Merck Patent GmbH

Patent Trials and Appeals Board

Feb 17, 2021

2020005857 (P.T.A.B. Feb. 17, 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.
15/343,570 11/04/2016 Bayard R. HUCK 000683US 1047
151167 7590 02/17/2021
Gruneberg and Myers PLLC
1775 Tysons Blvd
5th Floor
Tysons, VA 22102
EXAMINER
PAGONAKIS, ANNA
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
02/17/2021 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):
em@gandmpatent.com
kg@gandmpatent.com
patent@gandmpatent.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
_________________

Ex parte BAYARD R. HUCK, SAMANTHA M. GOODSTAL,
and CLAUDE GIMMI-MCKIM

_________________

Appeal 2020-005857
Application 15/343,570
Technology Center 1600
_________________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and
DAVID COTTA, Administrative Patent Judges.

KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appellant1 seeks our review2, under 35 U.S.C. § 134(a), of the
Examiner’s decision to reject claims 9–12, 17–20, and 22–26.3 We have
jurisdiction under 35 U.S.C. § 6(b). We AFFIRM.

1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant
identifies the real party-in-interest as Merck Patent GmBH And Telios
Pharmaceuticals, Inc. (Appeal Br. 2.)
2 We consider the Non-Final Office Action issued June 19, 2019 (“Non-
Final Act.”), the Appeal Brief filed February 18, 2020 (“Appeal Br.”), the
Examiner’s Answer issued on June 12, 2020 (“Ans.”), the Reply Brief filed
August 12, 2020 (“Reply Br.”) and the oral argument held on February 2,
2021, in reaching our decision.
3 Claims 13–16 and 21 have been withdrawn.
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The Examiner rejects claims 9–12, 17–20, and 22–26, all of
Appellant’s pending claims, under 35 U.S.C. § 103(a) over Hodous4 and
Wang.5 (Ans. 3–4.)
Appellant’s specification is directed to pyrimidine and pyridine
compounds used as therapeutics in the treatment of cancer, specifically
compounds that irreversibly inhibit Bruton’s tyrosine kinase (“BTK”).
(Spec. 1:13–16.)
Appellant’s claim 9 recites: “A method of treating lymphoma,
comprising: administering to a subject in need thereof a therapeutically
effective amount of a compound of formula (II) . . . .” (Appeal Br. 21.) The
generic structure of formula (II) is provided on pages 20–24 of the Appeal
Brief.
Appellant’s claim 10 limits the method of claim 9 to a compound of
formula (II) selected from the group consisting of a large number of species,
provided as “Table 2.” (See id. v 24–58.) One of the compounds listed in
Table 2 is referred to as “A225.” (See id. 46.) Thus, Appellant’s currently
pending claims encompasses methods of treating lymphoma comprising
administering the compound A225 and certain claims limit the lymphoma to
Non-Hodgkin’s lymphoma and mantle cell lymphoma.6

4 Hodous et al., International Patent Application Publication WO
2012/170976 A2, published December 13, 2012.
5 Wang, et al., Targeting BTK with Ibrutinib in Relapsed or Refractory
Mantle-Cell Lymphoma, New England J. Med., 369:507–16 (2013.)
6 Appellant elected compound A225 in response the Examiner’s restriction
requirement. (See Response to Restriction Requirement filed June 26, 2017.
We note that Appellant’s claim 18 recites compound A250, but Appellant
does not argue for the separate patentability of claim 18. (See Appeal Br.
65.)
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Appellant argues for the patentability of claims 9–12 and 17–20 as a
group and for the patentability of claims 22–26 as a group. (See Appeal Br.
5.) We focus on claim 10, which recited the elected species of compound
A225, first.
Findings of Fact
1. Hodous teaches pyrimidine and pyridine compounds that are
irreversible Bruton’s tyrosine kinase (BTK) inhibitors for use in treating
cancer. (Hodous abstract 1:8–13.)
2. Hodous teaches the specific BTK inhibitor A225. (See Hodous
236 (Table 2).)
3. Hodous teaches that A225 has an IC50 of less than 100 nM in a
time-dependent BTK enzyme assay, indicating that A225 inhibits BTK at a
concentration of less than 100 nM. (See Hodous 228:1–28, 236 (Table 2).)
4. Hodous presents claim 16, which recites: “Use according to
Claim 15 [of treating a solid tumor with compounds including A225], where
the solid tumour originates from the group of tumours of . . . the lymphatic
system . . . .” (Hodous 273.)
5. Hodous does not teach that A225 can be used to treat
lymphoma specifically.
6. Wang teaches that BTK inhibitors are known to be mediators of
B-cell-receptor signaling pathways implicated in the pathogenesis of B-cell
cancers. (See Wang abstract.)
7. Wang teaches:
Constitutive activation of B-cell receptor signaling appears to
be essential for the survival and proliferation of malignant B
cells, an observation that has led to the design of inhibitors of
B-cell receptor-associated kinases. Bruton’s tyrosine kinase
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(BTK) has been identified as an essential component of the B-
cell-receptor signaling pathway.

(Wang 508.)

8. Wang teaches that a BTK inhibitor called ibrutinib, which is
distinct from A225, has anti-tumor activity in several types of non-
Hodgkin’s lymphoma, including mantle-cell lymphoma. (See Wang
abstract.)
Analysis
The Examiner finds that one of ordinary skill in the art would have
considered it obvious to administer A225 for the treatment of non-Hodgkin’s
lymphoma, including mantle cell lymphoma, because Hodous teaches that
A225 is a known BTK inhibitor and Wang teaches that BTK inhibitors are
known to be effective in treating non-Hodgkin’s lymphomas, including
mantle cell lymphomas. (See Final Act. 4; see FFs 1–5, 8.) The Examiner
cites Wang for the teaching that B-cell receptor signaling appears to be
essential for the survival and proliferation of malignant B cells and that BTK
has been identified as an essential component of the B-cell-receptor
signaling pathway. (See Ans. 5; see FFs 6, 7.) From these teachings the
Examiner finds that Wang links BTK inhibitory activity to the treatment of
non-Hodgkin’s lymphoma, including mantle-cell lymphoma, leading to the
determination that there would have been a reasonable expectation of
success in using A225 to treat mantle cell lymphoma. (See Ans. 5.)
Appellant argues that the Examiner erred because BTK inhibitors are
known to have wide ranging and unpredictable effects. (See Appeal Br. 6–
8.) Appellant argues that Wang reports the efficacy of only one BTK
inhibitor in treating mantle cell lymphoma. (See id. 6–7, 14.) Appellant
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cites to a reference published after Appellant’s filing date, Liang,7 as
evidence that BTK is involved in other signaling pathways, which could
cause undesirable, off-target effects. (See id. 7–8; see Reply Br. 2–4.)
Appellant also relies on the teaching in Liang of 14 different BTK inhibitors
that target different signaling pathways, some of which are involved in
clinical trials, but Appellant notes that Liang lacks evidence that all of these
compounds would be effective in treating Non-Hodgkin’s Lyphomas. (See
Appeal Br. 7.) According to Appellant, one of ordinary skill in the art would
not have had a reasonable expectation that any BTK inhibitor would be
useful in treating lymphoma from a single instance of success with one BTK
inhibitor because of the potential side effects. (See id. 8.)
At the outset, we disagree with Appellant’s assertion that Wang fails
to teach that BTK inhibitors are known to be effective for treating
lymphoma because Wang teaches that at least one BTK inhibitor, ibrutinib,
is effective for the treatment of lymphomas. (See Appeal Br. 6.)
Furthermore, even if Wang does not address other BTK inhibitors, Wang
teaches that interference with the B-cell receptor signaling pathway, with a
BTK inhibitor, is effective against lymphomas. (See Wang abstract, 508.)
Because Wang teaches that B-cell signaling is “essential for the survival and
proliferation of malignant B cells,” we agree with the Examiner that an
inhibitor of such signaling would be reasonably expected to be a treatment
effective for lymphomas. (Wang 508; see Ans. 5.) That other BTK

7 Liang et al., The development of Bruton’s tyrosine kinase (BTK) inhibitors
from 2012 to 2017: A mini-review, Euro. J. Med. Chem., 151:315–26
(2018).
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inhibitors have not yet been assessed in clinical trials for lymphoma does not
persuade us otherwise.
We are also unpersuaded by Appellant’s argument because the
Examiner’s rejection is not based on Wang alone, but rather on the
combination of Hodous with Wang. (See Ans. 11.) Hodous demonstrates
that it was known in the art to use A225 to treat cancers in general. (See
Hodous 30:4–8 (“When treating or preventing cancer, inflammation or other
proliferative diseases for which compounds of the present invention are
indicated . . . .”).) Hodous states further that “BTK plays a well documented
role in the B-cell signaling pathway linking cell surface B-cell receptor
stimulation to downstream intracellular responses.” (Hodous 2:21–22.) And
Hodous presents a claim to the use of compounds including A225 in treating
solid tumors including those of the lymphatic system. (See Hodous 273; see
Ans. 6.) Given Wang’s teaching that BTK is a mediator of B cell receptor
signaling pathways that have been implicated in the pathogenesis of non-
Hodgkin’s lymphomas, including mantle cell lymphoma, we are persuaded
that one of ordinary skill in the art would have considered there to have been
a reasonable expectation of success in Appellant’s claimed methods.
Appellant’s argument that the claimed methods were unobvious
because BTK was taught to be associated with ailments other than cancer or
lymphoma or was taught to be involved in other signaling pathways is also
unpersuasive. Even if a compound is never actually given to a patient, using
it as a treatment may have been obvious under 35 U.S.C. § 103 because the
standards for what is approved as a safe and effective drug are not the same
as the standards for patentability. Cf. In re Brana, 51 F.3d 1560, 1567 (Fed.
Cir. 1995) (quoting In re Krimmel, 292 F.2d 948, 953 (CCPA 1961) (“one
who has taught the public that a compound exhibits some desirable
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pharmaceutical property in a standard experimental animal has made a
significant and useful contribution to the art, even though it may eventually
appear that the compound is without value in the treatment in humans.”).).
Appellant argues further, citing Liang that it is not clear why some
BTK inhibitors are “good clinical candidates” and why others are not and
argues, citing Pan, 8 that minor structural changes can result in “major
changes in potency.” (See Reply Br. 4–5.) We are not persuaded by this
argument because Appellant’s claims do not limit the method of treatment to
a specific potency or range of potencies or to any other parameter regarding
effectiveness. Thus, we are not persuaded that the prior art must teach that
A225 has a certain level of efficacy to render the claimed methods obvious.
Instead, if the art would have suggested to one of ordinary skill that a
compound could be useful as a treatment to some extent, it is obvious under
35 U.S.C. § 103, even if ancillary issues, such as side effects, cost, or
production difficulties, prevent its actual use. See Trustees of Columbia
Univ. in City of New York v. Illumina, Inc., No. 2019-2302, 2021 WL
317661, at *5 (Fed. Cir. Feb. 1, 2021) (“a reasonable expectation of success
does not mean achieving the best of all possible results.”).
Appellant argues that the BTK inhibitor taught in Wang has an
“entirely different structure” than A225. (See Appeal Br. 9.) Appellant
notes that A225 has a single heteroaryl ring, a pyridine or pyrimidine ring
core, whereas ibrutinib has a fused bicyclic heteroaryl group. (See id.)
Appellant argues that nothing in the record teaches using a compound
similar to the claimed compound, having a pyridine or pyrimidine ring core,

8 Pan et al., Discovery of Selective Irreversible Inhibitors for Bruton’s
Tyrosine Kinase, ChemMed Chem 2:58–61 (2007).
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with any effect on Non-Hodgkin’s lymphoma and/or mantle cell lymphoma
and thus there would not have been a reasonable prediction that such a
compound could be effective in the treatment of Non-Hodgkin’s lymphoma
and/or mantle cell lymphoma. (See id. 10.) Appellant cites to Pan to argue
that if minor changes in the structure of ibrutinib have dramatic effects on
potency, then changing the core from a double ring, as in ibrutinib, to a
single ring, as in A225, would be predicted to have a huge consequence,
whose effect could not be predicted based upon the structure of ibnitinib
alone. (Id. 10–11.) According to Appellant, one cannot determine the
effectiveness of a BTK inhibitor on its structure alone.
We are not persuaded by Appellant’s argument because Hodous
teaches that A225 is effective at inhibiting BTK, with an IC50 of less than
100 nM, the highest level reported for the time-dependent BTK enzyme
assay. (See Hodous 236, Table 2.) Thus, Hodous provides data to show the
inhibitory activity of A225. Given that Wang teaches a functional
connection between the activity of BTK and the survival and proliferation of
malignant B cells, we are not persuaded that one of ordinary skill in the art
would lack a reasonable expectation of success for A225 in light of the
activity taught in Hodous. Although Appellant argues that Liang indicates
not all BTK inhibitors behave similarly, Appellant fails to direct us to
evidence that the specific structure of A225, compared to other inhibitors,
indicates that it would perform any differently against lymphomas than
ibrutinib, given the teachings of Hodous and Wang. (See Appeal Br. 7–8
and 9–11.)
We are further unpersuaded by Appellant’s argument because the
authors of Pan concluded that they had discovered a series of irreversible
inhibitors for Bruton’s tyrosine kinase, with different structures, that are
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highly potent in both in vitro and in vivo. (See Pan 60–61; see Ans. 9.)
Thus, although Pan teaches that there are differences in BTK inhibitors, it
also teaches that several inhibitors might be effective, other than ibrutinib.
In general, Appellant argues that the teaching in Wang that BTK is
implicated in the pathogenesis of B-cell cancers does not give rise to the
assertion of a reasonable expectation of success in the use of a specific BTK
inhibitor to treat a specific cancer because ibrutinib is chemically distinct
from the recited BTK inhibitor A225. (See Reply Br. 2.) Wang teaches not
only that BTK is “implicated” in B-cell cancers, but that BTK is an
“essential component of the B-cell-receptor signaling pathway” and that
“[c]onstitutive activation of B-cell receptor signaling appears to be essential
for the survival and proliferation of malignant B cells . . . .” (Wang 508.)
We are persuaded that this teaching creates a reasonable expectation of
success that the claimed methods would have been obvious, absent evidence
to the contrary, even if the prior art does not teach that all BTK inhibitors
would be effective in treating lymphomas. We are not persuaded that the
prior art must provide an absolute expectation of success by, for example,
anticipating the claimed methods, for the methods to have been obvious.
Appellant argues that the Examiner erred in rejecting the pending
claims over Hodous and Wang because neither presents experimental data
on the effectiveness in using A225 to treat Non-Hodgkin’s lymphoma or
mantle cell lymphoma. (See Appeal Br. 12–16; see Reply Br. 5–7.)
Appellant compares the facts of the prior art cited by the Examiner to the
facts of OSI Pharmaceuticals, LLC v. Apotex, Inc., 939 F.3d. 1375 (Fed. Cir.
2019), arguing that Hodous lacks any in vitro or in vivo efficacy data for use
with the claimed compounds of the present application in the treatment of
the recited lymphomas. (See Appeal Br. 13.)
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We are not persuaded that OSI is informative for this appeal. First,
OSI is the review of an inter partes reexamination by the Board, not the
review of the Board’s determination of a rejection by the Examiner. See
OSI, 939 F.3d at 1381. In an inter partes review, there is a presumption of
patentability and the burden of persuasion is on the petitioner to prove
unpatentability by a preponderance of the evidence and that burden never
shifts to the patentee. Dynamic Drinkware, LLC v. Nat'l Graphics, Inc., 800
F.3d 1375, 1378 (Fed. Cir. 2015). In contrast, during ex parte prosecution,
the claims have not been determined to be patentable. Once an examiner
finds a prima facie case of unpatentability upon initial review of the prior art
or on any other statutory condition of patentability, the burden shifts to the
applicant to come forward with rebuttal evidence or argument. In re Brandt,
886 F.3d 1171, 1176 (Fed. Cir. 2018). We are persuaded that the Examiner
has presented a prima facie case for obviousness based on the cited prior art
and Appellant fails to rebut that case with persuasive evidence.
The OSI court explained that it has not changed the standard for a
prima facie case of obviousness, stating:
To be clear, we do not hold today that efficacy data is always
required for a reasonable expectation of success. Nor are we
requiring “absolute predictability of success.” . . . .We conclude
only that, on these particular facts, a reasonable fact finder
could not find a reasonable expectation of success.
OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019)
(citation omitted). Thus, under the reasoning in OSI, if the facts compel a
determination that there would have been a reasonable expectation of
success, claimed subject matter is obvious even if the prior art does not
provide efficacy data. In contrast to the facts of OSI, the prior art cited by
the Examiner provides a clear statement of the functional characteristics
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needed to treat malignant B-cells: inhibition of BTK, an essential component
of B-cell signaling pathway, which is, in turn, essential to survival and
proliferation of B-cells. (See Wang 508; see Ans. 5, 10 (“In the instant case,
one would reasonably expect that a known inhibitor of BTK would be
effective for the treatment of non-Hodgkin’s lymphoma and mantle cell
lymphoma since BTK inhibition is known to be effective for treatment of
these diseases.”).)
Appellant asserts that the current Specification exemplifies treatment
with the claimed compound for: (1) 11 “primary CLL” patient samples
(Example 1), (2) “MCL/ABL-DLBCL” cell lines (Example 2) and (3) in
vivo “MCL model data,” but that none of the cited prior art presents
treatment data for the use of the claimed compounds and lymphomas.9 (See
Appeal Br. 15, citing Spec. 53–54 and Figs. 1–4e.) The disclosure of
Appellant’s Specification does not persuaded us that the cited prior art must,
on its own, teach each and every element of the claimed methods. Instead,
the
case law is clear that obviousness cannot be avoided simply by
a showing of some degree of unpredictability in the art so long
as there was a reasonable probability of success. . . . Indeed, a
rule of law equating unpredictability to patentability . . . would
mean that any new salt—including those specifically listed in
the [prior art patent] itself—would be separately patentable,
simply because the formation and properties of each salt must
be verified through testing. This cannot be the proper standard

9 We note that Appellant’s Specification provides one set of in vivo
experiments – in what seems to be a mouse model of mantle cell lymphoma.
(See Spec. 4:5–9 (legend to Figure 4a–e.) Appellant does not direct us to,
and we do not find, data in the Specification regarding an absence of side
effects, toxicities, or off-target actions with A225, which Appellant argues is
a flaw in the cited prior art. (See Appeal Br. 7–8; see Reply Br. 3–4.)
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since the expectation of success need only be reasonable, not
absolute.

Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Were we
to require efficacy data for the treatment of lymphoma with the claimed
compound, we would be requiring an absolute expectation of success, not a
reasonable one. Instead, we take into account what the prior art would have
taught to one of ordinary skill in the art to indicate it would have been
obvious to try the claimed compound for treatment of lymphomas, with a
reasonable expectation of success.
Appellant does not persuade us that the Examiner erred in rejecting
claim 10 and does not provides separate arguments against the rejection of
claims 9, 11, 12, and 17–20. Accordingly, we affirm the Examiner’s
rejection of these claims.
Appellant argues that claims 22–26 are separately patentable from the
other rejected claims. (See Appeal Br. 16–20.) Appellant’s claim 22 is an
independent claim that recites: “A method of treating lymphoma,
comprising: administering to a subject in need thereof a therapeutically
effective amount of . . . (A 225), or pharmaceutically acceptable salts, or
tautomers or stereoisomers thereof; wherein said lymphoma is Non-
Hodgkin’s lymphoma mantle cell lymphoma.” (Appeal Br. 67.) Although
Appellant refers to these claims separately, Appellant asserts the same
arguments as asserted against the rejection of the other pending claims. (See
id. 16–20.) For example, Appellant argues that “the combination of the
applied art does not give rise to a reasonable expectation of success for a
BTK inhibitor with a pyridine or pyrimidine ring core, such as A225, would
have a desirable effect in the treatment of [mantle cell lymphoma]” because
of the variety of different effects of BTK inhibitors, the differences in
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chemical structures, and the lack of efficacy data in the cited prior art.
(Appeal Br. 19.) For the reasons explained above, we are not persuaded by
these arguments. Accordingly, we are not persuaded that the Examiner erred
in rejecting claims 22–26 and affirm the rejection of these claims as well.
Conclusion
Upon consideration of the record and for the reasons given, we affirm
the Examiner’s rejection.
In summary:
Claims
Rejected
35 U.S.C. § Basis Affirmed Reversed
9–12, 17–20,
22–26
103 Hodous, Wang 9–12, 17–20,
22–26

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

AFFIRMED