APB and lacosamide.93 The 464 application also describes the administration of
`
`the compounds of the invention with various pharmaceutical carriers for
`
`anticonvulsant activity.94
`
`117
`
`The 464 application discloses that
`
`present compounds
`
`obviously exist in stereoisomeric fonns and the products obtained thus can be
`
`mixtures of the isomers which can be resolved.9D Consistent with the literature
`
`discussed above the 464 application reports data showing that the
`
`stereoisomer96 was tenfold more potent than the
`
`stereoisomer for the compounds
`
`reported.97
`
`Marked Stereospecificity in
`Harold Kohn et
`New Class of Anticonvulsants 457 Brain Res 371-375
`1988 Kohn 1988
`
`118 Kohn 1988 is prior art to the 551 patent because it published in 1988
`
`which is prior to March 15 1996
`
`931d atcl
`
`Id at 541-635 530-32 645-46
`
`Id at 527-28
`
`96
`
`In this case the D-enantiomers for which data was reported correspond the
`POSA would have known
`configuration which
`
`971d.atl2Tbl
`
`-70-
`
`
`
`the compounds of the invention with various pharmaceutical carriers for
`
`anticonvulsant activity.94
`
`117
`
`The 464 application discloses that
`
`present compounds
`
`obviously exist in stereoisomeric fonns and the products obtained thus can be
`
`mixtures of the isomers which can be resolved.9D Consistent with the literature
`
`discussed above the 464 application reports data showing that the
`
`stereoisomer96 was tenfold more potent than the
`
`stereoisomer for the compounds
`
`reported.97
`
`Marked Stereospecificity in
`Harold Kohn et
`New Class of Anticonvulsants 457 Brain Res 371-375
`1988 Kohn 1988
`
`118 Kohn 1988 is prior art to the 551 patent because it published in 1988
`
`which is prior to March 15 1996
`
`931d atcl
`
`Id at 541-635 530-32 645-46
`
`Id at 527-28
`
`96
`
`In this case the D-enantiomers for which data was reported correspond the
`POSA would have known
`configuration which
`
`971d.atl2Tbl
`
`-70-
`
`
`
`119 Kohn 1988 reports studies of anticonvulsant potency of the racemates
`and individual enantiomers of N-acetyl-alanine-N-benzylamide AAB and
`acetyl-phenylglycine-N-benzylamide APB which are depicted below and
`which differ only in the substituent aftached to the stereocenter methyl in AAB
`
`and phenyl in APB98
`
`NH3
`
`Nacetyt-DLaIanine-Nbenzyamide
`DL-AAB
`
`NacetyDL-phenytgyci neN-benzyIamde
`DL-APB
`
`The main conclusions of the study were that the anticonvulsant activity is due to
`
`the D-stereoisomer99 and the L-stereoisomer
`
`is virtually inactive as an
`
`anticonvulsant
`
`98 Ex 1021 at 371 abstr
`
`in this case the D-stereoisomers refened to correspond to the
`POSA would have known
`which
`Id at 371 abstr see also Id at 372-74
`
`configuration
`
`-71-
`
`
`
`Harold Kohn Ct
`Preparation and Anticonvulsant
`Activity of Series of Functionalized a-Aromatic and
`a-Heteroaromatic Amino Acids 33 Med Chem
`919-926 1990 Kohn 1990
`
`120 Kohn 1990 is prior art to the 551 patent because it published in 1990
`
`which is prior to March 15 1996
`
`121
`
`The Kohn 1990 study used APB as
`
`starting point and explored
`
`replacement of the phenyl group aftached to the a-carbon by
`
`number of other
`
`aromatic or heteroaromatic groups
`
`101
`
`After evaluating 23 analogs of APB Kohn
`
`and coworkers concluded that the most active compounds
`
`are RS-a-acetamido
`
`N-benzyl-2 -furanacetamide
`pyrroleacetamide 2i the structures of which are shown below 102
`
`-a-acetamido-N-benzyl-2-
`
`and
`
`Kohn 1990 Furanyt Derivative 2g
`
`Kohn 1990 Pyrrolyl Derivative 2t
`
`On the basis of this SAR study Kohn and coworkers concluded that
`
`is
`
`presented that placement of
`
`relatively small electron-rich heteroaromatic moiety
`
`at the a-site leads to
`
`substantial enhancement
`
`in the anticonvulsant activity of the
`
`Ex 1022 at 919
`
`102 Id at 919 abstr Tbl
`
`-72-
`
`
`
`drug candidate relative to APB 103 As with AAB and APB the
`
`of
`
`the two individual enantiomers of 2g demonstrated that the anticonvulsant activity
`
`resided in the
`
`stereoisomer
`
`104
`
`European Patent Application No 0263 506 The
`506 application
`
`122
`
`The 506 application is prior art to the 551 patent because it
`
`published on April 13 1988 which is prior to March 15 1996
`
`123
`
`The 506 application discloses compounds having central nervous
`
`system CNS activity which are useful
`
`in the treatment of epilepsy having the
`
`following general forniula
`
`R-NHC_CNH C-R
`OR3
`
`nil
`
`II
`
`The 506 application further discloses that R2 can include lower alkyl groups
`
`substituted or unsubstituted where the substitution can be an alkoxy group which
`
`103 Id at 919 922
`
`41d at 919 922 Tbl III
`5Ex 1023 at22-10 318-2188-10
`
`-73-
`
`
`
`would include the methoxymethyl of lacosamide 106 The 506 application reported
`
`the same data discussed above demonstrating that the D-enantiomer7 possessed
`
`about tenfold greater anticonvulsant activity than the L-enantiomer 108
`
`European Patent Application No
`440 application
`
`400 440 The
`
`124
`
`The 440 application is prior art to the 551 patent because it was
`
`published on December
`
`1990 which is prior to March 15 1996
`
`125
`
`The 440 application discloses compounds exhibiting central
`
`nervous system CNS activity which are useful
`
`in the treatment of epilepsy..
`
`the following general formula9
`
`OR3
`
`According to the 440 application these compounds exhibit excellent
`
`anticonvulsant activity.0
`
`61d at 251314
`
`107 In this case the D-enantiomers for which data was reported correspond to the
`POSA would have known
`configuration which
`
`108 Id at 18 Tbl
`
`109 Ex 1024 at 32-12
`
`-74-
`
`
`
`126
`
`The 440 application also states that
`
`compounds of the
`
`present
`
`invention have the following general
`
`forniula
`
`wherein
`
`is
`
`or lower alkyl
`
`...
`
`it
`
`is preferred that
`
`is hydrogen
`
`127
`
`The 440 application stated that
`
`present compounds obviously
`
`exist in stereoisomeric forms and the products obtained thus can be mixtures of the
`
`isomers which can be
`
`12 The 440 application then describes various
`
`art-recognized techniques for synthesizing and separating stereoisomers
`
`Table
`
`reports the anticonvulsant activity for both the
`
`and
`
`stereoisomers of the 2-
`
`furanyl derivative4 showing that the
`
`stereoisomer was much more potent than
`
`the
`
`stereoisomer.11D
`
`Id at 1127-29 see also id at 425-28
`
`Id at 530-42
`
`21d at 1057-58
`3M at 1058-1126
`
`In this case the D-stereoisomer
`POSA would have known
`which
`
`5Id atTbl
`
`referred to corresponds to the
`
`configuration
`
`-75-
`
`
`
`Harold Kohn et al Preparation and Anticonvulsant
`Activity of Series of Functionalized a-Heteroatom
`Substituted Amino Acids 34 Med Chem 2444-
`2452 1991 Kohn 1991
`
`128 Kohn 1991 is prior art to the 551 patent because it was published in
`
`1991 which is prior to March 15 1996
`
`129 Kohn 1991 was
`
`continuation of the work following the identification
`
`of the promising amino acid derivatives AAB APB the 2-pyrrolyl derivative and
`
`the 2-furanyl derivative 2a-2d
`
`H3C-C-C--C2CJ 0N1H3
`
`2a R2
`R2
`
`CH3
`Ph
`
`R2
`
`R2
`
`2-pyrroyt
`
`2-furany
`
`Kolin 1991 describes the synthesis and testing of 26 amino acid derivatives for
`
`anticonvulsant activity which further define the structure-activity relationships
`
`for this class of amino acid derived anticonvulsant agents.7 All 26 compounds
`
`6Ex 1010 at2444
`
`7Jd at 2444
`
`-76-
`
`
`
`contain both an N-benzylamide moiety and an acetylated amino group and vary
`
`only by the substituent at the a-carbon defined as
`
`in the structure below8
`
`CH3LH HNHCH2Ph
`
`fN CH3
`
`Of the 26 compounds tested
`
`most active compounds were RS-2-
`
`acetamido-N-benzyl-2-methoxyaminoacetamide 31 and
`benzyl-2-methoxymethylaminoacetamide 3n the structures of which are
`
`S-2-acetamido-N-
`
`represented below
`
`CH3
`
`NHO
`N1CH
`
`CH3
`
`CH3
`
`NO
`ffNCH3
`
`Kohn 1991 methoxyamino
`derivative 3U
`
`Kohn 1991 methoxymethylamino
`derivative 3n
`
`130 Kohn 1991 reported that
`
`anticonvulsant activities of racemic 31
`
`and 3n .. were comparable to that of the RS-2-furanyl derivative 2d .. and
`
`phenytoin.2 Kohn 1991 also describes several
`
`important observations about
`
`Id at 2445 Tbl
`
`9Id at 2444 abstr 2445 Tbl
`
`120 Ex 1010 at 2447
`
`-77-
`
`
`
`the structure-activity relationships of this class of compounds
`
`including that
`
`the ct-amino
`
`derivative
`
`displayed anticonvulsant activit comparable to that
`
`observed for the a-methyl analogue
`
`that there are stringent steric
`
`requirements that exist for maximal anticonvulsant activity in this class of
`
`compounds and
`
`in the most potent analogues 2d 31 and 3n
`
`functionalized oxygen atom existed two atoms removed from the a-carbon
`
`atom.2
`
`Harold Kohn et
`Synthesis and Anticonvulsant
`Activities of a-Heterocyclic a-Acetamido-N
`Benzylacetamide Derivatives 36 Med Chem 3350-
`3360 1993 Kohn 1993
`
`131 Kohn 1993 is prior art to the 551 patent because it was published in
`
`1993 which is prior to March 15 1996
`
`132 Kohn 1993 reports the synthesis and anticonvulsant evaluation of an
`
`expanded set of Ca-heteroaromatic analogs.22 Kohn 1993 provides further
`
`support that
`
`improved activity resulted by the positioning of heteroatom two
`
`atoms removed from the Ca-site
`
`The authors noted that they previously had
`
`observed that the anticonvulsant activity .. decreased in proceeding from oxygen
`
`121 Id at 2447
`
`122 Ex 1025 at 3350 abstr
`
`231d at 3354
`
`-78-
`
`
`
`to nitrogen to sulfur containing Ca-heteroaromatic derivatives.24 Moreover
`
`Kohn 1993 suggest that
`
`increased anticonvulsant activity generally
`
`accompanied the placement of
`
`substituted alkylated heteroatom two atoms
`
`removed from the amino acid
`
`133 Kohn 1993 also prepared several enantiopure congeners ofR-4
`
`2-furanyl derivative to demonstrate that this absolute configuration afforded
`
`compounds with marked anticonvulsant activity.26 Kolrn 1993 concluded that
`
`the pharmacological stereospecificity that distinguishes this novel class of
`
`anticonvulsant agents was reaffirmed by the biological data ..
`
`which Kohn
`
`1993 noted
`
`significant
`
`improvement
`
`in anticonvulsant activity of R-30
`
`versus the corresponding racemate.127
`
`Harold Kohn et
`Anticonvulsant Properties of N-
`Substituted aa-Diamino Acid Derivatives 83
`Pharmaceutical Sci 689-691 May 1994 Kohn
`1994
`
`134 Kohn 1994 is prior art to the 551 patent because it was published in
`
`1994 which is prior to March 15 1996
`
`241d at 3354
`
`l2DId at 3354
`
`261d at 3350
`
`271d at 3355
`
`-79-
`
`
`
`135 Kohn 1994 highlights the potent anticonvulsant effects of the
`
`methoxyamino derivative 2c arid the methoxymethylamirio derivative 2d
`
`reported in Koirn 1991128
`
`CH3
`
`NHO
`fNCH3
`
`CH3
`
`NO
`
`CH3
`
`NJNJLcH
`
`Methoxyamino
`derivative 2c
`
`MethoxymethyIamno
`derivative 2d
`
`The research reported by Kohn and coworkers in their 1994 publication was
`
`intended to find out the effect of conversion of the basic amino substituent at the
`
`stereocenter
`
`to
`
`neutral derivative such as carbamate 2e or urea 2g 129
`
`CH3O
`cLi
`
`CH
`
`CH3NH4
`
`Carbamate
`derivative 2e
`
`Urea
`derivative 2g
`
`total of 10 such N-acyl derivatives were synthesized and evaluated Most were
`
`inactive and all were significantly less potent than 2c and 2d 130
`
`128 Ex 1026 at 689
`
`291d at 689
`
`30Id at 691
`
`-80-
`
`
`
`U.S Patent No 5378729 The 729 patent
`
`136
`
`The 729 patent
`
`is prior art to the 551 patent because it
`
`issued on
`
`January
`
`1995 which is prior to March 15 1996
`
`137
`
`The 729 patent discloses compounds .. having central nervous
`
`system CNS activity which are useful
`
`in the treatment of epilepsy and other CNS
`
`disorders of the following general
`
`fonnula 131
`
`RNHtCCNHCRi
`
`General formula describing
`compounds of the 729 patent
`
`The 729 patent also discloses that compounds of the present
`
`invention exhibit
`
`excellent anticonvulsant activity32 that
`
`the compounds
`
`are administered with
`
`pharmaceutically
`
`acceptable carrier33 and that
`
`use of such media and
`
`agents for pharmaceutical active substances is well known in the art.34
`
`131 Ex 1008 col 130-220
`
`321d at 165-7
`
`331d at 1753-54
`
`341d at 1754-58
`
`-81-
`
`
`
`138
`
`The 729 patent discloses that
`
`preferred compounds
`
`are those
`
`wherein
`
`is
`
`... The preferred value of
`
`is .. especially benzyl...
`
`The
`
`most preferred
`
`group is methyl.l3D
`
`RNHtC-CNHiC_Ri
`
`fJCH2NHNH --CH3
`
`General formula descrthing
`compounds of the 729 patent
`
`General formula of the 729
`patent with preferred features
`
`139
`
`The 729 patent states that
`
`present compounds obviously exist
`
`in stereoisomeric fonns and the products obtained thus can be mixtures of the
`
`isomers which can be resolved.36 The 729 patent then describes various art-
`
`recognized teclmiques for synthesizing and separating stereoisomers
`
`137 The 729
`
`patent also identifies that
`
`stereoisomer is preferred.38 The biological
`
`data provided in Table
`
`further support
`
`preference for the
`
`stereoisomer 139
`
`In
`
`the three instances where the
`
`and
`
`stereoisomers were both tested AAB APB
`
`35Id at 514-19
`
`136 Id at 1529-3
`
`see also id at 956-68
`
`37Id at 1531-164
`
`8Id at 1027
`
`39Id at 58-61 Tbl
`
`-82-
`
`
`
`and the 2-furanyl derivative the
`
`stereoisomer4 was at least tenfold more potent
`
`than the
`
`stereoisomer
`
`141
`
`140
`
`The 729 patent contains claims that cover lacosamide.42 However
`
`during the prosecution history of the 551 patent as with the 301 patent
`
`the
`
`applicant represented to the PTO that
`
`the 729 patent does not disclose lacosamide
`
`Specifically the applicant asserted that
`
`the 729 patent does not disclose the basic
`
`structure wherein at least one of R2 and R3 is specifically alkoxymethyl as
`
`specifically claimed.43 However this statement
`
`is incorrect and misconstrues
`
`basic chemistry principles because the 729 patent allows R2 or R3 to be
`
`alkoxymethyl
`
`i.e methylene substituted with methoxy
`
`Summary
`
`141
`
`POSA would take away several
`
`important structure-activity
`
`relationships from the work published by Kohn and his coworkers First the class
`
`140
`
`In this case the D-enantiomers for which data was reported conespond to the
`POSA would have known
`configuration which
`
`Id
`
`142
`
`Lacosamide is the R-enantiomer of the claimed compound
`See e.g id at cl
`is aryl lower alkyl i.e the especially
`benzyl col
`where
`17-
`18 Ri is lower alkyl i.e the most preferred .. methyl col 517-18-19
`and one of R2 and R3 is hydrogen and the other lower alkyl i.e methylene
`least one electron donating substituent i.e methoxy
`substituted with .. at
`col 437
`
`43Ex 1006 at2
`
`-83-
`
`
`
`of compounds studied by Kohn et al starting initially from AAB had been
`
`modified at three positions the ct-carbon the amide substituent and the N-acyl
`
`group44
`
`ri
`
`Nacy group
`
`N-acetyaanne-N-benzyIamide
`Coney 1987 Cmpd Ia AAB
`
`142 Generally modification of the benzyl red in the structure below
`
`substituent except fluoro substitution decreased the anticonvulsant activity of the
`
`series
`
`c1LNACH3
`
`berzy
`
`143 Modification of the N-acyl group to substituents other than methyl
`
`blue in the structure below resulted in decreased anticonvulsant activity
`
`146
`
`44Ex 1017 at 568
`
`See e.g Id at 572
`
`146
`
`See e.g Id at 572
`
`-84-
`
`
`
`ONCH3
`
`methy
`
`144 Modification of the
`
`substituent green in the structure below could
`
`be used to modulate the anticonvulsant activity of the compounds
`
`147
`
`145 Kohn et aT had investigated
`
`number of different
`
`substituents and
`
`published that increased anticonvulsant activity generally accompanied the
`
`placement of
`
`substituted alkylated heteroatom two atoms removed from the
`
`amino acid a-carbon48 which is displayed generically as follows
`
`POSA would have been aware that as of March 1996 the most potent
`
`racemate
`
`identified was the compound where the
`
`group was methoxyamino highlighted
`
`in green below
`
`See e.g Ex 1010 Ex 1022 Ex 1025 all discussed in detail above
`
`148 Ex 1025 at 3354
`
`-85-
`
`
`
`HN
`
`LNrNLCH
`
`Kohn 1991 methoxyamino
`derivative 31
`
`146 Finally POSA would have been aware that Kohn and coworkers had
`
`published
`
`preference for the
`
`enantiomer as the stereoisomer in which the
`
`anticonvulsant activity primarily resides
`
`149
`
`This preference was based on results
`
`finding stereospecific activity of compounds where the cicarbon is directly
`
`substituted with carbon e.g AAB APB 2-furanyl analog 150
`
`The Substitution of Methyl for Amino Groups was
`Commonly Performed in the Prior Art
`
`C.W Thornber Isosterism and Molecular
`11odification in Drug Design Chemical Socy Revs
`563 1979 Thornber 1979
`
`147
`
`Thomber 1979 is prior art to the 551 patent because it was published
`
`in 1979 which is prior to March 15 1996
`
`148
`
`Thomber 1979 defines bioisosteres as groups or molecules which
`
`have chemical or physical similarities producing broadly similar biological
`
`49E.g Ex 1008 729 patent col 1027
`
`Ex 1008 729 patent Tbl
`Kolrn 1990 at 919 922 Tbl III
`
`Ex 1021 Kohn 1988 at 371 abstr Ex 1022
`
`-86-
`
`
`
`properties and recognizes that methyl and amino groups are classical
`
`bioisosteres
`
`152
`
`Gisvolds Textbook of Organic Medicinal
`Wilson
`and Pharmaceutical Chemistry Ch Delgado
`
`Remers eds 1991 WG 1991
`149 WG 1991 is prior art to the 551 patent because it was published in
`
`199 which is prior to March 15 1996
`150 WG 1991 discloses that amine -NH- and methylene -CH2-
`
`groups .. are sufficiently alike in their steric nature to be frequently
`
`interchangeable
`
`in drugs.b3
`
`Silverman The Organic Chemistry of
`Richard
`Drug Design and Drug Action Ch 1992
`Silverman 1992
`
`151 Silvennan 1992 is prior art to the 551 patent because it was published
`
`in 1992 which is prior to March 15 1996 Silverman 1992 recognizes that methyl
`
`and amino groups are classical bioisosteres
`
`14
`
`Bioisosteres are substituents or
`
`1D1 Id at 563
`
`iD2Ex 1027 at 564 Tbl
`
`Ex 1028 at 30
`
`Ex 1029 at 19 quotation from Ex 1027 Tbl 2.2
`
`-87-
`
`
`
`groups that have chemical or physical similarities and which produce broadly
`
`similar biological propePies
`
`The Prior Art Taught The Preparation Of Enantiomerically
`Pure D-Serine And Its Derivatives
`
`152
`
`The prior art discloses how to synthesize and isolate the
`
`enantiomerlD6 of serine as well as its 0-methyl derivative as demonstrated by the
`
`following references which are all prior art to the 551 patent under because they
`
`published prior to March 15 1996
`
`New Route to the Synthesis of Amino Acids
`Rosa Amoroso et al
`Through the Mercury Cyclization of Chiral Amidals 57 Org Chem
`1082-1087 1992 Amoroso 1992
`Amoroso and coworkers reported
`
`new synthetic procedure for the
`
`preparation of enantiomerically pure amino acids through simple
`
`steps and under mild conditions.7 One of the synthetic procedures
`
`illustrating the new method provided D-serine in 65% yield
`
`Cerrini et al
`0-Membered Cyclodepsipeptides 41
`erine-Containing
`Peptide Protein Res 282-290 1993 Cerrini 1993
`Intl
`Cerrini and coworkers described the preparation of
`family of
`
`tripeptide lactones One of the building blocks employed in this study
`was the following protected form of D-serine in which the serine OH
`
`DId at 19
`
`156
`
`the
`
`In the case of D-serine and D-O-methylserine the D-enantiomer corresponds to
`POSA would have known
`configuration which
`
`Ex 1030 at 1085
`
`-88-
`
`
`
`and NH2 groups are protected as
`
`benzyl ether and
`
`phenylacetamide respectively
`
`158
`
`PhO
`HO Ph
`
`D-serne derivative
`
`Svarite Axelssoll et al Versatile Synthesis of Stereospecifically
`Chem Soc Perk/n
`Labelled D-Amino Acids via Labelled Aziridines
`806-8 14 1994 Axelsson 1994
`Trans
`Axelsson and coworkers developed
`
`new method for stereospecific
`
`synthesis of amino acids one of the examples was D-serine which
`
`was prepared from the isomeric compound S-isoserine
`
`1D9
`
`.NH2
`
`OH
`
`HO
`
`S-isoserine
`
`steps
`
`-CPh3
`
`HO2C
`
`HCIO4
`100C
`97%
`
`HO
`
`OH
`
`NH
`
`RSeflne
`D-seri ne
`
`Oliver Keil et al New Hydantoinases from Thermophilic Microorganisms
`Synthesis of Enantiomerically Pure D-Amino Acids
`Tetrahedron
`Asymmetiy 1257-1260 1995 Keil 1995
`In this article Keil and coworkers reported that 14 D-a-amino acids
`
`were prepared from the corresponding racemic hydantoins by
`
`employing two novel hydantoinases from thermophilic
`
`1D8Ex 1031 at 288
`
`159 Ex 1032 at 809 812
`
`-89-
`
`
`
`microorganisms.6 One of the examples prepared in 97%
`
`enantiomeric purity was D-serine 161
`
`OH
`
`OH
`
`pH 85
`
`HN
`
`NH
`
`50C
`
`HN
`
`NH
`
`enzyme
`Dhydantoinase
`
`OH
`COOH
`HN
`-NH2
`
`L-hydantoin
`
`D-hyda ntoi
`
`NcarbamoyI-Dserine
`
`chemical or
`enzymatica
`transformation
`
`OH
`
`HO
`
`OH
`
`COOH
`
`D-serine
`
`Jaeger et al Enzymatic Resolution of O-Methyl-N-Acetyl-DL-Serine
`Amino Acids XXXII 28 Croat Chem ACTA 5-8 1956 Jaeger 1956
`As discussed in 88 Jaeger and coworkers62 prepared N-acetyl-O
`methyl-D-serine in 1956 by enzymatic deracemization of racemic
`
`acetyl-dl-serine prepared by the method of Synge
`
`163
`
`160 Ex 1033 abstr
`
`161 Id at Tbl compound D-23
`
`62Ex 1016 at6
`
`163 Ex 1015 at 1934
`
`-90-
`
`
`
`HO
`HO2CNCH3
`
`N-acetyt-DLserine
`
`CH3 Ag20 acetone
`saponification
`
`CH3
`
`HO2C
`
`NCH3
`
`Nacety-OmethyI
`
`-DLserine
`
`CH3
`
`CH3
`
`CH3
`
`Hog Kidney
`
`HO2C1NH3
`
`HO2C1NH3
`
`HO2CH2
`
`NacetyI.O-methyI-
`D-serine 76%
`
`O-methy-L-serine
`
`The Differences Between the Prior Art and Claims
`
`153
`
`In addition to anticipating claims 1-13 of the 551 patent the same
`
`disclosures of the LeGall thesis described above make claims 1-13 of the 551
`
`patent obvious in view of other prior art
`
`Claims and 3-8 of the 551 Patent Would Have Been
`Obvious in View of the LeGall Thesis and Other Prior Art
`
`154 As set forth above Claims
`
`and 3-8 of the 551 patent are claims
`
`directed to chemical compounds that include lacosamide Lacosamide is the
`
`enantiomer in racemic compound 107e in the LeGall thesis
`
`CH3
`
`3JI 1N CH3
`
`R-enantiomer of Ole
`lacosamide
`
`-91-
`
`
`
`POSA Would Understand that the LeGal Thesis
`Discloses Racemic Lacosamide
`50/50 Mixture of
`Lacosamide and its
`Enantiomer
`
`155
`
`The LeGall thesis identifies the synthesis of compound 107e as
`
`racemate ..
`
`rather than the individual eiaitioiers.164 Racernic compound
`
`07e
`
`is
`
`50/50 mixture of the R-enantiomer
`
`lacosamide and an S-enantiomer As
`
`described above in 37 claims
`
`and 3-8 cover compounds
`
`in which the
`
`enantiomer is present
`
`in any amount in an enantiomeric mixture Therefore
`
`because the racemate 107e of the LeGall thesis contains 50% of the R-enantiomer
`
`lacosamide the LeGall thesis discloses lacosamide
`
`species of the compounds
`
`claimed by claims
`
`and 3-7 and the compound specifically covered by claim
`
`Other prior art confirnis that POSA would understand that compound 107e is
`
`racemic mixture made up of half
`
`stereoisomer lacosamide and half
`
`stereoisomer For example the 729 patent which covers compound 107e see
`
`140 recognizes that
`
`compounds of the present
`
`invention are either the
`
`stereoisomer or the D-stereoisomer and may be found in mixtures of the
`
`and
`
`and
`
`stereoisomer e.g racemic mixtures.l6D
`
`164 Ex 1005 at 135
`
`165 Ex 1008 col 1022-28 The 729 patent also notes that
`is well known in
`can also be described as
`chiral carbon ..
`the art that the configuration around
`orS Id at 961-63
`
`-92-
`
`
`
`POSA Would Have Been Motivated to Select
`the
`Lacosamide Structure Disclosed in the LeGall Thesis
`as an Anticonvulsant Compound with Reasonable
`Expectation of Success
`
`156 Not only does the LeGall thesis disclose racemic lacosamide 107e it
`
`discloses why POSA would be motivated to make and use the compound with
`
`reasonable expectation of success The structural analogy of compound 107e with
`
`another compound he identified to have good anticonvulsant activity led LeGall to
`
`believe that compound 107e may have good anticonvulsant activity.66 This
`
`would have motivated
`
`POSA to make and use compound 107e of the LeGall
`
`thesis as an anticonvulsant compound that could be used to treat epilepsy and other
`
`central nervous system disorders The reasonable expectation of success is
`
`demonstrated by LeGalls expectation that compound 107e would have good
`
`anticonvulsant activity based on its close structural analogy to another
`
`compound with anticonvulsant activity
`
`167
`
`157
`
`The additional prior art confirms that POSA would have been
`
`motivated to use the lacosamide structure identified in the LeGall thesis as an
`
`anticonvulsant compound
`
`POSA would be aware of the key structure-activity
`
`relationships of the class of compounds
`
`including lacosamide from the prior art
`
`166 Ex 1005 at 155
`
`671d
`
`-93-
`
`
`
`158 First POSA would have been aware that the most promising
`
`compounds identified by Kohn and others in the prior art shared the following
`
`stnicture
`
`ONCH3
`
`159 Kohn and coworkers direct POSA to the above structure by the
`
`preferences that they identify after investigating the structure-activity relationships
`
`of the series of compounds For example Kohn and his collaborators identified
`
`preference for especially benzyl as the substituent on one end of the amino
`
`chain 168
`
`NyANLCH
`
`160 On the other end of the chain the most preferred substitution of the
`
`acyl group is methyl 169
`
`168 Ex 1008 col 517-18
`
`69Jd at 519 Ex 1024 at 516
`
`-94-
`
`
`
`OL YN H3
`
`Ly
`
`161 Furtherniore Kohn and his collaborators also identified that it
`
`is
`
`preferred that one of the substituents on the a-carbon is hydrogen 170 which
`
`leaves
`
`as represented above at the a-carbon as the only variable
`
`162
`
`That
`
`POSA would have identified the above structure as promising
`
`is evidenced by the most promising compounds identified by Kohn and coworkers
`
`in prior art publications After identifying AAB
`
`methyl as among the most
`
`active compounds observed with anticonvulsant activity7 Kohn and coworkers
`
`identified AAB as parent compound from which structural analogs were
`
`made 172 Upon further investigation Kolm and coworkers identified APB
`
`phenyl which they found to have enhanced anti convulsant activity relative to
`
`AAB
`
`Thereafter
`
`the LeGall thesis reports the preparation and evaluation of
`
`derivatives of the potent anticonvulsant agent
`
`and
`
`finding two
`
`170 See e.g Ex 1008 col 612 see also Ex 1024 at 526
`
`Ex 1009 at 601 abstr compound 6d
`
`172 Ex 1018 at vii 26 compound 30 Ex 1017 at 568 abstr compound la
`
`Ex 1018 at 65-67 compound 53c Ex 1017 at 571 compound id
`
`-95-
`
`
`
`derivatives
`
`2-furanyl 2-pyrrolyl that were more potent
`
`than the parent
`
`compound APB.74
`
`163 Koirn 1991 is illustrative of how POSA would have viewed the
`
`promise of the above structure In Koirn 1991 Koirn and his coworkers continued
`
`to publish on additional derivatives using the structure and varying the
`
`substituent As
`
`starting point Kohn 1991 describes the above compounds AAIB
`
`APB the 2-pyrroiyi derivative and the 2-furanyl derivative compounds 2a-2d 17D
`
`CH3NH--N HCHf
`
`R2CH3
`Ph
`Rz 2-pyrrolyl
`Rc 2-turanyl
`
`Kohn 1991 then describes the synthesis and anticonvulsant properties of novel
`
`series
`
`compounds of cL-heteroatom-substituted
`
`amino acid derivatives.76
`
`These 26 compounds all share the above structure with various replacements for
`
`identified as R2 in Kohn 1991 Kohn and coworkers reported that
`
`most
`
`103 2-furanyl compound 69a 2-pyrrolyl compound 69b Ex
`Ex 1005 at
`1022 at 919 2-furanyl compound 2g 2-pyrrolyl compound 2i
`
`Ex 1010 at 2444
`
`761d
`
`-96-
`
`
`
`active compounds were
`
`methoxyamino derivative 31 and
`
`methoxymethylamino derivative 3n77 which had activity comparable with the
`
`2-furanyl derivative
`
`178 These promising findings for the methoxyamino and
`
`methoxymethylamino derivatives prompted
`
`investigation of racemic N-
`
`substituted amino acid derivatives all modified at the a-carbon substituent
`
`179
`
`164
`
`Indeed the compounds that Kohn published as having the most
`
`promising anticonvulsant activity and that prompted investigation of derivatives
`
`based on the same lead structure are shown in the table below
`
`OLyNiCH3
`
`77Id at 2444 abstr
`
`781d at 2447
`
`179 Ex 1026 at 689
`
`-97-
`
`
`
`Table
`
`Compounds Of The Prior Art Kohn References
`
`Prior Art Citation of
`Corn Pound
`
`Substituent
`
`N-Acetyl-alanine-N-
`
`benzylamide AAB
`Conley 1987 la
`
`CH3
`
`methyl
`
`N-Acetyl-
`
`phenylglycine-N-
`benzylamide APB
`Kohn 1988
`
`2-pyrrolyl derivative
`
`phenyl
`
`NH
`
`2-pyrrolyl
`
`2-furanyl derivative
`Kohnl99O2g
`
`Methoxymethylamino
`derivative Kohn
`1991 3n
`
`2-furanyl
`
`H3C
`
`OCH3
`
`methoxymethytamino
`
`Anticonvulsant
`Activity ED0
`of
`mg/kgfl
`Racemate
`
`180
`
`DL
`
`76.54
`
`32.1
`
`Anticonvulsant
`Activity EDo
`mg/kg of
`Stereoisomers
`
`D- 54.80 IKohii
`1988
`
`L- 548.37
`Kohn 1988
`
`D- 26.4 Kohn
`1988
`
`L-
`
`300 Kohn
`1988
`
`16.1
`
`reported
`
`10
`
`D-3.3Kohn
`1990
`
`L-25Kohn
`1990
`
`6.7
`
`reported
`
`180
`
`Compounds with higher anticonvulsant efficacy have lower ED50
`
`-98-
`
`
`
`Methoxyamino
`derivative Kohn
`1991 31
`
`0CH3
`
`HN
`
`methoxyamno
`
`6.2
`
`reported
`
`Of the compounds published by the Kohn studies summarized in Table
`
`the
`
`racemic compound with the greatest anticonvulsive potency was the
`
`methoxyamino derivative 31 reported in Kohn 1991
`
`165
`
`POSA would have viewed the promise of compounds sharing the
`
`above structure favorably to other anticonvulsant compounds because of the
`
`anticonvulsant activity displayed by the series Indeed several analogs having the
`
`structure 2-furanyl methoxyamino methoxymethylamino had favorable activity
`
`compared to phenytoin8 the most prescribed drug of the time for epilepsy
`
`182
`
`166
`
`Based on the disclosures of the prior art POSA would have had
`
`reasonable expectation that using methoxymethyl substituent for
`
`as was used
`
`in compound 107e of the LeGall thesis in the above structure would result in
`
`compound with good anticonvulsant activity
`
`POSA would have understood
`
`181 Ex 1005 at 103 Ex 1022 at 922 abstr Ex 1010 at 2444 2445 Tbl
`1034 at 4568
`
`Ex
`
`182 Ex 1005 at 108
`treatment of epilepsies
`
`is the most widely prescribed drug today for the
`
`-99-
`
`
`
`from the prior art that favorable activity occurs with an alkylated oxygen atom two
`
`atoms removed from the a-carbon atom
`
`Alk
`
`NCH3
`
`For example Kohn 1991 teaches that
`
`in the most potent analogues
`
`2d 31 and 3n functionalized oxygen atom existed two atoms removed from the
`
`a-carbon atom83 and Kohn 1993 discloses additional derivatives which provided
`
`support for
`
`suggestion that
`
`increased anticonvulsant activity generally
`
`accompanied the placement of
`
`substituted alkylated heteroatom two atoms
`
`removed from the amino acid a-carbon.84
`
`167
`
`POSA would have known that the simplest alkylated oxygen atom
`
`is methoxy where the Alk substituent above is methyl Furthennore POSA
`
`would also have known that Kolrn and his collaborators had identified the
`
`methoxyamirio compound as the most active racemate
`
`183 Ex 1010 at 2447
`
`184 Ex 1025 at 3354 see also Ex 1034 at 4568
`
`-100-
`
`
`
`CH3
`
`NH
`gNCH3
`
`Kohn 1991 methoxyamino
`derivative 31
`
`The methoxyamino compound has an oxygen atom two atoms removed from the a-
`
`carbon that is substituted with methyl i.e methoxy group In the methoxyamino
`
`compound an amino group -NH- is substituted directly on the a-carbon
`
`in the
`
`general structure in 166
`
`168
`
`POSA would have had
`
`reasonable expectation of maintaining
`
`activity with the substitution of methylene -CH2- in place of the amino group
`
`-NH- for several reasons Indeed methylene -CH2- and amino -NH- groups
`
`are classical
`
`isosteres that are generally known to be interchangeable and
`
`produce broadly similar biological properties when substituted for one
`
`another 185
`
`169 More importantly the prior art suggests that in the case of these
`
`particular amino acids the substitution of methylene for amino would be expected
`
`to produce
`
`compound with similar anticonvulsant activity Kolrn 1991 in and of
`
`itself
`
`illustrates this to POSA Kohn 1991 observes that the a-amino
`
`185 Ex 1028 at 30 Ex 1029 at 19 Ex 1027 at 563-64
`
`-101-
`
`
`
`derivative .. displayed anticonvulsant activit comparable to that observed for
`
`the a-methyl analogue.86
`
`170
`
`The methoxyamino NIHOCH3 compound however had an
`
`approximate 10-fold increase in activity ED50 of 6.2 vs 65.1 relative to the
`
`unsubstituted amino NH2 compound
`
`POSA likewise would have been
`
`motivated to substitute the methoxymethyl CH2OCH3 for the methyl with
`
`reasonable expectation that the compound racemic lacosamide compound 107e
`
`from the LeGall thesis would also have promising anticonvulsant activity
`
`186 Ex 1010 at 2447 see id at 2445 Tbl
`
`871d at 2445 Tbl
`
`-102-
`
`
`
`ONH3
`
`Compound 3a
`ED50
`65.1 mg/kg
`
`Comparable
`anticonvutsant
`
`activity
`
`Compound 31
`6.2 mglkg
`ED50
`
`Compound 2a
`ED50
`76.5 mg/kg
`
`racemic lacosamide
`LeGal thesis compound 107e
`
`171
`
`POSA would have had
`
`reasonable expectation that compound
`
`07e from the LeGall thesis with its substitution of methoxymethyl for
`
`yielding
`
`lacosamides structure would have anticonvulsant activity consistent with
`
`LeGalls teaching that the structure may have good ant/convulsant
`
`activity.88 In
`
`addition the 729 patent and its foreign counterpart applications and patents
`
`expressly teach that compounds within the formula disclosedincluding the
`
`lacosamide structureare useful anticonvulsant agents.89 These patents disclose
`
`188 Ex 1005 at 155 emphasis added
`
`89See e.g Ex 1008 col 130-35 cl 132 Ex 1003 cl 47
`
`-103-
`
`
`
`the use of these compounds including lacosamide as an anticonvulsant
`
`in the
`
`claimed methods of treating CNS disorders
`
`190
`
`In addition the expectation of
`
`success is further enhanced because the lacosamide structure employs preferred
`
`substituents of the fomiulas disclosed in the 729 patent
`
`172 Therefore claims
`
`and 3-8 of the 551 patent are obvious to POSA
`
`in light of the LeGall thesis and other prior art
`
`of the 551 Patent Would Have Been
`Claims and
`Obvious in View of the LeGall Thesis and Other Prior Art
`
`173 Claims
`
`and
`
`of the 551 patent place limits on enantiopurity of the
`
`R-enantiomer of the claimed compounds including lacosamide The only
`
`difference between compound 107e of the LeGall thesis and the requirements of
`
`claim and
`
`of the 551 patent
`
`is that compound 107e is
`
`50/50 racemic mixture
`
`of the
`
`enantiomer lacosamide and the
`
`enantiomer whereas claims
`
`and
`
`require greater enantiopurity of the
`
`enantiomer lacosarnide Claim requires the
`
`enantiomer to be substantially enantiopure whereas claim requires at least
`
`90% w/w stereoisomer
`
`174
`
`The analysis set forth in J87-9 shows that POSA would have been
`
`able to prepare lacosamide i.e the
`
`enantiomer in enantiopure forni
`
`In other
`
`190 Ex 1008 Ex 1003
`
`-104-
`
`
`
`words as discussed the prior art enabled
`
`POSA to obtain greater than 90
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