UNITED STATES PATENT AND TRADEMARK OFFICE
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________________
`
`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED,
`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED,
`PETITIONER,
`PETITIONER,
`
`V.
`v.
`
`BIOVIE, INC.,
`BIOVIE, INC.,
`
`PATENT OWNER
`PATENT OWNER
`
`________________________________
`
`CASE IPR2018-00974
`CASE IPR2018-00974
`PATENT 9,655,945 B2
`PATENT 9,655,945 B2
`
`________________________________
`
`PETITIONER’S OPPOSITION TO
`PETITIONER’S OPPOSITION TO
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________________
`
`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED,
`MALLINCKRODT PHARMACEUTICALS IRELAND LIMITED,
`PETITIONER,
`PETITIONER,
`
`V.
`v.
`
`BIOVIE, INC.,
`BIOVIE, INC.,
`
`PATENT OWNER
`PATENT OWNER
`
`________________________________
`
`CASE IPR2018-00974
`CASE IPR2018-00974
`PATENT 9,655,945 B2
`PATENT 9,655,945 B2
`
`________________________________
`
`PETITIONER’S OPPOSITION TO
`PETITIONER’S OPPOSITION TO
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`PATENT OWNER’S CONTINGENT MOTION TO AMEND
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................ 1
`
`II.
`
`PRIOR ART RENDERS THE PROPOSED SUBSTITUTE CLAIMS
`
`OBVIOUS FOR THE SAME REASONS AS PROVIDED IN THE
`
`PETITION .................................................................................................... 2
`
`A.
`
`Fimiani in view of Robertson or Angeli Renders Obvious
`
`Substitute Claims 15-28 ...................................................................... 2
`
`B.
`
`Ground 2 – Robertson Renders Obvious Substitute Claims 15-
`
`17, 19, 21, 22 and 24 ......................................................................... 18
`
`III.
`
`SUBSTITUTE CLAIMS 15-28 ARE NOT SUPPORTED UNDER 35
`
`U.S.C. 112 .................................................................................................. 21
`
`A.
`
`‘945 Specification Does Not Provide Written Description
`
`Support For Administering Terlipressin as a “continuous
`
`infusion dose of about 1.0 mg…for about one day” for “treating
`
`ascites” (claim 15) or for “reducing the accumulation of ascitic
`
`fluid in the abdominal cavity” (claim 21) .......................................... 21
`
`B.
`
`‘945 Specification Does Not Enable Terlipressin
`
`Administration to Non-HRS (claims 18, 23, 26-28) or Non-
`
`Hospitalized Patients (claims 19, 21-28) to Treat Ascites ................. 24
`
`IV. CONCLUSION .......................................................................................... 25
`
`
`
`
`
`
`ii
`
`
`
`
`
`PETITIONER’S EXHIBIT LIST
`
`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
`
`Exhibit 1005
`
`Exhibit 1006
`
`Exhibit 1007
`
`Robertson, et al., Continuous Outpatient Terlipressin Infusion
`for Hepatorenal Syndrome as a Bridge to Successful Liver
`Transplantation, Hepatology, December 2014, pp. 2125–2126
`(“Robertson”)
`
`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”)
`
`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”)
`
`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
`
`Excerpts of File Wrapper of Application No. 15/198,050,
`which became the ‘945 patent (“the ‘945 file wrapper”)
`
`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”)
`
`Exhibit 1011
`
`Salerno et al., Diagnosis, Prevention and Treatment of
`Hepatorenal Syndrome in Cirrhosis. Gut, 2007, 56:1310-
`
`
`
`
`iii
`
`
`
`
`
`Exhibit 1012
`
`Exhibit 1013
`
`Exhibit 1014
`
`Exhibit 1015
`
`1318. (“Salerno”)
`
`Gerbes et al., Terlipressin for Hepatorenal Syndrome:
`Continuous Infusion as an Alternative to IV Bolus
`Administration, Gastroenterology, 2009, 137: 1179-1189
`(“Gerbes”)
`
`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”)
`
`Wong et al., Working Party proposal for a revised
`classification system of renal dysfunction in patients with
`cirrhosis, Gut, 2011, 60:702-709. (“Wong”)
`
`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”)
`
`Exhibit 1016
`
`Transcript of deposition of Dr. Jaime Bosch taken on May 9,
`2019.
`
`Exhibit 1017
`
`Supplemental Expert Declaration of Dr. Paul Gow
`
`Exhibit 1018
`
`Exhibit 1019
`
`Exhibit 1020
`
`Solanki, et. al., Beneficial effects of terlipressin in
`hepatorenal syndrome: A Prospective, randomized placebo-
`controlled clinical trial, Journal of Gastroenterology and
`Hepatology, 2003, 18, 152-156.
`
`Romanelli et. al., Long-term albumin infusion improves
`survival in patients with cirrhosis and ascites: An unblended
`randomized trial, World Journal of Gastroenterology, 2006,
`12(9):1403-1407 (“Romanelli”)
`
`Kalambokis et. al., Effects of terlipressin on water exceretion
`after oral water load test in nonazotemic cirrhotic patients
`with ascites without hyopnatremia, Scandanavian Journal of
`Gastroenterology, 2010, 45:1509-1515 (“Kalambokis 2010”)
`
`
`
`
`iv
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Petitioner, Mallinckrodt Pharmaceuticals Ireland Limited (“Petitioner”),
`
`provides this Opposition to BioVie Inc.’s (“Patent Owner”) Contingent Motion to
`
`Amend filed on March 7, 2019 (“PO Mot.”). See also Paper #14 at 1 (stipulation of
`
`due date for this Reply).
`
`Patent Owner’s Motion to Amend largely repeats the arguments in the Patent
`
`Owner’s Response. This is because the only substantive amendment is to amend
`
`issued claim 1 to recite what Patent Owner improperly tries to read into claim 1
`
`through claim construction – namely treating ascites. However, the Petition already
`
`addresses how the prior art renders obvious treating ascites.
`
`In addition, the proposed amended claims are unpatentable under 35 U.S.C.
`
`112 for lack of written description and enablement. There is no written description
`
`supporting the proposition that administering “about 1.0 mg [of telripressin]…per
`
`day to the patient for about one day” can treat ascites. In addition, the only written
`
`description for administering terlipressin to treat ascites in non-HRS or non-
`
`hospitalized patients is a research proposal which does not enable the claims
`
`reciting those limitations.
`
`For these reasons, the Board should deny entry of Patent Owner’s Motion to
`
`Amend and find that all substitute claims 15-28 are unpatentable.
`
`
`
`
`
`1
`
`
`
`
`
`II.
`
`PRIOR ART RENDERS THE PROPOSED SUBSTITUTE CLAIMS
`OBVIOUS FOR THE SAME REASONS AS PROVIDED IN THE
`PETITION
`
`The only substantive difference in the substitute claims compared to the
`
`issued claims is the added limitation of “treating ascites” recited in substitute claim
`
`15. See PO Mot. at 28-29. Substitute claims 16-28 are substantively identical to
`
`issued claims 2-15. Id. However, the Petition already explained how Fimiani in
`
`view of Robertson or Angeli renders obvious “treating ascites” in addition to the
`
`un-amended limitations of the substitute claims. See e.g., Petition at 38-39
`
`(“Fimiani discloses that administering terlipressin…reduces peripheral fluid
`
`accumulation as measured by body weight, and reduces the severity of ascites.”);
`
`44-45, 53, and 59. Thus, this opposition will primarily address the issues the Patent
`
`Owner raises in its Motion to Amend.
`
`In addition, the Petition also explained how Robertson renders obvious
`
`administering terlipressin to reduce accumulation of ascitic fluid (with respect to
`
`issued claim 7), which would likewise render obvious the broader limitation of
`
`“treating ascites” now recited in substitute claim 15. The evidence developed
`
`during the course of this proceeding further confirms the correctness of the
`
`Robertson obviousness argument raised in the Petition.
`
`A.
`
`Fimiani in view of Robertson or Angeli Renders Obvious
`Substitute Claims 15-28
`
`Patent Owner raises four arguments with respect to the substitute claims: 1)
`
`
`
`2
`
`
`
`
`
`Fimiani does not teach that terlipressin treats ascites, 2) no motivation to combine
`
`Fimiani with Robertson or Angeli, 3) no reasonable expectation of success, and 4)
`
`“additional considerations.” PO Mot. at 16-25. None of these arguments are
`
`persuasive and each will be addressed in turn below.
`
`1.
`
`treats ascites,
`terlipressin
`teaches
`Fimiani
`reducing ascitic fluid in the abdominal cavity
`
`including
`
`In order to overcome the teachings of Fimiani, Patent Owner tries to read a
`
`requirement into the claims that the treatment must be caused by terlipressin
`
`“alone.” PO Mot. at 16. Even though this is not a requirement of the claims,
`
`Fimiani expressly states that the improvements in ascites were due to the
`
`“synergistic effect of terlipressin.” Ex. 1006 at 589. Patent Owner’s contention that
`
`Fimiani’s statements attributing the ascites improvement to terlipressin are wrong,
`
`contradicting Fimiani and the other evidence of record. Finally, Dr. Bosch’s
`
`testimony regarding Fimiani should be attributed little weight as Dr. Bosch
`
`testified that he “refused to take into consideration” Fimiani as evidence. Ex. 1016
`
`at 104:18-23.
`
`All of these issues are discussed in more detail below.
`
`a) Substitute claims do not require treating ascites (claim 15)
`
`or reduction in ascitic fluid (claim 21) be due to terlipressin
`
`alone
`
`Patent Owner argues that the improvements of ascites provided in Fimiani
`
`are not caused by the terlipressin alone. PO Mot. at 16 and 19 (alleging none of
`
`
`
`3
`
`
`
`
`
`Fimiani, Robertson, or Angeli teach “that continuous infusion terlipressin itself
`
`could have those effects on ascites.”). However, the claims do not require the
`
`treatment or reduction in ascitic fluid be caused by terlipressin alone. Rather the
`
`substitute claims recite a method “comprising administering terlipressin.” PO Mot.
`
`at 30. It is black-letter patent law that “comprising” is an open-ended transition
`
`that means “including but not limited to.” CIAS, Inc.v. Alliance Gaming Corp., 504
`
`F.3d 1356, 1360 (Fed. Cir.2007). In the context of the claims at issue, the claimed
`
`methods include but are not limited to “administering terlipressin.” In other words,
`
`the claims encompass administering other agents, such as albumin and diuretics, in
`
`addition to administering terlipressin.
`
`Neither the Patent Owner nor Dr. Bosch dispute the treatment of ascites in
`
`Fimiani was due to the combination of terlipressin, albumin and diuretics. PO Mot.
`
`at 17 (“the Fimiani authors properly reported that the observed results were the
`
`result of the combination of agents used in the study”); Ex. 2023 at ¶¶105-106 (“it
`
`was the drug combination, rather than terlipressin alone, that was responsible for
`
`the effect observed in Fimiani 2011.”).
`
`In short, there is no dispute that Fimiani’s observed results that terlipressin
`
`treated ascites and reduced the accumulation of ascitic fluid in the abdominal
`
`cavity in at least 16 out of the 26 patients is due to the administration of a therapy
`
`that includes, but is not limited to, terlipressin. See e.g., Pet. at 44-46 (citing Ex.
`
`
`
`4
`
`
`
`
`
`1006 at 588). This is all that substitute claims 15 and 21 require. Therefore, the
`
`Board should find that Fimiani in view of Robertson or Angeli renders obvious
`
`substitute claims 15-28 as set forth herein and in the Petition for issued claims 1-
`
`14. See Pet. at 35-65.
`
`b) Addition of terlipressin caused a “synergistic effect” in the
`
`improvement in ascites
`
`As Dr. Gow explained, a POSITA would have understood the improvements
`
`in ascites found in Fimiani were caused by the inclusion of terlipressin. See e.g.,
`
`Ex. 1002 at ¶38. Indeed, this conclusion is inescapable as the authors of Fimiani
`
`stated on three different occasions that the study shows “a synergistic effect of
`
`terlipressin” when combined with the standard therapy of albumin plus diuretics.
`
`Ex. 1016 at 587 (“In conclusion, our study shows a synergistic effect of terlipressin
`
`vs. treatment with albumin plus diuretics in patients with refractory ascites.”); id. at
`
`589 (“our study shows a synergistic effect of terlipressin when added to albumin
`
`and diuretics in patients with refractory ascites.”); and id. at 590 (“A synergistic
`
`effect of terlipressin vs standard therapy (albumin plus diuretics) in patients with
`
`refractory ascites has been postulated.”).
`
`When questioned on Fimiani’s use of the word synergistic during cross
`
`examination Dr. Bosch acknowledged that, “[t]he word ‘synergistic’ implies that
`
`you have a greater effect by a combination of therapies in that case than by any
`
`single therapy separately.” Ex. 1016 at 95:12-19. Thus, there can be no reasonable
`
`
`
`5
`
`
`
`
`
`dispute that the Fimiani reference expressly teaches that the inclusion of
`
`terlipressin in the therapy led to a greater improvement in the patients’ ascites
`
`compared to the standard therapy of albumin and diuretics that did not include
`
`terlipressin.
`
`Despite the clear statements in Fimiani of terlipressin’s synergistic effect for
`
`improving the treatment for refractory ascites, Patent Owner makes the incredulous
`
`statement that “[t]he Fimiani authors did not (because they could not) state that
`
`terlipressin (or either of the other agents in the treatment regimen) caused the
`
`observed improvements in ascites.” PO Mot. at 17-18. While Patent Owner
`
`wrongly disagrees with the conclusion stated in Fimiani, as discussed in the next
`
`section, it goes beyond the pale to suggest that the authors in Fimiani did not find
`
`that terlipressin caused the observed improvement in ascites. 1
`
`c) Patent Owner’s argument that Fimiani’s conclusion was
`
`wrong is legally irrelevant and incorrect
`
`Instead of crediting the improvements in ascites to the addition of
`
`terlipressin as the Fimiani authors and Dr. Gow concluded, Patent Owner and Dr.
`
`Bosch argue that a POSITA could not have come to that conclusion given the
`
`
`1 While not relied on by Patent Owner, Dr. Bosch’s declaration opines that the
`
`Fimiani authors merely “postulated” the synergistic effect. Ex. 2023, FN 32. This
`
`is untrue as what was “postulated” was the mechanism underlying the synergistic
`
`effect and not its existence. See Ex. 1006 at 589-590.
`
`
`
`6
`
`
`
`
`
`purported “lack of necessary controls” in Fimiani’s study despite Fimiani’s
`
`statement that “the pretreatment period was considered as internal control group.”
`
`PO Mot. at 16-17; see Ex. 1006 at 588.
`
`Before addressing the flaws in Patent Owner’s position, it is important to
`
`note that Fimiani is prior art for all that it teaches, including a conclusion that is
`
`alleged to be based on incomplete data. See Beckman Instruments, Inc. v. LKB
`
`Produkter AB, 892 F.2d 1547, 1551 (Fed.Cir.1989) (“Even if a reference discloses
`
`an inoperative device, it is prior art for all that it teaches”); see also Symbol Techs.
`
`Inc. v. Opticon Inc., 935 F.2d 1569, 1578 (Fed. Cir. 1991) (“A non-enabling
`
`reference may qualify as prior art for the purpose of determining obviousness”).
`
`Thus, even if the Board were to accept the Patent Owner’s position, it is legally
`
`irrelevant as Fimiani’s conclusion that terlipressin caused a synergistic effect in the
`
`treatment of ascites is prior art regardless of purported issues with the control
`
`group in Fimiani’s study.
`
`Turning back to Patent Owner’s argument, Patent Owner argues that Fimiani
`
`does not expressly state what dosage of albumin was provided in the pretreatment
`
`period and that Patent Owner believes the dosage of albumin was lower in the
`
`pretreatment period compared to the study period. PO Mot. at 16-17. Patent
`
`Owner’s position is that during the pre-treatment period Fimiani would have
`
`administered the “standard albumin therapy following their LVP [large volume
`
`
`
`7
`
`
`
`
`
`paracentesis]…of 6-8 grams of albumin per liter of ascitic fluid removed”
`
`compared to the treatment period that provided 12.5 to 25grams of albumin per
`
`day. Id. at 17.
`
`However, this assumption by Patent Owner contradicts the explicit teachings
`
`of Fimiani’s study design. In particular, Fimiani states:
`
`This prospective study was aimed at evaluating whether terlipressin
`
`in addition to standard therapy (diuretics plus albumin) might
`
`improve the outcome of refractory ascites in cirrhotic patients without
`
`HRS.
`
`Ex. 1006 at 588. The use of the phrase “terlipressin in addition to standard therapy
`
`(diuretics plus albumin)” is significant as Fimiani only administered terlipressin
`
`during the treatment period and not the pre-treatment period. Hence, the reference
`
`to “standard therapy (diuretics plus albumin)” is unmistakably referring to the
`
`dosage of diuretics and albumin provided during the treatment period, which is
`
`12.5 to 25grams of albumin per day. Ex. 1006 at 588. Thus, under the Patent
`
`Owner’s very logic that “a POSITA would have understood that those patients [in
`
`the pretreatment period] received standard albumin therapy,” that standard therapy
`
`according to Fimiani was the dosage administered in the treatment period – making
`
`the dosage of albumin in the pre-treatment and treatment periods the exact same.
`
`Patent Owner’s citation to other studies that refer to “6-8 grams of albumin
`
`per liter of ascitic fluid removed” as allegedly showing a universal standard
`
`
`
`8
`
`
`
`
`
`albumin therapy cannot override the express teaching in Fimiani of what Fimiani’s
`
`standard therapy was. See PO Mot. at 16-17. Patent Owner wrongly assumes that
`
`Fimiani’s pre-treatment would have only provided albumin after paracentesis
`
`instead of a daily dose of albumin.2 However, the usage of long term daily dose of
`
`albumin to treat ascites was “widely used in Italy” with 77% of Italian doctors and
`
`79% of Italian hospitals reporting that they did so. Ex. 1019 at 1406 (citing Ex.
`
`2008, Gentilini). Fimiani’s study was performed by Italian doctors at Italian
`
`hospitals. Ex. 1006 at 587.
`
`In fact, as Patent Owner has noted, two studies prior to Fimiani showed
`
`benefits of daily dosages of albumin in the range of 12.5 to 25 grams per day with
`
`diuretics. PO Resp. at 28-29 (“Two papers from 1999 [Gentilini and Schindler]
`
`reported that administration of daily albumin (12.5-22.1g/day) with diuretics was
`
`effective in the treatment of ascites in patients with cirrhosis.”). Fimiani’s authors
`
`would have been aware of the benefits of daily albumin dosage in these previous
`
`studies in establishing the “standard therapy (albumin plus diuretics)” as 12.5-
`
`25g/day of albumin in the Fimiani study. See PO Resp. at 52 (“other information,
`
`including Gentilini and Schindler…was information available to a POSITA (and
`
`
`2 Even if the amount of albumin provided after paracentesis were relevant, Dr.
`
`Gow testified the amount varies between hospitals with the standard at his hospital
`
`being more than the suggested 6-8g. Ex. 2039 at 36:8-17.
`
`
`
`9
`
`
`
`
`
`the Fimiani authors)”); see also PO Mot. at 18.
`
`Finally, it bears noting that literature published after Fimiani cites to Fimiani
`
`for identifying that the addition of terlipressin in the therapy was effective in
`
`treating ascites. Ex. 1015 at 125, Table 1 and 126, Section 4.6 (see FN 30). Indeed,
`
`one review paper provided a “Level of evidence” grade to various studies and gave
`
`Fimiani a grade of B (on an A-B-C scale), which contradicts Patent Owner’s
`
`theory that a POSITA would have considered Fimiani’s study to be so critically
`
`flawed the conclusions reached could not be trusted. Ex. 1015 at 125, Table 1.
`
`In sum, it is legally improper to not consider Fimiani’s conclusion due to an
`
`alleged poor study design as Patent Owner suggests and even if it were proper the
`
`Patent Owner’s criticism of Fimiani’s study are based on an incorrect assumption
`
`of Fimiani’s pre-treatment period that contradicts Fimiani’s express teachings.
`
`d) Dr. Bosch testimony regarding Fimiani should be given little
`
`weight since he “refused to take into consideration” Fimiani
`
`as evidence
`
`When Dr. Bosch was questioned about Fimiani during his deposition, he
`
`stated that “I refuse to take into consideration such evidence” as the Fimiani paper
`
`because it did not show the patients provided consent. Ex. 1016 at 104:18-23 (“this
`
`paper [Fimiani] is not acceptable as to medical evidence because the patients didn't
`
`consent to the treatment…I refuse to take into consideration such evidence.”). Dr.
`
`Bosch also directed numerous personal attacks against the Fimiani authors as being
`
`
`
`10
`
`
`
`
`
`unethical – even going so far as to compare the Fimiani study to “Nazi
`
`experiments” See e.g., Ex. 1016 at 102:17-103:10 (“You know, unethical trials
`
`gave unethical results. This is what they say about the Nazi experiments in the
`
`second world war.”).
`
`Although Petitioner disagrees with the underlying premise of Dr. Bosch’s
`
`testimony, these personal attacks against the Fimiani authors are irrelevant to the
`
`legal question of obviousness. However, they do reflect that Dr. Bosch’s opinions
`
`regarding Fimiani in this proceeding should be accorded little weight due to the
`
`bias Dr. Bosch exhibited against Fimiani’s purported lack of medical ethics, and
`
`particularly given Dr. Bosch’s statement that he “refused to take into consideration
`
`such evidence” as Fimiani.
`
`2.
`
`A POSITA would have been motivated to combine Fimiani
`with Robertson or Angeli
`
`As stated in the petition, a POSITA would have been motivated to substitute
`
`the bolus dose taught by Fimiani with the continuous infusion taught by Robertson
`
`or Angeli to lower the dosage of terlipressin, which increases safety and reduces
`
`cost, while maintaining or improving the effectiveness of the terlipressin. Pet. at
`
`35-36 and 51-53. Patent Owner does not dispute these advantages of continuous
`
`infusion taught by Robertson or Angeli.
`
`Rather, Patent Owner argues that there is no motivation to combine because
`
`a POSITA would not have given terlipressin to Fimiani’s population of non-HRS
`
`
`
`11
`
`
`
`
`
`patients in the first place. Patent Owner reaches this result by reiterating its
`
`argument that Fimiani does not teach that terlipressin treats ascites as well as
`
`suggesting that terlipressin would have been too dangerous to give to Fimiani’s
`
`patients. Both of these assertions directly contradict Fimiani and are inconsistent
`
`with the other evidence of record.
`
`a) Fimiani teaches terlipressin treats ascites
`
`Patent Owner’s first argument is merely a re-iteration of its argument that
`
`Fimiani does not teach that terlipressin treats ascites. PO Mot. at 19-20. As
`
`discussed above, Fimiani teaches terlipressin treats ascites. See Section II(A)(1).
`
`b) Terlipressin was safe enough for Fimiani’s non-HRS patient
`
`population
`
` Patent Owner argues that some literature “cautioned against using
`
`terlipressin in non-HRS patients, such as the patients in Fimiani.” PO Mot. at 20
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`(referring to Exhibit 2011). The significance of Patent Owner’s argument is
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`difficult to understand as there is no dispute that Fimiani teaches administering
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`terlipressin to the patients in his study. Ex. 1006 at 588; see also id. at 589
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`(“During treatment with terlipressin, no significant adverse events were seen.”).3
`
`Moreover, the literature is filled with studies beyond Fimiani where ascites
`
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`3 Further, the reference that Patent Owner refers to was published years before
`
`Fimiani. See Ex. 2011. Patent Owner fails to explain why a POSITA would still
`
`consider those teachings after reading Fimiani.
`
`
`
`12
`
`
`
`
`
`patients without HRS are administered terlipressin, including from the author of
`
`Exhibit 2011 that Patent Owner relies on. See e.g., Ex. 1020 at 1515 (“In
`
`conclusion, terlipressin increases water excretion during a formal water load test in
`
`patients with cirrhosis and ascites without hyponatremia or HRS…”); see also e.g.,
`
`Ex. 1010 at 1870 (“In conclusion, the V1 receptor agonist terlipressin improves
`
`renal function and induces natriuresis in patients with cirrhosis and ascites without
`
`HRS.”).
`
` Likewise, Patent Owner’s argument that “the risks of terlipressin to the
`
`clinically stable patients in Fimiani were greater than the potential benefits of
`
`continuous infusion administration of the drug” contradicts the record. PO Mot. at
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`22. If a bolus dose of terlipressin was safe enough for non-HRS patients (as
`
`Fimiani and other evidence cited above expressly teaches), then the continuous
`
`infusion taught by Robertson or Angeli would have only improved the safety by
`
`lowering the dosage of terlipressin. Ex.1002 at ¶¶158 and 216; Ex. 1004 at 2125;
`
`Ex. 1005 at 241 and 245; see also Ex. 2004 at 13. Patent Owner’s argument is not
`
`about the reason to combine but is instead a thinly veiled attack against Fimiani’s
`
`express teaching to give terlipressin to non-HRS patients.
`
`Notwithstanding the fact that Fimiani itself contradicts Patent Owner’s
`
`argument, a POSITA would have known that terlipressin was widely reported to be
`
`safer than, or as safe as, other alternatives including ornipressin or midodrine with
`
`
`
`13
`
`
`
`
`
`octreotide. Ex. 1017 at ¶6; Ex. 1011 at 1312; Ex. 1018 at 153; Ex. 2004 at 12 and
`
`25. In addition, a POSITA would have been aware of and able to manage
`
`terlipressin’s side effects, which were usually self-limiting and not life threatening.
`
`Ex. 1017 at ¶7-8; See e.g., Ex. 1018 at 155 (“The terlipressin treatment was
`
`associated with transient self-limiting side-effects”). For example, a POSITA
`
`would likely not have administered terlipressin to a patient if the patient exhibited
`
`pre-existing cardiac or ischemic conditions. Ex. 1017 at ¶9; see also Ex. 1006 at
`
`588; Ex. 1005 at 243 (“most studies excluded patients with known severe
`
`cardiovascular or ischemic conditions.”). Further, a patient’s terlipressin dosage
`
`would generally start low and be incremented over time to determine patient
`
`tolerance and minimize side effects. Ex. 1002 at ¶¶254-255; Ex. 1006 at p. 588. As
`
`such, a POSITA would have understood that the risk of administering terlipressin
`
`in patients without severe cardiovascular or ischemic conditions would have been
`
`low enough to warrant administering terlipressin to non-HRS patients to treat
`
`ascites, as disclosed in Fimiani. Ex. 1017 at ¶10.
`
`In addition, a patient would first be monitored in the hospital for any adverse
`
`reactions to terlipressin before being discharged for treatment with terlipressin on
`
`an outpatient basis, such as taught by Robertson. Ex. 1017 at ¶¶11-12; Ex. 1004 at
`
`2125. A POSITA would understand that terlipressin’s vasoconstrictive properties
`
`would affect the patient shortly after administering the drug so that any adverse
`
`
`
`14
`
`
`
`
`
`cardiac or ischemic effect would likely been seen within twenty-four hours. Ex.
`
`1017 at ¶¶11. If a patient exhibits no serious adverse reaction to terlipressin after a
`
`few days of monitoring in a hospital, then a POSITA could discharge that patient
`
`on an outpatient basis without substantial concern of a serious adverse reaction
`
`occurring. Ex. 1017 at ¶12. For example, considering an average of 12% of
`
`patients treated with terlipressin report a severe adverse effect, that would leave
`
`approximately 88% of patients as candidates for outpatient treatment using
`
`terlipressin Ex. 1017 at ¶12; see Ex. 1005 at 243.
`
`Finally, this argument is contrary to the statements in the ‘945 patent that the
`
`continuous infusion of terlipressin could be administered “safely with no serious
`
`side effects” in non-HRS ambulatory patients. Ex. 1001 at 4:25-31. Importantly, as
`
`Dr. Bosch acknowledged, the ‘945 patent uses the same method to administer
`
`continuous infusions of terlipressin that was admitted to be known in the prior art.
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`Ex. 1016 at 48:2-22; see also Ex. 1001 at 2:50-67. Patent Owner cannot credibly
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`argue the methods of administering terlipressin to non-HRS ambulatory patients
`
`was so unsafe at the time of the invention they would not be used, yet magically
`
`those exact same methods became safe “with no serious side effects” when the
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`‘945 patent was filed.
`
`At best, the record reflects that terlipressin had known side effects that
`
`needed to be considered. However, the record also reflects a POSITA would have
`
`
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`15
`
`
`
`
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`been aware of those side effects and could manage them to safely administer
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`terlipressin to both non-HRS patients and outpatients.
`
`3.
`
`A POSITA would have reasonable expectation of success to
`combine Fimiani with Robertson of Angeli
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`Patent Owner argues that neither Robertson nor Angeli teach that terlipressin
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`treats ascites and that “Fimiani does not establish that terlipressin was the cause of
`
`the improvement in ascites.” PO Mot. at 23. This argument is not persuasive as
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`Patent Owner is wrong about Fimiani as discussed above. See Section II(A)(1).
`
`Patent Owner does not contest that administering terlipressin by continuous
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`infusion (taught by Robertson and Angeli) would succeed in treating ascites, if a
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`bolus dose of terlipressin treats ascites (as taught by Fimiani).
`
`Patent Owner also criticizes Petitioner’s reliance on the PharmaIN Press
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`Release because according to Patent Owner the PharmaIN Press Release is based
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`on “speculat[ion].” PO Mot. at 23. This is untrue as the press release notes the
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`FDA granted “orphan-drug designation for terlipressin for the treatment of
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`ascites.” Ex. 1007 at 1. To obtain orphan drug status from the FDA (now and at the
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`time of the PharmaIn Press Release), the sponsor of the orphan drug must disclose
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`“the scientific rationale to establish a medically plausible basis for the use of the
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`drug for the rare disease or condition,” which is more than mere speculation. 37
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`C.F.R. §316.20(b)(4).
`
`In addition, numerous other papers published prior to Fimiani expected that
`
`
`
`16
`
`
`
`
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`terlipressin would treat ascites, expectations that were ultimately proven true by
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`Fimiani’s study. Ex. 2027 at 403, Section 2.2.5 (“Other treatments” for refractory
`
`ascites include “terlipressin”); Ex. 1010 at 1870 (vasoconstrictors including
`
`terlipressin “may represent a novel future treatment” for patients with cirrhosis and
`
`ascites without HRS); and Ex. 1020 at 1515 (terlipressin could benefit prognosis of
`
`“patients with cirrhosis and ascites without hyponatremia or HRS”).
`
`4.
`
`Patent Owner’s “Additional Considerations” are Not
`Persuasive
`
`Patent Owner appears to argue that there existed “long-felt and unmet”
`
`needs, but other than citing case law, provides no evidentiary support of such a
`
`position or what needs were supposedly “long-felt and unmet.” PO Mot. at 24.
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`Prior to the ‘945 patent, terlipressin had been identified along with numerous other
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`pharmacological treatments for the treatment of ascites. Ex. 1015 at 125, Section
`
`4.4 and Table 1 (drugs counteracting “the main cause of ascites formation” include
`
`“albumin, terlipressin, satavaptan, midodrine, and nonselective β-blocker.”); see
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`also Ex. 2027 at 403, Section 2.2.5; Ex. 1007 at 1; Ex. 1006 at 588.
`
`Finally, Patent Owner’s reliance on the CONFIRM trial is misplaced. PO
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`Mot. at 24 (citing Ex. 2005 and 2006). First, Patent Owner admits this evidence
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`post-dates the time of the invention, so it is unclear how it impacts the obviousness
`
`analysis at the time of the invention. Second, the mere fact that a study unrelated to
`
`Fimiani uses bolus over continuous infusion is not evidence relevant to whether a
`
`
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`17
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`
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`POSITA would use continuous infusion in combination with Fimiani’s teaching
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`for the reasons provided in the Petition (such as for safety, cost savings, etc.).
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`B. Ground 2 – Robertson Renders Obvious Substitute Claims 15-17,
`19, 21, 22 and 24
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`The only issue Patent Owner raises with respect to Robertson is if a POSITA
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`would find that improving the renal function of Robertson’s patient, as evidenced
`
`by reduced serum creati
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