`UNITED THERAPEUTICS CORPORATION
`
`IPR2016-00006
`U.S. Patent No. 8,497,393
`November 29, 2016
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`
`
`Petitioner Bears the Burden of Proving Invalidity
`
`• “In an inter partes review, the burden of persuasion is on the
`petitioner to prove ‘unpatentability by a preponderance of the
`evidence,’ 35 U.S.C. § 316(e), and that burden never shifts to the
`patentee.”
`•
`In re Magnum Oil Tools International, Inc. (Fed. Cir. 2016), citing Dynamic Drinkware, 800 F.3d at 1378; Paper No. 48.
`• “[T]he petitioner continues to bear the burden of proving
`unpatentability after institution, and must do so by a preponderance
`of the evidence at trial.”
`
`•
`• “[T]he Board has an obligation to assess the question anew after trial
`based on the totality of the record.”
`
`In re Magnum Oil Tools International, Inc. (Fed. Cir. 2016); Paper No. 48.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`•
`
`Id.
`
`2
`
`
`
`Prior Art at Issue
`
`• The only prior art treprostinil examples in this IPR are (a) the
`single example in Moriarty 2004 of treprostinil acid (Ex. 1004, p.
`13) and (b) the single example in Phares WO 2005/007081 of
`diethanolamine salt of treprostinil, form B (Ex. 1005, pp. 87-88).
`
`• Kawakami and Ege do not disclose treprostinil or any prostacyclin
`derivative and do not disclose how to purify such compounds
`specifically.
`
`• To the extent Petitioner’s evidence shifts burden of production,
`Patent Owner need only present sufficient evidence to rebut that
`evidence relied upon by Petitioner.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`3
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`
`
`Claim Construction in an IPR Analysis
`
`•
`
`“While it is true that, as a general rule, the words of a patent claim are to
`be given their plain, ordinary and accustomed meaning to one of ordinary
`skill in the relevant art, Toro Co. v. White Consol. Indus., Inc., 199 F.3d
`1295, 1299 (Fed. Cir. 1999), a court must nevertheless examine the
`remaining intrinsic evidence to determine whether the patentee has set
`forth an explicit definition of a term contrary to its ordinary meaning, has
`disclaimed subject matter, or has otherwise limited the scope of the
`claims.”
`•
`Day Intern., Inc. v. Reeves Brothers, Inc., 260 F.3d 1343, 1349 (Fed. Cir. 2001) (emphasis added) (PO Resp. at pp. 13-14).
`• The Federal Circuit in SafeTCare Mfg incorporated limitations into claim
`construction where the specification repeatedly indicated that the
`invention operated by “pushing (as opposed to pulling) forces,” and then
`characterized the “pushing forces” as “an important feature of the
`present invention.”
`•
`SafeTCare Mfg., Inc. v.Tele-Made, Inc., 497 F.3d 1262, 1269-70 (Fed. Cir. 2007)(PO Resp. at p. 14).
`
`
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`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`4
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`
`
`Proper Claim Construction Requires Consideration of
`Impurities Present In The Product
`
`Example 6 in the ’393 Patent specification
`indicates the purity of a working example of
`the invention is 99.9% whereas purity of
`former Moriarty product was ~99.0%
`
`• Ex. 1001, 17:step 53. (PO Resp. at p. 16)
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`IPR2016-00006
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`5
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`
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`Proper Claim Construction Requires Consideration of
`Impurities Present In The Product
`
`•
`
`’393 patent specification further
`identifies differences in impurities
`
`“impurities carried over from intermediate
`steps (i.e., alkylation of triol and hydrolysis of
`benzindene nitrile) are removed during the
`carbon treatment and salt formation step”
`
`•
`
`Ex. 1001, 17:29-32.
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`IPR2016-00006
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`6
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`
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`Proper Claim Construction Requires Consideration of
`Impurities Present In The Product
`• Prosecution history clarified that impurity profiles were
`important to the claimed invention
`•
`“[e]ach of treprostinil as the free acid and treprostinil diethanolamine
`prepared according to the process specified in claim 1 or 10 . . . is
`physically different from treprostinil prepared according to the
`process of ‘Moriarty’ due to differences in their impurity profiles.”
`•
`Ex. 1002 at 344. (emphasis added) (PO Resp. at p. 16)
`• UTC thereafter filed the Walsh Declaration, which demonstrated that
`the claimed product had a different impurity profile and higher purity
`than a representative batch of Moriarty’s product.
`•
`Ex. 1002 at 347-349. (PO Resp. at p. 16)
`• Claims allowed within eight days of the submission of Walsh’s
`Declaration demonstrating differences in impurities.
`
`•
`
`Id. at 354.
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`IPR2016-00006
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`
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`Proper Claim Construction Requires Consideration of
`Impurities Present In The Product
`
`• The ’393 patent specifically distinguishes the purification
`limitation [eliminating purification after step (a) as required in
`claims 8 & 16] over the prior art. Ex. 1001, Example 6.
`Moriarty expressly discloses that the compound of formula
`(VI) from step (a) is purified.
`
`•
`Ex. 2020 at ¶104; PO Resp. at p. 32.
`• No evidence from Petitioner of the impact of eliminating
`column purification step from Moriarty 2004 publication; the
`only direct comparative evidence in the record for claims 8
`and 16 is Ex. 6 in ‘393 patent.
`
`•
`
`Ex. 2020 at ¶104; PO Resp. at p. 32.
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`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`8
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`Phares Does Not Anticipate Any ’393 Patent Claim
`
`• Phares was disclosed on the face
`of the ’393 patent
`• Phares fails to disclose any
`detailed synthesis of treprostinil
`• Phares fails to disclose any
`impurity or impurity profile for
`treprostinil or treprostinil
`diethanolamine
`• Phares fails to disclose any purity
`level for treprostinil
`diethanolamine
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`
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`Synthesis Disclosed In Phares Is Not For Treprostinil
`
`• Dr. Williams confirmed the synthesis in
`Phares is for the enantiomer of
`treprostinil, a different product.
`•
`Ex. 2059, 264:13-265:18; 265:20-23; Ex. 2020 ¶79
`• Phares fails to disclose the source of
`treprostinil used in single step example
`making treprostinil diethanolamine.
`•
`Ex. 1005, p. 24; Ex. 2020, ¶79.
`• Only reference to treprostinil synthesis
`in Phares is to early syntheses
`resulting in impure substances.
`•
`Ex. 1005, p. 9; Ex. 2020, ¶78.
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`IPR2016-00006
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`10
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`Phares Fails to Disclose Purity of Treprostinil Diethanolamine
`
`• Dr. Williams confirmed broad approximate 10 degree melting point range
`from Phares indicated a less pure substance. Ex. 2020, ¶76.
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`11
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`
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`Phares Form B Diethanolamine Salt Example Is Not the
`Same as the ’393 Patent Product
`
`Williams’ Declaration
`
`Rogers’ Declaration
`
`Melting point range is “broad” (¶ 76)
`
`Melting Point range is “narrow” (¶ 87)
`
`Cites to Marti reference (Ex. 2031) (¶ 76) NO SUPPORT
`
`Conclusion: Cannot determine purity
`from melting point range of Phares (¶ 76)
`
`Conclusion: Phares at least as pure as
`‘393 (¶ 88)
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`UT Ex. 2061
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`IPR2016-00006
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`Phares Does Not Anticipate Any Claim of the ’393 Patent
`
`• Petitioner’s expert Dr. Rogers acknowledges Phares form B has a
`different melting point range than the ‘393 patent products and “[a]ny
`difference in their measured melting point, Ts, is due to differing levels
`of impurities.”
`
`•
`Ex. 1022, ¶72 and 82
`• Phares form B sample made for polymorph screen by a very different
`process that converts to form B from form A, it is not clear where the
`specific batch of form B used for analysis came from, and is not a large
`scale batch.
`
`•
`Ex. 2020, ¶73; PO Resp., p. 25.
`• Petitioner has failed to show the Phares product is the same as the
`products disclosed in the ’393 patent.
`
`•
`
`PO Resp. at pp. 22-26.
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`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`13
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`Phares and Moriarty Do Not Render the ’393 Claims Obvious
`
`• Moriarty was disclosed on the face
`of the ’393 patent
`• Moriarty fails to disclose steps (c)
`or (d) from the ’393 patent in the
`synthesis of treprostinil and does
`not disclose treprostinil
`diethanolamine
`• Moriarty fails to disclose any
`impurity or impurity profile for
`treprostinil
`• Purity level disclosed in Moriarty
`cannot be compared to ’393
`Patent purity
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
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`14
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`
`
`Winkler Improperly Compared Purity Levels
`
`• “When purity is determined by comparison of a sample to a
`reference standard such as assay purity, one cannot directly
`compare the purity values of two samples in any meaningful way
`unless each value was achieved by comparison to the same
`reference standard. Neither the Walsh Declaration nor Moriarty
`identifies a specific reference standard.” (emphasis supplied)
` Ex. 2034, pp. 28-29; Ex. 2035, pp. 5-8; Ex. 2020, ¶ 88; PO Resp., pp. 2, 29
`
`
`• Moriarty 2004 purity of “99.7%” cannot be compared to Walsh,
`‘393 data or any FDA data in the record.
`
`•
`
`Ex. 1004, p. 13
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`UT Ex. 2061
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`IPR2016-00006
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`
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`Winkler Improperly Compared Purity Levels
`
`• Winkler mistakenly thought that an “assay” purity in the ‘393
`patent represented HPLC error rate rather than a relative
`purity level compared to a reference standard, which gave rise
`to his further misunderstanding about the Walsh Declaration,
`the ‘393 specification, & Moriarty purity measurements.
`•
`Ex. 1001, col. 13, l. 2; Ex. 2020 ¶¶ 89-93; PO Resp. at pp. 29-30
`• Winkler later acknowledged that assay purity determinations
`over 100% and FDA purity measurement limits are valid;
`however, the Institution Decision was based on Winkler’s
`erroneous initial purity conclusions.
`•
`PO Response at 3; Ex. 2051 at 64:7-9; Paper No. 12 at pp. 8, 17, 19, 48
`
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`SteadyMed v. United Therapeutics
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`IPR2016-00006
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`16
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`Winkler Improperly Compared Purity Levels
`
` Dr. Wiliams: “the level of detection for measuring impurities in
`these treprostinil samples was somewhere between 0 and 0.05%,
`not something in excess of 0.4% as Dr. Winkler erroneously
`concludes” (emphasis supplied).
`
` Ex. 2020, at ¶92; PO Resp. at p. 3
` Dr. Ruffolo: the Certificates of Analysis purity data presented in the
`Walsh, Ruffolo and Williams Dec.’s is the same data required by
`FDA in its purity specification for treprostinil and relied upon by UT
`to comply with FDA’s requirements .
` Ex. 2022 at ¶32; Ex. 2020 at ¶94; PO Resp. at pp. 3-4
`
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`UT Ex. 2061
`SteadyMed v. United Therapeutics
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`IPR2016-00006
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`17
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`Petitioner Bears the Burden of Proving Invalidity
`
`• Institution Decision was based on Winkler’s erroneous initial
`purity conclusions (Paper No. 12 at pp. 8, 17, 19, & 48)
`• ‘393 comparative data, FDA data submitted in this IPR & Walsh’s
`Declaration should all be credited over Winkler’s debunked
`Declaration/misunderstanding of purity
`• When Winkler’s mistaken testimony about purity levels is
`removed, Petitioner has not carried its threshold burden
`
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`UT Ex. 2061
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`IPR2016-00006
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`18
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`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Dr. Williams analyzed over 170 batches of treprostinil and treprostinil
`diethanolamine made by either the Moriarty process or the ’393 patent
`process to analyze impurities and total related substances
`
`•
`
`Ex. 2020, ¶¶94-98
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`IPR2016-00006
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`19
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`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Greater than 100 fold reduction in 1AU90 and 2AU90 impurities
`•
`Ex. 2020, ¶¶94-98
`
`
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`20
`
`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Twenty fold reduction in methyl ester impurity
`
`
`
`•
`
`Ex. 2020, ¶¶94-98
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`IPR2016-00006
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`21
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`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Significant reductions in 750W93, 751W93, and 3AU90 impurities
`• 97W86 impurity eliminated in ’393 patent process
`
`
`
`•
`
`Ex. 2020, ¶¶94-98
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`IPR2016-00006
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`22
`
`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Overall reduction in impurities by approximately 0.7%
`•
`Ex. 2020, ¶¶94-98
`
`
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`IPR2016-00006
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`23
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`
`
`Significant Differences Exist Between Batches Made by the
`’393 Patent and Moriarty Processes
`
` Moriarty Process Impurities (Average Percent Detected)
`
`751W93
`750W93
`3AU90
`2AU90
`1AU90
`0.1025
`0.1646
`0.2545
`0.0407
`0.0473
`’393 Patent Process Impurities (Average Percent Detected)
`
`97W86
`0.0405
`
`ethyl ester methyl ester
`0.0889
`0.1028
`
`1AU90
`0.0004
`
`2AU90
`0.0004
`
`3AU90
`0.0455
`
`750W93
`0.0643
`
`751W93
`0.0488
`
`97W86
`0
`
`ethyl ester methyl ester
`0.1208
`0.005
`
`Total Related
`Substance
`0.9545
`
`Total Related
`Substance
`0.2944
`
`• Ethyl ester actually increased in ’393 patent demonstrating
`another difference between the ’393 and Moriarty batches
`•
`Ex. 2020, ¶¶94-98
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`24
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`
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`‘393 Product Has Higher Ethyl Ester Impurities Than
`Moriarty
`
` • Dr. Williams also found that ethyl ester unexpectedly increased
`in the ‘393 product of the batches he reviewed compared to the
`Moriarty batches he reviewed
`
`•
`
`Ex. 2020, ¶¶94-98; PO Resp. at p. 10
`
`
`• This point is not challenged by Petitioner
`
`‘393 product is different regardless of claim construction due to
`higher impurity level of ethyl ester compared to Moriarty
`
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`25
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` •
`
`
`
`Petitioner Challenges Averages But Ignores Other Evidence
`Supporting Williams Declaration
`
`• “Looking past the average data, it is also worth noting that, out of
`all the batches of treprostinil product made by the ’393 patent
`process which I reviewed, 1AU90 was only detected in a single
`batch (01A07001) and 2AU90 was also only detected in a single
`batch (01A07003), and both impurities were only detected at a
`level of 0.05% or less. Furthermore, batches 01A07001 and
`01A07003 were both identified as ‘optimization batches’ (as
`distinguished from commercial batches).” (emphasis supplied).
`•
`Ex. 2020 at ¶ 97, PO Resp. at p. 4
`
`
`• Dr. Williams relied on these individual impurity values and trends,
`not just calculated averages to support his conclusion that the
`products are different.
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`UT Ex. 2061
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`IPR2016-00006
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`26
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`
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`Petitioner Challenges Averages But Ignores Other Evidence
`Supporting Williams Declaration
`
`• “the averages presented in the Process Optimization Report still
`show significant differences between ’393 treprostinil products
`and the Moriarty treprostinil products. Specifically, Table 2 of the
`Process Optimization Report shows that on average 97W86 was
`detectable in these 96 batches, and that these 96 batches
`contained higher average levels of 3AU90, 750W93, 751W93, and
`total impurities as compared to the averages for the ’393
`treprostinil product. Ex. 2005 at 7; Appendix B. ” (emphasis
`supplied) .
`
`•
`
`UT Ex. 2005, at 7; Ex. 2020 at footnote 1
`
`
`• These 96 batches relied upon by Williams were not used in the
`other average calculations criticized by Petitioner for including
`development batches.
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`
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`Petitioner Objects To Admissibility Of Certain Moriarty
`Batches But Filed No Motion To Exclude Them
`
`• Petitioner’s Reply objects to relevance of certain Moriarty
`batches, but yet Petitioner filed no Motion to Exclude as to
`this evidence.
`
`•
`Paper No. 52, p. 7.
`• However, Petitioner also objected to relevance of the
`Moriarty batches in its evidentiary objections, in response to
`which Patent Owner supplemented the record with
`authenticating Declarations.
`
`•
`Ex. 2052; Paper No. 43, p. 11.
`• Petitioner cannot maintain its position on lack of relevance
`after objecting and then failing to move to exclude, depriving
`Patent Owner of its right to rely on timely served
`supplemental evidence.
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`
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`[intentionally left blank]
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`[intentionally left blank]
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`Additional Comparative Data in Dr. Williams Declaration Stands
`Unchallenged By Petitioner and Confirms Dr. Williams Conclusions
`
`
`
`•
`
`Ex. 2005 at 7; Ex. 2020 at FN 1.
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`
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`Additional Comparative Data in Dr. Williams Declaration Stands
`Unchallenged By Petitioner and Confirms Dr. Williams Conclusions
`
`• The averages of impurities presented in the Process
`Optimization Report analyzing 96 Moriarty batches also show
`significant differences between ’393 treprostinil products and
`the Moriarty treprostinil products.
`
`•
`
`Ex. 2005 at 7; Ex. 2020 at FN 1.
`
`
`• These 96 batches contained higher average levels of 3AU90,
`750W93, 751W93, and total impurities as compared to the
`averages for the ’393 treprostinil product and lower overall
`average impurities.
`
`•
`
`Ex. 2005 at 7; Ex. 2020 at FN 1.
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`32
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`
`FDA Expressed a Long-Felt Need For Each Individual
`Known Impurity To Be Minimized
`
`• Each of the known impurities are “sources of potential
`adverse toxicities to patients. Impurities, therefore, can only
`add to the risk assessments, which are often unknown, made
`by regulatory agencies in the evaluation of new drug
`products.”
`
`•
`Ex. 2040 at 3-4 and 5-8; Ex. 2022 at ¶ 36; PO Resp. at p. 7.
`• Even trace impurities can pose serious health risks.
`•
`Ex. 2022 at ¶ 40; PO Resp. at p. 12.
`• To FDA, a product is different if it presents a reduced risk
`profile due to reduced amounts of individual known
`impurities, even if there is currently no known adverse effect
`in patients attributable to those impurities.
`•
`Ex. 2022 at ¶ 36; PO Resp. at pp. 7-8.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`33
`
`
`
`
`
`The ’393 Patent Met the Long-Felt Need of Improved Purity
`
`• Patent Owner requested and FDA approved a higher purity
`specification to reflect the treprostinil product resulting from
`Patent Owner’s switch to the ‘393 patent steps.
`•
`Ex. 2006, 2003; PO Resp. at p. 12.
`
`
`• “[W]hile FDA approval is not determinative of
`nonobviousness, it can be relevant in evaluating the objective
`indicia of nonobviousness.”
`•
`Knoll Pharm. Co., Inc. v. Teva Pharm. USA, Inc., 367 F.3d 1381, 1385 (Fed. Cir. 2004); PO Resp. at p. 48.
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`34
`
`
`
`The ’393 Patent Met the Long-Felt Need of Improved Purity
`
`• FDA initially rejected UT’s requested purity specification change, leading
`to resubmission with additional evidence.
`•
` Ex. 2006 at 1; Ex. 2022 at ¶ 66; PO Resp. at pp. 12 and 48.
`• “any change in the synthesis or manufacture of the drug substance that
`may affect its impurity profile and/or the physical, chemical, or biological
`properties of a drug is considered a major change.”
`•
`Ex. 2050 at 17. (emphasis added); Ex. 2022 at ¶72; PO Resp. at p. 12.
`• “Because the FDA allowed the drug specification for purity to be changed
`to reflect the higher level of purity, from a lower level of 97% to 98%,
`around means of 99% to 100%, respectfully, resulting from the ‘393
`patent process, it is clear that the FDA considered this to represent a
`major/significant change.”
`
`•
`
`Ex. 2022 at ¶72; PO Resp. at p. 12.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`35
`
`
`
`[intentionally left blank]
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`36
`
`
`
`[intentionally left blank]
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`37
`
`
`
`FDA’s Drug Purity Specifications Are Rigorously Analyzed &
`Commercially Important
`
`• Purity data must be prepared according to detailed FDA
`guidelines.
`•
`Ex. 2022, ¶53, citing: Ex. 2006 p. 6, Ex. 2044 pp. 34-35, and Ex. 2035 pp. 8-11
`• UT’s data had to meet these requirements.
`
`•
`Ex. 2022 ¶ 57
`• If a Certificate of Analysis for a batch does not meet the FDA’s
`purity specification in any aspect, it cannot be sold for use by
`patients.
`
`•
`
`Ex. 2022 ¶ 32; PO Resp. p. 12
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`38
`
`
`
`’393 Patent Product Is Structurally Different Regardless Of
`Batch-To-Batch Variability In Starting Material
`
`• Petitioner has not established that any specific batch
`of Moriarty treprostinil is not physically changed by
`performing step (c), and all the evidence suggests
`that it is.
`
`PO Resp. at p. 12
`
`•
`• Petitioner presents no test data of its own.
`• The FDA agreed that the evidence presented by the
`Patent Owner in this IPR warranted a change in
`purity specification.
`•
`
`PO Resp. at p. 12; Ex. 2006 at 4-6; Ex. 2022 at ¶¶66-72.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`39
`
`
`
`The ’393 Patent Product Is Structurally Different Regardless
`Of Batch-To-Batch Variability In Starting Material
`
`• “The chemical manufacturing steps have not changed during the
`transfer to [supplier A] and [supplier B] from the process used by
`UT in Chicago to prepare benzindene triol.”
`
`•
`Ex. 2006 at 3.
`• “There is a release specification for benzindene triol that must be
`achieved for each lot of benzindene triol before it is released for
`use by UT to prepare treprostinil. This is the same specification
`that was used by United Therapeutics in our Chicago facility.”
`
`•
`• “In all lots [of benzindene triol from suppliers A, B, C, and D], the
`total unidentified impurity level (%AUC) decreased from triol [step
`(a)] to UT-15C intermediate [step (c)].”
`
`Id.
`
`•
`
`Id.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`40
`
`
`
`Winkler Fundamentally Misunderstood Certain Purity
`Measurements
`
`• The level of detection for measuring impurities in these
`treprostinil samples was somewhere between 0 and 0.05%, not
`something in excess of 0.4% as Dr. Winkler erroneously concluded.
`Ex. 2020 at ¶92; PO Resp. at p. 3.
`•
`• The Certificates of Analysis purity data presented in the
`declarations of Drs. Walsh and Williams is the same data required
`by FDA in its purity specification for treprostinil and relied upon by
`UT to comply with FDA’s requirements
`•
`Ex. 2022 at ¶32; Ex. 2020 at ¶94; PO Resp. at pp. 3-4.
`• Walsh’s Declaration should be credited over Winkler’s debunked
`Declaration/misunderstanding of purity
`• Petitioner did not depose Dr. Walsh, a further reason to credit Dr.
`Walsh’s Declaration over Dr. Winkler
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`41
`
`
`
`
`
`Petitioner’s Expert Dr. Winkler Fundamentally Misunderstood
`Certain Purity Measurements
`
`• Dr. Winkler mistakenly thought that an “assay” purity in the
`’393 patent represented HPLC error rate rather than a relative
`purity level compared to a reference standard, which gave
`rise to his further misunderstanding about the Walsh
`Declaration, the ‘393 specification, & Moriarty purity
`measurements.
`
`Ex. 2020 at ¶¶ 89-93; PO Resp. at pp. 29-30.
`•
`• Winkler later acknowledged that assay purity determinations
`over 100% and FDA purity measurement limits are valid,
`however, the Institution Decision was based on Dr. Winkler’s
`erroneous initial purity conclusions.
`•
`PO Response at 3; see also Ex. 2051 at 64:7-9; Paper No. 12 at pp. 8, 17, 19, & 48.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`42
`
`
`
`Claims 6,10, 15, 21, & 22 Are Not Obvious
`
`• Only instituted ground for claims 6, 10, 15, 21, and 22 is
`obviousness based on Moriarty, Phares, Kawakami & Ege
`Institution Decision at 37.
`•
`• “the absence of a known or obvious process for making the
`claimed compounds overcomes any presumption that the
`compounds are obvious based on close relationships between
`their structures and those of prior art compounds.”
`•
`In re Hoeksema, 399 F.2d 269, 274 (C.C.P.A. 1968); PO Response at p. 45.
`• Petitioner fails to provide any motivation or reason a POSA
`would look to Kawakami or Ege to purify treprostinil or any
`related prostacyclin.
`
`•
`
`PO Resp. at pp. 34-44.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`43
`
`
`
`
`
`No Reasonable Expectation To Further Purify Moriarty
`By Combining Phares, Ege, & Kawakami
`
`• Petitioner contradicts itself by asserting that Moriarty is
`already as pure as the ‘393 product, but yet a POSA would be
`motivated to apply further purification efforts to Moriarty
`based on Phares, Ege & Kawakami.
`•
`Compare Petitioner Reply at 4-6 and 19-20.
`• Kawakami relates to use of a different salt to purify a different
`impurity present in a much larger amount (at least 22.8%) in a
`different compound
`
`•
`PO Response at pp. 39-44.
`• A POSA would have no reason to turn to Kawakami or Ege
`given these differences.
`
`•
`
`Ex. 2020 at ¶ 106, PO Response at p. 37.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`44
`
`
`
`A POSA Would Not Turn to Kawakami
`
`•
`
`• Kawakami uses a different salt to
`remove a different sort of impurity
`from a different structure.
` a POSA would have no reason to
`combine the teachings of Kawakami
`with Moriarty and Phares in the
`particular manner of the asserted
`grounds in the Petition, or a
`reasonable expectation of success
`of achieving a more pure
`treprostinil product by such a
`combination.
`•
`
`Ex. 2020 ¶114; PO Resp. at p. 41.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`45
`
`
`
`
`
`Kawakami Teaches Away From Claim 15
`
`• Petition selectively uses
`Kawakami only for teaching
`regenerating the acid after salt
`formation, while ignoring the
`fact that it suggests using a
`different salt than what is taught
`by Phares for the purpose of
`purifying a much less pure
`starting material.
`
`•
`
`PO Resp. at p. 41.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`46
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Petitioner alleged that Williams did not know
`if 10 data points in his analysis were produced
`under the Moriarty process.
`• Petitioner’s Reply pp. 2 & 6.
`• Dr. Williams clarified on redirect that they
`“were made by the Moriarty process.”
`• Ex. 2059, 254-256.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`47
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Petitioner also falsely alleged that the Moriarty
`batches were “cherry-picked” by including
`developmental batches with poor results.
`•
`Petitioner’s Reply pp. 2 & 6.
`• Dr. Williams clarified that he relied on Dr. Aristoff’s
`selection of Moriarty batches from a separate case,
`United Therapeutics v. Sandoz.
`
`•
`• Those same batches were previously used to show
`how good the Moriarty batches were compared to a
`previous method.
`
`Ex. 2059, 94:29-95:9.
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`48
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• In United Therapeutics v. Sandoz, Inc., the Court ruled that the
`same Moriarty batches used by Dr. Williams had fewer
`amounts of impurities and a lower amount of total related
`substances over batches made by the prior art.
`•
`2014 WL 4259153, C.A. Nos. 12–CV–01617, 13–CV–316 (D.N.J. August, 29, 2014).
`
`
`• Dr. Williams also clarified that developmental batches for
`both the Moriarty and ’393 patent process were used in his
`analysis.
`
`•
`
`Ex. 2059, 101:21-102:13.
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`49
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Petitioner also alleged that Dr. Williams “had no explanation
`for why he included 10 development batches… for his analysis
`of Moriarty batches, but only 5 development batches… for his
`analysis of ‘393-Patent batches”.
`
`•
`
`Petitioner’s Reply p. 7.
`
`
`• But Dr. Williams actually testified that “these were all the
`batches we could find records for”.
`
`•
`
`Ex. 2059, 94:25- 95:9
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`50
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Dr. Williams’ testimony stated only that calculation was
`correct, not that it was a “a fair analysis” as claimed in
`Petitioner’s reply.
`
`•
`
`Ex. 2059 p. 219; Petitioner’s Reply p. 2
`
`
`• Petitioner also alleged that Dr. Williams testimony suggested
`that Steadymed’s calculation of 99.7% “should be relied
`upon.” Dr. Williams merely confirmed that calculation was
`correct using Steadymed’s selected numbers.
`•
` Petitioner’s Reply pp. 2-3;
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`51
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Petitioner also alleged that Dr. Williams did not perform
`calculations on data in Appendices A and B of his declaration,
`“having relied solely on counsel’s work”. Dr. Williams actually
`testified that he “checked the calculation” performed by
`counsel.
`
`•
`
`
`
`Petitioner’s Reply pp. 8-9; Ex. 2059, 102:12-20
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`52
`
`
`
`Petitioner Mischaracterizes Dr. Williams Testimony Regarding Batch
`Analysis
`
`• Petitioner also alleged that the free acid is less pure than the
`diethanoleamine salt, and not more pure as UT represented
`to the FDA in Exhibit 2006. Dr. Williams could not provide an
`explanation for this discrepancy, which contradicts the Walsh
`Declaration. Dr. Williams stated that this wasn’t something he
`considered in forming his opinion, and that he’d need more
`time to consider it; he simply wasn’t able to provide an
`immediate explanation.
`•
`Petitioner’s Reply p. 12; Ex. 2059, 199:6-18; Ex. 2059, 198:1-199:5, 199:19-21
`
`
`
`
`
`
`UT Ex. 2061
`SteadyMed v. United Therapeutics
`IPR2016-00006