`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`
`_______________
`
`Case IPR2020-00770
`Patent 9,604,901
`_______________
`
`
`
`PATENT OWNER’S SUR-REPLY
`
`
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`Patent Owner Sur-Reply
`
`
`
`TABLE OF CONTENTS
`
`
`
`
`
`I.
`
`II.
`
`Summary of the Argument .............................................................................. 1
`
`The Final Written Decision of the ’393 Patent Does Not Control this
`
`Proceeding ....................................................................................................... 3
`
`A.
`
`B.
`
`Liquidia Ignores Limitations of the ’901 Patent Claims ....................... 4
`
`Liquidia’s Reply Advances New Theories While Failing to
`
`Apply or Address Proper Claim Construction ...................................... 5
`
`1.
`
`2.
`
`“Pharmaceutical Batch” .............................................................. 6
`
`“Storing”/“Storage” .................................................................. 11
`
`C.
`
`Liquidia Fails to Apply the Appropriate Level of Ordinary Skill
`
`in the Art .............................................................................................. 13
`
`III. Even Considering the ’393 Final Written Decision, Petitioner Has Not
`
`Met Its Burden for Ground 1 or Ground 2 .................................................... 16
`
`A. Ground 1: Phares Alone Did Not Render the ’901 Claims
`
`Obvious ............................................................................................... 16
`
`B.
`
`Ground 2: Moriarty Combined with Phares Do Not Render the
`
`’901 Claims Obvious ........................................................................... 19
`
`1.
`
`Issue Preclusion Is Inapplicable ................................................ 19
`i
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`2.
`
`A Motivation to Combine Moriarty with Phares Is
`
`Lacking ...................................................................................... 20
`
`IV. Ambient Temperature Storage Stability—as Claims 6 and 7
`
`Require—Was Unexpected ........................................................................... 24
`
`V.
`
`Liquidia’s Attacks on Dr. Pinal Are Not Warranted ..................................... 25
`
`VI. Conclusion and Relief Requested .................................................................. 27
`
`Certificate of Compliance With Word Count .......................................................... 28
`
`
`
`4843-1715-7862.2
`
`ii
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`TABLE OF AUTHORITIES
`
`
`Am. Med. Sys., Inc. v. Biolitec, Inc., 618 F.3d 1354, 1361-62 (Fed. Cir. 2010) ........ 7
`
`Pages
`
`Dynamic Drinkware, LLC v. National Graphics, Inc., 800 F.3d 1375, 1378 (Fed.
`
`Cir. 2015) ............................................................................................................. 16
`
`FedEx Corp. v. Ronald A Katz Tech. Lisc., CBM2015-00053, Paper 9, 7–8
`
`(P.T.A.B. June 29, 2015) ..................................................................................... 26
`
`In re Katz Interactive Call Processing Patent Litig., 639 F.3d 1303, 1311 (Fed. Cir.
`
`2011) .................................................................................................................... 19
`
`Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1360-61 (Fed. Cir. 2015) ...... 22
`
`4843-1715-7862.2
`
`iii
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`EXHIBIT LIST
`
`Exhibit No
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`Intentionally left blank
`
`Declaration of Rodolfo Pinal, Ph.D.
`
`Curriculum Vitae of Rodolfo Pinal, Ph.D.
`
`21 C.F.R. § 210.3 (April 1, 2007 edition)
`
`Intentionally left blank
`
`Complete Prosecution History of U.S. Patent No. 9,604,901
`
`Stahl, P. H., & Wermuth, C. G. (Eds.). (2002). Handbook of
`Pharmaceutical Salts (1st ed.). Weinheim, Germany: Wiley-VCH,
`pp. 1-7, 41-81, 135-220, 259-63
`Batra, H., et al., Crystallization Process Development for a Stable
`Polymorph of Treprostinil Diethanolamine (UT-15C) by Seeding,
`Org. Proc. Res. Dev., 13, 242-49 (2009)
`
`Wiberg, K., Laboratory Technique in Organic Chemistry (1960),
`pp. 75-119
`
`Schoffstall, A. M., et al., Microscale and Miniscale Organic
`Chemistry Laboratory Experiments, 2nd ed. (2004), pp. 22-27,
`537-59
`
`Intentionally left blank
`
`Comparing IPR2020-00770 Ex. 1002 to the Petition in IPR2020-
`00770
`
`4843-1715-7862.2
`
`iv
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`Exhibit No
`
`Description
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`Intentionally left blank
`
`Intentionally left blank
`
`U.S. Department of Health and Human Services, Food and Drug
`Administration, Center for Drug Evaluation and Research,
`Guidance for Industry: ANDAs: Pharmaceutical Solid
`Polymorphism, Chemistry, Manufacturing, and Controls
`Information (July 2007)
`Anderson, Practical Process Research and Development, Second
`Ed., Academic Press, Oxford, UK, 2012
`Gad, Pharmaceutical Manufacturing Handbook, Production and
`Processes, John Wiley & Sons, Hoboken, NJ (2008)
`Levin, Pharmaceutical Process Scale-Up, Taylor & Francis, Boca
`Raton, FL (2006)
`Bennett, Pharmaceutical Production. An Engineering Guide,
`INSTITUTION OF CHEMICAL ENGINEERS (ICHEME), Rugby,
`Warwickshire, UK (2003)
`Qiu, et al., Identification of pharmaceutical impurities, J. LIQUID
`CHROMATOGRAPH. REL. TECHS., 30, 877-935
`Ahuja, et al., Assuring quality of drugs by monitoring impurities,
`ADV. DRUG DELIVERY REV., 59, 3-11 (2007)
`Paul, et al., Design of Reaction Systems for Specialty Organic
`Chemicals, CHEM. ENGINEER. SCI., 43, 1773-82 (1988) (“Paul”)
`Wadekar, et al., Evaluating Impurities in Drugs (Part I of III),
`PHARM. TECH., 36(2), 46-51 (2012)
`Declaration of Rodolfo Pinal, Ph.D. Supporting Patent Owner
`Response
`
`2026
`
`Winkler Deposition Transcript, December 14, 2020
`
`4843-1715-7862.2
`
`v
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`Patent Owner Sur-Reply
`
`
`
`Exhibit No
`
`Description
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`U.S. Patent No. 9,593,066
`
`Prosecution History of U.S. Patent Application No. 13/933,623
`
`Linked-In Profile of Ken Phares,
`https://www.linkedin.com/in/ken-phares-4b62198 (last accessed
`April 5, 2021)
`Linked-In Profile of David Mottola,
`https://www.linkedin.com/in/david-mottola-phd (last accessed
`April 5, 2021)
`Linked-In Profile of Bob Moriarty,
`https://www.linkedin.com/in/bob-moriarty-7581539 (last accessed
`April 5, 2021)
`
`2032
`
`Second Winkler Deposition Transcript, April 5, 2021
`
`2033
`
`2034
`
`Supplemental Declaration of Robert R. Ruffolo, Ph.D., April 2,
`2021 (United Therapeutics Co. v. Liquidia Techs., Inc., Case No.
`1:20-cv-00755-RGA (D. Del.))
`Ruffolo Deposition Transcript, April 15, 2021 (United
`Therapeutics Co. v. Liquidia Techs., Inc., Case No. 1:20-cv-
`00755-RGA (D. Del.))
`
`
`
`
`
`
`4843-1715-7862.2
`
`vi
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`I.
`
`SUMMARY OF THE ARGUMENT
`Rather than marshal relevant evidence against the ’901 patent claims, Liquidia
`
`relies heavily upon a final written decision finding different claims of a different
`
`United Therapeutics (“UTC”) patent (the ’393 patent) unpatentable. However, in its
`
`blind reliance, Liquidia fails to account for (1) a difference in the proper level of
`
`ordinary skill in the art, (2) different claim limitations and scope, and (3) different
`
`claim constructions. Simply put, the ’393 final written decision cannot bear the
`
`weight Liquidia requires it to hold.
`
`Once the ’393 final written decision is considered in correct context,
`
`Liquidia’s oversimplification of the two technologies and selective reading of the
`
`references is striking. First, Liquidia discounts the unpredictability of the
`
`technology. For example, Dr. Winkler trivializes the complexities and lack of
`
`predictability
`
`in salt selection and
`
`formation, crystal morphology, and
`
`bioavailability. See, e.g., Ex. 2032, 171:23-175:5 (acid neutralization), 250:11-
`
`252:16 (bioavailability), 252:18-274:22 (counterion selection), 321:1-322:9 (crystal
`
`morphology). Second, Liquidia fails to consider references in their entirety. Liquidia
`
`cherry picks isolated quotations to support unduly simplistic conclusions. For
`
`example, Liquidia’s expert cites Berge (Exhibit 1034) to argue that salt selection is
`
`trivial. However, Berge expressly discusses the unpredictability of salt selection, and
`
`4843-1715-7862.2
`
`1
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`the many (often contradictory) factors that go into it. These are not isolated
`
`incidents—this approach permeates its Petition.1
`
`Liquidia then moves beyond the four corners of the Petition to devise new
`
`arguments it could have but chose not to raise previously. Liquidia argues for the
`
`first time in reply that alleged “safety,” improved bioavailability, and crystalline
`
`morphology would have provided motivations to combine the Phares and Moriarty
`
`references. Paper 15 (“Reply”), 13-16. When pressed, Dr. Winkler asserted that he
`
`had the information to support those opinions previously but continued to evade
`
`questions regarding the scope and import of those disclosures to a POSA. Ex. 2032,
`
`250:11-252:16 (bioavailability), 287:6-296:19 (clinical safety), 321:1-322:9 (crystal
`
`morphology).
`
`
`
`While UTC does not bear the burden of proof, it offered credible testimony
`
`from the one expert in the case who actually has real-world experience with
`
`
`
`1 Liquidia’s corner cuts were apparent from the outset. Liquidia’s Petition was
`
`unsupported by any sworn declaration. Instead of addressing UTC’s concern,
`
`Liquidia filed a belated declaration a year after its Petition in a half-hearted effort
`
`to “cure” its failure. See infra §IV.
`
`2
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`manufacturing pharmaceutical batches. Unable to address that testimony head-on,
`
`Liquidia resorts
`
`to accusing
`
`this world-class pharmaceutical scientist of
`
`“adulterating” Liquidia’s expert opinions. Reply, 1. The Board is more than
`
`sophisticated enough to determine which expert is true to the references and the
`
`science. UTC respectfully encourages the Board to read the experts’ complete
`
`deposition transcripts (Ex. 1018; Ex. 2026; Ex. 2032).
`
`
`
`The Board previously expressed concern that Liquidia had not met its burden
`
`as to claims 6 and 7. Paper 7 (“Inst.”), 28-32. The flaws in Liquidia’s case as to those
`
`claims have widened and deepened. See infra §§II-III. And the gaps in Liquidia’s
`
`arguments surround the remaining claims have gone unfilled. UTC respectfully
`
`requests that the Board deny this Petition and confirm the patentability of the claims
`
`of the ’901 patent.
`
`II.
`
`THE FINAL WRITTEN DECISION OF THE ’393 PATENT DOES
`NOT CONTROL THIS PROCEEDING
`Liquidia oversimplifies the technology and issues to paint the ’901 patent
`
`claims as substantively identical to those of the ’393 patent. Reply, 1, 10-12. They
`
`are not.
`
`The Board’s analysis of the ’393 patent cannot merely be recycled and
`
`reapplied to the ’901 patent claims. First, the ’901 patent claims recite limitations
`
`4843-1715-7862.2
`
`3
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`that are absent from the ’393 patent claims. Liquidia, by contrast, treats “product”
`
`and “pharmaceutical batch,” and “comprising” and “consisting of” identically. This
`
`approach violates fundamental tenets of patent law. Second, the appropriate claim
`
`constructions demonstrate that the claims of these different patents have different
`
`scope. Third, these different claim terms and constructions directly affect the level
`
`of ordinary skill in the art, making the cases dispositively different.
`
`A. Liquidia Ignores Limitations of the ’901 Patent Claims
`The POR outlined the differences between the ’901 and ’393 patents’ claims
`
`in detail. Paper 12 (“POR”), 4-16; Ex. 2025, ¶¶43-44. Yet Liquidia and its expert
`
`unequivocally stated that, “[t]he only differences that I considered, in other words,
`
`the differences as a scientist that I felt were important here are the ones that I’m
`
`showing” in bold in Exhibit 1017 paragraphs 68-69. Ex. 2032, 197:7-198:4; see also
`
`Reply 11. In particular, Liquidia and its expert considered only “an impurities
`
`limitation in the preamble and an amount of treprostinil limitation at the end of the
`
`claim.” Ex. 1017, ¶¶68-69; Reply, 11. The only way to legitimize this conclusion is
`
`to read words out of the claims.
`
`For example, Liquidia and
`
`its expert simply
`
`ignore
`
`the
`
`terms
`
`“pharmaceutical” and “batch” as they appear in the ’901 patent claims. See Ex. 1017,
`
`¶¶68-69 (equating “pharmaceutical batch” with the different term “product”); Reply,
`
`4843-1715-7862.2
`
`4
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`10-12. A product is a chemical compound resulting from a reaction. A
`
`pharmaceutical batch, as the Board identified in its institution decision is a specific
`
`quantity of treprostinil (or its salt) that is intended to have uniform character and
`
`quality, within specified limits, and is produced according to a single manufacturing
`
`order during the same cycle of manufacture, wherein the uniform character and
`
`quality is such that it still contains impurities resulting from the method by which it
`
`is produced. Inst., 15-16. Similarly, Liquidia does not recognize any difference
`
`between the transitional phrase “comprising” found in the ’393 versus the closed
`
`transitional phrase “consisting of” in the ’901 patent. Reply, 10-12; Ex. 1017, ¶¶68-
`
`69. Because Liquidia’s analysis of the ’901 patent claims does not account for these
`
`differences, they fail to support a finding of unpatentability.
`
`B.
`
`Liquidia’s Reply Advances New Theories While Failing to Apply
`or Address Proper Claim Construction
`In its Petition, Liquidia chose not to advance any construction for the claim
`
`terms, and instead argued that “terms should be given their plain and ordinary
`
`meaning….” Paper 1 (“Pet.”), 19. UTC proffered constructions consistent with a
`
`POSA’s plain and ordinary understanding. Liquidia now argues that UTC’s
`
`construction of “pharmaceutical batch” and “storing”/“storage” adopted by the
`
`Board are improper. Reply, 3-8. Liquidia, however, does not and cannot argue that
`
`4843-1715-7862.2
`
`5
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`a POSA would be unaware of or misunderstand pertinent FDA regulations in this
`
`pharmaceutical context. Liquidia’s new positions should be disregarded as lacking
`
`factual or legal basis.
`
`1.
`
`“Pharmaceutical Batch”
`(1) Liquidia’s New, Unsupported Arguments
`Liquidia failed to address the appropriate construction of “pharmaceutical
`
`batch” in its Petition. In its Reply, Liquidia ignores the claim construction adopted
`
`by the Board, and asserts, for the first time, an affirmative construction for the
`
`“pharmaceutical batch” term (Reply, 5), despite Dr. Winkler’s unequivocal opinion
`
`that “a person of ordinary skill in the art would understand each of the claim terms
`
`to take on its plain and ordinary meaning.” Ex. 1002, ¶35; see also Pet., 18 (“[f]or
`
`the purposes of resolving this IPR, Petitioner does not believe construction of claim
`
`terms is required.”).
`
`Liquidia now suggests that UTC “ignores statements it made to overcome
`
`prior art.” Reply, 5. Not so. First, Liquidia cites 16:66-17:1 of the ’901 patent
`
`specification, as supporting its new construction but the citation merely describes
`
`additional “advantages” of the present invention. Id. The Federal Circuit has
`
`repeatedly held that, where “present invention” language refers to advantages and
`
`4843-1715-7862.2
`
`6
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`“preference[s],” it is not limiting. Am. Med. Sys., Inc. v. Biolitec, Inc., 618 F.3d 1354,
`
`1361-62 (Fed. Cir. 2010).
`
`Second, Liquidia cites Example 6, Step 12, but Example 6 is merely a
`
`“working example” and it is improper to import such limitations from illustrative
`
`embodiments. Reply, 5.
`
`Third, Liquidia cites the ’393 IPR, but conflating the ’393 patent with the ’901
`
`patent is erroneous where claim 16 of the ’393 patent explicitly excludes
`
`purification, and such statements did not overcome the prior art. See, e.g., Ex. 1004,
`
`claim 16 (“wherein the process does not include purifying the compound…”).
`
`Fourth, Liquidia misquotes the POPR and POR by excerpting a statement
`
`concerning the proposed level of skill in the art and removing the word “e.g.”. Paper
`
`6 (“POPR”), 56 (“This perspective is critical in the context of the claimed
`
`pharmaceutical composition, in which, e.g., no purification steps appear between
`
`alkylation and salt formation.”) (emphasis added). UTC’s statement is accurate—no
`
`purification step “appear[s]” in the claims pre-salt formation. See POR, 25.
`
`Finally, Liquidia cites testimony from Dr. Pinal agreeing that, as previously
`
`discussed, the “present invention” provides “advantages.” Reply, 5. This excerpt of
`
`the specification, and Dr. Pinal’s agreement with the specification’s language, does
`
`not limit the claims. See Am. Med. Sys., 618 F.3d at 1361-62.
`7
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`Admittedly, UTC’s POR mistakenly contained short-hand language to
`
`reference a claim limitation that would not be understood by a POSA as consistent
`
`with the ’901 patent’s claims, its specification, or prosecution history. For example,
`
`POR at 11 inaccurately suggests that the language of claim 1 means treprostinil is
`
`“not isolated” from the solution formed in step (b) before forming a salt in step (c).
`
`See, e.g., POR, 15, 29, 34, 53; Paper 9 (“Rehear. Req.”), 3. These statements are
`
`unsupported and a POSA would not have understood them as consistent with the
`
`claims read in light of the specification. Dr. Pinal clearly and unambiguously stated
`
`that “this isolation limitation…is actually a limitation from the ’066 patent—not
`
`isolating the treprostinil before contacting it with a base is not an explicit limitation
`
`of claim 1 of the ’901 patent.” Ex. 2025, ¶157 (emphasis added).
`
`Liquidia is now using this attorney argument from the POR in co-pending
`
`district court litigation to argue that the ’901 patent claims cannot include even
`
`simple work-up steps (e.g., in vacuo removal of solvent, solvent extraction, etc.). In
`
`the same co-pending district court litigation, Dr. Robert Ruffolo was asked to
`
`consider the POR statements and explained that “a POSA would understand that the
`
`passage in the Patent Owner’s Response upon which Liquidia relies is incorrect to
`
`the degree it suggests that Examples 2 and 3 describe synthesizing treprostinil
`
`without isolating it prior to salt formation.” Ex. 2033 (“Ruffolo Decl.”), ¶15
`8
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`(submitted pursuant 37 CFR §42.51(b)(1)(iii))2; Ex. 2034 (“Ruffolo Depo.”), 247-
`
`48 (same).
`
`Because statements made in the POR suggesting that the ’901 patent requires
`
`that treprostinil not be isolated before forming a salt are inaccurate and inconsistent
`
`with the claims, specification and prosecution history, UTC hereby withdraws those
`
`statements. To be clear, the claims do not require isolation, but also do not require
`
`omission of an isolation step.
`
`Moreover, even after it was on notice of the Board’s construction of
`
`“pharmaceutical batch,” Liquidia continued to disregard this term’s meaning and
`
`context of the term in pharmaceutical manufacturing. Reply, 9-10 (asserting a POSA
`
`need not have experience with pharmaceutical batches, including requirements for
`
`purity, FDA compliance, or commercial scale). Through divorcing the claim term
`
`
`
`2 Liquidia suggests that UTC’s positions are inconsistent. While UTC maintains
`
`that Liquidia is taking the statements out of context, UTC hereby withdraws any
`
`statements the Board considers inconsistent and serves Exhibits 2033 and 2034
`
`from the litigation out of an abundance of caution and in compliance with 37
`
`C.F.R. § 42.51(b)(1)(iii).
`
`4843-1715-7862.2
`
`9
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`from its express “pharmaceutical” context, Liquidia seeks to avoid the complexities
`
`and purity concerns that pharmaceutical sciences require.
`
`(2) A Pharmaceutical Batch Must Be Stable Enough to
`Provide for Finished Dosage Forms
`In its Institution Decision, the Board adopted Patent Owner’s construction of
`
`“pharmaceutical batch.” Inst., 15-16. This construction requires
`
`that
`
`the
`
`pharmaceutical batch “have uniform character and quality, within specified limits.”
`
`Id. In the Rehearing Request Denial, the Board clarified that it did not formally find
`
`claim 1 to “require ‘a storage stable batch.’” Paper 14 (“Rehear. Dec.”), 6. Liquidia
`
`wrongly asserts that storage stability cannot be a limitation of claim 1. Reply, 6.
`
`As Dr. Pinal explains a storage stable batch is required by the claim term
`
`“pharmaceutical batch.” Pharmaceutical batches are a source of material from which
`
`portions may be utilized over time to make finished drug products. The “uniform
`
`character and quality” of the pharmaceutical batch is required for the pharmaceutical
`
`manufacturing process, such that these finished drug products can be made. Ex.
`
`2025, ¶78, citing Ex. 2004.
`
`Dr. Pinal further testified that if a pharmaceutical batch “is not sufficiently
`
`stable to be stored for an extended period of time while maintaining its purity and
`
`integrity, then the batch must be discarded.” Id., ¶212. This means that “the
`
`4843-1715-7862.2
`
`10
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`pharmaceutical batch of claim 1 also requires storage stability.” Id., ¶170 citing Ex.
`
`2004; see also id., ¶91 (noting that “the stability advantage is a function of the
`
`specific impurities and levels thereof, present in the batch” and citing Ex. 2028, Guo
`
`Declaration, which references FDA’s stability guidance for pharmaceutical batches
`
`at Appendix B).
`
`Liquidia’s expert Dr. Winkler does not offer any testimony that contradicts or
`
`refutes Dr. Pinal’s analysis and conclusions.
`
`2.
` “Storing”/“Storage”
`Liquidia posits three alleged “flaws” in the “storing” construction adopted by
`
`the Board.
`
`Liquidia’s argument that “importing a stability limitation violates claim
`
`differentiation canon, because the term ‘stable’ is separately defined in the ’901
`
`specification” (Reply, 7) is unavailing because “stable” does not appear in the claims
`
`of the ’901 patent. There is no “claim differentiation” to consider.
`
`The “storage” terms are only used as an express limitation in claims 6 and 7,
`
`which relate to an embodiment that specifies storage at “ambient temperature.” The
`
`use of these separate limitations relating to storage at ambient temperature in no way
`
`calls into question the earlier proper construction of “pharmaceutical batch,” which,
`
`as set forth in §II.B.1.(2), above, must have sufficient stability and uniformity to be
`
`4843-1715-7862.2
`
`11
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`useful in pharmaceutical manufacturing. Instead, it further limits the stability
`
`requirement by adding a temperature limitation.
`
`Second, Liquidia’s second alleged “flaw” regarding statements made in a
`
`declaration of Dr. Guo during prosecution of a related ’786 patent (Reply, 7-8) are
`
`similarly irrelevant. Dr. Guo was discussing the term storage from the perspective
`
`of what the minimal amount of time would be necessary from an FDA confirmatory
`
`testing perspective. The paragraph immediately above Dr. Guo’s quoted sentence
`
`makes clear that she is addressing materials that “can be” stored—not what must be
`
`stored. Ex. 2028, 193. As such, the statements are not in any way limiting, and are
`
`entirely consistent with the Board’s construction.
`
`Moreover, Liquidia’s second articulated “flaw” is at odds with its third point.
`
`Reply, 7-8. Liquidia’s proffered general dictionary definition of “storage” (“[a]ny
`
`method of keeping raw materials, chemicals, food products, and energy while
`
`awaiting use, transportation, or consumption”) is consistent only with UTC’s natural
`
`reading of the Guo declaration. Id.; Ex. 1038, 1180 (defining storage). It is also only
`
`consistent with the construction offered by UTC and adopted by the Board. See Inst.,
`
`17. To be sure, the claims relate to pharmaceutical batches, pharmaceutical products,
`
`and related methods of making the same. The construction offered by UTC is
`
`4843-1715-7862.2
`
`12
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`tailored to the meaning of “storing”/“storage” in the context of those claims and, in
`
`particular, claims 6 and 7.
`
`For at least these reasons, the Board’s construction of “storing”/“storage” in
`
`its Institution Decision was proper.
`
`C. Liquidia Fails to Apply the Appropriate Level of Ordinary Skill
`in the Art
`UTC has maintained that the ’901 patent claims require a level of skill that
`
`includes experience with pharmaceutical manufacturing. POR, 22-27; POPR, 55-57.
`
`Liquidia characterizes this definition as “unnecessarily elevated.” In so doing,
`
`Liquidia avoids the claim term “pharmaceutical”, as well as the levels of skill of the
`
`authors of the very art it asserts in this proceeding. Ex. 2032, 225:16-239:21.
`
`For example, Dr. Phares, the first inventor listed on the Phares PCT (Ex. 1008)
`
`had a Ph.D. in pharmaceutical chemistry as of 1993, served as vice president of
`
`pharmaceutical development for nearly 20 years, starting in 2001, and had
`
`experience in pharmaceutical development activities from API characterization to
`
`drug product development process scale-up. Ex. 2029; Ex. 2032, 225:16-230:2. Dr.
`
`Winkler agreed that the definition of a POSA included those with advanced degrees
`
`in pharmaceutical chemistry. Ex. 2032, 229:18-230:2.
`
`4843-1715-7862.2
`
`13
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`David Mottola, the second inventor listed on the Phares PCT, had a Ph.D. in
`
`pharmacology, and guided clinical affairs and product development, including
`
`quality and process improvement. Ex. 2030; Ex. 2032, 230:4-236:12. Upon viewing
`
`the credentials of Dr. Phares, Dr. Winkler also agreed that the definition of a POSA
`
`included those with advanced degrees in pharmacology. Ex. 2032, 226:6-12.
`
`Dr. Winkler testified that he did not know whether Bob Moriarty, the lead
`
`author of Moriarty (Ex. 1009) also had experience with commercial organic
`
`synthesis. Ex. 2032, 237:20-24. He does. In fact, Prof. Moriarty was the president
`
`and founder of Steroids Ltd. from 1989-2014, a company which focused specifically
`
`on “commercial organic synthesis.” Ex. 2031; Ex. 2032, 236:13-239:21.
`
`Each of the above examples makes clear that POSAs, including the authors of
`
`the asserted ground references, are individuals with specific training and experience
`
`in process chemistry applied in an industrial setting. This experience included
`
`performing commercial organic synthesis and
`
`large-scale pharmaceutical
`
`development. This experience and expertise reflects the correct level of skill of the
`
`POSA in this case.
`
`As Dr. Winkler’s own analysis makes clear, someone without appropriate
`
`experience in pharmaceutical manufacturing is prone to dismiss issues surrounding
`
`salt-purification of multi-gram amounts of a structurally-complex product. Dr.
`14
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`Winkler, for example, equates the novel salt-purification of the ’901 patent with
`
`undergraduate chemistry laboratory training exercises. See, e.g., Ex. 1017, ¶¶54-57,
`
`114, 135. Industrial chemists working in pharmaceutical manufacturing facilities are
`
`not working with undergraduate exercises chosen specifically to provide predictable,
`
`and easily accessible results. Indeed, treatises have been published on difficulties
`
`surrounding pharmaceutical manufacturing, including late-stage purification and
`
`salt selection. See, e.g., Ex. 2025, ¶¶56-62, 219-20 (citing Ex. 2008), 159-60 (citing
`
`Ex. 2020), 289-99 (citing Exs. 2018-19, 2021-24).
`
`A person having only a Ph.D. in organic or medicinal chemistry or a closely
`
`related field without experience in pharmaceutical manufacturing likely has never
`
`encountered a situation like the problem facing the inventors of the ’901 patent
`
`claims. While Liquidia points to Exhibits 1020 and 1021 to support a contention that
`
`benchtop scale-type work in a lab includes working on over 2.9 grams, these
`
`references are multi-step processes, and ultimately, as in Exhibit 1021, result in 5
`
`mg (1.5% yield) of end product. Ex. 2032, 306:6-307:11. Neither of these references
`
`support a proposition that benchtop scale-type work includes salt purification of
`
`compounds as complex as treprostinil on a pharmaceutical batch scale. And two
`
`references that came from industry chemists at larger scale cited by Liquidia stand
`
`for the unremarkable proposition that big pharmaceutical companies have access to
`15
`
`4843-1715-7862.2
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`larger reaction vessels and have to address challenges of performing multi-gram,
`
`large scale syntheses on a case-by-case basis.
`
`Because Liquidia’s errors on claim language, claim scope, and the level of
`
`skill skew its analysis, UTC respectfully submits that Liquidia’s reliance on the Final
`
`Written Decision of the ’393 patent is misplaced, and necessitates a finding that
`
`Liquidia failed to meet its burden.
`
`III.
`
`EVEN CONSIDERING THE ’393 FINAL WRITTEN DECISION,
`PETITIONER HAS NOT MET ITS BURDEN FOR GROUND 1 OR
`GROUND 2
`“In an inter partes review, the burden of persuasion is on the petitioner to
`
`prove ‘unpatentability by a preponderance of the evidence,’ and that burden never
`
`shifts to the patentee.” Dynamic Drinkware, LLC v. National Graphics, Inc., 800
`
`F.3d 1375, 1378 (Fed. Cir. 2015) (quoting 35 U.S.C. § 316(e)). Liquidia has not met
`
`its burden.
`
`A. Ground 1: Phares Alone Did Not Render the ’901 Claims Obvious
`In its institution decision, the Board recognized the highly factual nature of
`
`the disputes regarding Ground 1. Since then, Liquidia has offered nothing further to
`
`supplement the conclusory points made in its Petition. UTC and its expert, Dr. Pinal,
`
`by contrast have painstakingly addressed each factual point with analysis and
`
`evidentiary support.
`
`4843-1715-7862.2
`
`16
`
`
`
`Case IPR2020-00770
`Patent 9,604,901
`
`
`
`Patent Owner Sur-Reply
`
`
`
`As stated above, Phares does not teach or suggest forming a “pharmaceutical
`
`batch” or how to produce treprostinil or its salt in a quantity that is large enough and
`
`stable enough to be capable of being used as a pharmaceutical batch for
`
`manufacturing finished dosage forms. Ex. 2025, ¶¶118, 124, 161, 164-71, 204-23.
`
`Liquidia’s Reply asserts that Phares’ detail-free synthetic approach for the opposite
`
`treprostinil enantiomer together with the salt formation example are sufficient to
`
`render the ’901 patent claims unpatentable.
`
`As Dr. Pinal explains, there is insufficient information in the skeletal scheme
`
`to support scaling up such a method to provide a “pharmaceutical batch” of
`
`treprostinil. Ex. 2025, ¶274. Indeed, Liquidia has not identified any teaching in
`
`Phares of a detailed operative synthetic method for treprostinil capable of yielding
`
`2.9 grams or more of treprostinil.
`
`And even if such a synthesis were to be assumed to be within the ambit of a
`
`POSA, Liquidia identifies no information whatsoever in Phares relating to impurities
`
`from any particular step or how those impurities may be addressed. Nor does Phares
`
`describe treprostinil salt formation beyond a two-sentence general description. Ex.
`
`1008, 22.
`
`Moriarty, which relates to producing treprostinil