Phigenix, Inc.v.ImmunoGen, Inc.

Patent Trial and Appeal Board

Oct 27, 2015

11949351 (P.T.A.B. Oct. 27, 2015)

Trials@uspto.gov Paper 39
571-272-7822 Entered: October 27, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

PHIGENIX, INC,
Petitioner,

v.

IMMUNOGEN, INC.,
Patent Owner.
____________

Case IPR2014-00676
Patent 8,337,856 B2
____________

Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
ZHENYU YANG, Administrative Patent Judges.

BONILLA, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73

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I. INTRODUCTION
Phigenix Inc. (“Petitioner”) filed a Petition requesting inter partes
review of claims 1–8 of U.S. Patent No. 8,337,856 (“the ’856 patent”).
Paper 5 (“Pet.”). Immunogen, Inc. (“Patent Owner”) filed a Preliminary
Response. Paper 10 (“Prelim. Resp.”). Thereafter, we determined that the
information presented in the Petition demonstrated that there was a
reasonable likelihood that Petitioner would prevail in showing claims 1–8 as
unpatentable. Paper 11 (“Dec. to Inst.”), 2, 23. Pursuant to 35 U.S.C. § 314,
we instituted this proceeding on October 29, 2014, to review whether claims
1–8 of the ’856 patent would have been obvious under 35 U.S.C. § 103 over
Chari 1992
1
in view of the HERCEPTIN
®
Label,
2
further in view of
Rosenblum 1999
3
and Pegram 1999.
4
Id. at 23.
After institution of trial, Patent Owner filed a Patent Owner Response.
Paper 18 (“PO Resp.”), and Petitioner filed a Reply to the Response. Paper

1
Chari et al., Immunoconjugates Containing Novel Maytansinoids:
Promising Anticancer Drugs, 52 CANCER RES.127–131 (1992) (“Chari
1992”) (Ex. 1012).
2
HERCEPTIN
®
(Trastuzumab) Label, dated September 1998 (“the
HERCEPTIN
®
Label”) (Ex. 1008).
3
Rosenblum et al., Recombinant Immunotoxins Directed against the c-
erbB-2/HER2/neu Oncogene Product: In Vitro Cytotoxicity,
Pharmacokinetics, and In Vivo Efficacy Studies in Xenograft Models, 5
CLIN. CANCER RES. 865–874 (1999) (“Rosenblum 1999”) (Ex. 1018).
4
Pegram et al., Inhibitory effects of combinations of HER-2/neu antibody
and chemotherapeutic agents used for treatment of human breast cancers,
18 ONCOGENE 2241–2251 (1999) (“Pegram 1999”) (Ex. 1020).
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24 (“Reply”). Petitioner also filed a Motion to Exclude certain evidence
submitted by Patent Owner. Paper 28. Patent Owner responded by filing an
Opposition to the Motion to Exclude (Paper 29), as well as an unopposed
Motion to Seal two exhibits filed by Patent Owner in connection with the
Opposition (Paper 31, 1). Petitioner filed a Reply to the Opposition to the
Motion to Exclude. Paper 35.
An oral hearing was held on July 9, 2015. A transcript of the hearing
has been entered into the record. Paper 38 (“Tr.”).
We have jurisdiction under 35 U.S.C. § 6(c). This Final Written
Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
For the reasons that follow, we determine that Petitioner has not shown by a
preponderance of the evidence that claims 1–8 of the ’856 patent are
unpatentable. We deny Petitioner’s Motion to Exclude Evidence, and we
grant Patent Owner’s Motion to Seal.
A. Related Proceeding
About a month after filing the current Petition, Petitioner filed a
Petition requesting inter partes review of claims 1–20 and 25–27 of U.S.
Patent No. 7,575,748 (“the ’748 patent”) in Case No. IPR2014-00842.
Patent Owner of the ’748 patent, Genentech, Inc., a real party-in-interest in
the current proceeding, filed a Preliminary Response. IPR2014-00842,
Paper 9. On December 9, 2014, we declined to institute review in that case.
Phigenix, Inc. v. Genentech, Inc. and ImmunoGen, Inc., Case IPR2014-
00842 (PTAB Dec. 9, 2014) (Paper 10).
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The ’748 patent, at issue in that case, is a continuation application of
U.S. Patent No. 7,097,840 (“the ’840 patent”). IPR2014-00842, Ex. 1001.
The ’856 patent, at issue here, is a divisional application of a continuation
application of the ’840 patent. Ex. 1001.
B. The ’856 Patent (Ex. 1001)
The ’856 patent relates to immunoconjugates comprising an anti-ErbB
antibody, such as the humanized anti-ErbB2 antibody known as
HERCEPTIN
®
(huMAb4D5-8), linked to a maytansinoid toxin. Ex. 1001,
1:20–52, 35:47–36:39; see also id. at 3:6–16 (discussing HERCEPTIN
®
),
6:50–67 (defining “ErbB2”), 10:40–52 (defining “humanized”), 16:23–28
(defining “epitope 4D5”).
The term “ErbB2” is synonymous with “HER2,” “p185
neu
”, or “neu,”
and refers to a member of the ErbB family of receptor tyrosine kinases,
which mediate cell growth, differentiation, and survival. Id. at 1:45–60,
6:50–58. Overexpression of ErbB2 on cell surfaces can lead to cancer in
humans, such as certain breast and ovarian cancers. Id. at 1:54–66, 8:55–60.
The specification teaches that maytansinoids, such as DM1, are highly
cytotoxic, i.e., inhibit or prevent cell function and/or destroy cells, but
induce “severe systemic side-effects primarily attributed to their poor
selectivity for tumors” when administered alone. Id. at 1:38–44, 17:45–52;
see also id. at 5:7–13 (referring to Figure 3, showing the structure of the
maytansinoid designated “DM1”). The specification describes making anti-
ErbB antibody-maytansinoid conjugates using “a variety of bifunctional
protein coupling agents,” i.e., linkers, such as N-succinimidyl-3-(2-
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pyridyldithio)propionate (“SPDP”), N-succinimidyl-4-(2-
pyridylthio)pentanoate (“SPP”), and succinimidyl-4-(N-maleimidomethyl)-
cyclohexane-1-carboxylate (“SMCC”). Id. at 36:13–31.
The specification states that the “present invention is based on results
obtained in a novel murine HER2-transgenic tumor model in which
HERCEPTIN
®
or the murine antibody 4D5 from which HERCEPTIN
®
was
derived, had little effect on tumor growth.” Id. at 21:65–22:1. In this
context, the specification states that “it was surprisingly found that while the
transplanted tumor obtained from such transgenic mice responded poorly to
HERCEPTIN
®
treatment, the HERCEPTIN
®
-maytansinoid conjugates were
highly efficacious.” Id. at 22:2–7.
C. The Challenged Claims
Petitioner challenges claims 1–8 of the ’856 patent. Of those, only
claim 1 is independent, which recites:
1. An immunoconjugate comprising an anti-ErbB2 antibody
conjugated to a maytansinoid, wherein the antibody is
huMAb4D5-8.
Id. at 81:28–31. Dependent claim 2 recites that the maytansinoid is DM1
having a specific structure, where the antibody is linked to the maytansinoid
via a disulfide or thioether group at “R” shown in the structure. Id. at 81:31–
53. Dependent claim 3 requires that the immunoconjugate “comprises from
3 to 5 maytansinoid molecules per antibody molecule.” Id. at 82:27–30.
Dependent claim 5 recites a pharmaceutical composition comprising the
immunoconjugate and a pharmaceutically acceptable carrier. Id. at 82:37–
39. Claims 4 and 6–8, which ultimately depend on claim 1 or 2, recite that
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the antibody and maytansinoid are conjugated by specific chemical linkers,
i.e., SPDP, SPP, or SMCC. Id. at 82:30–36, 39–51.
II. ANALYSIS
A. Claim Construction
For inter partes review, claim terms in an unexpired patent are given
their broadest reasonable interpretation in light of the patent specification.
37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
1278–79 (Fed. Cir. 2015). Claim terms are given their ordinary and
customary meaning, as would be understood by one of ordinary skill in the
art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a claim term
must be set forth in the specification with reasonable clarity, deliberateness,
and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
As noted in our Decision to Institute, Petitioner offers claim
construction of the phrase “pharmaceutically-acceptable carrier,” recited in
dependent claim 5, as “including ‘bacteriostatic water for injection (BWFI),
phosphate-buffered saline, Ringer’s solution and dextrose solution.’” Dec.
to Inst. 6–7 (citing Pet. 7 (citing Ex. 1001, 42:4–9)). Patent Owner does not
dispute this claim construction, nor offer construction of other claims terms.
Based on the record currently available, Petitioner’s proposed construction is
the broadest reasonable construction of the phrase. We construe other claim
terms as carrying their ordinary meaning, consistent with their use in the
specification.
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B. Obviousness over Chari 1992 in view of HERCEPTIN® Label,
further in view of Rosenblum 1999 and Pegram 1999
Petitioner contends that claims 1–8 would have been obvious over
Chari 1992 in view of the HERCEPTIN
®
Label, further in view of
Rosenblum 1999 and Pegram 1999, relying on a Declaration by Michael G.
Rosenblum, Ph.D. (Ex. 1016). Pet. 8–22. Patent Owner contends otherwise,
relying on a Declaration by Geoffrey A. Pietersz, Ph.D. (Ex. 2134), as well
as Declarations by Linda T. Vahdat, M.D. (Ex. 2103), Joyce
O’Shaughnessy, M.D. (Ex. 2105), and John C. Jarosz (Ex. 2131) in relation
to objective indicia of non-obviousness. PO Resp. 2–60.
1. Chari 1992 (Ex. 1012)
Chari 1992 describes immunoconjugates comprising an anti-ErbB2
mouse monoclonal antibody, TA.1, chemically coupled to the maytansinoid
toxin, DM1, using SPDP or SMCC as a linker. Ex. 1012, 128–129; id. at
Fig. 2 (see maytansinoid 3 and figure legend). As stated in Chari 1992, the
TA.1 antibody binds HER-2/neu oncogene protein (i.e., ErbB2), which is
expressed at high levels on human breast tumor cells. Id. at 129, 1st col.,
1st ¶. The reference discloses conjugates having a range of one to six
maytansinoid molecules per antibody molecule, such as four maytansinoid
molecules per antibody molecule. Id., see also id. at 2nd col., Table 2.
Chari 1992 teaches that the conjugates, called “TA.1(-SS-May)n,”
were cytotoxic when tested in vitro on the human breast cancer cell line, SK-
BR-2. Id. at 129, 1st col., 2nd ¶, 2nd col. Fig. 3. In addition, the reference
teaches that conjugate TA.1(-SS-May)4 was at least 1000-fold less cytotoxic
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toward neu-negative KB cells in tissue culture. Id. It teaches that
cytotoxicity can be increased by linking more maytansinoid molecules per
antibody molecule, “and it reached its maximum value at n = 4 (Table 2).”
Id. at 1st col., 3rd ¶. The reference also discloses that conjugate A7(-SS-
May)6, where A7 is an antibody directed against a human colon cancer cell
line antigen, shows similar cytotoxicity results and is not toxic in mice. Id.
at 1st col., 3rd ¶ – 2nd col., 2nd ¶.
Chari 1992 states that the “high specific cytotoxicity of maytansinoid
conjugates toward tumor cell lines in conjunction with their low systemic
toxicity indicates that these potent conjugates may possess a therapeutic
index sufficient for the effective treatment of human cancer.” Id. at 130, 1st
col., 2nd ¶; see also id. at 127, Abstract (stating that the immunoconjugates
“show high antigen-specific cytotoxicity for cultured human cancer cells
. . . , low systemic toxicity in mice, and good pharmacokinetic behavior”). It
also states that the “development of ‘humanized’ antibodies will offer an
opportunity to produce drug conjugates that would be less immunogenic
than similar conjugates of murine antibodies.” Id. at 130, 1st col., 3rd ¶.
2. HERCEPTIN® Label (Ex. 1008)
The HERCEPTIN
®
Label describes HERCEPTIN
®
, also known as
Trastuzumab or huMAB4D5-8, as a humanized form of the mouse
monoclonal antibody 4D5, which binds HER2/ErbB2. Ex. 1008, 1, 1st col.
The Label describes intravenous injection administration of HERCEPTIN
®

after reconstitution with “Bacteriostatic Water for Injection (BWFI),” among
other components. Id. at 1st col.
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The Label describes HERCEPTIN
®
as being indicated for “the
treatment of patients with metastatic breast cancer whose tumors
overexpress the HER2 protein and who have received one or more
chemotherapy regimens for their metastatic disease.” Id. at 2nd col. In
addition, the Label describes HERCEPTIN
®
in combination with paclitaxel
as being “indicated for treatment of patients with metastatic breast cancer
whose tumors overexpress the HER2 protein and who have not received
chemotherapy for their metastatic disease.” Id.
Table 1 in the Label shows clinical trial data regarding “Phase III
Clinical Efficacy in First-Line Treatment” in patients treated with
chemotherapy alone or chemotherapy combined with HERCEPTIN
®
. Id. at
1st col. The Label states that “[c]ompared with patients randomized to
chemotherapy alone, the patients randomized to HERCEPTIN and
chemotherapy experienced a significantly longer time to disease progression,
a higher overall response rate (ORR), a longer median duration of response,
and a higher one-year survival rate.” Id. (citing Table 1).
3. Rosenblum 1999 (Ex. 1018)
Rosenblum 1999 discloses an immunoconjugate comprising an anti-
ErbB2 human chimeric antibody (“BACH-250”) chemically coupled to a
ribosomal-inhibiting plant toxin gelonin (“rGel”), using SPDP as a linker.
Ex. 1018, 865, Abstract, 866, 2nd col. Immunoconjugates, antibodies alone,
and toxin alone, were tested in vitro against human tumor cells expressing
various levels of HER2, and in vivo against human tumor xenograft models
(athymic mice bearing s.c. or i.p. SKOV-3 tumors). Id. at Abstract.
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The reference states that although “binding of both BACH-250 and
BACH-250/rGel conjugate to target cells was essentially equivalent,” in
SKOV-3 cells “the IC50 of BACH-250/rGel [conjugate] was 97 pM (17
ng/ml), whereas BACH-250 and rGel alone showed no cytotoxic effects.”
Id. The reference also states there “was a clear correlation between
expression levels of HER-2/neu and cytoimmunotoxin.” Id.; see also id. at
869, 1st col. (stating that cytotoxic effects of TAB-250/rGel (mouse
antibody conjugate) was greatest against the SKBR-3 cell line having the
highest number of cell surface HER2, as compared to other cell lines
expressing lower levels).
In in vivo xenograft studies in mice using BACH-250 conjugates,
“immunotoxin treatment slowed tumor growth by 99 and 94% at days 35
and 49 after implantation, respectively, and lengthened the median survival
by 40% (from 30 to 50 days) in mice bearing lethal i.p. tumors.” Id. at
Abstract, 871–872 (describing “impressive antitumor effects” as compared
to tumor growth in control groups). Rosenblum 1999 concluded “that
clinical development of BACH-250/rGel may be warranted in patients with
HER2/neu-expressing malignancies.” Id. at Abstract.
4. Pegram 1999 (Ex.1020)
Pegram 1999 states that “[p]revious studies have demonstrated a
synergistic interaction between rhuMAb HER2 and the cytotoxic drug
cisplatin in human breast and ovarian cancer cells.” Ex. 1020, 2241,
Abstract. Pegram 1999 conducted studies in “preclinical models in vitro and
in vivo” using rhuMAb HER2 in combination with other cytotoxic drugs.
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Id., see also id. at 2241, 2nd col., 2242, 2nd col. The reference describes
observing “[s]ynergistic interactions at clinically relevant drug
concentrations” for rhuMAb HER2 in combination with cisplatin, thiotepa,
or etoposide, and “[a]dditive cytotoxic effects” with rhuMAb HER2 plus
doxorubicin, paclitaxel, methotrexate, or vinblastine. Id. at Abstract.
The reference indicates that “rhuMAb HER2” is a recombinant,
humanized form of 4D5. Id. at 2241, 2nd col. It states that when “compared
to murine 4D5, rhuMAb HER2 exhibits a stronger binding affinity for
p185
HER-2/neu
but has similar specific antiproliferative activity against HER-
2/neu-overexpressing cell lines and xenografts.” Id. The reference also
states that in in vivo studies using human breast cancer xenografts in athymic
mice, vinblastine (“VBL”), a microtubule inhibitor, combined with rhuMAb
HER2 “significantly reduced MCF7/HER-2 xenograft volume compared to
treatment with VBL alone or single agent rhuMAb HER2 (Figure 6b).” Id.
at 2245, 2nd col.; see also id. at 2248, ¶ spanning 1st and 2nd col.
(describing “significantly superior anti-tumor efficacy” of rhuMAb HER2
when combined with different chemotherapy drugs, such as VBL, as
compared to effects of each drug alone).
5. Petitioner’s Contentions
Petitioner contends that Chari 1992 teaches all limitations recited in
claims 1–8 of the ’856 patent, except that it does not disclose huMAB4D5-8
(as recited in independent claim 1) or a pharmaceutically acceptable carrier
(as recited in claim 5). Pet. 13; see id. at 9–13. For example, Petitioner
contends that Chari 1992 discloses an immunoconjugate comprising an anti-
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ErbB2 antibody conjugated to a maytansinoid, such as DMI having the
structure recited in claim 2, where the immunoconjugate comprises four
maytansinoid molecules per antibody molecule (as recited in claim 3), and
where the antibody and maytansinoid are conjugated by chemical linkers,
such as SPDP or SMCC (as recited in claims 4 and 6–8). Pet. 9–12 (citing
Ex. 1012).
Petitioner also contends that the HERCEPTIN
®
Label describes the
use of huMAB4D5-8 (i.e., HERCEPTIN
®
) for the treatment of patients with
metastatic breast cancer, as well as the combination of HERCEPTIN
®
with a
pharmaceutically acceptable carrier, i.e., Bacteriostatic Water for Injection.
Pet. 13 (citing Ex. 1008, 1). Most relevant to our analysis, Petitioner further
contends, relying on the Rosenblum Declaration (Ex. 1016), that it would
have been obvious to the ordinarily skilled artisan, at the time the ’856
patent was filed, to substitute the mouse monoclonal TA.1 antibody in the
immunoconjugate of Chari 1992 with the humanized mAb huMAB4D5-8 to
produce the claim-recited immunoconjugates “based on the teachings of
Chari 1992 and HERCEPTIN
®
Label, as well as the general knowledge in
the art at that time.” Pet. 13–14.
Specifically, Petitioner contends that an ordinary artisan would have
been motivated to do such a substitution because it was known that:
(1) humanized mAbs, such as huMAB4D5-8, were preferred over their
mouse-derived counterparts for clinical applications, as indicated in Chari
1992 (Ex. 1012, 130, 1st col.); (2) huMAB4D5-8 selectively bound with
high affinity to HER2 and had been approved for use to treat breast tumors
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in humans, as indicated in the HERCEPTIN
®
Label; and (3) clinical studies
indicated that huMAB4D5-8 worked well in combination with microtubule-
directed chemotherapy agents for the treatment of breast cancer, as indicated
in the HERCEPTIN
®
Label (Ex. 1008, 1, 1st col.). Pet. 13–15.
In addition, Petitioner contends that an ordinary artisan would have
had a reasonable expectation of success regarding the recited
immunoconjugates because it was known that: (1) huMAB4D5-8 was more
effective in treating breast cancer when used in combination with the
microtubule targeting drug paclitaxel, as described in the HERCEPTIN
®

Label; (2) Chari 1992’s maytansinoid conjugates targeted the same cells as
huMAB4D5-8; and (3) an immunoconjugate containing a humanized
antibody was less immunogenic, and therefore more effective in humans,
than an immunoconjugate containing a mouse antibody. Id. at 16.
Petitioner also contends that other prior art references, such as
Rosenblum 1999 and Pegram 1999, provided additional reasons to use the
humanized antibody disclosed in the HERCEPTIN
®
Label in the
immunoconjugate of Chari 1992, with a reasonable expectation of success.
Id. at 19–22. Petitioner refers to, for example, the in vivo efficacy data of a
similar immunoconjugate, as taught in Rosenblum 1999. Id. at 20 (citing
Ex.1018, Figs. 12 and 13; Ex. 1016 ¶ 18). Petitioner also notes that Pegram
1999 states that “ʻ[t]he synergistic interaction of rhuMab HER2 with
alkylating agents . . . as well as the additive interaction with taxanes, . . . in
HER-2/neu-overexpressing breast cancer cells demonstrates that these are
rational combinations to test in human clinical trials’ (emphasis added).”
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Id. at 22 (quoting Ex. 1020, Abstract). Petitioner contends that Pegram 1999
indicates a reasonable expectation of success because it suggested that
HERCEPTIN® and maytansinoid may act independently and have an
additive effort in inhibiting the growth of breast tumor cells. Id. (citing
Ex. 1016 ¶ 21).
Petitioner also refers to teachings in prior art references, such as in
Pegram 1999 and the HERCEPTIN
®
Label, which disclose synergistic or
additive effects between HERCEPTIN
®
and other chemotherapeutic agents,
such as the antimicrotubule agent paclitaxel. Id. at 49. Petitioner also
contends that Chari 1992 taught that “maytansinoid immunoconjugates were
demonstrated to be substantially free of toxicity, based on the same kinds of
assays described in the ’856 patent.” Id. at 54–55 (citing Ex. 1012, Abstract,
129, 1st col., 130 1st col.). Petitioner further cites Liu (Ex. 1023)
5
and Chari
1998 (Ex. 1015)
6
to rebut the position that one would have expected
“unacceptable cytotoxic side effects for such an immunoconjugate,” and that
nothing before the ’856 patent addressed “the unpredictability in the art” in
relation to a reasonable expectation of success. Pet. 55–57 (citing Ex. 1028
¶ 14).

5
Liu et al., Eradication of large colon tumor xenografts by targeted
delivery of maytansinoids, 93 PROC. NATL. ACAD. SCI., USA 8618–8623
(1996) (Ex. 1023).
6
Chari, Targeted delivery of chemotherapeutics: tumor-activated prodrug
therapy, 31 ADV. DRUG DEL. REV. 89–104 (1998) (Ex. 1015).
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6. Analysis regarding claims 1–8
In response to the Petition, Patent Owner argues that Petitioner has not
established a prima facie case that claims 1–8 would have been obvious over
the cited art. PO Resp. 2–26. Patent Owner contends that an ordinary
artisan would not have had a reason to substitute the mouse monoclonal
TA.1 antibody in the immunoconjugate of Chari 1992 with the humanized
mAb huMAB4D5-8, i.e., Herceptin
®
. Id. at 1–3.
As noted above, Petitioner argues that an ordinary artisan would have
had reason to substitute the mouse monoclonal TA.1 antibody in the
immunoconjugate of Chari 1992 with huMAB4D5-8 (HERCEPTIN
®
) in
particular because it was known that (1) humanized antibodies were
preferred over mouse counterparts for clinical applications, (2) huMAB4D5-
8 had been FDA approved for use to treat breast tumors in humans, and (3)
clinical studies indicated that huMAB4D5-8 worked well in combination
with microtubule-directed chemotherapy agents for the treatment of breast
cancer. Pet. 14–15 (citing Ex. 1012, 130; Ex. 1008, 1); see also id. at 19–20
(stating that “Rosenblum 1999 teaches the use, efficacy and safety of an
immunotoxin having humanized ErbB2 extracellular domain-targeted
monoclonal antibody chemically linked to a cytotoxic moiety”); id. at 22
(stating that Pegram 1999 suggested that HERCEPTIN
®
and maytansinoid
had “an additive effort in inhibiting the growth of breast tumor cells”).
Petitioner also relies on different prior art references when arguing that one
would have had an expectation of success in using the immunoconjugate to
treat breast cancer in humans. Id. at 16–17; Ex. 1016 ¶ 16.
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In other words, when asserting that an ordinary artisan would have
had a reason to combine certain teachings in the cited references and,
therefore, prepare a HERCEPTIN
®
-maytansinoid immunoconjugate,
Petitioner relies on the position that an ordinary artisan would have expected
such an immunoconjugate to work clinically to treat tumors in humans upon
reading the cited references.
Patent Owner provides persuasive evidence, however, that in March
2000, at the time the ’856 patent was filed, prior art indicated that
HERCEPTIN
®
-maytansinoid immunoconjugates would have been expected
to exhibit unacceptable levels of antigen-dependent toxicity in normal
human liver tissue in patients. PO Resp. 1–13. For example, Patent Owner
points to Pai-Scherf 1999 (Ex. 2029),
7
which describes a Phase I clinical
study of human patients receiving an immunoconjugate (erb-38) comprising
a portion of the anti-HER2 monoclonal antibody e23 fused to a truncated
form of Pseudomonas exotoxin A. As stated by Patent Owner, although the
Pai-Scherf group “initiated the study in humans based on ‘excellent
antitumor activity and acceptable animal toxicities,’” it nonetheless observed
unacceptable hepatotoxicity in all patients in the treatment group. PO Resp.
4 (citing Ex. 2029, 2311, 2nd col., Abstract).
Pai-Scherf 1999 indicates that, in a clinical study, human patients
experienced “hepatic injury” when exposed to erb-38. Ex. 2029, 2313–14.

7
Pai-Scherf et al., Hepatotoxicity in Cancer Patients Receiving erb-38, a
Recombinant Immunotoxin That Targets the erbB2 Receptor, 5 CLINICAL
CANCER RESEARCH 2311–15 (1999) (Ex. 2029).
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Pai-Scherf 1999 discloses that the “toxicity of erb-38 is most likely due to
the presence of erbB2 on hepatocytes, not detected by immunohistochemical
staining in earlier publications.” Id. at 2314, 1st col., 2315, 1st col. The
reference further discloses that “[d]espite the fact that there is a very large
difference in the amount of erbB2 on the surface of cancer cells relative to
the small amount present on liver cells, liver toxicity was the first biological
effect seen in this study.” Id. at 2314, 2nd col. Pai-Scherf 1999 explains
that a factor contributing to this finding is that “hepatocytes [normal liver
cells] are more rapidly exposed to agents injected into the circulation than
tumor cells,” because “mixing within tumors is solely by diffusion and,
therefore, very slow,” and “tumors are often poorly vascularized.” Id.
Pai-Scherf 1999 also discusses HERCEPTIN
®
in particular, noting
that the “antibody alone has been found to produce objective responses in
breast cancer and when combined with chemotherapy results in an increased
response rate.” Id. Pai-Scherf 1999 states that “[i]t is likely that the
antitumor activity of the antibody in this setting is dependent on genetic
perturbations that alter the configuration of downstream signaling events,”
where “the mechanism of killing depends on a genetic abnormality present
in the cancer cells.” Id. at 2314, 2nd col. – 2315, 1st col. By contrast,
according to Pai-Scherf 1999, “if the antibody is used to deliver a cytotoxic
agent, such as a bacterial toxin or radioisotope, the death of the target cell
will be principally dependent on the amount of agent delivered to the cell.”
Id. at 2315, 1st col. Thus, Pai-Scherf 1999 indicates that the mechanism of
cytotoxicity of the antibody alone differs from that of the antibody
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conjugated to a toxin. In this context, Pai-Scherf 1999 concludes that “the
toxicity observed with erb-38 is most likely due to the presence of erbB2 on
hepatocytes,” and the “targeting of tumors with antibodies to erbB2 that are
armed with . . . toxic agents may result in unexpected organ toxicities due to
erbB2 expression on normal tissues.” Id. at 2315, 2nd col.
Patent Owner further cites evidence indicating that HERCEPTIN
®
and
maytansinoids each caused toxicity to normal human cells, including liver
cells, on their own. PO Resp. 7–13; Ex 1008, 1, 2nd col., 2, 2nd col.
(observing heart toxicity generally, and “hepatic failure” in at least one
patient); PO Resp. 7–8 (citing a number of exhibit references discussing
hepatic toxicity and injury upon administering maytansinoids to patients).
In response, Petitioner contends that Pai-Scherf 1999 is not relevant to
our analysis because it describes the use of a “fusion protein,” not an
antibody-drug conjugate. Reply 4–6. We disagree that Pai-Scherf 1999 is
not relevant. Although the reference discloses clinical studies using a
“single-chain” immunoconjugate comprising a portion of an anti-
HER2/erbB2 antibody and a truncated form of a toxin, Pai-Scherf 1999
discusses generally the “targeting of tumors with antibodies to erbB2 armed
with radioisotopes or other toxic agents.” Ex. 2029, 2311, Abstract, 2315,
2nd col. As noted above, the reference also expressly states that the
“toxicity of erb-38 is most likely due to the presence of erbB2 on
hepatocytes,” i.e., normal liver cells that “are more rapidly exposed to agents
injected into the circulation than tumor cells” (Ex. 2029, 2314, 1st and 2nd
col.)—a situation equally applicable when using a full-length anti-HER2
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19
antibody linked to a toxin, i.e., “an antibody-drug conjugate,” as Petitioner
calls it. Reply 5; PO Resp. 20 (citing Ex. 2111, 8987, 2nd col. (stating that
“treatment of solid tumors presents a potential problem because full-length
antibodies must diffuse into the tumor against a hydrostatic pressure gradient
and into disordered vasculature”)).
Patent Owner persuades us that one would have considered the
teachings of Pai-Scherf 1999 when reading Chari 1992, the HERCEPTIN
®

Label, as well as other references cited by Petitioner, such as Rosenblum
1999 and Pegram 1999. Chari 1992 states generally, based on
clearance/degradation studies in mice and in vitro cytotoxicity studies on
human cells in tissue culture, that maytansinoid conjugates “may possess a
therapeutic index sufficient for the effective treatment of human cancer,”
and “development of ‘humanized’ antibodies will offer an opportunity to
produce drug conjugates.” Ex. 1012, 130. Petitioner does not establish by a
preponderance of the evidence that those general statements in Chari 1992,
in view of teachings years later in the HERCEPTIN
®
Label, Pai-Scherf
1999, and other references regarding liver toxicities, would have motivated
an ordinary artisan to substitute the mouse TA.1 antibody in the
immunoconjugate of Chari 1992 with HERCEPTIN
®
on the basis that one
would have expected that modified immunoconjugate to work to treat
human tumors. Pet. 14–15 (citing Ex. 1016 ¶¶ 12–15); PO Resp. 5–6, 19;
Ex. 2134 ¶¶ 29, 52–57.
Petitioner’s citation to Rosenblum 1999 and Pegram 1999, which
disclose the testing of other anti-HER2-toxin immunoconjugates or
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20
combinations of antibodies and toxins (using different anti-HER2 antibodies
and different toxins) in in vitro tissue culture, and in vivo in mice expressing
human tumors (mouse xenograft models), does not persuade us otherwise.
8

Pet. 17–22; Reply 6–8, 11–12. Patent Owner persuades us that an ordinary
artisan would have understood that such studies would not have provided
adequate information regarding toxicities to normal human cells in vivo. PO
Resp. 12–13, 23–24; Ex. 2134 ¶¶ 22–27, 51. By contrast, the human clinical
study in Pai-Scherf 1999 provided such information and observed
hepatotoxicity when using a relevant immunoconjugate and suggested
“unexpected organ toxicities due to erbB2 [HER2 expression] on normal
cells” in relation to all anti-HER2 antibodies linked to toxins. Ex. 2029,
Abstract.
To establish that the challenged claims would have been obvious,
Petitioner must show that “a skilled artisan would have had reason to
combine the teaching of the prior art references to achieve the claimed
invention, and that the skilled artisan would have had a reasonable

8
In its Petition, Petitioner also relies on Hudziak 1998 (Ex. 1017), Baselga
1998 (Ex. 1019), Liu (Ex. 1023), and Chari 1998 (Ex. 1015), which likewise
disclose studies conducted in tissue culture in vitro and/or in xenograft mice
expressing human tumor cells using different antibodies and toxins. Pet. 17–
21, 55–56; Hudziak, et al., U.S. Patent No. 5,770,195, issued June 23, 1998,
18:51–19:48 (Ex. 1017); Baselga et al., Recombinant Humanized Anti-HER2
Antibody (HerceptinTM) Enhances the Antitumor Activity of Paclitaxel and
Doxorubicin against HER2/neu Overexpressing Human Breast Cancer
Xenografts, 58 CANCER RES. 2825–2831 (1998) (Ex. 1019); Ex. 1023, 8618–
22; Ex. 1015, 97–102.
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21
expectation of success from doing so.” Par Pharm. Inc. v. TWI Pharms.
Inc., 773 F.3d 1186, 1193 (Fed. Cir. 2014). As noted above, Petitioner’s
rationale for substituting HERCEPTIN
®
for the antibody used in the
immunoconjugate of Chari 1992 was to make an immunoconjugate useful in
treating tumors in human patients. Patent Owner, however, advances
persuasive evidence that ordinary artisans would not have had a reasonable
expectation that any immunoconjugate, much less the claimed Herceptin®-
maytansinoid immunoconjugate in particular, would be useful to treat solid
tumors in humans. PO Resp. 18–22 (describing prior failures in developing
immunoconjugates for treating solid tumors), 47–51 (discussing long-felt
need). As noted by Patent Owner, “[r]esearchers had targeted tumors with
immunoconjugates for about 40 years before the ’856 patent” without
success. Id. at 21–22 (citing numerous exhibits). Patent Owner sufficiently
points to evidence of record indicating that preparing any antibody-toxin
immunoconjugate for use in the treatment of human tumors was difficult and
unpredictable. PO Resp. 22; Ex. 2006, 385–89; Ex. 2007, 67, 72–86. Thus,
viewing the record as a whole, Petitioner does not persuade us that a
preponderance of the evidence establishes that a skilled artisan would have
had a reasonable expectation of success in 2000 that a Herceptin®-
maytansinoid immunoconjugate would be useful in the treatment of breast
tumors in humans, as Petitioner asserts. Pet. 16–17, 20, 22; PO Resp. 22–23
(citing Ex. 2134 ¶¶ 101–113 (citing numerous exhibits)).
For the reasons given above, and in light of the record before us,
Petitioner does not establish by a preponderance of the evidence that claims
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Patent 8,337,856 B2
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1–8 of the ’856 patent would have been obvious over Chari 1992 in view of
the HERCEPTIN
®
Label, further in view of Rosenblum 1999 and Pegram
1999.
7. Additional analysis regarding claims 6 and 8
Dependent claims 6 and 8 of the ’856 patent differ from other
challenged claims in that they further recite a specific non-cleavable linker,
succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (“SMCC”).
Ex. 1001, 82:39–51; PO Resp. 26. Claim 8 additionally requires that the
maytansinoid be DM1, and is directed specifically to the commercial
product “T-DM1,” marketed under the name Kadcyla
®
. PO Resp. 35.
As noted by Patent Owner, evidence of record indicates that the prior
art emphasized the importance of releasing a drug, such as a maytansinoid,
from an immunoconjugate for biologic activity, such as via cleavable
linkers. PO Resp. 27–28 (citing Ex. 2006, 385; Ex. 1015, 97; Ex. 1014,
169–170). For example, Chari 1992 states, that “to exploit the cytotoxic
potential of maytansine in the conjugate, . . . it is necessary to release the
drug at the target cell in fully active form.” Ex. 1012, 128, 1st col.; PO
Resp. 27. Consistently, in its in vitro tissue culture studies, Chari 1992
found that a monoclonal antibody TA.1-maytansinoid immunoconjugate
comprising a non-cleavable linker “was 200-fold less potent under the same
conditions (Fig. 3c),” as compared to a similar conjugate comprising a
cleavable linker. Ex. 1012, 129, 1st col.; PO Resp. 26, 29–34.
Petitioner responds that although Chari 1992, Fig. 3c, may indicate
that the immunoconjugate with a non-cleavable linker works less well, the
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Patent 8,337,856 B2
23
immunoconjugate still exhibits cytotoxic effects in the tested cells in tissue
culture. Reply 12–17.
When considering evidence of record as a whole, we are persuaded
that evidence cited by Patent Owner, including Chari 1992 and other prior
art references, provided reasons not to use a non-cleavable linker in an
immunoconjugate, such as one comprising an anti-HER2 antibody and
maytansinoid, in particular. See Ex. 2006, 385 (stating that “unfavorable
pharmacokinetics and pharmacodynamics observed in animals with such
conjugates discouraged further development,” when using conjugates
linking drugs “directly to antibodies via noncleavable bonds”).
9
In addition
to evidence discussed in the previous section, such evidence further bolsters
our conclusion that Petitioner has not established by a preponderance of the
evidence that a skilled artisan would have had reason to combine the
teaching of the cited references to make the immunoconjugates of claim 6
and 8.
Although failure to establish a reason to combine the cited teachings
is sufficient, by itself, to conclude non-obviousness, Patent Owner cites
substantial evidence of objective indicia of non-obviousness in relation to
claim 8, which is directed to the T-DM1/Kadcyla
®
commercial product. PO
Resp. 34–60 (citing evidence regarding T-DM1 and unexpected superior

9
Blättler et al., “Immunoconjugates,” in Cancer Therapeutics:
Experimental and Clinical Agents, Chapter 17, 371–394 (1996) (Ex. 2006).
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Patent 8,337,856 B2
24
results as compared to closest prior art compositions, fulfilling a long-felt
and unmet need, praise in the field, and commercial success).
For example, Patent Owner provides evidence that T-DM1 fulfilled a
long-felt, unmet need for an immunoconjugate capable of targeting a solid
tumor in patients without excessive toxicity. Id. at 46–57 (citing, for
example, Ex. 2103 ¶¶ 24–48; see id. at ¶¶ 26–28 (citing exhibits including
Ex. 2062) (discussing numerous clinical trials testing ability of
immunoconjugates to treat solid tumors before March 2000, where “none of
these immunoconjugates proved safe and effective for treating solid
tumors”); Ex. 2134 ¶ 106 (citing exhibits). Patent Owner also provides
evidence regarding the commercial success of T-DM1/Kadcyla
®
. PO. Resp.
57–60 (citing, for example, Ex. 2131 (testimony by Mr. Jarosz, analyzing
sales and prescription data, and marketing and promotional efforts relating to
Kadcyla
®
)).
In view of the specific components recited in claim 8, i.e., a specific
antibody, linker, and toxin, which are the same as those in T-DM1/Kadcyla
®

(PO. Resp. 35 (citing Ex. 2025, 14), we are persuaded that Patent Owner
establishes a sufficient nexus in relation to the cited objective evidence of
nonobviousness. See, e.g., In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir.
1995) (stating that for objective evidence to be accorded substantial weight,
the record “must establish a nexus between the evidence and the merits of
the claimed invention”); In re Kao, 639 F.3d 1057, 1068–69 (Fed. Cir. 2011)
(unexpected results); Rambus Inc. v. Rea, 731 F.3d 1248, 1256 (Fed. Cir.
2013) (long-felt need); Muniauction, Inc. v. Thomson Corp., 532 F.3d 1318,
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Patent 8,337,856 B2
25
1328 (Fed. Cir. 2008) (praise); In re Huang, 100 F.3d 135, 140 (Fed. Cir.
1996) (commercial success).
Petitioner’s contentions do not persuade us that results obtained using
T-DM1/Kadcyla
®
were expected in view of cited prior art references, for the
reasons discussed in the section above. See supra § II.B.6; Reply 18–19.
We also are not persuaded by Petitioner’s position that the alleged
unexpected results are not commensurate in scope with claim 8, or that a
lack of nexus exists between the asserted industry praise and commercial
success. Id. at 19–23. Claim 8 is directed to a very specific immunotoxin
comprising the humanized antibody huMAb4D5-8 (HERCEPTIN
®
)
conjugated to the maytansinoid DM1 toxin via the SMCC linker. The
specification of the ’856 patent discloses, and claim 8 recites, the very
components that led to the unexpected results, praise and commercial
success. See, e.g., GPAC, 57 F.3d at 1580 (stating, in relation to commercial
success, that the evidence must show “that the thing (product or method) that
is commercially successful is the invention disclosed and claimed in the
patent”) (quoting Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851
F.2d 1387, 1392 (Fed. Cir. 1988))).
Patent Owner sufficiently establishes that it is the exact combination
of those components recited in claim 8, rather than different components
previously combined in the prior art, that provided the unexpected results at
issue, and led to praise and commercial success. PO Resp. 35–46 (citing
evidence in support). For example, Patent Owner provides evidence that T-
DM1/Kadcyla
®
provides unexpectedly superior results in patients, as
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Patent 8,337,856 B2
26
compared to HERCEPTIN® plus a chemotherapy agent, in HERCEPTIN
®
-
resistant patients. Id. at 35–46 (citing, for example, Ex. 2105 ¶¶ 24–35; Ex.
2012).
For the additional reasons given above, Petitioner does not establish
by a preponderance of the evidence that claims 6 or 8 of the ’856 patent
would have been obvious over Chari 1992 in view of the HERCEPTIN
®

Label, further in view of Rosenblum 1999 and Pegram 1999.
C. Petitioner’s Motion to Exclude
In its Motion to Exclude, Petitioner seeks to exclude Exhibits 2240–
44, 2256, 2319, and 2320, as well as certain paragraphs in the Jarosz
Declaration (Ex. 2131) relying on those exhibits. Paper 28. Patent Owner
cites those exhibits and paragraphs in relation to assertions regarding
commercial success of T-DM1/Kadcyla
®
. PO Resp. 57–59. Petitioner
contends that Exhibits 2240–44, 2256, 2319, and 2320 lack foundation under
Federal Rule Evidence (“Fed. R. Evid.”) 901, and are inadmissible hearsay
under Fed. R. Evid. 801, 802 as “out-of-court statements by another that are
relied upon for the truth of the matter asserted therein.” Paper 28, 7–8.
Petitioner also contends that those exhibits are not qualified to be the basis
for an expert opinion under Fed. R. Evid. 703, and that paragraphs in the
Jarosz Declaration relying on those exhibits are hearsay and lack foundation.
Id. at 8–9.
As stated in his Declaration, Mr. Jarosz is an economist and Managing
Principal of Analysis Group, Inc., “an economic, financial, and strategy
consulting firm.” Ex. 2131 ¶¶ 6–7. Mr. Jarosz testifies that “Exhibits 2240–
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2244, 2256, 2319–2320 provide a summary of voluminous IMS [Health]
revenue and prescription data, as well as marketing and promotional efforts
relating to Kadcyla.” Id. ¶ 12. He also testifies that “I and others working
under my direction prepared these exhibits.” Id.
As an initial matter, we note that Petitioner does not establish
sufficiently that the challenged claims would have been obvious, even if we
do not consider any evidence of commercial success of T-DM1/ Kadcyla®
cited by Patent Owner. For the reasons discussed above, Petitioner does not
establish a prima facie case of obviousness of claims 1–8 of the ’856 patent
by a preponderance of the evidence in the first instance—meaning we come
to our determination even in the absence of evidence of objective indicia of
non-obviousness. In any event, as also discussed above regarding claim 8,
Patent Owner provides persuasive evidence of unexpected results, fulfilling
a long-felt and unmet need, and praise in the field, even if we ignore all
evidence relating to commercial success. Thus, even if we excluded
Exhibits 2240–44, 2256, 2319, and 2320, and paragraphs in the Jarosz
Declaration citing those exhibits, it would not impact our decision in this
case.
In any event, Mr. Jarosz testifies in his Declaration, as an expert, that
he personally “considered information from a variety of sources,” and opines
“that Kadcyla has achieved substantial commercial success in the United
States,” and that a nexus exists between that success and the claims of the
’856 patent. Ex. 2131 ¶¶ 2, 10–16. Mr. Jarosz considered various other
clinical treatments on the market and the relevant marketplace. Id. ¶¶ 23–
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28
36. In providing details of the basis of his opinion, he cites information,
including that summarized in the exhibits at issue in the Motion to Exclude.
Id. ¶¶ 37–109.
Federal Rule of Evidence 703 states the following.
An expert may base an opinion on facts or data in the
case that the expert has been made aware of or personally
observed. If experts in the particular field would reasonably
rely on those kinds of facts or data in forming an opinion on the
subject, they need not be admissible for the opinion to be
admitted. But if the facts or data would otherwise be
inadmissible, the proponent of the opinion may disclose them to
the jury only if their probative value in helping the jury evaluate
the opinion substantially outweighs their prejudicial effect.
Fed. R. Evid. 703, “Bases of an Expert’s Opinion Testimony.” Although our
proceedings do not involve juries, Fed. R. Evid. 703 is informative in our
analysis regarding Petitioner’s assertion of hearsay.
In his Declaration, Mr. Jarosz provided his expert opinion by direct
testimony based on facts or data of which he was made aware or that he
personally observed. See 37 C.F.R. § 42.53(a) (“Uncompelled direct
testimony must be submitted in the form of an affidavit.”); Fed. R. Evid.
703. Because that Declaration corresponds to Mr. Jarosz’s direct testimony
in this trial, we are not persuaded that any part of his Declaration constitutes
an “out-of-court statement” or hearsay, as Petitioner contends.
In addition, in relation to the other exhibits at issue (cited in Mr.
Jarosz’s Declaration and in the Patent Owner Response when citing that
Declaration), we are persuaded that the summaries of “voluminous” data and
marketing efforts, as prepared by Mr. Jarosz personally or by others working
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Patent 8,337,856 B2
29
under his direction, provide probative value that substantially outweighs any
possible prejudice to Petitioner. Fed. R. Evid. 703.
For the reasons discussed above, we deny Petitioner’s Motion to
Exclude Exhibits 2240–44, 2256, 2319, and 2320, and certain paragraphs in
the Jarosz Declaration (Ex. 2131) relying on those exhibits.
D. Patent Owner’s Motion to Seal
Patent Owner has filed an unopposed Motion to Seal requesting to
seal Exhibits 2347 and 2348 filed by Patent Owner in connection with its
Opposition to Petitioner’s Motion to Exclude. Paper 31, 1.
There is a strong public policy in favor of making information filed in
an inter partes review open to the public, especially because the proceeding
determines the patentability of claims in an issued patent and, therefore,
affects the rights of the public. Thus, the standard for granting a motion to
seal is “for good cause.” 37 C.F.R. § 42.54(a). The party moving to seal
bears the burden of proof in showing entitlement to the requested relief, and
must explain why the information sought to be sealed constitutes
confidential information. 37 C.F.R. § 42.20(c).
We do not rely on Exhibits 2347 and 2348 in making our decision
regarding the obviousness challenge of claims 1–8 of the ’856 patent, or
when deciding Petitioner’s Motion to Exclude. We have reviewed Exhibits
2347 and 2348 for the purpose of addressing the Motion to Seal, and are
persuaded that good cause exists to have these documents remain under seal.
Those exhibits contain confidential information regarding Patent Owner’s
non-public marketing and sales-related proprietary information. Patent
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Patent 8,337,856 B2
30
Owner persuades us that Exhibits 2240–44, 2256, 2319, and 2320, which are
unsealed, will fulfill adequately the needs of the public to maintain a
complete and understandable record in this case.
For the above-mentioned reasons, we grant Patent Owner’s
unopposed Motion to Seal Exhibits 2347 and 2348.
III. CONCLUSION
For the foregoing reasons, Petitioner has not demonstrated by a
preponderance of the evidence that claims 1–8 of the ’856 patent would have
been obvious over Chari 1992 in view of the HERCEPTIN® Label, further
in view of Rosenblum 1999 and Pegram 1999.
IV. ORDER
For the reasons given, it is
ORDERED that claims 1–8 of the ’856 patent are not held
unpatentable;
FURTHER ORDERED that Petitioner’s Motion to Exclude is
denied;
FURTHER ORDERED that Patent Owner’s Motion to Seal is
granted;

FURTHER ORDERED that, because this is a Final Written
Decision, the parties to the proceeding seeking judicial review of the
decision must comply with the notice and service requirements of 37 C.F.R.
§ 90.2.
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31
For PETITIONER:

Ping Wang
PingWang@andrewskurth.com

For PATENT OWNER:

Eldora Ellison
eellison-PTAB@skgf.com

Eric Steffe
esteffe-PTAB@skgf.com