Phigenix, Inc.v.ImmunoGen, Inc.

Patent Trial and Appeal Board

Dec 10, 2014

11488545 (P.T.A.B. Dec. 10, 2014)

Trials@uspto.gov Paper 10
571-272-7822 Entered: December 9, 2014

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

PHIGENIX, INC,
Petitioner,

v.

GENENTECH, INC. and IMMUNOGEN, INC.,
Patent Owner.
____________

Case IPR2014-00842
Patent 7,575,748 B1
____________

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

BONILLA, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
37 C.F.R. § 42.108

IPR2014-00842
Patent 7,575,748 B1

2
I. INTRODUCTION
Phigenix Inc. (“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”). Paper 1
(“Pet.”). Genentech, Inc. and ImmunoGen, Inc. (“Patent Owner”) filed a
Preliminary Response. Paper 9 (“Prelim. Resp.”). We have jurisdiction under
35 U.S.C. § 314(a), which provides that an inter partes review may not be
instituted “unless . . . there is a reasonable likelihood that the petitioner would
prevail with respect to at least 1 of the claims challenged in the petition.”
Upon consideration of the Petition and the Preliminary Response, and for the
reasons explained below, we determine that Petitioner has not established a
reasonable likelihood of prevailing on any of the claims challenged in the Petition.
Accordingly, we do not institute an inter partes review.
A. Related Proceeding
About a month before filing the current Petition, Petitioner filed a Corrected
Petition requesting inter partes review of claims 1–8 of U.S. Patent No. 8,337,856
(“the ’856 patent”) in Case IPR2014-00676, and, thereafter, Patent Owner filed a
Preliminary Response. IPR2014-00676, Papers 5, 10. We instituted inter partes
review in that case on October 29, 2014. IPR2014-00676, Paper 11. The ’748
patent, at issue here, is a continuation application of U.S. Patent No. 7,097,840
(“the ’840 patent”). Ex. 1001. The ’856 patent is a divisional application of a
continuation application of the ’840 patent. IPR2014-00676, Ex. 1001. Claims of
the ’856 patent are directed to immunoconjugate compounds. Id. at cols. 81–82.
As discussed below, claims of the ’748 patent are directed to methods for treating a
tumor comprising administering an immunoconjugate.
IPR2014-00842
Patent 7,575,748 B1

3
B. The ’748 Patent (Ex. 1001)
The ’748 patent relates to methods of treating cancer using ErbB receptor-
directed cancer therapies. Ex. 1001, 1:2–23; 4:10–14. The ’748 patent describes
immunoconjugates comprising an anti-ErbB antibody, such as the humanized anti-
ErbB2 antibody known as HERCEPTIN® (huMAb4D5-8), linked to a
maytansinoid toxin. Id. at 1:20–52; 35:54–36:42; see also id. at 3:6–16 (discussing
HERCEPTIN®); 6:51–67 (defining “ErbB2”); 10:41–65 (defining “humanized”);
16:26–31 (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 1:45–59; 6:51–59. Overexpression
of ErbB2 on cell surfaces can lead to cancer in humans, such as certain breast and
ovarian cancers. Id. at 1:53–67; 8:56–60.
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; 17:48–55; see also id. at 5:7–12
(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-pyridyldithio)propionate (“SPDP”), N-succinimidyl-
4-(2-pyridylthio)pentanoate (“SPP”), and succinimidyl-4-(N-maleimidomethyl)-
cyclohexane-l-carboxylate (“SMCC”). Id. at 36:16–32.
The Specification states that the “present invention is based on the
IPR2014-00842
Patent 7,575,748 B1

4
unexpected experimental finding that HERCEPTIN®-maytansinoid conjugates are
highly effective in the treatment of HER2 (ErbB2) overexpressing tumors that do
not respond, or respond poorly to HERCEPTIN® therapy.” Id. at 4:10–14. The
Specification describes that the conjugates “are expected to have superior clinical
activity compared to treatment with HERCEPTIN® alone, including a better
objective response rate and/or longer duration of response and/or increased
survival.” Id. at 4:14–18.
In this context, the Specification discusses “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 22:3–6. 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 22:7–12.
C. The Challenged Claims
Petitioner challenges claims 1–20 and 25–27 of the ’748 patent. Of those,
claims 1 and 2 are independent. Claim 1 is representative, and is reproduced
below.
1. A method for the treatment of a tumor in a mammal, comprising
the steps of
(i) identifying said tumor as being characterized by
overexpression of an ErbB2 receptor and as being a tumor that does
not respond, or responds poorly, to treatment with an anti-ErbB
antibody, and

IPR2014-00842
Patent 7,575,748 B1

5
(ii) intravenously administering to the mammal a
therapeutically effective amount of a conjugate of a humanized
antibody huMab 4D5-8 covalently linked via a thioether linking group
with a maytansinoid DM1 having the structure

at a dose of between about 0.2 mg/kg and about 10 mg/kg
(antibody-maytansinoid conjugate weight/body weight) and
at a frequency of dosing selected from the group of dosing
frequencies consisting of bolus, less than about 1 time per week, one
time per week, two times per week, more than two times per week,
and continuous infusion,
whereby said tumor characterized by overexpression of an
ErbB2 receptor and that does not respond, or responds poorly, to
treatment with an anti-ErbB antibody, is treated.
Id. at 81:34–82:36 (spacing and indentation added). Independent claim 2 is
identical to claim 1, but recites treating a human, rather than a mammal. Id. at
82:37–83:5. Dependent claims recite specific doses, tumors, linking groups, that
the method further comprises administering a cytotoxic agent, or that the conjugate
comprises 3 to 4 maytansinoid molecules per antibody. Id. at 83:6–84:60.
IPR2014-00842
Patent 7,575,748 B1

6
D. Asserted Grounds of Unpatentability
Petitioner contends that the challenged claims are unpatentable under
35 U.S.C. § 103(a) based on the following grounds. Pet. 9.
References Basis Claims Challenged
1 Chari 1992 (Ex. 1012)
1
and HERCEPTIN® Label
(Ex. 1008)
2

§ 103 1–20 and 25–27
2 Chari 1992, HERCEPTIN® Label, and
Baselga 1999 (Ex. 1032)
3

§ 103 1–20 and 25–27
3 Chari 1992, HERCEPTIN® Label, and
Morgan 1990 (Ex. 1021)
4

§ 103 1–20 and 25–27
4 Chari 1992 and HERCEPTIN® Label, further in
view of Morgan 1990, Hudziak 1998 (Ex. 1017)
5

and/or Rosenblum 1999 (Ex. 1018)
6

§ 103 1–20 and 25–27

1
Chari et al., Immunoconjugates Containing Novel Maytansinoids: Promising
Anticancer Drugs, 52 CANCER RES. 127–131 (1992).
2
HERCEPTIN® (Trastuzumab) Label, dated September 1998.
3
Baselga et al., Phase II Study of Weekly Intravenous Trastuzumab (Herceptin®)
in Patients With HER2/neu-Overexpresing Metastatic Breast Cancer, SEMIN.
ONCOL. 26, Suppl 12:78–83 (1999).
4
Morgan et al., Immunotoxins of Pseudomonas exotoxin A (PE): effect of linkage
on conjugate yield, potency, selectivity and toxicity, 27(3) MOL. IMMUNOL. 273–
282 (1990).
5
Hudziak et al., U.S. Patent No. 5,770,195, issued June 23, 1998.
6
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).
IPR2014-00842
Patent 7,575,748 B1

7
References Basis Claims Challenged
5 Chari 1992 and HERCEPTIN® Label, further in
view of Morgan 1990, Hudziak 1998 and/or
Rosenblum 1999, and further in view of Baselga
1998 (Ex. 1019)
7
and/or Pegram 1999 (Ex.1020)
8

§ 103 1–20 and 25–27
6 Cohen 1999 (Ex. 1022)
9
in view of
HERCEPTIN® Label, and Morgan 1990
§ 103 1–20 and 25–27

II. ANALYSIS
A. Claim Construction
The Board interprets claims in an unexpired patent using the “broadest
reasonable construction in light of the specification of the patent in which [they]
appear[].” 37 C.F.R. § 42.100(b); see also Office Patent Trial Practice Guide
(“Practice Guide”), 77 Fed. Reg. 48756, 48766 (Aug. 14, 2012). There is a “heavy
presumption” that a claim term carries its ordinary and customary meaning. CCS
Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359, 1366 (Fed. Cir. 2002).
Neither party offers construction of any claims terms. Generally, we
construe claim terms of the ’748 patent as carrying their ordinary meaning,

7
Baselga et al., Recombinant Humanized Anti-HER2 Antibody (Herceptin
TM
)
Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER2/neu
Overexpressing Human Breast Cancer Xenografts, 58 CANCER RES. 2825–2831
(1998).
8
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).
9
Cohen, U.S. Pat. Appl. Publ. No. 2003/0170235 A1, published Sept. 11, 2003.
IPR2014-00842
Patent 7,575,748 B1

8
consistent with their use in the Specification. Most relevant to our analysis here,
we note that the last phrase in each independent claim requires treatment of a
tumor that “does not respond, or responds poorly, to treatment with an anti-ErbB
antibody.” We consider the phrase “method for the treatment of a tumor” in the
preamble to be limiting, especially when read in combination with the “whereby”
clause reciting that “said tumor” is “characterized by overexpression of an ErbB2
receptor” and “does not respond, or responds poorly, to treatment with an anti-
ErbB antibody, is treated.”
10
Those limitations define a critical component of the
challenged claims.
As defined in the Specification, a “tumor which ‘does not respond, or
responds poorly, to treatment with a monoclonal anti-ErbB antibody’ does not
show statistically significant improvement in response to anti-ErbB antibody
treatment when compared to no treatment or treatment with placebo in a
recognized animal model or a human clinical trial, or which responds to initial
treatment with anti-ErbB antibodies but grows as treatment is continued.” Ex.

10
“A claim’s preamble may limit the claim when the claim drafter uses the
preamble to define the subject matter of the claim.” August Tech. Corp. v. Camtek,
Ltd., 655 F.3d 1278, 1284 (Fed. Cir. 2011). A preamble generally limits a claim if
it “recites essential structure or steps, or if it is necessary to give life, meaning, and
vitality to the claim.” NTP, Inc. v. Research In Motion, Ltd., 418 F.3d 1282, 1305
(Fed. Cir. 2005) (quoting Catalina Mktg. Int’l, Inc. v. Coolsavings.com, Inc., 289
F.3d 801, 808 (Fed. Cir. 2002)). For example, when “limitations in the body of the
claim rely upon and derive antecedent basis from the preamble, then the preamble
may act as a necessary component of the claimed invention.” Id. at 1306 (quoting
Eaton Corp. v. Rockwell Int’l Corp., 323 F.3d 1332, 1339 (Fed. Cir. 2003)).

IPR2014-00842
Patent 7,575,748 B1

9
1001, 16:56–63.
B. Obviousness over Chari 1992 and HERCEPTIN® Label
Petitioner contends that claims 1–20 and 25–27 would have been obvious
over Chari 1992 and the HERCEPTIN® Label, relying on a Declaration by Dr.
Michael G. Rosenblum (Ex. 1016). Pet. 10–26.
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, ¶ spanning 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., ¶ 1. 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 2d 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., ¶ 2, 2d col., Fig. 3. In addition, the reference teaches that
conjugate TA.1(-SS-May)4 was at least 1000-fold less cytotoxic toward neu-
negative KB cells. 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., ¶ 3. The reference also discloses that
conjugate A7(-SS-May)6, where A7 is an antibody directed against a human colon
IPR2014-00842
Patent 7,575,748 B1

10
cancer cells line antigen showed similar cytotoxicity results and was not toxic in
mice. Id. at 1st col., ¶ 3–2d col., ¶ 2.
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., ¶ 2; 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
¶ 3.
2. HERCEPTIN® Label (Ex. 1008)
The HERCEPTIN® Label (or “the Label”) describes HERCEPTIN®, also
known as trastuzumab or huMAB4D5-8, as a humanized form of the mouse
monoclonal antibody 4D5, which binds HER2. 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.
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 2d col. In addition, the Label describes HERCEPTIN® in
combination with paclitaxel as being “indicated for treatment of patients with
IPR2014-00842
Patent 7,575,748 B1

11
metastatic breast cancer whose tumors overexpress the HER2 protein and who
have not received chemotherapy for their metastatic disease.” Id.
The Label describes a clinical trial with patients who “were randomized to
receive chemotherapy alone or in combination with HERCEPTIN given
intravenously as a 4 mg/kg loading dose followed by weekly doses of
HERCEPTIN at 2mg/kg.” Id. at 1st col. In that trial, all patients received
“chemotherapy” of either: (1) paclitaxel; or (2) an anthracycline (i.e., doxorubicin
or epirubicin) plus cyclophosphamide. Id. Table 1 in the Label presents data
regarding “Phase III Clinical Efficacy in First-Line Treatment” in those patients.
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).
The Label also describes a second “single agent” clinical trial, where
patients “who had relapsed following one or two prior chemotherapy regimens for
metastatic disease” received HERCEPTIN®. Id. In relation to that trial, “ORR
(complete response + partial response) . . . was 14%, with a 2% complete response
rate and a 12% partial response rate.” Id. at ¶ spanning 1st and 2d cols. The Label
states that the “degree of HER2 overexpression was a predictor of treatment
effect.” Id. at 2d col.
3. Analysis
Petitioner contends that Chari 1992 teaches the elements of the conjugate
recited in the challenged claims of the ’748 patent, except that Chari 1992 does not
IPR2014-00842
Patent 7,575,748 B1

12
disclose huMAB4D5-8 in particular. For example, Petitioner contends that Chari
1992 discloses an immunoconjugate comprising an anti-ErbB2 antibody
conjugated to a maytansinoid, such as DMI having the structure recited in claims 1
and 2, where the immunoconjugate comprises four maytansinoid molecules per
antibody molecule (as recited in claims 15, 16, 25 and 26), where the antibody and
maytansinoid are conjugated by chemical linkers, such as SMCC (as recited in
claims 14 and 27). Pet. 11–16 (citing Ex. 1012). Patent Owner does not contend
otherwise. See Prelim. Resp. generally.
Petitioner further contends that the HERCEPTIN® Label describes the use
of huMAB4D5-8 (i.e., HERCEPTIN®) for the treatment of human patients with
metastatic breast cancer, and specifically tumors characterized by overexpression
of an ErbB2 receptor. Pet. 10 (citing Ex. 1008, 1). Petitioner also contends that
Chari 1992 teaches administering mice a dose of 8 mg/kg (by antibody) of the
conjugate, and the HERCEPTIN® Label teaches administering humans doses of 4
mg/kg of the antibody as a 90-minute infusion. Pet. 12 (citing Ex. 1012, 129–130;
Ex. 1008, 2, 2
nd
col.). Patent Owner does not contend otherwise.
The primary dispute between the parties relates to the limitations in the
claims of identifying and treating a tumor that “does not respond, or responds
poorly, to treatment with an anti-ErbB antibody.” Petitioner contends that the
HERCEPTIN® Label discloses the “identifying” such a tumor, and an ordinary
artisan would have been motivated to treat such a tumor using a HERCEPTIN®
conjugate. Pet. 10–12 (citing Ex. 1008, ¶ spanning 1st and 2d cols.).
Specifically, Petitioner points to the Label’s teaching that in patients
receiving HERCEPTIN, “ORR (complete response + partial response) . . . was
IPR2014-00842
Patent 7,575,748 B1

13
14%, with a 2% complete response rate and a 12% partial response rate.” Ex.
1008, ¶ spanning 1st and 2d cols. Thus, according to Petitioner, “96% (48/50) of
patients with 2+ HER2 overexpression and 83% (143/172) of patients with 3+
HER2 overexpression did not show complete or partial response to the
HERCEPTIN® treatment.” Pet. 18. Petitioner contends that this teaching
indicates that the HERCEPTIN® Label discloses identifying a tumor that does not
respond, or responds poorly, to treatment with an anti-ErbB antibody, i.e.,
HERCEPTIN®. We are persuaded that the HERCEPTIN® Label discloses or
suggests this limitation, albeit indirectly.
We are not persuaded by Petitioner’s contentions, however, in relation to
treating a tumor that “does not respond, or responds poorly, to treatment with an
anti-ErbB antibody,” also required in the independent claims. In relation to this
limitation, Petitioner points to the same “ORR” disclosure in the HERCEPTIN®
Label that Petitioner cites regarding the “identifying” step. Pet. 10–11, 12 (citing
Ex. 1008, ¶ spanning 1st and 2d cols.). We agree with Patent Owner that
“[i]dentifying patients that do not respond (or respond poorly) to a particular type
of therapy does not suggest whether or how to treat these patients.” Prelim. Resp.
6.
Petitioner acknowledges that the Label does not describe conjugates
containing the HERCEPTIN® antibody. Pet. 19. Petitioner relies on Chari 1992
in combination with the HERCEPTIN® Label for suggesting the recited conjugate.
Id. at 19–20. As noted above, Petitioner points to Table 1 in the HERCEPTIN®
Label as disclosing that, compared to patients receiving chemotherapy only,
patients receiving chemotherapy plus HERCEPTIN® “experienced a significantly
IPR2014-00842
Patent 7,575,748 B1

14
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. at 20 (citing
Ex. 1008, 1, 1st col., Table 1).
Based on teachings in both references, according to Petitioner, an ordinary
artisan would have been motivated to use a HERCEPTIN® conjugate (as
suggested by Chari 1992 and the Label) to treat “tumors that overexpress HER2
and do not respond to HERCEPTIN® treatment” because it was known that:
(1) humanized antibodies were preferred over murine counterparts; (2) the
huMAB4D5-8 antibody (HERCEPTIN® ) selectively bound HER2 with high affinity;
(3) clinical studies, as described in the HERCEPTIN® Label, indicated that treatment
with HERCEPTIN® alone was not effective in the majority of HER2 overexpressing
tumors; and (4) conjugation of DM1 to huMAB4D5-8 allowed for selective delivery
of DM1 toxin to cells, thereby reducing systemic toxicity. Pet. 22–23 (citing Exs.
1012, 1008).
In support, Petitioner contends that, “as described in the Declaration of Dr.
Rosenblum, HERCEPTIN® Label 1998 provides a clear motivation for treating
tumors that do not respond, or respond poorly, to treatment with an anti-ErbB
antibody because of the low-responsive rate to HERCEPTIN® treatment alone.”
Pet. 18, 24 (citing Ex. 1016 ¶¶ 12–18). In addition, Petitioner contends that “the
relatively low efficacy obtained with HERCEPTIN® alone (i.e., 14% ORR)
mandates the need for a better treatment, including HERCEPTIN® in combination
with a potent cytotoxic agent (maytansinoid DM1) with an established mechanism
of action and good pharmacokinetic behavior as suggested by Chari 1992.” Pet.
24–25.
IPR2014-00842
Patent 7,575,748 B1

15
Petitioner further contends that an ordinary artisan would have had a
reasonable expectation of success in treating “HER2 overexpressing, HERCEPTIN®-
resistant” tumors with a HERCEPTIN® conjugate because it was known that:
(1) huMAB4D5-8 (HERCEPTIN®) was “more effective in treating breast cancer
when used in combination with the microtubule targeting drug paclitaxel,” as
compared to chemotherapy alone, as described in the HERCEPTIN® Label;
(2) conjugates of Chari 1992 would bind the same cells as huMAB4D5-8 to deliver
the DM1 toxin; (3) an immunoconjugate containing a “humanized” antibody was
less immunogenic than one with a mouse antibody; and (4) the effect of the
conjugate in Chari 1992 was dose-dependent. Id. at 25–26 (citing Exs. 1008,
1012).
Even if we assume both sets of Petitioner’s contentions (1)–(4), as discussed
above, are accurate, we conclude that Petitioner does not establish a reasonable
likelihood that it would prevail in showing that an ordinary artisan would have had
reason to use the recited conjugate, i.e., one containing the HERCEPTIN®
antibody, to treat ErbB2 receptor-overexpressing tumors in patients (or mammals) that
failed to exhibit a complete or partial response rate when treated with the antibody in
the non-conjugate form. We are not persuaded that Chari 1992 or the
HERCEPTIN® Label alone, or when read together, provided a reason to do so.
We agree with Petitioner that the HERCEPTIN® Label teaches or suggests
that certain patients failed to respond to HERCEPTIN®, and that HERCEPTIN®
increased the effectiveness of chemotherapy, such as paclitaxel, in patients who
responded to HERCEPTIN® and chemotherapy. We are not persuaded, however, that
the Petition has advanced sufficient reasoning, based on a rational underpinning, to
IPR2014-00842
Patent 7,575,748 B1

16
support its contention that the Label (alone or in combination with Chari 1992)
discloses or suggests that patients unresponsive to HERCEPTIN® would respond to
the HERCEPTIN® antibody, if administered with chemotherapy.
We do not agree with Petitioner that the HERCEPTIN® Label teaches or
suggests that “the efficacy of huMAB4D5-8 for treatment of breast cancer is
improved in combination with paclitaxel.” Pet. 23 (citing Ex. 1008, 1, 1st col.)
Rather, the Label indicates that efficacy of paclitaxel is improved in combination with
huMAB4D5-8 in patients who responded to huMAB4D5-8. Ex. 1008, 1, 1st col. In
addition, while we can see from the discussion of the second “single agent” study that
only 14% of patients responded to HERCEPTIN® when given alone, the Label does
not disclose or suggest whether the other 86% patients (who did not respond to
antibody alone) would have responded to HERCEPTIN® if also given chemotherapy,
i.e., above and beyond a response to the chemotherapy alone.
We are persuaded by Patent Owner’s position that that neither the Petition nor
Dr. Rosenblum’s Declaration adequately explains how, or provides sufficient
evidence indicating that, the teaching in HERCEPTIN® Label that certain patients
failed to respond to HERCEPTIN® would have motivated an ordinary artisan to
treat such patients using a HERCEPTIN® (huMab 4D5-8) conjugate. Prelim.
Resp. 9; see, e.g., 1016 ¶ 12 (stating, without support, that “this provides
motivation to treat this patient population with a modified HERCEPTIN® product,
such as HERCEPTIN®-DMI conjugate”), ¶ 15 (stating, without support, that it
would have been “common practice” to subject patients “first to the available
HERCEPTIN® treatment, and starting the HERCEPTIN®-DMI conjugate
treatment in those patients who are resistant to the HERCEPTIN® treatment”),
IPR2014-00842
Patent 7,575,748 B1

17
¶¶ 16–18 (stating, without support, that it would have been obvious to treat such
patients with a HERCEPTIN®-DMI conjugate—explaining only why a
HERCEPTIN®-DMI conjugate would have been obvious over the corresponding
mouse antibody conjugate disclosed in Chari 1992 in view of the HERCEPTIN®
Label, but not why one would have thought such a conjugate might be useful to
treat mammals/patients resistant to the antibody); see also Pet. 18–26 (citing
same).
We also are persuaded by evidence offered by Patent Owner indicating that
ordinary artisans would have thought it likely that HERCEPTIN® resistance
occurred in patients because obstacles prevented the antibody from binding its
ErbB2 receptor target, or due to other events that prevented HERCEPTIN® from
working as expected. Prelim. Resp. 11 (citing Ex. 2001, Abstract). The Petition
and Dr. Rosenblum do not explain why an ordinary person skilled in the art would
have thought HERCEPTIN® would be a good choice, rather than “a particularly
poor choice for an immunoconjugate to treat such patients.” Id. at 12.
Based on the record before us, we are not persuaded that Petitioner has
established a reasonable likelihood that an ordinary artisan, reading Chari 1992 and
the HERCEPTIN® Label, would have been motivated to treat a tumor
“characterized by overexpression of an ErbB2 receptor and that does not respond,
or responds poorly, [e.g., does not “show statistically significant improvement in
response to”] to treatment with an anti-ErbB antibody” using the recited huMab
4D5-8 conjugate, or would have had a reasonable expectation of success in doing
so. Ex. 1001, 16:56–63 (defining “does not respond, or responds poorly”). Thus,
we are not persuaded that there is a reasonable likelihood that Petitioner would
IPR2014-00842
Patent 7,575,748 B1

18
prevail in relation to the ground that claims 1–20 and 25–27 would have been
obvious over Chari 1992 and the HERCEPTIN® Label.
C. Obviousness over Chari 1992, HERCEPTIN® Label, and Baselga 1999
Petitioner contends that Baselga 1999 (Ex. 1032) provides further
motivation for a method comprising “identifying” a tumor “characterized by
overexpression of an ErbB2 receptor and as being a tumor that does not respond, or
responds poorly, to treatment with an anti-ErbB antibody.” Pet. 27. In support,
Petitioner notes that Baselga 1999 states that “while not achieving a complete or
partial response, 37% of patients in this trial achieved minimal responses or stable
disease.” Id. (quoting Ex. 1032, 82, 1st col.). Petitioner also contends that Baselga
1999 teaches that its results “support the concept that trastuzumab, given alone or
in combination with chemotherapy, will be a useful tool for the treatment of
patients with HER2-over-expressing breast cancer.” Id. at 28 (quoting Ex. 1032,
82, 2d col.).
Petitioner relies on Dr. Rosenblum’s Declaration to support its assertion that
because Baselga 1999 “identifies” relevant tumors (by teaching that trastuzumab
did not work on some patients), an ordinary artisan would have been motivated “to
treat such patient population with trastuzumab in combination with
chemotherapy.” Id. at 28 (citing Ex. 1016, ¶¶ 13–14).
As discussed above regarding the HERCEPTIN® Label, “identifying”
patients that do not respond, or respond poorly, to an anti-ErbB antibody does not
teach or suggest how to treat such patients, much less teach or suggest treating
such patients with an anti-ErbB antibody conjugate. Patent Owner does not point us
to where Baselga 1999 suggests treating patients who do not respond well to
IPR2014-00842
Patent 7,575,748 B1

19
trastuzumab with a conjugate comprising an anti-ErbB antibody. Pet. 27–29. Dr.
Rosenblum’s conclusory statements to the contrary do not persuade us otherwise. Ex.
1016 ¶¶ 13–14.
Thus, we are not persuaded that there is a reasonable likelihood that
Petitioner would prevail in relation to ground that claims 1–20 and 25–27 would
have been obvious over Chari 1992, the HERCEPTIN® Label, and Baselga 1999.
D. Obviousness over Chari 1992, HERCEPTIN® Label, and Other Cited
References
Petitioner contends that Morgan 1990 (Ex. 1021) provided reason to use
SMCC to link huMAB4D5-8 antibody to maytansinoid DM1. Pet. 29–30.
Petitioner also contends that Hudziak 1998 (Ex. 1017) and Rosenblum 1999 (Ex.
1018) provided reasons to modify “the TA.l-maytansinoid conjugate with
huMAB4D5-8” to form the recited conjugate “for [the] treatment of breast cancer.”
Id. at 32–34. In addition, Petitioner contends that Baselga 1998 (Ex. 1019) and
Pegram 1999 (Ex. 1020) provided reasons “for modifying Chari 1992’s TA.l-
maytansinoid conjugate into a HERCEPTIN®-maytansinoid conjugate.” Id. at 35–
38.
Petitioner cites the above-mentioned references to show that an ordinary
artisan would have been motivated to make the recited conjugate and use it in a
method for treating tumors that overexpress an ErbB2 receptor generally.
Petitioner does not indicate, however, where or how those references cure the
deficiencies of Chari 1992, HERCEPTIN® Label and/or Baselga 1999, i.e., none
teach or suggest treating patients who do not respond well to trastuzumab with a
conjugate comprising an anti-ErbB antibody, as discussed above.
IPR2014-00842
Patent 7,575,748 B1

20
Thus, we are not persuaded that there is a reasonable likelihood that
Petitioner would prevail in relation to ground that claims 1–20 and 25–27 would
have been obvious over Chari 1992, the HERCEPTIN® Label, and Morgan 1990
alone, or Morgan 1990, Hudziak 1998 and/or Rosenblum 1999, alone or further in
view of Baselga 1998 and/or Pegram 1999.
E. Obviousness over Cohen 1999, HERCEPTIN® Label, and Morgan 1990
Petitioner argues that Cohen 1999 teaches or suggests the recited conjugate
containing huMab4D5-8 linked to maytansinoid through the linker SMCC. Id. at 47–
48, 51–53. Petitioner relies on Morgan 1990 (Ex. 1021) as providing an additional
reason to use SMCC to link huMAB4D5-8 antibody to maytansinoid DM1. Id. at
49–50.
Again, Petitioner relies on the same “ORR” disclosure in the HERCEPTIN®
Label, discussed above, to support its contention that the Label discloses the
“identifying” step in the challenged independent claims, and “provides a
motivation for treating tumors that do not respond, or respond poorly, to treatment
with an anti-ErbB antibody.” Pet. 43, 48–49, 51 (citing Ex. 1008, ¶ spanning 1st
and 2d cols.; Ex. 1016 ¶ 12). As with other grounds, the Petition and Dr.
Rosenblum do not explain adequately how, nor provide sufficient evidence indicating
that, the teaching in HERCEPTIN® Label that certain patients failed to respond to
HERCEPTIN® would have motivated an ordinary artisan to treat such patients
using a HERCEPTIN® (huMab 4D5-8) conjugate.
Thus, we are not persuaded that there is a reasonable likelihood that
Petitioner would prevail in relation to ground that claims 1–20 and 25–27 would
have been obvious over Cohen 1999, the HERCEPTIN® Label, and Morgan 1990.
IPR2014-00842
Patent 7,575,748 B1

21
III. CONCLUSION
For the foregoing reasons, we are not persuaded that there is a reasonable
likelihood that Petitioner would prevail with respect to at least one of claims 1–20
and 25–27 of the ’748 patent based on the grounds of unpatentability advanced in
the Petition.
IV. ORDER
It is
ORDERED that the Petition is denied as to all challenged claims and no trial
is instituted.

IPR2014-00842
Patent 7,575,748 B1

22
For PETITIONER:

Ping Wang
PingWang@andrewskurth.com
fayelazo@andrewskurth.com

Gregory Porter
GregPorter@andrewskurth.com

For PATENT OWNER:

Eldora Ellison
eellison-PTAB@skgf.com

Matthew Kreeger
mkreeger@mofo.com

Catherine Polizzi
cpolizzi@mofo.com

Eric Steffe
esteffe-PTAB@skgf.com