Immunomedics, Inc.

Patent Trials and Appeals Board

Apr 20, 2021

2020004291 (P.T.A.B. Apr. 20, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
15/429,671 02/10/2017 Chien-Hsing Chang IMM366US1 4619
63322 7590 04/20/2021
IMMUNOMEDICS, INC. c/o Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
EXAMINER
MOSELEY II, NELSON B
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
04/20/2021 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
IPDocketing@gilead.com
tbrener@immunomedics.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte CHIEN-HSING CHANG and
DAVID M. GOLDENBERG1
________________

Appeal 2020-004291
Application 15/429,671
Technology Center 1600
________________

Before ERIC B. GRIMES, JOHN G. NEW, and RACHEL H. TOWNSEND,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the term “Appellant” to refer to the “applicant” as defined in
37 C.F.R. § 1.142. Appellant identifies Immunomedics, Inc., as the real
party-in-interest. App. Br. 1.
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SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1, 4, 9, 12–14, 16, 17, 19–24, and 26–
32 as unpatentable under 35 U.S.C. § 103 as being obvious over the
combination of Govindan et al. (US 2014/0227180 A1, August 14, 2014)
(“Govindan”) and R. Yamazaki et al., Novel Acrylonitrile Derivatives, YHO-
13177 and YHO-13351, Reverse BCRP/ABCG2-Mediated Drug Resistance
In Vitro and In Vivo, 10(7) MOL. CANCER THER. 1252–63 (2011)
(“Yamazaki”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to therapeutic antibody-drug
conjugates (“ADCs”) comprising a drug, preferably SN-38, attached to an
anticancer antibody or antigen-binding antibody fragment, preferably one
which binds to Trop-2, and in which the therapy is used to treat a Trop-2
positive cancer. Spec. Abstr.

REPRESENTATIVE CLAIM
Independent claim 1 is the sole independent claim and recites:
1. A method of treating a Trop-2 positive cancer comprising:

a. administering to a human patient with a Trop-2
positive cancer an anti-Trop-2 antibody-drug
conjugate (ADC) comprising SN-38 conjugated to
an anti-Trop-2 hRS7 antibody or antigen-binding
fragment thereof; and
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b. administering to the patient an ABCG2 inhibitor
selected from the group consisting of fumitremorgin
C, Kol43, GF120918 and YHO-13351;

wherein the patient has relapsed from or failed to respond to
therapy with irinotecan or SN-38, prior to administration of the
ADC and ABCG2 inhibitor.

App. Br. Claims App’x A at 2.

ISSUES AND ANALYSES
We adopt the Examiner’s findings, reasoning, and conclusion that the
claims on appeal are prima facie obvious over the combined cited prior art.
We address the arguments raised by Appellant below.

1. Rejection of claim 1 under 35 U.S.C. § 103

Issue 1

Appellant argues that the Examiner erred because a person of ordinary
skill in the art could not have had a reasonable expectation that combination
of anti-Trop-2-SN-38 antibody-drug conjugate (“ADC”) with an ABCG2
inhibitor would show superior efficacy compared to ADC alone and/or
ABCG2 inhibitor alone, when the ABCG2 inhibitor had no significant effect
on sensitivity to unconjugated SN-38. App. Br. 6.

Analysis
The Examiner finds that Govindan teaches:
[T]herapeutic immunoconjugates with improved ability to target
various cancer cells, infectious disease organisms and/or for
treating autoimmune diseases, which conjugates contain an
antibody moiety and a drug moiety selected from the
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camptothecin group of drugs. The antibody and drug moieties are
linked via an intracellularly cleavable linkage that increases
therapeutic efficacy. Most preferably, the camptothecin is SN-38
and the linker joining the antibody moiety and the drug moiety is
CL2A…. In particular embodiments, the immunoconjugates
may be administered at specific dosages and/or schedules of
administration that provide for optimal efficacy and minimal
toxicity. The optimized dosages and schedules of administration
of SN-38-conjugated antibodies for human therapeutic use
disclosed herein show unexpected superior efficacy that could
not have been predicted from animal model studies, allowing
effective treatment of cancers that are resistant to standard anti-
cancer therapies, including the parental compound, irinotecan
(CPT-11).

Non-Final Act. 3–42 (quoting Govindan ¶ 3 (emphasis added)). The
Examiner also finds that Govindan teaches that “SN-38 is attached to the
antibody or antibody fragment using a CL2A linker, with 1–12, more
preferably 6 or less, most preferably 1–5 SN-38 moieties per antibody or
antibody fragment.” Id. at 4 (quoting Govindan Abstr.).
The Examiner also finds that Govindan teaches that antibodies for use
in the invention may bind to any disease-associated antigen, including EGP-
1 (Trop-2), and further expressly teaches the anti-Trop-2 antibody, hRS7.
Non-Final Act. 4 (citing Govindan ¶¶ 14–15). The Examiner finds that
Govindan teaches:

2 The Examiner has maintained the same rejection through four Non-Final
Rejections (filed July 26, 2017, March 26, 2018, August 27, 2018, and
January 18, 2019) and four Final Office Actions (filed November 8, 2017,
June 27, 2018, October 26, 2018, and April 8, 2019). We cite to the
original Non-Final Office Action of July 26, 2017, in which the Examiner
details the basis of the rejection.
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In particularly preferred embodiments, the immunoconjugates
and dosing schedules may be efficacious in patients resistant to
standard therapies. For example, an hMN-14-SN-38
immunoconjugate may be administered to a patient who has not
responded to prior therapy with irinotecan, the parent agent of
SN-38. Surprisingly, the irinotecan-resistant patient may show a
partial response to hMN-14-SN-38. The ability of the
immunoconjugate to specifically target the tumor tissue may
overcome tumor resistance by improved targeting and enhanced
delivery of the therapeutic agent.… Other antibody-SN-38
immunoconjugates may show similar improved efficacy and/or
decreased toxicity, compared to alternative standard therapeutic
treatments, and combinations of different SN-38
immunoconjugates, or SN-38-antibody conjugates in
combination with an antibody conjugated to a radionuclide, toxin
or other drug, may provide even more improved efficacy and/or
reduced toxicity. A specific preferred subject may be a metastatic
colon cancer patient, a triple-negative breast cancer patient, a
HER+, ER+, progesterone+ breast cancer patient, a metastatic
non-small-cell lung cancer (NSCLC) patient, a metastatic
pancreatic cancer patient, a metastatic renal cell carcinoma
patient, a metastatic gastric cancer patient, a metastatic prostate
cancer patient, or a metastatic small-cell lung cancer patient.

Id. at 4–5 (quoting Govindan ¶ 27).
The Examiner also finds that Govindan teaches an hRS7-CL2A-SN-
38 immunoconjugate that, “[g]iven its tumor-targeting and safety profile, …
may provide an improvement in the management of solid tumors responsive
to irinotecan.” Non-Final Act. 6 (quoting Govindan ¶ 256). Specifically,
Govindan teaches that:
Given the RS7 antibody’s broad reactivity with epithelial cancers
and its internalization ability, we hypothesized that an RS7-SN-
38 conjugate could benefit not only from the sustained release of
the drug, but also from direct intracellular delivery. Therefore,
we prepared and tested the efficacy of SN-38 conjugates using a
humanized version of the murine RS7 antibody (hRS7).…
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Herein, we show the efficacy of the hRS7-SN-38 conjugate in
several epithelial cancer cell lines implanted in nude mice at
nontoxic dosages, with other studies revealing that substantially
higher doses could be tolerated. More importantly, toxicity
studies in monkeys that also express TROP-2 in similar tissues
as humans showed that hRS7-CL2A-SN-38 was tolerated at
appreciably higher amounts than the therapeutically effective
dose in mice, providing evidence that this conjugate is a
promising agent for treating patients with a wide range of
epithelial cancers.

Id. (quoting Govindan ¶ 261).
Summarizing, the Examiner concludes that a person of ordinary skill
in the art would have been motivated to apply these teachings of Govindan,
and with a reasonable expectation of success, to develop a method of
treating a Trop-2 positive cancer, including a Trop-2 positive cancer that has
developed resistance to SN-38 or irinotecan, as recited in claim 1. Non-
Final Act. 6–7.
The Examiner acknowledges that Govindan neither teaches nor
suggests co-administration of an ABCG2 inhibitor, as recited in claim 1.
Non-Final Act. 7. However, the Examiner finds that Yamazaki teaches that
it was well known in the art that:
Drug resistance is a major problem in cancer chemotherapy. The
best-characterized mechanism of drug resistance is mediated by
P-glycoprotein/ABCB1, a member of the ATP-binding cassette
(ABC) transporter superfamily, which pumps out a variety of
structurally unrelated anticancer drugs such as the
anthracyclines, vinca alkaloids, and taxanes from cells in an
energy-dependent manner, resulting in a decrease in the
intracellular accumulation of the drugs and resistance.… Breast
cancer resistance protein (BCRP/ABCG2) is another member of
ABC transporters that mediates drug resistance. BCRP has been
found to efflux camptothecins, including 7-ethyl-10-
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hydroxycamptothecin (SN-38, an active metabolite of
irinotecan) and topotecan, and to confer resistance to this class
of drugs. BCRP has also been shown to confer resistance to
mitoxantrone, methotrexate, flavopiridol, gefitinib, and imatinib
by reducing the intracellular accumulation of these drugs.

Id. at 7–8 (quoting Yamazaki 1252 (internal citations omitted)).
The Examiner finds that Yamazaki also teaches that expression of
BCRP/ABCG2 may be responsible for clinical drug resistance, because
there is an association between BCRP expression and poor responses to
chemotherapy, and that cancer chemotherapy may be improved by inhibiting
BCRP/ABCG2-mediated drug export. Non-Final Act. 8 (citing Yamazaki
1253). The Examiner finds that Yamazaki teaches that one such means of
inhibiting BCRP/ABCG2-mediated drug export may be through the use of
small-molecule BCRP inhibitors, such as YHO-13351, the water-soluble
prodrug of the acrylonitrile derivative YHO-13177. Id. (citing Yamazaki
1253). The Examiner finds that Yamazaki demonstrates that YHO-13177
has a reversing effect on BCRP/ABCG2-mediated drug resistance,
specifically:
YHO-13177 reversed resistance to SN-38, mitoxantrone, and
topotecan, which are substrates of BCRP, in the BCRP-
transduced cells, HCT116/BCRP, and the cells that acquired
BCRP-mediated resistance to SN-38, A549/SN4, but had little or
no effect in the parental cells.… In addition, YHO-13177
enhanced the cytotoxicity of SN-38 in NCI-H460, NCI-H23,
RPMI-8226, and AsPC-1 cells that intrinsically expressed
BCRP.

Id. (quoting Yamazaki 1260 (internal citations omitted)).
The Examiner notes that, due to the low solubility of YHO-13177 in
water, Yamazaki employed YHO-13351, the water-soluble prodrug of
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YHO-13177, for in vivo studies, observing that YHO-13351 was rapidly and
efficiently converted to YHO-13177. Non-Final Act. 8–9 (citing Yamazaki
1260). The Examiner finds that Yamazaki further teaches that “a
concentration of YHO-13177 sufficient to reverse BCRP-mediated drug
resistance is achievable via the administration of YHO-13351 in vivo. In
fact, YHO-13351 significantly increased the survival time of irinotecan [a
camptothecin]-treated mice inoculated with P388/BCRP cells.” Id. at 9
(quoting Yamazaki 1261).
The Examiner therefore concludes that it would have been obvious to
a person of ordinary skill in the art, with a reasonable expectation of success,
to combine the teachings of Govindan with the teachings of Yamazaki to
develop a method of treating a Trop-2-positive cancer (including a Trop-2-
positive cancer that has developed resistance to SN-38 or irinotecan), as
recited in claim 1. Non-Final Act. 9. The Examiner observes that Govindan
teaches that ADCs comprising an anti-Trop-2 antibody and SN-38 can
overcome resistance to SN-38, and that Yamazaki teaches that YHO-13177
is a small molecule inhibitor of ABCG2 that suppresses the ABCG2-
mediated energy-dependent efflux of SN-38, thereby reversing ABCG2-
mediated SN-38 resistance. Id. at 10. The Examiner reasons that, by
modifying the invention of Govindan to include co-administration of an
ABCG2 inhibitor, such as YHO-13177 or YHO-13351, a skilled artisan
would have reasonably expected to observe an increase in the intracellular
concentration of the anti-Trop-2 antibody/SN-38 ADC in Trop-2- expressing
cells. Id. The Examiner concludes that a person of ordinary skill in the art
would have been motivated to combine the teachings of the two references
to achieve an improved therapeutic benefit to patients having Trop-2-
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expressing tumors, and particularly in such patients in which the tumor had
been previously characterized as resistant to SN-38. Id.
Appellant argues that a person of ordinary skill in the art, considering
the likely effect of ABCG2 inhibitors on cancer cell therapy, would
reasonably expect that, to be efficacious, the ABCG2 inhibitor should
improve the efficacy of unconjugated SN-38 on cancer therapy. App. Br. 5.
Appellant points to paragraph [05] of the Specification, which discloses that:
“Typically, the drug conjugate is released intracellularly after internalization
of the ADC, although in some cases extracellular release from the cell-
bound ADC may also occur.” Id. Appellant reasons that, although the ADC
may assist in delivery of a cancer therapeutic drug to a tumor cell, the
effectiveness of the ADC is still related to the presence of unconjugated SN-
38 in the cell, not to the ADC per se. Id. Therefore, Appellant contends, a
person of ordinary skill would reason that, if the ABCG2 inhibitor does not
potentiate the efficacy of unconjugated SN-38, the same artisan would have
no reasonable expectation that the same ABCG2 inhibitor would improve
the efficacy of ADC-conjugated SN-38. Id.
Appellant next points to Example 18 of the Specification, which,
Appellant argues, demonstrates that the combination of ABCG2 inhibitor
with unconjugated SN-38 resulted in no significant increase in survival in
mice injected with an SN-38 resistant tumor cell line. App. Br. 5 (citing
Spec. ¶ 458, Fig. 38B). Appellant contends that, unexpectedly, and despite
the lack of a significant effect of ABCG2 inhibitor combined with
unconjugated SN-38, the combination of ABCG2 inhibitor and SN-38-
conjugated ADC resulted in a statistically significant 62% improvement in
survival. Id. Appellant argues that this evidence of unexpected superior
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technical effect of the claimed combination is sufficient to overcome the
Examiner’s prima facie case of obviousness. Id.
Appellant rejects the Examiner’s contrary finding that, because
Govindan discloses that SN-38 conjugated antibodies show unexpected
superior efficacy compared with SN-38 alone, including in tumors that are
resistant to the irinotecan parent of SN-38, a skilled artisan would have
expected that the combination of SN-38-conjugated ADC with ABCG2
inhibitor could have been reasonably expected to show efficacy, even if the
combination of unconjugated SN-38 with ABCG2 did not. App. Br. 5.
Appellant contends that the issue on appeal is whether a person of ordinary
skill in the art could have reasonably predicted that the combination of anti-
Trop-2-SN-38 ADC with an ABCG2 inhibitor would show superior efficacy
compared to ADC alone and/or ABCG2 inhibitor alone, when the ABCG2
inhibitor had no significant effect on sensitivity to unconjugated SN-38. Id.
at 6. Appellant asserts that, because ABCG2 transports only unconjugated
SN-38, and not antibody-SN-38 ADC, there would have been no way to
predict that an ABCG2 inhibitor would increase sensitivity to antibody-SN-
38 ADC, but not unconjugated SN-38. Id.
We are not persuaded by Appellant’s arguments because we fail to see
the logic of it. Govindan teaches that it was well-known in the art that
immunoconjugates have improved ability to target various cancer cells.
Govindan ¶ 3. More specifically, conjugation of a chemotherapeutic agent
to a monoclonal antibody (“Mab”) is advantageous because:
(a) the chemotherapeutic drug itself is structurally well defined;
(b) the chemotherapeutic drug is linked to the MAb protein using
very well defined conjugation chemistries, often at specific sites
remote from the MAbs antigen binding regions; (c) MAb-
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chemotherapeutic drug conjugates can be made more
reproducibly than chemical conjugates involving MAbs and
bacterial or plant toxins, and as such are more amenable to
commercial development and regulatory approval; and (d) the
MAb-chemotherapeutic drug conjugates are orders of magnitude
less toxic systemically than radionuclide MAb conjugates.

Id. at ¶ 5. Govindan also teaches that “[t]he antibody and drug moieties are
linked via an intracellularly cleavable linkage that increases therapeutic
efficacy.” Id. at ¶ 3. Govindan also teaches that “[t]he conjugates of the
instant invention possess greater efficacy than unconjugated or ‘naked’
antibodies.” Id. ¶ 9.
Govindan also teaches that: “[g]iven the RS7 antibody’s broad
reactivity with epithelial cancers and its internalization ability, we
hypothesized that an RS7-SN-38 conjugate could benefit not only from the
sustained release of the drug, but also from direct intracellular delivery.”
Govindan at ¶ 261 (emphasis added). Govindan’s results demonstrate that
“the efficacy of the hRS7-SN-38 conjugate in several epithelial cancer cell
lines implanted in nude mice at nontoxic dosages, with other studies
revealing that substantially higher doses could be tolerated.” Id.
Specifically Govindan teaches that:
In vitro cytotoxicity studies demonstrated that hRS7-CL2A-SN-
38 had IC50 values in the nmol/L range against several different
solid tumor lines (Table 8). The IC50 with free SN-38 was lower
than the conjugate in all cell lines. Although there was no
correlation between TROP-2 expression and sensitivity to hRS7-
CL2A-SN-38, the IC50 ratio of the ADC versus free SN-38 was
lower in the higher TROP-2-expressing cells, most likely
reflecting the enhanced ability to internalize the drug when more
antigen is present.

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Id. at ¶ 280 (emphases added). Summarizing, Govindan teaches: “With our
ADC, this disparity (i.e., ratio of potency with free vs. conjugated SN-38)
decreased as the TROP-2 expression levels increased in the tumor cells,
suggesting an advantage to targeted delivery of the drug.” Id. at ¶ 301
(emphasis added).
In short, Govindan teaches that its immunoconjugated SN-38 is more
effective, and at lower doses, than free SN-38 because it specifically targets
cells expressing TROP-2, and because of its enhanced ability to internalize
the drug when the TROP-2 antigen is present.
The Mab-SN-38 conjugate of Govindan is cleaved intracellularly,
which increases the efficacy of the therapeutic agent. See Govindan ¶ 3.
Yamazaki teaches that the ABCG2 inhibitor YHO-131773 potentiates the
cytotoxicity of SN-38 in tumor cells expressing the BCRP/ABCG2 protein.
Yamazaki Abstr, 1252. Yamazaki explains that, in such tumor cells where
the ABCG2 is not inhibited, SN-38 is effluxed from the cells in an energy-
dependent manner, which confers a resistance upon the cells. Id.
Presumably the ABCG2 inhibitor YHO-13177 inhibits the efflux of SN-38,
and thus the intracellular concentration of this potent topoisomerase-1
inhibitor is maintained intracellularly where it can be effective against the
tumor cell. See Govindan ¶ 299.

3 Yamazaki also teaches that YHO-13351, recited in claim 1, is known in the
art to be the water-soluble prodrug of YHO-13177. See, e.g., Yamazaki,
Abstr., 1253, 1260 (“In mice, YHO-13351 was rapidly converted into
YHO-13177, and YHO-13351 itself was undetectable in plasma after i.v.
and oral administration”).
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Consequently, we see no logic in Appellant’s argument that a skilled
artisan would “would reasonably expect that, to be efficacious, the ABCG2
inhibitor should improve the efficacy of unconjugated SN-38 on cancer
therapy,” because it is the increased internalization of the Mab-SN-38
conjugate compared with free SN-38 that makes such administration at once
more cytotoxic than administration of free SN-38, though not removing the
possibility of its expulsion from the cell by ABCG2, if the ABCG2 were not
inhibited. We agree with the Examiner that a person of ordinary skill in the
art, comprehending these teachings of the prior art, would realize that the
targeted cytotoxic advantages of the SN-38 immunoconjugate need not be
lost if the ABCG2 pump can simultaneously be inhibited. And this is what
Yamazaki teaches: that the sensitivity of the cell to intracellular SN-38 is
increased in cells expressing ABCG2 when it is co-administered with YHO-
13177, an effective ABCG2 inhibitor. We consequently agree with the
Examiner that a person of ordinary skill in the art would have been
motivated to combine the references to achieve a more effective therapeutic
treatment by suppressing the efflux of SN-38 in cancer cells expressing
ABCG2 and thereby increasing the cytotoxicity of the agent.

Issue 2
Appellant next argues that the field of therapy with ABCG2 inhibitors
in cancer patients was sufficiently unpredictable that the person of ordinary
skill could not have reasonably expected the combination therapy to show
such a significant increase in efficacy. App. Br. 6.

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Analysis
In support of this argument, Appellant first cites D.L. Nielsen et al.,
Implications of ABCG2 Expression on Irinotecan Treatment of Colorectal
Cancer Patients: A Review, 18 INT. J. MOL. SCI. 1926–41 (2017)
(“Nielsen”). According to Appellant, Nielsen teaches that “[f]ew studies
have evaluated the association between ABCG2 gene or protein and
prognosis in CRC patients. Discordant results have been reported.” App. Br.
6 (quoting Nielsen Abstr.). Appellant notes that Nielsen teaches that “[o]nly
one large study evaluated the ABCG2 protein expression and efficacy of
irinotecan4 in mCRC (CAIRO study, n = 566). This study failed to
demonstrate any correlation between ABCG2 protein expression in the
primary tumor and response to irinotecan-based treatment.” Id. Appellant
argues that Nielsen concludes that “[t]he biological role of ABCG2 in
predicting clinical irinotecan sensitivity/resistance in CRC is uncertain,” and
that “[s]everal studies have shown a decreased expression of ABCG2 in
tumor tissues compared to normal colon tissues.” Id. (quoting Nielsen
Abstr., 1935) (emphasis omitted).
Appellant summarizes Nielsen’s teaching with respect to the field of
ABC transport inhibitors in cancer therapy as stating that “[i]n general,
however, studies on inhibitors of ABC transporters have been
disappointing,” and that “[t]he potential increase in irinotecan toxicity in
normal cells expressing ABCG2 efflux pumps ... will always be of great
concern.” App. Br. 6 (quoting Nielsen 1936). Appellant also points to
Nielsen’s additional summarization that “[b]ased on this review, we

4 SN-38 is the active metabolite of irinotecan. See Yamazaki Abstr.
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conclude that the biological role of ABCG2 in clinical drug resistance is still
unknown….” Id. Appellant therefore argues that Nielsen teaches that, as of
2017 (after the filing date of Appellant’s application), the state of ABCG2
therapy, including combination therapy with camptothecins such as SN-38,
was so unpredictable that the role of ABCG2 in cancer drug resistance was
still unknown. Id. at 6–7.
Appellant next points to the teachings of J.W. Ricci et al., ABCG2
Inhibitors: Will They Find Clinical Relevance? 4 J. DEVELOP. DRUGS 138–
43 (2015) (“Ricci”). According to Appellant, Ricci states that:
Despite many publications reporting the discovery of ABCG2
inhibitors since their discovery, only a few have reported
successes in reversing MDR in animal models, and fewer still
have been investigated in human trials with none moving past
phase II trials and no observed clinical benefit. Thus, the future
of ABCG2 inhibitors and their efficacy in humans remains in
question.

App. Br. 7 (quoting Ricci 1–2). Appellant notes that Ricci, in discussing the
results of the sole phase II study reported as of 2015, teaches that the
combination of lapatinib with topotecan (TPT), “did not show clinical
benefit in patients and was canceled due to substantial hematologic side
effects.” Id. (quoting Ricci 140). Appellant notes that Ricci further teaches
that “it was concluded that the inhibition of ABCG2, ABCB1 and erbB
signaling was insufficient to reverse TPT resistance….” Id.
Appellant therefore argues that the combined teachings of Nielsen and
Ricci demonstrate the lack of predictability of combining ABCG2 inhibitors
with ADCs, such as the claimed anti-Trop-2 hRS7-SN-38 ADC. App. Br. 7.
Appellant contends that this alleged lack of predictability is demonstrated by
several lines of evidence. Id.
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First, argues Appellant, although the ABCG2 inhibitor YHO-13351
increased the sensitivity of SN-38 resistant cell lines to SN-38 in vitro by
over 90%, the same combination failed to provide a statistically significant
improvement in survival in vivo, even though the combination of YHO-
13351 with hRS7-SN-38 ADC resulted in a statistically significant 64%
improvement in survival. App. Br. 7. Appellant asserts that these
inconsistent results demonstrate the unpredictability of combining ABCG2
inhibitors with unconjugated SN-38 or SN-38-conjugated ADC. Id.
Second, Appellant argues that Nielsen and Ricci together further
support the unpredictable effects of ABCG2 inhibitors used in combination
with SN-38 or its parent compound irinotecan. App. Br. 7–8. Appellant
contends that the evidence of unexpected superior results with the
combination of ABCG2 inhibitor and SN-38-conjugated ADC, along with
the evidence of unpredictability of the combination therapy and skepticism
of experts in the field is sufficient to overcome the Examiner’s prima facie
case of obviousness. Id. at 8.
We disagree. Neither Nielsen nor Ricci teach or suggest anything
relating to antibody-drug conjugates. Nielsen surveys studies investigating
the relationship between cellular expression of ABCG2 and prognoses for
cancer patients. See Nielsen Abstr. Nielsen also teaches that “our recent
exploratory study of ABCG2 mRNA expression in 580 patients with stage III
primary CRC (subgroup from the randomized PETACC-3 study) indicated
that high ABCG2 tumor tissue mRNA expression might be predictive for
lack of efficacy of irinotecan.” Nielsen Abstr., 1931. This prediction is
consistent with the studies of Yamazaki, which teaches that cells expressing
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ABCG2 actively pump SN-38 out of the intracellular space, decreasing its
efficacy as a cytotoxin. See Yamazaki 1252.
Ricci teaches that “ABCG2 is unique in that it seems to be mainly
expressed in solid tumors. Despite the recent discovery of many compounds
that inhibit its activity, it remains one of the least well-studied transporters in
both animal models and in humans with regard to its contribution to
[multiple drug resistance].” Ricci Abstr. Ricci further teaches that: “Of the
specific ABCG2 antagonists, only YHO-13177 and our recently reported
compounds 177, 724, and 505 were reported to have an antitumor effect
when combined with [topotecan].” Ricci 139. This, too, is consistent with
the teaching of Yamazaki that application of YHO-13177 restores the
cytotoxicity of SN-38 in cells expressing ABCG2. See Yamazaki 1260–61.
Appellant’s argument citing art published both prior and subsequent
to the references cited by the Examiner is not persuasive of such
unpredictability in the art that a person of ordinary skill would not have
found it obvious to combine the references, and with a reasonable
expectation of success. First, neither Nielsen nor Ricci teach a combination
therapy employing YHO-13177 and an MAb-conjugated drug, let alone the
anti-Trop-2 hRS7 antibody conjugated with SN-38, as recited in claim 1, and
as taught by the combination of Govindan and Yamazaki.
Second, we have explained in our analysis of Issue 1 supra why a
person of ordinary skill in the art would have been motivated to combine the
teachings of the references, and with a reasonable expectation of success.
Specifically, we have found that Govindan teaches that SN-38-conjugated
ADC increases the internalization of the conjugate into the intracellular
environment, where SN-38 is cleaved from the antibody into its cytotoxic
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form, and that Yamazaki teaches that YHO-13177 inhibits ABCG2 from
pumping out the SN-38 from the cellular interior. Furthermore, we note that
“[o]nly a reasonable expectation of success, not absolute predictability, is
necessary for a conclusion of obviousness.” In re Longi, 759 F.2d 887, 897
(Fed. Cir. 1985). We conclude, as we have explained, that the Examiner has
met that standard, based upon the teachings of the prior art.
Finally, Appellant appears to argue that the increased efficacy of the
combination therapy recited in claim 1 demonstrates unexpected or
surprising results that overcome the Examiner’s prima facie conclusion of
obviousness. We are not persuaded. “[W]hen unexpected results are used
as evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.” In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991). We have explained why neither Nielsen nor Ricci
are closer prior art than those cited by the Examiner, not least because
neither reference teaches the use of ADCs in combination with ABCG2
inhibitors. Appellant has made no persuasive showing why the combined
teachings of the prior art would not have the properties recited in claim 1, or
why a person of ordinary skill in the art would have been surprised by such
results. Having failed to meet this burden, Appellant’s arguments are not
persuasive of error upon the Examiner’s part.

2. Rejection of claim 4 under 35 U.S.C. § 103
Independent claim 4 is essentially identical to claim 1, with the
exception that limitation b recites: “administering to the patient an ABCG2
inhibitor, wherein the ABCG2 inhibitor is YHO-13351.” Claim 4 is thus
Appeal 2020-004291
Application 15/429,671

19
restricted to a single species, the prodrug of the ABCG2 inhibitor YHO-
13177. App. Br. Claims App’x A at 2.
Appellant argues that the arguments presented supra with respect to
claim 1 are even more strongly justified for claim 4, in which the scope of
the ABCG2 inhibitor is limited to YHO-13351. App. Br. 8. Appellant
contends that almost all of the studies cited above were performed with
YHO-13351, and that therefore the evidence of unexpected superior results,
lack of predictability and skepticism of experts is even more convincing with
respect to claim 4. Id.
We are not persuaded, for the same reasons we have explained supra
with respect to claim 1. Particularly, we agree with the Examiner that
Yamazaki expressly teaches the increased cytotoxicity of SN-38 in cells
thatin which ABCG2 is inhibited, and we agree that the increased
internalization into the cell of the SN-38-conjugated anti-Trop-2 hRS7
monoclonal antibody and its subsequent cleavage to produce free SN-38
intracellularly, would increase the efficacy of the drug when the export
ABCG2 protein is inhibited by the inhibitor YHO-13177. See Yamazaki
Abstr.; Govindan ¶ 260. We consequently affirm the Examiner’s rejection
of claim 4.
Furthermore, Appellant makes no separate arguments with respect to
dependent claims 9, 12–14, 16, 17, 19–24, and 26–32. We consequently
summarily affirm these claims. See 37 C.F.R. § 41.37(c)(iv) (“[A]ny
arguments or authorities not included in the appeal brief will be refused
consideration by the Board for purposes of the present appeal”).

Appeal 2020-004291
Application 15/429,671

20
CONCLUSION
The Examiner’s rejection of claims 1, 4, 9, 12–14, 16, 17, 19–24, and
26–32 under 35 U.S.C. § 103 is affirmed.
The Examiner’s rejection of claims 1–5, 7, 14–26, and 40–54 under
the nonstatutory doctrine of obviousness-type double patenting is reversed.

AFFIRMED

Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 4, 9, 12–
14, 16, 17,
19–24, 26–32
103 Govindan,
Yamazaki
1, 4, 9,
12–14, 16,
17, 19–24,
26–32