BRIEF OF APPELLANT MEDICHEM, S.A.

Appeal Nos. 02- 1461, - 1480
. .
MEDICHEM, S.A.,
Plain tiff-Appellant,
-v. ROLABO, S-L.,
Defendant-Cross-Appellant.
APPEALS FROM THE UNITED STATES DISTRICT COURT FOR THE SOUTHERN
DISTRICT OF NEW YORK IN CASE Ol-CV-3087, JUDGE JED S. RAKOFF
BRIEF OF APPELLANT
MEDICHEM,
S.A.
Barry S. White
JamesK. Stronski
Tedd W. Van Buskirk
John G. Taylor
FROMMER LAWRENCE & J~AUG LLP
745 Fifth Avenue
New York, New York 10151
(212) 588-0800
Attorneys for Plaint@-Appellant
Medichem, S.A.
October 23,2002
___-.
CERTIFICATE
Counsel for Plaintiff-Appellant
1.
S.A. certifies the following:
S.A.
The name of the real party in interest is:
MEDICHEM,
3.
MEDICHEM,
The full name of every party represented by me is:
MEDICHEM,
2.
OF INTERES’T
S.A.
All parent corporations and any publicly held companies that own 10
percent or more of the stock of the party represented by me are:
CORPORACIGN
.-
4.
MEDICHEM,
S .L.
The names of all law firms and the partners, or associates that have
appeared for the party now represented by me in the trial court or are expected to
appear in this Court are:
Barry S. White, Esq.
James K. Stronski, Esq.
Tedd W. Van Buskirk, Esq.
John G. Taylor, Esq.
FROMMERLAWRENCE&HAUGLLP
745 Fifth Avenue
New York, New York 10151
TABLE OF CONTENTS
OF INTEREST . ... . . .. .. . .. . .. .. . . ... . . .. .. . .. . .. . . .. .. . .. . .. .. . . .. . .. . .. . .. . .. . .. .. . .. .. . .. .. . i
CERTIFICATE
TABLE OF AUTHORITIES
STATEMENT
OF RELATED CASES .. . .. .. . . .. .. . .. . .. . .. .. . . .. .. . .. . .. . .. . . .. .. . .. . . .. .. . .. . .. .. . .. .. vii
STATEMENT
OF JURISDICTION
STATEMENT
OF THE ISSUES . . .. .. . .. . .. .. . .. . .. . .. . .. .. . . .. .. . .,.........................................
STATEMENT
OF THE CASE .. .. . .. . .. . .. . .. .. . .. . .. .. . .. . .. . .. . ...a.................................
. . .. .. . .. . .. . .. .. . . .. .. . . ... . ..I. .. .. . .. . . .. . .. . .. .. . . .. .. . .. . .. . .. .. . .. . 1
2
. .. .. . .. 4
I.
Introduction . .. . . .. .. . .. . .. . .. .. . .. . .. . .. .. . .. . .. .. . . .. .. . ...~.........................................
II.
Procedural History Of The Case .. . .. .. . . .. .. . .. . .. . . .. .. . .. . .. . .. . . .. .. . .. . .. . .. . .. .. .. . .. 6
SUMMARY
ARGUMENT
I.
II.
4
OF FACTS . . .. . .. . .. .. . . ... . . .. .. . .. . .. .. . . ... . . .. .. . . .. -.........................................
8
.. . .. .. . .. . .. .. . . ... . . .. . .. . ..~.......................................
14
. .. . .. . . .. . .. . .. . .. .. . . .. . .. . .. .. . . ... . . .. .. . .. . .. .. . . ... . . .. .. . . ..~.......................................
15
STATEMENT
-
.. .. . . .. .. . .. .. . .. . .. .. . . ... . . .. .. . .. . .. . . .. .. . .. . .. .. . . .. . .. . .. . .. . .. . .. .. . .. .. . .. .iv
OF THE ARGUMENT
The Standard Of Review And Applicable L,aw . .. .. . .. . . .. . .. .. . .. . . .. .. . .. .. . .. 15
A.
Interference And Claim Construction Are Matters Of
Law, Reviewed De Novo By This Court . .. . .. . . .. .. . .. . . ... . . .. .. . .. .. . .. 15
B.
Application Of The Two-Way Patentability Test To
Determine Interference Under 35 U.S.C. 8 29 1 .. . .. . .. . .. . .. .. . .. .. . .15
C.
A Judicial Interference Is Determined By Reference To
A “Description Of Interfering Subject Matter” Similar To
A “Count” In A Patent Office Interference . .. .. . . .. . .. . .. .. . .. . .. . .. .. . 18
The District Court Applied The Two-Way Patentability Test To
Misconstrued Claims And Concluded That The Patents Did Not
Interfere. Properly Construed, The Claims Of The Patents
Interfere Because They Define The Same Patentable Invention. .. .. . ..2O
A.
Taking The Medichem Patent As Prior Art Under The
Two-Way Patentability Test, The Colurt Erred In
ii
Determining That Rolabo’s Claims Are Not Obvious In
View Of Medichem’s . .. . . .. .. . .. . .. . . ... . . .. . .. .. . .. . . .. . .. .. . .. . . .. .. . .. . .. .. . .. .. 25
B.
III.
Taking The Rolabo Patent As Prior Art Under The TwoWay Patentability Test, The District Court Properly
Determined That Medichem’s Claims Are Obvious. . .. . . ... . . .. .. . 29
The District Court’s Unappealed Award Of Priority To
Medichem Renders Rolabo’s Claims Invalid Under 35 U.S.C. 3
102(g)( 1) Because Medichem’s Claims Anticipate Rolabo’s
Claims . . . . .. .. . .. . . ... . . .. . .. . .. .. . .. . .. . .. .. . .. .. . .. . .. . .. . .. .... .. . . .. . .. . .. .. . . .. . .. . .. .. . . .. .. . .. .. . 31
A.
Rolabo’s Claim 17 Is Invalid Because It Is Anticipated
By Medichem’s Claims 2-13 .. . .. . .. . .. .... . .. . .. . .. . .. .. . . .. . .. . .. .. . . .. .. . .. .. . 34
B.
Rolabo’s Claims l-l 1 and 13-16 (Directed To The Genus
Cycloheptene) Are Invalid Because They Are
Anticipated By Medichem’s Claims 2-13 (Directed To
The Species Loratadine) . . .. . .. .. . . .. .. . ...~.......................................
C.
CONCLUSION
34
Rolabo’s Claim 12-Directed To An Inherent
Intermediate Diol-Is Invalid Because It Is Inherently
Anticipated By Medichem’s Claims :2-13 . .. . . .. . .. . .. . .. .. . . .. .. . .. .. . .. 36
. . .. . . .. . .. .. . . .. . .. . .. . .. .. . .. . .. . .. .. . .. .. . .. . .. . .. . .. . .. .. . ..1.......................................
...
111
39
TABLE OF AUTHORITIES
Cases
Advance Transformer Co. v. Levinson, 231 USPQ 1 (N.D. Ill. 1986),
afd in pertinent part, 837 F.2d 1081,5 USPQ2d 1600 (Fed.
Cir. 1988) .. . . . .. .. . . .. . .. .. . .. . . .. . .. .. . .. .. . .. . .. . .. .. . .. . .. .. . .. . .. . ..I.......................................
15
AFG Indus., Inc. v. Cardinal IG Co., Inc., 239 F.3d 1239,57 USPQ2d
1776 (Fed. Cir. 2001) .. . . .. .. . .. . .. .. . .. . .. . .. . .. .. . .. .. . .. . .. . .. ... .. . . .. . .. . .. . .. .. . . .. . .. . .. .. . .. .. . .. 19
Albert v. Kevex Corp., 729 F.2d 757, 221 USPQ 202 (Fed. Cir. 1984) .. . .. .. . .. .. . .. .. . 14
Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342,51 USPQ2d 1943
(Fed. Cir. 1999) ..,..........................................................................................
33
Beckson Marine, Inc., v. NFM, Inc., 292 F.3d 718,63 LJSPQ2d 103 1
(Fed. Cir. 2002) .. . . .. .. . .. . .. .. . . .. .. . .. .. . .. . .. . .. .. . . .. .. . .. .. . . .. .. . .. . .. . .. . . .. .. . .. . . .. .. . .. . .. . .. .. .. . 26
CCS Fitness, Inc. v. Brunswick Corp., 288 F.3d 1359,62 USPQ2d
1658 (Fed. Cir. 2002) . . . .. .. . . .. .. . .. .. . .. .. . .. . .. . .. . .. .. . .. . .. . .. . .. . .. . .. .. . . .. . .. . .. .. . . .. .. . .. .. . .. . 18
Credle v. Bond, 25 F.3d 1566, 30 USPQ2d 1911 (Fed. Cir. 1994). . .. . .. . .. . .. . .. . .. .. .. . .14
Eli Lilly and Co. v. Barr Labs., Inc., 25 1 F.3d 955,58 USPQ2d 1869
(Fed. Cir. 2001) . . .. .. . . .. . .. . .. .. . . ... . . .. .. . .. .. . .. . .. .. . . .. .. . .. . .. . . .. .. . .. . .. . .. . .. . .. . .. . .. . .. . .. .. .. . . 31
Ex parte Standish, 10 USPQ2d 1454 (Bd. Pat. App. & Imterf. 1988) . .. .. . .. . 16, 21,22
Fiddes v. Baird, 30 USPQ2d 1481 (Bd. Pat. App. & Interf. 1994) .. .. . .. . .. . . .. .. . .. .. . .. . 15
Genentech, Inc. v. Chiron Corp., 112 F.3d 495,42 USPQ2d 1608
(Fed. Cir. 1997) . . .. ..~.................~.......................................~..........~...........
14,19
Glaxo Inc. v. Novopharm Ltd., 52 F.3d 1043,34 USPQ2d 1565 (Fed.
Cir. 1995) . . .. . . .. .. . . .. .. . . .. .. . .. . .. .. . .. .. . . .. .. . .. . .. . .. .. . . .. .. . .. .. . .. . . .. .. . . .. .. . . .. . .. .. . .. . .. . .. . 23,33
Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966) .. . .. . .. . .. . .. . .. . .. . .. .. . .. .27
In re Baxter Travenol Labs., 952 F.2d 388,21 USPQ2d 1281 (Fed.
Cir. 1991) . .. . .. . .. . . ...~.................~~..........~.................~........................................
23
In re Berg, 140 F.3d 1428,46 USPQ2d 1226 (Fed. Cir. 1998) .. . .. . . .. . .. . .. .. . . .. .. . .. .. . .31
iv
In re Deckler, 977 F.2d 1449, 24 USPQ2d 1448 (Fed. Cir. 1992) . .. . .. .. . . .. . .. .. . .. .. . .. 29
In re Dembiczak, 175 F.3d 994, 50 USPQ2d 1614 (Fed. Cir. 1999) . .. . .. . .. . .. .. . .26, 27
In r-eHiniker Co., 150 F.3d 1362, 47 USPQ2d 1523 (Fed. Cir. 1998) . . .. .. . .. . .. . 13, 19
In re Paulsen, 30 F.3d 1475, 31 USPQ2d 1671 (Fed. Cir. 1994) . .. . .. .. . . .. .. . .. . .. . .. .. .. 23
In re Petering, 301 F.2d 676, 133 USPQ 275 (C.C.P.A. 1962) . .. . .. . .. .. . . .. . .. . .. .. . .. . .. . 3 1
In re Slayter, 276 F.2d 408, 125 USPQ 345 (C.C.P.A. 1960) . .. .. . .. . . .. .. . .. . .. . . ... . . .. .. . 32
Znt ‘1 Visual Corp. v. Crown Metal Mfg. Co., Inc., 991 F.‘2d 768,26
USPQ2d 1588 (Fed. Cir. 1993) . .. . .. . .. .. . .. .. . .. . .. . .. . .. .... .. . . .. . .. .. . .. . . .. .. . . .. .. . . ... . . .. .. . 19
Kimberly-Clark
Corp. v. Procter & Gamble Distrib. Co., Inc., 973
F.2d 911,23 USPQ2d 1921 (Fed. Cir. 1992) . . .. . .. .... . .. . .. . .. . .. .. . . .. . .. . .. .. . . .. .. . .. .. . 28
Markman v. Westview Instruments, Znc., 52 F.3d 967, 34 USPQ2d
1321 (Fed. Cir. 1995), afS’d 517 U.S. 370 (1996) .,,.......................................
14
Mikus v. Wachtel, 504 F.2d 1150, 183 USPQ 752 (C.C.P.A. 1974) . . .. .. . .. . . .. .. . .. .. . .. 31
Minnesota Mining and Mfg. Co. v. Berwick Zndus., Inc., 373 F. Supp.
851,182 USPQ 111 (M.D. Pa. 1974) .. . .. . .. . .. . .. .. . . . ... . .. . .. . .. . . .. .. . .. . . ... . . .. .. . .. .. . .. 29
Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261,229 USPQ
805 (Fed. Cir. 1986) . .. .. . . .. .. . .. .. . .. . .. . .. . .. . .. .. . .. .. . .. . .. ..I.................................
20,22
Oka v. YousseJLeh,849 F.2d 581, 7 USPQ2d 1169 (Fed. Cir. 1988) .. . .. . .. . .. .. . . ... . . 3 1
Polaroid Corp. v. Eastman Kodak Co., 789 F.2d 1556, ‘229 USPQ
561 (Fed. Cir. 1986) . .. . .. . .. . .. . .. .. . .. .. . . .. .. . .. .. . .. . .. .. . . .. . .. . .. .. . . .. . .. .. . .. . . .. . .. .. . .. . .. . .. .. . 25
Slip Track Sys., Inc. v. Metal-Lite, Znc., 159 F.3d 1337 (Fed. Cir.
1998) . .. . .. . .. . . .. .. . . .. . .. .. . .. . . .. . .. .. . .. .. . . .. .. . .. .. . .. . .. .. . . .. .. . .. . .. . . ... . . .. . .. . .. . .. . .. . .. . .. .. . .. . .. .. . 14
Slip Track Sys., Inc. v. Metal-Lite, Inc., 304 F.3d 1256 (IFed. Cir.
2002) . .. . . .. . .. . . .. . .. .. . .. . . .. . .. .. . .. . .. .. . .. . .. . .. .. . .. .. . .. . .. . .. . .. . .. .. . . .. . .. .. . . .. . .. . .. . 14, 16, 17, 18
Titanium Metals Corp. of America v. Banner, 778 F.2d ‘775, 227
USPQ 773 (Fed. Cir. 1985) . .. .. . .. . .. . .. .. . .. . .. . .. .. . .. . .. .. . . .. .. . . .. .. . . .. . .. .. . .. . . .. . .. .. . .. .. . . 31
V
Vehicular Techs. Corp. v. Titan Wheel Int ‘I, Inc., 212 F..3d 1377, 54
USPQ2d 1841 (Fed. Cir. 2000) .. .. . .. .. . . .. .. . .. . .. . .. .. . . .. .. . .. . .. . .. . . .. .. . .. . . .. .. . .. . .. . 19,22
Winter v. Fujita, 53 USPQ2d 1234 (Bd. Pat. App. & Interf. 1999) .. . .. . . .. .. . 15, l&28
Statutes
28 U.S.C. $ 1295(a)(l) . .. . .. .. . .. . .. . .. . .. .. . .. . .. .. . .. . .. . .. . .. .. . . .. .. ..I.........................................
1
28 U.S.C. 5 1331 . . .. .. . . .. . .. . .. . .. .. . . .. .. . .. . .. . .. .. . .. . .. . .. .. . .. .. . . .. . .. .. . .. . .. . . .. .. . .. . . .. .. . .. . .. . .. .. . .. . .. .. . 1
28 U.S.C. 8 1338(a) ..........................................................
..........................................
1
28 U.S.C. 8 2107 .........................................................................................................
35 U.S.C. 8 102(g) ............................................................................................
1
passim
35 U.S.C. 8 103(a) ...........................................................
.........................................
26
35 U.S.C. 5 135 ................................................................
.........................................
15
. . .. .. . . .. .. . .. . .. . .. .. . . .. . .. .. . .. . . .. . .. .. . .. . . .. .. .passim
35 U.S.C. 9 291 . . ...a.....................*...............
Rules
Federal Rule of Appellate Procedure 4(a) . .. . .. . .. . .. . .. . .. .. . ..I.........................................
1
Regulations
37 C.F.R. 5 1.601(f) ...........................................................................................
16,17
37 C.F.R. 8 1.601(i) .................................................................................................
15
37 C.F.R. 5 1.601(j) .................................................................................................
15
37 C.F.R. 8 1.601(n) ............................................................................................
-
vi
2, 16
STATEMENT OF RELATED CASES
There has been no previous appeal from this action before any appellate
court, nor is there any other case presently pending before this Court that will be
affected directly by this Court’s decision in the pending appeal.
But there are two Patent Interferences pending before the Board of Patent
Appeals and Interferences, Hon. Michael P. Tierney, that may be affected by, or
that may affect, this Court’s decision in this appeal:
(1)
Rey v. Stampa, Patent Interference No. 105.,001 involving Defendant-
Cross Appellant Rolabo S.L’s (“Rolabo”) U.S. Patent No. 6,093,827 (“the ‘827
patent”), one of the two patents at issue in this appeal, and the pending application
of a third party; and
(2)
Rey v. Jackson, Patent Interference No. 105,002 involving Plaintiff-
Appellant Medichem, S.A.‘s (“Medichem”)
U.S. Patent No. 6,084,100 (“the ‘100
patent”), the other of the two patents at issue in this appeal, and the same pending
application of the same third party in Interference No. 105,001.
In addition, Rolabo has pending a continuation application, Serial No.
09/525,894 (“the Rolabo/Jackson application”), which claims priority to its ‘827
patent at issue in this appeal. Claims 1-17 of the Rolabo/Jackson application are
believed to be identical to claims 1-17 of the ‘827 patent except for the use of a
“consisting essentially of’ transition in place of the “comprising” transition used in
vii
the ‘827 patent. New claims 18-28 of the Rolabo/Jackson application continue to
employ a “comprising” transition.
And Medichem has filed for reissue of the ‘ 100 patent at issue in this appeal.
See Medichem, S.A.‘s Reply In Support Of Motion To Stay Proceedings (filed
September 3,2002). The pending reissue application, Serial No. 10/234,659 (“the
Medichem/Stampa reissue application”), is a narrowing reissue that adds new
claims 14- 18. Original claims 1- 13 have not been changed.
Administrative Patent Judge Tierney in Interference Nos. 105,001 and
105,002 has requested that the parties to this action submit papers on the issue of
declaring an interference between Rolabo’s ‘827 patent ;andthe Medichem/Stampa
reissue application. Rolabo filed and served its paper on October 15,2002, and
Medichem will file and serve its paper on or before October 28,2002.
STATEMENT OF JURISDICTION
The jurisdiction of the United States District Court over this action was
based upon 28 U.S.C. $8 1331 and 1338(a) and 35 U.S.C. 8 291. This Court’s
jurisdiction is based upon 28 U.S.C. 6 1295(a)(l).
In accordance with 28 U.S.C. 9 2107 and Fed. R. App. P. 4(a), this appeal
was timely filed on June 12,2002 (A000213, AO10406-,4010407), within thirty
days of the district court’s entry of final judgment on May 13, 2002. AOOOOOl,
A000213.
1
STATEMENT OF THE ISSUES
This is an appeal from a judicial interference action. Two patents define the
same patentable invention-and
therefore interfere-where
a claim of one patent is
anticipated by or obvious in view of a claim of the other, and vice versa. 37 C.F.R.
8 1.601(n) (2002). This analysis is known as the two-way patentability test.
1.
Medichem’s and Rolabo’s patents both claim a process for making the
same pharmaceutical compound (loratadine) by coupling the same starting
materials (two specific ketones) via the same chemical reaction (the “McMurry
reaction”) using the same reagent (low-valent titanium generated by zinc). The
only difference is that Medichem’s claims specify an additional reaction condition.
Applying the two-way patentability test, the district court found (1) that
Medichem’s claims were obvious in view of Rolabo’s, but (2) that Rolabo’s claims
were not obvious in view of Medichem’s. The court did. so because it implicitly
construed Rolabo’s “comprising” claim to require exclusion of the additional
reaction condition of Medichem’s claim. Did the court err in construing
“comprising” to exclude additional elements and consequently err in dismissing
the case for lack of interference?
2.
The district court properly found that Medilchem had established
priority of invention but did not hold Rolabo’s patent invalid. Did the district court
2
err in failing to invalidate Rolabo’s patent under 35 U.S.C. 8 102(g) in view of
Medichem’s earlier invention of claims that anticipate Rolabo’s claims?
3
STATEMENT OF THE CASE
I.
Introduction
This appeal presents a straightforward claim construction issue-the
district
court erroneously construed the term “comprising” in Rolabo’s patent claims to
exclude additional elements, and as a result incorrectly held that Medichem’s and
Rolabo’s patents did not interfere. The court also found that Medichem was
entitled to priority-a
finding that Rolabo did not appeal.. But the court failed to
hold Rolabo’s patent invalid.
The result is unsustainable under 35 U.S.C. 0 102(g). Medichem’s patent
claims meet each and every element of Rolabo’s patent claims, and Medichem has
been finally determined to be the earlier inventor. This compels a ruling that
Rolabo’s patent claims are invalid under 35 U.S.C. 8 102(g). Yet the district
court’s decision allowed Rolabo’s patent to stand.
Medichem’s and Rolabo’s patents issued within weeks of each other. Both
claim a process for making the same pharmaceutical compound, loratadine. The
starting materials, the reaction, and the reagent are the same. In fact, the parties
agreed that the claimed reactions are the same, except that Medichem’s claims
recite one additional reaction condition: that the reaction takes place “in the
presence of a tertiary amine.”
4
To determine whether the patents interfered, the district court applied the
standard “two-way patentability” test. Under this test, the patents interfere if one
claim of each is anticipated by or obvious in view of one: claim of the other. Here,
the court correctly determined that Medichem’s claims were obvious in view of
Rolabo’s. Therefore, it was required to find interference: if Rolabo’s claims were
anticipated by or obvious in view of Medichem’s.
But the district court incorrectly held that Rolabo’s claims were neither
anticipated by nor obvious in view of Medichem’s and, thus, found no interference.
The district court’s ruling was based on two fundamental legal errors:
l
the district court failed to recognize that “comprising” claims
encompass additional elements and incorrectly treated Rolabo’s
claims as if they exclude a tertiary amine in holding that they were
patentability distinct; and
0
the district court erroneously based its patentability determination on
unclaimed limitations imported from Rolabo’s commercial and
patent-example processes.
As a matter of law, Medichem’s claims anticipate Rolabo’s. Rolabo’s
“comprising” claims cannot be construed to exclude the addition of a tertiary
amine. And the Court erred by conflating Rolabo’s commercial and patentexample processes with its claims. Neither of these errors can change the fact that
5
Medichem’s claims contain every element of Rolabo’s and therefore anticipate
them.
Claim construction and interference are matters of law subject to de nova
review by this Court.
II.
Procedural History Of The Case
Medichem’s and Rolabo’s respective U.S. patents claiming a process for
making loratadine via the McMurry reaction issued within weeks of each other in
July 2000. AOOOlOl-A000109.
After receiving cease and desist letters from
Rolabo alleging that Medichem’s process for making loratadine infringed Rolabo’s
patent, Medichem filed this interfering-patents action under 35 U.S.C. 3 291 to
protect its U.S. patent rights against Rolabo. A000203, A000205, AOlOOOlA010014, A010149-A010192.
Rolabo’s Answer denied1that the patents interfered
and counterclaimed for a declaratory judgment of patent infringement.
A000204-
A000205, AO10015-A010032, A010193-A010217.
Rolabo then moved to dismiss Medichem’s Complaint for lack of subject
matter jurisdiction, arguing that the patents did not interfere within the meaning of
35 U.S.C. 8 291. A000204, A010044. After briefing and oral argument, the
district court did not grant Rolabo’s motion. A000204-A000205, A01 1020A01 1022. The court later granted Medichem’s motion to dismiss Rolabo’s
._--
...
-. _----
declaratory judgment patent infringement counterclaim for lack of case or
controversy. A000208, A010218-A010242, A01 1023, A01 1063-AOl1066.
After the close of discovery, the parties cross-moved for summary judgment
on the interfering-patents claim. A000209. The district court denied those
motions and set the case on the trial calendar. A010294..
The court held a bench trial between April 29 and May 7,2002. A000004A000020, A004062-A004780.
The court denied Rolabo’s motion for directed
verdict at the close of Medichem’s case-in-chief. A004656-A004658.
Ruling
from the bench on May 7, the court held that Medichem had established priority.
AOOOOlO. The court also determined that Medichem had not carried its burden of
proving interference, denied Rolabo’s request for attorneys’ fees, and ordered that
judgment dismissing the case be entered in favor of Rolabo. AOOOOOl-A000020.
Medichem appeals from the district court’s judgment of no interference.
A000213, A010406-A010407.
Rolabo cross-appeals on the issue of attorneys’
fees. A000214, AO10408-A010409. The award of priority in favor of Medichem
has not been appealed. A000214, A010408-A010409.
7
STATEMENT OF FACTS
Medichem and Rolabo are both Barcelona-based manufacturers of “active
pharmaceutical ingredients” that own issued U.S. patents directed to a process for
preparing cycloheptene compounds through a well-known carbonyl coupling
reaction called the “McMurry”
reaction. A000 10 1-A000 109. There are hundreds
of prior-art publications concerning McMurry couplings. A001372-A001399,
AOO1513-A001537, A003353-A003411, A010300, A010363, A010366-A010370,
A010378 AO10385AO10386.
One compound of specific interest in both patents
is loratadine, a species within the cycloheptene genus. A00010 1-A000109.
Loratadine is the active pharmaceutical ingredient in the multi-billion
dollar
antihistamine sold by Schering Corporation under the brand name CLARITIN@.
Claims l- 13 of Medichem’s patent and claim 17 of Rolabo’s patent all claim
a process for preparing the species, loratadine. AOO0104, A0001 09. Claims l-l 1
and 13-16 of Rolabo’s patent are more broadly directed to preparing the genus,
cycloheptene, which includes loratadine. A000 108-A000 109. Rolabo’ s claim 12
is directed to preparing a diol intermediate that is inherently formed in carrying out
the McMurry reaction to prepare loratadine or any of the other cycloheptene
compounds encompassed by Rolabo’s claims. AOO0108. All of Rolabo’s claims
use the open-ended “comprising”
claims all contain a recitation-not
transition. A0001 08-A000 109. Medichem’s
present in but not excluded by Rolabo’s
8
claims-that
the reaction takes place “in the presence of a tertiary amine.”
AOO0104.
Medichem’s patent issued on July 4,200O. A000 101. Rolabo’s patent
issued on July 25, 2000. A000105. Believing that the two patents interfere,
Medichem filed this judicial interference action under 35 U.S.C. 5 291 to have a
court determine which party had priority to the patented invention. A000203,
A000205, AOlOOOl-A010014, A010149-A010192.
At trial, the district court
considered the parties’ respective dates of conception and reduction to practice and
determined that Medichem had established priority of invention:
[B]oth the documents and the testimony and evidence of
Medichem’s reduction to practice of its invention in the
Spring of 1996 is so strong as to overcome any doubt that
the Court may have had in this regard. . . . By contrast,
defendant, by its own position, does not claim that its
reduction of practice occurred before the fall of 1996.
And so, accordingly, I find that plaintiff [Medichem]
has established priority.
A000010 (emphasis added). Rolabo has not appealed this factual finding.
A000214, A010408-A010409.
On the question of interference, the district court framed the issue as
follows:
Turning, then, to the element of interference, the Court
finds that the key question is whether th’e inclusion of
tertiary amine in Medichem’s patent claims is material in
a way that negates obviousness and makes the patents
noninterfering.
9
AOOOOlO-AOOOOl l. The court applied the two-way patentability test to
Medichem’s claims, assuming Rolabo’ s claims to be the prior art. AOOOOlOA00001 3, A00001 6. In this direction, the court properly found that Medichem’s
claims, which recite that the reaction takes place “in the presence of a tertiary
amine,” were obvious in view of Rolabo’ s claims. A00001 2.
The district court also applied the test to Rolabo’s claims, assuming
Medichem’s claims to be the prior art. A000012-A0000 17. In this direction, the
district court framed the issue as:
whether someone reasonably skilled in the art would find
the elimination of a tertiary amine obvious or anticipated
in light of the prior art at the relevant time, which was
around 1996.
A000012 (emphasis added). Rather than eliminate the use of a tertiary amine,’
however, Rolabo’s claims encompass that very use because they employ the
“comprising” transition. A000108-A000109.
By construing Rolabo’s claims as if
they exclude the use of a tertiary amine, the court effectively construed those
claims as if they employ the “consisting of’ transition.
The court appears to have misunderstood the anticipation/obviousness
inquiry required under the two way-patentability test. Rather than focusing on the
’ Rolabo’s commercial process for making loratadine does not use a tertiary
amine. A010300.
10
--
obviousness of Rolabo’s claims vis-a-vis Medichem’s claims, the court instead
analyzed whether Rolabo’s alleged “elimination”
of a tertiary amine would have
had an obvious and material effect on the underlying reaction. This is best
illustrated in the following portions of the opinion below:
Yet, the presence or use of a tertiary amine appears
nowhere in the Rolabo ‘827 patent, strongly suggesting
that that patent is a materially different process.
Whatever [Medichem inventors] Dr. Onrubia and Dr.
Bosch may now be averring in the context of this lawsuit,
the Court finds that at all relevant times in and around
1996 they, as skilled organic chemists, understood that
tertiary amine was important to plaintiff’s patent process
and that they did not at all regard as obvious what would
occur if it were eliminated.
someone skilled in the art in and around 1996 would
have viewed the inclusion of tertiary amine in
Medichem’s patent as a material element Iof each of the
claims of that patent and would have viewe:d the effect of
the removal of tertiary amine in Rolablo’s patent as
significant but far from obvious in the prior art.
AOOO012, A000014-A000015 (emphasis added).
The court first determined that Medichem’s “inclusion” of a tertiary amine
would be obvious to one of skill in the art in light of the “extensive literature.”
11
A000015A000016.
But relying on Rolabo’s expert’s analysis of Rolabo’s
commercial and patent-example processes for making loratadine, the court held:
What someone skilled in the art would not find obvious,
however, was what would be the result if tertiary amine
were eliminated from the process, that is!. the removal
of the added tertiary amine (beyond any tIerGary amine
automatically present in the molecular structure), and
what would happen then if the other elements of the
process, such as temperature, were then varied. It was
left to Rolabo to make these changes and to come up
with a process for making loratadine that, because it
dispensed with tertiary amine but still produced
loratadine, was easier, faster, and gave a potentially
higher yield.
Rolabo, in effect, built a better mousetrap. Thus, far
from being the same invention, Rolabo’s patented
process is a considerably improved process that in no
way interferes with plaintiff’s process.
A000016-A000017 (emphasis added). But Rolabo did not claim an improved
process for making loratadine by eliminating tertiary amine. A000 1OS-A000 109.
Nor do Rolabo’s claims have any temperature, time or yield limitations.
AOOOlOS-A000109.
Medichem appeals from the district court’s holding of no interference-a
legal issue-based
on its erroneous claim construction and misapplication of the
two-way patentability test. A000213, AO10406-AO10407. Rolabo does not appeal
the district court’s finding of priority in Medichem’s favor. A000214, A010408A010409.
12
SUMMARY OFTHE ARGUMENT
After finding that Medichem had established priority of invention in this
judicial interference, the district court erroneously held that the patents did not
interfere and dismissed the case. This erroneous dismissal stems from two related
legal errors. First, the court misconstrued Rolabo’s “comprising”
claims and
treated them as if they were “consisting of’ claims when it incorrectly equated
those claims with Rolabo’s specific patent-example and commercial processes,
which do not employ a tertiary amine. Second, when it applied the two-way
patentability test, the court improperly focused its obviousness inquiry on the
alleged improvement of Rolabo’s commercial and patent-example processes, rather
than on the obviousness of Rolabo’s claims vis-a-vis Medichem’s claims. But
Rolabo’s claims encompass the use of a tertiary amine. And the “the name of the
game is the claim.”
In re Hiniker Co., 150 F.3d 1362, 1369,47 USPQ2d 1523,
1529 (Fed. Cir. 1998) (citing Giles Sutherland Rich, Extent of Protection and
Interpretation of Claims-American
Perspectives, 21 Int’l Rev. Indus. Prop. &
Copyright L. 497,499 (1990)).
It is these errors in claim construction-legal
review-that
errors subject to de novo
when corrected require reversal and entry of judgment in
Medichem’s favor.
13
ARGUMENT
I.
The Standard Of Review And Applicable Law
A.
Interference And Claim Construction Are Matters Of Law, Reviewed
De Nova By This Court
Claim construction is a question of law that this Court reviews de nuvo.
Markman v. Westview Instruments, Inc., 52 F.3d 967,979,34
USPQ2d 1321, 1329
(Fed. Cir. 1995), af’d 517 U.S. 370 (1996). Whether two patents interfere is also a
question of law. Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 500,42 USPQ2d
1608,1612 (Fed. Cir. 1997); Credle v. Bond, 25 F.3d 1566,1571,30
USPQ2d
1911, 19 15 (Fed. Cir. 1994). As this appeal presents purely legal issues, this Court
should construe the claims of the patents and apply the two-way patentability test
anew to determine interference.
B.
Application Of The MO-Way Patentability Test To Determine
Interference Under 35 U.S.C. 6 291
Two or more patents interfere when they claim “tlhe same or substantially
the same subject matter.” Slip Track Sys., Inc. v. Metal-Lite, Inc., 304 F.3d 1256,
1263 (Fed. Cir. 2002); see also Slip Track Sys., Inc. v. Metal-Lite, Inc., 159 F.3d
1337, 1338 (Fed. Cir. 1998) (“Although the claims of the two patents do not use
identical language, the two patents claim identical subject matter.“); Albert v.
Kevex Corp., 729 F.2d 757,758 n.l,221 USPQ 202,204 n.1 (Fed. Cir. 1984)
(“Two or more patents interfere . . . when they claim the same subject matter”);
Advance Transformer Co. v. Levinson, 231 USPQ 1,18 (N.D. Ill. 1986) (two or
14
more patents interfere when, “in light of the specification, drawings, and prior art,
they claim in whole or in part substantially
added), afd
in pertinentpart,
the same invention.“)
(emphasis
837 F.2d 1081, 5 USPQ2d 1600 (Fed. Cir. 1988).
The test for interfering patents under 35 U.S.C. 8 1291is the same as that for
an interference in the Patent Office under 35 U.S.C. 8 135. Advance Transformer,
231 USPQ at 14 (“The test for determining whether two patents interfere, within
the meaning of 35 U.S.C. Section 291, is not different from the test for resolving
an interference proceeding in the Patent and Trademark Office.“); see also 37
C.F.R. Q 1.601(i).
Two patents are said to interfere when at least one claim of a party’s
patent, which is designated to correspond to a count, and at least one claim of an
opponent’s patent, which also corresponds to the count, define the “same
patentable invention.” 37 C.F.R. 8 1.601(j); Winter v. Fujita, 53 USPQ2d 1234,
1243 (Bd. Pat. App. & Interf. 1999); Fiddes v. Baird, 301USPQ2d 1481, 1484 (Bd.
Pat. App. & Interf. 1994). The test for determining whether claims define the
“same patentable invention,” referred to as the two-way patentability test, is set
forth in 37 C.F.R. 8 1.601(n), which states:
Invention “A” is the same patentable
invention “B” when invention “A” is
U.S.C. 102) or is obvious (35 U.S.C.
invention “B” assuming invention “B”
respect to invention “A.”
15
invention as an
the same as (35
103) in view of
is prior art with
37 C.F.R. 8 1.601(n) (italics in original, emphasis added); Winter, 53 USPQZd at
1243 (Bd. Pat. App. & Inter-f. 1999) (“The claimed invention of Party A is
presumed to be prior art vis-a-vis Party B and vice versa. The claimed invention of
Party A must anticipate or render obvious the claimed invention of Party B and the
claimed invention of Party B must anticipate or render obvious the claimed
invention of Party A.“); Exparte Standish, 10 USPQ2d 1454, 1459 (Bd. Pat. App.
& Interf. 1988) (the interference test “plainly and simply” is whether one
inventor’s claims render another’s claims either obvious or anticipated).
c.
A Judicial Interference Is Determined By Reference To A
“Description Of Interfering Subject Matter” Similar To A “Count”
In A Patent Oflice Interference.
As this Court recently pointed out, “[mlost interferences arise in the PTO,
involve an interference between two applications or an a.pplication and one or more
patents, and begin with the creation of a ‘count.“’ Slip Track, 304 F.3d at 1263.
Under 37 C.F.R. 8 1.601(f):
A count defines the interfering subject matter. . . . A
claim of a patent . . . that is designated to correspond to a
count and is identical to the count is said to correspond
exactly to the count. A claim of a patent . . . that is
designated to correspond to a count but is not identical to
the count is said to correspond substantially to the count.
When a count is broader in scope than all claims which
correspond to the count, the count is a phantom count.
Id. (italics in original).
16
For each “same patentable invention” so defined, a count is drafted by an
Administrative Patent Judge from the Board of Patent Appeals and Interferences to
describe that invention. Competing claims are deemed to1be interfering if they are
identical to the count (“correspond exactly”), substantially the same as the count
(“correspond substantially”) or are covered by a phantom count. 37 C.F.R. $
1.601(f).
But as in Slip-Track, this case is “one of a handful” between issued patents
that arose in a district court. Slip Track, 304 F.3d at 1263. Because this case was
brought in a district court under Section 291-and
Slip Track-there
before this Court’s guidance in
was neither a count drafted by the PTO nor an articulated
description of interfering subject matter. So Rolabo and Medichem proposed the
following count in accordance with the rules of interference practice for the district
court’s use in deciding the issues of interference and priority:
A process for preparing loratadine comprising reacting 8chloro-5,6-dihyrobenzo[5,6]cyclohepta[
1,2--b]pyridin- 11
with ethyl 4-oxopiperidine- 1-carboxylate in the presence
of low valent titanium wherein said low valent titanium is
generated by zinc.
A010049, A010261. This count is identical to Rolabo’s claim 17. But neither this
proposed count nor any other appears to have played a role in the district court’s
decision. A000004-A000020.
17
Medichem submits that the count proposed by the parties to the district court
is a “description of interfering subject matter . . . broad enough to encompass the
common subject matter in the claims of both patents.” Slip Track, 304 F.3d at
1265 (emphasis added). Claim 17 of Rolabo’ s patent corresponds exactly to this
description of interfering subject matter. AOO0109. Claims 2-13 of Medichem’s
patent correspond substantially to this description and thus, also interfere.
AOO0104. Rolabo’s claims 1-16 are directed to processes for making cycloheptene
compounds, including loratadine and an intermediate die-l inherently formed in
carrying out these processes. AOOOlOS-A000109. And since these claims are all
anticipated by and/or obvious in view of the description of interfering subject
matter, they also interfere. A00453 1-A004540.
II.
The District Court Applied The Tkvo-Way Patentability Test To
Misconstrued Claims And Concluded That The Patents Did Not Interfere.
Properly Construed, The Claims Of The Patents Interfere Because They
Define The Same Patentable Invention.
The district court applied the two-way patentability test to misconstrued
patent claims. The court improperly conflated Rolabo’ s preferred, commercial and
patent-example processes for making loratadine-neither
tertiary amine-with
of which employs a
Rolabo’s claims, which encompass’the use of a tertiary amine
by virtue of the “comprising” transition. A000105A000109,
A004665-A004674,
A010300. This was legal error. CC’S Fitness, Inc. v. Bnmswick Corp., 288 F.3d
1359, 1370,62 USPQ2d 1658, 1665 (Fed. Cir. 2002) (“In the course of construing
18
the disputed claim terms, a court should not ordinarily rely on the preferred
embodiments alone as representing the entire scope of the claimed invention.“);
Int’l Visual Corp. v. Crown Metal Mfg. Co., Inc., 991 F.2d 768,771-72,26
USPQ2d 1588, 1591 (Fed. Cir. 1993) (“Infringement is determined on the basis of
the claims, not on the basis of a comparison with the patentee’s commercial
embodiment of the claimed invention”); see also Hiniker., 150 F.3d at 1369 (Fed.
Cir. 1998) (“the name of the game is the claim.“).
Having misconstrued Rolabo’s claims in this manner, the district court then
erred by focusing its two-way patentability analysis on “whether someone
reasonably skilled in the art would find the elimination of a tertiary amine obvious
or anticipated in light of the prior art at the relevant time, which was around 1996.”
AOOO012. But that was not the proper inquiry since Rolabo’s “comprising”
claims do not claim the elimination or absence of a tertiary amine. Comprising
claims are open-ended and do not exclude additional, unrecited elements or
method steps. Genentech, 112 F.3d at 501,42 USPQ2d at 1613; see AFG Indus.,
Inc. v. Cardinal IG Co., Inc., 239 F.3d 1239, 1245,57 USPQ2d 1776, 1780 (Fed.
Cir. 2001) (“We have consistently held that the word ‘comprising is an open
transition phrase.“); Vehicular Techs. Corp. v. Titan Wheel Int’l, Inc., 212 F.3d
1377, 1383,54 USPQ2d 1841, 1845 (Fed. Cir. 2000) (a patentee uses the phrase
“comprising” to mean “I claim at least what follows and potentially more.“);
19
Moleculon Research Corp. v. CBS, Inc., 793 F.2d 1261, I27 1,229 USPQ 805, 8 12
(Fed. Cir. 1986). Therefore, the district court adopted a legally incorrect claim
construction.
The district court’s errors were clearly demonstrated when it considered
Medichem’s claimed process for making loratadine-whi.ch
reaction take place in the presence of a tertiary amine-as
recites that the
prior art to Rolabo’s
claims under the two-way patentability test. Supposedly comparing Rolabo’s
claims to Medichem’s, the court stated that “far from being the same invention,
Rolabo’s patented process is a considerably improved process that in no way
interferes with plaintiff’s process.” A00001 7 (emphasis added).
To reach that conclusion, the court employed the following reasoning:
What someone skilled in the art would not find obvious,
however, was what would be the result if tertiary amine
were eliminated from the process, that is, the removal of
the added tertiary amine . . . and what would happen then
if the other elements of the process, such a,stemperature,
were then varied. It was left up to Rolabo to make these
changes and to come up with a process for making
loratadine that, because it dispensed with tertiary amine
but still produced loratadine, was easier, faster, and gave
a potentially higher yield.
Rolabo, in effect, built a better mousetrap.
A0000 16 (emphasis added).
The problem with this reasoning is that Rolabo’s claims encompass the
prior-art mousetrap as well as the supposed better mousetrap. In other words,
20
Rolabo’s “comprising”
claims encompass not only its alleged improved process for
making loratadine in the absence of a tertiary amine, but also Medichem’s
process-assumed
to be prior art under the two-way patentability test-for
making
loratadine in the presence of a tertiary amine. By construing Rolabo’s claims as if
they were directed to an improved process for making loratadine by removing the
tertiary amine, the district court erred.
This was the kind of error warned of by the Board (of Patent Appeals and
Interferences in Ex parte Standish:
we note that the appellant and the examiner have devoted
much discussion and argument to the question of whether
it would have been obvious to remove Hanna’s
floatation devices from his claimed lure. We have not
considered this question since it is not germane to the
issue of whether appellant’s claimed invention is
obvious in view of patentee’s claimed invention. This
is because the claims on appeal are sufficiently broad in
scope as to encompass a lure having floating devices. In
other words, the appealed claims do not exclude
floatation devices and therefore do not distinguish
themselves from the floatation devices claimed by
Hanna.
Standish, 10 USPQZd at 1459 (emphasis added).
But the district court did not heed this warning. Instead, it applied the twoway patentability test and construed Rolabo’s “comprising” claims as if they
exclude or forbid the use of the tertiary amine recited in Medichem’s claims. So
just as the Board in Standish decided that the “claims on appeal are sufficiently
21
broad in scope as to encompass” the interfering subject matter, this Court should
construe Rolabo’s “comprising” claims so as to encompass a process for making
loratadine using a tertiary amine. Id. And as in Standish, the district court’s focus
on eliminating a tertiary amine from the process is “not germane to the issue of
whether [Rolabo’s] claimed invention is obvious in view of [Medichem’s] claimed
invention.” Id.
If Rolabo believed that a process for making loratadine in the absence of a
tertiary amine were patentably distinguishable from an otherwise identical process
that takes place in the presence of a tertiary amine, Rolabo could have claimed it
as such. For example, Rolabo could have drafted its claims in such a way as to
exclude steps or ingredients other than those recited by ulsing the closed
“consisting of’ transition. AFG, 239 F.3d at 1245,57 USPQ2d at 1780 (“‘closed’
transition phrases such as ‘consisting of’ are understood to exclude any elements,
steps, or ingredients not specified in the claim.“). But it did not. Instead, Rolabo
claimed its process with “comprising” claims, which rea.d on Medichem’s prior
invention under 35 U.S.C. 8 102(g)(l).
Vehicular Techs.., 212 F.3d at 1382-83,54
USPQ2d at 1845; Moleculon Research, 793 F.2d at 1271., 229 USPQ at 812.
Properly construed, the patents interfere as a matter of law because
application of the two-way patentability test demonstrates that (1) Rolabo’s
22
“comprising”
claims are anticipated by Medichem’s claims, and (2) Medichem’s
claims are obvious in view of Rolabo’s.
A.
Taking The Medichem Patent As Prior Art IJnder The ‘Vitro-Way
Patentability Test, The Court Erred In Determining That Rolabo’s
Claims Are Not Obvious In View Of Medich.em’s.
Taking Medichem’s patent as prior art under the two-way patentability test,
Rolabo’s claims are not merely obvious, but anticipated--the
ultimate case of
obviousness. See In re Baxter Travenol Labs., 952 F.2d 388, 391,21 USPQ2d
1281, 1285 (Fed. Cir. 1991) (“[S] ince anticipation is the ultimate of obviousness,
the subject matter of these claims is necessarily obvious and we need not consider
them further.“); In re Paulsen, 30 F.3d 1475, 1481, 3 1 USPQ2d 1671, 1675 (Fed.
Cir. 1994). A claim is anticipated and therefore invalid when a single prior art
reference expressly or inherently discloses each and every limitation of the claim.
Glaxo Inc. v. Novopharrn Ltd., 52 F.3d 1043, 1047,34 USPQ2d 1565,1567 (Fed.
Cir. 1995).
The simplest case of anticipation-and
that focuse:d on at trial-can
be seen
by taking Medichem’s claim 2 as prior art under the two,-way patentability test, and
comparing it to Rolabo’s claim 17. A004522-A004530.
As shown in the chart
below, each and every element of Rolabo’s claim 17 (rewritten to include the
limitations of claim 1, from which it depends) is disclosed in Medichem’s claim 2.
23
Medichem’s Claim 2 as Prior Art
Rolabo’s Claim 17
A process for preparing Loratadine
comprising reacting
A process for the preparation of
loratadine consisting of reacting in an
organic solvent and in the presence of a
tertiary amine
a dibenzosuberone or aza derivative
thereof
8-chloro-5,6dihydrobenzo[5,6]cyclohepta[ 1,2blpyridin- 11-one, of formula VII
with an aliphatic ketone
and ethyl 4-oxopiperidine- 1-carboxylate
of formula IV
in the presence of low-valent titanium
wherein said low valent titanium is
generated by zinc.
with low-valent titanium species,
wherein the low-valent titanium species
are generated lby reduction of titanium
tetrachloride with zinc dust.
A000104 (emphasis added), AOOO108-A000109.
There is no dispute that the formula VII compound of Medichem’s claim 2 is
the specific aza derivative of a dibenzosuberone necessary to make loratadine
according to claim 17 of Rolabo’s ‘827 patent. A000108-A000109, A010299.
There is also no dispute that the formula IV compound of Medichem’s claim 2 is
the specific aliphatic ketone necessary to make loratadinle according to claim 17 of
Rolabo’s ‘827 patent. AOOO108-A000109, A010299. Thus, applying the two-way
patentability test in this direction, Rolabo’s claim 17 is anticipated by Medichem’s
claim 2.
24
Anticipation is also evident from the fact that Rolabo’s claim 17 reads on
Medichem’s claim 2. And Rolabo conceded as much. In moving to dismiss for
lack of subject matter jurisdiction, Rolabo said:
Although the ‘827 patent does not require the use of a
tertiary amine in its claimed process, it allows for the
use of a tertiary amine or other reactants by virtue of
the use of the term “comprising” in the claims. Thus, a
process for making loratadine that involves reacting 8
chloro-5,6-dibenzo[5,6]cyclohepta-[l,2-b]pyridin-l
l-one
and ethyl 4-oxopiperidine- 1-carboxylate in the presence
of low valent titanium, where the low valent titanium is
generated by zinc infringes as least claim 1 and claim
17 of the ‘827 patent, even if that Iprocess uses
additional reactants, such as a tertiary amine [e.g.
Medichem’s claim 21, or contains additional steps.
A010051 (emphasis added); A010411.
But since “that which infringes if later anticipates if earlier,” by accusing
Medichem of infringement, Rolabo effectively admitted that Medichem’s claimed
process for making loratadine anticipates Rolabo’s claim 17 (as well as Rolabo’s
claim l-the
broadest claim of its ‘827 patent). Polaroid Corp. v. Eastman Kodak
Co., 789 F.2d 1556, 1573,229 USPQ 561, 574 (Fed. Cir. 1986) (citing Peters v.
Active Mfg. Co., 129 U.S. 530,537 (1889)).
So, applying the two-way patentability test in this direction, Rolabo’s claim
17 encompasses, and is therefore anticipated by, MedichLem’s claim 2.
25
B.
Taking The Rolabo Patent As Prior Art Under The ‘Ikvo-Way
Patentability Test, The District Court Properly Determined That
Medichem’s Claims Are Obvious.
Applying the two-way patentability test in the other direction-in
Rolabo’s claim 17 is assumed to be the prior art-every
which
element of Medichem’s
claim 2 is present except for the recitation that the reaction take place “in the
presence of a tertiary amine.” This is the only difference between the claimed
invention (Medichem’s claim 2) and the assumed prior art (Rolabo’s claim 17).
But as the district court properly decided, the use of tertiary amines in carrying out
McMurry reactions was well-known and obvious to those of ordinary skill in the
art. A000015A000016.
That decision rests on a wealth of chemical literature,
including the seminal 1989 review article of Professor McMurry himself.
AOOl372-A001383, AOO1513-A001514, AOO1519-A001537, A003355-A003399.
A claimed invention is unpatentable for obviousness if the differences
between it and the prior art “are such that the subject matter as a whole would have
been obvious at the time the invention was made to a person having ordinary skill
in the art.” 35 U.S.C. § 103(a) (2002); see also Beckson Marine, Inc., v. NFM,
Inc., 292 F.3d 718,725,63
USPQ2d 1031, 1035 (Fed. Cir. 2002). Obviousness is
a legal conclusion based on underlying findings of fact. See In r-eDembiczak, 175
F.3d 994,998, 50 USPQ2d 1614, 1616 (Fed. Cir. 1999). The underlying factual
inquiries are: (1) the scope and content of the prior art; l(2) the level of ordinary
26
skill in the prior art; (3) the differences between the claimed invention and the
prior art; and (4) objective evidence of nonobviousness. See Graham v. Joh.n
Deere Co., 383 U.S. 1, 17-18, 148 USPQ 459,467 (1966); Dembiczak, 175 F.3d at
998,50 USPQ2d at 1616.
After defining the scope and content of the prior art, and the level of
ordinary skill in the art, the district court explained its basis for determining that
Medichem’s claimed process was obvious in view of Rolabo’s under the two-way
patentability test:
someone skilled in the art would have understood the key
role played by the addition of tertiary amine in the
Medichem patent was to reduce acidity and increase
basicity, exactly as McMurry himself had stated in his
1989 article. This would be significant in furthering the
loratadine-producing reaction in a manner recommended
by the Medichem process, as Medichem itself described
in its own experiments. But someone skilled in the art
would also recognize that the addition of tertiary amine
would extract a price in terms of longer reaction time,
lower yield, and an additional workup. A person skilled
in the art would know this both by reference to the
extensive literature and also by consideration of the
changes that occur in the chemical structure of the
titanium reagent when additional pyridine2 is added, as in
Medichem’s process.
2 Pyridine is the tertiary amine used by Medichem in its commercial process and a
well-known tertiary amine used in the art of McMurry couplings. A010300.
27
A000015-A000016 (emphasis added). In other words, the district court found that
assuming Rolabo to be the prior art, Medichem’s recitatioln of a tertiary amine in
its claims was obvious. A000015-A000016.
Moreover, the use of tertiary amines
in carrying out McMurry reactions was well-known and studied since the 1970s.
AOO1372-A001383, A001513-A001514, A001519-A001537, A003355-A003399.
Accordingly, applying the two-way patentability test in this direction, the court
properly concluded that Medichem’s claimed process wa:s obvious in view of
Rolabo’ s claims.
III.
The District Court’s Unappealed Award Of Priority To Medichem Renders
Rolabo’s Claims Invalid Under 35 U.S.C. 8 102(g)(l) Because Medichem’s
Claims Anticipate Rolabo’s Claims.
Because Medichem’s claim 2 and Rolabo’s claim 17 define the “same
patentable invention” under the two-way patentability test, the patents interfere.
Winter, 53 USPQ2d at 1243 (“An interference-in-fact ex.ists when at least one
claim of a party that is designated to correspond to a count and at least one claim
of an opponent that is designated to correspond to the count define the same
patentable invention.“) (emphasis added). And as interfering patents, the proper
“relief’ under 35 U.S.C. 5 291 is “a declaration of priorilty and the subsequent
elimination of an invalid patent that claims the same subject matter.” KimberlyClark Corp. v. Procter & Gamble Distrib. Co., Inc., 973 F.2d 911,914,23
USPQ2d 1921, 1924 (Fed. Cir. 1992).
28
Because the district court found that Medichem invented its claimed process
before Rolabo, this Court should hold Rolabo’s claims invalid under 35 U.S.C. 8
102(g) (1). That statute provides, in pertinent part:
A person shall be entitled to a patent unless-during the course of an interference conducted under
section . . . 29 1, another inventor involved therein
establishes . . . that before such person’s invention
thereof the invention was made by such other inventor
and not abandoned, suppressed, or concealed, . . .
35 U.S.C. 8 102(g)(l) (emphasis added).
In other words, in light of Medichem’s priority of invention, Rolabo, as the
losing party, should be estopped from maintaining any claims that are patently
indistinguishable from the claims corresponding to the description of interfering
subject matter, i.e., Rolabo’s claim 17 and Medichem’s claims 2-13. See In ye
Deckler, 977 F.2d 1449, 1452,24 USPQ2d 1448, 1449 (Fed. Cir. 1992) (“The
interference judgment conclusively determined that, as between Deckler and
Grataloup, Grataloup was entitled to claim the patentable subject matter defined in
the interference count. It is therefore proper, and consistent with the policies of
finality and repose embodied in the doctrines of res judicata and collateral
estoppel, to use that judgment as a basis for rejection of claims to the same
patentable invention.“); Minnesota Mining and Mfg. Co. v. Bet-wick Indus., Inc.,
373 F. Supp. 85 1,859, 182 USPQ 111, 116 (M.D. Pa. 11374)(“If the second
29
claimant sustains his contention of priority, the claims in question of the issued
patent are invalidated and cancelled from the patent. Moreover, the activities of
the second claimant who thus prevails on the issue of priority will generally
become prior art over which the validity of any remaining claims of the issued
patent will be judged under $8 102 and 103 of 35 U.S.C.“).
As detailed below, the trial record shows that Rolalbo’s claims 1-17 are
patentably indistinguishable from the description of interfering subject matter.
A004522-A004540.
Accordingly, judgment should be entered under 35 U.S.C. 8
102(g)( 1) invalidating these claims.
A.
Rolabo’s Claim 17 Is Invalid Because It Is Anticipated By
Medichem’s Claims 2-13
Rolabo’s claim 17 corresponds exactly to the description of interfering
subject matter to which Medichem has priority.
Therefore, Rolabo’s claim 17 is
invalid under 35 U.S.C. § 102(g)(l).
B.
Rolabo’s Claims l-11 and 13-16 (Directed To The Genus
Cycloheptene) Are Invalid Because They Are Anticipated By
Medichem’s Claims 2-13 (Directed To The S~ecksLoratadine).
Claims l- 11 and 13- 16 of Rolabo’s patent are broader than claim 17 in that
they are directed to a process for making compounds of the cycloheptene genus.
A000 108-A000109. Loratadine is a species of the cycloheptene genus. AOOO108AOO0109. The only difference between the description of interfering subject
matter and claims 1- 11 and 13- 16 of Rolabo’ s patent is that the former is directed
30
specifically to loratadine while the latter are directed generally to cycloheptenes,
including loratadine. A000 108-A000 109.
This Court’s case law firmly establishes that a later genus claim is
anticipated by, and therefore not patentably distinct from, an earlier species claim.
Eli Lilly and Co. v. Barr Labs., Inc., 25 1 F.3d 955,971, 58 USPQ2d 1869, 1880
(Fed. Cir. 2001); In ye Berg, 140 F.3d 1428,1437,46 USPQ2d 1226, 1233 (Fed.
Cir. 1998). Where a patent claims a genus (e.g., cycloheptene), reduction to
practice of a species within the genus (e.g., loratadine) establishes priority to the
genus itself. Oka v. Youssefyeh, 849 F.2d 581,584,7 USPQ2d 1169, 1171 (Fed.
Cir. 1988); Mikus v. Wachtel, 504 F.2d 1150, 1151, 183 lJSPQ 752,753 (C.C.P.A.
1974) (“A prior reduction to practice of the species precludes another party from
claiming that he is the first inventor of the genus claiming the species”); see aEso
Eli LiEZy,251 F.3d 971, 58 USPQ2d at 1880.
Similarly, when a claim covers several compositions, either generically or as
alternatives, the claim is deemed anticipated if any of the compositions within the
scope of the claim is known in the prior art. Titanium Metals Corp. of America v.
Banner, 778 F.2d 775, 782,227 USPQ 773,778 (Fed. Cir. 1985); see also In re
Petering, 301 F.2d 676,682, 133 USPQ 275,280 (C.C.F’.A. 1962) (holding a
generic claim encompassing a compound described in a prior-art reference
unpatentable under 35 U.S.C. 8 102(b)); In re Slayter, 2’76 F.2d 408,411, 125
31
USPQ 345, 347 (C.C.P.A. 1960) (“It is well settled that a generic claim cannot be
allowed . . . if the prior art discloses a species falling within the claimed genus; in
other words, whatever would infringe if subsequent will anticipate if prior.“).
In addition, as discussed in Section II above, Rolabo effectively admitted
that its claim 1 is anticipated by Medichem’s claim 2. A000204, A01005 1.
c.
Rolabo’s Claim E-Directed
To An Inherent Intermediate Diol-Is
Invalid Because It Is Inherently Anticipated By Medichem’s Claims
2-13
Rolabo’s claim 12 is invalid because it claims a precursor that is inherently
formed in the process of Medichem’s claims 2-l 3. Undisputed evidence at trial,
including the testimony of Rolabo’s expert and prior art published by Professor
McMurry, compel this conclusion.
Rolabo’s claim 12 claims the preparation of an “intermediate dial” of a
specified formula (also called a “pinacol” or “diolate”).
A000 106-A000 108,
A001 372-A001373. At trial, Rolabo’s expert conceded that this intermediate diol
is inherent in carrying out both parties’ claimed processes for making loratadine:
In your opinion, both Medichem’s claim process
and Rolabo’s claim process for making loratadine
proceed through the formation of a diol
intermediate, right?
A.
Diol or diolate, yes.
Q-
Both of them proceed either through a diol or a
diolate, is that correct?
32
A.
That’ s correct.
Q-
And isn’t the formation of such an intermediate
inherent in carrying out McMurry reactions?
A.
Yes, I would believe so. Yes.
A004726.
And as Professor McMurry described in his comprehensive 1989 review
article, the formation of this intermediate diol or pinacol ‘was in 1996 a well-known
and inherent step in carrying out the McMurry reaction:
The carbonyl-coupling reaction takes place in two steps:
(1) reductive dimerization of the starting ketone or
aldehyde to form the carbon-carbon bond, and (2)
deoxygenation of the 1,2-diolate intermediate to yield the
alkene.
*
*
*
The first step is simply a pinacol reaction and is not
unique to low-valent titanium.
It has been known
since 1859 that reducing metals are capable of adding an
electron to a ketone or aldehyde car-bony1group, yielding
an anion radical that dimerizes. The evidence for this
first step in the titanium-induced coupling reaction is
straightforward, because the intermediate pinacols can
be isolated in high yield if the carbonyl-coupling
reaction is carried out at 0°C rather than at solvent reflux
temperature.
AOOl372-A001373 (emphasis added).
A patent claim is anticipated if it is inherent in the prior art. See Glaxo, 52
F.3d at 1047, 34 USPQ2d at 1567; Atlas Powder Co. v. h-eco Inc., 190 F.3d 1342,
1347, 5 1 USPQ2d 1943, 1946-47 (Fed. Cir. 1999) (“Under the principles of
33
inherency, if the prior art necessarily functions in accordance with, or includes, the
claimed limitations, it anticipates . . . the discovery of a previously unappreciated
property of a prior art composition, or of a scientific explanation for the prior art’s
functioning, does not render the old composition patentably new to the
discoverer.“).
Because the diol intermediate of Rolabo’s claim l;! is inherent in carrying
out the process set forth in the description of interfering s’ubject matter-or
other McMurry reaction for preparing cycloheptenes for that matter-claim
any
12 is
necessarily anticipated by, and therefore invalid in view of, Medichem’s prior
invention.
34
CONCLUSION
As a matter of law, application of the two-way patentability test to properly
construed claims shows that the patents define the same paltentable invention in
_
both directions and therefore interfere. Moreover, Rolabo’s claims l-16 are
patently indistinguishable from the description of interfering subject matter and,
thus, also interfere. And Rolabo has not appealed the district court’s finding of
priority in favor of Medichem. Accordingly, the district court’s judgment
dismissing the case for lack of interference should be reversed and judgment
should be entered awarding Medichem priority and invalidating Rolabo’s claims.
Respectfully submitted,
Dated: October 23,2002
Barry S. White
James K. Stronski
Tedd W. Van Buskirk
John G. Taylor
FROMMERLAWRENCE~~HAUGLLP
745 Fifth Avenue
New York, New York 110151
Telephone: (2 12) 588-0800
Facsimile: (2 12) 5 88-0500
Attorneysfor Plaint@Appellant Medichem,S.A.
35
I
STATE OF NEW YORK
COUNTY OF NEW YORK
)
)
)
ss.:
AFFIDAVIT
OF SERVICE
BY OVERNIGHT FEDERAL
EXPRESS NEXT DAY AIR
BARRY BARON
se: OLIVER PLACE
&ATN
ISLAND, NY 10814
, betng duly sworn, depose and say that deponent is not a
party to ;he action, is over 18 years of age and resides at the address shown above or at
OU
OCT2 3 2002
deponent served the within: Brief for Appellant Medichem, S.A.
upon:
Jeffrey S. Ward
Michael Best & Friedrich, LLP
Attorneys for Defendant-Cross-Appellant
One South Pickney Street
Madison, WI 53701
(608) 257-3501
the address
designated by said attorney(s) for that purpose by depositing 2 true
copy(ies) of same, enclosed in a properly addressedwrapper in an Overnight Next Day
Air Federal Express Official Depository, under the exclusive custody and care of Federal
Express, within the State of New York.
Sworn to before me on
OCT2 3 ZfJ@
Notary Public State of New York
No. 41-0930908
Qualified in Queens County
Commission Expires January 3 1,2006
Job # 176628/8758
CERTIFICATE
OF COMPLIANCE
I hereby certify, pursuant to Rule 32(a)(7)(C) of the Federal Rules of
Appellate Procedure that, according to the word processing system used to prepare
this brief of the Plaintiff-Appellant
Medichem, S.A., this brief contains 7,275
words and therefore complies with the type-volume limkation set forth in Rule
32(a)(7)(B) of the Federal Rules of Appellate Procedure.
00090837.DOC
ADDENDUM
c4I
ADDENDUM
Judgment,enteredMay 13,2002 ................................................................ A000001
Order of U.S.D.J. Jed S. Rakoff, datedMay 8, 2002, ..................A000002-A000003
A000004-A000020
Decision (Trial Transcript of May 7,2002) .....................m...........
I
United StatesPatentNo. 6,084,100..................................*...........AOOOlOl-A000104
United StatesPatentNo. 6,093,827..............................................A000105A000109
i
-
UNITED STATES DISTRICT
COURT
SOUTHERN
DISTRICT
OF NEW YORK
__--_-_--___-_______________________I___-x
MEDICHEM,
Sk,
Plaintiff,
-against-
ROLAE30, S.L.,
Defendant.
Whereas this matter having come on for trial before the Court, and all claims but plaintiffs
claim for interference having been previously dismissed or withdrawn in accordance with the prior
orders of the Court, and he Court having now found in favor of defendant on plaintiffs
claim for
interference for the reasons state from the bench-on May 7,2002, and ihe matter having come before
the Honorable Jed S. Rakoff, United States District Judge, and the Court, on May 8,2002, having
rendered its Order directing the Clerk of the Court to enter judgment dismissing the case, it is,
ORDERED,
ADJUDGED
AND DECREED:
That for the reasons stated in the
Court’s Order dated May 8, 2002, the comphtint is dismissed.
The Court finds that while this
dismissal, while otherwise with prejudice, is without prejudice to the defendant’s proposed motion
to reinstate the counterclaim that was previously withdrawn, or to plaintiff’s proposed cross-motion
to reinstate Counts 5 and 6 of its Complaint that were previously dismissed &&out
Dated:
prejudice.
New York, New York
May 9,2002JAMES M. PARKISON
Clerk of Court
/
6
IDeputy CIerk
A000001
._._.___
--.
i
I
-
.
.
UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF NEW YORK
--------------------________________c___
x
:
..
MEDICHEM, S-A.,
:
Plaintiff,
:
..
:
:
:
:
:
..
-VROLABO, S.L.,
Defendant.
----_--_---_--_-----________^___________
01 Civ.
3087 (JSR)
QRDER
,
i
JHD S. RAKOFF, U.S.D.J.
This
all
matter
claims
dismissed
defendant
for
claim
interference
and the Court having
on plaintiff's
claim
for
the Court
enter
judgment
otherwise
with
proposed
motion
withdrawn,
Counts
without
now directs
the case.
prejudice,
is without
or to plaintiff's
5 and 6 of its
prejudice.
SO ORDERED.
with
This
for
the prior
of
reasons
the
of the Court
-1
prejudice
to
while
dismissal,
to the defendant's
that
proposed cross-motion
that
been
transcript,
the counterclaim
Complaint
and
now found in favor
the Clerk
dismissing
to reinstate
having
interference
from the bench on May 7, 2002, w
accordingly,
bef,ore the Court,
in accordance
or withdrawn
of the Court,
stated
come on for trial
but plaintiff's
previously
orders
having
were previously
was previously
to
reinstate
dismissed
QJLg&g
J@# S.
Dated:
New York,
May
8,
RAKWF,
New York
2002
..-
m-
A000003
U.
-D-J.
257-medf
1
2
UNITED STATES DISTRICT
COURT
SOUTHERN DISTRICT
OF NEW YORK
-_____________________________
3
MEDICHEM,
I
Plaintiff,
5
01 Civ.
V.
ROLABO,
03087
E;ench Trial
S.L.
Defendant.
7
8
X
S.A.
4
6
653
------------------------------x
9
10
May 7, 2002
l2:05
p.m.
11
12
Before:
13
HON. JED S. RAKOFF,
14
15
District
APPEARANCES
16
17
18
19
FROMMER LAWRENCE & HAUG, L.L.P.
Attorneys
for Plaintiff
BY:
BARRY S. WHITE
JOHN TAYLOR
JAMES K. STRONSKI
TEDD W. VAN BURSKIRK
20
21
22
MICHAEL BEST & FRIEDRICH,
L.L.P.
Attorneys
for Defendant
THOMAS P. HENEGHAN
BY:
JEFF WARD
CHARLENE YAGER
23
24
Page 1
A000004
Judge
(JSR)
.-
257-medf
25
SOUTHERN DISTRICT
Y
(In
open
You were
yesterday
to
(212)
P.C.
805-0300
654
court)
All
THE COURT:
matters.
REPORTERS,
going
plaintiff's
right.
A couple
of
to
back
exhibit
give
the
preliminary
that
I gave
counsel.
MR. WHITE:
Court
Exhibit
7.
(Handing)
And I'm
THE COURT:
8
deputy
Court
Now,
9
filed
in
the
12
13
about
the
court
my courtroom
8 to be filed
pretrial
Plaintiff's
public
to
order?
have
file,
and docketed.
no objection
your
to
it
being
Honor.
No objection
from
defendants,
your
Honor.
So I'll
THE COURT:
deputy
to
docket
and
I received
16
17
course,
18
Tyco
19
readdressed,
something
Europe
S.A.
be.
It
yesterday,
sent
in
be our
that
also
and I have
initially
Barcelona
I should
might
give
to
my courtroom
file.
say,
MR. HENEGHAKJ:
20
21
what
MR. HENEGHAN:
14
15
1 through
MR. WHITE:
10
11
Exhibits
now handing
to Kelly,
and then
and sent
Judge,
original
to
I think
lab
not
opened,
Drye
recycled
of
& Warren
from
and/or
me.
I know what
notebooks.
that
Because
might
of
Page 2
A000005
-
22
discussions
23
in
24
make
case
257-medf
we had Farmhispani'a
on Friday,
there
was a reason
to
send
Let
see it.
the
originals
me just
open
(212)
805-0300
it
to
sure.
That's
25
what
it
is,
SOUTHERN DISTRICT
Judge.
REPORTERS,
P-C.
655
1
As it
THE COURT:
2
that
3
case.
notebook
All
was not
material
me say
also
5
think
I had occasion
6
was a very
7
be commended
8
helpful
9
professional
manner.
10
will
disappointed
11
One side
12
will
13
clear
14
excellently,
upon
the
be very
will
that
the
I thought
and you
status
in
of
this
both
sides
tried
have
the
THE COURT:
to
get
all,
genuinely,
to
Thank
the
I
It
case.
in
will
Court's
but
this
was very
a most
one side
be very
happy.
and the
other
I want
case
gratitude
side
to make
most
for
that.
and
sort
of
ask
the
court
you.
Thank
I'm
most
on my brilliance
appeal,
17
this
and one side
the
as I
I thought
a few moments,
until
MR. HENEGHAN:
on what
in
that,
days. ago,
was done
You know,
16
reporter
physical
my decision
presented
Everything
MR. WHITE:
on notes
a few
way you
be remarking
Wait
I give
You are
case.
15
19
remark
Court.
be saying,
rely
the
to my determination
before
to
well-tried
to
18
out,
right.
Let
4
turns
you.
going
to
say now,
me an expedited
Page
half
and I wl~ll
copy
3
read
of
the
transcript.
half
I'll
257-medf
20
go through
21
substance
it
for
will
typos
be exactly
As both
22
23
proceedings
24
single
25
Section
in
sides
this
are
that
is
the
patent.
2
jurisdiction
3
parties
4
defendant
Rolabo
5
companies
organized
6
each
7
are
8
which
9
Medichem
10
6,084,100
11
Loratadine,"
12
refer
13
for
specifically
has
both
its
to
this
14.
15
6,093,827
16
loratadine
S.L.
and
is
the
to
assignee
entitled,
of
active
other
'100
patent
on April
Rolabo'
is
the
which
is
also
and which
for
of
in
13th,
and
Spain
and
They
ingredients
companies.
States
filed
patent
No..
of
2000 and which
Medichem
The
both
of
preparation
4,
656
has
Barcelona.
United
the
July
patent.
its
we will
application
1998.
assignee
and owner
a process
issued
laws
pharmaceutical
and owner
issued.on
as the
are
pharmaceutical
"Process
which
business
Court
plaintiff
They
the
a
district.
as the
under
to
805-0300
this
this
defendant.
place
sell
that
in
pretrial
with
(212)
P.C.
S.A.
the
35 U.S.C.
interferes
proper
existing
of
under
agree
Medichem
as the
principal
then
reduced
REPORTERS,
are
manufacturers
they
has been
claim
is
the
now.
patent
venue
but
of
case
The parties
and that
that,
as a result
plaintiff's
SOUTHERN DISTRICT
plaintiff's
it
aware,
defendant's
1
like
as I say
case,
which
claim,
291,
and things
on July
for
the
25,
of
U.S.
Patent
preparation
2000,
and we'll
No;
of
refer
Page 4
A000007
~__ -----.-
.____
17
to
that
18
August
as the
26,
20
this
21
defendant
22
Section
seeks
Now,
25
part:
its
application
on
counterclaims
seeking
both
parties
of
attorneys'
award
seek
damages
an award
fees
remain
of
under
in
costs,
and
35 U.S.C.
285.
23
under
or
However,
case.
34
filed
1999.
No claims
19
257-medf
Rolabo
patent.
'827
as I mentioned,
Section
35 U.S.C.
the
291,
SOUTHERN DISTRICT
remaining
which
claim
is
provides,
in
pertinent
P.C.
(212)
REPORTERS,
brought
805-0300
657
1
3
"The owner of an interfering
may- have relief
- patent
against
the owner of another
by civil
action,
and the court
may adjudge
the question
of the invalidity
of any of the
in whole or in part.."
interfering
patents,
As the latter
part
of that
sentence
makes clear,
the
4
question
2
-5
for
of
the
whether
for
example,
112 F.3d
495,
500
(Fed.
Cir.
of
the
7
"interfere"
8
prior
9
same invention."
pertinent
they
Levinson,
12
two-way
i4
which
claim
light
in
whole
That's
part
at
test
patentability
837 F.2d
for
1,
a question
or
1997:).
in
part
from
(Fed.
is
versus
Chiron
Cir.
and
the
Transformer
1986)
forth
law
drawings
substantially
affirmed
Co.
in
1988).
sometimes
set
of
Two patents
Advance
18 (ND Ill.
1081
Inc.
specification,
interference,
test,
is
Genetech,
a quote
231 U.S.P.Q.
The
13
"in
when,
art,
11
interfere
See,
Corp.,
v.
patents
Court.
6
10
two
at
called
the
37 CFR S 1.601(n)
states:
Page 5
A000008
.^_--__-
-.-
~_~__I_
-..-
-
257-medf
17
Invention
"A" is the same patentable
invention
as an
"A" is the same as or is obvious
"B" when invention
invention
in view of invention
"B" assuming
invention
"B" is prior
art
with
respect
to invention
"A".
See also Ex Parte Standish,
U.S.P.Q.
1454, 1459 (Bd.
18
Pat.
19
claim
are,
20
claim
substantially
21
that
22
the
23
convenient
24
turn
15
16
App.
& Interf.
1988).
The elements
first,
interference,
that
that
is,
claimed
to
the
the
conceived
before
to begin
is,
same invention
plaintiff
invention
of
that
with
the
and,
patents
second,
priority,
and reduced
I find
defendant.
my analysis
an interference
priority
to practice
it
more
and only
then
priority
is
interference.
The question
25
here
under
SOUTHERN DISTRICT
the
REPORTERS,
rubric
of
P.C.
(212)
to
805-0300
658
determine
reduced
when each
to
processes
plaintiff's
5
Exhibit
6
was reduced
7
document.
8
that
9
practice
87,
preparation
process,
it
which
practice
More
cast
invention
in
that
the
first
here
that
find
are
Regarding
that
the
Plaintiff's
Medichem
was a fraudulently
? do not
plaintiff's
inventions
con'ceded
attest
1995,
was
loratadine.
virtually
to
generally,
patent
backdated
sufficient
evidence
process
was reduced
defendant's
view
to
1995.
However,
fact
is
of
purported
establishes
10
11
the
to
in
patented
As mentioned,
practice.
for
4
party's
meaningful
I do not
doubt
share
on the
substantial
that
this
documentation
Page 6
A000009
..- .-_.--_
12
and testimony
that
13
practice
14
testimony
15
chiefly
16
with
17
willingness
18
Exhibit
19
recordkeeping
20
failure
to
21
shortly
a week
22
referenced
23
the
24
plaintiff's
25
have.
in
the
of
Spring
IS0
to
was reduced
one thing,
that
deal
the
with
It
to
with
fraudulently
practices
very
before
important
in
the
parallel
that
it
cannot
testimony
the
both
the
SOUTHERN DISTRICT
that
recently
--
same reliance
documents
REPORTERS,
case
until
they
had been
does
convince
on
might
otherwise
and the
testimony
(212)
P.C.
by its
this
after
as it
the
Plaintiff's
in
then
was
punctilious
litigation
and documents
Nonetheless,
than
documents
Spanish
place
true
most
and only
trial,
the
noncompliance
is
less
as evidenced
--
I credit
backdate
Medichem's
to
backdating
their
requirements.
Medichem
produce
For
1996.
attempt
coupled
87,
invention
witnesses
regulatory
of
Court
of
plaintiff's
a belated
the
257-medf
Medichem
the
and
805-0300
659
1
evidence
2
in
3
that
4
regard,
5
examples.
6
not
claim
7
fall
of
8
established
9
the
of
Medichem's
Spring
the
of
Court
reduction
1996
may have
Plaintiff's
1996.
so strong
had in
Exhibits
By contrast,
that
is
its
of
accordingly,
practice
as to
this
22,
defendant,
reduction
And so,
to
of
overcome
24,
by
just
it;s
practice
in
this
by way of
own position,
occurred
I find
invention
any doubt
See,
regard.
23,
its
that
before
plaintiff
does
the
has
priority.
Turning,
then,
to the element
Page 7
of
interference,
the
257-medf
10
Court
finds
11
tertiary
amine
12
way that
negates
13
noninterfering.
14
Medichem's
15
of
16
that
17
Claim
18
incorporates
19
prepared
"in
20
the
only
example
21
the
claim
22
as follows:
the
in
question
Medichem's
patent
patent
17 under
of
it
the
process
the
presence
of
the
patent
process,
of
'100
the
in
each
1, which
of
2,
to
through
the
one
claim
Rolabo's
specifically
claims
amine".
provides
a
and every
Claim
compare
tertiary
in
runs
analysis
Claim
presence
material
of
patents
example,
Court
inclusion
amine
patentability
the
is
the
present
For
that
the
claims
tertiary
is
claims.
a two-way
whether
and makes
--
proposes
is
patent
obviousness
'100
Medichem
placed...
stirring.
pyridine
key
The presence
Medichem's
23
24
that
a process
Similarly,
of
how to
a tertiary
amine
in
perform
is
recited
"In a two-liter
vessel...
dry tetrahydrofuran
was
Titanium
tetrachloride
was slowly
added with
Then, zinc dust was added with
stirring...
Then
was added with
stirring."
25
SOUTHERN DISTRICT
REPORTERS,
(212)
P.C.
805-0300
660
1
That's
2
patent,
and,
3
example
of
4
from
of
'100
patent
6
very
nature,
course,
a tertiary
Now,
5
Example
is
this
as everyone
4 and 5 of
agrees,
pyridine
the
is
'100
an
amine.
presence
of
significant
cause
Columns
1,
tertiary
because
a chemical
Page
tertiary
reaction
8
A00001 1
amine
of
throughout
amines,
the
other
the
by their
7
ingredients
8
the
9
nothing
as shown,
adding
of
that
the
11
necessary
12
Conversely,
13
similar
14
presence
15
Rolabo
16
materially
'100
atent
9
ingredient
it
to
of
patentability
19
in
.iO
obvious
21
relevant
22
Standish,
23
the
24
patents-in-suit
25
chemistry.
the
or
find
the
the
patent
it
is
a
result.
one could
appears
achieve
yet,
amine.
nowhere
that
of
test
whether
of
that
light
of
was around
of
the
a
the
in
the
patent
is
a
was,
at
SOUTHERN DISTRICT
reasonably
skilled
a tertiary
art
See,
again,
In
this
inventions
claimed
a minimum,
synthetic
REPORTERS,
two-way
prior
1996.
1454 and 1459.
the
the
someone
elimination
in
which
art
that
suggesting
the
is
10 U.S.P.Q.
relevant
one knows
Ibecause
desired
that
process.
anticipated
time,
the
fact
If
rseading
amine
amine
specifically,
would
undisputed
a tertiary
strongly
analysis,
art
just
be obvious
adding
the
exothermic.
from
a tertiary
different
More
is
tertiary
not
patent,
by
achieving
without
or use
18
think
adds
would
result
17
amine
one would
'827
257-medf
example,
a tertiary
else,
10
for
amine
at
the
Ex Parte
case,
in
in
1996,
the
organic
(212)
P.C.
805-0300
661
1
More
2
forth
in
the
3
the
relevant
4
Bachelor's
particularly,
Pretrial
art
degree
according
Order),
would
in
to
a person
be a synthetic
chemistry
plus
Page 9
A00001 2
of
plaintiff
ordinary
organic
about
(as set
five
chemist
years
skill
in
with
of
a
257-medf
5
experience
in
6
literature
concerning
7
according
8
in
9
.ordinary
1996
included
some of
11
reactions
12
which
expert
15
knowledge
16
Dr.
17
credentials
18
experts
19
this
20
assume
21
case
22
standard
23
of
of
the
were
all
of
or
In
Onrubia,
met
the
the
someone
listed
the
art
one of
reactions,
carbonyl
coupling
and some of
in
to
that
those
the
for
in
the
other
purposes
of
I will
who testified
witnesses
was
his
of
However,
skill
his
reaction,
own stipulations,
chemists
ordinary
approach,
McMurry
notes
trial.
or percipient
of
McMurry
particularly
Court
parties
organic
to
plaintiff's
superior
this
the
experts
under
the
at
relevant
amine.
and of
considerably
the
amine
standard,
generally,
in
met
this
the
relevant
art
as
thereabouts.
this
the
regard,
chemists
on Medichem's
Court
employed
SOUTHERN DISTRICT
1
a tertiary
even
that,
the
primary
Further,
titanium
a tertiary
and given
as either
1996
with
the
available
to
low-valent
who testified
that
relating
to
order,
publications
literature
More
ruling,
Dr.
art
note
who best
Leckta.
24
the
access
Pretrial
of
without
I would
the
reaction.
the
proceeded
proceeded
14
McMurry
in
described
that
13
with
hundreds
in
which
synthesis,
the
to plaintiff
skill
10
25
industrial
that
by plaintiff
REPORTERS,
patent
finds
Bosch
who were
(212)
P.C.
as inventors
Dr.
and
both
805-0300
662
of
its
claimed
Page 10
A00001 3
__-_ .-__
-
2
process,
clearly
3
appreciable
4
loratadine
5
protest
6
difference
difference
-in
and
the
that
after
9
loratadine,
their
added
pyridine
11
loratadine.
It
12
particularly
with
13
Dr.
14
tertiary
15
view
16
of
17
plaintiff's
1.8
tertiary
amine.
19
averring
in
20
at
21
organic
22
to
23
regard
Bosch's
the
all
25
trial
respect
that
the
fact
times
Dr.
of
in
patent
process
what
respect
would
to
plaintiff,
SOUTHERN DISTRICT
the
Dr.
1996
and that
if
it
REPORTERS,
as
day
use
may now be
finds
that
as skilled
did
were
denominated
Finney
Court
art
this
to
amine
they
the
to
they,
tertiary
occur
in
Bosch
the
exclude
how they
continues
and Dr.
of
to
of
virtually
lawsuit,
that
of
rejection
skilled
that
and around
understood
traces
by her
process
this
get
they
be broadened
Onrubia
1996
evidence,
reasonably
the
in
to produce
confirmation
commercial
context
as obvious
patent
further
is
to
Onrubia
Dr.
situation
loratadine,
by further
to
no
experiment
began
corroborated
of
present
makes
the
and behold,
Whatever
chemists,
viewed
reaction
as persons
relevant
amine
lo
preferred
for
how they
McMurry
thereafter
With
at
process.
made an
production
their
to produce
situation
plaintiff's
24
claimed
And still
the
for
failed
is
amine
notwithstanding
a tertiary
suggestion
and
process
that
of
tertiary
as L-l,
and,
amine.
that
of
first
known
their
find
because
10
1996
I
their
It's
8
in
presence
to
7
257-medf
in 1996
believed
was important
not
at
all
eliminated.
experts
who testified
and Dr.
Camps,
as well
P.C.
(212)
805-0300
as
663
Page
11
257-medf
1
two
2
and Dr.
3
these
4
and,
5
direct,
6
adversary
7
the
8
than
logic.
9
firm
conclusions
10
.
of
the
experts
who testified
the
deMarch,
experts
more
Court
knew all
importantly,
responsive
fact
that
or
their
much about
none
of
them
to
conclusions
the
whatever
Court,
None of
reactions
able
give
to
put
a clear
premised
would
on the
Gratzia
McMurry
questions
were
Court
the
seemed
simple
by the
Dr.
disappointed.
that
often
Overall,
defendant,
was frankly
answers
counsel
for
by
indication
on bias
be hesitant
basis
of
to
any of
of
rather
draw
any
their
testimonies.
11
In
12
wholly
credible
13
for
14
sense
15
way
16
viewed
17
a material
element
18
would
viewed
19
in
20
prior
the
have
Rolabo's
finds
that
and that
obtained
both
and that,
the
Court
and convincing
results
someone
the
contrast,
in
under
the
skilled
in
inclusion
view,
the
in
of
tertiary
of
each
the
effect
patent
claims
the
as significant
made logical
showed
and around
the
of
that
in
removal
but
far
the
1996 would
Medichem's
of
was
an explanation
definitively
amine
of
Leckta
he gave
patents
Court's
art
Dr.
that
of
from
have
patent
patent
and
tertiary
obvious
as
amine
in
the
art.
21
As Dr.
22
would
have
23
of
24
and increase
tertiary
Lectka
understood
amine
in
basicity,
testified,
that
the
the
someone
key
Medichem
exactly
Page
role
patent
as McMurry
12
A00001 5
skilled
played
in
by
the
art
the
addition
was to
reduce
acidity
himself
had
stated
25
in
his
257-medf
This would
1989 article.
SOUTHERN DISTRICT
1
the
loratadine-producing
2
the
Medichem
3
experiments.
4
recognize
5
price
6
additional
7
this
8
consideration
9
structure
10
in
the
terms
of
A person
of
changes
the
the
12
obvious,
13
amine
14
of
15
automatically
16
would
17
as temperature,
18
make
19
loratadine
20
still
21
potentially
were
eliminated
added
these
then
in
if
the
were
changes
that,
produced
would
the
loratadine,
also
would
amine
would
lower
yield,
in
the
art
art
the
by
its
own
extract
a
and an
would
know
and also
by
chemical
pyridine
that
any
come up with
dispensed
was easier,
if
is,
is
find
tertiary
the
tertiary
of
the
was left
and what
process,
to
a process
with
such
Rolabo
for
tertiary
faster,
removal
amine
structure),
elements
It
not
result
process,
varied.
it
would
be the
to
making
amine
and gave
but
a
yield.
in
effect,
built
Page 13
A00001 6
_..-.-
art
when additional
molecular
other
and to
higher
in
literature
occur
(beyond
the
then
because
Rolabo,
in
amine
present
happen
skilled
from
tertiary
recommended
described
the
extensive
that
805-0300
process.
was what
however,
in
reagent
Medichem's
someone
time,
skilled
the
titanium
the
tertiary
reaction
to
What
the
of
by reference
as in
11
22
longer
workup.
of
added,
addition
a manner
in
furthering
664
itself
skilled
in
(212)
P.C.
in
as Medichem
someone
that
both
REPORTERS,
reaction
process,
But
be significant
a better
mousetrap.
Thus,
257-medf
23
far
24
is
25
with
from
being
the
a considerably
improved
plaintiff's
process
that
patented
in
process
no way interferes
process.
SOUTHERN DISTRICT
"
Rolabo's
same invention,
REPORTERS,
P.C.
(212)
805-0300
665
the
Accordingly,
not
carried
must
patent
law
6
prevailing
7
plaintiff's
8
asto
9
Court's
10
motion
party
in
for
12
copy
of
13
make
any
14
appropriate,
15
clerk
16
will
to
then
to
attorneys'
be neither
frivolous
nor
on any
fees
the
is
court
typographical
hopefully
in
ground.
hereby
denied.
reporter
to
of
the
get
errors
I will
defendant
while
to
Court
the
finds
so unjustified
in
the
Accordingly,
the
me an expedited
by tomorrow,
Therefore,
favor
fees
an award,
other
grammatical
few.
judgment
such
hopefully
or
fees,
attorneys'
here
proceedings,
enter
for
is
has
defendant.
award
nor
plaintiff
and judgment
cases,"
attorneys'
today's
request
an award,
ask
the
interference,
favorof
Court
warranted
I will
that
"exceptional
to
such
view,
11
17
the
claim
warrant
in
defendant's
permits
finds
to prove
be entered
As for
5
19
burden
therefore
4
18
its
Court
that
and I'll
are
direct
the
and the
judgment
further
from
issue.
Is
there
anything
that
counsel
needs
Court?
MR. HENEGHAN:
Judge,
just
Page 14
one thing.
Given
the
the
20
Court's
ruling,
21
because
our
22
process
of
23
now be allowed
25
understanding
not
shouldn't
of
reinstate
the
in
the
U-S,
to
in
the
U.S.
sell
this
case
be allowed
to
is
I'm
Medichem's
worried
at
I think
that
REPORTERS,
counterclaim
which
concluded
sell.
SOUTHERN DISTRICT
our
way in
selling
Because
24
257-medf
like
to
we would
that
this
P.C.
they
level,
their
prior
would
they
obligation
(212)
805-0300
666
to
sell,
and
like
to
reinstate
1
is
not
2
would
3
we'd
4
a preliminary
like
to
that
9
Count
we have
probably
11
also
in
13
favorably
inclined,
14
would
like
you
15
MR.HENEGHAN:
16
17th.
17
try
However,
to
sell.
in
the
regard.
but
if
you
Claims
start
you
may convince
in
those
Judge,
based
but
I think
on the
way
that's
I understand.
with
to
the
me yet.
reinstate
Court
How long
papers?
I'd
meantime,
We understand
off
your
but
you may make a motion
doesn't
schedule
5 and 6.
Judge,
day,
and
reinstate
I understand
a different
but
to put
that
argument
Well,
infringement
and perhaps
their
ruling,
and we
sell
estoppel
THE COURT:
It
for
that,
this
counterclaim.
now passed
I understand
for
your
is
then,
reinstate
an argument
12
in
Of course,
a collateral
1 was read
can't
hearing
MR. HENEGHAN:
8
10
you
order
counterclaim
TRO so they
injunction
counterclaim,
7
Court's
our
THE COURT:
5
6
seek
the
-Page 15
like
to
my concern
have
is
until
that
the
they
may
257-medf
THE COURT:
18
I'm
No,
not
going
to
issue
a TRO at
this
point.
19
MR. HENEGHAN:
20
21
submit
our
papers
THE COURT:
23
MR.HFNEGHAN:
24
THE COURT:
plaintiff's
that
by this
22
25
In
counsel
case,
All
So that
right.
--
the
want
lOth,
would
to
be --
to
and how long
does
respond?
REPORTERS,
MR. WHITE:
A week
2
THE COURT:
All
4
MR. WHITE:
Thank
you.
5
THE COURT:
Does
defense
or
ten
right.
(212)
P.C.
805-0300
667
days,
your
Honor.
So 1'11
give
you until
the
20th.
.
counsel
want
to put
in
reply
papers?
7
Just
MR. HFNEGHAN:
THE COURT:
.8
9
like
The 10th.
1
6
we would
Friday.
SOUTHERN DISTRICT
3
Judge,
Make
sure
10
possible
11
them,
12
at
the
papers
so that
and we'll
you
hear
five
So that
are
would
faxed
to
each
have
oral
argument
on May 30.
13
MR. HFNEGHAN:
Thank
14
THE COURT:
Well,
the
each
you,
good
Page 16
A00001 9
Judge.
be the
full
5 o'clock
May 30.
days,
24th,
other
as soon
opportunity
on that.
a Friday.
to
Let's
as
review
take
a look
Judge.
news,
then,
is
I'm
going
15
to
see all
16
see your
you
case
folks
again,
257-medf
The bad news
again.
but
else
we'll
deal
we need
18
MR. WHITE:
19
MR. HENEGHAN:
Thank
you,
your
Honor.
20
MR. STRONSKI:
Thank
you,
your
Honor.
21
THE DEPUTY CLERK:
i2
(Trial
your
All
I'm
going
as appropriate.
Anything
you,
take
it
that
17
Thank
to
with
is
up?
Honor.
rise.
concluded)
23
24
25
SOUTHERN DISTRICT
REPORTERS,
Page
17
A000020
P.C.
(212)
805-0300
to
United States Patent [I91
[II]
Stampa et al.
1451
WI
PROCESS FOR THE PREPARATION
LORATXDINE
OF
[751 Inventors: Alberta
Stampa; Pelayo Camps, both
of Barcelona; Gloria Rodriguez; Jordi
Bosch, both of Girona; Maria de1
Carmen Onrubii, Barcelona, all of
Spain
l731
Medichem,
Pll
Appl. No.: 09/058,837
WI
Filed:
6,084,lOO
Patent Number:
Date of Patent:
Jul. 4,200O
The process consists of the reductive coupling between the
compounds: 8-cbloro-5,6-dihydrobenzoC5.6]cyclohept~l,
Z-blpyridin-11-one (formula Wr)
VII
c&JcY
?.A., Barcelona, Spain
0
Apr. 13,l!J98
and ethyl 4-oxopiperidine-l-carboxylate
(formula IV)
Related U.S. Application Data
Provisional application No. 6OKl48,083,May 30,1997.
[Ml
P11 Int. Cl.’
WI U.S. Cl.
PI Field of
. ..._.............................................
CWD ZZl/O6
. . .. . .. .. .. .. . .. .. .. .. .. . .. .. .. .. . .. .. .. . .. ... . .. .. . ... .. . .. .. .. 546/B
*. . .. .. .. .. . .. .. .. .. .-... 546/93
Search _.....................
Primary Extiner-Dwayne
C. Jones
Attorney, Agent, or Fim-Scully,
Scott, Murphy & Presser
PA
N
0
N-CXOCHfi
==c
through the action of low-valent titanium species.
13 Claims, No Drawings
ABSTRACT
-
A000101
6,084,100
2
1
preparation of intermediate II, which require tbe use of
PROCESS FOR THE PREPARATION
OF
superacids and Grignard reagents.
LOFLtTADLNE
Process (B) from scheme 1, disclosed in the ES patent
2.040.177, implies the use of kimetbyl phospbite. whose
This application claims benefit from U.S. Provisional
Application Ser. No. 60/04&Ot33, filed on May 30,1997.
5 manipulation from an industrial viewpoint is inconvenient.
Process (C) from scheme 1, disclosed in the ES patents
2.009.465 and 2.009.466, is, in practice, a simple variation
FIELD OF THE INVENTION
of process (A) in which the order of their two last reactions
The present invention concerns to a process for tbe
has been interchanged.
preparation of loratadine, based on tbe cross reductive 1o Finally, process (D) was disclosed in the ES patent
coupling
between 8-cbloro-5,6-dihydrobenzo[5.6]
2.080.700 and in the Canada patent 2.134.128, while the
cyclobept~l,Zblpyridin-ll-one
and ethyl 4-oxopiperidinepreparation of intermediate VI, also disclosed in the ES
1-carboxylate.
patent 2.080.699, was carried out through a multy-step and
complex process.
PRIOR ART
15
Accordiug to the previous knowledge, it remains the need
Loratadine is a known antibistaminic disclosed for the
for the development of processes: a) shorter, b) involving
reaction conditions easy to be carried out industrially, for
first time by F. J. Villani in the U.S. Pat. No. 4,2%2,233.
scheme1
II
,a
Several alternative processes for the preparation of lorainstance, not requiring the use of superacids or Grignard
tadine are known, which can be summarized through the
reagents, c) not involving the use of unstable reagents, such
reactions shown in Scheme I.
6o as 4-chloro-N-methylpiperidine.,
or of inconvenient manipuProcess (A) from scheme 1 was disclosed in the above
lation from an industrial viewpoint, such as trimetbyl pboscited U.S. Pat. No. 4,282,233 and in the ES patent 503.085,
phite.
while the required intermediate II, can be obtained through
a multi-step cumbersome process disclosed in the U.S. Pat.
ORJECT OF THE INVENTION
No. 3326,924, which requires the use of Grignard reagents. 65
The object of tbe present invention is a process for tbe
The U.S. Pat. Nos. 4,659,716, 4,731,447 and 4,%‘3335
disclose complex and multi-step alternative processes for tbe
preparation of loratadine, based on the use of easily avail-
6,084,100
3
4
species, preferably an ethereal solvent such as diethyl ether,
able starting compounds and reaction conditions easily IO
apply in an industrial process.
1,4-dioxane, 12-dimethoxyethane,
tetrahydrofuran, etc.,
can be used.
DESCRIPTlON OF THE INVENTlON
The tertiary amines are well-known by the expert and
TLbe process for the preparation of loratadine of the 5
among
them,
for instance,
triethylamine,
present invention is characterized by reacting, in an organic
ethyldiisopropylamine,
triiutylamine and pyridioe, can be
solvent and in the presence of a tertiary amine, g-chloro-5,
6-dihydrobenzo[5,6]cyclohepta[l,2-b]pyridin-ll-one
cited.
(formula VII)
A preferred but not limitative sequence of operations to
10 carry out the process of the present invention can be as
a) the low-valent titanium species are prepared by reduczinc dust in an appropriate
6
c) a mixture of ketones VII and IV is added, and the
mixture is heated for the required time to complete the
and ethyl 4-oxopiperidine-1-carboxylate
(formula IV)
reaction, and
20
d) loraladine is isolated from the reaction mixture.
Iv
In this preferred but not limitative sequence of operations,
the reaction can be performed as shown below.
0
-bus&
In an adequate reaction vessel, the reaction solvent is
==c
25 charged (usually,
diethyl ether, 1.4-dioxane,
1,2dimethoxyethane, tetrahydrofuran, etc.) and the solvent is
with low-valent titanium species.
cooled to a temperature comprised between 10 and -20” C.
The conversion of the starting comuounds. VII and IV,
Then, titanium tetrachloride is slowIy added (1 to 4 mol per
into loratadine, I, takes place by reduitive cross coupling;
mol VII) and zinc dust (2 to 8 mol per mol VII) keeping at
based on the reaction known as the McMurry reaction.
30 any time the temperature of the reaction mixture between the
Many papers on the McMurry reaction have been
above indicated values, Then, a spcci6c amount of a tertiary
published, as can be seen from the revision published by J.
amine (pyridine, triethylamine, etc., 1 to 3 mol per mol Vll)
E. McMurry in Chem. Rev., 89, 1513-1524 (1989).
and finally, a solution of VII and IV (1 to 2 mol per mol of
Most of the descriied reactions consist in the dimerization
VII) in the same solvent used before are added, keeping the
of a carbonyl compound and, although there are know cross
couplings between two different carbonyl compounds, most 35 temperature in the above cited range. The mixture thus
obtained is stirred at room temperature for several hours and
of them are intramolecular reactions. In an intermolecular
then
it is heated to a temperature comprised between 30’ C.
cross coupling reaction between two carbonyl compounds,
and the reflux temperature of the solvent, for 6 to 72 hours.
three kind of products can be formed two corresponding to
When the reaction is completed, loratadine is isolated from
the dimerization of each carbonyl component and one corresponding to the cross coupling. A priori, a statistic distri- 40 the reaction mixture by conventional procedures and purified by crystallization in an appropriate solvent.
bution of these products, which could be modified by using
The process of this invention show advantages vs the
an excess of one of the catbonyl components, is to be
previously disclosed processes since, giving rise to the
expected. In any case, the result would be the formation of
product in an acceptable yield, reduces the number of
a mixture of products, whose separation might be dif3icult.
Consequently, it was not foreseeable to the expert that the 45 synthetic operations avoiding tbe use of corrosive
(superacids)
or unstable
reagents
(4-chloro-Nreductive coupling of 8-cbloro-5,6-dibydrobenz45,6]
methylpiperidine) or of inconvenient manipulation from an
cyclohepta[l,2-blpyridin-11-one,
VII, and ethyl
industrial viewpoint (trimethyl phospbife).
4oxopiperidine-l-carboxyiate,
IV, induced by low-valent
titanium species could be adequate for the industrial prepaAn example of the application of this process, which
ration of loratadine.
50 should be considered as illustrative and not limitative of the
Compound
VII, 8-chloro-5,6-dibydrobenzo[5,6]
scope of the present invention, is described below
cyclobepta[l,2-bbyridin-ll-one,
can be easily obtained
according to the U.S. Pat. No. 3,326,924 or to ES patent
EXAMPLE 1
554.898.
Compound IV, ethyl 4-oxopiperidine-1-carboxylate,
is an 55
Preparation of Loratadine
easily available compound, cited and disclosed in many
scientific references, for instance in the ES patent 2.040.177.
The reducing low-valent titanium species may be generated by reduction of titanium trichloride with lithium aluminum hydride, potassium, magnesium, or by reduction of 60
titanium tetrachloride with zinc, among other procedures.
However, from an industrial viewpoint, the use of titanium
tetracbloride in combinatioo witb zinc dust is highly
preferred, since titanium trichloride is very expensive and is
unstable vs the air oxygen and the humidity.
65
Any inert organic solvent, i.e.: a solvent neither able to
react with the starting compounds nor with the reactive
A0001 03
6,084,100
6
c&ID
5
0
10
and ethyl 4-oxopiperidine-l-carboxylate
of formula IV
15
In a two-liter vessel provided with a thermometer, a reflux
condenser and nitrogen atmosphere, dry tetrahydrofnran
with low-valent titanium species.
(343 ml) was placed, and cooled between 0 and -5” C.
2. The process of claim 1, wherein the low-valent titanium
Titanium tetrachloride (28.5 ml, 49.5 g, 0.255 mol) was 7.0 species
are generated by reduction of titanium tetrachloride
slowly added with stirring (17 min.), keeping the temperawith zinc dust.
ture in the above indicated range, a yellow suspension being
3. The process of claim 2, wherein the preparation of the
formed. After the addition was finished, stirring was u3nlow-valent titanium species is carried out at a temperature
tinued for 10 min. Then, zinc dust (34.5 g, 0.524 mol) was
comprised between 10 and -20’ C.
added with stirring in approximately 15 min. keeping the 2.5 4. The process of claim 3, wherein the preparation of the
temperature in the above cited range, and after addition was
low-valent titanium species is carried out at a temperature
finished, stirring was continued at this temperature for 20
comprised between 0 and -5” C.
min., a blue suspension being formed. Then, pyridine (17
5. The process of claim 1, wherein the organic solvent
ml, 0.21 mol) was added with stirring, keeping the temperaused is an ether.
ture in the above range, and then, a solution of ft-cholro-5, 30
6. The process of claim 5, wherein such ether is diethyl
6-dihydrobenzo[5,6jcyclohepta[l,2-b)pyridin-ll-one,
VII,
ether, tetrahydrofuran, 12-dimethoxyethanc, lp-dioxane.
(30.0 g, 0.123 mol) and ethyl I-oxopiperidine-l7. The process of claim 1, wherein the tertiary amine is
carboxylate, IV (25.2 g, 0.147 mol) in anhydrous tetrahytriethylamine, ethyldiisopropylamine,
triiutylamine,
or
drofuran (96 ml) was added in about 20 min., with stirring
pyridine.
and keeping the temperature in the above cited range. The, 35
8. The process of claim 7, wherein the tertiary amine is
thus obtained, dark brown mixture was stirred for 3 h
pyridine.
keeping the temperature in the above cited range, then was
9. The process of claim 1, wherein the reaction of the
allowed to heat to room temperature and kept at this temcompound of formula VII and the compound of formula IV
perature for 2 h and then heated to 40” C. for 17 h, keeping
is carried out at a temperature comprised between 30’ C. and
the stirring all over this period of time.
40 the reflux temperature of the used solvent.
10. The process of claim 9, wherein the reaction is carried
The tetrabydrofuran was distilled off from the reaction
out at a temperature comprised between 30 and. 50” . C mixture to give a black resin that was dissolved in dichlo11. The process of claim 1. wherein the reaction time for
romethane
(300 ml) and acidified by addition of
the reaction of the compound of formula WI and the
isopropanolAiC17.2 N (97 ml). The mixture was stirred for
10 min, and the phases were separated, being the aqueous 45 co;rInd
of formula IV is comprised between 4 and 72
one extracted with dichloromethane (150 ml). The combined
I.2 The process of claim 11, wherein the reaction time is
organic phases were washed 6 times with a mixture of water
comprised between 6 and 24 hours.
(125 ml) and 35% aqueous HCl(7.5 ml). Then, the organic
13. A process to obtain loratadine consisting of the steps
phase was bassed to pH 7.5-8.0 by addition of 30%
aqueous NH,. The mixture was stirred for 10 min. and the so of
a) preparing low-valent titanium species by reduction of
phases were separated, and then washed 3 times with water
titanium tetrachloride with zinc dust in an organic
(250 ml). The organic phase was dried with anhydrous
sodium sulfate, filtered and the solvent eliminated in vacua
sohrent,
to give a residue (47.47 g) that was treated with acetonitrile
b) adding a tertiary amine,
(97 ml). The, thus formed, solid was filtered and crystallized 55
c) adding a mixture of S-chloro-5,6dihydrobenzo[5,6>
from the same solvent lo give pure loratadine, m.p.
cyclohepta[1,2-blpyridin-ll-one
and ethyl
132-133O C. (18.8 g, 40% yield).
4-oxopiperidine-lcarboxylate
and heating the reaction
mixture for the required time to complete the reaction,
What we claim is:
and
1. Aprocess for the preparation of loratadine consisting of
reacting, in an organic solvent and in the presence of a m
d) isoIating loratadine from the reaction mixture.
tertiary amine, S-chloro-5,6aibyrobenzoC5,6~ycIob~ta[l,
* * * * *
2-blpyridin-ll-one,
of formula VII
A0001 04
USOO6093827A
United States Patent 1191
[II]
Jackson
[4q
Patent Number:
Date of Patent:
6,093,827
Jul. 25,200O
[54]
PROCESS FOR THE PREPARATION
OF
lO,ll-DIHYDRO-SH-DIBENmA,D]
CYCLOHEPT-S-ENES
AND DERIVATKVES
THEREOF
Chemical Abstracts, vol. 101, No. 15, Oct. 8,1984, Columbus Ohio, US; abstract No. 130367, XPO02068293; see
abstract & P. Lemmen et al.: Chem. Ber., vol. 117, No. 7,
1984, pp. 2300-2313.
[75]
Inventor:
William Paul Jackson, Twickenham,
United Kingdom
M.M. Cid et al.: Tetrahedron, vol. 44, No. 19,1988, Oxford
GB, pp. 61974200, XPOO2068290, cited in tbe application,
see whole document.
[73]
Assignee:
Rolalm S-L., Barcelona, Spain
[21]
Appl. No.: 09/383,878
[22]
Filed:
Aug. 26,1999
Foreign Application
1301
Chemical Abstracts, vol. 84, No. 15, Apr. 12,1976, Columbus Ohio, US; abstract No. 105080, XPOO2068294; see
abstract & J.E. McMurry et al.: J. Org. Chem., vol. 41, No.
5,1976, pp. 896897.
Feb. 26, 1997
Feb. 26, 1998
[GB]
[WO]
United
WIPO
Priority
Data
Kingdom
.. . .. .. ... . . .... . .. 9703992
.. . .. ... . .. . ... . .. . .. PCI7GB98/QO6OS
[51] Knt. CL7 . .. . .. ... . .. . . .. .. . .. .. CO7D 23X/M, CWD 2114
[ 521 US. Cl. . . .. . .. . ... .. . .. . ... . .. .. .. .. . .._..._........
546/194; 546f203
[58] Field of Search . ... ... .. . ... . .. . .. ... . .. . .. . ... ._... 546J194.203
References Cited
1561
U.S. PATENT DOCUMENTS
3,905,972
9f1975
Doslert
et al. ._..........,.........
5W2U.3 X
FOREIGN PATENT DOCUMENTS
2266676
2337736
lo/1975
S/l977
France .
France.
OTHER PUBLICAIIONS
Chemical Abstracts, vol. 94, No. 17, Apr. 27,1981, Columbus, Ohio, US; abstract No. 139113, XPOO2068291; see
abstract & D. Lenoir et al.: J. Cbem. Res. Syoop., vol. 12,
1980, pp. 396-397.
ChemicaIAbstrac(s, vol. 89, No. 15, Oct. 9,1978, Columbus
Ohio, US; abstract No. 128558, XPOO2068292; see abstract
& J.E. McMurry et aI. RRY J. Org. Chem., vol. 43, No. 17,
1978, pp. 3255-3266.
Chemical Abstracts, vol. 81, No. 13, Sep. 30,1974, Columbus Ohio, US; abstract No. 78113, XPOO2068295; see
abstract & J.E. McMurry et al.: Journal of the American
Chemical Society, vol. 96, No. 14, 1974, DC US, pp.
47084709.
Chemical Abstracts, vol. 97, No. 5, Aug. 2,1982, Cohtmbus
Obio,US; abstract No. 38616,XP002068296; see abstract &
A. clerici et al.: J. Org. Cbem., vol. 47, No. 15, 1982, pp.
2852-2856.
Chemical Abstracts, vol. 96, No. 5, Feb. 1,1982, Columbus
Ohio, US; abstract No. 34276, XPO8206897; see abstract &
R. Dams et al.: J. Org. Cbem., vol. 47, No. 2, 1982, pp.
248-259.
Primary
Attorney,
Exnminer--Fiona T. Powers
Age*
or Firm-Karen
Lee Orzecbowski
[571
ABSTRACT
5,6-Dihydro-llH-dibenxo[a,djcyclohept-11-enes
are prepared by reacting a dibenzosuberone or an aza derivative
thereof with an aliphatic ketone in the presence of low valent
titanium.
A0001 05
17 Claims, No Drawings
6,093,827
2
1
heptadine. The process suffers from the disadvantages that
low valent titanium has to be generated using lithium metal
which is hazardous on industrial scale and by the need to use
about 12 equivalents of titanium reagent to prevent the
reaction stopping at the diol stage.
In general there exists a need for im roved processes for
The present invention relates to a process for the prepapreparing fO,ll-dihydro-SH-dibenz
opa,dJ-cycIoheptenes
ration of lO,lldihydro-SHdibenzo[a,d~yclohept-S-enes
which use less hazardous materials and provide improved
such as loratadioe.
yields and selectivity, particularly on industrial scale proThe anti-histamine ethyl 4-(8-chloro-5,6dihydro-llHduction. The present invention se&s to provide such an
ben~5,6Jcyclohept~l,Z-blpyridin-ll-ylidene)
piperidineimproved process.
1-carboxylate (loratadine) is a potent, long acting derivative
It has now surprisingly been found that hetero-coupling
of azatadine which shows negligible CNS side effects.
of a tricyclic aromatic ketone with an aliphatic cyclic ketone
in the presence of low valent titanium gives a high yield of
unsaturated coupled product with only traces of homocoupled ketones. Typically, the low valent titanium is
present as titanium (II) And only a slight excess of titanium
reagent is required.
Thus viewed from one aspect the present invention
provides a process for preparing 5,6-dihydm-11Hdibenxo
u) [a,dlcyclohept-11-enes comprising reacting a dibenzosubcrone or an aza derivative thereof with an aliphatic ketone in
the presence of low valent titanium, ie. TrO), Tii) or Ti(I1)
wherein said low valent titanium is generated by zinc.
I
Preferably the low valent titanium consists essentially of
CW
LDRATADINE
25 ww.
Preferably the dibenzosuberone or axa derivative thereof
compound is of formuIa I:
PROCESS
FOR THE PREPARATION
OF
11-DIHYDROSH-DIBENZO]
CYCLOHEPl’-S-ENES
AND DERIVATIVES
THEREOF
10,
\; :I
‘:x:’
0
N
30
I
lhe
35
AUTADINE
The presence of the chlorine atom at the &position
makes the chemistry of loratadine uniquely problematical
and reductive preparations are ineffective because of the
removal of chlorine at the 8-position.
US. Pat. No. 3,326,924 (Villani et al) discloses processes
for preparing various aza-dibenzr$a,d]-cycloheptene derivatives which involve production of a tricyclic ketone which is
reacted with a Grignard reagent derived from 4-chloro-Nmethyl piperidine. Dehydration gives the N-methyl product.
The process is, however, hindered by the amount up to 30%
of 1,6-addition product which is generated in the Grignard
reaction causing problems in yield and purification. U.S. Pat.
No. 4,282,233 (Villani) discloses the preparation of loratadine from the product of the above reaction by
demethylation/carboethoxylation.
Asynthetic route to loratadine is disclosed in U.S. Pat.
No. 4,6.59,716 (Villani et al), U.S. Pat. No. 4,731447
(Schumacher et al), U.S. Pat. No. 4873,335 (Schumacher et
al) and Journal of organic Chemistry, 1989, Vol
542242-2244 (Schumacher et al.) which iwolves
alkylation of the dianion of the t-butylamide of 2-cyano-3-methylpyridine, m-generation of the nitrile, Grignard reaction,
cyclisation
with
HF/BF,
and demethylation/
carboethoxylation. This process is, however, hampered by
the need to use hazardous organometallic reagents (IDA or
butyl lithium) and a super-acid environment of liquid HP
and BF, gas.
Cid et al have reported (Tetrahedron, 1988, Lb1 44,
6197-6200) that cross coupling reactions between a tricyclic
ketone and a cyclic ketone can take place using low valent
titanium to give biphenylmethylene pip&dines or cypro-
(wherein:
X denotes nitrogen or CH;
40 and R’, R’, R’ and R4 which may be the same or different
independently denote hydrogen or a halogen (eg. F, Cl
or Br)).
Preferably the dibenzosuberone compound is one in
which R* denotes a halogen (eg. chloro) and RI, R3 and R4
4s denote hydrogen and particularly preferably in which in
addition X is nitrogen.
In further embodiments, X which is nitrogen may be at the
2,3 or 4 position as defined in formula I.
Preferably the aliphatic ketone is cyclic and particularly
so preferably is an optionally
N-substituted piperidone
compound, for example a compound of formula 11:
55
(wherein:
Y denotes hydrogen, lower alkyl (eg C,,-alkyl), COaR’,
SOaR’, CON(R
SO,N(R’X,
C02COR5 or a
N-protecting group; and
6s
R5 is hydrogen, a C,-,a-alkyl (preferably C,-,-alkyl)
group optionally substituted by one or more amino or
6,093,827
4
3
C,,-alkylamino
groups, a phenyl group optionally
substituted by one or more halo or C,,-aIky1 groups, a
&.a-phenylalkyl
group optionally substituted at the
phenyl by one or more halo or C,-,-a&y1 groups,
2piperidyl, 3piperidyl or piperidyl substituted at the s
nitrogen atom by a C,,-alkyl group);
and the salts thereof.
Preferably the piperidone is one in which Y is the group
co&t.
The reaction proceeds via an intermediate diol which, if
desired, may be isolated by conducting the reaction at a lo
lower temperature. The oletin may be prepared from the
intermediate diol in a subsequent step in a conventional
manner.
The diol intermediate itself is novel and forms a further
aspect of the invention. Thus the present invention provides 15
a compound of formula III:
30
(wherein R,, R,, R,, R,, X are Y are as defined
hereinbefore).
The preferred compound is:
35
40
45
‘Ihe dibenzosuberone and aliphatic ketone reagents are
preferably reacted in substantially equimolar quantities;
however an excess of either reagent can be tolerated, eg. the
two reagents may be present in molar ratios of from 1:2 to
2:1, preferably 1.51 to 1:1.5, especially preferably l.l:l to
1:l.l.
Low valent titanium may be prepared in situ, using zinc
eg. by reaction of a Ti (III) or Ti (IV) compound or
complexes thereof with zinc. In one preferred embodiment
of the method according to the invention, a combination of
titanium (IV) chloride or a complex thereof’ and zinc is used
to generate low talent titanium. This embodiment has the
advantage that zinc is relatively cheap and safe to use on an
industrial scale. Acombination of titanium (III) chloride and
zinc may be used with equal success.
In accordance with the invention, Zn and Ti may be
conveniently used in molar ratios of 41 to l:l, preferably
3:l to 2:l.
Typically, a slight molar excess of titanium reagent is used
over the amount of ketone present, althougb a larger excess
may be used if desired.
The titanium reagent is preferably used at a molar ratio of
iom 0.51 to 6:1, preferably 1.51 to 4:1, particularly 2:l to
1:l relative to the diinzosuberone.
The reaction may be conveniently conducted in etherial
dioxane and
I solvents such as for example tetrahydrofuran,
limethoxyetbane which are commonly used in coupling
.eactions involving titanium. Nevertheless ethyl acetate,
so-propyl acetate, t-butylacetate, DMF and acetonitrile are
:quaIIy effective for this purpose. Tetrahydrofuran is pre&red.
The reaction temperalure may be conveniently in the
:ange -10’ C. to the reflux temperature of the chosen
&vent, but is preferably 100” C. or less, especially 2.0to 60”
C. To prepare the diol the reaction temperature is preferably
>elow 10” C.
As noted above, Y may represent an N-protecting group
and suitable
groups
includes
acetyl, benzoyl,
ethoxycarbonyl,
t-butoxycarbonyl,
benzyloxycarbonyl,
benzyl, methoxy benzyl or 2,4-methoxybenzyl groups. The
optional subsequent cleavage of a N-protecting group may
fbr example be carried out by conventional means eg.
hydrolytically, hydmgenolytically or in the presence of an
oxidising agent or acid. Further examples of N-protecting
groups and appropriate deprotection reactions are descrrbed
in the literature (see for example McOmie, “Protecting
groups in organic chemistry”, Plenum, 1973 and Greene,
-Prolective groups in organic synthesis”, Wiley Interscience
1981).
The process according to the invention is typically carried
out at elevated temperature (eg. under reflux) for at least one
hour, preferably 1-l hours, particularly preferably l-2 hours
and at ambient pressure.
The process according to the invention provides a yield of
a lO,lldihydro-5Hdibenzo[a,d]cyclo-heptene
typically in
excess of 60% and often 80% or more.
The invention is illustrated in a non-limiting fashion by
the following examples in which all ratios and percentages
are by weight unless otherwise stated:
EXAMPLE 1
Preparation
of ethyl 4-(5,6-dihydro-llH-benzo[5,6]
cycloheptan)piperyhdene-lcarboxylate
Amixture of 4-carboethoxypiperidone (5.64 g, 33 mmole)
and dlbenzosuberone (6.24 g, 30 mmole) are dissolved in
tetrahydrofuran (82 ml) under a nitrogen atmosphere. Zinc
(8.83 g, 135 mmole) is added and the mixture cooled to 0”
C. Titanium tetrachloride (7.4 ml, 67.5 mmole) is added over
15 minutes so that the temperature does not exceed 30’ C.
The mixture is then heated at retlux for about 1.5 hours.
About 50 ml of THF is removed by distillation under
reduced pressure and the residue is partitioned between
toluene (100 ml) and 2M HCI (100 ml). ‘Ihe layers are
separated and the aqueous phase extracted with a further 100
ml toluene. The combined organic phase is washed with 50
ml 10% potassium carbonate solution and dried over magnesium sulphate.
Removal of the solvent and chromatography of the residue (10.3 g) on silica gel using etherdichloromethane (5:95)
gives 9.3 g (89%) product at constant weight as a viscous oil
which crystallises on standing to give a solid (MP 87-90’
C.).
EXAMPLE2
Preparation
of ethyl 4-(5,6-dibydro-llHbenzo[5,6]
cycloheptan)-pipe-l-carboxylate
A mixture of4tarboethoxypiperidone
(3.8 g, 22 mmole)
and dibenzosuberone (4.4 g, 20 mmole) are dissolved in
ethyl acetate (50 ml). Zinc (6.4 g, 100 mmole) is added and
the mixture cooled to 0” C. Titanium tetrachloride (4.9 ml,
45 mmole) is added over about 5 minutes so that the
temperature stays below 15” C. (If required, the diol may be
6,093,827
6
5
isolated at this stage by addition to water.) The reaction is
heated to rellux for 2 hours. The mixture is allowed to cool
and 75 ml 2M HCl is added. The aqueous phase is extracted
with a further 50 ml ethyl acetate. lbe combined organic
phase is washed with 50 ml 10% potassium carbonate
solution and dried over magnesium snlphate.
The solvent is removed to constant weight tmder vacuum
to give 6.8 g crude product which is contaminated with a
small amount of deoxygenated tricycle.
EXAMPLE 3
Preparation of Loratadine
8-Chloro-5,6-dihydro-llH-benzo[5,63cyclohepta[l,2-b]
pyridin-ll-one
(2.45 g, 10 mmole) (see J. Heterocyclic
Compounds,
vol.
8, 1971,
page
73) and
4-carboethoxypiperidone (1.8 g, 10 mmole) are dissolved in
30 ml tetrahydrofuran. Zinc (5 g, 78 mmole) is added and the
mixture cooled to 0” C. Titanium tetrachloride (3 ml, 27
mmole) is added over about 10 minutes. The mixture is then
heated at reflux for 1 hour. The mixture is added to 100 ml
water and 50 ml toluene. Most of the aqueous phase is
separated and the organic phase is washed with 20 ml
ammonium hydroxide solution.
The mixture is filtered through celite and the celite
washed with a further 50 ml toluene. The organic phase is
separated and dried over magnesium sulphate.
The solvent is removed and the residue (3.75 g) is
crystallised from butyl ether to give 2.5 g loratadine (68%).
HPLC shows the product to be r98% pure.
What is claimed is:
1. A process for preparing 5,6-dihydro-llHdibenzo[a,d]
cyclohept-11-enes comprising reacting a dibenzosuberone
or an aza derivative thereof with an aliphatic ketone in the
presence of low valent titanium wherein said low valent
&mum is generated by zinc.
2. A process as claimed in claim 1 wherein said dibenzcsuberone or aza derivative thereof is of formula I:
10
(wherein:
Y denotes hydrogen, lower alkyl, CO,R’, S02R5, CON
(R5h, SO,N(R’& C02COR5 or a N-protecting group;
15
and
R5 is hydrogen, a C,,,-alkyl group optionally substituted
by one or more amino or C,,-alkylamino
groups, a
phenyl group optionally substituted by one or more
halo or C,-e-alkyl groups, a C,-,,-phenylalkyl
group
20
optionally substitnted at the phenyl by one or more halo
or C,-,-alkyl groups, 2-piperidyl, 3-piper&l
or piperidyl substitnted at the nitrogen atom by a C,,-alkyl
group)
25 and the salts thereof.
9. A process as claimed in claim 8 wherein Y is CO,Et.
10. A process as claimed in claim 1 wherein Ti is present
in a molar ratio range 1.5:1 to 4:l relative to the dibenzo30 suberone.
ll. A process as claimed in claim 10 wherein Ii is present
in a molar ratio range 21 to 3:l relative to the drbcnzosuberone.
12. A process as claimed in claim 1 comprising
35 preparation of an intermediate diol of formula III:
the
rn
RI
wherein X denotes nitrogen or CH:
wherein:
and RI, R’, R3 and R4 which may he the same or different
X denotes nitrogen or CH;
independently denote hydrogen or a halogen
and R’, R*, R’ and R4 which may be the same or different 55 Y denotes hydrogen, lower alkyd, C02R5, SO,R’, CON
independently denote hydrogen or a halogen.
CL, SO,N(R’), CO,COR’ or a N-protecting group;
3. A process as claimed in claim 2 wherein Rx is a
iSlO
halogen.
R’
is hydrogen, a C,e,,-alkyl
group optionally substituted
4. A process as claimed in claim 2 wherein R’, R3 and R4
by one or more amino or C,&kylamino
groups, a
denote hydrogen.
60
phenyl group optionally substituted by one or more
5. A process as claimed in claim 2 wherein X is nitrogen.
halo or C,,-alkyl groups, a &,-phenylalkyl
group
6. A process as claimed in claim 1 in which the aliphatic
optionally substituted at the phenyl by one or more halo
ketone is cyclic.
C,.,-alkyl groups, 2piperidy1, Zpiperidyl or piperidyl
7. A process as claimed in claim 6 wherein said cyclic
substituted at the nitrogen atom by a C,&kyl
group.
aliphatic ketone is an optionally N-substituted piperidone.
6s
8. Aprocess as claimed in claim 7 wherein said piper&me
13. A process as claimed in claim 1 wherein said low
is of formula II:
valent litanium consists essentially of Ti (II).
A0001
08
6,093,82’7
-.
7
8
14. A process as claimed in claim 1 wherein low valent
16. A process as claimed in claim 15 wherein said
titanium compound is titanium(Il1) chloride or titanium(W)
chloride or a comolex thereof.
17. A process 2 claimed in claim 1 for preparing Lora15. A process as claimed in cIaim 14 wherein low valent
titanium is prepared by reacting a li(Il1) or Ii(IV) corn- 5 tadiue.
pound or complex with said zinc.
l
+
*
*
+
titanium is prepared in situ.
A0001 09