UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`ROSELLINI SCIENTIFIC, LLC,
`Petitioner,
`
`v.
`
`GRÜNENTHAL GMBH,
`Patent Owner.
`__________
`
`Case IPR2016-00471
`Patent 7,994,364
`__________
`
`
`
`GRÜNENTHAL’S PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`

`
`
`
`I.
`
`II.
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`Case No. IPR2016-00471
`Patent 7,994,364
`
`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`
`Background ...................................................................................................... 7
`
`A.
`
`Crystals, Polymorphs, and Methods To Study Crystal Forms .............. 7
`
`1.
`
`2.
`
`Crystals and Polymorphs ............................................................ 7
`
`X-ray Powder Diffraction ........................................................... 8
`
`B.
`
`Crystallization .....................................................................................10
`
`C. Grünenthal’s Discovery of Form A of Tapentadol
`Hydrochloride ......................................................................................11
`
`D.
`
`The ’364 Patent ...................................................................................13
`
`III. Level of Skill in the Art .................................................................................14
`
`IV. Claim Construction ........................................................................................14
`
`V.
`
`The Prior Art Cited by Rosellini....................................................................15
`
`A.
`
`B.
`
`EP 0 693 475 Does Not Teach Form A of Tapentadol
`Hydrochloride ......................................................................................15
`
`Bartholomäus Does Not Teach Form A of Tapentadol
`Hydrochloride ......................................................................................16
`
`VI. The Petition Fails To Establish a Reasonable Likelihood that Any
`Claim of the ’364 Patent is Inherently Anticipated .......................................17
`
`A.
`
`B.
`
`Standard for Granting Inter Partes Review ........................................17
`
`Rosellini’s Petition Should be Denied Because Ground 1 Does
`Not Establish Inherent Anticipation of Claims 1–4 and 24–27 ..........18
`
`1.
`
`There Is No Inherent Anticipation Because Marita
`Mueller, a Scientist at Grünenthal, Faithfully Replicated
`Example 25 on Two Separate Occasions and Obtained
`Form B with No Detectable Amount of A ................................19
`
`i
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`Case No. IPR2016-00471
`Patent 7,994,364
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`i.
`
`ii.
`
`iii.
`
`Marita Mueller’s 2002 Reproductions of Example
`25 of the EP ʼ475 Patent Produced Form B ...................22
`
`Synthesis of GB-BN200/Patent (GB-Bu322-1-1) ..........23
`
`Synthesis of GB-Bu322-1-3 ...........................................25
`
`iv. XRPD Analysis of Ms. Mueller’s Tapentadol
`Hydrochloride Products Show Form B, with No
`Detectable Amount of Form A .......................................26
`
`v. Ms. Mueller’s 2009 Replication of Step 3 of
`Example 25 of the EP ’475 Patent (PG1026-001-1-
`1) also Produced Form B ................................................32
`
`2.
`
`Dr. Bihovsky’s “Replications” of Example 25 Are Not
`Faithful Reproductions and Therefore Fail to Establish
`Inherent Anticipation ................................................................34
`
`i.
`
`ii.
`
`By Replacing the Synthesis Steps of Example 25
`with Commercially Available Tapentadol
`Hydrochloride, Dr. Bihovsky Fails to Faithfully
`Reproduce the Example ..................................................35
`
`Dr. Bihovsky Inexplicably Used Different Steps
`and/or Conditions than Example 25 for the
`Formation of Tapentadol and Tapentadol
`Hydrochloride .................................................................40
`
`a.
`
`b.
`
`Dr. Bihovsky’s experiments are inconsistent
`with the preparation of tapentadol free base
`in the EP ’475 patent ............................................40
`
`Dr. Bihovsky further deviates from Example
`25 ..........................................................................42
`
`iii. Rosellini Fails to Provide Any Information about
`when the Final Samples were Made, Shipped, or
`Analyzed by X-Ray Powder Diffraction ........................44
`
`C.
`
`Rosellini’s Petition Should be Denied Because Ground 2 Does
`Establish the Inherent Anticipation of Claims 1–4 and 24–27 ...........45
`
`ii
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`Case No. IPR2016-00471
`Patent 7,994,364
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`1.
`
`2.
`
`Bartholomäus Does Not Anticipate Claims 1–4 and 24–
`27 Because It Does Not Expressly or Inherently Disclose
`Form A of Tapentadol Hydrochloride ......................................46
`
`Petitioner Misconstrues Grünenthal’s Statements During
`the Prosecution of the ’364 patent’s European
`Counterpart ................................................................................50
`
`VII. Additional Flaws in Rosellini’s Petition Warrant Denying Institution
`of Inter Partes Review...................................................................................53
`
`A.
`
`B.
`
`The Coalition for Affordable Drugs VI LLC is an Unnamed
`Real Party-in-Interest ..........................................................................53
`
`The Petition Is an Improper Use of the IPR Proceeding and/or
`an Abuse of Process Under AIA, §§ 316(a)(6) & 316(b) ...................55
`
`VIII. Conclusion .....................................................................................................57
`
`
`
`
`
`iii
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`Case No. IPR2016-00471
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) .......................................................................... 21
`
`In re Armodafinil Patent Litig. Inc.,
`939 F. Supp. 2d 456 (D. Del. 2013).................................................... 3, 19, 35, 38
`
`Coalition for Affordable Drugs VI LLC v. Celgene Corp.,
`IPR2015-01169, Paper 1 (PTAB May 7, 2015) ................................................. 55
`
`Coalition for Affordable Drugs VI LLC v. Celgene Corp.,
`IPR2015-01096, Paper 1 (PTAB April 23, 2015) .............................................. 55
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015), cert. granted sub nom. Cuozzo
`Speed Techs., LLC v. Lee, 136 S. Ct. 890 (2016) ............................................... 14
`
`Eli Lilly & Co. v. Barr Labs.,
`251 F.3d 955 (Fed. Cir. 2001) ............................................................................ 21
`
`Glaxo Inc. v. Novopharm Ltd.,
`52 F.3d 1043 (Fed. Cir. 1995) ........................................................................ 4, 22
`
`Glaxo, Inc. v. Novopharm Ltd.,
`830 F. Supp. 871 (E.D.N.C. 1993), aff’d, 52 F.3d 1043 (Fed. Cir.
`1995) ............................................................................................................... 3, 35
`
`Hansgirg v. Kemmer,
`102 F.2d 212 (C.C.P.A. 1939) ............................................................................ 21
`
`Kropa v. Robie,
`187 F.2d 150 (C.C.P.A. 1951) ............................................................................ 21
`
`Merck & Cie v. Watson Labs., Inc.,
`125 F. Supp. 3d 503 (D. Del. 2015).................................................................... 36
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) .......................................................................... 15
`
`iv
`
`

`
`
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ............................................................................ 21
`
`Case No. IPR2016-00471
`Patent 7,994,364
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`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) .............................................................................. 21
`
`In re Robertson,
`169 F.3d 743 (Fed. Cir. 1999) ............................................................................ 21
`
`Schering Corp. v. Geneva Pharm., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) ............................................................ 3, 4, 17, 21
`
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) .......................................................................... 21
`
`Valeant Int’l (Barbados) SRL v. Watson Pharm., Inc.,
`No. 10-20526-CIV, 2011 WL 6792653 (S.D. Fla. Nov. 8, 2011) ,
`aff’d sub nom. Valeant Int’l Bermuda v. Actavis, Inc., 534 F.
`App’x 999 (Fed. Cir. 2013)
` ................................................................................................................... 3, 19, 36
`
`Federal Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 17
`
`35 U.S.C. § 312 ........................................................................................................ 54
`
`35 U.S.C. § 314 ........................................................................................................ 17
`
`35 U.S.C. § 316 .................................................................................................... 6, 55
`
`Other Authorities
`
`37 C.F.R. § 42.8 ....................................................................................................... 54
`
`37 C.F.R. § 42.106 ..................................................................................................... 6
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.108 ................................................................................................... 17
`
`77 Fed. Reg. 48,756 (Aug. 14, 2012)................................................................. 17, 54
`
`v
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`Case No. IPR2016-00471
`Patent 7,994,364
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`TABLE OF ABBREVIATIONS
`
`Definition
`Trimethylsilyl chloride, also called
`Trimethylchlorosilane
`X-ray powder diffraction
`
`Methyl ethyl ketone, also called 2-
`butanone
`
`
`
`
`
`vi
`
`Abbreviation
`
`TMSCl or TMCS
`
`XRPD
`
`MEK
`
`

`
`Introduction
`
`Case No. IPR2016-00471
`Patent 7,994,364
`
`
`Patent Owner Grünenthal GmbH (“Grünenthal”) submits this Patent Owner
`
`I.
`
`
`Preliminary Response under 37 C.F.R. § 42.107 to the Petition by Rosellini
`
`Scientific, LLC (“Rosellini”) for inter partes review of U.S. Patent No. 7,994,364
`
`(“the ’364 patent”) (Ex. 1001). The Patent Trial and Appeal Board (the “Board”)
`
`should deny Rosellini’s petition because it does not establish that Rosellini has a
`
`reasonable likelihood of prevailing with respect to any challenged claim.
`
`
`
`The ’364 patent is directed to a novel crystalline form of tapentadol
`
`hydrochloride, identified in the patent as “Form A.” (Ex. 1001 at 1:58–60.)
`
`Tapentadol hydrochloride is a powerful pain killer. For example, unlike many
`
`existing pain medications, this compound is a centrally acting analgesic with two
`
`mechanisms of action combined in a single molecule: μ opioid receptor agonism
`
`and norepinephrine reuptake inhibition. (Ex. 2001 at 1; Ex. 2002 at 1.) This unique
`
`dual mechanism of action in a single molecule offers superior advantages over
`
`other known analgesics, including potent pain relief coupled with an improved side
`
`effect profile. (See, e.g., Ex. 2001 at 3; Ex. 2002 at 2–3.) Tapentadol hydrochloride
`
`received FDA approval in 2008.
`
`
`
`When tapentadol hydrochloride was first synthesized in 1994, no one could
`
`have predicted the nature of its crystal form landscape. (See Ex. 2003 at 34.) For
`
`example, even today when a new molecule is synthesized, there is no way to
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`predict whether a molecule will crystallize in multiple crystal forms. (See id.)
`
`Indeed, polymorphism investigations are routinely plagued by uncertainty and
`
`unpredictability. (See id.) Tapentadol hydrochloride was no different, and after
`
`several years of working with the molecule, the inventors of the ’364 patent
`
`discovered Form A.
`
`
`
`As the ’364 patent explains, Form A “is different from the form already
`
`known (Form B) obtained by the procedure described in [the first disclosure of
`
`tapentadol hydrochloride,] example 25 of U.S. Patent No. 6,248,737 [the U.S.
`
`counterpart to European Patent No. 0 693 475 B1 (“the EP ’475 patent”)].” (Ex.
`
`1001 at 1:58–63.) Notably, the inventors also determined that crystalline Form A
`
`“has the same pharmacological activity as Form B but is more stable under
`
`ambient conditions,” and thus can be advantageously used as an active ingredient
`
`in pharmaceutical compositions. (Id. at 4:14–17.)
`
`
`
`It is undisputed that the prior art does not report the existence of Form A.
`
`And, moreover, the ’364 patent and its prosecution history explain and demonstrate
`
`that the very prior art relied on by Rosellini’s petition does not necessarily and
`
`inevitably produce Form A.
`
`
`
`But Rosellini’s petition ignores the law of inherency and brushes aside the
`
`previous reproductions of the prior art provided in the patent and during
`
`prosecution history. Indeed, Rosellini argues that claims 1–4 and 24–27 are
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`inherently anticipated by the very disclosures already shown to produce Form B:
`
`Example 25 of the EP ’475 patent and, alternatively, by the disclosure of Example
`
`1 of International Patent Application Publication No. WO 09/035053 to
`
`Bartholomäus (“Bartholomäus”). (See Pet. at 14.) The defects of Rosellini’s
`
`petition, however, are fatal.
`
`
`
`To be inherent, the claimed invention must be the “‘natural result flowing
`
`from’ the explicit disclosure of the prior art.” Schering Corp. v. Geneva Pharm.,
`
`Inc., 339 F.3d 1373, 1379 (Fed. Cir. 2003). To prove inherent anticipation, it is
`
`necessary to follow the express disclosure of the prior art. See id. In particular, the
`
`party must demonstrate that its reproductions are consistent with how a person of
`
`ordinary skill in the art would have performed the experiment. See, e.g., Glaxo,
`
`Inc. v. Novopharm Ltd., 830 F. Supp. 871, 876–77 (E.D.N.C. 1993), aff’d, 52 F.3d
`
`1043 (Fed. Cir. 1995); see also In re Armodafinil Patent Litig. Inc., 939 F. Supp.
`
`2d 456, 470 (D. Del. 2013) (“[T]he court concludes that the defendants have not
`
`demonstrated clearly and convincingly that their reproductions of the ’855 Patent’s
`
`Preparation I were consistent with how a person of ordinary skill in the art would
`
`have performed the Preparation[.]”); Valeant Int’l (Barb.) SRL v. Watson Pharm.,
`
`Inc., No. 10-20526-CIV, 2011 WL 6792653, at *5 (S.D. Fla. Nov. 8, 2011) (Ex.
`
`2004), aff’d sub nom. Valeant Int’l Berm. v. Actavis, Inc., 534 F. App’x 999 (Fed.
`
`Cir. 2013) (Ex. 2005) (“Thus, because Dr. Adlington did not follow the explicit
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`disclosure of Example 1 of the Mehta patent, his experiment is simply not
`
`probative of the issue of inherent anticipation, as it clearly does not demonstrate
`
`that Form I bupropion hydrobromide is the ‘natural result flowing from the explicit
`
`disclosure of the prior art.’”). Thus, for Rosellini to meet its burden, it must prove
`
`that Form A of tapentadol hydrochloride “necessarily and inevitably” flows from
`
`the practice of what is disclosed in the EP ’475 patent or Bartholomäus. See
`
`Schering, 339 F.3d at 1378.
`
`
`
`But Grünenthal’s reproductions of the prior art have already demonstrated
`
`that Form A of tapentadol hydrochloride does not necessarily and inevitably flow
`
`from the prior art. Accordingly, Rosellini has failed to meet its burden.
`
`Specifically, Grünenthal has shown that the disclosures in EP ’475 and
`
`Bartholomäus result in Form B, not Form A. For example, Grünenthal has repeated
`
`Example 25 in its entirety on two occasions (and step 3 of Example 25 on one
`
`occasion) and has confirmed that this process results in Form B with no detectable
`
`amount of Form A. See Glaxo Inc. v. Novopharm Ltd., 52 F.3d 1043, 1047–48
`
`(Fed. Cir. 1995) (affirming the district court’s finding that the claimed crystalline
`
`form was not anticipated by the disclosure of a prior art process that produced that
`
`form thirteen times because the testing evidence demonstrated that the prior art
`
`could yield crystals of either the claimed polymorph or a different polymorph).
`
`Moreover, Grünenthal has shown that Form B did not convert to Form A under
`
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`normal tableting conditions such as those in Bartholomäus’s Example 1. (See, e.g.,
`
`Ex. 1002 at 65.) In view of Grünenthal’s evidence, combined with the lack of any
`
`credible evidence provided by Rosellini, the Board cannot conclude that Rosellini
`
`has met its burden to establish that the EP ’475 patent or Bartholomäus inherently
`
`anticipates the claims of the ’364 patent.
`
`
`
`Finally, even if the Board were not to consider Patent Owner’s affirmative
`
`evidence, the Petition is nevertheless fatally flawed. Regarding Example 25 of the
`
`EP ’475 patent, Rosellini failed to show that Form A necessarily and inevitably
`
`results from practicing the EP ’475 patent because its conclusion is based on
`
`experiments that failed to faithfully follow the procedure set forth in Example 25.
`
`This failure to follow the disclosure of the prior art is fatal to the Petition. For
`
`example, all of the Rosellini experiments are defective because they side step the
`
`multi-step procedure in Example 25,1 and instead use commercially available Form
`
`A of tapentadol hydrochloride as their starting material. While Rosellini’s
`
`declarant contends that only the latter half of step 3 of Example 25 would influence
`
`the crystalline form of the product, (see Pet. at 22), as explained herein, the
`
`difference in impurity profile of the starting material can influence the final form.
`
`1 Example 25 refers back to Example 2. Example 2 and Example 25 viewed in
`
`combination consist of four steps.
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`As a result of this deviation from the express disclosure of the Example 25, along
`
`with others discussed herein, Rosellini’s experiments are not faithful reproductions
`
`of Example 25, and cannot support a conclusion that Form A of tapentadol
`
`hydrochloride is the inevitable or natural result of practicing the EP ’475 patent.
`
`
`
`Regarding Bartholomäus, Rosellini fails to put forth any evidence to support
`
`its contention and surprisingly attempts to rely merely on attorney argument—with
`
`no data—to establish inherent anticipation. Rosellini has also failed to meet its
`
`burden to prove that Form A necessarily and inevitably results from practicing
`
`Example 1 of Bartholomäus, at least because Rosellini has submitted no data to
`
`support this contention. Thus, Rosellini’s unsupported claims are insufficient to
`
`establish inherent anticipation.
`
`
`
`Additional reasons for denial of inter partes review include Petitioner’s
`
`failure to name at least Coalition for Affordable Drugs VI LLC as a real party-in-
`
`interest. Therefore, the Petition is incomplete and should not be accorded a filing
`
`date. See, e.g., 37 C.F.R. § 42.106(b). Furthermore, Rosellini’s Petition is an
`
`improper use of the inter partes review proceeding and/or an abuse of process
`
`under 35 U.S.C. §§ 316(a)(6), 316(b).
`
`
`
`In sum, because Rosellini has failed to establish that Form A of tapentadol
`
`hydrochloride “necessarily and inevitably” flows from the practice of what is
`
`disclosed in the EP ’475 patent or Bartholomäus, and Rosellini plainly failed to
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`faithfully reproduce the prior art, it cannot prevail on inherent anticipation as to
`
`any claim of the ’364 patent. Accordingly, for these and other reasons developed
`
`below, Petitioner has failed to meet its burden to prove that any claim of the ’364
`
`patent is unpatentable. The Board should therefore deny institution of an inter
`
`partes review.
`
`II. Background
`A. Crystals, Polymorphs, and Methods To Study Crystal Forms
`Crystals and Polymorphs
`1.
`Crystals are solids in which the atoms or molecules are arranged in a
`
`
`
`periodic repeating pattern that extends in three dimensions. (Ex. 2006 at ¶ 16.) The
`
`internal structure or framework of a crystal (called the crystal structure) is
`
`determined by the position of the molecules relative to each other and extending in
`
`three dimensions. (Id. at ¶ 17.) Each crystal system or form has a unit cell with a
`
`distinct fundamental shape. (Id. at ¶ 19.)
`
`
`
`Although the order displayed by molecules in a crystal is characteristic of a
`
`crystalline form, a given chemical species may crystallize in more than one crystal
`
`structure. (Id. at ¶ 21.) This is called polymorphism.2 (Id.) Because the properties
`
`
`2 Materials may also crystallize along with water, the result being a hydrate, or
`
`along with a solvent, the result being a solvate. These can also exhibit different
`
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`7
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`of a solid material depend in part on its crystalline form, polymorphic structures of
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`the same compound can and often do exhibit different chemical, physical, and
`
`biological properties such as Form A and Form B of tapentadol hydrochloride.
`
`(Id.) In the pharmaceutical industry, the fact that compounds of interest have
`
`multiple polymorphs can be of great significance, particularly because the different
`
`polymorphs may have significantly different chemical and physical characteristics,
`
`which may affect the manufacturability, performance, and/or quality of any
`
`ultimate drug product. (Id.)
`
`
`
`The lattice parameters of a crystalline structure are unique and can be used
`
`to distinguish one crystalline form, i.e., polymorph, of a molecule from another.
`
`(Id. at ¶ 23.)
`
`X-ray Powder Diffraction
`
`2.
`X-ray powder diffraction (also called powder X-ray diffraction, PXRD, or
`
`
`
`XRPD) is a technique used to identify crystals and to determine crystal structure.
`
`(Id. at ¶ 24.) In the pharmaceutical industry, XRPD is the most commonly used
`
`method of X-ray analysis for identifying solid forms, including polymorphs. (Id.)
`
`
`structures, or polymorphism. An amorphous solid, exhibiting no long range order,
`
`may also be formed.
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`When X-rays interact with a crystalline substance, the X-rays will be scattered by
`
`the electrons of the atoms of the crystalline structure. (Id. at ¶ 25.) As a result of
`
`this scattering, the X-rays travel in well-defined beams in a few directions. (Id.)
`
`This phenomenon is referred to as diffraction. (Id.)
`
`
`
`Every crystalline substance gives a diffraction pattern characteristic of that
`
`solid. (Id. at ¶ 26.) Thus, the X-ray diffraction pattern of a pure crystal is analogous
`
`to a fingerprint of that solid; it is unique in the same way that a human fingerprint
`
`is unique. (Id.) The X-ray diffraction pattern contains information on the
`
`arrangement of the atoms (or molecules) of the chemical species in the crystalline
`
`state. (Id.) The XRPD plot is often recorded as measurements of “relative”
`
`intensity (relative to the strongest reflection which is given an arbitrary value of
`
`100 on the vertical axis) plotted against the recorded angle of diffraction
`
`(horizontal axis). (Id. at ¶ 28.) The recorded angle of diffraction is often referred to
`
`as “2Θ” (pronounced “two theta”). (Id.) This pattern of peaks can be used to
`
`identify the material in the sample. (Id.) In the chemical literature it is not
`
`uncommon to find solid compounds identified by the listing of X-ray diffraction
`
`peaks or patterns because the XRPD pattern produced by a particular crystal form
`
`of a compound is unique to that crystal form. (Id. at ¶ 26.)
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`9
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`B. Crystallization
`Although crystals have been made for hundreds of years, crystallization
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`remains more of an art than a science. While there are well-known procedures and
`
`skills that all chemists learn in practicing that art, a priori none of these guarantee
`
`success in forming a given crystal. (See Ex. 2003 at 6–33.) When trying to induce a
`
`material to crystallize from a solution, chemists routinely employ techniques such
`
`as stirring, scratching, lowering the temperature with an ice bath or refrigerator, or
`
`adding a small amount of a solid, upon which crystals may begin to grow. (See id.
`
`at 30, 37.) The latter technique is called seeding, and the added material is called
`
`seeds. (Id. at 30.) Although seeding need not employ the desired crystal form, and
`
`can be any particle on which the crystallization process may be initiated, the
`
`desired solid crystalline material is commonly used. (Id. at 30–31.)
`
`
`
`While intentional seeding with the desired crystal form is a procedure that
`
`potentially increases the chemist’s control over the crystallization process,
`
`unintentional seeding can also occur. (Id.) Seeds can be inadvertently added to the
`
`crystallizing medium from the atmosphere, dust, the apparatus surface, the
`
`chemist’s clothes or hair, etc. (See id. at 31.) Indeed, it can be difficult—sometimes
`
`impossible—to prepare a metastable form of a polymorph in a laboratory where a
`
`more stable form has already been formed. (See id. at 29–32; see generally Ex.
`
`2007–2010.) As first noted by Ostwald in 1897, newly appearing crystal forms are
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`10
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`
`generally more stable than earlier discovered ones. (Ex. 2003 at 8.) As a result,
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`unintentional seeds of the more stable polymorphic forms may hinder or prevent
`
`formation of the previously prepared metastable forms. (See, e.g., id. at 29–32.)
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`C. Grünenthal’s Discovery of Form A of Tapentadol Hydrochloride
`When tapentadol hydrochloride (i.e., (–)-(1R,2R)-3-(3-dimethylamino-1-
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`
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`ethyl-2-methylpropyl)-phenol hydrochloride) was first synthesized in 1994, the
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`nature of its crystal form landscape was unknown and unpredictable. (See Ex. 2003
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`at 34.) Over the course of time and after several years working with the molecule,
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`the inventors of the ’364 patent discovered that tapentadol hydrochloride exists in
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`at least two polymorphic forms, Form A and Form B. (See Ex. 2011 at 6–7; Ex.
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`1001 at 1:55–67.) As is the case with research and development of most
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`polymorphic substances, the Patent Owner’s understanding of the properties of,
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`and interconversions between, Form A and Form B evolved over time. (See
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`generally Ex. 2011 at 14–17.)
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`
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`Although Grünenthal characterized Form A by single crystal structure in
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`1998, Grünenthal did not appreciate that Form A was a new form until 2002. (See,
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`e.g., id. at 9–12.) For example, in 2002, Grünenthal conducted resynthesis
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`experiments to repeat Example 25 of the EP ’475 patent. (See id.) These
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`resynthesis experiments produced only Form B, not Form A. (Id.) And even after
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`this, Grünenthal continued their polymorphism investigations on tapentadol
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`hydrochloride. (See, e.g., id. at 14–17.) However, as is typical in many polymorph
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`Case No. IPR2016-00471
`Patent 7,994,364
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`investigations, the results of their experiments were not predictable and not always
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`consistent with initial hypotheses. (Id.)
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`
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`For example, in 2008, Grünenthal evaluated the stability of Forms A and B
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`under the application of 2 tons of pressure for 60 seconds. (Id. at 16.) In these
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`experiments (“the 60-second pressure experiment”), Grünenthal subjected various
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`samples of Forms A and B to two tons of pressure for 60 seconds and found that
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`while Form A remained unchanged, Form B converted into mixtures of various
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`compositions of Forms A and B. (Id.)
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`
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`However, over a year later in 2009, Grünenthal performed another pressure
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`experiment—this time investigating the effect of more normal tableting conditions
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`on Form B of tapentadol hydrochloride. (Id. at 17.) Unlike the previous pressure
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`experiments, which evaluated the effect of pressure on tapentadol hydrochloride in
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`the absence of other ingredients, this experiment evaluated Form B in the presence
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`of excipients. (Id. at 16–17.) In addition, this experiment involved tableting with a
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`Korsch EK0 single tablet press, rather than the application of pressure for 60
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`seconds. (See id. at 17; Ex. 2012 at 1; Ex. 2013 at 1; see also Ex. 2014.) No
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`conversion to crystalline Form A could be detected by XRPD after tableting. (Ex.
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`2011 at 17; Ex. 2015.)
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`D. The ’364 Patent
`The ’364 patent, entitled “CRYSTALLINE FORMS OF (–)-(1R,2R)-3-(3-
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`Case No. IPR2016-00471
`Patent 7,994,364
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`DIMETHYLAMINO-1-ETHYL-2-METHYLPROPYL)-PHENOL
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`HYDROCHLORIDE,” issued on August 9, 2011, and names inventors Andreas
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`Fischer, Helmut Buschmann, Michael Gruss, and Dagmar Lischke. Claim 1 of the
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`’364 patent recites: “A crystalline Form A of [tapentadol hydrochloride] exhibiting
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`at least X-ray lines (2-theta values) in a powder diffraction pattern when measured
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`using Cu Kα radiation at 15.1±0.2, 16.0±0.2, 18.9±0.2, 20.4±0.2, 22.5±0.2,
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`27.3±0.2, 29.3±0.2 and 30.4±0.2.” (Ex. 1001 at 18:66–19:4.) Claims 2–4 and 24,
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`which depend from claim 1, describe the same crystalline Form A of tapentadol
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`hydrochloride with varying degrees of specificity. (Id. at 19:5–19, 20:36–55.)
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`Claims 25–26 describe a solid pharmaceutical composition comprising crystalline
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`Form A of tapentadol hydrochloride exhibiting the same 8 peaks described in
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`claim 1. (Id. at 20:56–22:4.) Claim 27 describes a method of treating or inhibiting
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`pain or urinary incontinence comprising administering crystalline Form A of
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`tapentadol hydrochloride to a subject in need thereof. (Id. at 22:5–13.)
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`
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`The ’364 patent explains that “[t]he present invention provides a new form
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`(Form A) of [tapentadol hydrochloride] which is different from the form already
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`known (Form B) obtained by the procedure described in Example 25 of U.S. Patent
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`No. 6,248,737 [the U.S. counterpart to European Patent No. 0 693 475 B1 (“the EP
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`Case No. IPR2016-00471
`Patent 7,994,364
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`’475 patent”)].” (Id. at 1:58–63.) Example 7 of the ’364 patent establishes that
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`following Example 25 resulted only in Form B. (Id. at 7:30–41.) As explained
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`above, the new form that was discovered by the inventors had the same efficacy as
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`the previously obtained form, but also had the advantage of being more stable
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`under ambient conditions.
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`III. Level of Skill in the Art
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`In June 2004, a person of ordinary skill in the art of the ’364 patent would
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`have had a bachelor’s degree in chemistry, chemical engineering, or related
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`disciplines and either: (i) at least three years of experience related to organic
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`synthesis, API manufacturing and formulation, or detection and/or evaluation of
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`solid state forms in the pharmaceutical industry; or (ii) an advanced degree in
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`chemistry, chemical engineering, or related disciplines. Such a person would have
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`a working knowledge of the preparation, characterization, and analysis of solid
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`state forms, including a working knowledge of crystallography. A person of
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`ordinary skill in the art may work as part of an interdisciplinary team that could
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`include persons with a Pharm. D., M.D., or other relevant advanced degree and/or
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`relevant experience with analgesics.
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`IV. Claim Construction
`Claim terms are given their broadest reasonable interpretation in inter partes
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`review proceedings. In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1279 (Fed.
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`Cir. 2015), cert. granted sub nom. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct.
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`890 (2016). This interpretation must nonetheless be consistent with the claim
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`language, specification, and prosecution history. Microsoft Corp. v. Proxyconn,
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`Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015) (“A construction that is ‘unreasonably
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`broad’ and which does not ‘reasonably reflect the plain language and disclosure’
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`will not pass muster.”). Solely for purposes of this proceeding, Patent Owner
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`submits that the claim terms should be given their plain meaning as understood by
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`one of ordinary skill in the art and consistent with the disclosure. Id. Patent Owner,
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`however, reserves the right to propose its own claim construction in the Patent
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`Owner Response if the Board institutes inter partes review.
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`V. The Prior Art Cited by Rosellini
`A. EP 0 693 475 Does Not Teach Form A of Tapentadol
`Hydrochloride
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`
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`The EP ’475 patent is the first disclosure of tapentadol hydrochloride and
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`describes the synthesis of this