Paper No. 12
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Petitioner,
`
`v.
`
`FOREST LABORATORIES HOLDINGS LIMITED
`Patent Owner
`________________
`
`Case IPR2016-00379
`Patent 6,545,040
`________________
`
`PRELIMINARY RESPONSE UNDER 37 C.F.R. § 42.107
`OF PATENT OWNER
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`
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`Preliminary Response in IPR2016-00379
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`Table of Contents
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`Summary of the Argument ........................................................................... 1
`
`I.
`
`II.
`
`Background of the Invention, the ’040 Patent and the Prior Art ............. 4
`A. Nebivolol ............................................................................................... 4
`B.
`The ’040 Patent .................................................................................... 6
`C.
`Effective Filing Date of the ’040 Patent and Person of Ordinary
`Skill in the Art ...................................................................................... 7
`Prosecution History of the ’040 Patent .............................................. 7
`1.
`The Examiner Rejected the Claims as Obvious Over the ’362
`Patent ........................................................................................... 7
`The Board Found Substantial Evidence of Unexpected Results
`Rendered the Claims Non-Obvious .......................................... 11
`Further Prosecution Narrowed the Claims and Provided
`Additional Evidence of Non-Obviousness ............................... 13
`The Primary Reference of the Grounds – the ’362 Patent ............ 14
`1.
`The ’362 Patent Does Not Describe the Absolute
`Stereochemistry of Any of the Disclosed Compounds ............. 16
`The ’362 Patent Does Not Describe RSSS-Nebivolol or the
`Combination of RSSS- and SRRR-Nebivolol .......................... 18
`The ’362 Patent Provides Biological Data Demonstrating
`Cardioselectivity for Many Compounds ................................... 20
`The Secondary References ................................................................ 21
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`D.
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`E.
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`F.
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`2.
`
`3.
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`2.
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`3.
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`III. Claim Construction ..................................................................................... 22
`
`IV. The PTAB Should Dismiss the Petition and Not Institute Trial ............. 23
`The Petition Fails to Set Forth a Prima Facie Showing of
`A.
`Obviousness of the Claims Over the ’362 Patent ........................... 24
`1.
`The Petition Fails to Identify a Credible Basis for Selecting
`Compound 84 for Further Investigation ................................... 24
`a.
`The Arbitrary >15,000 Cardioselectivity Ratio Theory Is
`Inconsistent with the ’362 Patent Disclosure ................. 28
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`Preliminary Response in IPR2016-00379
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`b.
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`c.
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`The Prior Art Does Not Support Petitioner’s Arbitrary
`>15,000 Relative Cardioselectivity Value as Being the
`Sole Selection Criteria for Investigating Compounds .... 32
`Petitioner’s Selection of Compound 84 Conflicts Even
`With Its Own Rationale for Selecting Compounds for
`Further Investigation ....................................................... 35
`A Skilled Person Would Not Have Modified the Prior Art to
`Yield the Claimed Compound and Composition ...................... 37
`The Board Found Secondary Considerations Rendered the
`Contested Claims Not Obvious over the ’362 Patent ..................... 44
`1.
`The Evidence Before the Board During Examination
`Established the Inventions of Claims 1 and 2 Had Significant
`Unexpected Results ................................................................... 46
`The Petition Does Not Substantively Challenge the Evidence of
`Objective Considerations .......................................................... 51
`The Board Should Deny the Petition Under § 325(d) .................... 56
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`2.
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`2.
`
`B.
`
`C.
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`V. Conclusion .................................................................................................... 60
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`Preliminary Response in IPR2016-00379
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`Table of Authorities
`
`Cases
`Aventis Pharma Deutschland GMBH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir 2007) ............................................................... 38, 39, 40
`
`Page(s)
`
`Brown & Williamson Tobacco Corp. v. Philip Morris Inc.,
`229 F.3d 1120 (Fed. Cir. 2000) .......................................................................... 53
`
`Conoco, Inc. v. Energy & Envtl. Int’l, L.C.,
`460 F.3d 1349 (Fed. Cir. 2006) .......................................................................... 23
`
`C.R. Bard, Inc. v. Med. Components, Inc.,
`IPR2015-01660, Paper 9 (Feb. 9, 2016) ............................................................. 28
`
`Daiichi Sankyo Co., v. Matrix Labs.,
`619 F.3d 1346 (Fed. Cir. 2010) .................................................................... 24, 37
`
`Forest Labs., Inc., v. Ivax Pharms., Inc.,
`501 F.3d 1263 (Fed. Cir. 2007) .......................................................................... 44
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 52
`
`Harmonic Inc. v. Avid Tech., Inc.,
`815 F.3d 1356 (Fed. Cir. Mar. 1, 2016) .............................................................. 28
`
`Hoechst Celanese Corp. v. BP Chem. Ltd.,
`78 F.3d 1575 (Fed. Cir. 1996) ............................................................................ 30
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 54
`
`Kinetic Techs., Inc. v. Skywork Solutions, Inc.,
`IPR2014-00529, Paper 8 (Sept. 23, 2014) .......................................................... 28
`
`Knoll Pharm. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) .......................................................................... 52
`
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 11 (Feb. 24, 2016) ......................................................... 60
`
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`Sanofi-Aventis Deutschland GmbH v. Glenmark Pharms., Inc.,
`748 F.3d 1354 (Fed. Cir. 2014) .......................................................................... 52
`
`Sensus USA, Inc. v. Certified Measurement LLC,
`IPR2015-01311, Paper 13 (Dec. 8, 2015)........................................................... 28
`
`Spectrum Pharmaceuticals, Inc. v. Sandoz, Inc.,
`802 F.3d 1326 (Fed. Cir. 2015) .......................................................................... 38
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ......................................................................... 24
`
`Torrent Pharm. Ltd. v. Merck Frosst Canada & Co.,
`IPR2014-00559, Paper 8 (Oct. 1, 2014) ............................................................. 24
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) .......................................................................... 22
`
`Statutes
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`35 U.S.C. § 103 .................................................................................................. 40, 42
`
`35 U.S.C. § 325(d) ................................................................................... 4, 24, 56, 60
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`Exhibit List
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`2002
`
`2003
`
`Exhibit # Reference Name
`2001
`Brodde, O.-E., “Bisoprolol (EMD 33512), Highly Selective β1-
`Adrenoceptor Antagonist: In Vitro and In Vivo Studies,” Journal of
`Cardiovascular Pharmacology, vol. 8(Suppl. 11) S29-S35 (1986)
`Rimele et al., “Comparison of the β-Adrenoceptor Affinity and
`Selectivity of Cetamolol, Atenolol, Betaxolol, and ICI-118551,”
`Journal of Cardiovascular Pharmacology, vol. 12:208-217 (1988)
`Haeusler, G., “Pharmacology of β-Blockers: Classical Aspects and
`Recent Developments,” J. Cardiovascular Pharmacology 16(Supp.
`5):S1-S9 (1990)
`Lopressor® (metoprolol tartrate) Prescribing information
`Tenormin® (atenolol) Prescribing information
`Inderal® (propranolol hydrochloride) Prescribing information
`
`2004
`2005
`2006
`
`
`
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`Preliminary Response in IPR2016-00379
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`I.
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`Summary of the Argument
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`In its Petition, Lower Drug Prices for Consumers, LLC (“Petitioner”) asserts
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`the compositions and methods of claims 1-6 of U.S. Patent No. 6,545,040 (“the
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`’040 patent”) would have been obvious to a person of ordinary skill in the art based
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`on U.S. Patent No. 4,654,362 (“the ’362 patent”) (Ex. 1004) in view of known
`
`techniques for separating stereoisomers. Paper 6, Corrected Petition (“Pet.”) at 6.
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`But the Board has already found precisely the contrary to be true—it reversed
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`rejections holding comparable claims obvious based on the same ’362 patent
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`during original examination of the ’040 patent. It should do so again, as the
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`Petition advances no new evidence or theories that compel a different result.
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`The contested claims cover, inter alia, the pharmaceutical product nebivolol,
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`along with methods of using that product to treat hypertension and reduce blood
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`pressure. Nebivolol is a powerful β-blocker that selectively blocks β1-adrenergic
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`receptors, resulting in beneficial effects on both systolic and diastolic cardiac
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`performance. It has achieved a remarkable degree of commercial success due to
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`the unique properties directly linked to its particular chemical makeup. As the
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`record shows, neither nebivolol nor its use to treat patients would have been
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`obvious over the prior art.
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`Despite this record, and particularly the Board’s finding that the contested
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`claims were not obvious over the ’362 patent, Petitioner argues in its petition that
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`the contested claims would have been obvious over the same prior art yet it fails to
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`engage the evidence which the Board found established the contrary. The Petition
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`should be denied for any of three independent reasons.
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`First, Petitioner has not established the contested claims would have been
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`prima facie obvious over the ’362 patent. Petitioner’s theory is that out of the
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`large genus of compounds disclosed in the ’362 patent, a person of ordinary skill in
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`the art would have selected a single composition, denoted “Compound 84,” as a
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`lead for further investigation. But to reach that conclusion, Petitioner employs a
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`flawed and artificial test for selecting compounds for further investigation; namely,
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`that a skilled person would select compounds having a β1-receptor to β2-receptor
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`selectivity ratio of 15,000:1 or higher. Pet. at 22, 33. Petitioner provides no
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`explanation for why “15,000:1” was chosen and cites no literature to support it.
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`Petitioner’s theory is contrary to the teachings of both the ’362 patent and
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`the prior art. For example, Petitioner’s criteria excludes all of the compounds the
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`’362 patent identifies as the “most preferred” compounds for development. Even if
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`that criteria were used, Petitioner does not explain why a skilled person would
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`have been led to Compound 84 when other compounds in the ’362 patent have a
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`higher selectivity ratio. The >15,000 β1-receptor to β2-receptor selectivity ratio
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`figure also finds no support in the prior art, which identifies compounds having
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`ratios far below that cutoff as warranting further investigation.
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`Petitioner’s obviousness theory should be seen for what it is—a hindsight-
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`driven attempt to artificially limit both the number and the identity of the
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`compounds which the ’362 patent indicates should be investigated further. The
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`>15,000 figure is simply a prop for the Petitioner’s backward-looking obviousness
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`theory, and without it Petitioner’s obviousness case collapses.
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`Second, the Board should dismiss the Petition because it has already found
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`that substantial evidence of unexpected properties defeats Petitioner’s theory of
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`obviousness. During original examination, the Examiner rejected broader claims
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`as obvious over the disclosure of Compound 84 in the ’362 patent in combination
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`with known techniques for separating mixtures of stereoisomers. On appeal, the
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`Board simply assumed the Examiner had established a prima facie case of
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`obviousness and then proceeded to reverse those rejections based on the
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`compelling evidence of unexpected results presented by Patent Owner. The Board
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`specifically found that declarations submitted during examination showed that a
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`person of ordinary skill in the art would not have expected one of the stereoisomers
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`of Compound 84 to have a potentiating property on a second of those
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`stereoisomers, and that the unexpected potentiating property was not insignificant.
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`Rather than contesting the substance of the evidence of unexpected results,
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`Petitioner simply recycles the Examiner’s discredited obviousness theory,
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`contending the claimed compositions would have been obvious over Compound 84
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`in view of chromatography techniques that could be used to separate Compound 84
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`into individual stereoisomers, which could then be formulated into one or two-
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`stereoisomer compositions. Critically, Petitioner presents no contrary evidence
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`about the presence of unexpected results in the claimed compositions. Petitioner’s
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`failure to substantively address, much less refute, that evidence which the Board
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`already found sufficient to overcome a prima facie case of obviousness over the
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`’362 patent, is fatal to the Petition. Simply put, Petitioner cannot show that it has a
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`reasonable likelihood of success (the prerequisite finding to justify institution of
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`this proceeding) because it has not even challenged the evidence of unexpected
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`results that the Board has already found dispositive of non-obviousness.
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`Third, the Board should exercise its discretion under 35 U.S.C. § 325(d) and
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`dismiss this petition because Petitioner simply recycles the obviousness arguments
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`considered and rejected by the Board during prosecution. Because Petitioner has
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`provided no new evidence that could cast doubt on the Board’s previous findings,
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`the Board should not waste its limited resources reconsidering factual issues it
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`already decided. The Board should decline to institute trial.
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`II. Background of the Invention, the ’040 Patent and the Prior Art
`A. Nebivolol
`Nebivolol hydrochloride is the active ingredient of the drug called
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`BYSTOLIC, which is used to treat hypertension. Nebivolol is a racemic mixture
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`of two stereoisomers1, RSSS- and SRRR-nebivolol, depicted below.
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`Preliminary Response in IPR2016-00379
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`As shown in the figures, various atoms are “chiral centers” and each such atom is
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`denoted with the letter R or S, which indicates its spatial configuration. Thus,
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`“SRRR-nebivolol” indicates that the first chiral center is in the S orientation, the
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`second chiral center is in the R orientation, and so on. Because RSSS- and SRRR-
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`nebivolol have opposite orientations at every chiral center, they are enantiomers,
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`i.e., the compounds are non-superimposable mirror images of one another.2
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`Nebivolol (i.e., RSSS-, SRRR-nebivolol) has β-adrenergic blocking activity
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`(i.e., beneficial effects on systolic and diastolic cardiac performance) as well as
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`vasodilating properties (i.e., relaxation of blood vessels). Ex. 1002 at 223, 229
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`1
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`Stereoisomers are compounds with the same chemical formula and sequence
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`of atoms, but different three-dimensional orientations of the atoms.
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`2
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`Stereoisomeric compounds may also be diastereomers, i.e., compounds with
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`different spatial configurations at one or more (but not all) of the chiral centers and
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`that are not mirror images of each other. For example, RSRR-nebivolol is a
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`diastereomer of RSSS-nebivolol.
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`(Dupont Decl.). The drug combines highly selective β1-receptor blockade,
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`mediated by the SRRR compound, with vasodilation, which is mainly mediated by
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`the RSSS compound. Id. at 229. Studies show that the combination of both
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`compounds produces nebivolol’s unique pharmacodynamic profile. Id.
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`The ’040 Patent
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`B.
`The ’040 patent relates generally to nebivolol and methods of using
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`nebivolol to treat hypertension. In particular, claim 1 of the ’040 patent is directed
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`to a composition consisting of RSSS-nebivolol. Ex. 1001 at 11:22-32. Claim 2
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`specifies a pharmaceutical composition consisting of two stereoisomers: (i) RSSS-
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`nebivolol, and (ii) the blood pressure reducing compound SRRR-nebivolol, in
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`combination with a pharmaceutically acceptable carrier. Claims 3-6 further
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`specify additional limitations or methods of treating hypertension comprising
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`administering an effective amount of the RSSS-, SRRR-nebivolol pharmaceutical
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`composition. Id. at 11:33-12:35.
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`The claimed invention is based on the discovery that the potency of
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`nebivolol is due in part to the unexpected properties of the RSSS-nebivolol
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`stereoisomer. While RSSS-nebivolol has low activity as a blood pressure reducing
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`agent, it significantly and substantially potentiates the blood-pressure reducing
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`activity of its enantiomer SRRR-nebivolol. Ex. 1002 at 44 (Xhonneux Decl.), 129-
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`32 (Response). This is so despite the fact that RSSS-nebivolol has about 100 times
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`lower binding affinity to β1-adrenergic receptors than SRRR-nebivolol and when
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`given in combination does not result in significant additional heart rate reduction.
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`See, e.g., Ex. 1002 at 39-40 (Pauwels Decl.), 41-45 (Xhonneux Decl.), 96-100
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`(Response), 151-157 (Appeal Brief), 220-223 (Dupont Decl.), 214-217
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`(Amendment); see also Ex. 1001 at 10:31-11:19. In addition, the hemodynamic
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`profile (i.e., its beneficial effects on blood pressure and circulation), which is
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`different from typical β1-adrenergic blockers (such as SRRR-nebivolol alone),
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`results from the combined activity of the RSSS-nebivolol and SRRR-nebivolol
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`compounds. Ex. 1002 at 221, 225-229 (Dupont Decl.).
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`C. Effective Filing Date of the ’040 Patent and Person of Ordinary
`Skill in the Art
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`Patent Owner agrees with Petitioner’s contention that the ’040 patent has an
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`effective filing date of March 23, 1988. Pet. at 8 n.1.
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`For the purposes of this preliminary response, Patent Owner does not dispute
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`Petitioner’s description of a person of ordinary skill in the art in the field of the
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`’040 patent. See Pet. at 25-28.
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`D.
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`Prosecution History of the ’040 Patent
`1.
`
`The Examiner Rejected the Claims as Obvious Over the
`’362 Patent
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`During examination of the ’040 patent, the Examiner rejected claims
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`analogous to the contested claims3 as obvious over the ’362 patent. See e.g., Ex.
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`1002 at 114, 116 (Final Rejection). The Examiner found that the ’362 patent
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`teaches “all position isomers,” that “[i]t is well settled patent law that the skilled
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`artisan possessing the racemate, possesses the optical isomers,” and that “[a]bsent
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`information to the contrary, the skilled artisan would have seen optical isomer
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`separation as a routine procedure leading to the compounds claimed herein.” Id.
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`In addition, the Examiner contended that “[b]iological testing for the claimed
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`compounds would have been well within the skill of the artisan, and such artisan
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`would have expected the various biological activity levels set forth herein,” and
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`activity levels were an expected activity of the compound, i.e., an inherent
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`function, that did not distinguish it over the prior art. Id. at 114-15.
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`The claims rejected by the Examiner were closely analogous, but broader,
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`than the claims issuing in the ’040 patent, as shown in the comparison of issued
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`claims 1-3 of the ’040 patent with then-pending claims 25-26, below:
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`3
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`The rejected claims used the phrase “consisting essentially of” to define the
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`compositions. See Ex. 1002 at 216 (Amendment). The claims issued in the ’040
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`patent, by contrast, use the narrower term “consisting of” but otherwise preserve
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`the language of those prior claims. See Ex. 1001 at claims 1 & 2.
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`Rejected Claim
`25. A composition consisting essentially
`of [the RSSS stereoisomer of α, α ‘-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]].
`26. A pharmaceutical composition
`consisting essentially of a
`pharmaceutically acceptable carrier and,
`as active ingredients: (a) the blood
`pressure reducing compound [the SRRR
`stereoisomer of α, α’-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]]
`and (b) [the RSSS stereoisomer of α, α’-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]],
`Compound (b) being present in an
`amount capable of potentiating the
`blood pressure lowering effect of
`compound (a), above.
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`Preliminary Response in IPR2016-00379
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`’040 Patent Claim
`1. A composition consisting of [the
`RSSS stereoisomer of α, α ‘-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]].
`2. A pharmaceutical composition
`consisting of a pharmaceutically
`acceptable carrier and, as active
`ingredients: (a) the blood pressure
`reducing compound [the SRRR
`stereoisomer of α, α’-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]]
`and (b) [the RSSS stereoisomer of α, α’-
`[iminobismethylene]bis[6-fluoro-3,4-
`dihydro-2H-1-benzopyran-2-methanol]].
`
`3. A composition according to claim 2
`wherein compound (b) is present in an
`amount capable of potentiating the
`activity of the blood pressure reducing
`compound (a).
`
`
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`In other words, the rejected claims defined the compositions as “consisting
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`essentially of” one or two of the stereoisomers, while the claims issued in the ’040
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`patent define those compositions using the term “consisting of” but otherwise
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`preserving the language of the claims.
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`Patent Owner responded to the rejections, inter alia, by providing evidence,
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`in the form of a declaration from Dr. Raymond Xhonneux. Ex. 1002 at 41-45. Dr.
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`Xhonneux described the results of studies conducted on spontaneous hypertensive
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`rats given varying doses of RSSS-nebivolol, SRRR-nebivolol, or combinations of
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`the two compounds. Id. The studies assessed the effect of the compounds or
`
`placebo on systolic and diastolic blood pressure and on heart rate. Id. Based on
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`the results, Dr. Xhonneux reached several conclusions:
`
`(a) The potentiating (RSSS)-compound only minimally affects blood
`pressure when administered alone (Ex. 1002 at Table 1);
`(b) The blood pressure reducing (SRRR)-compound is a potent blood
`pressure reducing agent when administered alone (Ex. 1002 at Table
`2); and
`(c) The blood pressure reducing effect of the (SRRR)-compound
`administered at a dose of 1.25 mg/kg i.p. is potentiated significantly
`when the potentiating (RSSS)-compound is administered
`concommittantly at a dose ranging from 0.16 to 5 mg/kg i.p.
`(d) At 1.25 mg.kg-1, the (SRRR)-compound significantly reduces
`heart rate, an effect which is not potentiated by the (RSSS)-compound
`in doses up to 1.25mg.kg-1.
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`Id. Thus, according to Dr. Xhonneux, “[a]ll these findings indicate that the
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`(RSSS)-compound potentiates the antihypertensive effects of the (SRRR)-
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`Preliminary Response in IPR2016-00379
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`compound, but not the bradycardiac affects of the (SRRR) compound.” Id. at 44.4
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`Relying on this evidence, Patent Owner argued that the claims “illustrate a
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`classic case of synergistic results wherein the benefits of the two materials used in
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`combination far exceed the additive effect that would have been expected from the
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`properties exhibited by each alone.” Id. at 98 (Response).
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`Despite this evidence, the Examiner maintained the rejections. According to
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`the Examiner, the declaration provided by Dr. Xhonneux was not probative of
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`patentability because the optical isomer comparisons had not been compared to the
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`“natural racemic mixture” and because the differences stated with regard to the
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`isomers are “differences in degree, not patentably distinct differences in kind.” Id.
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`at 114, 116 (Final Rejection).
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`Patent Owner appealed the obviousness rejection to the Board. Id. at 137-
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`142, 151-157 (Appeal Brief), 169-175 (Examiner’s Answer), 177-180 (Reply
`
`Brief), 183-186 (Supplemental Examiner’s Answer).
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`2.
`
`The Board Found Substantial Evidence of Unexpected
`Results Rendered the Claims Non-Obvious
`On appeal, the Board accepted without deciding that the Examiner had
`
`established a prima facie case of obviousness, but then reversed the Examiner’s
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`obviousness rejection “on the strength of appellants’ rebuttal evidence establishing
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`4 Bradycardiac effects include a slowing of the heart rate, which can be dangerous.
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`that the claimed subject matter possesses unexpectedly superior results.” Id. at 200
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`(Decision on Appeal) (stating it “accept[ed], without deciding,” that the pending
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`claims were prima facie obvious over the ’362 patent).
`
`The Board explicitly noted that the ’362 patent discloses Compound 84, an
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`unresolved mixture of RSSS, SRRR, RSRR, and SRSS stereoisomers of α,α’-
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`[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]. Id.
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`at 198-199. The Board also stated that the ’362 patent discloses that “[p]ure
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`stereochemically isomeric forms of the compounds . . . may be obtained by the
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`application of art-known procedures.” Id. at 199 (alteration in original).
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`The Board determined, however, that the declaration of Dr. Xhonneux
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`rebutted the presumed prima facie case. The Board explained that the declaration
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`“presents evidence supporting a conclusion that the RSSS stereoisomer, unlike its
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`enantiomer, SRRR, ‘only minimally affects blood pressure when administered
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`alone’ but significantly ‘potentiates the antihypertensive effects of the (SRRR)-
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`compound, but not the bradycardiac affects [sic] of the (SRRR)-compound.’” Id.
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`at 199-200. The Board determined that the Examiner did not provide any reason
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`why a person having ordinary skill in the art would have expected the RSSS
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`stereoisomer to have those properties or “that the potentiating property, described
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`in the declaration, is insignificant.” Id. at 200. The Board thus reversed the
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`Examiner’s rejection of the claims as obvious over the ’362 patent and remanded
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`the case to the Examiner to consider whether the claims encompassed Compound
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`84 in view of the claims’ use of the “consisting essentially of” phrase. Id. at 204.
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`3.
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`Further Prosecution Narrowed the Claims and Provided
`Additional Evidence of Non-Obviousness
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`On remand, Patent Owner cancelled the pending claims and added new
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`claims using the phrase “consisting of” instead of “consisting essentially of,”
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`resulting in claims that were narrower than those considered by the Board. See id.
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`at 210-12, 216 (Amendment). The claim limitation reciting the inherent property
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`of potentiation of the SRRR enantiomer by the RSSS enantiomer was also moved
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`to a dependent claim (issued as claim 3). Rather than amend the independent
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`claims, new claims were provided, specifically claims 27- 29 (which issued as
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`claims 1-3 of the ’040 patent). Claims 21 and 22 were then amended to depend
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`from claims 29 and 28, respectively, and claims 20, 25 and 26 were cancelled. The
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`amended claims, thus, were the same or narrower in all respects relative to the
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`claims considered during the Board appeal.
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`Patent Owner also provided a declaration by Dr. Alain Dupont. Id. at 232-
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`43. Dr. Dupont’s declaration provided evidence that the RSSS enantiomer
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`possesses additional unexpected properties relative to those that had been shown in
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`Mr. Xhonneux’s declaration. In particular, Dr. Dupont explained that the RSSS
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`enantiomer showed enhancement of the vasodilation properties required to produce
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`nebivolol’s unique pharmacodynamic profile. Id. at 222-224, 226-229.
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`Dr. Dupont also discussed two published articles relating to nebivolol’s
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`effects in human clinical investigations. Dr. Dupont explained that the articles
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`would not have been seen as providing any insights into the pharmacological
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`properties of the claimed compositions because they (1) lacked sufficient trial
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`sensitivity to detect a potentiating effect or (2) showed results from testing in
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`healthy volunteers and thus were not designed to answer the questions regarding
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`possible potentiation of blood pressure lowering effect by the RSSS enantiomer.
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`Id. at 221-23, 214-15 (Amendment).
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`The Examiner subsequently allowed the amended claims after considering
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`the Board’s decision and the declaration of Dr. Dupont. Id. at 248 (Notice of
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`Allowability).
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`The Primary Reference of the Grounds – the ’362 Patent
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`E.
`The ’040 patent at issue in this proceeding builds on the compounds and
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`techniques disclosed in the ’362 patent to Van Lommen et al. As discussed above,
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`the ’362 patent was extensively considered during prosecution of the ’040 patent.
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`Indeed, the ’362 patent formed the basis for the Examiner’s obviousness rejections,
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`and was considered by the Board on appeal, which reversed the Examiner’s
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`rejections in light of substantial evidence of unexpected results.
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`The ’362 patent relates to the general class of 2,2’-iminobisethanol
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`compounds, which are said to have increased β-adrenergic blocking activity as
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`compared to prior art compounds. Ex. 1004 at 1:18-22. According to the patent,
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`the compounds have the following general formula I:
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`The patent explains that each of the variables (e.g., R1, R2, A1, A2…) can be one of
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`a number of possibilities, and as such, the patent discloses a vast number of
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`compounds falling within the general class of 2,2’-iminobisethanol compounds.
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`According to the patent, the “most preferred compounds is α,α’ -
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`[iminobis(methylene)]bis[3,4-dihydro-2H-l-benzopyran-2-methanol]).” Id. at
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`2:40-42. This includes what the ’362 patent discloses as compounds 75 to 83. Id.
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`at Example 23. Notably, because the “most preferred” structures do not include
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`fluorine, the “most preferred” structures do not encompass nebivolol, which has
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`fluorine substitutions on both rings. See § II.A, supra.
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`The ’362 patent further describes the preparation of over 100
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`iminobisethanol derivatives falling within the general class of 2,2’-iminobisethanol
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`compounds, including compounds that are both symmetrical (e.g., molecules
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`identical on both sides of the central nitrogen molecule) and asymmetrical (e.g.,
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`compounds that are different on either side of the central nitrogen molecule).
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`1.
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`The ’362 Patent Does Not Describe the Absolute
`Stereochemistry of Any of the Disclosed Compounds
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`The ’362 patent explains that the compounds it describes can be prepared by
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`coupling two intermediates, i.e., two “halves” of the final compound. See id. at
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`3:1-56. However, according to the patent, “[i]n many compounds and starting
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`materials the stereochemical configuration is not experimentally determined” and
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`that “[i]n those cases it is conventionally agreed to designate the stereochemically
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`isomeric form which is first isolated as ‘A’ and the second as ‘B,’ without further
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`reference to the actual stereochemical configuration.” See id. at 4:59-65
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`(emphasis added).
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`The ’362 patent further explains that “[f]or the most preferred compound” it
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`was experimentally determined that “the ‘A’ form corresponds with the RS or SR
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`configuration at the chiral centers 1 and 2 or 3 and 4” and “the ‘B’ form
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`corresponds with SS or RR configuration at the said chiral centers.” See id. at
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`4:66-5:4. A person of ordinary skill in the art would understand, therefore, that the
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`designation “A” would denote a combination of the RS and the SR diastereomers,
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`while the designation “B” would denote a combination of both the SS and the RR
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`stereoisomers. See Ex. 1002 at 143 (Appeal Brief), 201 (Decision on Appeal).
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`Based on this description