`
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
