Jean-Claude Pascal

Patent Trials and Appeals Board

Dec 21, 2020

2020003126 (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.
14/122,892 11/27/2013 Jean-Claude Pascal 552453: ETA9-002US 2751
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 2020-003126
Application 14/122,892
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 1–14 and 16–20 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 2020-003126
Application 14/122,892

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STATEMENT OF THE CASE
The Examiner rejected claims 1–14 and 16–20 in the Final Office
Action2 as follows:
Claims 1–14 and 16–20 under 35 U.S.C. § 103(a) over Verhaar et al.
(WO 2004/041839 A2, published May 21, 2004) (“Verhaar”), Heathcock et
al. (J. Am. Chem. Soc., 1982, 104:6081–6091) (“Heathcock”), Green &
Long (J. Chem. Soc., 1961, 2532–2543) (“Green”), Wang et al.
(Tetrahedron, 2007, 63:7977–7984) (“Wang”), and Takeuchi et al. (Bull.
Chem. Soc. Japan, 2001, 74:363–370) (“Takeuchi”). 2018 Final Act. 2; Ans.
3.
There are two independent claims on appeal, claims 1 and 14.
Independent claim 14 has the same synthesis steps recited in claim 1. Claim
1 is representative and reproduced below:
1. A process for the preparation of a compound of formula (I)

comprising the steps of
a) reacting a compound of formula (II) with a silylating
agent to produce a compound of formula (III), wherein P1 is R2-
Si-R3-R4, 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;

2 Final Office Action dated Oct. 4, 2018 (“2018 Final Act.”); the most recent
Final Office Action is dated Feb. 21, 2019.
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Application 14/122,892

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b) halogenation or sulfinylation of the compound of
formula (III) to produce a compound of formula (IV); wherein
X is halo, or -SO-R5, and R5 is a group selected from
C6-10 aryl or heteroaryl, each group being optionally substituted
by one or more substituents independently selected from chloro
or C1-4 alkyl;
wherein the halogenation or sulfinylation is performed by
directly reacting the compound of formula (III) with a
halogenation or sulfinylation reagent;

c) direct dehalogenation or desulfinylation of the
compound of formula (IV) to produce compound of formula
(V); and

d) reacting the compound of formula (V) with a reducing
agent to produce compound of formula (I).
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Application 14/122,892

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REJECTION
Claim 1 is directed to a method of making a compound of formula (I).
Step a) of the claim comprises reacting a compound of formula (II) with a
silylating agent to produce a compound of formula (III). The formula (II)
compound is silylated at its 3-position of the steroid ring. The Examiner
found that Verhaar in Schemes 1 and 3 describes adding a protecting group
to the 3-position as in step a) of claim 1, but not a silyl group as required by
the claim. 2018 Final Act. 2–3. However, the Examiner found that
Heathcock teaches a silyl protecting group and determines that the silyl
group is interchangeable with the protecting groups described in Verhaar.
2018 Final Act. 6.
In steps b) and c) of claim 1, the silylated compound (III) is
halogenated or sulfinylated to form compound (IV), which is then
dehalogenated or desulfinylated to introduce a double-bond in the five-
membered ring of the compound of formula (IV) to form compound (V).
The Examiner found that Verhaar does not teach introducing a double-bond
in this manner, but finds that each of Wang, Green, and Heathcock describe
halogenation and dehalogenation as recited in the claim to introduce a
double-bond (2018 Final Act. 4), and that Takeuchi describes the same using
sulfinylation and desulfinylation (2018 Final Act. 5)
For the last step of claim 1 in which the formula (V) compound is
reacted with a reducing agent to produce the formula (I) compound, the
Examiner appeared to rely on Scheme 1 of Verhaar. 2018 Final Act. 3.

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DISCUSSION
The Examiner cited Schemes 1 and 3 of Verhaar to meet step a) of
claim 1 where a silyl protecting group is added to the 3-position of a steroid
ring. Scheme 1 of Verhaar is copied below (compound (III) is annotated
with 3 and 17 to indication the 3- and 17-positions):

In Scheme 1 of Verhaar shown above, compound III, which is 15-
dehydroestrone, is reacted to place an acyl group at its 3- and 17-positions to
form compound VIb. Compound (III) of Verhaar differs from compound (II)
of claim 1. Compound (II) of claim 1 is an estrone and lacks the double-
bond in the five-membered ring.
Verhaar also does not teach silylation as required by step a) of the
claim. Appeal Br. 11.
The Examiner stated that “although Scheme 1 of Verhaar does not
utilize estrone, the reference renders obvious the utilization of estrone for the
production of estetrol” (Ans. 11), but provided no explanation as to why it
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would have been obvious to do so when the starting material and end-
product are different from the claimed starting and ending compounds.
Scheme 3, also cited by the Examiner, is closer to what is claimed.
Scheme 3 is copied below with annotations to show the 3-and 17-positions
of the estrone ring:

Scheme 3 of Verhaar, reproduced above, shows compound (I), an
estrone and the same compound (II) which is claimed, reacted with reagents
to add protecting groups to the 3- and 17-positions. The resulting compound
(II) is further reacted by “a bromination/base catalyzed dehydrobromination”
to form a double-bond in the five-membered ring. Verhaar 3:9–10. The
Examiner stated that bromination/debromination steps described by Verhaar
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are not the same as those recited in steps b) and c) of claim 1, but found that
each of Heathcock, Green, and Wang teach such steps and found it obvious
to do so using these methods. Final Act. 4–5.
While the starting compound in Scheme 3 of Verhaar is the same as
compound (II) of step a) of claim 1, the subsequent step of adding protecting
groups is different because the claim adds a silyl group to only position 3,
while Verhaar adds different protecting groups to positions 3 and 17, neither
of which are silyl groups. Therefore, the structure of compound IVa of
Verhaar differs from compound (III) of claim 1 by the absence of protecting
group at the 3-position and the presence of protecting group at the 17-
position, albeit not a silyl group as required by the claim.
In the subsequent step of Verhaar, in which the double-bond is added
to the five-membered ring, the protecting group from the 3-position is
removed. See Verhaar, conversion of compound (II) to compound (IVa). In
the claimed reaction, the introduction of the double-bond (compound (IV) to
compound (V) in step c)) does not remove the protect silyl group at the 3-
position and does not require a protecting group on the 17-position as used
in Verhaar when compound II is converted to compound IVa.
The Examiner cited several publications for teaching the introduction
of double-bond using halogenation and dehalogenation, as recited in steps b)
and c) of the claim. Wang is closest and a part of the synthetic scheme is
reproduced below (with annotations to show the
halogenation/dehalogenation steps and the position of the double-bond
which is introduced) (Wang 7979, Scheme 2):

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As shown above, Wang performs the same
halogenation/dehalogenation steps as steps b) and c) of claim 1, but does not
use the same starting compound and does not provide a protecting group at
the 3-position of the steroid ring as there is in compounds (III), (IV), and (V)
of claim 1. Furthermore, Wang does not further react the compound with the
double-bond, compound 5b, with a reducing agent as in step d) of claim 1,
but follows a different synthetic pathway to produce a different compound
than the formula (I) end product of the synthesis recited in rejected claim 1.
Heathcock and Green describe compounds which are structurally
different from the claimed compound and reactions (Appeal Br. 15–16) and
not as close structurally to the claimed compound as the compound in Wang.
The Examiner did not explain what would have motivated one of
ordinary skill in the art to place a silyl group at the 3-position of the estrone
ring and keep it there, when Verhaar in Scheme 3 removes the protecting
group at the 3-position in the step in which the double-bond is introduced.
The Examiner did not further provide a reason to have the protecting group
at the 3-position during the halogenation/dehalogenation steps. Wang does
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not compensate for the deficiency because Wang also does not use a
protecting group at the 3–position during halogenation and dehalogenation.
Furthermore, Scheme 3 of Verhaar protects the 17-position in the
five-membered ring with a bulky ring structure before introducing the
double-bond (conversion of compound II to compound IVa), and claim 1
does not use such a protecting group at this position in the analogous step of
the claim when the double-bond is introduced (conversion of claimed
compound (III) to compound (V)). Appeal Br. 14. The Examiner did not
address these differences in the Answer.
The Examiner relied on Takeuchi for its description of adding a bond
by sulfinylation/desulfinylation, but the compound is structurally different
the claimed compound and provides no reason to place a silyl at the 3-
position of the Verhaar compound.
In sum, we find too many differences between the prior art cited by
the Examiner, and insufficient explanation as to why one of ordinary skill in
the art would have modified the prior art to have arrived at the synthetic
process recited in claim 1. Specifically, Verhaar places a different protecting
group at the 3-position and removes it during the introduction the double-
bond in contrast to the claimed reaction. The claim also only has a carbonyl
group at the 17-position during the halogenation/dehalogenation steps while
Verhaar has a protecting ring moiety. The Examiner did not adequately
explain why these differences would have been obvious to one of ordinary
skill in the art. The Examiner mentioned adjusting reaction conditions to
achieve increased yields, but did not provide evidence that the cited
publications relied upon for these processes would have been reasonably
expected to produce higher yields than those in Verhaar. Ans. 12.
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For the foregoing reasons, the obviousness rejection of claim 1 is
reversed, and of claim 14 which recites the same steps. Dependent claims 2–
13 and 16–20 incorporate all the limitations of claims 1 and 14 and are
reversed for the same reasons.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–14, 16–20 103 Verhaar,
Heathcock, Green,
Wang, Takeuchi
1–14, 16–20

REVERSED