Paper No. ______
`
`Filed on behalf of Apotex Inc.
`By: Kenneth J. Burchfiel
`
`Grant S. Shackelford
`
`Sughrue Mion, PLLC
`
`2100 Pennsylvania Ave., NW
`
`Washington, DC 20037
`
`Telephone: 202-293-7060
`
`Facsimile: 202-293-7860
`
`email:
`kburchfiel@sughrue.com
`gshackelford@sughrue.com
`
`
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`APOTEX INC.
`Petitioner
`
`v.
`
`MERCK & CO., INC.
`Patent Owner
`__________________
`
`Patent No. 5,691,336
`__________________
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,691,336
`
`
`
`Filed on behalf of Apotex Inc.
`By: Kenneth J. Burchfiel
`
`Grant S. Shackelford
`
`Sughrue Mion, PLLC
`
`2100 Pennsylvania Ave., NW
`
`Washington, DC 20037
`
`Telephone: 202-293-7060
`
`Facsimile: 202-293-7860
`
`email:
`kburchfiel@sughrue.com
`gshackelford@sughrue.com
`
`
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`APOTEX INC.
`Petitioner
`
`v.
`
`MERCK & CO., INC.
`Patent Owner
`__________________
`
`Patent No. 5,691,336
`__________________
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,691,336
`
`
`
`TABLE OF CONTENTS
`
`Page
`TABLE OF CASES .......................................................................................... IV
`EXHIBITS CITED ............................................................................................. V
`
`I.
`II.
`
`INTRODUCTION ..................................................................................... 1
`COMPLIANCE WITH REQUIREMENTS FOR AN INTER
`PARTES REVIEW PETITION ................................................................... 1
`A. Grounds for Standing ....................................................................... 1
`
`Payment of Fee for Inter Partes Review ........................................... 1
`B.
`C. Mandatory Notices (37 C.F.R. §42.8(b)) ........................................... 2
`
`1.
`2.
`
`3.
`4.
`
`Real Party-in-Interest (37 C.F.R. §42.8(b)(1)) ......................... 2
`Related Matters (37 C.F.R. §42.8(b)(2)) .................................. 2
`
`Lead and Backup Counsel (37 C.F.R. §42.8(b)(3)) .................. 2
`Service Information (37 C.F.R. §42.8(b)(4))............................ 2
`
`III.
`
`Power of Attorney (37 C.F.R. §42.10(b)) ................................ 2
`5.
`STATEMENT OF PRECISE RELIEF REQUESTED.................................. 3
`A.
`Identification of Prior Art and Challenged Claims ............................. 3
`
`Supporting Evidence Relied Upon .................................................... 3
`B.
`IV. OVERVIEW OF THE ʼ336 PATENT......................................................... 4
`
`V.
`
`A. Disclosure of the ’336 patent ............................................................ 4
`THE BROADEST REASONABLE CONSTRUCTION OF
`CLAIM TERMS........................................................................................ 8
`VI. FORMATION OF A PRODRUG OF APREPITANT WITH
`ENHANCED AQUEOUS SOLUBILITY ................................................. 14
`A. Aprepitant and its poor aqueous solubility were known ................... 14
`
`i
`
`
`
`
`
`B.
`
`Use of prodrugs to improve aqueous solubility was
`known ........................................................................................... 18
`
`1.
`
`Fosphenytoin was a known prodrug with enhanced
`aqueous solubility over its parent compound ......................... 20
`
`2.
`
`3.
`
`Direct phosphorylation of nitrogenous heterocycles
`to improve aqueous solubility without formation of
`an N-Mannich base was known............................................. 23
`Phosphorylation of 1,2,4-triazolin-3-one groups
`and isosteres was known....................................................... 26
`VII. DETAILED EXPLANATION OF GROUNDS FOR
`OBVIOUSNESS ..................................................................................... 32
`A. Ground 1: Claims 1, 3-8, and 10-25 are obvious over
`Dorn ’699 in view of Murdock ʼ082. .............................................. 32
`1.
`Aprepitant and the bis(N-methyl-D-glucamine) salt
`thereof, a pharmaceutical composition comprising
`aprepitant and a pharmaceutically acceptable
`carrier, and the use of aprepitant as a tachykinin
`receptor antagonist were obvious .......................................... 33
`Preparation of N-phosphoryl (phosphoramidate)
`prodrugs with enhanced aqueous solubility by
`direct phosphorylation of nitrogenous heterocycles
`was obvious ......................................................................... 38
`N-phosphorylation of aprepitant to obtain
`fosaprepitant and pharmaceutically acceptable salts
`thereof, the compositions thereof, and the use of
`fosaprepitant and pharmaceutically acceptable salts
`thereof was obvious.............................................................. 41
`
`2.
`
`3.
`
`B.
`
`Ground 2: Claims 1, 3-8, and 10-25 are Obvious Over
`Dorn’699 in view of Murdock’082, Atanassova et al. and
`Van Den Bos’926 .......................................................................... 48
`
`1.
`
`Phosphorylation of aprepitant’s 1,2,4 triazolin-3-
`one group was obvious ......................................................... 49
`
`ii
`
`
`
`
`
`2.
`
`Direct phosphorylation of aprepitant to obtain
`fosaprepitant and pharmaceutically acceptable salts
`thereof, the compositions thereof, and the use of
`fosaprepitant and pharmaceutically acceptable salts
`thereof in was obvious.......................................................... 50
`C. Ground 3: Claims 12, 15, 16, 18, 19 and 23 are obvious
`over Dorn ʼ699, in view of Murdock ʼ082, Atanassova et
`al., Van Den Boss et al., Sommer et al., Veronesi and
`Chromy et al.................................................................................. 53
`VIII. CONCLUSION ....................................................................................... 56
`
`
`
`
`
`
`iii
`
`
`
`TABLE OF CASES
`
`KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) ................. 45, 48, 53, 56
`
`Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999
`(Fed. Cir. 2009) ............................................................................. 45
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ..................46, 54
`Ranbaxy Labs. Ltd. v. Vertex Pharma. Inc., IPR2013-00024,
`Paper 16 (March 5, 2013) ............................................................... 45
`
`
`
`
`
`iv
`
`
`
`EXHIBITS CITED
`
`Ex. 1001 U.S. Patent No. 5,691,336 to Dorn et al.
`
`Ex. 1002 Declaration of Longqin Hu, Ph.D. ("Hu Decl.")
`Ex. 1003 U.S. Patent No. 5,637,699 to Dorn et al.
`
`Ex. 1004 U.S. Patent No. 5,070,082 to Murdock et al.
`Ex. 1005 Murdock, K.C., et al., N-Phosphoryl Derivatives of Bisantrene.
`Antitumor Prodrugs with Enhanced Solubility and Reduced Potential
`for Toxicity, J. MED. CHEM., 36, 2098-2101 (July 23, 1993)
`
`Ex. 1006 U.S. Patent No. 3,661,926 to Van Den Bos et al.
`Ex. 1007 Atanassova, T. et al., Synthesis of N-substituted 2-imidazolidinone,”
`PHARMAZIE, 42(9), 670-671 (1991)
`Ex. 1008 Bundgaard, H. et al., Prodrugs as drug delivery systems IV: N-
`mannich bases as potential novel prodrugs for amides, ureides,
`amines, and other NH-acidic compounds, J. PHARM. SCI., 69, 44-46
`(1980)
`Ex. 1009 Bundgaard, H. (ed.), Design of Prodrugs, Chapter 1: “Design of
`prodrugs: Bioreversible derivatives for various functional groups and
`chemical entities,” Preface and 1-92 (1985)
`Ex. 1010 Bundgaard, H. (ed.), Design of Prodrugs, Chapter 7: “Prodrugs for
`improved formulation properties,” 243-269 (1985)
`Ex. 1011 Bundgaard, H., Formation of Prodrugs of Amines, Amides, Ureides,
`and Imides, METHODS IN ENZYMOLOGY, 112, 347-359 (1985)
`Ex. 1012 Balant, L.P. et al., Prodrugs for the improvement of drug absorption
`via different routes of administration, EUR. J. DRUG METABOL.
`PHARMACOKIN., 15(2), 143-153 (1990)
`
`Ex. 1013 Avis, K.E. et al. (eds.), Pharmaceutical Dosage Forms: Parenteral
`Medications Volume 1, Chapter 2: Duma, R.J. et al. Parenteral Drug
`Administration: Routes, Precautions, Problems, Complications and
`Drug Delivery Systems,” 17-58 (1992)
`
`
`
` v
`
`
`
`Ex. 1014 Varia, S.A. et al., Phenytoin Prodrugs III: Water-Soluble Prodrugs
`for Oral and/or Parenteral Use, J. PHARM. SC. 73(8) 1068-1073
`(1984)
`Fischer, J.H., et al., Fosphenytoin Clinical Pharmacokinetics and
`Comparative Advantages in the Acute Treatment of Seizures, CLIN.
`PHARMACOKINET., 42(1), 33-58 (2003)
`
`Ex. 1015
`
`Ex. 1016 Kearney, et al., The in Vitro Enzymic Labilities of Chemically Distinct
`Phosphomonoester Prodrugs, PHARM. RES., 9(4), 497-503 (1992)
`
`Ex. 1017
`
`Sommer, F.G., et al., Pain Accompanying Leg Venography: A
`Comparison of Sodium and Methylglucamine Diatrizoates,
`RADIOLOGY, 133, 790-791 (1979)
`Ex. 1018 Chromy, V., et al., D(-)-N-Methylglucamine Buffer for pH 8.5 to 10.5,
`CLIN. CHEM., 24(2), 379-381 (1978)
`Ex. 1019 U.S. Patent No. 3,981,994 to Hoffmann et al.
`
`Ex. 1020 U.S. Patent No. 3,867,397 to Bohner et al.
`Ex. 1021 Berge, S.M. et al., Pharmaceutical Salts, J. PHARM. SCI., 66(1), 1-19
`(1977)
`
`Ex. 1022 U.S. Patent No. 4,748,174 to Veronesi
`Ex. 1023 Merck & Co. Emend® (aprepitant) Drug Information Label
`Ex. 1024 Merck & Co. Emend® (fosaprepitant dimeglumine) Drug Information
`Label
`
`Ex. 1025 U.S. Patent Application Serial No. 08/169,889, filed December 17,
`1993, abandoned
`
`
`
`
`
`
`
` vi
`
`
`
`
`
`I.
`
`INTRODUCTION
`Pursuant to 35 U.S.C. § 311 and 37 C.F.R. § 42.100, Apotex Inc.
`
`(“Petitioner”) requests inter partes review of Claims 1, 3-8, and 10-25 of U.S.
`
`Patent No. 5,691,336 (“the ’336 patent”, Ex. 1001) assigned on its face to Merck &
`
`Co., Inc. (“Patent Owner”). This Petition demonstrates that there is a reasonable
`
`likelihood that Petitioner will prevail with respect to at least one of the challenged
`
`claims, and thus a trial for inter partes review must be instituted. Evidence in this
`
`petition establishes that Claims 1, 3-8, and 10-25 of the ’336 patent are
`
`unpatentable under 35 U.S.C. § 103(a). Petitioner respectfully requests that Claims
`
`1, 3-8, and 10-25 of the ’336 patent be judged unpatentable and canceled.
`
`II. COMPLIANCE WITH REQUIREMENTS FOR AN INTER PARTES
`REVIEW PETITION
`A. Grounds for Standing
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner certifies that the ʼ336 patent is
`
`available for inter partes review and that Petitioner is not barred or estopped from
`
`requesting an inter partes review challenging the ’336 patent claims on the
`
`grounds identified herein.
`
`Payment of Fee for Inter Partes Review
`B.
`The Director is authorized to charge the fees specified by 37 C.F.R. §
`
`42.15(a) to Deposit Account No. 194880.
`
`
`
`1
`
`
`
`
`
`C. Mandatory Notices (37 C.F.R. §42.8(b))
`Real Party-in-Interest (37 C.F.R. §42.8(b)(1))
`1.
`The real parties-in-interest for this petition are Apotex Inc., Apotex Corp.,
`
`and Apotex Holdings, Inc. (collectively referred to as “Apotex”).
`
`Related Matters (37 C.F.R. §42.8(b)(2))
`2.
`On information and belief the ’336 patent is involved in litigation styled
`
`Merck Sharp & Dohme Corp. v. Sandoz Inc., Civil Action No. 12-3289
`
`(PGS)(LHG) (D.N.J.). Apotex is not a party to that litigation.
`
`Lead and Backup Counsel (37 C.F.R. §42.8(b)(3))
`
`3.
`LEAD COUNSEL
`Kenneth J. Burchfiel
`Reg. No. 31,333
`Sughrue Mion, PLLC
`2100 Pennsylvania Ave., NW
`Washington, DC 20037
`Phone: 202-293-7060
`Fax: 202-293-7860
`kburchfiel@sughrue.com
`
`BACKUP COUNSEL
`Grant S. Shackelford
`Reg. No. 70,504
`Sughrue Mion, PLLC
`2100 Pennsylvania Ave., NW
`Washington, DC 20037
`Phone: 202-293-7060
`Fax: 202-293-7860
`gshackelford@sughrue.com
`
`Service Information (37 C.F.R. §42.8(b)(4))
`4.
`Petitioner consents to electronic service by e-mail at the e-mail addresses of
`
`counsel provided above.
`
`Power of Attorney (37 C.F.R. §42.10(b))
`5.
`A power of attorney accompanies this Petition.
`
`
`
`
`
`2
`
`
`
`
`
`III. STATEMENT OF PRECISE RELIEF REQUESTED
`Pursuant to 37 C.F.R. §§ 42.22(a)(1) and 42.104(b), Claims 1, 3-8, and 10-
`
`25 of the ’336 patent are unpatentable for the following reasons.
`
`Identification of Prior Art and Challenged Claims
`
`A.
`Ground 1: Claims 1, 3-8, and 10-25 are unpatentable under 35 U.S.C.
`
`§103(a) as being obvious over Dorn ’699 (Ex. 1003) in view of Murdock ʼ082 (Ex.
`
`1004).
`
`Ground 2: Claims 1, 3-8, and 10-25 are unpatentable under 35 U.S.C.
`
`§103(a) as being obvious over Dorn ʼ699 (Ex. 1003) in view of Murdock ʼ082 (Ex.
`
`1004), Atanassova et al. (Ex. 1007) and Van Den Bos (Ex. 1006).
`
`Ground 3: Claims 12, 15, 16, 18, 19 and 23 are unpatentable under 35
`
`U.S.C. §103(a) as being obvious over Dorn ʼ699 (Ex. 1003) in view of Murdock
`
`’082 (Ex. 1004), Atanassova et al. (Ex. 1007) and Van Den Bos (Ex. 1006), and
`
`further in view of Sommer et al. (Ex. 1017), Veronesi (Ex. 1022), and Chromy et
`
`al. (Ex. 1018).
`
`Supporting Evidence Relied Upon
`B.
`Pursuant to 37 C.F.R. §§ 42.22(a)(2) and 42.104(b)(4) and (5), a full
`
`statement of the reasons why each of claims 1, 3-8, and 10-25 of the ’336 Patent
`
`should be held unpatentable under 35 U.S.C. § 103(a) is provided in Section VII
`
`below by reference to the supporting evidence, including the exhibits identified
`
`above. Petitioner relies on the expert Declaration of Longqin Hu, Ph.D. (Ex. 1002,
`
`
`
`3
`
`
`
`
`
`“Hu Decl.”). Dr. Hu has worked for 19 years as a research chemist with expertise
`
`in synthetic medicinal chemistry and bioorganic chemistry and is named as an
`
`inventor on 7 U.S. patents relating to therapeutic agents and the development
`
`thereof. Dr. Hu is also an author on 75 peer reviewed publications concerning
`
`issues related to medicinal chemistry, including prodrugs. (Ex. 1002, ¶ 3.) Dr.
`
`Hu’s curriculum vitae is attached to his declaration as Appendix A.
`
`IV. OVERVIEW OF THE ʼ336 PATENT
`A. Disclosure of the ’336 patent
`U.S. Patent 5,691,336 (Ex. 1001), entitled Morpholine Compounds Are
`
`Prodrugs Useful As Tachykinin Receptor Antagonists, issued on November 25,
`
`1997 from application Ser. No. 525,870, filed September 8, 1995, which is a
`
`continuation-in-part of PCT application No. PCT/US95/02551, filed February 28,
`
`1995, which is in turn a continuation-in-part of application Ser. No. 08/206,771
`
`filed March 4, 1994, now abandoned. The ’336 patent names as inventors Conrad
`
`P. Dorn, Jeffrey J. Hale, Malcolm Maccoss and Sander G. Mills. (Id.)
`
`The ’336 patent relates to morpholine compounds and prodrugs represented
`
`by “structural formula I,” depicted below (see, e.g., id. at 5:15-32 and claim 1):
`
`
`
`
`
`4
`
`
`
`
`
`These compounds of structural formula I are described as tachykinin receptor
`
`antagonists that may be used as active ingredients in pharmaceutical formulations
`
`in the treatment of inflammatory diseases, pain or migraine, asthma, and emesis.
`
`(Id. at 5:33-39.)
`
`The specification states that the disclosed compounds are prodrugs of their
`
`“parent compounds” (id. at 12:26-29; 17:56-58) and identifies 2-(R)-(1-(R)-(3,5-
`
`bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-
`
`1,2,4-triazolo)methyl-morpholine (“aprepitant”) as parent compound 96 (id. at
`
`39:1-22):
`
`
`The Detailed Description of the Invention identifies the structure of 2-(R)-
`
`(1-(R)-(3,5- bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluoro)phenyl l-4-(3-(1-
`
`phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine (“fosaprepitant”) as one of
`
`
`
`5
`
`
`
`
`
`nine “[s]pecific compounds within the scope of the present invention,” where K+ is
`
`a pharmaceutically acceptable counterion. (Id. at 41:1-17; 43:18.)
`
`
`
`The ’336 patent also teaches that the compounds of structural formula I may
`
`be in the form of salts (id. at 71:45-60) and identifies fosaprepitant bis(N-methyl-
`
`D-glucamine) salt as “a specific particularly preferred compound within the scope
`
`of the present invention” (id. at 43:19-27). N-methyl-D-glucamine is a well-
`
`known pharmaceutical salt. (Ex. 1002, ¶ 66; see, e.g., Tables I and III of Ex. 1021,
`
`published 1977.)
`
`The Background of the Invention references articles dating back to 1975 to
`
`describe the use of prodrugs to deliver a parent drug in vivo (id. at 4:57–5:6):
`
`Prodrugs are entities structurally related to a biologically active
`substance (the “parent drug”) which, after administration, release the
`parent drug in vivo as the result of some metabolic process, such as
`enzymatic or chemical hydrolysis of a carboxylic, phosphoric or
`sulfate ester or reduction or oxidation of a susceptible functionality
`(see, for example, discussions by (1) A. A. Sinkula and S. H.
`Yalkowsky, J. Pharm. Sci. 64, 181 (1975); (2) L. A. Svensson, Pharm
`Weekbl, 122, 245-250 (1987); (3) L. P. Balant, E. Doelker and P. Buri
`Eur. J. Drug Metab. and Pharmacokinetics, 15, 143-153 (1990); (4)
`N. Bodor, Drugs of the Future, 6, 165-182 (1981); (5) Design of
`
`
`
`6
`
`
`
`
`
`
`
`Biopharmaceutical Properties through Prodrugs and Analogs, E. B.
`Roche, Ed., American Pharmaceutical Association Academy of
`Pharmaceutical Sciences, Washington, D.C.,
`(1977);
`(6) H.
`Bundgaard Advanced Drug Delivery Reviews, 3, 39-65 (1989)).
`
`The Background of the Invention also explains that the benefits and
`
`motivation to use prodrugs were also well known (id. at 5:6-12):
`
`The advantage of a prodrug may lie in its physical properties, such as
`enhanced water solubility for parenteral administration compared to
`the parent drug, or it may enhance absorption from the digestive tract,
`or it may enhance drug stability for long-term storage. In general, a
`prodrug possesses less biological activity than its parent drug.
`
`In line with these well-known advantages, the ’336 patent explains that the
`
`disclosed prodrugs are precursors that provide enhanced solubility in aqueous
`
`solutions relative to their parent compounds and, following administration and
`
`absorption, release the drug in vivo via some metabolic process. (Id. at 12:26-37.)
`
`The ʼ336 patent states that the disclosed prodrugs, such as fosaprepitant,
`
`may be administered intravenously for the treatment of clinical conditions and
`
`diseases associated with the neuropeptide receptors for substance P (neurokinin-1
`
`receptors). (Id. at 44:53-47:63, 48:44-49 and 49:34-36.) These pharmaceutical
`
`preparations are described as comprising the pharmaceutical compound of formula
`
`I and a pharmaceutically acceptable carrier suitable for external, enteral or
`
`parenteral applications, such as water. (Id. at 48:50-61.) “Parenteral” is defined to
`
`include subcutaneous injections, intravenous, intramuscular, intrasternal injection
`
`or infusion techniques. (Id. at 50:6-8.)
`
`7
`
`
`
`
`
`
`
`V. THE BROADEST REASONABLE CONSTRUCTION OF CLAIM
`TERMS
`
`Pursuant to 37 C.F.R. §§ 42.104(b)(3) and 42.100(b), Petitioner states that
`
`Claims 1, 3-8, and 10-25 of the ’336 patent do not require further construction.
`
`When given their broadest reasonable interpretation in light of the specification,
`
`Claims 1-19 encompass fosaprepitant and pharmaceutical salts thereof, Claims 20-
`
`23 recite pharmaceutical compositions containing the compounds, and Claims 24
`
`and 25 relate to methods of using the compounds. (Ex. 1002, ¶¶ 74-97.) The
`
`proposed constructions set forth below are not binding upon Petitioner beyond this
`
`inter partes review.
`
`Independent Claim 1 recites a compound of structural formula
`
`
`wherein the substituents encompass fosaprepitant bis(N-methyl-D-glucamine), as
`
`shown below:
`
`Abbreviation
`R2 & R3
`(independently)
`R6, R7 & R8
`(independently)
`
`Substituent
`Hydrogen
`
`Hydrogen &
` –CF3
`
`
`
`8
`
`
`
`
`
`R11, R12 & R13
`
`(independently)
`A
`B
`
`Hydrogen &
`Halogen
`C1-6 alkyl
`
`P
`X
`Y
`Z
`
`
`
`0
`–PO(O-)2·2M+
`–O–
`C1-6 alkyl
`
`
`Dependent Claim 3 recites that Z of the compound of Claim 1 is C1-4 alkyl,
`
`which encompasses fosaprepitant when Z is –CH3.
`
`Dependent Claim 4 recites that Z of the compound of Claim 1 is –CH3,
`
`which encompasses fosaprepitant.
`
`Dependent Claim 5 recites that A of the compound of Claim 1 can be –CH2–
`
`which encompasses fosaprepitant.
`
`Dependent Claim 6 recites that –B of the compound of Claim 1 can be
`
`, which encompasses fosaprepitant.
`
`Dependent Claim 7 recites that –A–B of the compound of Claim 1 can be
`
`the phosphorylated 1,2,4-triazolin-3-one group of fosaprepitant:
`
`
`
`9
`
`
`
`
`
`
`
`Dependent Claim 8 recites that X of the compound of Claim 1 can be -
`
`PO(O-)2 • 2M+, where M+ is a pharmaceutically acceptable monovalent
`
`counterion. The pharmaceutically acceptable monovalent counterion includes N-
`
`methyl-D-glucamine (Ex. 1001 at 71:45-60). Therefore, Claim 8 encompasses
`
`fosaprepitant, bis(N-methyl-D-glucamine) salt.
`
`Dependent Claim 10 defines the compound of Claim 1 as structural formula
`
`III or pharmaceutically acceptable salt thereof:
`
`,
`
`which encompasses the structural formula of fosaprepitant and fosaprepitant bis(N-
`
`methyl-D-glucamine) salt.
`
`Independent Claim 11 lists compounds including (3), which is 2-(R)-(1-(R)-
`
`(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-
`
`monophosphoryl-5-oxo-1H-1,2,4-triazolo)methylmorpholine or a pharmaceutically
`
`acceptable salt thereof. Compound (3) is fosaprepitant. (Ex. 1002, ¶ 85.)
`
`
`
`10
`
`
`
`
`
`Dependent Claim 12 recites the compounds of Claim 11, including
`
`fosaprepitant, where the salt is the bis(N-methyl-D-glucamine) salt. (Id. at ¶ 86.)
`
`Independent Claim 13 lists compounds including the following structural
`
`formula, which is a pharmacologically acceptable salt of fosaprepitant:
`
`
`Independent Claim 14 recites the compound 2-(R)-(1-(R)-(3,5-
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`bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-
`
`oxo-4H-1,2,4-triazolo)methylmorpholine, which is fosaprepitant, or a
`
`pharmaceutically acceptable salt thereof.
`
`Dependent Claim 15 specifies that the salt of Claim 14 is the bis(N-methyl-
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`D-glucamine) salt.
`
`Independent Claim 16 recites the compound 2-(R)-(1-(R)-(3,5-
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`bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(1-phosphoryl-5-
`
`oxo-4H-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine), which is
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`fosaprepitant bis(N-methyl-D-glucamine) salt.
`
`Independent Claim 17 recites the following structural compound, which is
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`fosaprepitant with K+ as pharmaceutically acceptable counterions. The compound
`
`
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`11
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`
`
`
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`encompasses a pharmaceutically acceptable salt of fosaprepitant, such as
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`fosaprepitant, bis(N-methyl-D-glucamine). (Id. at 71:45-60.)
`
`
`Dependent Claim 18 defines the pharmaceutically acceptable counterion K+
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`of fosaprepitant as N-methyl-D-glucamine.
`
`Claim 19 recites the following structural compound, which is fosaprepitant,
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`bis(N-methyl-D-glucamine):
`
`
`Dependent Claims 20-22 are directed to pharmaceutical compositions
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`comprising an effective amount of the compound of Claim 1 and a
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`pharmaceutically acceptable carrier. The carrier is defined in Claim 21 as water,
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`and in Claim 22 as physiologically acceptable saline solution. Claims 20-22 thus
`
`
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`12
`
`
`
`
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`encompass fosaprepitant or its pharmaceutically acceptable salt in a composition
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`with a pharmaceutically acceptable carrier, as defined in Claims 20-22.
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`Independent Claim 23 is directed to a pharmaceutical composition
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`comprising a pharmaceutically acceptable carrier and an effective amount of the
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`following structural compound:
`
`,
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`which is fosaprepitant dimeglumine, as similarly depicted in Claim 19.
`
`Dependent Claim 24 is directed to a method of antagonizing the effect of
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`substance P at its receptor by blockade of the neurokinin-1 receptors comprising
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`administering the compound of Claim 1 to a mammal in an amount that is effective
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`for antagonizing the effect of substance P at its receptor site or blockade of
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`neurokinin-1 receptors. The compound used in Claim 24 includes fosaprepitant or
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`a pharmacologically acceptable salt thereof, as discussed above for Claim 1.
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`Dependent Claim 25 is directed to a method of treating or preventing pain or
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`nociception comprising administering the compound of Claim 1, which includes
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`
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`13
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`
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`fosaprepitant or pharmacologically acceptable salt thereof, as discussed above for
`
`Claim 1.
`
`VI. FORMATION OF A PRODRUG OF APREPITANT WITH
`ENHANCED AQUEOUS SOLUBILITY
`
`An understanding of the formation of prodrugs, such as fosaprepitant, and
`
`the use of prodrugs to improve the aqueous solubility of a parent compound, such
`
`as aprepitant, underlies each of the grounds of unpatentability set forth below. In
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`particular, the understanding of a POSA (“POSA”) of the relationship between pKa
`
`and aqueous solubility of an intravenous preparation, the ability to alter
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`physicochemical properties, such as aqueous solubility, of a drug compound
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`through development of a prodrug entity and the suitability of a 1,2,4-triazolin-3-
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`one group for direct phosphorylation, is set forth in this section, and in Ex. 1002,
`
`¶¶ 10-61. A POSA in the field of the ’336 patent would have been a chemist with
`
`at least a M.S. degree, with three years of additional experience in pharmaceutical
`
`formulation, or a Ph.D. degree in Medicinal Chemistry who is familiar with
`
`pharmaceutical formulation. (Id. at ¶¶ 7-9.)
`
`A. Aprepitant and its poor aqueous solubility were known
`The compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-
`
`(4-fluoro)-phenyl-4-(3-(5-oxo-1,2,4-triazolo)methyl-morpholine (Ex. 1001 at 39:1-
`
`22) has the generic name “aprepitant” and is the parent compound for the prodrug
`
`compound (2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-
`
`
`
`14
`
`
`
`
`
`fluoro)phenyl-4-(3-(1-phosphoryl-5-oxo-4H-1,2,4-triazolo)methylmorpholine) (id.
`
`at 41:1-17), which has the generic name “fosaprepitant.” (Ex. 1002, ¶ 10.) The
`
`difference between aprepitant and fosaprepitant is that in fosaprepitant, the 1, 2, 4-
`
`triazolin-3-one group is N-phosphorylated, i.e., a secondary nitrogen is substituted
`
`with a phosphonate group, as indicated below. (Id. at ¶ 13; compare Ex. 1023 at 1
`
`with Ex. 1024 at 1.)
`
`
`Aprepitant has a morpholine core with two substituents attached to adjacent
`
`ring carbons and a third substituent attached to the morpholine ring nitrogen. (Ex.
`
`1002, ¶ 16.) The substituent groups attached to adjacent ring carbons are
`
`trifluoromethylated phenyl ethoxy and 4-fluorophenyl. (Id.) The third substituent
`
`attached to the morpholine ring nitrogen is a 5-substituted 1,2-dihydro-1,2,4-
`
`triazolin-3-one group. (Id.)
`
`
`
`15
`
`
`
`
`
`Aprepitant is a reversible human neurokinin-1-receptor (hNK1) antagonist
`
`(Ex. 1003 at 1:28-30) that is used orally for the prevention of acute and delayed
`
`nausea/vomiting associated with initial and repeat courses of highly emetogenic
`
`cancer chemotherapy (Ex. 1003 at 21:32-34 and Ex. 1023 at pages 9 and 16) and is
`
`“practically insoluble in water” (Ex. 1023 at 1; see also Ex. 1001 at 13:9-12). (Ex.
`
`1002, ¶ 14.)
`
`Aprepitant’s poor aqueous solubility would have been expected from the
`
`compound’s weakly acidic and weakly basic groups. Based on known pKa values,
`
`a POSA would have expected aprepitant’s 1, 2, 4-triazolin-3-one group to have a
`
`pKa of around 8.1 and act as a weak acid. (Id. at ¶ 17-18.) Further, a POSA would
`
`recognize aprepitant’s substituted morpholine group to act as a weak base, its
`
`conjugate acid having a pKa of around 4.4. (Id. at ¶¶ 18-19.) Thus, at
`
`physiological pH 7.4, these groups would be in their neutral, water insoluble form.
`
`(Id. at ¶ 20.)
`
`The water solubility of an organic drug like aprepitant is mostly determined
`
`by the presence of polar functional groups relative to nonpolar functional groups in
`
`the drug molecule and by its ability to form more water-soluble charged species in
`
`aqueous solution under a given pH. (Id.) pH needs to be about two pH units
`
`higher than the pKa of an acid drug in order to keep the acid drug in its fully
`
`negatively charged, water-soluble form. (Id. at ¶ 21.) Likewise, pH needs to be
`
`
`
`16
`
`
`
`
`
`about two pH units lower than the pKa of a base drug in order to keep the base drug
`
`in its fully positively charged, water-soluble form. (Id.) Thus, an intravenous
`
`preparation of aprepitant would need to be kept at around pH 10 or higher or pH 2
`
`or lower to avoid reverting back to the neutral, water insoluble form of the drug.
`
`(Id. at ¶ 22.)
`
`A POSA would have recognized that an injection solution with such high (or
`
`low) pH value would not be suitable for intravenous use. (Id. at ¶ 23; see also,
`
`e.g., Ex. 1015 at page 35, summarizing complications with parenteral
`
`administration of an alkaline (pH 12) phenytoin solution.) When such a
`
`preparation is diluted in blood upon injection, the pH of the solution changes to the
`
`physiological pH 7.4, causing rapid precipitation of the drug. (Ex. 1002, ¶ 23; see
`
`also Ex. 1015 at page 35.) Moreover, the relatively high (or low) pH of an
`
`intravenous preparation of aprepitant would cause pain, burning and phlebitis at
`
`the injection site. (Id.) Accordingly, a POSA in 1994 would understand that
`
`aprepitant’s weak acidic and basic functional groups prevent its formulation in an
`
`injection solution suitable for intravenous administration to patients. (Ex. 1002, ¶
`
`23.)
`
`Despite aprepitant’s inherent solubility problems, a POSA would have been
`
`highly motivated to prepare an intravenous formulation of aprepitant to maximize
`
`clinical flexibility of the compound. For use as an antiemetic, an intravenous
`
`
`
`17
`
`
`
`
`
`formulation offers advantages over oral formulations that were well known prior to
`
`1994. (Id. at ¶ 24.) For example, parenteral administration ensures the delivery of
`
`an adequate amount of active moiety that reaches the systemic circulation, the
`
`targeted tissues and organ. (Id.; Ex. 1013 at pages 18-19.) It allows direct control
`
`over certain pharmacologic parameters, such as time of drug onset, serum peak and
`
`trough levels and tissue concentrations, and it can be used to produce an immediate
`
`physiological response when such quick action is needed, which can be a prime
`
`consideration in emergency situations. (Ex. 1002, ¶ 24.) Additionally, parenteral
`
`administration is the preferred route of administration for uncooperative, nauseous
`
`or unconscious patients, which make it particularly suitable for an antiemetic. (Id.)
`
`Furthermore, storage of active ingredients in solutions as prodrugs could also offer
`
`an improvement in the shelf life of parenterals. (Id.; Ex. 1012 at pages 146 and
`
`149.)
`
`B. Use of prodrugs to improve aqueous solubility was known
`A POSA would have considered formation of aprepitant prodrugs to deliver
`
`the active drug intravenously in a manner suitable for clinical use. “A prodrug is a
`
`pharmacologically inactive derivative of a parent drug molecule that requires
`
`spontaneous or enzymatic transformation within the body in order to release the
`
`active drug, and that has improved delivery properties over the parent drug
`
`molecule.” (See Ex. 1009 at Preface.) As of 1994, it was generally known to
`
`
`
`18
`
`
`
`
`
`persons of ordinary skill in the art that physicochemical properties, such as water
`
`solubility, could be improved through modifications to an existing chemical entity,
`
`through preparation of prodrugs. (Ex. 1002, ¶ 25; Ex. 1012 at page 143.)
`
`By 1994, prodrugs were known to increase bioavailability, increase aqueous
`
`solubility, increase drug product stability, enhance patient compliance by
`
`minimizing taste and odor problems, eliminate pain on injection, and decrease
`
`gastro-intestinal irritation. (Ex. 1002, ¶ 27) In particular, the use of phosphate as a
`
`water-solubilizing group in the development of prodrugs for drugs with low water-
`
`solubility, as in fosaprepitant, was well-recognized and used for a number of drugs
`
`for parenteral formulation. (Id.; Ex. 1016 at page 497; Ex. 1012 at page 146; Ex.
`
`1005 at page 2098; Ex. 1014 at page 1068.)
`
`Although most of the water-soluble phosphate prodrugs were for hydroxyl-
`
`containing parent drug molecules, phosphate prodrugs were also prepared for
`
`nitrogenous parent drugs, like aprepitant. (Ex. 1002, ¶ 28; Ex. 1011 at paragraph
`
`bridging pages 347-348 and pages 353-354.) For example, fosphenytoin, a
`
`phosphoryloxymethyl prodrug, and bis(phosphonoguanidinic acid), a
`
`phosphoramidate prodrug, were both prepared from nitrogenous parent drugs. (See
`
`Ex. 1005 at page 2098; Ex. 1014 page 1068.) In seeking to improve the poor
`
`aqueous solubility of aprepitant, a POSA would have considered prodrugs of other
`
`
`
`19
`
`
`
`
`
`poorly water soluble drugs, which have poor bioavailability and cause local
`
`irritation and tissue damage after parenteral dosing. (Ex. 1002, ¶ 29.)
`
`1.
`
`Fosphenytoin was a known prodrug with enhanced aqueous
`solubility over its parent compound
`
`One prominent example of a poorly soluble drug was phenytoin, an
`
`anticonvulsant drug that had been formulated as a parenteral injection using its
`
`sodium salt. (Id.; see Ex. 1014 at page 1068.)
`
`
`Due to its low solubility, phenytoin sodium parenteral formulation was mixed in a
`
`vehicle containing 40% propylene glycol and 10% alcohol in water for i
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