Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 1 of 40 PageID #: 370
`Case 1:18-cv-01363-CFC Document1-8
`Filed 09/04/18
`Page 1 of 40 PagelD #: 370
`
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`EXHIBIT H
`EXHIBIT H
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`

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`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 2 of 40 PageID #: 371
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`Illll Mllll Ill Illll Illll Illll Illll Illll Illll Illll Illll Illlll Illl Illl Illl
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`US007371379B2
`
`(12) nited States Patent
`Baughman et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`S 7,371,379 B2
`May 13, 2008
`
`(54) DOSAGES FOR TREATMENT WITH
`ANTI-ERBB2 ANTIBODIES
`
`(75)
`
`Inventors: Sharon A. Baughman, Ventura, CA
`(US); Steven Shak, Burlingame, CA
`(us)
`
`(73) Assignee: Genentech, Inc., South San Francisco,
`CA (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 540 days.
`
`(21)
`
`Appl. No.: 10/600,152
`
`(22)
`
`Filed:
`
`Jun. 20, 2003
`
`(65)
`
`(62)
`
`(60)
`
`Prior Publication Data
`
`US 2004/0037824 A1 Feb. 26, 2004
`
`Related U.S. Application Data
`
`Division of application No. 09/648,067, filed on Aug.
`25, 2000, now Pat. No. 6,627,196.
`
`Provisional application No. 60/213,822, filed on Jun.
`23, 2000, provisional application No. 60/151,018,
`filed on Aug. 27, 1999.
`
`(51) Int. CI.
`A 61K 39/395
`(2006.01)
`(52) U.S. CI ................................ 424/138.1; 424/130.1;
`424/133.1; 424/141.1; 424/142.1; 424/143.1;
`424/155.1; 424/156.1; 424/174.1
`(58) Field of Classification Search ............. 424/130.1,
`424/133.1,138.1,141.1,142.1,143.1,155.1,
`424/156.1,174.1
`See application file for complete search history.
`
`(56)
`
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`
`Primary Examiner Alana M. Harris
`Assistant Examiner Anne L. Holleran
`(74) Attorney, Agent, or Firm Wendy M. Lee
`
`(57)
`
`ABSTRACT
`
`The present invention concerns the treatment of disorders
`characterized by the overexpression of ErbB2. More spe-
`cifically, the invention concerns the treatment of human
`patients susceptible to or diagnosed with cancer overex-
`pressing ErbB2 with anti-ErbB2 antibody.
`
`40 Claims, 5 Drawing Sheets
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 3 of 40 PageID #: 372
`
`US 7,371,379 B2
`Page 2
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`

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`

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`* cited by examiner
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 6 of 40 PageID #: 375
`
`U.S. Patent
`
`May 13, 2008 Sheet 1 of 5
`
`US 7,371,379 B2
`
`3H4 aa 541-599
`4D5 aa 529-625
`7C2 aa 22-53
`7F3
`aa 22-53
`
`300
`I
`
`400
`I
`
`i
`
`1 ?0
`
`200
`I
`
`I 22-537 C2 7F3
`
`22
`
`I
`248
`
`500
`I
`
`600
`I
`
`645
`
`3H4
`1" " " " J
`541 599
`
`!
`
`561
`
`!
`
`625
`
`100
`I
`
`200
`I
`
`300
`I
`
`400
`I
`
`500
`I
`
`3H4 epitope (SEQ ID NO:8) 58 residues
`
`VEECR(cid:127)-LQGLPREYVI(cid:127)ARHCLPCHPECQPQNGSVTCFGPEADQCVA(cid:127)PPFCVAR
`I
`541
`
`I
`599
`
`4D5 epitome (SEQ ID NO=9) 64 residues
`
`LPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSIq4PIWKFPDEEGACQP
`i
`I
`625
`561
`)
`t
`
`Y
`FIG._1
`
`MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPA
`1
`SPETHLDMLRHLYQGCQWQGNLELTYLPTNASLSFL
`38
`QDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDN
`75
`112 YALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEI
`149 LKGGVLIQRNPQLCYQDTILWKDIFHKNNQLALTLID
`186 TNRSRA
`
`FIG._2
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 7 of 40 PageID #: 376
`
`IIII
`
`IIII
`
`IIII
`
`IIII
`
`IIII
`
`IIII
`
`IIII
`
`IIII
`
`Mean Trough Serum Concentration (l(cid:127)g/ml)
`¯ ,,, .,-. n
`
`(cid:127)}
`
`80"
`
`.
`
`70
`
`6O
`
`Mean Trough 50
`Concentration
`(l(cid:127)g/m!) 40
`
`t
`
`a
`
`i
`
`30
`
`2O
`
`10
`
`- 20O
`
`150
`
`100
`
`M
`
`lll{]llllil
`
`D.
`
`- 50
`
`.[’7
`
`FIG._3 o
`
`I
`
`I
`
`I
`
`I
`
`I I"’ "(cid:127) I
`
`I I I I
`
`I I l I
`
`I I I I
`
`0
`
`5
`
`10
`
`5 20
`Week
`
`25
`
`3O
`
`35
`
`0
`4O
`
`=.
`(’(cid:127)
`(’(cid:127)
`
`(cid:127)q
`
`-,,.I
`
`-,,.I
`
`-,,.I
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 8 of 40 PageID #: 377
`
`--0-- E25_4 mg_kg_lV
`--,E3,,-- IV 1 mg_kg_anti-HER2
`¯ ,..z(cid:127).. IV 2 mg_kg_anti-HER2
`
`---(cid:127)--- IV_4 mg_kg_anti-HER2
`"- SC 2 mg_kg_anti-HER2
`
`S(cid:127)
`#
`
`s
`41,
`
`30OO
`
`2500
`
`2000
`
`1500
`
`1000
`
`5OO
`
`0
`
`Cell Mean for
`TUMOR VOL
`(mm3)
`
`FIG._4A
`
`-5OO
`
`I
`DAY 6
`
`I
`DAY 10
`
`I
`DAY 21
`
`I
`DAY 24
`
`I
`DAY 28
`
`I
`DAY 31
`
`"(cid:128)
`
`t--F
`
`=-
`t(cid:127)
`t(cid:127)
`
`.,4
`
`.,4
`
`.,4
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 9 of 40 PageID #: 378
`
`10000
`
`1000-
`
`--O-- E25_4 mg_kg_lV
`IV 1 mg_kg_anti-HER2
`¯ "(cid:127)"" IV_2_mg_kg_anti-HER2
`---(cid:127)--- IV_4 mg_kg_anti-HER2
`= SC_2_mg_kg_anti-HER2
`
`oO ........ O
`
`Cell Mean for
`TUMOR VOL
`(mm3)
`
`m m m m
`
`100-
`
`FIG._4B ,o
`
`I
`DAY 6
`
`I
`DAY 10
`
`I
`DAY 21
`
`I
`DAY 24
`
`I
`DAY 28
`
`I
`DAY 31
`
`t(cid:127)
`t(cid:127)
`
`.,4
`
`.,4
`
`.,4
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 10 of 40 PageID #: 379
`
`U.S. Patent
`
`May 13, 2008 Sheet 5 of 5
`
`US 7,371,379 B2
`
`VARIABLE LIGHT
`40
`30
`20
`i0
`1
`DTVMTQSHKIMSTSVGDRVSITC [KASQDVSIGVA .... ] WYQQRP
`W
`W*(cid:127)W *
`W
`WW
`DIQMTQSPSSLSASVGDRVTITC [KASQDVSIGVA .... ] WYQQKP
`
`2C4
`
`574
`
`hum kI
`
`DIQMTQSPSSLSASVGDRVTITC [RASQSVSTSSYSYMH] WYQQKP
`
`2C4
`
`80
`70
`60
`50
`GQSPKLLIY [SASYRYT] GVPDRFTGSGSGTDFTFTISSVQA
`
`574
`
`GKAPKLLIY [SASYRYT] GVPSRFSGSGSGTDFTLTISSLQP
`
`hum kI
`
`GKAPKLLIY [AASSLES] GVPSRFSGSGSGTDFTLTISSLQP
`
`2C4
`
`574
`
`hum kI
`
`i00
`90
`EDLAVYYC [QQYYIYPYT] FGGGTKLEIK (SEQ ID NO: 10)
`
`EDFATYYC [QQYYIYPYT] FGQGTKVEIK (SEQ ID NO: 12)
`w**
`EDFATYYC [QQYNSLPYT] FGQGTKVEIK (SEQ ID NO:I4)
`FIG._SA
`
`VARIABLE HEAVY
`40
`20
`30
`i0
`1
`EVQLQQSGPELVKPGTSVKISCKAS [GFTFTDYTMD] WVKQS
`W *(cid:127)W **
`*
`W* *W *
`EVQLVESGGGLVQPGGSLRLSCAAS [GFTFTDYTMD] WVRQA
`
`2C4
`
`574
`
`humIII
`
`EVQLVESGGGSVQPGGSLRLSCAAS [GFTFSSYAMS] WVRQA
`
`2C4
`
`574
`
`humIII
`
`2C4
`
`574
`
`humIII
`
`70
`80
`60
`50
`HGKSLEWIG [DVNPNSGGSIYNQRFKG] KASLTVDRSSRIVYM
`WW* W
`W(cid:127)WW W
`W*
`W
`*
`PGKGLEWVA [DVNPNSGGSIYNQRFKG] RFTLSVDRSKNTLYL
`* W*W(cid:127)WW
`(cid:127)W *WWW
`*. W *
`PGKGLEWVS [VISGDGGSTYYADSVKG] RFTISRDDSKNTLYL
`
`90 i00 ii0
`ELRSLTFEDTAVYYCAR [NLGPSFYFDY] WGQGTTLVTSS (SEQ ID NO:f1)
`
`QMNSLRAEDTAVYYCAR [NLGPSFYFDY] WGQGTLVTVSS (SEQ ID NO:I3)
`*W *W*
`QMNSLRAEDTAVYYCAR [GRGGGS--DY] WGQGTLVTVSS (SEQ ID NO:I5)
`FIG._5B
`
`

`

`Case 1:18-cv-01363-CFC Document 1-8 Filed 09/04/18 Page 11 of 40 PageID #: 380
`
`US 7,371,379 B2
`
`1
`DOSAGES FOR TREATMENT WITH
`ANTI-ERBB2 ANTIBODIES
`
`RELATED APPLICATIONS
`
`This application is divisional ofU.S. Ser. No. 09/648,067
`filed Aug. 25, 2000 (now U.S. Pat. No. 6,627,196), which
`claims priority under 35 USC l19(e) to provisional appli-
`cation Nos. 60/151,018, filedAug. 27, 1999 and 60/213,822,
`filed Jun. 23, 2000, the contents of which are incorporated 10
`heroin by reference.
`
`5
`
`2
`these cells. In Drebin et al. PNAS (USA) 83:9129-9133
`(1986), the 7.16.4 antibody was shown to inhibit the tum-
`origenic growth of neu-transformed NIH-3T3 cells as well
`as rat neuroblastoma cells (from which the neu oncogene
`was initially isolated) implanted into nude mice. Drebin et
`al. in Oncogene 2:387-394 (1988) discuss the production of
`a panel of antibodies against the rat neu gene product. A1 of
`the antibodies were found to exert a cytostatic effect on the
`growth of neu-transformed cells suspended in soft agar.
`Antibodies of the IgM, IgG2a and IgG2b isotypes were able
`to mediate significant in vitro lysis of neu-transformed cells
`in the presence of complement, whereas none of the anti-
`bodies were able to mediate high levels of antibody-depen-
`dent cellular cytotoxicity (ADCC) of the neu-transformed
`cells. Drebin et al. Oncogene 2:273-277 (1988) report that
`mixtures of antibodies reactive with two distinct regions on
`the p 185 molecule result in synergistic anti-tumor effects on
`neu-transformed NIH-3T3 cells implanted into nude mice.
`2o Biological effects of anti-neu antibodies are reviewed in
`Myers et al., Meth. Enzym. 198:277-290 (1991). See also
`WO94/22478 published Oct. 13, 1994. Hudziak et al., Mol.
`Cell. Biol. 9(3): 1165-1172 (1989) describe the generation of
`a panel of anti-ErbB2 antibodies which were characterized
`25 using the human breast tumor cell line SKBR3. Relative cell
`
`FIELD OF THE INVENTION
`
`The present invention concerns the treatment of disorders
`characterized by the overexpression of ErbB2 or disorders
`expressing epidermal growth factor receptor (EGER), com-
`prising administering to a human or animal presenting the
`disorders a therapeutically effective amount of an antibody
`that binds ErbB2. More specifically, the invention concerns
`the treatment of human patients susceptible to or diagnosed
`with cancer overexpressing ErbB2 or expressing EGER,
`where the treatment is with an anti-ErbB2 antibody admin-
`istered by front loading the dose of antibody during treat-
`ment by intravenous and/or subcutaneous administration.
`The invention optionally includes treatment of cancer in a
`human patient with a combination of an anti-ErbB2 antibody
`and a chemotherapeutic agent, such as, but not limited to, a
`taxoid. The taxoid may be, but is not limited to paclitaxel or
`docetaxel. The invention further includes treatment of can-
`cer in a human patient with a combination of anti-ErbB2
`antibody and a chemotherapeutic agent, such as, but not
`limited to, an anthracycline derivative. Optionally, treatment
`with a combination of anti-ErbB2 and an anthracycline
`derivative includes treatment with an effective amount of a
`cardioprotectant. The present invention further concerns
`infrequent dosing of anti-ErbB2 antibodies.
`
`BACKGROUND OF THE INVENTION
`
`Proto-oncogenes that encode growth factors and growth
`factor receptors have been identified to play important roles
`in the pathogenesis of various human malignancies, includ-
`ing breast cancer. It has been found that the human ErbB2
`gene (erbB2, also known as her2, or c-erbB-2), which
`encodes a 185-kd transmembrane glycoprotein receptor
`(p185arER2) related to the epidermal growth factor receptor
`(EGFR), is overexpressed in about 25% to 30% of human
`breast cancer (Slamon et al., Science 235:177-182 [ 1987];
`Slamon et al., Science 244:707-712 [1989]).
`Several lines of evidence support a direct role for ErbB2
`in the pathogenesis and clinical aggressiveness of ErbB2-
`overexpressing tumors. The introduction of ErbB2 into
`non-neoplastic cells has been shown to cause their malignant
`transformation (Hudziak et al., Proc. Natl. Acad. Sci. USA
`84:7159-7163 [1987]; DiFiore et al., Science 237:78-182
`[1987]). Transgenic mice that express HER2 were found to
`develop mammary tumors (Guy et al., Proc. Natl. Acad. Sci.
`USA 89:10578-10582 [1992]).
`Antibodies directed against human erbB2 protein prod-
`ucts and proteins encoded by the rat equivalent of the erbB2
`gene (neu) have been described. Drebin et al., Cell 41:695-
`706 (1985) refer to an IgG2a monoclonal antibody which is
`directed against the rat neu gene product. This antibody
`called 7.16.4 causes down-modulation of cell surface p185
`expression on B104-1-1 cells (NIH-3T3 cells transfected
`with the neu proto-oncogene) a inhibits colony formation of
`
`15
`
`proliferation of the SKBR3 cells following exposure to the
`antibodies was determined by crystal violet staining of the
`monolayers after 72 hours. Using this assay, maximum
`inhibition was obtained with the antibody called 4D5 which
`3o inhibited cellular proliferation by 56%. Other antibodies in
`
`40
`
`the panel, including 7C2 and 7F3, reduced cellul