Filed on behalf of Phigenix, Inc.
`By:
`Ping Wang, M.D., Esq.
`Gregory Porter, Esq.
`Michael Ye, Ph.D., Esq.
`ANDREWS KURTH, LLP
`
`1350 I Street, NW
`
`Suite 1100
`
`Washington, DC. 20005
`Tel.: (202) 662—2700
`Fax: (202) 662—2739
`Email: PingWanggQAndrewsKurth.com
`
`UNITED STATES PATENT AND TRADEMARK OFFICE I
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`PHIGENIX, INC.
`Petitioner
`
`V.
`
`IMMUNOGEN, INC.
`
`Patent Owner of
`
`US. Patent No. 8,337,856 to Walter Blattler, et al.
`
`Issued on December 25, 2012
`Appl. No. 11/949,351 filed on December 3, 2007
`
`IPR Trial No. IPR2014—00676
`
`CORRECTED PETITION FOR INTER PARTES REVIEW OF US.
`
`PATENT NO. 8,337,856
`
`PURSUANT TO 35 U.S.C. §312 AND 37 C.F.R. §42.108
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`US. Patent & Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`TABLE OF CONTENTS
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PAT. NO. 8,337,856 ......... l
`
`I.
`
`INTRODUCTION ....................................................................... 1
`
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ........................ 1
`II.
`III. MANDATORY REQUIREMENTS, NOTICES AND FEES .................. l
`A.
`Real Party—In—Interest (37 C.F.R. § 42.8(b)(1)) ........................... l
`B.
`Related Matters (37 C.F.R. §42.8(b)(2)) .................................... l
`C.
`Lead and Back—Up Counsel (37 C.F.R. §42.8(b)(3)) and Service
`Information (37 C.F.R. §42.8(b)(4)) ........................................ 2
`Power of Attorney (37 C.F.R. §42.10(b)) .................................. 2
`D.
`Petition Fees (35U...SC §3l2(1)and 37C...FR §42.15) .............. 2
`E.
`Proof of Service (37 C. F R. §§ 42 6(c) and 42 105(a)) ................... 2
`F.
`STATEMENT OF THE PRECISE RELIEF REQUESTED (37 C. F R.
`§42.22(a)(l) ............................................................................ 3
`RELEVANT INFORMATION CONCERNING THE CONTESTED
`
`IV.
`
`V.
`
`PATENT .......................................................................................................... 3
`
`A.
`
`The ‘856 Patent ................................................................ 3
`
`Technical Background .......... '............................................................. 4
`B.
`Ordinarily Skilled Artisan (Person of Ordinary Skill in the Art) ....... 6
`C.
`Construction of Terms Used in the Claims ................................. 7
`y D.
`IDENTIFICATION OF CHALLENGE (37 C. F. R. §42. 104(b)) ............... 7
`A.
`Ground 1: Claims 1—8 Are Obvious Over Chari 1992 In View Of
`HERCEPTIN® Label ......................................................... 8
`
`VI.
`
`B.
`
`Ground 2: Claims 1— 8 Are Obvious Based on Chari 1992 In View Of
`
`HERCEPTIN® Label, Further In View Of Hudziak 1998 And/Or
`Rosenblum I999
`........................................................... 17
`
`C.
`
`Ground 3: Claims 1-8 Are Obvious Over Chari 1992 In View Of
`
`HERCEPTIN® Label, Further In View Of Hudziak 1998 And/Or
`
`Rosenblum 1999 And Further In View Of Baselga 1998 And/Or
`Pegram 1999 .................................................................. 20
`Ground 4: Claims 4 and 6-8 Are Obvious Based On Chari 1992 In
`
`. .23
`View Of HERCEPTIN® Label And Further In View Of Morgan. .
`Ground 5: Claims l—4 and 6-8 Are Obvious Based On Chari 1992 In
`
`View Of Carter 1992 ........................................................ 26
`
`D.
`
`E.
`
`F.
`
`Ground 6: Claims 1—5 and 7 Are Obvious Over Liu 1996 In View Of
`
`HERCEPTIN® Label ....................................................... 32
`
`ii
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`G.
`
`Ground 7: Claims 6 and 8 Are Obvious Over Liu 1996 In View Of
`
`HERCEPTIN® Label And Further In View of Morgan 1990 ......... 39
`Ground 8: Claims 1—8 Are Obvious Over Cohen 1999 In View Of
`
`H.
`
`Chari 1992 .................................................................. 41
`
`VII.
`
`ISSUES RAISED DURING PROSECUTION OF THE ’856 PATENT. ...48
`
`A.
`
`Patentee Argued the Existence of an Incompatible Mechanism
`of Action Between HERCEPTIN® and Maytansinoid .................. 48
`Reasonable Expectation ofSuccess.....................................;.53
`B.
`No Unexpected Results ...................................................... 57
`C.
`VIII. CONCLUSION ...................................................................... 59
`
`iii
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Asyst Techs., Inc. V. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir.
`2008) ........................................................................................................................ 58
`
`Ecolab, Inc. v. FMC Corp, 569 F.3d 1335, 1350 (Fed. Cir. 2009) .................. 14, 37
`
`In re Debaufi, 687 F.2d 459 (CCPA 1982)............................................... 47
`
`In re Huang, 100 F.3d 135, 139 (Fed.Cir.1996) ...................................................... 58
`
`In re Mathews, 408 F.2d 1393 (CCPA 1969) ............................... 46
`
`In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990) ......................................... 12, 29, 36
`
`In re Zierden, 411 F.2d 1325, 1328 (CCPA 1969) ...................................... 12, 29, 36
`
`Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed.
`Cir. 2004) .............'.................................................................................................... 58
`
`KSR Int’l Co. v. Teleflex Inc., 550 US. 398, 127 S.Ct. 1727, 1739,
`1741 (2007) .............................................................................................’................. 59
`
`iV
`
`

`

`EXHIBIT LIST
`
`
`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`
`US. Patent No. 8,337,856 (filattler, et a1.)
`
`December 25,
`
`1002
`
`1003
`
`1004
`
`May, 1989
`
`1
`
`Slamon, et (11., “Studies of the HER—2/neu proto—
`oncogene in human breast and ovarian cancer.”
`Science 244:707—712 (1989).
`Press, et al., “HER—2/neu gene amplification ‘
`charactenzed-by fluorescence 1n Sltu hybr1dizat1on: ” August, 1997
`poor progn051s 1n node—negative breast carcmomas.
`J. Clin. Oncol. 15:2894—2904 (1997).
`Phillips, et al., “Targeting HER2-positive breast
`November 15,
`cancer with trastuzumab-DMI, an antibody—
`2008
`cytotoxic drug conjugate.” Cancer Res. 68: 9280—
`
`9290 (2008L
`Hudziak, et al., “p185Hm monoclonal antibody has
`1005
`antiproliferative effects in vitro and sensitizes
`.
`human breast tumor cells to tumor necrOSIS factor.
`
`M01. Cell. Biol.,9:1165—1172(1989).
`
`1006 McKenzie, et 61]., “Generation and characterization
`
`,,
`
`March, 1989
`
`2012
`
`
`
`
`
`
`
`of monoclonal antibodies specific for the human neu
`oncogene product, p185.” Oncogene, 4:543—548
`
`(1989).
`Ring, ez‘ (11., “Identity of BCA200 and c—erbB-2
`indicated by reactivity of monoclonal antibodies
`with recombinant c—erbB—2.” M01. Immunol., 28:
`
`9159170991).
`HERCEPTIN® Label
`,
`'
`
`May, 1989
`
`August, 1991
`
`September,
`1998
`
`1007
`
`1008
`
`1009
`
`Blythman, et al., “Immunotoxins: hybrid molecules
`of monoclonal antibodies and a toxin subunit
`
`March 12,
`
`1981
`specifically kill tumour cells.” Nature, 290: 145-146
`(1981).
`
`

`

`
`
`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`1010
`
`Vitetta, er al., “Monoclonal antibodies as agonists:
`October 15,
`-
`.
`.
`,,
`1994
`an expanded role for then use 1n cancer therapy.
`
`Cancer Res., 54:5301—5309 (1994).
`
`1011 Maier, er al., “Requirements for the internalization
`October 1,
`of a murine monoclonal antibody directed against
`the HER—2/neu gene product c—erbB—2.” Cancer
`1991
`
`Res., 51: 5361-5369 (1991).
`Chari, et al., “Immunoconjugates containing novel
`January 1,
`.
`.
`.
`.
`.
`,,
`1992
`maytansmmds: prom1s1ng anticancer drugs. Cancer
`
`Res., 52:127-131 (1992).
`
`1012
`
`1013
`
`Batra, et al., “Recombinant anti—erbB2
`July, 1992
`immunotoxins containing Pseudomonas exotoxin.”
`Proc. Natl. Acad. Sci, USA, 89:5867-5871 (1992).
`
`
` Pegram, er al., “Inhibitory effects of combinations of
`
` April 1, 1999
`
`
`
`Liu, et al., “The development of antibody delivery
`February,
`systems to target cancer with highly potent
`1997
`maytansinoids.” Exp. Opin. Invest. Drugs, 6:169—
`
`172 (1997).
`Chari, “Targeted delivery of chemotherapeutics:
`tumor—activated prodrug therapy.” Adv. Drug Del.
`Rev., 31: 89-104 (1998).
`Declaration of Michael G. Rosenblum, Ph.D.
`
`1014
`
`1015
`
`1016
`
`Janua
`199%]
`
`1
`
`’
`
`1017
`
`1018
`
`1019
`
`1020
`
`US. Patent No. 5,770,195 (Hudziak, et al.)
`Rosenblum, et al., “Recombinant immunotoxins
`directed against the c-erbB—2/HER2/neu oncogene
`product: in vitro cytotoxicity, pharmacokinetics, and
`in viva efficacy studies in xenograft models.” Clin.
`Cancer Res., 5:865-874 (1999).
`Baselga, er al., “Recombinant humanized anti—HER2
`antibody (HerceptinTM) enhances the antitumor
`activity of paclitaxel and doxorubicin against
`HERZ/neu overexpressing human breast cancer
`xenografts.” Cancer Res., 58:2825—283 l, (1998).
`
`1
`
`HER-2/neu antibody and chemotherapeutic agents
`used for treatment of human breast cancers.”
`
`June 23, 1998
`
`April, 1999
`
`July 1, 1998
`
`Oncogene, 18:2241—2251 (1999).
`
`
`vi
`
`

`

`Patent No. 8,337,856
`
`
`Petition for Inter Parl‘es Review
`
`1021 Morgan, et al., “Immunotoxins of Pseudomonas
`exotoxin A (PE): effect of linkage on con'u ate
`
`yield, potency, selectivity and toxicity.” AJJOgZ.
`
`1022
`
`1023
`
`March, 1990
`
`May, 1992
`
`
`Immunol. 27:273—282 (1990).
`HER2
`Carter, et al., “Humanization of an anti—p185
`antibody for human cancer therapy.” Proc. Natl.
`Acad. Sci., USA, 89:4285—4289 (1992).
`
`Liu, et al., “Eradication of large colon tumor
`xenografts by targeted delivery of maytansinoids.”
`August, 1996
`
`lProc. Natl. Acad. Sci., USA, 93:8618-8623 (1996).
`1024 US. Patent No. 5,208,020 (Chari, et al.)
`May 4, 1993
`l
`
`1025
`Cohen, “Treatment With Anti—ErbB2 Antibodies,”
`September 1 1,
`US. Pre-Grant Publication No. 2003/0170235.
`2003*
`
`
`Response to Office Action of June 8, 2010, filed on
`July 6, 2010, in US. Application No. 11/949,351.
`Declaration by Mark X. Sliwokoswki, Ph.D. , filed 7
`1028
`on July 6, 2010, in us. Application No. 11/949,351. My 6’ 2010
`
`1029 Declaration by Barbara Klencke, M.D. , filed on
`Jul 6 2010
`July 6, 2010, in US. Application No. 11/949,351.
`y ’
`
`Suzuki, et al., “Immunoselective cell growth
`September,
`inhibition by antibody—Adriamycin conjugates
`1995
`targeting c—erbB2 product on human cancer cells.”
`Biol. Pharm. Bull. 18:1279-1282 (1995).
`
`
`Drewinko, et al., “Differential killing efficacy of
`twenty antitumor drugs on proliferating and
`nonproliferating human tumor cells.” Cancer Res.
`41:2328—2333 (1981).
`. 1032
`Curriculum vitae ofMichael G. Rosenblum, Ph.D.
`
`
`
`
`
`
`
`
`
`
`September 1 1,
`2012
`
`July 6, 2010
`
`1
`
`June 1981
`
`1026 Declaration of Walter Bl'attler and Ravi Chari filed
`
`on September 11, 2012, in US. Application No.
`11/949,351.
`
`1027
`
`1030
`
`1031
`
`* Priority to May 14, 1999
`
`vii
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`PETITION FOR INTER PARTES REVIEW OF US. PAT. NO. 8,337,856
`
`I.
`
`INTRODUCTION
`
`Phigenix Inc. (“Petitioner”) hereby requests Inter Partes Review (IPR) of
`
`Claims 1-8 (“challenged claims”) of US. Patent 8,337,856 (“the ‘856 patent”, Ex.
`
`1001) pursuant to 35 U.S.C. § 311 and 37 C.F.R. §§ 42.1 et seq.
`
`II.
`
`GROUNDS FOR STANDING (37 C.F.R. § 42.104gan
`
`Petitioner certifies that the ‘856 patent, which issued on December 25,
`
`2012, is available for IPR and that Petitioner is not barred or estopped from
`
`requesting an IPR for the challenged claims of the ‘856 patent.
`
`III. MANDATORY REQUIREMENTS, NOTICES AND FEES
`
`A. Real Party—In—Interest (37 C.F.R. § 42.8(b)(1))
`
`Petitioner Phigenix is the sole real party-in—interest.
`
`B. Related Matters (37 C.F.R. §42.8(b)(2))
`
`To the best of Petitioner’s knowledge, there are no other judicial or
`
`administrative matters that would affect, or be affected by, a decision in this
`
`proceeding.
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`C. Lead and Back—Up Counsel (37 C.F.R. §42.8(b)(3)) and Service
`Information (37 C.F.R. §42.8(b)(4))
`
`
`
` LEAD COUNSEL fl BACK—UP COUNSEL
`
`
`
`GregPorter@andrewskurth.com
`
`
`
`Ping Wang, M.D., Esq., Reg. No.
`48,328
`Andrews Kurth, LLP
`1350 I Street NW, Suite 1100
`
`Gregory Porter, Esq., Reg. No.
`40,131
`Andrews Kurth, LLP
`600 Travis, Suite 4200
`
`Washington, DC. 20005
`Phone No. (202) 662—3042
`Fax No. (202) 662—3729
`Email:
`PingWang@andrewskurth.com
`
`Houston, TX 77002
`Phone No. (713) 220-4621
`Fax No. (713) 220—4257
`Email:
`»
`
`Please address all papers concerning this matter to lead counsel and back—
`
`up counsel at the above addresses.
`
`D. Power of Attorney (37 C.F.R. §42.10(b))
`
`A Power of Attorney is submitted herewith pursuant to 37 C.F.R.
`
`§42.10(b).
`
`E. Petition Fees (35 U.S.C. § 312(1) and 37 C.F.R. § 42.15)
`
`The Director is authorized to charge the fee specified by 37 C.F.R. §
`
`42.15(a) to Deposit Account No. 50—2849.
`
`F. Proof of Service (37 C.F.R. §§ 42.6(e) and 42.105(a))
`
`Proof of service is provided herein at the end of this Petition.
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`IV.
`
`STATEMENT OF THE PRECISE RELIEF RE! QUESTED 137 C.F.R.
`
`§ 42.229211!
`
`The Petitioner requests Inter Partes Review under 37 C.F.R. § 42.108 as to
`
`Claims 1—8 ofthe ‘856 patent and a ruling that Claims 1—8 ofthe ‘856 patent are
`
`unpatentable based on one or more of the grounds under 35 U.S.C. § 103 for the
`
`reasons set forth herein. Petitioner’s detailed statement of the reasons for the
`
`relief requested is set forth in Section VI below.
`
`V.
`
`RELEVANT INFORMATION CONCERNING THE CONTESTED
`
`PATENT
`
`A. The ‘856 Patent
`
`The ‘856 Patent was filed as US Patent Application Serial No. 11/949,351
`
`on December 3, 2007, which is a divisional application of US Patent Application
`
`No. 11/488,545, filed on July 17, 2006, now US Patent No. 7,575,748, which is a
`
`continuation application of US Patent Application No. 09/811,123, filed on
`
`March 16, 2001, now US Patent No. 7,097,840, which claims priority from
`
`Provisional Application Nos. 60/238,327, filed on October 5, 2000, 60/ 189,844,
`
`filed on March 16, 2000 and 60/327,563, filed on June 23, 2000.
`
`The ‘856 patent purports to provide a “novel” composition comprising an
`
`anti—ErbB receptor antibody—maytansinoid conjugate. Independent Claim 1 of the
`
`‘85 6 patent recites an immunoconjugate comprising an anti—ErbB2 antibody
`
`conjugated to a maytansinoid, wherein the antibody is huMAb4D5—8. Dependent
`
`3
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`Claims 2—8 further recite the structure of the immunoconjugate and a
`
`pharmaceutical composition comprising the immunoconjugate (‘856 patent, Ex.
`
`1001)
`
`B. Technical Background
`
`The best known anti-ErbB2 antibody, trastuzumab (HERCEPTIN®),
`
`targets the extracellular domain of the ErbB2 receptor and was approved by the
`
`FDA in 1998 for treatment of patients with metastatic breast cancer whose tumors
`
`overexpress the ErbB2 receptor protein (HERCEPTIN® Label, Ex. 1008).
`
`ErbB2 (HERZ) is a membrane-bound receptor tyrosine kinase that plays
`
`critical roles in cancer development. Amplification and overexpression of ErbB2
`
`occur in 25—3 0% of human breast cancer and are predictive of poor clinical
`
`outcome (Slamon, et al., Science, 244:707—712 (1989), Ex. 1002; Press, et al., J.
`
`Clin. Oncol. 15: 2894—2904 (1997), Ex. 1003). ErbB2 is an ideal target for
`
`antibody-targeted drug delivery because it is highly differentially expressed on
`
`breast tumor cells (1—2 million copies per cell) compared with normal epithelial
`
`cells (Phillips, et 62]., Cancer Res. 68:9280—9290 (2008), Ex. 1004, page 9281, left
`
`col., 1st para.)
`
`Specific targeting of ErbB2 overexpressing tumors can be accomplished
`
`with antibodies directed against the extracellular domain of the ErbB2 receptor.
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`A number of anti-ErbB2 antibodies have been developed and tested in animal
`
`models for their efficacy in inhibiting tumor growth (Hudziak, et al., M01. Cell.
`
`Biol. 921165—1172 (1989), Ex. 1005; McKenzie, et a]. Oncogene 4:543—548
`
`(1989), Ex. 1006; and Ring, et al., M01. Immun. 28:915-917 (1991), Ex. 1007 ).
`
`The cytotoxicity of an antibody may be enhanced by conjugating the
`
`antibody to another cytotoxic agent, such as a chemotherapy drug, to form an
`
`immunoconjugate to kill a targeted cancer cell. The concept of using
`
`“immunoconjugates” or “immunotoxins” for killing cancer cells has been around
`
`for more than 30 years (Blythman, et al., Nature 290:145—146 (1981), Ex. 1009;
`
`Vitetta, et al., Cancer Res, 54:5301—5309, (1994); EX. 1010).
`
`Following the discovery of the correlation between ErbB2/HER2
`
`overexpression and breast cancer, a number of independent investigators created
`
`immunoconjugates targeting the ErbB2 receptor (Maier, et a[., Cancer Res.,
`
`51:5361—5369 (1991) (“Maier 1991”), Ex. 1011; Chari, et al., Cancer Res.
`
`522127—131 (1992) (“Chari 1992”), Ex. 1012; Batra, et al., Proc. Natl. Acad. Sci.,
`
`USA 89: 5867-5871 (July 1992) (“Batra 1992”), Ex. 1013). Batra 1992 describes
`
`a number of anti-ErbB2 immunoconjugates containing different anti—ErbB2
`
`monoclonal antibodies linked to a Pseudomonas exotoxin. Maier 1991 and Chari
`
`1992 describe anti—ErB2 immunoconjugates containing the anti—ErbB2
`
`monoclonal antibody TA.1 linked to the ricin toxin and the maytansine toxin,
`
`5
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`respectively. All of the above—described ErbB2—targeted immunoconjugates were
`
`found to selectively kill cells overexpressing ErbB2 (Ex. 1011, p. 5364, left
`
`column; Ex.41012, p. 129, left column).
`
`Maytansine is a highly cytotoxic drug that kills cells by interfering with the
`
`formation of microtubules and depolymerization of already formed microtubules.
`
`Maytansine is about 100— to 1000-fold more toxic for a range of human cancer
`
`cell lines than are most other anticancer drugs (Ex. 1012). Because of its potency
`
`and activity against microtubule polymerization, maytansine and maytansinoid
`
`derivatives are particularly attractive cytotoxic agents for use in antibody—drug
`
`therapy (EX. 1012; Liu, et al., Exp. 0pm. Invest. Drugs, 6:169-172 (1997) (“Liu
`
`1997”), Ex. 1014; Chari, Adv. Drug. Del. Rev., 31289-104 (1998) (“Chari 1998”),
`
`Ex. 1015).
`
`C. Ordinarily Skilled Artisan (Person of Ordinary Skill in the Art)
`
`An ordinarily skilled artisan is presumed to be aware of all pertinent art,
`
`thinks along conventional wisdom in the art, and is a person of ordinary
`
`creativity. With respect to' the ‘856 patent, an ordinarily skilled artisan would
`
`have had knowledge of the scientific literature concerning pharmaceutical
`
`compositions for the treatment of breast cancer as of 2000. An ordinarily skilled
`
`artisan would be a person having an MD. degree, and/or a Ph.D. degree in a
`
`Chemistry—, Pharmacology-, or Biology-related field, and at least five years of
`
`6
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`experience working with antibodies and immunoconjugates. An individual with
`
`. such credentials and experience as of March, 2000, would be well versed in
`
`techniques for producing immunoconjugates, as well as methods for testing the
`
`immunoconjugates in in vitro and in vivo systems (Rosenblum Declaration, Ex.
`
`1016, para. 7). Such a skilled artisan would have substantial familiarity, training
`
`or experience with compositions for the treatment of breast cancer.
`
`D. Construction of Terms Used in the Claims
`
`Petitioner submits that the terms recited in the claims of the ‘856 patent
`
`are to be given their broadest reasonable interpretation in light of the
`
`specification (37 C.F.R. §42.100(b)). Petitioner respectfully submits that the
`
`specification of the ‘856 patent defines a pharmaceutically—acceptable carrier
`
`as including “bacteriostatic water for injection (BWFI), phosphate~buffered
`
`saline, Ringer’s solution and dextrose solution” (EX. 1001, col. 42, lines 4—
`
`9). Petitioner further submits that the remainder of the terms recited in the
`
`claims of the “856 patent are to be given their ordinary and customary
`
`meaning known in the art.
`
`VI.
`
`IDENTIFICATION OF CHALLENGE 137 C.F.R. §42.104§bn
`
`Inter Partes Review of Claims 1-8 of the ‘856 patent (Ex. 1001) is
`
`requested on the grounds for unpatentability listed in the chart below. Per
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`37 CPR. §42.6(d), copies of the prior art references, as well as other references
`
`cited herein are filed herewith as Exhibits 1002-1032. In support of the proposed
`
`. grounds for unpatentability, this petition is accompanied by the Declaration of
`
`Michael G. Rosenblum, Ph.D., a technical expert, (Ex. 1016), which explains
`
`what the art would have conveyed to a person of ordinary skill in the art.
`
`
`Ground VClaim(s)
`Basis for Unpatentability
`
`
`1
`1—8
`Obvious (§103) over Chari 1992 in view of HERCEPTIN®
`
`Label
`
`2
`1~8
`Obvious (§103) over Chari 1992 and HERCEPTIN® Label,
`
`further in view of Hudziak 1998 and/or Rosenblum 1999
`
`
`
`
`
`
`
`
`3
`
`1~8
`
`Obvious (§103) over Chari 1992 and HERCEPTIN® Label,
`further in view of Hudziak 1998 and/or Rosenblum 1999,
`
`and further in view of Baselga 1998 and/or Pegram 1999
`4
`6, 8
`Obvious (§103) over Chari 1992 and HERCEPTIN® Label
`
`and further in view of Morgan 1990
`5
`1—8
`Obvious (§103) over Chari 1992 and Carter 1992 and
`
`common knowledge in the art
`6
`1—5, 7
`Obvious (§103) over Liu 1996 in view of HERCEPTIN®
`
`Label
`‘
`
`7
`
`6, 8
`
`Obvious (§103) over Liu 1996 in view of HERCEPTIN®
`Label and further in view of Morgan 1990
`f
`
`Obvious (§103) over Cohen 1999 in view of Chari 1992
`8
`1-8
`
`A. Ground 1: Claims 1-8 Are Obvious Over Chari 1992 In View Of
`
`HERCEPTIN® Label
`
`Chari 1992 (Ex. 1012) was published on January 1, 1992, more than a year
`
`before the earliest effective filing date of the ‘856 patent. HERCEPTIN® Label
`
`(Ex. 1008) was published in September 1998, more than a year before the earliest
`
`8
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`effective filing date of the ‘856 patent. As detailed in Table 1, the combination
`
`of Chari 1992 and HERCEPTIN® Label teaches or suggests each and every
`
`limitation recited in Claims 1-8.
`
`Table 1
`
`
`[Disclosure of Chari 1992 __ and HERCEPTIN®
`Claims
`
`*Label " , - , ‘
`
`
`
`
`
`
`1 . An immunoconjugate
`comprising
`
`an anti—ErbB2 antibody
`conjugated to a
`maytansinoid,
`
`wherein the antibody is
`huMAb4D5-8.
`
`“We therefore prepared antibody conjugates of the
`maytansinoid 3 and the murine monoclonal antibody
`TA.1 (Fig. 2), using linkers containing either a
`disulfide bond or a noncleavable thioether bond. The
`
`TA.1 antibody binds to the HER—2/neu oncogene
`protein (also known as c-erb—2) that is expressed at
`high levels on human breast tumor cells (17)” (Ex.
`1012, abridging paragraph between p. 128 and p.129)
`
`“HERCEPTIN® (Trastuzumab) is a recombinant
`DNA-derived humanized monoclonal antibody that
`selectively binds with high affinity in a cell—based
`assay (Kd=5nM) to the extracellular domain of the
`human epidermal growth factor receptor 2 protein,
`HER2. The antibody is an IgG1 kappa that contains
`human framework regions with the complementarity—
`determining regions of a murine antibody (4D5) that
`binds to HER2” (EX. 1008, p. 1, top left col.)
`
`
`
`
`
`
`
`HERCEPTIN. is synonymous with huMAb4D5—8
`“antibody 4D5 was humanized ....The humanized
`version designated HERCEPTIN® (huMAb4D5—8,
`rhuMAb HER2, US. Pat. No. 5,821,337) was tested
`in breast cancer patients whose tumors overexpress
`HER2 but who had progressed after conventional
`
`chemotherapy...” ( Ex. 1001, col. 3, lines 10—16)
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`2. The immunoconjugate
`of claim 1, wherein the
`
`maytansinoid is DMl
`having the structure:
`
`“We therefore prepared antibody conjugates of the
`maytansinoid 3 and the murine monoclonal antibody
`TA.1 (Fig. 2), using linkers containing either a
`disulfide bond or a noncleavable thioether bond”
`
`(Ex. 1012, abridging para. between p.128 and p. 129)
`H
`IC"\
`0
`
`3%N/kcwcuhm
`
`I
`CM
`
`(1:
`
`04,0
`
`0
`CHJQ "‘ E
`
`O
`
`Ch,
`
`u,
`
`:
`
`Ab” 58-May
`
`ii:
`
`: AbNSn‘rlny
`
`m c
`
`Fig. 2 of Chari 1992 (see above) shows
`maytansinoids and their conjugation to antibodies
`(Ex. 1012, p. 128, right 00].). Compound 3 is DMl,
`which reacts with loinker modified antibody (Ab)
`Ahmn
`\
`
`cum
`
`and
`
`wherein the antibody is
`chemically linked to the
`maytansinoid via a
`disulfide or thioether
`
`group at "R" shown in the
`Structure.
`
`immunoconjugate
`comprises from 3 to 5
`maytansinoid molecules
`per antibody molecule.
`
` 4. The immunoconjugate
` “ In order to generate antibody-drug conjugates the
`
`) via the -SH group (which
`o
`(”W’s—1"»j or
`corresponds to the “R” group in Claim 2) to form the
`immunoconjugate Ab~SS-May or Ab~S—May (Fig.
`2).
`3. The immunoconjugate
`Chari 1992 teaches the TA.1(-SS-May),, conjugates,
`of claim 1, wherein the
`where n is an average number of maytansinoid
`molecules per antibody and where n can be 4 (Ex.
`1012, p. 129. Table 2)
`
`of claim 1, wherein the
`
`antibody and the
`maytansinoid are
`conjugated by a chemical
`linker selected from N—
`
`antibody was modified with SPDP [N—succinimidyl—
`3-(2-pyridyldithio)—propionate] to introduce dithio~
`pyridyl groups, or with SMCC
`[succinimidyl—4—(N—maleimidomethyl)cyclohexane-
`1~carboxylate] to introduce maleimido groups. May-
`SS-Me _2_was reduced to May—SH _3_ (see “Materials
`succinimidyl—3-(2-
`
`10
`
`
`
`

`

`
`
`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`and Methods”) and reacted with the modified
`antibodies.”(Ex. 1012 p. 128, bottOm right col.
`Legend of Fig. 2)
`
`
`
`“Each Vial of HERCEPTIN® contains 440mg
`Trastuzumab, 9.9mg L-histidineHCl, 6.4mg L—
`histidine, 400mg 0t,0t-trehalose dihydrate, and 1.8 mg
`polysorbate 20, USP. Reconstitution with 20 mL of
`the supplied Bacteriostatic Water for Injection,. . ..”
`(Ex. 1008, p. 1, top left col.)
`
`“In order to generate antibody—drug conjugates the
`antibody was
`modified
`with SMCC
`
`[succinimidyl-4—(N—maleimidomethyl)cyclohexane-
`l—carboxylate] to introduce maleimido groups. May—
`SS-Me 2was reduced to May-SH 3 (see “Materials
`and Methods”) and reacted with the modified
`antibodies” (EX. 1012, p. 128, Legend ofFig.2)
`
`pyridyldithio)
`propionate, N-
`succinimidyl-4—(2—
`pyridylthio)pentanoate
`(SPP) and succinimidyl-4-
`(N-
`maleimidomethyl)cycloh
`exanel—l—carboxylate.
`5. A pharmaceutical
`composition comprising
`an immunoconjugate of
`any of claims 1 to 4, and
`a pharmaceutically
`acceptable carrier.
`
`1
`
`6. The immunoconjugate
`of claim 4, wherein the
`
`antibody and the
`maytansinoid are
`conjugated by
`succinimidyl—4—(N—
`maleimidomethyl)cyclohe
`xane— 1 —carboxylate.
`
`of claim 2, wherein the
`
`antibody and the
`maytansinoid are
`conjugated by a chemical
`linker selected from N-
`
` 7. The immunoconjugate
` “ In order to generate antibody-drug conjugates the
`
`
`antibody was modified with SPDP [N-succinimidyl-
`3—(2—pyridyldithi0)—pr0pi0nate] to introduce dithio-
`pyridyl groups, or with SMCC
`[succinimidyl-4-(N—maleimid0methyl)cyclohexane~
`l-carboxylate] to introduce maleimido groups. May—
`SS-Me 2 was reduced to May—SH 31 (see “Materials
`and Methods”) and reacted with the modified
`antibodies” (Ex. 1012, p. 128, Legend ofFig.2)
`
`succinimidyl—3-(2—
`pyridyldithio)propionate,
`N—succinimidyl—4—(2—
`pyridylthio)pentanoate
`(SPP) and succinimidyl-4—
`(N-
`maleimidomethyl)cyclohe
`xane— 1 -carboxylate.
`
`
`ll
`
`

`

`Patent No. 8,337,856
`
`
`Petition for Inter Partes Review
`
`
`
`
`
`“In order to generate antibody—drug conjugates the
`antibody was modified with
`SMCC
`[succinimidyl-4—(N—maleimidomethyl)cyclohexane-
`l-carboxylate] to introduce maleimido groups. May—
`SS-Me _2_was reduced to May—SH 3 (see “Materials
`and Methods”) and reacted with the modified
`antibodies. (EX. 1012, p. 128, Legend of Fig. 2)
`
`8. The immunoconjugate
`of claim 7, wherein the
`antibody and the
`maytansinoid are
`conjugated by
`succinimidyl—4—(N—
`maleimidomethyl)cyclohe
`xane- 1 -carboxylate.
`
`Intended use of a composition does not render the composition nonobvious
`
`Claims 1—8 are directed to an immunoconjugate comprising huMAb4D5—8
`
`conjugated to a maytansinoid. It is well established in patent law that intended
`
`use of a composition does not, in and of itself, render the composition nonobvious
`
`(see e.g, In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990) “Products of identical
`
`chemical composition cannot have mutually exclusive properties,” and In re
`
`Zierden, 411 F.2d 1325, 1328 (CCPA 1969) “A mere statement ofa new use for
`
`an otherwise old or obvious composition cannot render a claim to the composition
`
`patentable”).
`
`Chari 1992 and HERCEPTIN® Label teach every and each limitation of
`Claims 1—8 of the ‘856 patent
`
`As shown in Table 1 above, Chari 1992 discloses an immunoconjugate
`
`comprising a maytansinoid chemically linked to an anti—ErbB2—antibody (Ex.
`
`1012, Fig. 2). Chari 1992 also discloses that the maytansinoid is DMland that the
`
`antibody is chemically linked to the maytansinoid via a disulfide or thioether
`
`12
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`group at the “R” position (Ex. 1012, Fig. 2), as recited in Claim 2 ofthe ‘856
`
`patent. The immunoconjugate of Chari 1992 may comprise from 3—5
`
`maytansinoid molecules per antibody molecule (Ex. 1012, p. 129, bottom right
`
`col. Table 2), as recited in Claim 3 of the ‘856 patent. The antibody and the
`
`maytansinoid were conjugated by a chemical linker selected from SPDP or
`
`SMCC (Ex. 1012, p. 128, bottom right col., Fig. 2), as recited in Claims 4 and 6—8
`
`‘ ofthe ‘856 patent.
`
`Chari 1992 does not explicitly disclose huMAB4D5—8 (recited in Claim 1
`
`of the ‘856 patent) or a pharmaceutically acceptable carrier (recited in Claim 5 of
`
`the ‘856 patent). However, HERCEPTIN® Label describes the clinical use of
`
`huMAB4D5—8 (i. e., HERCEPTIN®), which is described as being indicated for
`
`the treatment of patients with metastatic breast cancer (EX. 1008, p. 1, right col.).
`
`HERCEPTIN® Label also describes the injection of HERCEPTIN® with a
`
`pharmaceutically acceptable carrier (BacterioStatic Water for Injection, EX. 1008,
`
`p. 1, left col.).
`
`As detailed below and confirmed by the Declaration of Dr. Rosenblum
`
`(Ex. 1016, para. 12—15), Chari 1992 teaches that the anti—ErbB2 antibody-
`
`maytansinoid conjugates exhibited high antigen—specific cytotoxicity for cultured
`
`human breast cancer cells, low systemic toxicity in mice, and good
`
`pharmacokinetic behavior (Ex. 1012, Abstract).
`
`It would be obvious to an
`
`13
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`ordinarily skilled artisan, at the time the ‘856 patent was filed, to simply
`
`substitute the mouse mAb TA.1 in the immunoconjugate of Chari 1992 with the
`
`humanized mAb huMAB4D5—8 to produce a maytansinoid—huMAB4D5—8
`
`conjugate based on the teachings of Chari 1992 and HERCEPTIN® Label, as
`
`well as the general knowledge in the art at that time. As noted by the Federal
`
`Circuit, combination of known elements would have been primafacie obvious if
`
`an ordinarily skilled artisan would have recognized an apparent reason to
`
`combine those elements and would have known how to do so (Ecolab, Inc. v.
`
`FMC Corp, 569 F.3d 1335, 1350 (Fed. Cir. 2009)).
`
`Reason to Combine and Reasonable Expectation ofSuccess
`
`As described in the Declaration of Dr. Rosenblum (Ex. 1016, para. 12—15),
`
`an ordinarily skilled artisan would be motivated to substitute the mouse mAb
`
`TA.1 in the immunoconjugate of Chari 1992 with the humanized mAb
`
`huMAB4D5-8 because:
`
`(1) It was well known in the art at the time of the priority date of the ‘856
`
`patent that humanized mAbs, such as huMAB4D5—8, were preferred over their
`
`mouse-derived counterparts for clinical applications, since humanized mAbs
`
`exhibit reduced immunogenicity. For example, Chari 1992 teaches that “[t]he
`
`development of ‘humanized’ antibodies will offer an opportunity to produce drug
`
`14
`
`

`

`Petition for Inter Partes Review
`
`Patent No. 8,337,856
`
`conjugates that would be less immunogenic than similar conjugates of murine
`
`antibodies” (Ex. 1012, p. 130, bottom left 001.);
`
`(2) huMAB4D5—8 selectively binds with high affinity to HER2 and has
`
`been approved for use in humans (Ex. 1008, p. 1, left 001.); and
`
`(3) clinical studies indicated that huMAB4D5-8 works well in combination
`
`with microtubule—directed chemotherapy agents for the treatment of breast cancer
`
`(Ex. 1008, p. 1, left col.).
`
`Substituting a mouse anti—ErbB2 antibody in an immunoconjugate with a
`
`humanized anti—ErbBZ antibody is no more than a simple substitution of one
`
`known element for another to obtain a predictable result, reduced immunogenicity
`
`for a human subject. Therefore, it would have been obvious to an ordinarily
`
`skilled artisan to apply a known technique (humanizing mouse antibody) to a
`
`known product (anti—ErbB2 antibody-maytansinoid conjugate) (Ex. 1016, para.
`
`13).
`
`Based on the detailed description in Chari 1992 and the general knowledge
`
`in the art about conjugation of maytansinoids with antibodies, an ordinarily
`
`skilled artisan would ha