MERCK & CIE

Patent Trials and Appeals Board

Sep 2, 2020

15711316 - (D) (P.T.A.B. Sep. 2, 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.
15/711,316 09/21/2017 Roger SCHIBLI MERCK-4432-C01 9717
23599 7590 09/02/2020
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON, VA 22201
EXAMINER
DONOHUE, SEAN R
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
09/02/2020 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):
docketing@mwzb.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte ROGER SCHIBLI, RUDOLF MOSER,
CRISTINA MAGDALENA MULLER, SIMON MENSAH AMETAMEY,
TOBIAS LUDWIG ROSS, and VIOLA GROEHN
__________

Appeal 2020-000496
Application 15/711,316
Technology Center 1600
__________

Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
LILAN REN, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL

Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–12 and 15–22. 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 MERCK & CIE, Schaffhausen,
Switzerland, as the real party in interest. Appeal Br. 1.
Appeal 2020-000496
Application 15/711,316

2
STATEMENT OF THE CASE
Appellant’s invention “is directed towards new 18F-folate
radiopharmaceuticals, wherein fluorine-18 is covalently linked to the
glutamate portion of a folate or derivative thereof.” Spec. 1.
Appellant’s claim 1, the sole independent claim on appeal, reads as
follows:
1. A compound of formula I,

wherein
P is a pteroyl group or a derivative thereof,
Xa, Xb are independently of each other C, N, O, or S,
Ra, Rb are independently of each other H or straight-chain
or branched C1–C12 alkyl, C3–C6 cycloalkyl, or C5–
C14 aryl or C5–C14 heteroaryl, which independently
of each other are unsubstituted or substituted by at
least one CN, Hal, or NO2, and wherein one or
more of embedded, non-adjacent CH2 groups may
independently be replaced by -O-, -CO-, -CO-O-, -
CO-NR’-, -SO2-, -CH=CH-, or -C≡C-
R’ is H or C1–C6 alkyl; and
Z1, Z2 are independently of each other H or 18F,
with the proviso that one of Z1 and Z2 is 18F.
Appeal Br. 25 (emphasis added).
Appeal 2020-000496
Application 15/711,316

3
The following rejections are before us for review:
(1) Claims 1–4, 7–11, 15, 16, and 18 under 35 U.S.C. § 103(a) as
being unpatentable over Bettio2 and Dinkelborg3 (Ans. 3–5);
(2) Claims 1–12, 15, 16, 18, 21, and 22 under 35 U.S.C. § 103(a) as
being unpatentable over Bettio, Dinkelborg, and Coward4 (Ans. 6–7); and
(3) Claims 1–4, 7–11, and 15–20 under 35 U.S.C. § 103(a) as being
unpatentable over Bettio, Dinkelborg, Arstad,5 and Low6 (Ans. 7–8).
DISCUSSION
The Examiner’s Prima Facie Case
In rejecting Appellant’s claim 1 over Bettio and Dinkelborg, the
Examiner cites Bettio as describing 18F-labeled folate derivatives useful for
positron emission tomography (PET) imaging of folate receptor-positive
tumors. Ans. 3–5. The Examiner notes in particular that the 18F-label is
attached to the native folate molecule as part of a fluorobenzylamine
prosthetic group. See id. at 4 (showing compounds 2 and 3 of Bettio).
The Examiner notes that native unlabeled folate, shown as compound
1 in Bettio’s Figure 1, “reads in part” on a compound of formula I of
Appellant’s claim 1. Ans. 4. In particular, the Examiner finds that the
native unlabeled folate taught in Bettio differs from the compound of

2 Andrea Bettio et al., Synthesis and Preclinical Evaluation of a Folic Acid
Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive
Tumors, 47 J. NUCL. MED. 1153–1160 (2006).
3 CA 2 667 395 A1 (published May 8, 2008).
4 US 4,628,090 (issued Dec. 9, 1986).
5 WO 2006/067376 A2 (published June 29, 2006).
6 WO 2006/071754 A2 (published July 6, 2006).
Appeal 2020-000496
Application 15/711,316

4
Appellant’s claim 1 in that Bettio “do[es] not teach a folate derivative of the
instant claims where at least one of Z1 or Z2 is 18F.” Id. at 5.
The Examiner cites Dinkelborg as evidence that the compound of
Appellant’s claim 1 would have been obvious despite the differences
between the claimed compound and the native unlabeled folate taught in
Bettio. Ans. 5. Specifically, the Examiner cites Dinkelborg as describing
the preparation of 18F-labeled glutamate derivatives, in which the 18F is
present at the position corresponding to the position of the 18F recited in
Appellant’s claim 1. Id.
Based on the references’ combined teachings, the Examiner concludes
that it would have been obvious to “modify the native folic acid taught by
Bettio et al. by incorporating 18F at the folic acid moiety as taught by
Dinkelborg et al. because it would advantageously enable minimum
deviation from its native structure without the [need] for a prosthetic group.”
Ans. 5. In addition, the Examiner reasons, it would have been obvious to
“detect cells overexpressing the folate receptor in vitro as taught by
Dinkelborg et al. because it would advantageously enable comparison with a
gold standard oncological investigations.” Id.
Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden . . . of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant in
response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
Appeal 2020-000496
Application 15/711,316

5
In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), although the
Supreme Court emphasized “an expansive and flexible approach” when
evaluating claims for obviousness, id. at 415, the Court nonetheless also
reaffirmed the importance of determining “whether there was an apparent
reason to combine the known elements in the fashion claimed by the patent
at issue.” Id. at 418.
Consistent with the flexible approach emphasized in KSR, our
reviewing court has explained that, in cases involving claims to new
chemical compounds, “it remains necessary to identify some reason that
would have led a chemist to modify a known compound in a particular
manner to establish prima facie obviousness of a new claimed compound.”
Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357
(Fed. Cir. 2007).
In other words, establishing that a chemical compound would have
been obvious requires “a showing that the prior art would have suggested
making the specific molecular modifications necessary to achieve the
claimed invention.” Takeda, 492 F.3d at 1356 (emphasis added; internal
quotations omitted). See also Innogenetics, N.V. v. Abbott Labs., 512 F.3d
1363, 1374 n.3 (Fed. Cir. 2008) (Even post-KSR, “[w]e must still be careful
not to allow hindsight reconstruction of references to reach the claimed
invention without any explanation as to how or why the references would be
combined to produce the claimed invention.”).
In the present case, having carefully considered all of the arguments
and evidence advanced by the Examiner and Appellant, Appellant persuades
us that the Examiner has not explained with sufficient specificity why the
combined teachings of Bettio and Dinkelborg would have suggested
Appeal 2020-000496
Application 15/711,316

6
preparing a folate derivative having an 18F atom at one of the specific
positions required by Appellant’s claim 1. We acknowledge, as the
Examiner contends, that folate includes a glutamate moiety within its
structure. See Ans. 9 (“The folate in Bettio is not structurally unrelated to
the glutamate in Dinkelborg because folate comprises glutamate.”). The
mere fact that folate might not be unrelated to glutamate does not persuade
us, however, that a skilled artisan would have been motivated to apply, to
folate, Dinkelborg’s teachings regarding 18F fluorination of glutamate. As
Appellant points out, the overall structure of native folate differs
significantly from the glutamate derivatives described in Dinkelborg as
being derivatized with 18F atoms. Compare Bettio 1154 (compound 1 of
Bettio’s Figure 1 showing native folate) to Dinkelborg 28–31 (showing
structures of glutamate derivatives 18F-fluorinated in Dinkelborg’s Schemes
1–3).
Given the significant differences between the structure of native folate
and the structures of the glutamate derivatives described in Dinkelborg as
being derivatized with 18F atoms, we agree with Appellant that, absent
improper hindsight gleaned from Appellant’s disclosure, a skilled artisan
would not have considered native folate to be interchangeable with
glutamate in Dinkelborg’s 18F-fluorination process. We therefore also agree
with Appellant that the Examiner has not explained sufficiently why the
combined teachings of Bettio and Dinkelborg would have suggested
preparing the specific compound recited in Appellant’s claim 1.
We acknowledge, as the Examiner contends, that claim 1 is directed
to a compound, rather than a method of synthesizing the compound. See
Ans. 8; see also id. at 10 (“[T]here are no method of synthesis claims under
Appeal 2020-000496
Application 15/711,316

7
rejection.”). Our reviewing court’s predecessor has explained, however, that
“if the prior art of record fails to disclose or render obvious a method for
making a claimed compound, at the time the invention was made, it may not
be legally concluded that the compound itself is in the possession of the
public.” In re Hoeksema, 399 F.2d 269, 274 (CCPA 1968); see also In re
Payne, 606 F.2d 303, 314 (CCPA 1979) (“References relied upon to support
a rejection under 35 USC § 103 must provide an enabling disclosure, [i]. e.,
they must place the claimed invention in the possession of the public. . . .
An invention is not possessed absent some known or obvious way to make
it.”) (emphasis added; citation and internal quotations omitted).
In the present case, given the significant differences between the
structure of native folate and the structures of the glutamate derivatives
described in Dinkelborg as being derivatized with 18F atoms, we are not
persuaded that the Examiner has explained with sufficient specificity how
the combined teachings of Bettio and Dinkelborg would have provided a
known or obvious way to make the compound of Appellant’s claim 1. As to
that issue, the Examiner argues as follows:
Bettio teaches that an unprotected folate, which includes an
unprotected pteroate, can be coupled to
4-[18F]fluorobenzylamine in only 30 min. On pg. 1154, Bettio
states that a DMSO solution containing folic acid was added to
the reaction vial and the coupling was formed by heating at
100°C for 30 min. On pg. 29, Dinkelborg teaches a 2 step
radiosynthesis of 4-[18F]fluoroglutamic acid when starting from
a nickel complex and pg. 31, Dinkelborg teaches the 1 step
radiosynthesis of protected 4-[18F]fluoroglutamic acid without a
Ni complex. A person of ordinary skill in the art would have
been motivated to couple the 4-[18F]fluoroglutamate derivative
in Dinkelborg to an activated pterote, which Bettio suggests can
be done in 30 min, in order to gain the following advantages: (i)
Appeal 2020-000496
Application 15/711,316

8
reduced number of impractical to separate regioisomers (greater
purity), and (ii) 18F-labeled derivative with minimal structural
deviation from native folate. Appellants have not provided any
evidence that the claimed 18F-labelled compounds were not
enabled prior to the instant invention.
Ans. 10–11.
We are not persuaded. The Examiner does not explain, specifically,
how Bettio’s teaching of coupling a fluorobenzylamine to an unprotected
folate suggests that a skilled artisan would have been able to perform the
distinct reaction posited by the Examiner, coupling Dinkelborg’s
fluoroglutamate to a pteroate moiety. Nor does the Examiner support this
alternative rationale by identifying persuasive evidence suggesting that,
rather than following Bettio’s teaching of coupling a fluorobenzylamine to
an unprotected folate, a skilled artisan would have been motivated instead to
perform a different reaction, the coupling of Dinkelborg’s fluoroglutamate to
a pteroate moiety.
We acknowledge, as the Examiner contends, that Appellant may rebut
the Examiner’s prima facie case by advancing evidence that the prior art did
not enable preparation of the claimed compound. See Ans. 11. The
Examiner, however, bears the initial burden of providing an evidentiary
basis to support a conclusion of obviousness. See In re Fritch, 972 F.2d
1260, 1265 (Fed. Cir. 1992) (“[The Examiner] can satisfy this burden only
by showing some objective teaching in the prior art or that knowledge
generally available to one of ordinary skill in the art would lead that
individual to combine the relevant teachings of the references.”).
In the present case, while we acknowledge the teachings in Bettio and
Dinkelborg identified by the Examiner, we are not persuaded that the
Examiner has explained with sufficient specificity why, absent improper
Appeal 2020-000496
Application 15/711,316

9
hindsight, those teachings suggest the specific compound recited in
Appellant’s claim 1. Nor are we persuaded that the Examiner has explained,
with sufficient specificity, why the identified teachings in Bettio and
Dinkelborg establish that a skilled artisan would have been able to make the
compound of Appellant’s claim 1. We therefore reverse the Examiner’s
rejection of claim 1, and its dependent claims, for obviousness over Bettio
and Dinkelborg.
In rejecting claim 1 over Bettio, Dinkelborg, and Coward, the
Examiner relies on teachings in Bettio and Dinkelborg cited in the rejection
discussed above, and additionally cites Coward “as discussed above.” Ans.
6. While the Examiner’s Answer does not previously mention Coward, the
Examiner’s Answer later cites Coward as teaching “folate analogs of the
instant formulas and there is a clear teaching and suggestion to place a
fluorine on the glutamate of the folate derivatives therein.” Ans. 9–10
(citing Coward 13:10–19 (claim 1)). Based on this teaching, the Examiner
reasons as follows:
The addition of fluorine to glutamate of a folate derivative can
be readily gleaned from Coward, prior art, and not hindsight
reconstruction. The substitution of one H on the glutamate of
folate with F reduces the structural deviation folate in
comparison to the fluorinated derivatives in Bettio because said
substitution merely replaces one atom for another (H for F;
Dinkelborg and Coward) in contrast to replacing an α- or γ-
carboxyl OH with a 4-fluorobenzylamine (Bettio).
Id. at 10; see also id. at 12 (“Coward was relied on for teaching the
replacement of a glutamate moiety of a folate derivative with a
4-fluoroglutamate. Bettio and Dinkelborg teach methods of 18F-labeling.”).
We find that the Examiner’s citation of Coward does not remedy the
deficiencies of the combination of Bettio and Dinkelborg, discussed above,
Appeal 2020-000496
Application 15/711,316

10
in relation to Appellant’s claim 1. In particular, even acknowledging that
Coward’s methotrexate includes a glutamate moiety within its structure, we
are not persuaded that the Examiner has identified any specific teachings in
Coward that explain sufficiently why a skilled artisan would have prepared
the compound of Appellant’s claim 1, when combined with Bettio and
Dinkelborg. While the Examiner asserts that addition of a fluorine to
glutamate of a folate derivative “can be readily gleaned from Coward” (Ans.
10), the Examiner does not point to any specific teaching in support of that
assertion, nor does the Examiner explain, specifically, why Coward would
have led a skilled artisan to that conclusion.
Similarly, while the Examiner asserts that a skilled artisan “could
have combined the publications[’] description of the invention with his or
her own knowledge to make the claimed invention” (Ans. 12 (citing MPEP
§ 2121.01)), we are not persuaded that the Examiner has explained with
adequate specificity why a skilled artisan could have, or even would have,
combined the cited teachings in the prior art in the manner required to arrive
at the compound recited in Appellant’s claim 1. Because we are not
persuaded that the Examiner has explained, with sufficient specificity, why
Bettio, Dinkelborg, and Coward would have suggested preparing the
compound of Appellant’s claim 1, we reverse the Examiner’s rejection of
claim 1, and its dependent claims, for obviousness over Bettio, Dinkelborg,
and Coward.
In rejecting Appellant’s claims 1–4, 7–11, and 15–20 over Bettio,
Dinkelborg, Arstad, and Low, the Examiner relied on Arstad and Low as
evidence that it would have been obvious to use an 18F-labeled folate
derivative in diagnostic processes recited in Appellant’s claims 15–20,
Appeal 2020-000496
Application 15/711,316

11
which depend from claim 1, discussed above. See Ans. 7–8. Accordingly,
because the Examiner does not identify, nor do we discern, any specific
teachings in Arstad and Low that remedy the deficiencies in the combination
of Bettio and Dinkelborg discussed above in relation to claim 1, we also
reverse the Examiner’s rejection of claims 1–4, 7–11, and 15–20 over Bettio,
Dinkelborg, Arstad, and Low.

DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–4, 7–11,
15, 16, 18
103(a) Bettio, Dinkelborg 1–4, 7–11,
15, 16, 18
1–12, 15,
16, 18, 21,
22
103(a) Bettio, Dinkelborg,
Coward
1–12, 15,
16, 18, 21,
22
1–4, 7–11,
15–20
103(a) Bettio, Dinkelborg,
Arstad, Low
1–4, 7–11,
15–20
Overall
Outcome
1–12, 15–
22

REVERSED