Ex Parte 6528666 et al

Board of Patent Appeals and Interferences

Oct 27, 2010

95000087 (B.P.A.I. Oct. 27, 2010)

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.
95/000,087 04/05/2005 6528666 515-4232 1171
32172 7590 10/27/2010
DICKSTEIN SHAPIRO LLP
1633 Broadway
NEW YORK, NY 10019
EXAMINER
HUANG, EVELYN MEI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
10/27/2010 PAPER
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.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
____________

FARMABIOS, S.P.A.
Requester and Respondent

v.

Patent of HOVIONE LIMITED
Patent Owner and Appellant
____________

Appeal 2010-007394
Reexamination Control 95/000,087
Patent US 6,528,666
Technology Center 3900
____________

Before ROMULO H. DELMENDO, RICHARD M. LEBOVITZ, and
JEFFREY B. ROBERTSON, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL1

1 The one-month time period for filing a request for rehearing, as recited in
37 C.F.R. § 41.79, and the two-month time period for filing an appeal, as
recited in 37 C.F.R. § 1.304 (see 37 C.F.R. § 1.983(b)(1)), both begin to run
from the “MAIL DATE” shown on the PTOL-90A cover letter attached to
this decision.

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Patent US 6,528,666

2
This is a decision on the appeal by the Patent Owner of U.S. Patent
No. 6,528,666 from the Patent Examiner’s rejections of claims 1-15 in an
inter partes reexamination proceeding. The Board’s jurisdiction in this
appeal is under 35 U.S.C. §§ 6(b), 134, and 315. We reverse.

STATEMENT OF THE CASE
The subject of this inter partes reexamination is U.S. Patent No.
6,528,666 (hereinafter “the ‘666 patent”) issued March 4, 2003. The named
inventors are Ivan Villax and Zita Mendes. The Patent Owner is Hovione
Limited, who is also the Appellant in this Appeal.
A request for an inter partes reexamination was made on April 5,
2005, pursuant to 35 U.S.C. §§ 311-318 and 37 C.F.R. § 1.915. The
Requester was Farmabios S.p.A., who is the Respondent in this appeal
(Revised Requester’s Respondent Brief filed October 7, 2009, which was
captioned “REVISED REQUESTER’S APPEAL BRIEF,” p. 1 (hereinafter
“Req. App. Br.”)). The Requester cited six printed publications said to raise
substantial new questions of patentability (Request for Inter Partes
Reexamination 1-2, dated April 5, 2005). The Requester proposed rejections
based on the publications (id. at 4-9). None of these rejections are on
appeal in this proceeding, although the printed publications provided by the
Requester are cited in the appealed rejection. The Requester did not appeal
the Examiner’s decision not to adopt the proposed rejections.
A Right of Appeal Notice (RAN) was mailed April 20, 2009
indicating that claims 1-15, all the pending claims in the reexamination
proceeding of the ‘666 patent, were rejected.
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The claims of the issued patent are directed to a process for preparing
flumethasone, flumethasone 21-acetate, or its 17-carboxyl analogue of the
formula I. According to the ‘666 patent, flumethasone is a corticosteroid
with enhanced anti-inflammatory activity, although “its clinical application
has not been widely used” (‘666 patent, col. 1, ll. 8-11). The claimed
method involves steps in which a 9,11-epoxysteroid is reacted with benzoyl
chloride to attach a benzoyl protection group at the 3-position to form a 3-
enolic ester, and then fluorinated at the 6-position, deprotected, and
fluorinated again at the 9-position.
The ‘666 patent was issued with 18 claims. Claims 16-18 were
cancelled during the reexamination proceeding. Claims 1-15 remain in the
patent and stand rejected under 35 U.S.C. § 103(a) as obvious in view of
Takahara,2 Godard,3 Jenkins,4 and Greene5 (Ans. 4). This is the only
rejection on appeal.
We heard oral arguments from both parties on September 22, 2010. A
written transcript will be entered into the record in due course.
No claim amendments were made during the reexamination
proceeding. Claim 1 is the only independent claim on appeal and reads as
follows:

2 Japanese Patent No. 60-6700 issued January 14, 1985; English translation
of record.
3 U.S. Patent No. 5,478,957 issued Dec. 26, 1995.
4 U.S. Patent No. 3,817,978 issued June 18, 1974.
5 Theodora W. Greene and Peter G. M. Wuts, PROTECTIVE GROUPS IN
ORGANIC SYNTHESIS 101-02 (2d. ed. 1991).
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1. A process for preparing flumethasone, 6α,9α-difluoro-11β,17α,21-
trihydroxy-16α-methyl-pregna-l,4-diene-3,20-dione, flumethasone 21-
acetate or its 17-carboxyl androsten analogue of the formula:

characterized by the fact that a compound of the formula:

is reacted with benzoyl chloride to form a 3-enolic ester of the
formula:

the enol benzoate (IIIa) thus obtained is reacted with an electrophilic
fluorination agent so as to introduce fluorine the 6α- position,
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the enol benzoate (IIIb) is deprotected at C3 to yield a compound of the
formula:

the 9,11-epoxy group of compound IV is fluorinated by reaction with
hydrofluoric acid to yield flumethasone 2 1-acetate, and optionally
the flumethasone 21-acetate is hydrolyzed in the presence or absence
of an oxidization agent to yield compound I or flumethasone, respectively.

ISSUE
Whether the Examiner, based on all the evidence of record, showed
that formation of compound IIIb of claim 1 was an inherent and necessary
result of carrying out Takahara’s process.

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LEGAL PRINCIPLES
“To establish inherency, the extrinsic evidence must make clear that
the missing descriptive matter is necessarily present in the thing described in
the reference . . . . Inherency, however, may not be established by
probabilities or possibilities. The mere fact that a certain thing may result
from a given set of circumstances is not sufficient.” In re Robertson, 169
F.3d 743, 745 (Fed. Cir. 1999) (internal quotation marks and citations
omitted).
Where, as here, the claimed and prior art products are identical
or substantially identical, or are produced by identical or
substantially identical processes, the PTO can require an
applicant to prove that the prior art products do not necessarily
or inherently possess the characteristics of his claimed product.
See In re Ludtke, supra. Whether the rejection is based on
“inherency” under 35 U.S.C. § 102, on “prima facie
obviousness” under 35 U.S.C. § 103, jointly or alternatively,
the burden of proof is the same, and its fairness is evidenced by
the PTO's inability to manufacture products or to obtain and
compare prior art products. See In re Brown, 459 F.2d 531, 59
CCPA 1036, 173 USPQ 685 (1972).
In re Best, 562 F.2d 1252, 1255 (CCPA 1977).

Once “the PTO shows sound basis for believing that the products of
the applicant and the prior art are the same, the applicant has the burden of
showing that they are not.” In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990).
An applicant may rebut a prima facie case of obviousness by
providing a “showing of facts supporting the opposite
conclusion.” Such a showing dissipates the prima facie holding
and requires the examiner to “consider all of the evidence
anew.” In re Piasecki, 745 F.2d 1468,1472 (Fed. Cir. 1984); In
re Rinehart, 531 F.2d 1048, 1052 (CCPA 1976).
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In re Kumar, 418 F.3d 1361, 1368 (Fed. Cir. 2005).

FINDINGS OF FACT (“FF”)
1. The following table is a summary of pertinent facts in claim 1 of the ‘666
patent, Takahara, Farmabios,6 and Godard. Each describes a process of
fluorinating a 9,11-epoxysteroid at the 6-position and deprotecting at the 3-
position of the 9,11-epoxysteroid compound. Since many of the facts in this
case involve specific positions of a steroid structure, we reproduce the
structure with each numbered carbon (reproduced from Takahara, p. 2):

The steroid structure is reproduced above with its carbon positions
numbered from 1 to 21.

6 Filippo La Loggia et al., US 6,794,503 B2 issued Sept. 21, 2004
(hereinafter “Farmabios”).
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Takahara
2. Takahara describes a method for preparing 6α-fluoro-9β, 11β-
epoxysteroid compounds (Takahara, p. 1).
3. Takahara describes the use of the fluorination agent CH3COOF to
fluorinate aromatic or saccharide compounds (id. at 3).
4. Takahara shows the following reaction schema:
9,11
epoxide
3-
position
16-position Androstane
or
Pregnane
Fluorination
Agent
Claim 1 Y benzoyl 16α-methyl Pregnane
Takahara Y benzoyl

(p. 8)
16β-methyl

(p. 8)
Pregnane

(p. 8)
CH3COOF

(p. 7-8)
Farmabios Y C1-C4

(col. 2,
ll. 45-65)
16α-methyl
16β-methyl

(col. 2, l. 43;
col. 6, Ex. 3-
4)
Pregnane

(col. 2, ll.
51-65)
Selectfluor

(col. 3, l.
43; col. 6,
Ex. 3-4)
Goddard Y benzoyl

(col. 5,
ll. 48-49;
col. 6, ll.
19-22)
16α-methyl

(col. 5, ll. 48-
49; col. 6, ll.
19-22)
Androstane

(col. 5, ll.
48-49; col.
6, ll. 19-22)
Selectfluor

(col. 6, ll.
25-26)
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The reaction schema reproduced above from Takahara shows an
aromatic compound (1) and a saccharide compound (2) in which CH3COOF
is used to introduce a fluorine (id. at 3).
5. Takahara states: “Generally speaking, in the aromatic ring of the
former reaction (1) hydrogen is replaced by fluorine and in the double bond
of the saccharide of the latter reaction (2) fluorine and acetoxy are added
respectively at each end.” (Id. at 3.)
6. In neither reaction (1) nor (2) are all the -OMe and -OAc removed
by the fluorination step (none in reaction (1) and one of three in reaction
(2)).
7. Takahara states that the “inventors . . . investigated the use of . . .
CH3COOF in the fluorination of 9β, 11β-epoxysteroid compounds and, quite
surprisingly, found out that the fluorination mechanism . . . is completely
different from the described mechanism[s] in (1) and (2).” (Id. at 3-4.)
8. The reaction of the 9β, 11β-epoxysteroid is shown as follows:
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The reaction scheme reproduced above from Takahara shows a
9,11-epoxysteroid treated with RCOOF (the fluorination agent), removing
an -AcO group at the 3-position and adding a fluorine at the 6-position. The
-AcO (“OAc”) at 21-position is not removed by the RCOOF.
9. According to Takahara, “fluorine is added selectively only at
position 6α, the electron disposition of A and B rings have been changed and
the acyl at position 3 has been replaced by [ketone].” (Id. at 4-5 & 10.)
10. The example on page 8 of Takahara shows the fluorination of a
compound having the following structure shown below:

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The compound reproduced above is a 9β, 11β-epoxysteroid with a
benzoyl at position 3 and an acyl group off position 21.
11. Takahara describes treatment with the fluorination agent, and
then “[a]fter 10 min stirring, 5 ml water solution of saturated sodium sulfite
has been added and stirring has continued . . . .” (Id. at 8.)
12. After all reaction steps are completed, the final compound is
shown as:

The compound reproduced above is a 9β, 11β-epoxysteroid with a
ketone at position 3 and an acyl group off position 21.

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Farmabios
13. Farmabios teaches that it “has surprisingly been found that a high
stereoselectivity of the fluorination at the 6-position can be obtained by
operating on substrates obtained in order that the 17α-hydroxy group
remains unreacted, and by using specific fluorinating agents.” (Farmabios,
col. 2, ll. 17-21.)
14. Farmabios describes the object of its invention as to produce
compounds of the following formula (I):

The formula (I) compound reproduced above is a 9β, 11β-
epoxysteroid with a ketone at position 3, a fluorine at position 6, and -OR’
group at position 21, where R’ is carboxyalkyl group with 1 to 4 carbons (id.
at col. 2, ll. 45-46).
15. A compound (III), reproduced below is “used as a substrate for
the fluorination of the invention to obtain the compound of formula (I)”:

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The formula (III) compound reproduced above is a 9β, 11β-
epoxysteroid with an acetyl group or -OR’ group, where R’ is carboxyalkyl
group with 1 to 4 carbons (id. at col. 4, ll. 18-19, 40-50; col. 2, ll. 45-46).
16. The preferred fluorination of the formula (III) compound is taught
by Farmabios to be Selectfluor® (id. at col. 3, ll. 34-5 & 43).
17. Farmabios states that: “At the aforementioned fluorination
conditions, the deprotection of the 3-ketonic function takes place
simultaneously.” (Id. at col. 3, ll. 55-60.)

Godard
18. Godard describes fluorination of a 9β,11β-epoxysteroid 3-benzoyl
androstane using Selectfluor® as a fluorination agent (Godard, col. 6, ll. 19-
26; Stage D; col. 5, ll. 48-49).
19. After the fluorination step, Godard describes in Stage D:
At the end of the introduction [of Selectfluor®], the suspension
was stirred at -1º to +1º C. for one hour and then it was poured
into a solution of 400 ml of water and 10 ml of 20% ammonium
hydroxide. 0.4 g of sodium metabisulfite were introduced and
stirring was continued for 30 minutes at ambient temperature.
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A sufficient quantity of 20% ammonium hydroxide was added
if necessary to adjust the pH to 8 . . . .
(Id. at col. 6, ll. 26-31.)
20. Stage D results in addition of 6α-fluorine and removal of a 3-
benzoyl group (id. at col. 6, ll. 19-21).
21. Prior to Stage D, Godard describes a stage in which a pregnane
compound is converted into an androstane comprising a step of adding
orthoperiodic acid, followed by the addition of sodium metabisulfite (id. at
col. 4, l. 60 to col. 5, l. 3).

Greene
22. Greene shows a chemical reaction involving a benzoate ester used
to protect alcohols. Greene writes: “Benzoates are less readily hydrolyzed
than acetates.” (Greene, at p. 100, No. 20.)

‘666 patent
23. The ‘666 patent teaches that the elimination of the 3-position enol
ester (3-benzoyl) of the 9β,11β-epoxysteroid is accomplished with “an
aqueous solution of sodium metabisulfite and ammonia” (‘666 patent, col. 4,
ll. 20-22).

Mendes
24. Zita Mendes, one of the named inventors and a scientist with
more than twenty years of experience in steroid chemistry, declared in
paragraph 3 of a declaration as follows:
I understand that the Reexamination Examiner has taken the
position that Takahara uses sodium sulfite to remove
(deprotect) a benzoyloxy group from the 3 position of a 16-β
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methyl pregnane. I am not aware of any literature which teaches
that the sodium sulfite will function in this way, and it is
apparent to me that Takahara was using this material for a
completely different purpose. It is and was well known in the
art to use sodium sulfite for the purpose of destroying excess of
a strong oxidant reactant before proceeding with the isolation of
a reaction product. Such destruction is necessary for safety
reasons. Typical examples of such use include, but are not
limited to, US 3,499,016 example 16 forming a 21-protected
9,11-bromohydrin employing hypobromous acid generated
using the strong oxidant perchloric acid and using a solution of
sodium sulfite to eliminate the reactant, and US 3,557,158,
example 12, which oxidizes the 11β-hydroxy group of a 16α-
methyl-pregnane with the brominating N-bromo-acetamide
oxidant also uses sodium sulfite for removing excess oxidant.
Another example is Godard’s Example 1, Stage A, which uses
sodium metabisulfite to destroy excess the [sic] periodic acid
oxidant. The acetyl hypofluorite being used by Takahara as a
fluorinating agent is a strong oxidant. It is clear to me, and
would be clear to those skilled in this art, that the sodium sulfite
is being used to remove excess acetyl hypofluorite from the
system.
(Zita Mendes Decl. ¶ 3.)

CLAIM INTERPRETATION
Claim 1 involves a process for preparing flumethasone, flumethasone
21-acetate, or its 17-carboxyl androsten analogue. The process involves
reacting a compound of formula (II) “with benzoyl chloride to form a 3-
enolic ester of” formula (IIIa). The “enolic benzoate (IIIa) [3-benzoyl] thus
obtained is reacted with an electrophilic fluorination agent so as to introduce
fluorine the [sic] 6α position,” shown as formula (IIIb). The claim recites
that “the enol benzoate (IIIb) is deprotected at C3 to yield a compound of the
formula . . . (IV).”
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We interpret the claim to require that the C3 deprotection (position 3
of the steroid ring) of the IIIb compound occur in a separate and sequential
step from the fluorination of the II compound to form compound IIIa. This
interpretation is based on the express recitation of the IIIa and IIIb
compounds in the claim, indicating these compounds occur independently
and sequentially in the claimed process.
The claim also covers the production of three compounds:
flumethasone, flumethasone 21-acetate, or its carboxyl androsten analogue
of the formula I. The flumethasone 21-acetate is formed by fluorination of
compound IV. The flumethasone and the carboxyl androsten analogue are
formed by optional and additional steps involving hydrolysis of the
flumethasone 21-acetate. Thus, preparation of each of the three compounds
requires that the recited compounds II, IIIa, IIIb, and IV are formed.

ANALYSIS
Claim 1 covers a process having the following reaction steps:
compound II is reacted with a benzoyl chloride to form compound IIIa with
a benzoyl protection group at C3 (position 3 of the steroid ring); compound
IIIa is reacted with a fluorination agent to form a fluorinated compound;
fluorinated compound IIIb is deprotected at C3 to yield compound IV; and
compound IV is fluorinated. Process claim 1 thus requires that deprotection
of compound IIIb (removing the 3-benzoyl group) is accomplished on a
different compound than the compound which is fluorinated. That is, the
claim requires fluorination and deprotection to occur in separate steps on
different compounds, IIIa and IIIb, respectively. The Examiner found that
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both steps were described by Takahara (Ans. 6). The Examiner
acknowledged that Takahara did not expressly disclose that compound IIIb
(with a 3-benzoyl and 6-fluorine) was formed, but found that it would have
been an inherent result of carrying out Takahara’s process (id. at 14).
When a claim limitation is not expressly described in a prior art
reference, whether the rejection is under 35 U.S.C. §§ 102 or 103, the
Examiner shoulders the burden of showing that such element is
“necessarily” present in the prior art reference. In re Robertson, 169 F.3d at
745; In re Best, 562 F.2d at 1255. That burden may be met by providing
evidence or sound scientific reasoning that the inherent feature is necessarily
possessed by the prior art. Upon challenge by a patent applicant or patent
owner in a reexamination proceeding, the Examiner must “consider all the
evidence anew” (Kumar, 418 F.3d at 1368 quoting from Piasecki, 745 F.2d
at 1472) and determine whether such evidence makes it certain that the
inherent feature is present in the prior art. Where there is credible evidence
to doubt that the prior art necessarily contains the inherent feature, that
evidence must be given proper weight.
The Examiner’s reason for believing that Takahara “inherently
produce[d] the intermediate compound IIIb” was based on similarities
between Takahara’s process and the process which is claimed and described
in the ‘666 patent (Ans. 14). In particular, the Examiner found that
Takahara’s process started and ended “with the same or similar” compounds
to those which are claimed. The Examiner focused on the separate
fluorination and deprotection steps recited in claim 1.
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As shown in the findings, Takahara’s process fluorinated an
epoxysteroid with a 3-benzoyl group – the same step recited in the claimed
process (FF1). Following fluorination, the Examiner found that Takahara
utilized sodium sulfite (FF11) to remove the 3-benzoyl protection moiety, a
step which the Examiner found was covered by the claim and similar to the
deprotection step described in the ‘666 patent using sodium metabisulfite
and ammonia (FF23). Based on these findings, the Examiner concluded that
compound IIIb “necessarily . . . formed in Takahara’s process.” (Ans.14.)
The Examiner’s reasoning is not persuasive.
First, Takahara shows and describes fluorination and deprotection as
occurring in one step. Page 3 of Takahara shows a chemical reaction
scheme in which a precursor 9,11-epoxysteroid is fluorinated and
deprotected in the same step (FF8). The only reagent shown to produce the
fluorinated (6-position) and deprotected (3-position) reaction product is
RCOOF (FF1; FF8). No intermediate that resembles compound IIIb is
shown.
In characterizing the fluorination of its 9,11-epoxysteroid with
RCOOF, Takahara specifically stated that the “fluorine is added selectively
only at position 6α, the electron disposition of A and B rings have been
changed and the acyl at position 3 has been replaced by [ketone].” (FF9.)
In other words, Takahara describes the fluorination step as modifying the 3-
and 6-positions at the same time. As Takahara does not expressly show or
describe a separate deprotection step, persons of ordinary skill in the art
would have reasonably understood from both the schematic and description
that the fluorinating agent is responsible for both the fluorine addition and
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the deprotection step (i.e., the replacement of the acyl group with a ketone).
Thus, Takahara on its face indicates that fluorination and deprotection occur
in a single step, not two steps as asserted by the Examiner.
Secondly, the Examiner’s contention that the processes are similar is
not persuasive. As pointed out by the Patent Owner, Takahara differs in
several ways from the claimed process: 1) Takahara’s example involves a
compound with a 16β-methyl group (FF1), not a 16α-methyl group as
claimed; 2) Takahara’s examples use sodium sulfite (FF11) rather than
sodium metabisulfite and ammonia as disclosed in the ‘666 patent (FF23);
and 3) different fluorination conditions are employed, such as the use of a
CH3COOF in Takahara (FF1 & FF8), rather than the SelectFluor® utilized
in the ‘666 patent to accomplish the dual step process.
The Examiner argued that the deprotection step disclosed in the ‘666
patent using sodium metabisulfite and ammonia (FF23) was the same as
Takahara’s step of using sodium sulfite (FF11). The Examiner’s reasoning
was based on evidence that commercial sodium bisulfite comprises sodium
metabisulfite, and scientific reasoning that, in the presence of ammonia, the
sodium bisulfite would become Takahara’s sodium sulfite (Ans. 22). The
Requester made the same argument (Req. App. Br. 6-8).
The Patent Owner offered another explanation. According to Zita
Mendes, one of the named inventors and a scientist with more than twenty
years of experience in steroid chemistry, Takahara utilized the sodium sulfite
to remove excess acetyl hypofluorite, a strong oxidant and the fluorinating
agent in Takahara’s process – and not to deprotect the benzoyl group from
the 3-position of the 16-β methyl pregnane (FF24). This opinion was
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supported by facts from three cited publications, including the cited Godard
publication in which sodium metabisulfite was used to remove orthoperiodic
acid (FF21).
Thus, there are two plausible explanations as to why Takahara utilized
sodium sulfite. The Examiner did not provide sufficient evidence to
establish that the sulfite accomplished deprotection in Takahara’s process,
rather than (or in addition to) removing the excess hypofluorite. The
evidence simply does not show that Takahara’s process necessarily
accomplished deprotection in a step separate from the fluorination step, and
that compound IIIb necessarily formed. To the contrary, there is credible
evidence that it did not.
In addition to the evidence in Takahara, there was other evidence that
made the Examiner’s inherency finding even less certain. This evidence is
discussed below.

Farmabios
The Farmabios patent describes a process in which a 9,11-
epoxysteroid is fluorinated and deprotected (FF1 & FF13-FF17). It is
undisputed that this compound shares structural similarity to the compound
recited in claim 1, differing, for instance, in having an acetoxy (R is alkane,
C1-C4 carboxyalkyl group) at the 3-position, rather than a benzoyl group
(aromatic) as in the claim (FF1). Appellant cited the Farmabios patent as
evidence that fluorination and deprotection occurred in a single step in
Takahara, rather than in two steps as claimed, with the production of the IIIb
intermediate. Specifically, the Farmabios patent expressly stated that
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fluorination and deprotection took place “simultaneously” under its
fluorination conditions (FF17), a fact Appellant contends is consistent with
Takahara’s disclosure single-step disclosure.
In response, the Examiner argued that the C1-C4 acetoxy protection
group at position 3 utilized in the Farmabios patent would have a different
rate of removal than the 3-benzoyl group in Takahara (and claim 1), and thus
would have been reasonably expected to behave differently. The Examiner
argued, based on Greene, that persons of ordinary skill in the art would have
understood that benzoyl is more stable to hydrolysis than acetoxy, and
therefore the production of IIIb in the claimed process, but not in the
Farmabios process, was not “unexpected” because of the different protection
groups at the 3-position (Ans. 15-16).
Greene describes a reaction involving 3-benzoyl on a simple alcohol
compound (FF22), not a 9,11-epoxysteroid as claimed and described in
Takahara. The compounds are different. Takahara explicitly showed that
fluorination with the same fluorination agent had a “completely different . . .
mechanism” when performed on structurally different compounds. For
example, in the aromatic reaction (1) only fluorine substitution occurred
without removal of a methoxy group (-OMe), while in the saccharide
reaction (2) an acetoxy was added, not removed (FF4 & 5). Thus, there is
explicit evidence in the record that the outcome is not the same when
structurally different compounds are fluorinated. Consequently, it was not
reasonable for the Examiner to reject Farmabios as evidence, based on the
chemical reaction described in Greene that is accomplished on a compound
with a different structure.
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To the contrary, it is as likely that the 9,11-epoxysteroids of
Farmabios and claim 1, having the same core structure, would behave the
same way when treated with the same fluorination agent. In Takahara, the
fluorination agent acts on an aromatic compound by adding a fluorine, and
on a saccharide, by adding a fluorine and an acetoxy group, while two other
acetoxy groups remain intact (FF4 and FF6). However, in contrast, when a
9,11-epoxysteroid is used, a fluorine is added and an acetoxy removed,
“completely different from [the latter’s] . . . reaction mechanism.” (FF7.)
Thus, the compound’s core structure influences the reaction outcome.
Takahara is more similar to Farmabios (see comparison table in FF1)
and less similar to Greene – making it as likely that Takahara’s reaction
would proceed as described in Farmabios. In fact, Takahara shows
fluorination as removing only one -OAc group on the 3-position, while
leaving the same -OAc intact near the 21-position (FF6). Thus, if -OAc
chemistry were as simple as the Examiner reduced it to be based on the
Greene publication, both -OAc groups might have been expected to be
removed by the fluorination agent.
The Examiner takes Takahara’s silence on the alleged need for a
separate reaction step to deprotect the 3-benzoyl group as evidence that the
ordinary skilled worker would have “understood that different protecting
groups would have different rates of removal” as shown by Greene (Ans.
19). However, the evidence of this knowledge was based on a reaction on
an alcohol compound which we conclude was insufficient to establish
knowledge that the deprotection of Farmabios’s 3-acetoxy compound would
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have been expected to behave differently than deprotection of Takahara’s 3-
benzoyl compound.

Godard
Godard describes fluorination of a 9β,11β-epoxysteroid 3-benzoyl
androstane using Selectfluor® as a fluorination agent (FF18). In the step
following fluorination, Godard describes the addition of sodium
metabisulfite and ammonium hydroxide to the reaction mixture (FF19).
Although Godard does not explain the reason for this step, the Examiner
contends it was for the purpose of removing the benzoyl group at
the 3-position (Ans. 23-24). Because Godard’s step is similar to Takahara’s
sulfite step, the Examiner relied upon Godard as further evidence that
Takahara’s process involved separate fluorination and deprotection steps as
claimed, where deprotection occurring the separate metabisulfite step (id.).
Even if it is true that Godard’s sodium metabisulfite/ammonium
hydroxide step served to deprotect Godard’s androstane, this fact does not
establish equivalence to Takahara’s sodium sulfite step when the totality of
the evidence is considered. Farmabios describes simultaneous
fluorination/deprotection on a pregnane steroid with a 3-alkoxy group
(FF17). Godard’s compound in the fluorination reaction is an androstane
with a 3-benzoyl group (FF1). The claimed compound is a pregnane with a
3-benzoyl group (FF1). There is at least one structural difference between
the claimed compound and that of Farmabios and Goddard, respectively.
The Examiner has not provided sufficient evidence that the
fluorination reaction of Takahara’s claimed pregnane/benzoyl compound
would proceed in the manner as did Godard’s androstane/benzoyl
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compound, rather than that of Farmabios’s pregnane/alkane (see comparison
table in FF1). In our view, under the Examiner’s facts, the differences
between Farmabios (one-step) and Godard (two-step, as alleged by the
Examiner) demonstrate uncertainty as to the fluorination mechanism and
how the fluorinating agent would behave. This uncertainty is further
buttressed by Takahara’s teaching that fluorination mechanism was
“surprisingly” different when fluorination was performed on compounds
with different core structure. These differences lead us to conclude that the
Examiner did not establish with certainly that Takahara’s process inherently
formed a compound having the IIIb structure recited in claim 1.

CONCLUSION OF LAW
The Examiner did not show that the formation of compound IIIb of
claim 1 was an inherent and necessary result of carrying out Takahara’s
process. There is credible evidence of record that compound IIIb was not
formed. The obviousness rejection under section 103 of claim 1 and
dependent claims 2-15 is reversed.

TIME FOR RESPONSE
In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the
appeal may file a request for rehearing of the decision within one month of
the date of: . . . The original decision of the Board under § 41.77(a).” A
request for rehearing must be in compliance with 37 C.F.R. § 41.79(b).
Comments in opposition to the request and additional requests for rehearing
must be in accordance with 37 C.F.R. § 41.79(c) & (d), respectively. Under
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37 C.F.R. § 41.79(e), the times for requesting rehearing under paragraph (a)
of this section, for requesting further rehearing under paragraph (d) of this
section, and for submitting comments under paragraph (c) of this section
may not be extended.
An appeal to the U.S. Court of Appeals for the Federal Circuit under
37 C.F.R. § 1.983 for an inter partes reexamination proceeding
“commenced” on or after November 2, 2002, may not be taken “until all
parties' rights to request rehearing have been exhausted, at which time the
decision of the Board is final and appealable by any party to the appeal to
the Board.” 37 C.F.R. § 41.81. See also 35 U.S.C. §§ 141-144 & 315;
Manual of Patent Examining Procedure, § 2682 (8th ed., Aug. 2001; Rev.
July 2008).

REVERSED

bim

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FOR APPELLANT:

EDWARD A. MEILMAN
DICKSTEIN SHAPIRO, LLP
1633 BROADWAY
NEW YORK, NY 10019-6708

FOR THIRD PARTY REQUESTER:

JAMES V. COSTIGAN
HEDMAN & COSTIGAN, P.C.
1230 AVENUE OF THE AMERICAS
7TH FLOOR
NEW YORK, NY 10020-1512