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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`____________
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`STEADYMED LTD.
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`Petitioner,
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`v.
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`UNITED THERAPEUTICS CORPORATION
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`Patent Owner.
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`Case IPR 2016-00006
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`Patent No. 8,497,393B2
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`____________
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`PETITIONER'S REPLY TO PATENT OWNER'S RESPONSE TO
`PETITION
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`37 C.F.R. § 42.23
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`Mail Stop "Patent Board"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`WEST\272027923.2
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`TABLE OF CONTENTS
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`Page
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`SUMMARY OF THE ARGUMENT ............................................................. 1
`I.
`II. UT MISCHARACTERIZES ITS OWN DATA. ........................................... 4
`A. UT's Moriarty Batches Have an Average Purity of 99.7±0.6%. .......... 4
`1.
`UT's Data Sources. ..................................................................... 5
`2.
`Are the 10 Batches Even Moriarty Samples? ............................ 7
`3.
`46 Known Moriarty Samples Average to 99.7±0.6%. ............... 8
`4.
`Any Difference in "Impurity Profiles" is Meaningless. ............. 9
`The Walsh Declaration Is Questionable. ............................................ 10
`B.
`III. DR. WILLIAMS' TESTIMONY CONFIRMS THAT PHARES
`ANTICIPATES CERTAIN '393 PATENT CLAIMS. ................................. 12
`A.
`Phares discloses steps(a) and (b) of the '393 Patent. .......................... 14
`B.
`Phares' Higher Melting Point Means It is at Least Equally Pure. ...... 14
`C. HPLC Analysis Has Error Bars Too Large to Distinguish the
`Tiny Differences in Purity Levels UT Relies Upon. .......................... 16
`IV. UT'S EXPERTS CONFIRM THE CLAIMS' OBVIOUSNESS. ................. 18
`A. Moriarty Was Recognized as the Best Method to Make
`Treprostinil Before the Phares Reference was Published. ................. 18
`B. UT's Experts Confirm That Crystallization Through A Salt To
`Purify Is Organic Chemistry 101. ...................................................... 19
`THE BOARD CONSTRUED THE CLAIMS CORRECTLY. ................... 21
`V.
`VI. NO LONG-FELT NEED FOR THESE CLAIMS' PRODUCTS. ............... 23
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`Petittioner SteaadyMed, Lttd. submitss this replyy pursuant tto 37 C.F.RR. § 42.23
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`ht in
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`SSUMMARRY OF THHE ARGUMMENT
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`As SSteadyMedd explainedd in its Petition, puriffying by crrystallizatiion is taug
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`undergrraduate cheemistry coourses: it's
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`Organic CChemistry
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`101. Evenn Patent Owwner
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`United TTherapeutiics' (UT) eexpert reco
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`gnizes thiss fact:
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`crystallizaation beenn around
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`as a mmethod of
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`A: I don't know how loong it's beeen around.
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`earn aboutt it when yoou were inn college att the unive
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`rsity?
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` And whenn did you ggo to collegge?
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`Q: How loong has
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`puurification??
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`Q: Before 20007?
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` Did you l
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` Yes, I didd. […]
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` In 1968 I started. Inn 1968.
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`farr back doess that go?
`: Decades.
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`Thhe Witness
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` ... But hoow far backk does doinng that proocess you j
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`just descriibed, how
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`(Ex. 20558, 175:199-176:22, 1179:11-17).
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`Evenn though thhe purificaation proceess claimedd in the '3
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`93 Patent
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`undergrraduate stuudent in thhe late 19660s would
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`know howw to do it,
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`UT mainttains
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`that a pproduct maade by thee '393 Patent processs is "mateerially andd functionaally"
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`distinct
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`from prodducts of thhe prior artt Moriarty
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`(Ex. 10044) and Phaares (Ex. 1
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`005)
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`referencces. UT rellies on 1755 measuremments showwing the avverage purrity of prodducts
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`made by one process included in the '393 Patent's claims is 99.7%. (Resp., 34; Ex.
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`2020, ¶¶ 94-99.) And it relies on measurements alleged to show that one version of
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`the Moriarty process produced an average purity of 99.0%. (Ex. 2020, ¶ 98.)
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`Except that the 99.0% value is a distortion of this data, that required UT, and its
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`attorneys who actually performed this calculation (Ex. 2059, 79:3-10, 81:2-13,
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`104:14-20), to select 10 data points from another source to lower the purity results
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`(id., 112:22-113:20).
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`As confirmed by Dr. Williams (id., 218:3-219:16), a fair analysis of the data
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`without the 10 data points shows that the value of 99.7%, reported in the Moriarty
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`reference (Ex. 1004) itself, is consistent with UT's purity measurements for batches
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`made according to the Moriarty process (Ex. 2059, 219:17-20). Data purporting to
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`show a lower purity, including UT's Walsh Declaration, mischaracterizes the
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`Moriarty process' purity.
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`UT's expert Dr. Williams initially believed UT's counsel's calculations. But Dr.
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`Williams conceded that: (1) he performed no calculations on this data himself; (2)
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`he only "spot-checked" the data that was selected by counsel; and (3) he "did not
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`know" whether the 10 data points were produced under the Moriarty process. (Ex.
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`2059, 81:2-13; 82:1-11; 103:24-104:20; 112:24-114:2). Accordingly, no weight
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`should be afforded to his declaration, or UT's reliance on his declaration. Dr.
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`Williams agreed that SteadyMed's calculation of 99.7% purity was correctly
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`performed, and should be relied upon (id., 217:11-219:20). This corrected
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`calculation supported what SteadyMed stated in its Petition: that the 99.7% purity
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`reported in the Moriarty reference showed that treprostinil made by Moriarty was
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`of similar purity, and similarly,
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`the particular example of
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`treprostinil
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`diethanolamine salt made by Phares was as pure as the examples in the '393 Patent.
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`This calculation confirms that the '393 Patent claims merit cancellation.
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`UT relies on these now-discredited differences in purity values to argue there
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`was a "long-felt unmet need" for more pure treprostinil. (Resp., 12, 47-48; Ex.
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`2022, ¶¶ 70-72). But UT's long-felt-need expert Dr. Ruffolo concedes that the
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`claims are not limited to treprostinil, nor treprostinil salt, but include hundreds of
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`thousands of other compounds, for which UT provides no evidence regarding long-
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`felt need or impurities. (Ex. 2059, 71:17-72:17; Ex. 2058, 234:16-235:17.) Except
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`for those claims that are limited to treprostinil alone (only claims 10 and 15), or
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`treprostinil diethanolamine salt (claims 14 and 17), Dr. Ruffolo is not offering an
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`opinion that there is a long-felt need for any other claims. (Ex. 2058, 109:18-
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`121:23.) And even for the products in claims 10, 14, 15, and 17, Dr. Ruffolo
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`concedes that: (1) the FDA requires only a 98% purity level, which is much lower
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`than any levels produced by the prior art, (Ex. 2058, 159:20-161:7); and, (2) the
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`FDA would allow treprostinil batches produced by the Moriarty process to be sold,
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`(Ex. 2058, 179:23-180:17), since Moriarty products are "highly, highly pure,"(id.
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`217:11--218:5). Seee also (Ex
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`UT ddevotes muuch of its RResponse tto argue thhat the commmon pateent claim teerms
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`"producct" and "coomprising"" were impproperly coonstrued bby the Boaard, and shhould
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`not have their usuual legally
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`defined mmeaning. (RResp., 5, 133-15). UT
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`contends tthese
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`in the '3393 Patentt, althoughh UT's exxpert
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`concedees that a p
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`lain and ordinary meeaning shoould applyy, and that
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`the patentt and
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`prosecuution history containn no languuage that
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`redefine tthese termms. (Ex. 22059,
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`248:24--249:13.) UUT cannot
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`meaningg of these tterms.
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`show "cleear and unaambiguouss disclaimeer" of the pplain
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` UII. UT MISCH
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`HARACTEERIZES IITS OWNN DATA.
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`AA. UT'ss Moriartyy Batches HHave an AAverage P
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`urity of 999.7±0.6%..
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`In itts Responsse and suppporting WWilliams Deeclaration ((Ex. 2020)), UT usess Dr.
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`Williamms to preseent the aveerage purityy of treproostinil madde by the MMoriarty pprior-
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`art methhod, in orrder to conntrast it too the '3933 Patent prroduct. Sppecifically,, Dr.
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`Williamms relied oon 56 battch Certificates of AAnalysis oof treprosttinil that wwere
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`allegedlly produceed under tthe Moriaarty methood (see Exx. 2020, AAppx. A),
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`contendded that the treprostinil producct producedd by the '3393 Patent t process hhad a
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`higher aaverage puurity than thhe Moriartty product
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`(99.71% vv. 99.05%)), and thus
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`"the
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`treprosttinil producct of the '3
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`93 patent hhas an averrage purityy that is 0.77% higher
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`Moriarty'ss." (Ex. 2020, ¶ 988; Resp., 44, 34, andd 45). Butt UT's couunsel
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`selected batches to include in its calculation, and cherry-picked 10 batches to drive
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`down the average purity value of the Moriarty product from 99.7% to 99.05%.
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`These 10 "development" batches, as UT calls them, come from a separate source,
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`and may not have been produced by the Moriarty method. When instead, the 46
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`"production" batches made by the Moriarty method, and under the same analytical
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`methods, are examined, the correct conclusion is that the Moriarty method
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`produces the same product as the product of the '393 Patent: a product with 99.7%
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`purity, just as Moriarty himself reported in his JOC article (Ex. 1004).
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`Because Dr. Williams and Dr. Ruffolo relied on UT's counsel's incorrect
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`calculation, UT's experts' opinions on differences between the Moriarty product
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`and the '393 Patent product should be disregarded.
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`1.
`UT attaches three exhibits that contain purity information for treprostinil made
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`UT's Data Sources.
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`under the Moriarty method: Exhibits 2036, 2052, and 2053. (Ex. 2020, Appx. A.)
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`Exhibit 2036 is the main source of this data, and contains 44 Certificates of
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`Analysis from either Magellan Laboratories or Cardinal Health for commercial lots
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`of treprostinil. Exhibit 2053 is UT's NDA Annual Report from 2003, which
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`summarizes Certificates of Analysis and purity information from 32 commercial
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`lots, including 30 lots that were already included in Exhibit 2036, plus two
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`additional lots not included in Exhibit 2036. Thus, Exhibits 2036 and 2053 contain
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`purity data for 46 lots of treprostinil.
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`Exhibit 2052 is an undated but older document entitled "UT-15 Injection Drug
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`Substance Volume 1.2 Chemistry, Manufacturing and Controls, NDA 21-272," and
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`appears to be a portion of UT's original New Drug Application to sell treprostinil.
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`It contains a summary of purity analyses for 13 lots of treprostinil made by third
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`party companies called "Upjohn," "Steroids Ltd.," and "SynQuest, Inc." (Ex. 2052,
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`25-30.) The two Upjohn lots, made in 1986, were not included in UT's Appendix
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`A. "These lots were manufactured by Pharmacia & Upjohn using a slightly
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`different route of synthesis." (id., at 25 n.4.) Lot UT15RP-98I001 was also not
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`included in UT's Appendix A. UT15MIX-99G001, "which was deliberately spiked
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`for use in toxicology studies," (id., at 29 n.2) was included by UT, as were "LRX-
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`98A01, and LRX-98B01 [which] were tested and released using different
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`analytical procedures previously submitted," and
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`for which "the
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`specifications do not apply ...," (id., at 25 n.3). The 10 samples selected from the
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`13 samples in Ex. 2052 were manufactured several years before Moriarty's 2004
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`Journal of Organic Chemistry article (Ex. 1004). As Dr. Williams confirmed, there
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`is no information provided on what method was used to make these lots, other than
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`the fact that the methods used for many of them were similar to methods Upjohn
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`used in 1986. These 10 data points have purity values far below the values reported
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`in Exhibits 2036 and 2053.
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`2.
`The dates of manufacture and footnotes recorded in Exhibit 2052 associated
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`Are the 10 Batches Even Moriarty Samples?
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`with UT's 10 cherry-picked samples make it unlikely that they were representative
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`of treprostinil made by the Moriarty process:
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`Q You don't know the details of how all these lots were made?
`A No. I haven't seen the detailed batch records of what went into those
`lots.
`Q Okay. So you don't know whether or not these lots were made by the
`'393 process, the Moriarty process, the older Aristoff process; is that
`right?
`THE WITNESS: Um, you know, I -- I'd have to investigate further. I
`don't know.
`Q Right. You -- you don't know if any of these are from the Moriarty
`process? At least not the ones on page 25?
`A So the Moriarty paper came out in 2003.
`...
`A So I don't think it's possible that any of these could have been made by
`Moriarty process just based on the dates.
`(Ex. 2059, 112:20-113:20). While Dr. Williams contends that these 10 samples
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`represent "development" batches included for "fairness" (id., at 81:23-82:7), he had
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`no explanation for why he included 10 development batches out of 56 samples for
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`his analysis of Moriarty batches, but only 5 development batches out of 157
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`samples for his analysis of '393-Patent batches. (Id., at 270:15-271:6).
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`3.
`Once the cherry-picked data points are eliminated, the average purity of the 46
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`46 Known Moriarty Samples Average to 99.7±0.6%.
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`remaining samples increases from 99.05% to 99.7±0.6%: the same purity as the
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`product produced by the '393 Patent process. SteadyMed prepared an Excel
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`spreadsheet containing these 46 data points (Ex. 1021), and had Dr. Williams
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`review every data point and calculation at his deposition to confirm that the 99.7%
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`number is correct, and consistent with the number reported in Ex. 1004:
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`Q: Okay. So now that we've – now that you've checked every single data
`point and looked at the calculations, you agree with me that this
`calculation of the purity is fair and accurate?
`A: The overall purity. But this does not reflect impurity profile.
`Q: Yeah I understand. I'm just talking about the overall – the level of
`purity.
`A: Yes.
`[…]
`Q: Okay. And so it is correct that for the samples from Exhibits 2036
`and 20[5]3, the 46 samples, the average level of purity was 99.7 percent
`for the samples made under the Moriarty process?
`A: Yes.
`Q: Okay. That 99.7% value, that is consistent with the value that
`Moriarty reports in his Journal of Organic Chemistry article?
`A: They're the same numbers.
`(Ex. 2059, 218:25-219:20). By contrast with Dr. Williams' careful review of
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`SteadyMed's calculation, Dr. Williams did not perform any calculations on UT's
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`data in Appendices A and B, having relied solely on counsel's work. (id., 81:2-13;
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`82:1-11; 103:24-104:20; 112:24-114:2).
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`When the science is done properly, UT's data proves that Dr. Moriarty's 99.7%
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`reported value in Ex. 1004 is correct.
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`4.
`UT still argues that the exact identity of the impurities generated by each
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`Any Difference in "Impurity Profiles" is Meaningless.
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`process in the tiny 0.3% set of impurities matters. UT ignores that the '393 Patent
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`claims contain at least hundreds of thousands of compounds (Ex. 2059, 71:17-22),
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`for which none of the impurities have ever been characterized, (id., 72:12-17). And
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`the '393 Patent does not even characterize the impurities of treprostinil (Ex. 2058,
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`234:16-235:12), which UT maintains as a trade secret requiring a protective order,
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`(Ex. 2058, 93:19-94:24, 233:5-12). As UT's expert Dr. Ruffolo conceded, "I see
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`primarily purities of the parent compound, which is what I believe the invention is
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`related to" and "so I see comparisons between the old process and new process
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`with purities, but – but I don't see, unless I've missed it, I don't see the impurities."
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`(Ex. 2058, 235:6-12.) Secret impurities not identified in the '393 patent for
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`treprostinil, or for hundreds of thousands of other compounds, cannot make the
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`claims patentable.
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`In any event, neither Dr. Williams nor Dr. Ruffolo opined that the impurity
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`profile of treprostinil mattered:
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`Q: Do ... any of these particular impurities have deleterious biological
`consequences? [...]
`A: I'm not a clinician, so I don't know.
`Q: You don't know?
`A: I don't know.
`(Ex. 2059, 47:4-13; see also Ex. 2058, 257:22-258:9.)
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`Dr. Ruffolo agrees that both the prior-art and '393 Patent treprostinil are
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`"highly, highly pure." (Ex. 2058, 217:24-218:5.) The FDA only requires 98%
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`purity for treprostinil, so achieving higher purity is immaterial to the product, (Ex.
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`2058, 159:20-161:7), and Moriarty-process treprostinil was, and can still be, sold
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`to the public, (Ex. 2058, 179:23-180:17). Where Moriarty and '393-Patent
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`treprostinil have the same purity, as proven by the 99.7%-purity level, there are no
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`functional differences between them, as Dr. Williams conceded. (Ex. 2059, 67:2-
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`15.)
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`The Walsh Declaration Is Questionable.
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`B.
`During prosecution of the '393 Patent, UT relied on the Walsh Declaration, and
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`differentiated the '393 Patent product from Moriarty's product by showing a
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`"representative sample" of Moriarty product containing 0.6% impurities, which
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`was contrasted with '393 Patent treprostinil diethanolamine salt and treprostinil
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`having 0.1% and 0.2% impurities, respectively. (Ex. 1002 at 343-350.). As noted
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`by UT, the '393 Patent claims were allowed after submission of the Walsh
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`Declaration. (Resp., 5).
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`The 46 samples contained in Exhibits 2036 and 2053, and a new exhibit
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`submitted by UT—Exhibit 2006—contradict the Walsh Declaration. As Dr.
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`Winkler observed, the data in the Walsh Declaration was derived from a single
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`sample, and significant batch-to-batch variations in the impurity profile of each
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`batch of treprostinil could affect the results. (Ex. 1009, ¶ 66).
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`Dr. Winkler's concern is confirmed by UT's results from the 46 batches. For
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`example, Moriarty Batch No. UT15-031202, dated January 25, 2004, and having a
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`purity of 99.7%, which is the average for these batches, had only three detectable
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`impurities: 3AU90, treprostinil ethyl ester, and 750W93. (Ex. 2036, 5.) According
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`to Dr. Walsh's June 4, 2013 Declaration, "treprostinil as the free acid prepared
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`according to the process specified in claim 1 or 10 of the present application has
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`only three impurities ...." (Ex. 1002, 348-49.) Moreover, "each of treprostinil as the
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`free acid and treprostinil diethanolamine prepared according to the process
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`specified in claim 1 or 10 of the present application is physically different from
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`treprostinil prepared according to the process of 'Moriarty' at least because neither
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`of them contains a detectable amount of any of benzindene triol, treprostinil methyl
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`ester, 1AU90 treprostinil stereoisomer and 2AU90 treprostinil stereoisomer, each
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`of which were present in detectable amounts in treprostinil produced according to
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`the process of "Moriarty." (Ex. 1002, 349.) Yet Moriarty Batch No. UT15-031202
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`did not contain detectable amounts of any of these impurities either, proving that
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`Dr. Wallsh could nnot make hhis conclusiion.
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`UT ttold the FDDA that treeprostinil ddiethanolammine salt mmade in acccordance
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`the '3933 Patent "sshowed sevveral impuurities deteected at loww levels, bbelow the
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`identificcation limiit of 0.1 percent. Thhese impuriities are noot carried
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`final APPI treprosttinil as desscribed beelow." (Ex.. 2006, 3-
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`supposeedly removved by carrrying out
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`step (d) inn the '393
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`through too the
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`6.) Yet theese impuriities,
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`describeed in the WWalsh Decclaration, wwhich insttead presennts "Impurrities ... [TTotal
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`Relatedd Substancees]" as 0.22% for the free acid,, and 0.1%% for the s
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`alt, (Ex. 1
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`002,
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`348), mmeaning thaat the free
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`acid is lesss pure thaan the dietthanolaminne salt, andd not
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`representeed to the FFDA in Exhhibit 2006
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`. Dr. Williiams couldd not
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`more puure as UT
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`providee an expllanation ffor this ddiscrepancyy (Ex. 22059, 199
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`:6-18), wwhich
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`contradicts the Waalsh Declaaration.
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` DIII. DR. WILL
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`AANTICIPAATES CERRTAIN '3
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`93 PATENNT CLAIMMS.
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`LIAMS' TEESTIMONNY CONFFIRMS THHAT PHAARES
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`Pharres (Ex.10005) makess the samee treprostinnil diethannolamine ssalt claimeed in
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`every cclaim of tthe '393 PPatent wheere optionnal step (dd) is not
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`completedd, as
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`explaineed in SteaddyMed's Petition andd Dr. Winkkler's Declaaration (Exx. 1009, ¶¶¶ 44-
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`71.) UTT respondss by rejectting the Board's claiim construuction, disccussed lateer in
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`this Repply, and with three faactual arguuments: (1)) that SteaadyMed cannnot showw that
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`Phares uused the MMoriarty prrocess, claimed in stteps (a) andd (b) of thhe '393 Pattent's
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`claims;
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`(2) that SSteadyMedd cannot shhow that PPhares' treeprostinil ddiethanolammine
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`27923.2
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`12
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`Form B salt has the same purity level as the '393 Patent's Form B salt; and (3) that
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`HPLC Assay Analysis can measure purity better than 0.4%, even though Dr.
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`Winkler pointed out that the error in UT's own equipment is at least 0.4%, (Ex.
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`1009, ¶ 70).
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`But Dr. Williams concedes that the process in Phares for making treprostinil's (-
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`)-enantiomer carries out the same alkylation step (a) and hydrolysis step (b) in the
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`'393 Patent's claims, thus disclosing these steps for treprostinil. And the attached
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`Declaration of Robin D. Rogers (Ex. 1022), SteadyMed's polymorph expert,
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`explains why the melting point of treprostinil diethanolamine salt Form B can be
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`compared between the '393 Patent and Phares reference, and that the particular
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`sample in Phares had at least the same purity as the '393 Patent's examples. Finally,
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`UT's own data showed that the average purity of Moriarty samples was
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`99.7±0.6%, proving that batch variation is at least 0.6%, and UT's representation
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`to the FDA stated that treprostinil purity will be maintained between 98% and
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`102%, (Ex. 2006), proving a ±2% variability applies to purity measurements.
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`Phares discloses steps(a) and (b) of the '393 Patent.
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`A.
`"Q. Okay. So what we see here is there's an alkylating step (a) and a
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`hydrolyzing step (b) on page 42 of the Phares reference. A. Yes." (Ex. 2059,
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`190:16-19). On Phares page 42 (Ex. 1005), as Dr. Williams concedes in this
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`testimony, steps (a) and (b) are carried out on the mirror image version of the
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`13
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`compounds described in the '393 Patent claims, and as Dr. Winkler explains, the
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`Phares patent at page 42 states that the enantiomer procedure is the same procedure
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`used to make "the commercial drug (+)-Treprostinil." (Ex. 1009 ¶ 56; Ex. 1005,
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`42.) Thus, in describing that the process for making both enantiomers uses steps (a)
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`and (b), and explaining that the process for the (-)-enantiomer is merely a variation
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`on the already known (+)-enantiomer process, Phares inherently discloses steps (a)
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`and (b) to create the (+)-enantiomer.
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`Phares' Higher Melting Point Means It is at Least Equally Pure.
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`B.
`Dr. Winkler explained that since the Phares treprostinil diethanolamine salt
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`Form B melted at 107oC, but the same Form B in the '393 Patent melted at around
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`106.6 oC, the Phares sample was necessarily as pure as the '393 Patent's samples.
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`Dr. Williams, who is "not a polymorph expert," (Ex. 2059, 158:17-18; 156:25-
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`157:2), contends nevertheless that the melting point of two samples of the same
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`polymorph (crystal form) cannot be compared to determine their relative purities.
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`(Ex. 2020 ¶ 75.) According to UT and Dr. Williams, how a polymorph is made,
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`including what solvents are used, can affect its melting point, even if the
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`polymorphs are identical. (Resp., 22-24; Ex. 2020 ¶ 75.)
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`As set forth in Dr. Rogers' Declaration (Ex. 1022, ¶¶ 49-52) and admitted by
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`Dr. Williams, melting point is one of the most common ways to identify different
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`polymorphs. (Ex. 2059, 158:20-25); see also Exs. 1024-1026. Dr. Williams
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`14
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`concedes that in the '393 Patent, treprostinil diethanolamine salt is identified as
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`being Form B based solely on its melting point. (Ex. 2059, 170:24-171:3.) And Dr.
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`Williams concedes that the same treprostinil diethanolamine salt polymorph—
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`Form B—is presented in the Phares reference and '393 Patent. (Id., 168:6-11).
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`While Dr. Williams relies on his "personal experience" observing different
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`melting points for crystals made with different solvents, he conceded that he knew
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`of no literature to support his opinion. (Id., 184:22-185:2.) Dr. Williams conceded
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`that the one article he relied upon in his declaration, Ex. 2030, in fact describes
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`different crystal forms having different melting points, and not the same crystal
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`form having different melting points. (Id., 180:9-25.)
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`By contrast, Dr. Rogers' Declaration cites several literature sources explaining
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`that melting point uniquely identifies a polymorph. (Ex. 1022, ¶¶ 49-52). Thus, for
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`the same polymorph, if the melting point differs, it is due to impurities contained in
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`the sample having a lower melting point. (Id., ¶ 64.) Dr. Rogers concludes that
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`Phares' higher melting point is necessarily due to higher or at least identical purity.
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`(Id., ¶ 74.) Moreover, the width of the DSC peak in the Phares reference is very
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`narrow, consistent with a very pure material. (Id., ¶ 84.)
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`C. HPLC Analysis Has Error Bars Too Large to Distinguish the Tiny
`Differences in Purity Levels UT Relies Upon.
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`As Dr. Winkler explained, it is not possible to measure treprostinil purity levels
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`better than 0.4%, as shown by UT's own data. (Ex. 1009, ¶ 70.) Now that UT has
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`provided multiple certificates of analysis for treprostinil, it is now confirmed that
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`UT's Moriarty purity varies by at least 0.6%, and indeed, Dr. Williams conceded he
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`had no reason to disagree with this 0.6% value. (Ex. 2059, 218:22-24.)
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`UT's own exhibits confirm that HPLC assay analysis has a wide error range:
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`"During the initial analytical method validation for the treprostinil assay, the
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`results indicated that there is about 2 percent variability in the assay." (Ex. 2006,
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`3.) UT's expert Dr. Williams agrees with this statement and that "2 percent
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`variability in the assay" refers to the HPLC assay for purity. (Ex. 2059, 133:17-25,
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`134:24-135:4.)
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`UT discounts that HPLC assay analysis has a wide error range by suggesting
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`that purity should instead be measured by totaling up "total related substances,"
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`which are measurements of particular impurities identified in the HPLC analysis.
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`(Resp., 2-3, 29-30.) But as acknowledged by Dr. Williams, some impurities will
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`not be detected in a total-related-substance analysis (Ex. 2059, 140:5-9.). UT's
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`expert Dr. Ruffolo confirmed that in the '393 Patent, all of the analyses are HPLC
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`analyses of
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`the
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`total
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`treprostinil against a reference standard, and not
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`measurements of total related substances. (Ex. 2058, 153:16-154:7.) And both UT
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`experts acknowledged that the FDA uses HPLC assay analysis to evaluate the
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`overall purity of treprostinil, and to decide whether that treprostinil meets a 98%
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`purity requirement that would allow it to be sold. (Ex. 2058, 159:20-161:7; Ex.
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`50:23-151
`2059, 1
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`UT ccriticizes DDr. Winkleer, falsely
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`stand not undersnkler does nstating thaat Dr. Wink
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`HPLC
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`analysis,
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`and does
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`not knoww anythingg about thhe error inn UT's H
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`PLC
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`equipment. (Resp., 3, 30.) DDr. Winklerr instead teestified thaat there is nno informaation
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`regardinng the errror in the amount
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`of "2AU990," an immpurity prresent in UUT's
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`treprosttinil at abbout 0.1%%. (Ex. 22051, 63:33-14.) Thee error inn the 2AAU90
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`measureement is iirrelevant
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`to the errror in treeprostinil ppurity, esppecially wwhere
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`is a numbber near 1000% (rangging from 998 to 102%%), 1000 tiimes
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`treprosttinil purity
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`larger tthan the
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`amount oof 2AU900. Regardiing error
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`in HPLCC Analysi
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`s of
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`treprosttinil purity,, Dr. Winkkler was unnequivocal
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`at his depoosition:
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`I thhink the thhing that I
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`am able too concludee from the
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`the HPLCC assay coould be as
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`6 oof this, of f this letterr is that thhe error in
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`higgh as 1 perrcent in thee first colummn and byy my analyysis could bbe as high
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`as 2 percent in the secoond columnn.
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`(Ex. 20551, 88:12-18.)
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`IV.
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` UUT'S EXPEERTS COONFIRM TTHE CLAAIMS' OBVVIOUSNEESS.
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`AA. Moriiarty Was Recognizzed as the BBest Methhod to Maake
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`Trepprostinil Before the PPhares Reeference wwas Publish
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`UT
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`contends tthat Pharess does nott anticipatee because
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`it does noot disclosee the
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`first twwo steps, stteps (a) annd (b), whhich were
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`used in thhe Moriartty processs. As
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`explaineed above, tthis contenntion is wrong. But eeven if it wwere true, UUT's exper
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`Williamms providedd testimony confirmiing that theere was a sstrong reasson to commbine
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`Moriarty with Phares: Moriarty was well-known to be the best way to make
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`treprostinil, and would have been the way Dr. Williams' own graduate students
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`would have made the treprostinil in Phares before turning it into its salt.
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`First, Dr. Williams confirmed that steps (a) and (b) in the '393 Patent claims
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`were disclosed by the Moriarty patent, Ex. 1003. (Ex. 2059, 53:19-54:7). Second,
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`Dr. Williams confirmed that "a person of ordinary skill in the art in 2005 reading
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`the Phares reference, that person would know that the best way to make treprostinil
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`is the Moriarty method ...." (id., 240:2-7). And third, he confirmed that "a typical
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`person of ordinary skill in the art, typical graduate student, they would have found
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`the Moriarty paper and used that technique to make treprostinil in 2005." (Id.,
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`244:10-21.) While UT's expert Dr. Ruffolo disagrees with Dr. Winkler regarding
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`the appropriate level of skill, it is Dr. Ruffolo's opinion that the skill level should
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`be higher than Dr. Winkler's, and that a person of ordinary skill should at least
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`have a Ph.D. (Ex. 2058, 52:2-17.) If a graduate student would use Moriarty, then
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`certainly a Ph.D. would do so. Thus, UT's experts essentially confirm that a person
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`of ordinary skill in the art would combine Moriarty with Phares when making
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`Phares' treprostinil salt.
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`B. UT's Experts Confirm That Crystallization Through A Salt To
`Purify Is Organic Chemistry 101.
`As shown by UT expert Dr. Ruffolo's testimony, supra, the process steps (c)
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`and (d), which crystallize a compound as its salt and then convert the salt back to
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`the acid, have been around for "decades," at least as far back as the late 1960s. (Ex.
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`2058, 175:19-176:22, 179:11-17.) "[I]f a technique has been used to improve one
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`device, and a person of ordinary skill in the art would recognize that it would
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`improve similar devices in the same way, using the technique is obvious unless its
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`actual application is beyond his or her skill." KSR Int'l Co. v. Teleflex Inc., 550
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`U.S. 398, 417 (2007). UT cannot claim that using this elementary chemistry
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`technique is nonobvious merely because UT applied it to treprostinil.
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`UT also argues that the particular impurities found in treprostinil, which are
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`said to be stereoisomers, would not have been removed using crystallization. First,
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`there is no teaching in the '393 Patent or the prior art of record regarding what
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`kinds of impurities are present in treprostinil, or, as conceded by UT's experts, of
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`the hundreds of thousands of other compounds included in the claims. (Ex. 2059,
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`74:18-25; Ex. 2058, 234:16-235:17.) UT maintains the identity of these impurities
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`as a trade secret, necessitating a Protective Order to cover these proceedings so that
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`information on these impurities is not revealed. UT's secret information regarding
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`these impurities' identity cannot be the basis for why a person of ordinary skill in
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`the art would not use cryst