants Orphan-Drug Designation for
`Novel Terlipressin Formulation for
`the Treatment of Ascites,
`PharmaIN
`website,
`April
`1,
`2013,
`available
`at:
`http://pharmain.com/fda-grants-orphan-drug-designation-for-novel-
`terlipressin-formulation-for-the-treatment-of-ascites (“PharmaIN Press
`Release”)
`
`Exhibit 1008
`
`File Wrapper of Application No. 15/198,050, which became the ‘945
`patent (“the ‘945 filewrapper”)
`
`Exhibit 1009 U.S. Patent No. 7,160,853 to Lebrec et al. (“Lebrec”)
`
`Exhibit 1010
`
`Krag et al., Terlipressin Improves Renal Function in Patients with
`Cirrhosis and Ascites Without Hepatorenal Syndrome, Hepatology,
`December 2007, pp. 1863-1871 (“Krag”)
`
`
`
`
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`Exhibit 1011
`
`Salerno et al., Diagnosis, Prevention and Treatment of Hepatorenal
`Syndrome in Cirrhosis. Gut, 2007, 56:1310-1318. (“Salerno”)
`
`Exhibit 1012
`
`Gerbes et al., Terlipressin for Hepatorenal Syndrome: Continuous
`Infusion as an Alternative to IV Bolus Administration,
`Gastroenterology, 2009, 137: 1179-1189 (“Gerbes”)
`
`Exhibit 1013
`
`Piano et al., Continuous recurrence of type 1 hepatorenal syndrome
`and long-term treatment with terlipressin and albumin: A new
`exception to MELD score in the allocation system to liver
`transplantation? Journal of Hepatology, 2011, 55: 491-496 (“Piano”)
`
`Exhibit 1014
`
`Wong et al., Working Party proposal for a revised classification
`system of renal dysfunction in patients with cirrhosis, Gut, 2011,
`60:702-709. (“Wong”)
`
`Exhibit 1015
`
`Shao-Jung Hsu and Hui-Chun Huang, Management of ascites in
`patients with liver cirrhosis: Recent evidence and controversies,
`Journal of the Chinese Medical Association, 2013, 76:123-130
`(“Hsu”)
`
`
`
`
`
`
`
`
`
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`I.
`
`Introduction
`
`I, Paul Gow, declare as follows:
`
`1.
`
`I have been retained on behalf of Mallinckrodt Pharmaceuticals Ireland
`
`Limited (“Petitioner”) to provide expert opinions in connection with an Inter
`
`Partes Review (“IPR”) of U.S. Patent No. 9,655,945 (Ex. 1001; “the ‘945
`
`patent”).
`
`2.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate of AUD$550 per hour. My compensation is not
`
`affected by the outcome of this matter.
`
`3.
`
`I have been asked to provide my opinions regarding whether claims 1-14 of
`
`the ‘945 patent (“the Challenged Claims”) are invalid as anticipated or
`
`would have been obvious to a person having ordinary skill in the art at the
`
`time of the alleged invention (“POSITA”).
`
`4.
`
`The ‘945 patent was filed on June 30, 2016 as Application No. 15/198,050
`
`(“the ‘050 application”) and
`
`identifies provisional application Nos.
`
`62/186,638 filed June 30, 2015, 62/267,510 filed December 15, 2015,
`
`62/321,558, filed April 12, 2016.
`
`5.
`
`For the purposes of my Declaration, I have been asked to assume that a
`
`patent or printed publication is prior art to the ‘945 patent if it was publicly
`
`accessible prior to June 30, 2015.
`
`
`
`
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`6.
`
`The face of the ‘945 patent names Paolo Angeli, Penelope Markham, and
`
`Jonathan Adams as the named inventors for the ‘945 patent, and identifies
`
`BIOVIE, Inc. as the named assignee. Ex.1001.
`
`7.
`
`In preparing this Declaration, I have reviewed the ‘945 patent, its
`
`prosecution file history, numerous prior art references, and technical
`
`references from the time of the alleged invention.
`
`8.
`
`In forming the opinions expressed in this Declaration, I relied upon my
`
`experience in the relevant field of the art, and have considered the viewpoint
`
`of a POSITA as of June 30, 2015. My opinion is also based, at least in part,
`
`on the following references in view of a POSITA:
`
`
`
`
`
`Exhibit
`
`Reference
`
`Date Filed or Published
`
`Exhibit 1004
`
`Exhibit 1005
`
`al.,
`Robertson,
`et
`Outpatient
`Continuous
`Terlipressin Infusion for
`Hepatorenal Syndrome as
`a Bridge
`to Successful
`Liver
`Transplantation,
`Hepatology,
`December
`2014,
`pp.
`2125–2126
`(“Robertson”)
`
`for
`Angeli, Terlipressin
`of
`the
`Treatment
`Hepatorenal Syndrome in
`Patients with Cirrhosis,
`Expert
`Opinion
`on
`Orphan Drugs, 1:3, 241-
`248,
`published
`online
`
`
`
`first
`Robertson was
`published online on May
`29, 2014
`and
`later
`published
`in
`the
`December 2014 print
`version of Hepatology,
`Volume 60, Issue 6.
`
`first
`was
`Angeli
`on
`online
`published
`February 8, 2013 and
`later published in 2013
`print version of Expert
`Opinion
`on Orphan
`Drugs, Volume 1, Issue
`
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`Exhibit 1006
`
`February
`(“Angeli”)
`
`8,
`
`2013
`
`3.
`
`Fimiani, et al., The Use of
`Terlipressin in Cirrhotic
`Patients with Refractory
`and
`Normal
`Renal
`Function: A Multicentric
`Study, European Journal
`of Internal Medicine, 22
`(6), 587-590, December
`2011 (“Fimiani”)
`
`first
`was
`Fimiani
`on
`online
`published
`August 2, 2011 and later
`published
`in
`the
`December 2011 print
`version of European
`Journal
`of
`Internal
`Medicine, Volume 22,
`Issue 6.
`
`
`
`II. Background Qualifications
`
`9.
`
`I am a physician with over 25 years of experience treating patients with
`
`ascites and hepatorenal syndrome (HRS) due to liver cirrhosis, and over 16
`
`years as a specialist treating patients with the same conditions. Attached to
`
`this declaration is a copy of my curriculum vitae. Ex.1003.
`
`10.
`
`I am currently a Deputy Director of Gastroenterology and Senior Consultant
`
`Hepatologist and Liver Transplant Physician in the Department of
`
`Gastroenterology and Liver Transplantation at the Austin Hospital in
`
`Heidelberg, Victoria, Australia.
`
`11.
`
`I also am an associate professor and honorary lecturer of the medical school
`
`at the University of Melbourne.
`
`
`
`
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`12.
`
`I hold a Bachelor of Medicine and Bachelor of Surgery (MMBS) from
`
`Monash University and a Doctor of Medicine (MD) from the University of
`
`Melbourne.
`
`13.
`
`I have 18 years of experience administering terlipressin to patients
`
`diagnosed with ascites due to liver cirrhosis as well as patients that have
`
`been diagnosed with HRS type 1 and HRS type 2. Terlipressin has been
`
`used in Australia and at hospitals in which I have worked for 15 years.
`
`14.
`
`In addition to my practical experience, I have authored and co-authored
`
`numerous papers, articles and presentations covering a broad range of topics
`
`related to the treatment of patients having liver cirrhosis and liver disease, as
`
`shown in my curriculum vitae. Ex. 1003.
`
`15. Other details concerning my background, professional service, and more, are
`
`set forth in my curriculum vitae. Ex.1003.
`
`16.
`
`In forming my opinion expressed in this report, I relied on my 25 years of
`
`professional experience treating patients with ascites and hepatorenal
`
`syndrome (HRS) due to liver cirrhosis and 18 years of experience
`
`administering terlipressin to patients.
`
`
`
`
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`III. Understanding of U.S. Patent Law
`
`17.
`
`I am not an attorney, though I have been provided with an understanding of
`
`U.S. patent law sufficient to conduct the analysis given in this report. The
`
`following represents my understanding of these issues.
`
`18. A patent or printed publication that predates June 30, 2015, is prior art
`
`against the ‘945 patent.
`
`19. A claim is invalid or unpatentable if that claim is either anticipated or
`
`obvious. In order to show anticipation of a claim, every element of a claim
`
`must be disclosed expressly or inherently in a single prior art reference.
`
`With respect to ranges recited in a claim, such as a dosage range or a range
`
`describing a duration of treatment, I understand that if the dosage or duration
`
`of treatment specifically taught in the prior art overlaps the recited range or
`
`is within the range, it anticipates the range. In order to show obviousness of
`
`a claim, the claim must be obvious from the perspective of POSITA at the
`
`time the alleged invention was made. A claim may be obvious in view of a
`
`single prior art reference, or may be obvious from a combination of two or
`
`more prior art references.
`
`20. An obviousness analysis requires an understanding of the scope and content
`
`of the prior art, any differences between the alleged invention and the prior
`
`art, and the level of ordinary skill in evaluating the pertinent art. In addition,
`
`
`
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`certain factors may support or rebut the obviousness of a claim, such as
`
`secondary considerations. Secondary considerations can include things such
`
`as commercial success of the alleged invention, skepticism of those having
`
`ordinary skill in the art at the time of the alleged invention, unexpected
`
`results of the alleged invention, any long-felt but unsolved need in the art
`
`that was satisfied by the alleged invention, the failure of others to make the
`
`alleged invention, praise of the alleged invention by those having ordinary
`
`skill in the art, and copying of the alleged invention by others in the field. I
`
`understand that there must be a nexus—a connection—between any such
`
`secondary considerations and the alleged invention. Contemporaneous and
`
`independent invention by others is a secondary consideration tending to
`
`show obviousness.
`
`21. A claim is invalid or unpatentable because it would have been obvious when
`
`it unites old elements with no change to a respective function, or alters prior
`
`art by mere substitution of one element for another known in the field, and
`
`that combination yields predictable results. Moreover, to facilitate a
`
`combination of prior art references, a reason to combine the prior art is
`
`helpful. However, common sense should be used as a guide and no rigid
`
`requirement of finding a teaching, suggestion, or motivation to combine is
`
`required. When a product is available, design incentives and other market
`
`
`
`
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`forces can prompt variations of it, either in the same field or different one. If
`
`a person having ordinary skill in the relevant art can implement a predictable
`
`variation, a finding of obviousness would likely prohibit patentability. For
`
`the same reason, if a technique has been used to improve one device and a
`
`person having ordinary skill in the art would recognize that it would improve
`
`similar devices in the same way, using the technique is obvious. A claim
`
`may be obvious if common sense directs one to combine multiple prior art
`
`references or add missing features to reproduce the alleged invention recited
`
`in the claims.
`
`22.
`
`I understand that claims in an Inter Partes Review proceeding are given
`
`their broadest reasonable interpretation in view of the patent specification
`
`and the understanding of a POSITA.
`
`IV. Level of Ordinary Skill in the Pertinent Art
`
`23.
`
`I have been advised that there are multiple factors relevant to determining
`
`the level of ordinary skill in the pertinent art, including the educational level
`
`of active workers in the field at the time of the alleged invention, the
`
`sophistication of the technology, the type of problems encountered in the art,
`
`and the prior art solutions to those problems.
`
`24. The Challenged Claims pertain to methods of treating patients with ascites
`
`due to liver cirrhosis using a continuous infusion dose. Terlipressin has been
`
`
`
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`used to treat patients diagnosed with ascites due to liver cirrhosis for at least
`
`18 years. Continuous infusion administration of terlipressin has been used
`
`for the treatment of patients diagnosed with ascites due to liver cirrhosis for
`
`at least 8 years.
`
`25.
`
`In view of the subject matter of the ‘945 patent, it is my opinion that a
`
`person having ordinary skill in the art as of June 30, 2015 was typically a
`
`person who had a Ph.D. in the areas of pharmacy, chemistry, biochemistry,
`
`or a related discipline, or a M.D. specializing in hepatology, internal
`
`medicine, and/or gastroenterology, and at least 5 years of experience treating
`
`patients with ascites due to liver cirrhosis and at least 3 years administering
`
`vasoconstrictors such as terlipressin for the treatment of patients diagnosed
`
`with liver cirrhosis. One of skill in the art would also be well versed in the
`
`relevant technical publications and be experienced in various routes of
`
`administration of drugs to treat ascites.
`
`26.
`
`I am directly familiar with the capabilities of such persons of ordinary skill
`
`in the art because I hired, supervised and worked with such persons in 2015.
`
`In 2015, I had at least this level of skill in the art, having a Doctor in
`
`Medicine (M.D.), with about 23 years of practical experience in the field.
`
`See Ex.1003.
`
`
`
`
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`V. The ‘945 Patent
`
`A. The Prosecution History
`
`27. The ‘945 patent was filed on June 30, 2016 as Application No. 15/198,050
`
`(“the ‘050 application”).
`
`28.
`
`I have reviewed the prosecution history of the ‘050 application. I understand
`
`that the claims of the ‘945 patent were initially rejected by the Examiner as
`
`obvious over U.S. Patent 7,160,853 (“Lebrec”) in view of U.S. Patent
`
`Publication No. 2011/0237494 (“Laporte”) or Lebrec in view of U.S. Patent
`
`Publication No. 2012/0157526 (“Jalan”), as well as Lebrec in view of
`
`Laporte in further view of U.S. Patent Publication No. 2014/0378660
`
`(“Short”). Ex. 1008, p. 277-283, Non-Final Rejection Dated October 6,
`
`2016.
`
`29.
`
`I understand that the claims of the ‘945 patent were allowed on the basis of
`
`amendments to claim 1 requiring a specific dose of terlipressin and a
`
`specific duration of administration, which the ‘945 patent Applicant asserted
`
`was not taught by the combination of references cited by the Examiner. Ex.
`
`1008, p. 309, Applicant Response Filed December 6, 2016 (“The short term
`
`and high dose terlipressin bolus of Lebrec combined with Laporte’s
`
`discouraging voice of the half-life and difficult titration of terlipressin would
`
`lead a person of ordinary skill away from taking Applicants’ path of
`
`
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`prolonged infusion with terlipressin.” See Ex. 1008, p. 345, Applicant
`
`response Filed March 13, 2017, “While Lebrec teaches a dose of I.V.
`
`administration of
`
`terlipressin
`
`to
`
`treat side effects associated with
`
`paracentesis, Lebrec does not provide any information about treatment of
`
`ascites or the reduction of the accumulation of ascitic fluid in the abdominal
`
`cavity. To the extent that Jalan teaches the intravenous administration of any
`
`compounds by infusion, the disclosure is simply a boiler plate and does not
`
`suggest a dose for continuous infusion of terlipressin of 1-12 mg/day for
`
`about 1 day to about 6 months as claimed.”)
`
`30.
`
`I understand that the ‘945 patent applicant presented no evidence of
`
`secondary factors such as commercial success, long-felt need, or the failure
`
`of others.
`
`VI. The State of the Art Relevant to the ‘945 Patent
`
`A. The Field of the ‘945 Patent
`
`31. The alleged invention of the ‘945 patent of treating a patient diagnosed with
`
`ascites due to liver cirrhosis, and of reducing the accumulation of ascitic
`
`fluid in the abdominal cavity in an ambulatory ascites patient, by
`
`administering to the patient terlipressin or salt thereof as a continuous
`
`infusion dose of about 1.0 mg to about 12.0 mg per day for about one day to
`
`
`
`
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`about twelve months with an ambulatory infusion pump, was already known
`
`and/or obvious to those of skill in the art as of June 30, 2015.
`
`32.
`
`It was well known at the time of the filing of the ‘945 patent that liver
`
`cirrhosis produces renal dysfunction that in turn results in adverse outcomes
`
`in a patient, including ascites and hepatorenal syndrome (HRS) (see figure 2
`
`from Ex. 1014 (Wong), below). Ex. 1014 at p. 705. Therefore, ascites and
`
`HRS are different manifestations of the same cause (i.e., liver cirrhosis).
`
`Accordingly, it was well known at the time of the filing of the ‘945 patent
`
`that a treatment for HRS is likely to be of benefit for ascites. Wong was
`
`published in the journal Gut, which is among the most widely read journals
`
`by POSITAs with respect to the treatment of patients having ascites due to
`
`liver cirrhosis. Note: in figure 2, below, GFR refers to glomerular filtration
`
`rate and AKI refers to acute kidney injury.
`
`
`
`
`
`
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`33. Clinically, at the time that the ‘945 patent was filed, HRS was divided into
`
`Ex. 1014, FIG. 2
`
`two types: HRS type 1, or acute HRS, and HRS type 2, or chronic HRS. Ex.
`
`1014 at p. 703. In 1996, the International Ascites Club defined HRS as a
`
`syndrome that occurs in patients with cirrhosis, among other criteria, and
`
`specified that HRS type 1 was characterized by a rapidly progressive
`
`reduction of renal function as defined by a doubling of the initial serum
`
`creatinine to >220 µmol/l (2.5 mg/dl), among other criteria. Ex. 1014 at p.
`
`703. HRS type 2 was defined as moderate renal failure that progressed
`
`gradually over weeks to months with a serum creatinine of 133-220 µmol/l
`
`(1.5-2.5 mg/dl), among other criteria. Ex. 1014 at p. 703. The International
`
`Ascites Club updated the definition and diagnostic criteria for HRS in 2005,
`
`without modifying the diagnostic criteria of HRS types 1 and 2 in terms of
`
`the serum creatinine concentrations. Ex. 1014 at p. 703; Ex. 1011 at pp.
`
`1315-1316.
`
`34.
`
`In 2007, Krag showed that the vasoconstrictor terlipressin significantly
`
`improves renal function in patients diagnosed with cirrhosis and refractory
`
`and nonrefractory ascites without hepatorenal syndrome. See Ex. 1010. The
`
`study concluded that “[v]asoconstrictors may represent a novel future
`
`treatment modality for these patients.” Ex. 1010 at p. 1863. Krag was
`
`
`
`
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`published in the journal Hepatology, which is among the most widely read
`
`journals by POSITAs with respect to the treatment of patients having ascites
`
`due to liver cirrhosis.
`
`35. Gerbes, in 2009, demonstrated that continuous infusion of terlipressin can be
`
`used as an alternative to intravenous bolus administration of terlipressin. Ex.
`
`1012. Specifically, Gerbes states that “[i]n our department in recent years,
`
`we have adopted continuous infusion rather than IV bolus dosing of
`
`terlipressin on a regular ward without observing very severe adverse events,”
`
`prompting randomized control trials in patients with HRS. Ex. 1012 at p.
`
`1179. The study concluded that “continuous terlipressin infusion may
`
`achieve response rates comparable with those of IV bolus administration, but
`
`possibly at lower daily dose and with less severe complications.” Id.
`
`Gerbes was published in the journal Gastroenterology, which is among the
`
`most widely read journals by POSITAs with respect to the treatment of
`
`patients having ascites due to liver cirrhosis.
`
`36.
`
`In 2011, Piano disclosed the successful treatment of patients with cirrhosis,
`
`ascites, and continuous recurrence of HRS type 1, before undergoing liver
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`transplant surgery, using continuous intravenous infusion of terlipressin. Ex.
`
`1013 at p. 491-496. Piano was published in the journal Journal of
`
`
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`Hepatology, which is among the most widely read journals by POSITAs
`
`with respect to the treatment of patients having ascites due to liver cirrhosis.
`
`37. Also in 2011, Fimiani reported the outcome of a clinical study designed to
`
`evaluate whether terlipressin in addition to standard therapy (diuretics plus
`
`albumin) improves refractory ascites in cirrhotic patients without HRS. Ex.
`
`1006 at p. 588.
`
`38. The study reported in Fimiani treated cirrhotic patients with refractory
`
`ascites using intravenous bolus administration of terlipressin. Ex. 1006.
`
`Fimiani states that “[o]ur data clearly show that the combined treatment with
`
`terlipressin plus diuretics and albumin might improve the outcome of
`
`refractory ascites in patients without HRS, decreasing the need for large
`
`paracentesis, increasing urinary sodium excretion and reducing abdominal
`
`circumference as well as ascites severity.” Ex. 1006 at p. 589. Additionally,
`
`the Fimiani study demonstrated a significant decrease in body weight during
`
`terlipressin administration,
`
`indicating
`
`that bolus administration of
`
`terlipressin is effective in the treatment of ascites, including reducing the
`
`accumulation of ascitic fluid in the abdominal cavity. Ex. 1006 at pp. 588-
`
`589.
`
`39. While studies such as Fimiani (Ex. 1006) had
`
`taught
`
`that bolus
`
`administration of terlipressin was effective for the treatment of ascites, other
`
`
`
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`studies, such as Gerbes (Ex. 1012) and Angeli (Ex. 1005), disclosed that
`
`continuous infusion of terlipressin can be more effective than intravenous
`
`boluses, and may be safer and less expensive as well.
`
`40. For example, Angeli stated with respect to the effectiveness of terlipressin in
`
`patients with HRS type 1, that “[t]he use of terlipressin and albumin in the
`
`treatment of type 1 HRS represents a landmark in the treatment of
`
`complications in patients with advanced cirrhosis.” Ex. 1005 at p. 243.
`
`41. Angeli found that “administration of terlipressin by continuous intravenous
`
`infusion can be more effective than by intravenous boluses, and may turn out
`
`to be safer and cheaper.” Ex. 1005 at p. 245.
`
`42. Thus, the Angeli reference provides an explicit teaching in the prior art more
`
`than 2 years before the effective filing date of the ‘945 patent to
`
`continuously infuse terlipressin, rather than administer it as a bolus, so as to
`
`improve safety, efficacy and costs.
`
`43. Hsu, in 2013, taught that terlipressin is likely to be an effective treatment for
`
`ascites, stating “[t]o sum up, terlipressin may have the potential to improve
`
`renal sodium excretion by enhancing renal perfusion and thus contributing to
`
`improved ascites control.” Ex. 1015 at p. 126. Hsu was published in the
`
`Journal of the Chinese Medical Association, which is a journal that may be
`
`
`
`
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`consulted by POSITAs with respect to the treatment of patients having
`
`ascites due to liver cirrhosis.
`
`44.
`
`In 2014, Robertson reported the first use of continuous infusion of
`
`terlipressin to treat a patient diagnosed with ascites due to cirrhosis on an
`
`outpatient basis. Ex. 1004 at pp. 2125-2126.
`
`45. Specifically, Robertson reported administering terlipressin to a 59-year-old
`
`man with cirrhosis complicated by diuretic-resistant ascites. Ex. 1004 at p.
`
`2125. The terlipressin was administered as an infusion, at a dose of 3
`
`mg/day for 5 days as an inpatient and for 22 days as an outpatient. Ex. 1004
`
`at p. 2125.
`
`46. FIG. 1 of Robertson shows that serum creatinine decreased following
`
`continuous terlipressin infusion at 3mg/day. Ex. 1004 at p. 2126.
`
`Bolus
`
`Infused
`
`
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`
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`47. As shown above, at the time that the ‘945 patent was filed, it was already
`
`known in the art to treat a patient diagnosed with ascites due to liver
`
`cirrhosis using a continuous infusion dose of terlipressin. Additionally, it
`
`was already obvious that continuous infusion of terlipressin could be used to
`
`reduce the accumulation of ascitic fluid in the abdominal cavity in an
`
`ambulatory ascites patient. Further continuous infusion doses of terlipressin
`
`of from about 1.0 mg to about 12.0 mg per day for about one day to about
`
`twelve months were already known at the time that the ‘945 patent was filed.
`
`48.
`
`It is my experience that journal articles such as Robertson (Ex. 1004),
`
`Angeli (Ex. 1005), Fimiani (Ex. 1006), Krag (Ex. 1010), Salerno (Ex. 1011),
`
`Gerbes (Ex. 1012), Piano (Ex. 1013), Wong (Ex. 1014), and Hsu (Ex. 1015)
`
`would be available to a POSITA online and in standard databases as of their
`
`online publication date. Based on this, these references were publicly
`
`available to POSITAs online, as a print journal, or through publicly available
`
`databases prior to the filing of the ‘945 patent.
`
`VII. Detailed Invalidity Analysis
`
`49.
`
`I have been asked to provide an opinion as to whether or not the Challenged
`
`Claims of the ’945 patent are invalid in view of the prior art. The discussion
`
`below provides a detailed analysis of how the prior art references identified
`
`
`
`
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`above invalidate the Challenged Claims based on the doctrines of
`
`anticipation and obviousness.
`
`50. As part of my anticipation analysis, I have considered whether every
`
`element of the claim is disclosed expressly or inherently in a single prior art
`
`reference.
`
`51. As part of my obviousness analysis, I have considered the scope and content
`
`of the prior art, and whether any differences between the alleged invention
`
`and the prior art are such that the subject matter, as a whole, would have
`
`been obvious to a person having ordinary skill in the art at the time of the
`
`alleged invention. I took the time of the alleged invention to be June 30,
`
`2015, which is the earliest date that could be claimed as the priority date of
`
`the application that issued as the ’945 patent.
`
`52.
`
`I have analyzed the scope and content of the prior art, and performed an
`
`element-by-element comparison of that prior art with the Challenged
`
`Claims.
`
`VIII. Background on the Prior Art References
`
`53. Before providing a detailed analysis of how the prior art invalidates the
`
`challenged claims, I provide a brief summary of the asserted prior art.
`
`
`
`
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`A. Background of Robertson
`
`54. Robertson et al., (hereinafter “Robertson”), entitled “Continuous Outpatient
`
`Terlipressin Infusion for Hepatorenal Syndrome as a Bridge to Successful
`
`Liver Transplantation,” was first published online on May 29, 2014 and
`
`subsequently published in the December 2014 print version of the journal
`
`Hepatology. Ex. 1004. I am one of the co-authors of the Robertson paper.
`
`55.
`
`I have personal knowledge that Robertson (Ex. 1004) was available to a
`
`POSITA as of the online publication date of May 29, 2014 and as was
`
`publicly available to POSITAS online, as a print journal, and through
`
`publicly available databases prior to the filing of the ‘945 patent. Robertson
`
`was published in the journal Hepatology, which is among the most widely
`
`read journals by POSITAs with respect to the treatment of patients having
`
`ascites due to liver cirrhosis.
`
`56. Robertson reports the first use of continuous infusion of terlipressin to treat a
`
`patient diagnosed with ascites due to cirrhosis on an outpatient basis. Ex.
`
`1004 at pp. 2125-2126.
`
`57. Specifically, Robertson reports administering terlipressin to a 59-year-old
`
`man with cirrhosis complicated by diuretic-resistant ascites. Ex. 1004 at p.
`
`2125. The terlipressin was administered as an infusion, at a dose of 3 mg
`
`terlipressin in 50 mL 5% dextrose delivered by a GemStar pump at a rate of
`
`
`
`
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`Page 24 of 90
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`2.1 mL/h, for 5 days as an inpatient and for 22 days as an outpatient. Ex.
`
`1004 at p. 2125. A dose of 3 mg / 50 ml at a rate of 2.1 ml/hr for 24 hours is
`
`3.024 mg per day.
`
`58. FIG. 1 of Robertson shows that serum creatinine decreased following
`
`continuous terlipressin infusion at 3mg/day. Ex. 1004 at p. 2126.
`
`Bolus
`
`Infused
`
`
`
`B.
`
`Background of Angeli
`
`59. Angeli (hereinafter “Angeli”), entitled “Terlipressin for the Treatment of
`
`Hepator