Ute Hoch et al.

Patent Trials and Appeals Board

May 11, 2020

14354080 - (D) (P.T.A.B. May. 11, 2020)

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.
14/354,080 04/24/2014 Ute Hoch SHE0431.00 9685
21968 7590 05/11/2020
NEKTAR THERAPEUTICS
455 Mission Bay Blvd., South, Suite 100
San Francisco, CA 94158
EXAMINER
OLSON, ERIC
ART UNIT PAPER NUMBER
1623
MAIL DATE DELIVERY MODE
05/11/2020 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte UTE HOCH, MICHAEL A. ELDON, and
ABRAHAM C.F. LEUNG
____________

Appeal 2019-004329
Application 14/354,080
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and
JOHN G. NEW, Administrative Patent Judges.

KATZ, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 seeks our review,2 under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 1 and 5–14. (Appeal Br. 4.)
We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Nektar
Therapeutics. (See Appeal Br. 1.)
2 We consider the Non-Final Office Action issued August 23, 2017 (“Non-
Final Act.”), the Appeal Brief filed December 7, 2018 (“Appeal Br.”), the
Examiner’s Answer issued on March 12, 2019 (“Ans.”), and the Reply Brief
filed May 13, 2019 (“Reply Br.”).
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INTRODUCTION
Appellant’s Specification is directed to a method of treating cancer by
administering a long-acting topoisomerase I inhibitor and a long-acting
topoisomerase II inhibitor. (Specification dated April 24, 2014 (“Spec.”)
¶ 10.) The long-acting topoisomerase I inhibitor may include a
pentaerythritol-based multi-arm polymer conjugate of irinotecan
(“PBMAPCI”) as described in U.S. Patent No. 7,744,861. (Id. ¶ 33.) The
Specification reports that the effective half-life of a long-acting irinotecan
polymer conjugate is about 50 days as compared about two days for
unmodified irinotecan. (Id. ¶ 31.) The long-acting topoisomerase II
inhibitor may include doxorubicin HCl liposome injection, commercially
available as DOXIL®. (Id. ¶ 35.)
Appellant’s claim 1 recites:
A method for treating a patient suffering from a cancer, the
method comprising the steps of:

(a) administering to the patient a topoisomerase II-
inhibiting amount of doxorubicin HCl liposome injection; and

(b) administering to the patient a topoisomerase I-
inhibiting amount of a composition comprising a long-acting
topoisomerase I inhibitor having a structure:
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wherein each n is an integer ranging from 40 to about
500, and pharmaceutically acceptable salts thereof, and further
wherein:

the topoisomerase I-inhibiting amount in step (b) is
greater than 100 mg/m2 based on irinotecan equivalents,

the cancer is selected from the group consisting of
ovarian cancer, colorectal cancer, breast cancer, lymphoma
cancers, leukemia cancers, rhabdomyosarcoma and
neuroblastoma; and

the long-acting topoisomerase I inhibitor has an effective
half-life of from about 5 days to about 60 days.

(Appeal Br. 15–16.)
The Examiner rejected the claims as follows:
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Non-Final
Office
Action
1, 5, 7, 8,
10–14
103(a) Morgensztern,3 Zhao4 2–4
6 103(a) Morgensztern, Zhao, Wilailak5 4
9 103(a) Morgensztern, Zhao, Gatti6 5
1, 5–14 103(a) Morgensztern, Chong7 5–6

ANALYSIS
As the Examiner finds, Morgensztern teaches a method of treating
cancer by administering irinotecan and pegylated-liposomal doxorubicin
(PLD) injection. (See Morgensztern 442, see Non-Final Act. 3.)
Morgensztern teaches administering chemotherapy over a 21-day cycle by
administering PLD on day 1, and administering 100 mg/m2 irinotecan
immediately following PLD infusion on days 1 and 8. (See Morgensztern
442, see Non-Final Act. 3.) Morgensztern teaches treating ovarian,
colorectal, and breast cancer with the combination therapy. (See
Morgensztern 443, see Non-Final Act. 3.) Morgensztern teaches that
administering the two agents together “would take advantage of combined
topoisomerase targeting” similar to other pre-clinical studies showing

3 Morgensztern et al., “A Phase I Study of Pegylated Liposomal Doxorubicin
and Irinotecan in Patients with Solid Tumors,” 55 Chemotherapy 441–445
(2009).
4 Zhao et al., US 7,744,861 B2, issued June 29, 2010.
5 Wilailak et al., “A Study of Pegylated Liposomal Doxorubicin in Platinum-
Refractory Epithelial Ovarian Cancer,” 57 Oncology, 183–186 (2004).
6 Gatti et al., US 4,946,831, issued August 7, 1990.
7 Chong et al., WO 2011/063158 A1, published May 26, 2011.
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synergism when administering irinotecan together with doxorubicin. (See
Morgensztern 441–442, see Non-Final Act. 7.)
The Examiner acknowledges that Morgensztern does not disclose a
long-acting irinotecan, having a half-life between 5 and 60 days. (See Non-
Final Act. 3.) The Examiner cites Zhao or Chong for teaching the instantly
claimed long-acting pentaerythritol-based multi-arm polymer conjugate of
irinotecan (“PBMAPCI”). (See id. at 3, 5.)
Zhao teaches PBMAPCI is more effective in suppressing tumor
growth than unmodified irinotecan over the course of 60 days. (See Zhao
51:1–17; 52:21–30; see Non-Final Act. 3.) Zhao further teaches that multi-
armed prodrug conjugates demonstrate additional improvements over
unmodified active compounds, including increased tumor retention time,
reduced clearance rate, and reduced adverse side effects. (See Zhao 7:1–12;
see Ans. 8.) The Examiner finds that Zhao’s dosing range of 40–90 mg/kg
PBMAPCI would correspond to an amount greater than 100 mg/m2 for an
adult human. (See Zhao 44:1–7; see Non-Final Act. 4.) The Examiner
determines a person of ordinary skill in the art would have been motivated
by Zhao’s teachings to substitute PBMAPCI for Morgensztern’s unmodified
irinotecan, thus arriving at the method of claims 1, 5, 7, 8, and 10–14. (Non-
Final Act. 4.)
Alternatively, the Examiner finds Chong teaches administering
PBMAPCI for treating colorectal, breast, and platinum-resistant ovarian
cancer, as well as lymphomas, leukemias, rhabdomyosarcoma, and
neuroblastoma. (Chong ¶¶ 10, 251–255; see Non-Final Act. 6.) Chong
teaches “the dosage of an irinotecan-conjugate will typically range from
about 50 mg/m2 to about 350 mg/m2.” (Chong ¶ 260; see Non-Final Act. 6.)
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The Examiner determines a person of ordinary skill in the art would have
been motivated by Chong’s teachings to substitute PBMAPCI for
Morgensztern’s unmodified irinotecan, thus arriving at the method of claims
1 and 5–14. (See Non-Final Act. 6.)
Appellant argues that the Examiner fails to present a prima facie case
of obviousness for several reasons. First, Appellant argues that
Morgensztern does not suggest combining a long-acting topoisomerase II
inhibitor with a long-acting topoisomerase I as taught by Zhao or Chong.
(Appeal Br. 8.) Appellant argues that Morgensztern teaches bimodal
therapy of a long-acting topoisomerase II inhibitor combined with non-long
acting topoisomerase I inhibitor. (Reply Br. 2.) Appellant argues
“Morgensztern is concerned with investigating combination therapy to
define the [maximum tolerated dose] MTD of the combination, but does not
require ‘simultaneous’ targeting.” (Id. at 3.)
We are not persuaded by Appellant’s arguments characterizing
Morgensztern. Rather, we agree with the Examiner that Morgensztern
teaches simultaneous administration of PLD and irinotecan to “take
advantage of combined topoisomerase targeting.” (Morgensztern 442.)
Moreover, we are not persuaded by Appellant’s arguments that
Morgensztern alone does not provide a reason to combine the references.
The Examiner determines that one of ordinary skill in the art would modify
Morgensztern’s combination therapy with a long-acting irinotecan based on
Zhao or Chong, and not Morgensztern alone. “Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references.” In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986).
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Second, Appellant argues there was no reason to modify
Morgensztern’s irinotecan with the claimed PBMAPCI because the prior art
teaches numerous long-acting forms of irinotecan. (Appeal Br. 8–9.)
Appellant argues that a different long-acting irinotecan liposome injection
(ONIVYDETM) was already approved for use. (Id.) Appellant argues that
Zhao teaches many different drugs and “large numbers of organic core
molecules and polymer arms,” in addition to modified-irinotecan. (Id. at 9.)
Appellant repeats the same argument as to Chong, arguing that one of skill
in the art would not have combined the references absent hindsight. (Id. at
13.)
We are not persuaded by Appellant’s argument that there is no reason
to combine the references. Zhao teaches multiple benefits of PBMAPCI as
compared to unmodified-irinotecan, including greater tumor suppression,
longer activity, and reduced adverse side effects. (See Zhao 7:1–12.)
Likewise, Chong teaches Zhao’s polymer conjugates can improve the water-
solubility of an active agent. (See Chong ¶ 4, citing U.S. Patent No.
7,744,861.) Chong also teaches conjugated versions of active agents often
exhibit clinically beneficial properties as to safety and efficacy. (See Chong
¶ 6.) That PBMAPCI was not approved at the time and was one of many
options does not negate the Examiner’s reason to combine the references.
“The motivation to combine inquiry is not limited to what products are
forthcoming or currently available on the market . . . Any motivation,
whether articulated in the references themselves or supported by evidence of
the knowledge of a skilled artisan, is sufficient.” Bayer Pharma AG v.
Watson Labs., Inc., 874 F.3d 1316, 1324 (Fed. Cir. 2017). As to Appellant’s
hindsight argument, the Examiner takes into account only knowledge which
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was within the level of ordinary skill at the time the claimed invention was
made, and, therefore, properly reconstructs the prior art. See In re
McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971).
Third, Appellant argues that there was no reason to administer greater
than 100 mg/m2 irinotecan equivalents. (Appeal Br. 10.) Appellant
contends Morgensztern teaches that 100 mg/m2 is the maximum tolerated
dose of irinotecan because a higher dose of 125 mg/m2 resulted in significant
and undesirable side effects. (Id.) Appellant contends that Zhao’s doses
higher than 100 mg/m2 “relate to administration solely of a long-acting
irinotecan.” (Id.) Appellant does not address Chong’s dose range. (See id.
at 13.)
We are not persuaded by Appellant’s argument. Morgensztern
teaches that for the specific trial, the maximum tolerated dose of unmodified
irinotecan was 100 mg/m2. (Morgensztern 443.) However, Morgensztern
also teaches that other studies determined a maximum tolerated dose of “300
mg/m2 of irinotecan when given every 21 days with growth factor support.”
(Id. at 442.) Accordingly, Morgensztern suggests that the dose amount of
irinotecan may vary depending on the dosing schedule, dosing regimen, and
other treatment parameters.
Moreover, as previously discussed, the Examiner rejected the claims
based on the combination of Morgensztern with Zhao or Chong, not
Morgensztern alone. Both Zhao and Chong expressly describe the beneficial
properties of polymer-active conjugates, e.g., PBMAPCI, as including
greater tumor suppression and reduced adverse effects. (Zhao 7:1–12; see
Chong ¶ 6.) Both references teach dose amounts greater than 100 mg/m2.
(See Zhao 44:1–7; see Chong ¶ 260.) Chong expressly teaches that the dose
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range for an irinotecan-polymer conjugate may be adjusted “[w]hen
administered conjointly with other pharmaceutically active agents.” (Chong
¶ 260.) Accordingly, one of ordinary skill in the art would have applied
Zhao’s or Chong’s dose ranges when modifying Morgensztern’s combined
therapy with a long-acting irinotecan. Because the prior art ranges overlap
the claimed amount of greater than 100 mg/m2, we agree with the
Examiner’s determination that the claims are prima facie obvious over the
prior art. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A
prima facie case of obviousness typically exists when the ranges of a
claimed composition overlap the ranges disclosed in the prior art.”).
Appellant argues that the claimed method “provides an unexpected
treatment benefit that is nowhere suggested by the cited art.” (Appeal Br.
10.) Particularly, Appellant argues that Example 2 of the Specification
demonstrates a significant difference in overall survival between the claimed
combination therapy and corresponding PBMAPCI and DLI monotherapies.
(Id. at 10–11, citing Spec. ¶ 75.) Appellant argues the combination therapy
“showed marked synergism demonstrated by complete response in all
animals . . . without additive toxicity.” (Id. at 11, citing ¶¶ 75–77.)
We are not persuaded by Appellant’s evidence of unexpected results.
“To be particularly probative, evidence of unexpected results must establish
that there is a difference between the results obtained and those of the closest
prior art, and that the difference would not have been expected by one of
ordinary skill in the art at the time of the invention.” Bristol-Myers Squibb
Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). As
explained by the Examiner, Appellant’s test results do not compare the
claimed invention to the closest prior art. (See Ans. 8–9.) The test results
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compare combination therapy to monotherapies in a xenograft mouse model.
(See Spec. ¶¶ 50–51.) In contrast, Morgensztern is the closest prior art as it
teaches combination therapy for cancer patients suffering from the claimed
cancers. (See Morgensztern 441.) Appellant’s results do not compare the
claimed combination of two long-acting topoisomerase inhibitors to a
similar combination therapy, albeit with a short-acting type I inhibitor and a
long-acting type II inhibitor.
Morgensztern further explains that a person of ordinary skill in the art
would have expected “synergism between topoisomerase I and II inhibitors.”
(Id.) Morgensztern expressly teaches that preclinical studies have shown
synergism due to combined topoisomerase targeting. (Id. at 442.)
Morgensztern explains that the absence of synergism was unexpected, and
provided a number of potential factors for that unexpected absence. (See
Morgensztern 444.) Morgensztern recommends further evaluation of the
combination, particularly for patients with ovarian cancer. (Id.) In view of
the recommendation for further evaluation, combined with the benefits of
PBMAPCI taught by Zhao and Chong, a person of ordinary skill in the art
would have expected the combination therapy of long-acting topoisomerase
I and II inhibitors to provide a synergistic effect. Therefore, Appellant’s
results are not unexpected and we agree with the Examiner’s conclusion that
the claims would have been obvious over Morgensztern combined with
Zhao or Chong.
Appellant argues the rejections of claims 6 and 9 separately. As to
claim 6, Appellant argues Wilailak fails to suggest administering a
combination of PEGylated liposomal doxorubicin with a long-acting form of
irinotecan. (Appeal Br. 11.) As to claim 9, Appellant argues “Gatti is not
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concerned with liposomal forms of doxorubicin, nor PEGylated liposomal
forms of doxorubicin, nor coadministration with a second anticancer drug of
any type.” (Id. at 12.) Appellant argues that Wilailak and Gatti individually
“fail[] to make up for the deficiencies of the combination of Morgensztern in
view of Zhao as set forth above.” (Id. at 11–12.)
We are not persuaded by Appellant’s arguments against Wilailak and
Gatti alone. The Examiner cites Wilailak for teaching administering
PEGylated liposomal doxorubicin to treating platinum-resistant ovarian
cancer. (See Wilailak 183, see Non-Final Act. 4.) The Examiner cites Gatti
for administering doxorubicin to treat leukemia and neuroblastoma. (See
Gatti 4:57–68, see Non-Final Act. 5.) The Examiner does not rely on either
reference for teaching combination therapy. (See Non-Final Act. 4–5.)
Rather, the Examiner relies on the references to teach a reasonable
expectation of success in administering the combination to treat the recited
cancers of claims 6 and 9. (Id.) Appellant has not addressed the Examiner’s
combination. Accordingly, we agree with the Examiner that it would have
been obvious to administer the combination therapy taught by Morgensztern
and Zhao to treat the cancers taught by Wilailak or Gatti.
Because we are not persuaded by Appellant’s arguments that the
Examiner erred, we affirm the rejection of claims 1 and 5–14.

CONCLUSION
Upon consideration of the record and for the reasons given, we
AFFIRM the Examiner’s rejection.
In summary:
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 5, 7, 8,
10–14
103(a) Morgensztern, Zhao 1, 5, 7, 8,
10–14

6 103(a) Morgensztern, Zhao,
Wilailak
6
9 103(a) Morgensztern, Zhao,
Gatti
9
1, 5–14 103(a) Morgensztern, Chong 1, 5–14
Overall
Outcome
1, 5–14

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.

AFFIRMED