Trials@uspto.gov Paper 17
`Tel: 571-272-7822
`Entered: October 16, 2015
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`LUPIN LIMITED,
`Petitioner,
`
`v.
`
`JANSSEN SCIENCES IRELAND UC,
`Patent Owner.
`_____________
`
`Case IPR2015-01030
`Patent 8,518,987 B2
`______________
`
`
`
`Before JACQUELINE WRIGHT BONILLA, GRACE KARAFFA
`OBERMANN, and CHRISTOPHER G. PAULRAJ, Administrative Patent
`Judges.
`
`
`BONILLA, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`Tel: 571-272-7822
`Entered: October 16, 2015
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_______________
`
`LUPIN LIMITED,
`Petitioner,
`
`v.
`
`JANSSEN SCIENCES IRELAND UC,
`Patent Owner.
`_____________
`
`Case IPR2015-01030
`Patent 8,518,987 B2
`______________
`
`
`
`Before JACQUELINE WRIGHT BONILLA, GRACE KARAFFA
`OBERMANN, and CHRISTOPHER G. PAULRAJ, Administrative Patent
`Judges.
`
`
`BONILLA, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`
`IPR2015-01030
`Patent 8,518,987 B2
`
`
`I.
`
`INTRODUCTION
`
`Petitioner Lupin Limited (“Petitioner”) filed a Petition requesting
`
`inter partes review of claims 1–19 of U.S. Patent No. 8,518,987 B2
`
`(Ex. 1001, “the ’987 patent”). Paper 1 (“Pet.”). Janssen Sciences Ireland
`
`UC (“Patent Owner”) filed a Preliminary Response. Paper 9 (“Prelim.
`
`Resp.”). We have jurisdiction under 35 U.S.C. § 314(a), which provides that
`
`an inter partes review may not be instituted “unless . . . there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of the
`
`claims challenged in the petition.”
`
`Upon consideration of the Petition and the Preliminary Response, and
`
`for the reasons explained below, we determine that Petitioner has not
`
`established a reasonable likelihood that it would prevail in showing the
`
`unpatentability of any claim challenged in the Petition. Accordingly, we
`
`decline to institute an inter partes review.
`
`A. Related Proceedings
`
`The parties identify the following as related district court proceedings
`
`regarding the ’987 patent: Janssen Prods., L.P. v. Lupin Ltd., C.A. No. 14-
`
`1370 (D.N.J.), now terminated and consolidated with Janssen Products, L.P.
`
`v. Lupin Ltd., C.A. No. 13-3891 (D.N.J.) (stayed pending appeal of Fed. Cir.
`
`case involving related U.S. Pat. No. 7,700,645 B2); Janssen Prods., L.P. v.
`
`Teva Pharm. USA, Inc., C.A. No. 13-7576 (D.N.J.) (terminated); Janssen
`
`Prods., L.P. v. Cipla Ltd., C.A. No. 14-1056 (D. Del.) (terminated); Janssen
`
`Prods., L.P. v. Cipla Ltd., C.A. No. 14-5093 (D.N.J.) (dismissed); Janssen
`
`Prods., L.P. v. Cipla Ltd., C.A. No. 15-0307 (D. Del.) (terminated); and
`
`Janssen Prods., L.P. v. Cipla Ltd., C.A. No. 15-2549 (D.N.J.) (dismissed).
`
`Pet. 5–6; Paper 6, 2–3; Paper 8, 2–4.
`
`
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`2
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`IPR2015-01030
`Patent 8,518,987 B2
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`
`B. The ’987 Patent
`
`The ’987 patent is directed to pseudopolymorphic forms (also called
`
`pseudopolymorphs) of an HIV protease inhibitor having a particular
`
`chemical structure of Formula (X), also known generally as darunavir.
`
`Ex. 1001, 1:17–58, 2:60–3:4; Pet. 1. The specification states that “it was
`
`unexpectedly found that certain modifications of the solid state of compound
`
`of formula (X) positively influenced its applicability in pharmaceutical
`
`formulations,” such that pseudopolymorphic forms contributed to improved
`
`stability and bioavailability. Ex. 1001, 2:51–64.
`
`The specification states that relevant pseudopolymorphs include
`
`alcohol solvates, hydrate solvates, alkane solvates, ketone solvates, and other
`
`solvates, where preferred pseudopolymorphs include the hydrate and
`
`ethanolate solvates. Id. at 3:5–21; 5:10–47. The term “pseudopolymorph”
`
`refers “to polymorphic crystalline forms that have solvent molecules
`
`incorporated in their lattice structures.” Id. at 4:67–5:2. The specification
`
`states that “ʻhydrates’ are substances that are formed by adding water
`
`molecules.” Id. at 4:59–62. In addition, a “solvate” is “a crystal form that
`
`contains either stoichiometric or non-stoichiometric amounts of solvent,”
`
`and because “water is a solvent, solvates also include hydrates.” Id. at 4:64–
`
`67. An “anhydrous form” is “a particular form essentially free of water.”
`
`Id. at 4:58–59.
`
`The specification discloses processes for the crystallization of
`
`pseudopolymorphs of compound of formula (X). Id. at 11:56–14:39, 16:15–
`
`58. The specification describes example pseudopolymorphs that include
`
`Form A (ethanolate) and Form B (hydrate) of the compound of formula (X),
`
`among other crystalline forms. Id. at 5:45–54. The specification teaches
`
`
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`3
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`IPR2015-01030
`Patent 8,518,987 B2
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`that “[s]olvent content of the crystal may vary in different ratios depending
`
`on the conditions applied,” and “the solvent may range between (5:1) and
`
`(1:5),” or in particular “from about 0.2 to about 3 molecules of solvent per 1
`
`molecule of compound of formula (X),” where “preferably the ratio is 1
`
`molecule of solvent per 1 molecule of compound of formula (X).” Id. at
`
`5:55–6:2. In Example 4, Table 10, the specification discloses chemical
`
`information for different forms, including Forms A and B, that are “Hemi-
`
`solvate,” “Mono-solvate,” “Di-solvate,” and “Tri-solvate.” Id. at 17:55–
`
`18:11.
`
`C. Illustrative Claims
`
`The ’987 patent contains nineteen claims. Independent claim 1 and
`
`dependent claims 2 and 19 are representative, and reproduced below.
`
`1. A hydrate of the compound (3R,3aS,6aR)-hexahydrofuro
`[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl]
`(isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate in which
`the ratio of the compound to water is about 1:0.5 to about 1:3.
`
`2. A hydrate having the formula:
`
`
`
`19. The composition of claim 3 further comprising amorphous
`(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-
`aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2-hydroxypr-
`opylcarbamate.
`
`Independent claim 3, upon which claim 19 (and other dependent claims)
`
`depend, is similar to claim 1, but further recites an inert carrier.
`
`
`
`4
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`Patent 8,518,987 B2
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`
`D. Proposed Grounds of Unpatentability
`
`Petitioner advances three grounds of unpatentability under 35 U.S.C.
`
`§ 102 or § 103 in relation to all challenged claims in the ’987 patent (Pet. 7):
`
` Reference[s]
`
`Ghosh 1998 (Ex. 1002)1
`
`Statutory
`Basis
`
`Challenged
`Claims
`
`§ 102
`
`1–19
`
`The ’775 patent (Ex. 1003)2
`
`§ 102
`
`1–19
`
`Ghosh 1998 (Ex. 1002) and the ‘775 patent
`(Ex. 1003) in view of Byrn (Ex. 1004),3
`Desiraju (Ex. 1005),4 and knowledge of one of
`ordinary skill in the art
`
`§ 103
`
`1–19
`
`
`In addition, Petitioner supports its challenges in the Petition with
`
`Declarations of Terence L. Threlfall, Ph.D. (“Threlfall Decl.”) (Ex. 1025),
`
`Keith B. Leffler, Ph.D. (“Leffler Decl.”) (Ex. 1062), Frederick J. Northrup,
`
`Ph.D. (“Northrup Decl.”) (Ex. 1069), and Aristotle G. Kalivretenos, Ph.D.
`
`(“Kalivretenos Decl.”) (Ex. 1082). Pet. 8.
`
`
`1 Ghosh et al., Potent HIV Protease Inhibitors Incorporating High-Affinity
`P2-Ligands and (R)-(Hydroxyethylamino)sulfonamide Isostere, 8
`BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 687 (1998) (“Ghosh 1998”)
`(Ex. 1002).
`2 Vazquez et al., U.S. Patent No. 6,248,775 B1, filed Apr. 8, 1999, issued
`Jun. 19, 2001 (“the ’775 patent”) (Ex. 1003).
`3 Byrn et al., Pharmaceutical Solids: A Strategic Approach to Regulatory
`Considerations, 12 PHARMACEUTICAL RES. 945 (1995) (“Byrn”) (Ex. 1004).
`4 Desiraju, Hydration in Organic Crystals: Prediction from Molecular
`Structure, 6 J. CHEM. SOC’Y CHEM. COMM. 426 (1991) (“Desiraju”) (Ex.
`1005).
`
`
`
`5
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`
`II. ANALYSIS
`
`A. Claim construction
`
`For inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable interpretation in light of the patent specification.
`
`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
`
`1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`
`504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a claim
`
`term must be set forth in the specification with reasonable clarity,
`
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`1. “Hydrate”
`
`Petitioner provides proposed constructions of certain terms in the
`
`challenged claims. Pet. 16–19. Most relevant here, Petitioner states that,
`
`although the plain and ordinary meaning of “hydrate” “typically refers to a
`
`crystalline form of a compound in which water is bound in a specific manner
`
`within a three-dimensional lattice structure,” Petitioner contends that the
`
`specification of the ’987 patent defines the term more broadly. Id. at 17
`
`(citing Ex. 1001, 4:59–62; Ex. 1025 ¶¶ 127, 129). Specifically, according to
`
`Petitioner, “hydrate” does not limit the recited compound to a crystalline
`
`form, but rather encompasses anything formed by adding water molecules to
`
`the recited compound, including those formed in the presence of water
`
`molecules via exposure to ambient humidity. Id. at 17–19; Prelim. Resp. 10.
`
`In support, Petitioner also refers to the prosecution history of the ’987
`
`patent, stating that Patent Owner “repeatedly argued that the Examiner was
`
`
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`6
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`IPR2015-01030
`Patent 8,518,987 B2
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`applying a ‘restrictive definition of “hydrate” that is at odds with the
`
`definition that Applicants provide in their specification.’” Pet. 18 (citing Ex.
`
`1013, 2–3; Ex. 1015, 5–7).
`
`Patent Owner, by contrast, responds that the term “hydrate” refers to a
`
`“crystal form that contains either stoichiometric or non-stoichiometric
`
`amounts of water, i.e., a crystalline substance that is formed by adding water
`
`molecules.” Prelim. Resp. 10. Patent Owner contends that even Petitioner’s
`
`expert, Dr. Threlfall, agrees that the “universally accepted” meaning of
`
`“hydrate” is “a specific crystalline form containing one or more water
`
`molecules aligned within its lattice.” Id. at 11 (citing Ex. 1025 ¶ 127).
`
`Patent Owner argues that neither the specification nor the prosecution
`
`history dictates a broader interpretation of the term such that it encompasses
`
`a non-crystalline form. Id. at 11–14. Patent Owner points to where the title,
`
`abstract, summary of the invention and elsewhere in the specification of the
`
`’987 patent clarifies that its invention relates to “pseudopolymorphic forms”
`
`of the compound in question. Id. at 12–14. In addition, according to Patent
`
`Owner, the Examiner repeatedly applied the “universal understanding” of
`
`the term “hydrate” during prosecution. Id. at 11 (citing Ex. 1009, 4, 7; Ex.
`
`1011, 4, 6–7).
`
`As Patent Owner notes, Petitioner’s own expert, Dr. Threlfall,
`
`expressly states that “[a]s of May 2003, a ‘hydrate’ was universally accepted
`
`to be a specific crystalline form containing one or more water molecules
`
`aligned within its lattice.” Ex. 1025 ¶ 127. Dr. Threlfall cites a number of
`
`scientific references in support of this definition, and acknowledges that “the
`
`Examiner of the ’987 patent also repeatedly applied this universal
`
`understanding of the term.” Id. Petitioner asks us to diverge from that well
`
`
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`7
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`IPR2015-01030
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`understood meaning of the term based on a single sentence in the
`
`specification and statements made by Patent Owner during prosecution.
`
`The sentence in the specification noted by Petitioner states:
`
`“ʻHydration’ refers to the process of adding water molecules to a substance
`
`that occurs in a particular form and ʻhydrates’ are substances that are formed
`
`by adding water molecules.” Ex. 1001, 4:59–62. That sentence does not
`
`persuade us to diverge from the ordinary and customary meaning of the term
`
`as understood by one of ordinary skill in the art, especially in the context of
`
`the entire disclosure in the specification, which clearly relates to
`
`pseudopolymorphic forms as a general matter. While generally indicating
`
`the formation of hydrates requires the addition of water molecules, the
`
`sentence does not state that “hydrates” encompass non-crystalline forms of
`
`the claimed compound—much less define that term as encompassing such
`
`forms.
`
`Moreover, the prosecution history cited by Petitioner indicates that the
`
`Examiner and Patent Owner disagreed, when addressing rejections under 35
`
`U.S.C. § 112, as to whether “hydrate” encompassed a composition including
`
`multiple hydrates or hydrates including ethanol as a solvent. In this context,
`
`Patent Owner argued, for example, that the claims did not “exclude the
`
`addition of other solvents,” i.e. solvents other than water. Ex. 1012, 8–9;
`
`Ex. 1013, 2–5; Ex. 1015, 4–7. Thus, when Patent Owner asserted during
`
`prosecution that the Examiner relied on a “restrictive definition of ‘hydrate’”
`
`(Ex. 1015, 7), Patent Owner did not suggest that the term “hydrate”
`
`encompassed a compound in a non-crystalline form.
`
`We adopt, therefore, as the broadest reasonable interpretation in light
`
`of the specification, the construction provided by Patent Owner for the claim
`
`
`
`8
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`IPR2015-01030
`Patent 8,518,987 B2
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`term “hydrate,” i.e., a “crystal form that contains either stoichiometric or
`
`non-stoichiometric amounts of water, i.e., a crystalline substance that is
`
`formed by adding water molecules.” Prelim. Resp. 10.
`
`2. “Ratio” Limitations
`
`In addition, we adopt Patent Owner’s construction of the “ratio”
`
`limitations as referring to the number of molecules of water per molecule of
`
`the recited compound (darunavir). Id. at 17–18; see also Pet. 16–17
`
`(providing a construction that does not conflict with Patent Owner’s
`
`proposed construction). In view of what is presented in the claim itself, we
`
`further construe the formula presented in claims 2 and 6, which include the
`
`depiction of “* H20,” as referring to one water molecule per molecule of the
`
`presented chemical compound, i.e., a 1:1 ratio of water molecule to
`
`darunavir molecule. Prelim. Resp. 18–19.
`
`3. Other Claim Terms
`
`For the purposes of our Decision, we adopt other proposed claim
`
`constructions asserted by Petitioner, such “composition,” “inert carrier,” and
`
`“pharmaceutically acceptable carrier.” Pet. 16. Those definitions are
`
`consistent with the specification and the ordinary and customary meanings
`
`of the terms, and do not diverge from Patent Owner’s proposed
`
`constructions in a manner that is material to our Decision. Prelim. Resp. 19–
`
`20.
`
`B. Asserted grounds of anticipation of claims 1–19 by Ghosh 1998
`(Ex. 1002) or the ‘775 patent (Ex. 1003)
`
`1. Asserted anticipation by Ghosh 1998
`
`Petitioner contends that Ghosh 1998 discloses darunavir and a process
`
`for making and using a composition comprising darunavir and an inert
`
`carrier. Pet. 20–21. Petitioner implicitly acknowledges that Ghosh 1998
`
`
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`does not expressly describe a “hydrate” of darunavir. Pet. 19–32. Petitioner
`
`contends, however, that the reference inherently describes producing the
`
`“hydrate,” relying on Petitioner’s definition of the term to encompass any
`
`darunavir composition formed by adding water molecules—whether that
`
`composition is crystalline or not. Id. at 22–23. For example, according to
`
`Petitioner, the authors of Ghosh 1998 exposed darunavir to water by using
`
`“aqueous NaHCO3” as a solvent, and by conducting studies in the Chicago
`
`area, which would have exposed darunavir to humidity. Id. (emphasis
`
`omitted) (citing Ex. 1002, 688).
`
` As discussed above, the term “hydrate” refers to a crystalline form of
`
`the recited compound. Even assuming Ghosh 1998 describes, expressly or
`
`inherently, exposing darunavir samples to water in some fashion, that fact
`
`alone does not establish sufficiently that Ghosh 1998 necessarily produced a
`
`crystalline form of darunavir. For the reasons discussed below, Petitioner
`
`does not otherwise establish adequately that exposure of darunavir to water
`
`necessarily produces a “hydrate” as we have construed that term, i.e., as a
`
`crystalline substance.
`
`For example, Petitioner contends that Patent Owner’s arguments
`
`during prosecution of the ’987 patent indicate that Ghosh 1998 necessarily
`
`produced crystalline forms of darunavir formed by adding water. Id. at 23–
`
`24. Petitioner asserts that Patent Owner “argued examples [in the
`
`specification] producing ‘hydrates’ derived via exposing amorphous material
`
`to relative humidity,” and suggests that this argument indicates that Ghosh
`
`1998 necessarily produces hydrate darunavir via exposure to humidity. Id.
`
`at 24 (citing Ex. 1012, 8–9). The prosecution history cited and emphasized
`
`by Petitioner, however, refers to Patent Owner’s discussion of its own
`
`
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`10
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`crystalline forms of darunavir presented in the specification, including Form
`
`B (hydrate) formed from previously prepared Forms A or B (already in
`
`crystalline form) via exposure to “adsorption/desorption tests.” Id. at 24.
`
`That discussion does not establish sufficiently that methods disclosed in
`
`Ghosh 1998 necessarily produced a hydrate form of darunavir, for example,
`
`from another hydrate or other crystalline form via exposure to humidity.
`
`Petitioner does not establish sufficiently how Patent Owner’s statement
`
`about how it formed its own hydrate form (Form B), as disclosed in the
`
`specification, indicates that Ghosh 1998 necessarily produced a hydrate form
`
`darunavir.
`
`In addition, Petitioner relies on Van Gyseghem (Ex. 1006)5 as
`
`indicating that darunavir hydrate, i.e., a hydrate crystalline form, necessarily
`
`forms in the presence of water. Pet. 24–25. In particular, Petitioner points
`
`to Figure 10 and related discussions in Van Gyseghem indicating that a
`
`conversion of “TMC114” (darunavir, PrezistaTM) in an “Anhydrous
`
`Amorphous” form to a “Hydrate Crystalline” form is “likely to occur under
`
`ambient conditions.” Id.; Ex. 1006, 489, 497, Figure 10. The fact that
`
`something is “likely to occur,” however, does not establish that it necessarily
`
`occurs, as needed to establish inherency. Inherency “may not be established
`
`by probabilities or possibilities. The mere fact that a certain thing may result
`
`from a given set of circumstances is not sufficient.” Bettcher Indus., Inc. v.
`
`Bunzl USA, Inc., 661 F.3d 629, 639 (Fed. Cir. 2011) (quoting In re Oelrich,
`
`666 F.2d 578, 581 (CCPA 1981)).
`
`
`5 Van Gyseghem et al., Solid State Characterization of the Anti-HIV Drug
`TMC114: Interconversion of Amorphous TMC114, TMC114 Ethanolate and
`Hydrate, 38 EUR. J. PHARM. SCI. 489 (2009) (“Van Gyseghem”) (Ex. 1006).
`
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`Lastly, Petitioner relies on testing by its own experts of darunavir
`
`compositions, allegedly prepared according to a process disclosed in Ghosh
`
`1998. Pet. 25–26 (citing Ex. 1082 ¶¶ 5–45 (describing synthesis); Ex. 1069
`
`¶¶ 7-8, 28–29 (describing testing and results)). According to Petitioner, such
`
`preparation and testing confirm that “Ghosh 1998 inherently discloses the
`
`claimed hydrates by disclosing at least amorphous darunavir with added
`
`water molecules.” Pet. 25 (citing Ex. 1025 ¶¶ 168–69, 171–72). As noted
`
`above, however, Petitioner does not establish sufficiently that the addition of
`
`water to amorphous darunavir, by itself, even assuming that occurred in
`
`Ghosh 1998, necessarily produces a crystalline form of darunavir.
`
`Moreover, Patent Owner persuades us that the method used by
`
`Petitioner’s expert, Dr. Kalivretenos, when preparing darunavir—allegedly
`
`“in the manner described in” Ghosh 1998 (Ex. 1082 ¶ 5, ¶¶ 6–48)—deviates
`
`from what is described in Ghosh 1998 in significant respects. Prelim. Resp.
`
`23–25. For example, Patent Owner points to evidence indicating that Dr.
`
`Kalivretenos: (1) purchased a necessary bis-THF component from a
`
`commercial supplier, rather than making it in the manner disclosed in Ghosh
`
`1998; (2) added filtering and concentration steps not described in Ghosh
`
`1998; (3) added a purification step not described in Ghosh 1998. Id. at 24
`
`(citing Ex. 1082 ¶¶ 33, 44). Patent Owner also cites information indicating
`
`that such changes to the method disclosed in Ghosh 1998 would have
`
`increased the likelihood of producing a crystalline form. Id. (citing various
`
`exhibits). Because information of record indicates that Dr. Kalivretenos
`
`used a method that notably differs from the method described in Ghosh
`
`1998, Petitioner’s assertions regarding Dr. Kalivretenos’ samples do not
`
`
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`establish sufficiently that Ghosh 1998 necessarily produced a hydrate, i.e.,
`
`crystalline form, of darunavir.
`
`Moreover, even assuming Dr. Kalivretenos crystallized darunavir
`
`(Compound 13, allegedly prepared by the process disclosed in Ghosh 1998)
`
`using ethanol or isopropanol, the information presented does not establish
`
`sufficiently that he crystallized darunavir using water or a water containing
`
`mixture. Prelim. Resp. 41; see also Ex. 1025 ¶¶ 169–170 (referring to
`
`“Compound 13”, “Compound 13 EtOH recrystallized,” and “Compound 13
`
`iPrOH recrystallized”); Ex. 1069 ¶¶ 7–8. Even Petitioner’s own witnesses
`
`state, at best, that certain assays performed by Dr. Northrup on Dr.
`
`Kalivretenos’ Compound 13 sample (“a predominantly amorphous darunavir
`
`sample”) provided data that were “consistent with the presence of water” in
`
`Compound 13. Ex. 1025 ¶ 172; Ex. 1069 ¶¶ 28–29. Those “consistent
`
`with” statements and corresponding information do not establish sufficiently
`
`that Dr. Kalivretenos necessarily prepared a hydrate form of darunavir as
`
`recited in the claims, even assuming he had followed the method of Ghosh
`
`1998.
`
`Petitioner also does not show sufficiently that Ghosh 1998 describes
`
`the ratios of water molecules to darunavir molecule recited in the challenged
`
`claims, either expressly or inherently. Pet. 26–29. Statements by Patent
`
`Owner made during prosecution, regarding its own hydrate Form B, as cited
`
`by Petitioner, do not establish sufficiently that relevant ratios existed in the
`
`samples described in Ghosh 1998. The prosecution history cited by
`
`Petitioner relates to Patent Owner’s asserted enablement and written
`
`description of its own claims. In that context, Patent Owner stated that the
`
`specification describes actual examples of the hemi-, mono- and di-hydrate
`
`
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`13
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`form of the recited compound, and that the claimed hydrates could be
`
`formed by subjecting Form A or Form B (both already in crystalline form) to
`
`various relative humidity. Pet. 27 (citing Ex 1010, 6–7), 29 (citing Ex. 1012,
`
`6–7). The prosecution history cited by Petitioner does not rise to an
`
`admission by Patent Owner that one can presume that the claimed ratios also
`
`existed in the samples described in Ghosh 1998.
`
`Petitioner also argues that “hemi-, mono-, di- and trihydrates are the
`
`most common stoichiometric ratios of water, with monohydrate being the
`
`most common.” Pet. 28 (citing Ex. 1025 ¶ 176). By way of support for that
`
`statement, however, Petitioner relies on a conclusory statement by Dr.
`
`Threlfall in his Declaration. Id.; Ex. 1025 ¶ 176 (stating “in my opinion, []
`
`hemi-, mono-, di- and tri-hydrates are the most common stoichiometric
`
`ratios of water, with monohydrate being the most common” without citation
`
`to scientific evidence in support). Even assuming that those are “common”
`
`stoichiometric ratios of water, that does not persuade us that “a person of
`
`ordinary skill in the art noting the darunavir structure disclosed in Table 1 of
`
`Ghosh 1998” would have “envisage[d] only a limited number of fixed
`
`integer hydrates,” as Petitioner contends, especially when Ghosh 1998 does
`
`not mention hydrates. Pet. 28.
`
`For the reasons discussed above, Petitioner has not established a
`
`reasonable likelihood of prevailing on the ground that Ghosh 1998
`
`anticipates any of claims 1–19 of the ’987 patent.
`
`2. Asserted anticipation by the ’775 patent
`
`Petitioner contends that the ’775 patent anticipates all challenged
`
`claims because “procedures set forth in Examples 1-21 [of the ’775 patent]
`
`disclose water molecules are added throughout the processes to prepare
`
`
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`14
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`IPR2015-01030
`Patent 8,518,987 B2
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`darunavir.” Pet. 32–38. In support of that contention, Petitioner relies on
`
`the same assertions addressed above in relation to Ghosh 1998 regarding the
`
`“hydrate” and the ratio limitations in the challenged claims, although
`
`Petitioner does not assert that its expert made or tested a darunavir
`
`composition prepared according to a process disclosed in the ’775 patent.
`
`Id. at 34–39. For the same reasons discussed above, Petitioner has not
`
`established a reasonable likelihood of prevailing on the ground that the ’775
`
`patent anticipates any of claims 1–19 of the ’987 patent.
`
`C. Asserted ground of obviousness of claims 1–19 over Ghosh 1998
`(Ex. 1002) and the ‘775 patent (Ex. 1003) in view of Byrn (Ex.
`1004), Desiraju (Ex. 1005), and the knowledge of one of ordinary
`skill in the art
`
`As in the grounds discussed above, Petitioner contends that Ghosh
`
`1998 and the ‘775 patent disclose darunavir, its structure, and processes for
`
`preparing it. Pet. 43. Petitioner also contends that “a person of ordinary
`
`skill in the art would have been motivated to evaluate darunavir and address
`
`routine regulatory issues” in relation to that compound, and therefore would
`
`have considered Byrn in relation to darunavir. Pet. 45. Specifically,
`
`Petitioner argues that Bryn relates to Food and Drug Administration
`
`(“FDA”) regulatory issues that would have arisen in connection with an
`
`investigation of a compound such as darunavir, disclosed in Ghosh 1998 and
`
`the ‘775 patent, and one reading those references in combination would have
`
`understood that forming the hydrate form of darunavir would be routine. Id.
`
`at 45–48.
`
`As Patent Owner points out, Byrn does not discuss darunavir or a
`
`structurally similar compound. Prelim. Resp. 43. Instead, when addressing
`
`solid drug substances generally, Byrn states that FDA drug substance
`
`
`
`15
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`IPR2015-01030
`Patent 8,518,987 B2
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`“guidelines” state that analytical procedures should be used to detect
`
`polymorphic, hydrated, or amorphous forms of the drug substance. Ex.
`
`1004, 945. Byrn further states that a New Drug Application (“NDA”)
`
`should contain information on solid state properties. Id. As also stated in
`
`Byrn, and noted by Petitioner, the “guidelines suggest the importance of
`
`controlling the crystal form of the drug substance.” Id.; Pet. 46.
`
`In this context, Bryn discloses a series of “decision trees,” or flow
`
`charts, that provide a “thought process that will lead to development of the
`
`most appropriate analytical controls.” Byrn teaches that “[f]our decision
`
`trees are described . . . : Polymorphs; Hydrates (Solvates); Desolvated
`
`Solvates; and Amorphous Forms.” Id. at 946. Byrn presents the four
`
`decision trees in Figures 1, 6, 9, and, 11, respectively. Id. at 946–952.
`
`Petitioner contends that those decision trees, as well as the directive in
`
`Byrn to crystallize substances “from a very limited selection of solvents,”
`
`such as water, provides “routine procedures for assessing crystallinity.”
`
`Pet. 46–47. Petitioner does not indicate adequately, however, why one
`
`would have necessarily thought to look for a hydrate form of the darunavir
`
`compound, in particular, upon reading the cited references. Id. At best,
`
`Petitioner relies on its argument that “Byrn 1995 discloses routine
`
`procedures for assessing crystallinity,” explaining “crystallization screening
`
`is routine” (Pet. 46–47), without explaining adequately why one would
`
`choose to assess darunavir via such a screen for its hydrate form in
`
`particular.
`
`Furthermore, Petitioner does not indicate adequately where Byrn
`
`discloses a specific method for crystallizing a drug such a darunavir to form
`
`a hydrate. Id. At most, Petitioner points us to where Byrn refers to
`
`
`
`16
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`IPR2015-01030
`Patent 8,518,987 B2
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`crystallization methods generally to make “polymorphs” using solvents such
`
`as “water, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile,
`
`ethyl acetate, hexane and mixtures if appropriate.” Ex. 1004, 946; Pet. 46.
`
`Petitioner also points to where Byrn provides a “separate flow chart relating
`
`specifically to screening for hydrates and counsels that the steps outlined in
`
`this second flow chart pertaining to hydrates should be ‘applied after the
`
`preliminary crystallizations have been completed.’” Pet. 47 (citing Ex.
`
`1004, 949). Such general teachings contrast with the specific crystallization
`
`methods described in the ’987 patent, for example, in relation to forming a
`
`mixture of Form D (acetonate) and Form B (hydrate), or forming Form B
`
`(hydrate) from Form A (ethanolate). Ex. 1001, 16:35–47 (e.g., Example 2),
`
`19:37–20:35 (Example 7).
`
`As mentioned above, Petitioner refers to “crystallization screens” as a
`
`means of performing the decision trees of Bryn, and contends that Bryn
`
`“notes that one of the solvents that should be used in these crystallization
`
`screens is water as well as ethanol.” Pet. 46–47 (citing Ex. 1004, 946).
`
`According to Petitioner, “such a crystallization screening is routine, . . . , and
`
`could be purchased in the relevant time frame from a number of different
`
`companies,” citing Dr. Threlfall’s Declaration. Id. at 47 (citing Ex. 1025
`
`¶¶ 203, 206–08). In this regard, Dr. Threlfall testifies that Byrn “discloses a
`
`handful of standard solvents, including water, that a person of ordinary skill
`
`in the art could utilize in running a routine crystallisation screen,” using
`
`“screening companies” that “provide for the investigation of new solid-state
`
`forms,” such four companies identified by Dr. Threlfall as allegedly set up
`
`before 2003. Ex. 1025 ¶¶ 203, 206–08.
`
`
`
`17
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`
`In further support, Petitioner contends that Patent Owner admitted in a
`
`related litigation that it “used a third-party company to conduct such a screen
`
`utilizing water as one of the solvents to confirm the existence of solid-state
`
`forms.” Pet. 47 (citing Ex. 1024, 466:14–17, 468:6–9 (Wigerinck)
`
`(indicating a third-party that conducted “an investigation of polymorphic
`
`behavior” of the compound); 2374:15–17, 2389:2–4 (Janssens)).
`
`Moreover, according to Petitioner, an ordinary artisan “would also
`
`have reasonably expected the formation of a hydrate in such routine
`
`crystallization efforts.” Pet. 48. In support, Petitioner relies on Desiraju,
`
`asserting that this reference “specifically taught that compounds like
`
`darunavir, in which there is an imbalance in the ratio of hydrogen bond
`
`donors to hydrogen bond acceptors, are more likely to form hydrates.” Id.
`
`(citing Ex. 1005, 427).
`
`In response, Patent Owner points out that while Ghosh 1998 and the
`
`‘775 patent disclose the darunavir compound, neither reference discloses a
`
`darunavir hydrate, “much less one having the darunavir-to-water ratio
`
`limitations recited in the challenged patent claims.” Prelim. Resp. 41–42.
`
`Patent Owner also contends that neither Byrn nor Desiraju mentions
`
`darunavir, nor taught or suggested the conditions needed to create a
`
`darunavir hydrate, nor provided a reasonable basis for expecting that it could
`
`be created, much less one meeting the ratio limitations recited in the
`
`challenged claims. Id. at 42–44, 52.
`
`In particular, Patent Owner contends that Bryn only lists possible
`
`variables, “without identifying the conditions that could lead to discovery of
`
`a hydrate of a particular compound.” Id. at 44. In support, Patent Owner
`
`points to a statement in Byrn explaining that “each individual compound has
`
`
`
`18
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`IPR2015-01030
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`its own peculiarities which require flexibility in approach.” Id. (quoting Ex.
`
`1004, 945). Patent Owner also contends that none of the cited art provided a
`
`reasonable expectation of success in creating a darunavir hydrate.
`
`In this regard, Patent Owner points to a number of references
`
`indicating that creating hydrates/solvates as a general matter was known to
`
`be very unpredictable at the time the ’987 patent was filed. Id. at 49–50
`
`(citing Ex. 2022–2027, Ex. 2013). Moreover, Patent Owner contends that
`
`none of the ref
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