Array BioPharma Inc.

Patent Trials and Appeals Board

Nov 17, 2020

14355903 - (D) (P.T.A.B. Nov. 17, 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.
14/355,903 05/02/2014 Darrin Stuart 019121.00936\US 3258
22907 7590 11/17/2020
BANNER & WITCOFF, LTD.
1100 13th STREET, N.W.
SUITE 1200
WASHINGTON, DC 20005-4051
EXAMINER
CHONG, YONG SOO
ART UNIT PAPER NUMBER
1627
NOTIFICATION DATE DELIVERY MODE
11/17/2020 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):
GPD@bannerwitcoff.com
eofficeaction@bannerwitcoff.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte DARRIN STUART and MEGHNA DAS THAKUR
____________

Appeal 2020-002370
Application 14/355,903
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and
MICHAEL A. VALEK, Administrative Patent Judges.

ADAMS, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s
decision to reject claims 1–4 and 6–33 (Appeal Br. 1). We have jurisdiction
under 35 U.S.C. § 6(b).
We REVERSE.

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 “Array
BioPharma Inc.” (Appellant’s August 15, 2019 Appeal Brief (Appeal Br.)
1).
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STATEMENT OF THE CASE
Appellant’s disclosure “relates to a method of suppressing resistance
to treatment with inhibitors of BRAF” (Spec.2 1). Appellant’s independent
claim 1 is reproduced below:
1. A method of treating a proliferative disease in a subject in
need thereof, wherein the proliferative disease is characterized
by a mutation in BRAF kinase, wherein the method comprises
suppressing resistance to treatment with a BRAF inhibitor of
the Formula II

by administering the BRAF inhibitor of Formula II to the
subject on an intermittent dosing schedule, wherein the
intermittent dosing schedule comprises administering the
BRAF inhibitor for a period of 1, 2, 3, 4, 5, or 6 weeks followed
by a period of 1, 2, 3, 4, 5, or 6 weeks wherein treatment with
the BRAF inhibitor of Formula II is withheld.
(Appeal Br. 18.)

2 Appellant’s May 2, 2014 Specification.
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Claims 1–4 and 6–33 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Huang,3 Haura,4 Gumerlock,5 and
Flaherty.6
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
FACTUAL FINDINGS (FF)
FF 1. Huang discloses the compound of Appellant’s formula (II) (see
Appeal Br. 5 (“[T]he compound of formula (II) in [Appellant’s] claim 1 is
compound ‘9’ in Huang.”); see generally Final Act.7 4).
FF 2. Huang discloses “methods for the treatment of kinase related disease,
particular B-Raf kinase related diseases; for example, metastatic
melanomas” (Huang ¶ 27; see generally Final Act. 4).
FF 3. Huang discloses the administration of its compounds
in therapeutically effective amounts via any of the usual and
acceptable modes known in the art, either singly or in
combination with one or more therapeutic agents. A
therapeutically effective amount may vary widely depending on

3 Huang et al., WO 2011/025927 A1, published Mar. 3, 2011.
4 Haura et al., A Phase II Study of PD-0325901, and Oral MEK Inhibitor, in
Previously Treated Patients with Advanced Non-Small Cell Lung Cancer, 16
Clin. Cancer Res. 2450–2457 (2010).
5 Gumerlock, US 2007/0099856 A1, published May 3, 2007.
6 Flaherty et al., Vemurafenib, 10 Nature Reviews: Drug Discovery, 811–
812 (2011).
7 Examiner’s July 23, 2018 Final Office Action.
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the severity of the disease, the age and relative health of the
subject, the potency of the compound used and other factors.
(Huang ¶ 50; see also id. ¶ 49 (“[T]he required dosage will vary depending
on the mode of administration, the particular condition to be treated and the
effect desired.).)
FF 4. “Huang does not disclose the intermittent dosing schedule required
by [Appellant’s] claims” (Appeal Br. 5–6; see also Final Act. 4 (“Huang
do[es] not expressly teach intermittent dosing with the BRAF Kinase
inhibitor of Formula II.”)).
FF 5. Haura discloses a phase II study of PD-0325901, an oral MEK
inhibitor, in previously treated patients with advanced non-small cell lung
cancer (Haura, Title; see Appeal Br. 6 (citing Haura, Title) (“Haura
describes a ‘Phase II study of PD-0325901’, which is an ‘Oral MEK
Inhibitor.’”); see generally Final Act. 5).
FF 6. Haura’s “phase II study initially evaluated 15 mg PD-0325901 twice
daily administered intermittently (3 weeks on/1 week off; schedule A). As
this schedule was not well tolerated, a second schedule was introduced as
follows: 5 days on/2 days off for 3 weeks, followed by 1 week off (schedule
B),” wherein “[t]he primary end point was objective response” (Haura,
Abstract; see Final Act. 5 (Haura discloses intermittent administration of its
MEK inhibitor, PD-0325901.); see also Appeal Br. 7).
FF 7. Haura discloses that “PD-0325901 did not meet its primary efficacy
end point” and recommends that “[f]uture studies should focus on PD-
0325901 schedule, rational combination strategies, and enrichment of patient
selection based on mode of action” (Haura, Abstract; see id. at 2456 (“The
primary objective of this study was not met according to a prespecified
criterion” and “[f]urther evaluation using a lower dose of PD-0325901 on
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the intermittent schedule may be warranted in selected patients with BRAF
mutation or in other tumor contexts in which downstream signaling is reliant
on MEK for tumor maintenance”).
FF 8. Gumerlock discloses the treatment of cancer in human patients,
wherein the cancer may be melanoma, including refractory melanoma
(Gumerlock ¶ 57; see generally Ans. 4).
FF 9. Gumerlock discloses the combined treatment with docetaxel
[(DOC)] and an epidermal growth factor receptor kinase inhibitor using an
intermittent dosing regimen (Gumerlock, Title; see Final Act. 5
(“Gumerlock teaches combined treatment that includes a kinase inhibitor,
using an intermittent dosing regimen.”); Appeal Br. 12 (“Gumerlock is
concerned with intermittent dosing of an EGFR inhibitor in combination
with chemotherapy.”)).
FF 10. Gumerlock discloses that “erlotinib HCl (also known as
TARCEVATM)” is “[a] preferred example of an EGFR kinase inhibitor that
can be used in practicing [Gumerlock’s] invention” (Gumerlock, Abstract).
FF 11. Gumerlock discloses:
Two dose escalating phase I trials (Arm A and Arm B)
were conducted simultaneously. DOC was administered every
21 days in both arms (70-75 mg/m2 IV). Arm A: erlotinib
given weekly days 2, 9, 16 (600-800 mg). Arm B: erlotinib
given days 2-16 (150-300 mg). . . .
42 patients with advanced solid tumors were treated,
including 22 [non-small-cell lung cancer (NSCLC)] patients. . .
. Arm A MTD: DOC 70 mg/m2 and weekly erlotinib 600 mg.
Arm B MTD[:] DOC 70 mg/m2 and erlotinib 200 mg day 2-16.
Of 22 NSCLC patients, there were 4 partial responses, 4 minor
responses, and 5 with stable disease. 4 N[S]CLC patients
remain on therapy at 23, 22, 15, and 10 months.
(Gumerlock ¶¶ 108, 113; see also Appeal Br. 12.)
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FF 12. Flaherty discloses:
The emergence of BRAF inhibitors has provided an opening for
exploiting the molecular underpinnings of melanoma, which
has historically been a treatment-refractory tumour type. It is
hoped that this approach will extend to the other solid tumours
in which activating BRAF mutations can be found, and that this
represents a building block for the development of targeted
combination regimens.
(Flaherty 812; see Final Act. 5 (“Flaherty teaches that melanoma has a
history of being a treatment refractory tumor type, wherein activating BRAF
tumors are found.”); see also Appeal Br. 14 (“Flaherty . . . points out that
melanoma ‘has historically been a treatment-refractory tumor.’”).)
FF 13. Appellant’s Figure 1 is reproduced below:

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Appellant’s Figure 1 provides a “[c]omparison of continuous and
intermittent dosing of a BRAF inhibitor of formula II shows that taking
away a growth advantage for the resistant cells by intermittent dosing delays
or prevents the onset of resistance to the BRAF inhibitor” (Spec. 1–2).
FF 14. Appellant discloses:
The following Example illustrates the present invention.
Example 1
Hmex1906 primary human melanoma tumors are implanted at
passage 3 into nude mice. The mice were monitored until the
implanted tumors reached 200-400mm3. Once this size is
reached, the mice are dosed . . . with 5mg/kg of a Raf inhibitor
(Compound of Formula II) for 4 weeks. Some of the mice
continue treatment while others are subject to an intermittent
treatment schedule of 4 weeks of treatment and 2 weeks of drug
holiday.[]
The results are shown in Figure 1. Resistance emerged in all
mice receiving the Compound of Formula II on a continuous
basis, but there is no evidence of resistance in the mice that
were subject to an intermittent dosing schedule.
(Spec. 5–6.)
ANALYSIS
Based on the combination of Huang, Haura, Gumerlock, and Flaherty,
Examiner concludes that, at the time Appellant’s invention was made, it
would have been prima facie obvious to use an intermittent dosing regimen,
such as that disclosed by Haura and Gumerlock, to administer Huang’s
MEK inhibitor to patients, because Flaherty discloses “that solid tumors,
with BRAF mutations, are historically treatment refractory” (see Final Act.
6–7; FF 1–11). In this regard, Examiner reasons that, at the time of
Appellant’s claimed invention, a person of ordinary skill in this art would
have found it prima facie obvious “to administer the claimed compound to
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treat melanoma under any dosing schedule that [was] known in the art”
(Ans. 4; see FF 3 (Huang discloses the administration of “therapeutically
effective amounts [of its MEK inhibitor] via any of the usual and acceptable
modes known in the art”)). Examiner further reasons:
[I]f a particular disease (melanoma in this case) is known to be
refractory or resistant to a known active agent, which the
Gumerlock reference clearly teaches, it would be obvious for
one of ordinary skill in the art to select intermittent dosing so as
to limit or minimize the developing resistance.
(Ans.8 4.) In this regard, Examiner reasons that a person of ordinary skill in
this art would utilize routine experimentation to optimization the intermittent
dosing schedule to treat Huang’s patients with MEK inhibitor and, thus,
Appellant’s intermittent administration schedule would have been prima
facie obvious to those of ordinary skill in this art (see generally Final Act.
7). We are not persuaded.
As Appellant explains, “Haura expressly states that PD-0325901 did
not meet its primary efficacy endpoint” (Appeal Br. 16; see also FF 7). In
addition, although Haura discloses, “schedule A,” an intermittent dosing
schedule that is encompassed by Appellant’s claimed invention, Haura
discloses that schedule A was discontinued because it “was not well
tolerated” (see Appeal Br. 16; see also FF 6). Thus, Haura recommends
further studies, i.e. experimentation, to develop an effective therapeutic
dosing regimen (see FF 7). Given the foregoing, we agree with Appellant’s
contention “that a person of ordinary skill [in this art] would [not] have been
motivated to apply the methods of Haura [to Huang] in order to arrive at the
presently claimed methods” (Appeal Br. 16).

8 Examiner’s November 22, 2019 Answer.
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Further, as Appellant explains, Gumerlock discloses “a compound that
is clearly unrelated to the compound recited in [Appellant’s] . . . claims, both
structurally and with respect to its mechanism” and “neither of Gumerlock’s
dosing schedules teaches or suggests the intermittent do[s]ing schedule
recited in [Appellant’s] claim 1” (Appeal Br. 13).
Thus, even if one were to assume, purely arguendo, that the
skilled artisan might somehow apply the Gumerlock dosing
schedules to the compound recited in the present claims - which
is both structurally and mechanistically unrelated to
Gumerlock’s -the resulting schedule would differ significantly
from [Appellant’s] claimed intermittent dosing. And modifying
Gumerlock in light of the teachings of Haura would not change
the conclusion of non-obviousness, since, as already discussed,
there would be no expectation of success given the failure of
the Haura study.
(Id.) We also agree with Appellant’s contention that Flaherty fails to
disclose a particular dosing schedule and, therefore, fails to cure the
deficiencies in the combination of Huang, Haura, and Gumerlock (see id. at
16).
In sum, Examiner established that because proliferative diseases, such
as melanoma, that are characterized by a mutation in BRAF kinase have a
history of being treatment refractory, a person of ordinary skill in this art
would have found it prima facie obvious to try intermittently dosing Huang’s
compound according to the dosing methodology set forth for different
compounds in the combination of Haura and Gumerlock. As discussed
above, however, the combination of Haura and Gumerlock, at best, provides
a general intermittent dosing approach and invites a person of ordinary skill
in the art to explore the use an intermittent dosing schedule to develop an
effective therapy.
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[A]n invention is not obvious to try where vague prior art does
not guide an inventor toward a particular solution. A finding of
obviousness would not obtain where “what was ‘obvious to try’
was to explore a new technology or general approach that
seemed to be a promising field of experimentation, where the
prior art gave only general guidance as to the particular form of
the claimed invention or how to achieve it.” . . . This expresses
the same idea as the KSR requirement that the identified
solutions be “predictable.”
Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341, 1347
(Fed. Cir. 2009) (citations omitted); see also In re O’Farrell, 853 F.2d 894,
903 (Fed. Cir. 1988) (“‘[O]bvious to try’ is not the standard under § 103.”).
CONCLUSION
The preponderance of evidence relied upon by Examiner fails to
support a conclusion of obviousness. The rejection of claims 1–4 and 6–33
under 35 U.S.C. § 103(a) as unpatentable over the combination of Huang,
Haura, Gumerlock, and Flaherty is reversed.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–4, 6–33 103 Huang, Haura,
Gumerlock,
Flaherty
1–4, 6–33

REVERSED