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Case 1 :04-cv—00171-GIVIS Document 161 Filed 12/01/2006 Page 1 of 4
CONNOLLY BOVE LODGE 8c HUTZ LLP
A ATTORNEYS AT LAW _ The Nemours Building
1007 North Orange Street
P.0. Box 2207
Wilmington DE 19899
Francis DiGiovanni TEL (302) 658 9141
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The Honorable Kent A. Jordan
United States District Court
District of Delaware
844 North King Street ~
Wilmington, DE 19801
Re: Glaxo Group Limited v. Teva Pharmaceuticals USA, Inc. and
Teva Pharmaceutical Industries Limited, No. 04-CV—171 (KA] Q
Dear Judge Jordan:
We represent plaintiff Glaxo Group Limited ("Glaxo") in the above-referenced patent
infringement action brought pursuant to the Hatch—Waxman Act. As your Honor is aware, there
are various summary judgment motions sub judice. We write to inform the Court, pursuant to
Local Rule 7.1.2(c), of a very recent Federal Circuit decision that bears directly on the parties’
motions for summary judgment on the issue of infringement under the doctrine of equivalents.
On November 15, 2006, the Federal Circuit decided Abraxis Bioscience, Inc. v. Mayne
Pharma (USA) Inc., Civ. No. 06-1118 (Fed. Cir. Nov. 15, 2006). A copy of the opinion is
attached. ln Abraxis, the patent—in—suit was directed to an improved pharmaceutical formulation
of DlPRlVAN®, a drug containing propofol as the active ingredient and used to induce and
maintain general anesthesia and sedation in patients. Abraxis, Slip. Op. at 2. The inventors,
trying to solve a problem with increased frequency of post-operative bacterial infections in
D1PRlVAN® patients, “discovered that one preservative in particular, disodium edetate, was
unexpectedly effective in retarding microbial growth in the propofol formulation .... " Id at 2-
3. The patent for the improved DIPR1VAN® formulation claimed "[a] sterile pharmaceutical
composition for parenteral administration . . . which further comprises an amount of edetate
sufficient to prevent a no more than 10-fold increase in growth of [listed bacteria] .... " Id at 7.
The defendant in Abraxis sought to market a generic version of the improved
DIPRlVAN® formulation by substituting an antimicrobial preservative called calcium trisodium
DTPA in place of the claimed "edetate" (a/k/a "EDTA") preservative. Abraxis, Slip. Op. at 4-5.
Because the parties agreed that calcium trisodium DTPA was not a derivative of EDTA, the
Federal Circuit held that there was no literal infringement of the claims in the patent-in-suit. Id.
at 13. The Abraxis case, therefore, turned on the doctrine of equivalents.

Case 1 :04-cv—OO171-GIVIS Document 161 Filed 12/O1/2006 Page 2 of 4
CONNOLLY Bova Looe; & Hutz LLP
Arronmavs AT LAW
The Honorable Kent A. Jordan
December 1, 2006
Page 2
The Federal Circuit approved the district court’s “well-reasoned opinion" utilizing the
function-way-result test of Grover Tank & Mfg. C0. v. Linde Air Products Co., 339 U.S. 605,
609 (1950), to find equivalence. Abraxis, Slip. Op. at 15. Although the Federal Circuit found
that defendant had waived its arguments concerning the function and result prongs of the test, id
at 16 n.8, it noted with tacit approval the district court°s very closely related definitions of the
function of edetate "as ‘retarding microbial growth in propofol oil—in—water emulsions,’” and
"that the result achieved was ‘retard[ing] microbial growth to the extent required by the
microbiological test set forth in the claim."’ Id at 15. This is precisely analogous to the ‘249
patent’s description of the function of ethanol as chemically enhancing the stability of ranitidine
in the claimed aqueous formulation for oral administration, with the resulting pharmaceutical
formulation therefore having the enhanced stability, i.e., improved shelf-life of the drug product.
(‘249 Patent Col. 1:40-56; Sept. 8, 2006 Oral Arg. Tr. at 43:22—45:l9); Glaxo Wellcome, Inc. v.
Pharmadyne Corp., 32 F. Supp. 2d 265, 285 (D. Md. 1998).
The Federal Circuit also found that the district court had properly determined that the V
"way" in which both EDTA and calcium trisodium DTPA performed their function of retarding
microbial growth in the formulation was by metal ion chelation. Abraxis, Slip Op. at 15-16.
Defendant contended that the proper definition of "way" was a much narrower, more specific
definition, “i. e., one that incorporates the specific metal ions that are chelated, the strength of the
bonds that are formed during chelation, and the stability constants." Id at 16. Because plaintiff
did not offer infringement evidence to establish these additional specific factors, defendant
argued that there was a failure of proof of infringement. Id In the present case, defendant Teva
has taken an analogous position arguing that the "way" in which ethanol and propylene glycol
function requires proof of a specific chemical pathway to stabilize ranitidine rather than simply
by using ethanol or propylene glycol to inhibit ranitidine degradation. (Sept. 8, 2006 Oral Arg.
Tr. at 41:10-42:3, 46:12-47:11). Contrary to the argument of the defendant in Abraxis, and Teva
here, the Federal Circuit held that the "way’° EDTA functioned was not so narrow and specific
and had been properly defined by the district court with reference to the context of the patent—in-
suit. Abraxis, Slip. Op. at 16-17.
Glaxo’s U.S. Patent No. 5,068,249 ("the ‘249 patent") describes the function of ethanol
as chemically enhancing the stability of ranitidine in an aqueous formulation for oral
administration. (‘249 Patent Col. 1:39-44). This is in contrast to physically stabilizing ranitidine
by, for example, refrigeration (inhibiting thermal degradation) or packaging the drug product in a
dark bottle (inhibiting degradation from exposure to light). The way in which that function is
accomplished is by adding a chemical——ethanol—-—to the formulation to inhibit ranitidine
degradation where, in an aqueous formulation for oral administration, the ethanol will inhibit
hydrolysis (degradation from exposure to water) and/or oxidation (degradation from exposure to
oxygen) of ranitidine. (Id. at Col. 1:39-44, 54-60; Kibbe Dep. at 18:9-20:12, Langer Decl. (D.l.
99 and 100), Ex. 24; Kibbe Dep. at 120:11-121:20, 145:1-149:11, 178:18-181:2, Langer 2d
Suppl. Decl. (D.l. 149), Ex. 7; Anderson Suppl. Rpt. {lil 16-21, Anderson Decl. (D.I. 98), Ex. C);
see Pharmadyne, 32 F. Supp. 2d at 285-286 ("Despite Drs. Wray and Long’s failure to
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CONNOLLY Bova Looea & Hurz LLP
Awoanevs AT LAW
The Honorable Kent A. Jordan
December 1, 2006
Page 3
understand the exact mechanics of how ethanol stabilizes ranitidine hydrochloride, both reached
the conclusion that ranitidine degrades through hydrolysis and that ethanol retards the hydrolytic
process. Dr. Long is not required to understand the exact mechanics of his invention, so long as
the ‘249 patent discloses to the ordinary formulator how to make and use the invention.”)
(citations omitted). Accordingly, the proper infringement analysis of the "way" requires only a
determination of whether propylene glycol, substituted in place of ethanol in Teva’s ANDA
product, chemically enhances the stability of ranitidine by inhibiting ranitidine degradation in the
aqueous formulation for oral administration. lt is undisputed that both ethanol and propylene
glycol chemically enhance the stability of ranitidine by inhibiting hydrolytic and/or oxidative
degradation of ranitidine in an aqueous formulation for oral administration. (Kibbe Dep. at 18:9-
20:12, Langer Decl. (D.l. 99 and 100), Ex. 24; Kibbe Dep. at 118:2-120:10, 145:1-149:11,
178:18-181:2, 193:7-194:6, Langer 2d Suppl. Decl. (D.I. 149), Ex. 7; Anderson Opening Rpt. {lil
80-84, Anderson Decl. (D.l. 98), Ex. A; Anderson Suppl. Rpt. {lll 16-21, Anderson Decl. (D.l.
98), Ex. C).
Teva’s only argument is that, despite the fact that both ethanol-stabilized and propylene
glycol-stabilized formulations produce the same ranitidine degradation impurities, propylene
glycol must be working in a different "way” than ethanol because the specific amounts of those
identical impurities are slightly different. (Sept. 8, 2006 Oral Arg. Tr. at 46:12-47:11). In
Abraxis, however, the Federal Circuit held that such a narrow, specific standard is not required
under the doctrine of equivalents. Abraxis, Slip Op. at 15-17. Rather, as held in Abraxis, it is
sufficient for Glaxo to show by a preponderance of the evidence that propylene glycol
chemically enhances the stability of ranitidine in the same way as ethanol by inhibiting the
hydrolysis and/or oxidation of ranitidine in an aqueous formulation for oral administration.
There is no legal requirement for anything more specific to satisfy the "way" prong of Gmver
Tank ’s function-way—result test.
The second point for which the Abraxis decision is pertinent to the parties’ summary
judgment motions is the Federal Circuit’s rejection of the defendant’s argument that "it was
impermissible as a matter of law for the meaning of edetate to extend to calcium trisodium
DTPA by equivalence because the patentees chose to narrowly claim their invention." Abraxis,
Slip Op. at 14. That is the identical "public policy" type of argument made by Teva in this case.
(Sept. 8, 2006 Oral Arg. Tr. at 63:7-69:22). Teva has argued that Glaxo "had an option to
broaden their claim or to narrow their claim, ethanol with a subset or ethanol, [within] a broader
class of chemicals. Based on the prior art of record, they narrowed [it to] ethanol and I believe
they gave up the rest of the lower aliphatic alcohols . . .". (Id. at 69:16-22). The Federal Circuit
rejected the identical argument in Abraxis:
Secondly, we reject Mayne’s argument that, as a matter of law, it is impermissible
for the meaning of edetate to extend to other polyaminocarboxylates by
equivalence. Mayne contends that by claiming their invention narrowly, i,_<~;,, by
limiting the claim to edetate, Abraxis is barred from capturing DTPA, or any
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CONNOLLY Bova Lone:-2 & Hurz LLP
ATTORNEYS AT LAW
The Honorable Kent A. Jordan
December 1, 2006
Page 4
other polyaminocarboxylate, as an equivalent. * * * There is no evidence that the _
patentees made a clear and tmmistakable surrender of other
polyaminocarboxylates, or calcium trisodium DTPA in particular, during
prosecution.
Abraxis, Slip Op. at 17-18. The Federal Circuit also distinguished defendant Mayne’s reliance
on T anabe Seiyaku Co. v. United States International Trade Commission, 109 F.3d 726 (Fed.
Cir. 1997), the same case relied on by Teva. Abraxis, Slip. Op. at 17-18. The Federal Circuit,
therefore, found that the inventors did not clearly disavow other polyaminocarboxylates merely
by restricting their patent claim to edetate. Id
The Federal Circuit held that it was the "very unforeseeability" of substituting calcium
trisodium DTPA in place of EDTA during the period of patent prosecution that supported the
finding of infringement by equivalents. Id at 18-19. Here, the unforeseeability of substituting
propylene glycol in place of ethanol as a ranitidine stabilizer during the period of the ‘249
patent’s prosecution has been acknowledged by both parties. (Kibbe Dep. at 87:18-88:9; 89:22-
91:21, 92:24—93:19, Langer 2d Suppl. Decl. (D.I. 149), Ex. 7; Anderson Rebuttal Rpt. 1111 28, 34,
41, 57, Anderson Decl. (D.l. 98), Ex. B; Long Decl. (D.l. 126), ilil 15, 18-19); see also
Pharmadyne, 32 F. Supp. 2d at 290-91 ("Nothing in the prosecution history of the ‘249 patent
shows that Glaxo considered the use of propylene glycol or any other constituent as a
stabilizer?). This acknowledgement supports the conclusion that Glaxo did not waive its right to
claim equivalents beyond ethanol. ‘
In sum, the doctrine of equivalents is designed to protect inventors from unscrupulous
copyists and unanticipated equivalents. Abraxis, Slip Op. at 19 (citations omitted). Teva’s
proposed ANDA product infringes Glaxo’s ‘249 patent under the doctrine of equivalents because
Teva’s substitution of propylene glycol in place of ethanol is an insubstantial difference that
accomplishes substantially the same function in substantially the same way to achieve
substantially the same result as the patented invention.
Respectfull b tted,
R °
¤#»t tt»=
Francis DiGiov i
Enclosure
cc: Brian P. Murphy, Esq. (via e-mail and U.S. Mail)
Mark D. Schuman, Esq. (via e—mail and U.S. Mail)
Josy W. Ingersoll, Esq. (via hand and e-mail)
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