Jean-Claude Pascal

Patent Trials and Appeals Board

Dec 21, 2020

2020002106 (P.T.A.B. Dec. 21, 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.
14/122,872 11/27/2013 Jean-Claude Pascal 552451: ETA9-001US 7410
12779 7590 12/21/2020
Lathrop GPM LLP
28 State Street
7th Floor
Boston, MA 02109
EXAMINER
BADIO, BARBARA P
ART UNIT PAPER NUMBER
1628
NOTIFICATION DATE DELIVERY MODE
12/21/2020 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):
bostonpatent@lathropgage.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JEAN-CLAUDE PASCAL

Appeal 2020-002106
Application 14/122,872
Technology Center 1600
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected the claims under 35 U.S.C. § 103 as obvious.
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s
decision to reject the claims. 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 ESTETRA
S.P.R.L. Appeal Br. 3.
Appeal 2020-002106
Application 14/122,872

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STATEMENT OF THE CASE
The Examiner rejected claims 1, 8–14, and 22 in the Final Office
Action as follows:
Claims 1, 8–14, and 22 under 35 U.S.C. § 103 as obvious in view of
Suzuki et al., Steroids, 1995, 60: 277–284 (“Suzuki”) and Li et al., Steroids,
2010, 75: 859–869 (“Li”). Final Act. 2–3; Ans. 3.
Claims 1, 8–14, and 22 under 35 U.S.C. § 103 as obvious in view of
Suzuki, Li, Bohlmann et al., U.S. Patent No. 4,923,640, issued May 8, 1990
(“Bohlmann”), and Takahashi et al., Tetrahedron, 1985, 41: 5747-5754
(“Takahashi”). Final Act. 2–3; Ans. 7.
There are two independent claims on appeal, claims 1 and 14. Claim 1
is representative and reproduced below:
1. A process for the preparation of a compound of formula (I)

said process comprising the steps of
a) reacting a compound of formula (II), with a silylating
agent to produce a compound of formula (II), wherein P1 is R2-
Si-R3R4, and P2 is R2-Si-R3R4, wherein R2, R3 and R4 are each
independently a group selected from C1-6 alkyl or phenyl, each
group being optionally substituted by one or more substituents
independently selected from fluoro or C1-4 alkyl;
Appeal 2020-002106
Application 14/122,872

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b) reacting the compound of formula (III) in the presence
of palladium acetate or palladium chloride to produce a
compound of formula (IV); and

c) reacting the compound of formula (IV) with a reducing
agent to produce the compound of formula (I).

Independent claim 14 has the same synthesis steps recited in claim 1.
The two obvious rejections are based on the same two primary prior
art publications and reasoning. However, two additional publications are
cited in the second rejection as further evidence of obviousness. We consider
both rejections together.

DISCUSSION
Claim 1 is directed to a method of making a compound of formula (I).
The Examiner begins the rejection by starting with the disclosure in Suzuki.
The Examiner finds that Suzuki describes reducing 15-dehydroestrone with
lithium aluminum hydride, a reducing agent, to reduce the carbonyl group on
the five-membered ring to a hydroxyl group. Ans. 3. This step corresponds
to step c) of claim 1 (claimed compound (IV) is a 15-dehydroestrone). The
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Application 14/122,872

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Examiner finds that Suzuki does not describe how to make the 15-
dehydroestone, but finds that Suzuki discloses that 15-dehydroestone is
derivable from estrone in five steps. Ans. 4. The Examiner therefore turns to
Li for describing the conversion of an estrone to 15-dehydroestone. Ans. 4–
5. The steps described in Li correspond to steps a) and b) of claim 1
(claimed compound (II) is an estrone).
The Examiner finds that Li describes compound (II) of claim 1, the
estrone, and reacting it with two different agents in two steps to add two
different protecting groups to the estrone, first adding a methyl group to the
3-position and then adding a silyl group to the 17-position. Ans. 4–5. Step a)
of the claim, however, requires the addition of silyl groups at both the 3- and
17- positions of the estrone to form compound (III). The Examiner finds,
however, that protecting groups are interchangeable, and therefore
determined it would have been obvious to one of ordinary skill in the art to
include two silyl protecting groups as required by claim 1, when compound
(II) is converted into compound (III) in step a) of the claim. Ans. 5.
The Examiner further finds that Li removes the silyl protecting group
from the 17-position with palladium as required by step b) of claim to
change the position of the double-bond in the five membered ring,
converting compound (III) to compound (IV), the latter which is the 15-
dehydroestrone used as a starting material in Suzuki. Ans. 5.
In the second rejection, the Examiner further cites Bohlmann for
teaching that palladium-catalyzed dehydration for the introduction of a 15-
double bond is advantageous and Takahashi for adding a silyl group to the 3-
position of a steroid ring as claimed. Ans. 9–10.
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Application 14/122,872

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The Examiner cites the following disclosure from Li to meet steps a)
and b) of claim 1 (annotations added):

Reaction Scheme 8 of Li is copied above. The reaction Scheme 8
begins with compound 39, which is an estrone, and the same compound (II)
depicted in step a) of claim 1. The compound is annotated to label the 3- and
17-positions. Li shows that the estrone (39) is treated with an iodide
compound in step a to add a methoxy group at the 3-position of the estrone
to produce compound 40. In step b, compound 40 is treated with a silylating
agent to add a silyl protecting group to the 17-position to produce compound
41. The structure of compound 41 is different from the compound produced
in step a) of claim 1. In claimed step a), the estrone is treated only with a
silylating agent which results in the production of compound (III) having a
silyl protecting group at both the 3- and 17-positions. In contrast, compound
41 of Li has a methoxy group at the 3-position and a silyl protecting group at
the 17-position. While the Examiner’s reasoning is that such a change is
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Application 14/122,872

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trivial because of the interchangeability of protecting groups, as Appellant
argues, the change is more complicated. Appeal Br. 10.
Specifically, as explained below, the subsequent reactions in which
the protecting groups are removed by palladium are different when step c of
Li is compared to step b) of rejected claim 1. Compare the conversion of
compound 41 to compound 42 in step c of Li to the conversion of compound
(III) to compound (IV) in step b) of claim 1.
Compound 41 is treated in step c of Li with palladium acetate to
preferentially remove only the silyl protecting group at the 17-position
which results in a change in the position of the double-bond, as shown by the
arrows in Scheme 8 reproduced above. The Examiner does not provide a
rationale, coupled with a reasonable expectation of success, that the
palladium reaction step c in Li, when applied to a compound with a silyl
groups at both the 3- and 17-positions, would preferentially remove only the
silyl group at the 17-position and leave the silyl group at the 3-position intact
as required by step b) of claim 1 to produced claimed compound (IV). In
other words, Li teaches that palladium removes the silyl group, but not the
methoxy group. See Li, reaction Scheme 8 showing the conversion of
compound 41 to compound 42. The Examiner does not provide a reason to
place a silyl group on the 3-position, rather than a methoxy group as in Li,
with a reasonable expectation that it would not be cleaved using palladium
under the reaction conditions described by Li. See also Declaration under 37
C.F.R. § 1.132 by Dr. Damien Cornut, dated Jan. 14, 2019 (“Cornut Decl.),
¶ 5 (“I understand that different protecting groups, for example: esters, alkyl
ethers, acyl, and silyl ethers, exhibit different ranges of stability under
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Application 14/122,872

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different reaction conditions, and can unpredictably impact the number of
steps used, and hence, the overall yield and feasibility of a process.”).2
The Examiner cites Bohlmann for teaching that it is advantageous to
introduce a double-bond using palladium catalyzed dehydration. Ans. 3. See
step b) of claim 1. Bohlmann described a silyl protecting group at the 17-
position, as in step b) of claim 1 when carrying out the palladium catalyzed
reaction, but the 3-position is protected by a different group (Bohlmann
1:38–2:41) and therefore does not provide evidence that, when both
positions are protected by silyl groups and then treated with the palladium
catalyst, one group would preferentially be cleaved, leaving the other silyl
group at the 3-position still intact. Bohlmann also does not provide evidence
that conditions could be routinely be optimized to remove the silyl group
from the 17-position and not the 3-position. Indeed, both publications that
the Examiner cites for the palladium catalyzed introduction of a double-bond
when converting compound (III) to compound (IV), do not have a silyl
group on the 3-position. The Examiner therefore did not meet the burden of
showing that it is interchangeable to use any protecting group on the 3-
position in view of the teachings in both Suzuki and Bohlmann that only the
position which is attacked to produce the double-bond has the silyl group.
The Examiner further cites Takahashi for its teaching of adding a silyl
group to the 3-position. Ans. 10 (citing Scheme 4 of Takahashi on page
5749). But the reaction described in Takahashi adds an acetate (-OAc) to the

2 Dr. Cornut states that he is “a Chemist in charge of the API synthesis
process development at Mithra Pharmaceuticals, Liege, Belgium, which is
directed to women's health, with a particular focus on fertility, contraception
and menopause.” Cornut Decl. ¶ 1.

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17-position and then preferentially removes the acetate in subsequent steps,
while leaving the silyl group intact. Takahashi therefore does not provide
persuasive evidence of a reason to place a silyl group at both the 3- and 17-
positions and preferentially only remove the silyl group from the 17-
position. As discussed by Appellant, Takahashi involves different synthetic
steps and produces a different product and therefore does not appear to be
particularly relevant to the process steps recited in claim 1. Appeal Br. 15.
The Examiner bears the burden of establishing a prima facie case of
unpatentability. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
Because that burden was not met here, we are compelled to reverse the
obviousness rejection of claim 1. Rejected claims 8–14 and 22 have the
same steps recited in claim 1 and are reversed for the same reasons.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 8–14, 22 103 Suzuki, Li 1, 8–14, 22
1, 8–14, 22 103 Suzuki, Li,
Bohlmann,
Takahashi
1, 8–14, 22
Overall
Outcome
1, 8–14, 22

REVERSED