UNITED STATES PATENT AND TRADEMARK OFFICE
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`___________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`LUPIN LTD. and LUPIN PHARMACEUTICALS, INC.
`Petitioner,
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`v.
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`HORIZON THERAPEUTICS, LLC
`Patent Owner
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`Case IPR2017-01159
`Patent 9,254,278
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`PETITIONERS’ MOTION TO EXCLUDE EVIDENCE
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`___________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`LUPIN LTD. and LUPIN PHARMACEUTICALS, INC.
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, LLC
`Patent Owner
`
`
`Case IPR2017-01159
`Patent 9,254,278
`
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`PETITIONERS’ MOTION TO EXCLUDE EVIDENCE
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`I.
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`Statement of Precise Relief Requested
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`Case IPR2017-01159
`Patent 9,254,278
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`Pursuant to 37 C.F.R. § 42.64(c), the Board’s Scheduling Order (Paper 11),
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`and the Federal Rules of Evidence, Petitioners Lupin Ltd. and Lupin
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`Pharmaceuticals, Inc. (collectively, “Petitioners”) hereby move to exclude Patent
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`Owner’s Exhibits 2019 and 2041, and the portions of the Declaration of Dr. Enns
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`(Ex. 2006) that rely on Exhibit 2019.
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`II.
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`Identification of Original Objections
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`On October 13, 2017, Petitioners timely filed objections to Exhibits 2019
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`and 2041. (Paper 12 at 4, 7-8.) Petitioners asserted that Exhibits 2019 and 2041
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`were, inter alia, dated after September 30, 2011, and thus irrelevant and prejudicial
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`under Federal Rules of Evidence (“FRE”) 402 and 403, respectively, to the extent
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`they were relied upon for any teaching prior to September 30, 2011. (Id.)
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`Petitioners also objected to the Declaration of Dr. Enns (Ex. 2006) to the extent it
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`includes or relies on such irrelevant information or information the probative value
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`of which is substantially outweighed by the danger of unfair prejudice, wasting
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`time, or needlessly presenting cumulative evidence. (Id. at 3.)
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`Case IPR2017-01159
`Patent 9,254,278
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`III.
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`Identification of Where Patent Owner Relied Upon Evidence
`A. Exhibit 2019
`Exhibit 2019 is a purported copy of a 2012 article by Häberle et al., entitled
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`Suggested Guidelines for the Diagnosis and Management of Urea Cycle Disorders,
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`published in ORPHANET JOURNAL OF RARE DISEASES.
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`In its Patent Owner’s Response (Paper 19), Patent Owner cited Exhibit 2019 in
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`support of the following assertions regarding the purported common practices of a
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`person of ordinary skill in the art at the time of the alleged invention:
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`• “Clinicians only considered plasma ammonia levels well above the upper
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`limit of normal as cause to take further action.” (Paper 19 at 10.) Dr. Enns
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`made a similar assertion in Ex. 2006 at ¶ 45 (cited at Paper 19 at 10).
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`• “When plasma ammonia levels are above the upper level of normal, which
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`is the highest level of plasma ammonia in the range of normal values, a
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`clinician may take action by initiating further evaluation or a change in
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`treatment.” (Enns Declaration (Ex. 2006) at ¶ 44.)
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`• “Moreover, nothing supports the assumption that a physician would have
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`been concerned or taken any action when a patient had a normal plasma
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`ammonia level; or that the action would be to increase the dosage of
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`nitrogen scavenging medication as opposed to focusing on adjustments to
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`the patient’s diet, health, or amino acid supplements. Dr. Vaux entirely
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`Case IPR2017-01159
`Patent 9,254,278
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`omits any discussion of these standard components of treating a urea cycle
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`disorder patient.” (Enns Declaration (Ex. 2006) at ¶ 92 (citations omitted).)
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`• “A normal level was viewed as acceptable because treating a patient with
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`urea cycle disorder involved such a difficult balance between diet, amino
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`acid supplements, nitrogen scavenging drugs, and the patient’s health. One
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`of ordinary skill treating a patient with urea cycle disorder was constantly
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`concerned about maintaining normal growth and avoiding
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`hyperammonemic episodes.” (Enns Declaration (Ex. 2006) at ¶ 105
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`(citations omitted).)
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`• “In addition, Häberle includes a table of the suggested actions for a POSA
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`to take in rendering treatment to symptomatic patients based on their
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`ammonia level. Notably the Table does not suggest any action when a
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`patient exhibits normal plasma ammonia. When the ammonia level rises to
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`‘above upper limit of normal,’ Häberle recommends stopping protein
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`intake, administering IV glucose, and continued monitoring of plasma
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`ammonia, but significantly does not recommend increasing the dosage of
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`nitrogen scavenging drugs. It is only once the ammonia level rises to the
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`next stage, well above the ULN (>100 μmol/L), that Häberle recommends
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`increasing the dosage of nitrogen scavenging drugs.” (Paper 19 at 26-27
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`(citations and emphasis omitted)). For this proposition, Patent Owner also
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`Case IPR2017-01159
`Patent 9,254,278
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`cited Dr. Enn’s declaration, including ¶ 112, which in turn relies on Exhibit
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`2019.
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`• “Furthermore, the prior art taught clinicians to conduct a holistic evaluation
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`of the patient’s diet, health, and supplements, to avoid unnecessary
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`increases in a patient’s dosage.” (Paper 19 at 28). For this proposition,
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`Patent Owner also cited Dr. Enns’s declaration, including ¶¶ 91-92, which
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`in turn rely on Exhibit 2019.
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`• “While Häberle acknowledges that LPI may cause hyperammonemia in
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`certain cases, it nonetheless expressly excludes LPI from its treatment
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`guidelines for UCDs because of the condition’s only ‘tangential relationship
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`with UCD.’” (Paper 19 at 44.) Dr. Enns made a similar assertion in Ex.
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`2006 at ¶¶ 121-22.
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`Patent Owner and Dr. Enns also cited Exhibit 2019 for the following general
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`propositions regarding urea cycle disorders:
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`• “It is estimated that only one out of 35,000 live births have this disorder,
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`resulting in only 113 new patients in the U.S. per year.” (Paper 19 at 7;
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`Enns Declaration (Ex. 2006) at ¶ 35.)
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`• “Because of the rarity of these disorders (only approximately 113 new
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`patients per year) and high mortality rate, a general pediatrician would not
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`Case IPR2017-01159
`Patent 9,254,278
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`have any exposure to these types of patients.” (Enns Declaration (Ex. 2006)
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`at ¶ 31.)
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`• “But even with frequent monitoring and specialized treatment, even well-
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`controlled UCD patients remain at risk for life-threatening episodic
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`hyperammonemia, which can lead to brain damage, coma and death.”
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`(Paper 19 at 8).
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`• “Even with the benefit of such treatments as alternative pathway therapy,
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`dietary protein restriction, nitrogen scavenging medication and/or amino
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`acid supplementation, patient outcomes remain poor, and inadequate
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`ammonia control and episodic hyperammonemia remain a serious challenge
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`for treatment providers.” (Enns Declaration (Ex. 2006) at ¶ 36).
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`• “Symptoms of this disorder often appear within 24 to 48 hours after a
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`normal birth when a newborn begins to exhibit progressive lethargy,
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`hypothermia, and apnea. Onset of symptoms, however, can appear at any
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`age.” (Enns Declaration (Ex. 2006) at ¶ 36 (citations omitted).)
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`• “The main goal of treatment is therefore a balance between correcting the
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`biochemical issue, preventing the development of hyperammonemia, and
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`ensuring that the patient’s nutritional needs for growth and development are
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`met.” (Enns Declaration (Ex. 2006) at ¶ 37.)
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`Case IPR2017-01159
`Patent 9,254,278
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`• “Chronic treatment of urea cycle disorders primarily involves the use of a
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`low-protein diet, amino acid supplementation, and alternative pathway
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`therapy with nitrogen scavenging drugs.” (Enns Declaration (Ex. 2006) at
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`¶ 38.)
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`• “Dietary treatment is the ‘cornerstone of therapy’ for UCD patients because
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`minimizing protein intake will decrease the nitrogen load on the urea cycle.
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`But protein restriction decreases the nutrients needed for growth and normal
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`development, and therefore essential amino acid supplementation and/or the
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`use of nitrogen scavenging drugs is often necessary to achieve good
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`metabolic control.” (Paper 19 at 8-9 (citations omitted).) Dr. Enns made a
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`similar assertion in Ex. 2006 at ¶ 39 (cited at Paper 19 at 8-9).
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`• “Treatment of a patient with a urea cycle disorder involves lifelong
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`monitoring of growth and development, dietary assessments, and laboratory
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`tests such as plasma glutamine levels, plasma ammonia levels, and amino
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`acid profiles.” (Enns Declaration (Ex. 2006) at ¶ 43.)
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`With respect to these propositions, Patent Owner’s citation of Exhibit 2019
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`is merely cumulative of other cited exhibits and Dr. Enns’s testimony.
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`Case IPR2017-01159
`Patent 9,254,278
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`B.
`Exhibit 2041
`Exhibit 2041 is a purported copy of the Prescribing Information for Ravicti®.
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`Patent Owner cites Exhibit 2041 on page 42 of Patent Owner’s Response (Paper
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`19) in support the following assertion:
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`• “In contrast, the ’859 Publication discusses the oral administration of
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`glyceryl tri-[4-phenylbutyrate], which is approved for the chronic
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`management of UCD patients, but is not indicated for the treatment of acute
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`hyperammonemia.”
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`Dr. Enns did not cite Ex. 2041.
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`IV. Objections and Explanations Thereof
`Exhibits 2019 and 2041 should be excluded for at least the following
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`reasons.
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`A. Exhibit 2019 Should Be Excluded Under FRE 402/403
`Patent Owner attempts to use Exhibit 2019 to prove the state of the art prior
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`to September 30, 2011 (the relevant priority date in this proceeding), specifically to
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`demonstrate that a person of ordinary skill in the art purportedly would not take
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`any treatment action in a UCD patient who has a normal plasma ammonia value.
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`See supra Section III(A). Exhibit 2019 states on its face that it was published on
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`May 29, 2012 (Ex. 2019 at 24), which is several months after the September 30,
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`2011 priority date of U.S. Patent No. 9,254,278 (“the ’278 patent”). In a footnote
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`in its Response, Patent Owner attempts to argue that, while Häberle was published
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`Case IPR2017-01159
`Patent 9,254,278
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`after the priority date of the ’278 patent, “it reflects the knowledge of a POSA prior
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`to the priority date” as it states that the guidelines were developed over a period
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`between October 2008 and August 2011. (Paper 19 at 26, n. 1.) The purported
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`fact that these guidelines were in development prior to the priority date does not
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`demonstrate that these guidelines were part of the state of the art. A POSA would
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`not have known about these guidelines until they were published. Accordingly,
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`Exhibit 2019 is not prior art, and is thus irrelevant for purposes of establishing the
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`purported prior art practices of persons of ordinary skill in the art. To the extent
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`Patent Owner relies on Exhibit 2019 for any other purposes, that reliance is merely
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`cumulative of other evidence on which Patent Owner relies. Having this irrelevant
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`document in the record is prejudicial, as Patent Owner is relying on it for improper
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`purposes.
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`The probative value of Exhibit 2019 is substantially outweighed by the
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`undue prejudice stemming from Patent Owner’s improper reliance on this non-
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`prior art document to show purported prior art practices, and by its cumulative
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`nature. Exhibit 2019 should therefore be excluded under FRE 402 and 403.
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`Exhibit 2041 Should Be Excluded Under FRE 402/403
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`B.
`Patent Owner uses Exhibit 2041 to argue that a person of ordinary skill in
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`the art would not have been motivated to combine Simell (Ex. 1005) with the ’859
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`Publication (Ex. 1007). Patent Owner’s reasoning is that the nitrogen scavenging
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`Case IPR2017-01159
`Patent 9,254,278
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`drugs in Simell, sodium benzoate and phenylacetate, are approved for different
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`indications than one of the nitrogen scavenging drugs discussed in the ’859
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`Publication, glyceryl tri-[4-phenylbutyrate], and that these drugs have different
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`routes of administration. (Paper 19 at 42-43.) In support of this argument, Patent
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`Owner relies in part on Exhibit 2041. But Exhibit 2041 states on its face that it
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`was revised in September 2016 (Ex. 2041 at 1), and fails to indicate its actual
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`publication date, which in any event must be several years after the September 30,
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`2011 priority date of U.S. Patent No. 9,254,278. Accordingly, because Patent
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`Owner has improperly used Exhibit 2041—which is dated after the September 30,
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`2011 priority date of U.S. Patent No. 9,254,278 and is thus not prior art—for the
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`exclusive purpose of establishing purported facts available to persons of ordinary
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`skill in the art as of the priority date, Exhibit 2041 should be excluded as irrelevant
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`and prejudicial under FRE 402 and 403.
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`Portions of Exhibit 2006 Should Be Excluded Under FRE 402/403
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`C.
`Horizon’s expert Gregory M. Enns, MD (Exhibit 2006) relies in part on
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`Exhibit 2019. See Section III(A). As stated above, Exhibit 2019 should be
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`excluded under FRE 402/403 as its probative value is substantially outweighed by
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`the undue prejudice stemming from Patent Owner’s improper reliance on this non-
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`prior art document to show purported prior art practices, and by its cumulative
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`nature. Therefore, to the extent Dr. Enns relies in his declaration on Ex. 2019 (e.g.
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`Case IPR2017-01159
`Patent 9,254,278
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`in Ex. 2006 ¶¶ 31, 35-39, 43-45, 91-92, 105, 112, 121-22), that reliance should
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`similarly be excluded under FRE 402/403.
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`V. Conclusion
`For at least the foregoing reasons, Petitioners respectfully request that this
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`motion be granted and that Patent Owner’s Exhibits 2019 and 2041 be excluded,
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`and that portions of Ex. 2006 be excluded to the extent they rely on Ex. 2019.
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`Dated: May 25, 2018
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`Respectfully submitted,
`/Cynthia Lambert Hardman/
`Elizabeth J. Holland (Reg. No. 47,657)
`Cynthia Lambert Hardman (Reg. No. 53,179)
`GOODWIN PROCTER LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018
`(212) 813-8800 (telephone)
`(212) 355-3333 (facsimile)
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`Counsel for Petitioners
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`CERTIFICATE OF SERVICE
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`Case IPR2017-01159
`Patent 9,254,278
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`The undersigned hereby certifies that PETITIONERS’ MOTION TO EXCLUDE
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`EVIDENCE was served electronically via email on May 25, 2018 on the
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`following:
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`Matthew Phillips (backup counsel, Reg. No. 43,403)
`LAURENCE & PHILLIPS IP LAW LLP
`mphillips@lpiplaw.com
`
`
`Robert Green (Reg. No. 27,555)
`Emer Simic (Reg. No. 61,235)
`Ann Kotze (Reg. No. 76,570)
`GREEN, GRIFFITH & BORG-BREEN, LLP
`rgreen@greengriffith.com
`esimic@greengriffith.com
`akotze@greengriffith.com
`
`
`Dennis Bennett (Reg. No. 34,457)
`GLOBAL PATENT GROUP LLC
`dennisbennett@globalpatentgroup.com
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`Dated: May 25, 2018
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`/Cynthia Lambert Hardman/
`Cynthia Lambert Hardman
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