Appendix — Dr. Reddy's Laboratories, Ltd. v. Eli Lilly and Co. (Nos. 06-1723, 06-1642)
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APPENDIX A — OPINION OF THE UNITED STATES
COURT OF APPEALS FOR THE FEDERAL
CIRCUIT DECIDED DECEMBER 26, 2006
UNITED STATES COURT OF APPEALS
FOR THE FEDERAL CIRCUIT
05-1396, -1429, -1430
ELI LILLY AND COMPANY and
LILLY INDUSTRIES LIMITED,
Plaintiffs-Appellees,
V.
ZENITH GOLDLINE PHARMACEUTICALS, INC.
(now known as Ivax Pharmaceuticals, Inc.),
Defendant-Appellant,
and
TEVA PHARMACEUTICALS USA, INC.,
Defendant-Appellant,
and
DR. REDDY’S LABORATORIES, LTD.,
Defendant-Appellant.
DECIDED: December 26, 2006
2a
oe
Appendix A
Before RADER, SCHALL, and GAJARSA, Circuit Judges.
RADER, Circuit Judge.
Zenith Goldline Pharmaceuticals, Inc. (now known as
IVAX Pharmaceuticals, Inc.) (IVAX); Dr. Reddy’s
Laboratories, Ltd. (DRL); and Teva Pharmaceuticals USA,
Inc. (Teva) (defendants), filed an Abbreviated New Drug
Application (ANDA). In response, the plaintiffs, Eli Lilly
and Company and Lilly Industries Ltd. (collectively Lilly),
filed suit against all defendants for infringement of United
States Patent No. 5,229,382 (°382 patent). Following a two
and one-half week bench trial, the United States District
Court for the Southern District of Indiana found the ’382
patent valid and infringed. Eli Lilly & Co. v. Zenith Goldline
Pharm., 364 F.Supp.2d 820 (S.D.Ind.2005) (Final
Judgment); Eli Lilly & Co. v. Zenith Goldline Pharm., 1:01-
cv-443-RLY-VSS (S.D.Ind. May 9, 2005) (Amended Final
Judgment ). In 221 pages of written analysis, the trial court _
documented its findings and conclusions. Eli Lilly & Co. v.
Zenith Goldline Pharm., 364 F.Supp.2d 820 (S.D.Ind.2005)
(Findings of Fact and Conclusions of Law ). The defendants
appeal the trial court’s conclusions on the validity of the ’382
patent and inequitable conduct. Finding no reversible error,
this court affirms.
I.
The °382 patent claims both olanzapine and use of the
compound to treat schizophrenia. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 830. A Lilly research
chemist first synthesized olanzapine in the United Kingdom
3a
Appendix A
in 1982. Jd. at 834. Lilly filed the °382 patent application on
May 22, 1992. The patent issued on July 20, 1993. The United
States Food and Drug Administration (FDA) approved
olanzapine, sold by Lilly under the trademark Zyprexa®, in
late 1996. Findings of Fact and Conclusions of Law, 364
F.Supp.2d at 830. By filing an ANDA, the defendants
stipulate to infringement if the °382 patent is valid and
enforceable. Amended Final Judgment, slip op. at 1.
Claims 1, 2, 3, 7, 8, and 15 of the °382 patent set forth
the boundaries of the invention:
1. 2-Methyl-10-(4-methyl-1-piperaziny])-
4H-thieno[2,3-b][1,5]benzodiazepine, or an acid
addition salt thereof.
2. A pharmaceutical composition comprising
a compound according to claim 1 or a
pharmaceutically acceptable acid addition salt
thereof together with a pharmaceutically
acceptable diluent or carrier therefor.
3. A pharmaceutical composition in capsule
or tablet form comprising from 2.5 to 5 mg of the
compound of claim 1 together with a
pharmaceutically acceptable diluent or carrier
therefor.
** * *
7. Amethod of claim 5 for treating an animal,
including a human, suffering from or susceptible
to schizophrenia.
4a
Appendix A
8. A method of claim 7 wherein the effective
amount is from 0.1 to 20 mg per day of 2-methyl-
10-(4-methy]-1-piperaziny!)-4H-thieno[2,3-b]
[1,5]benzodiazepine, or a pharmaceutically
acceptable acid addition solution salt thereof.
* * * *
15. A pharmaceutical composition in capsule
or tablet form comprising from 0.1 to 20 mg of
the compound of claim | together with a
pharmaceutically acceptable diluent or carrier
therefor.
*382 patent, col. 12, Il. 10-20, Il. 33-40, Il. 64-67.
Before discovery of olanzapine, Lilly discovered other
drugs in the same _ family of compounds
(thienobenzodiazepines), namely clozapine, flumezapine,
ethyl flumezapine and ethy! olanzapine (a.k.a. Compound
°222). Findings of Fact and Conclusions of Law, 364
F.Supp.2d at 831-33. These compounds share a common
Sa
Appendix A
structural nucleus as thienobenzodiazepines, namely a
piperazine ring (R), a benzene ring (R1), and a thiophene
ring (R2).
a
og
g?..
Benzo ' Diazepine: Thiophene
Lilly used clozapine to treat some forms of schizophrenia
in the late °60s and early ’70s. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 831. Clozapine was
thus the first “atypical” antipsychotic drug. Structurally,
olanzapine differs from clozapine in that olanzapine has a
methyl-substituted thiophene ring in place of the benzene
ring in clozapine. /d. at 846-47. Olanzapine also has hydrogen
in place of the chlorine on its benzene ring. Jd. at 847.
Despite its advantages, researchers discovered in 1975
that clozapine caused an often fatal blood disorder
(agranulocytosis) in one percent of patients. For that reason,
Lilly withdrew clozapine from the market. Jd. Nevertheless,
after a general failure to replace clozapine, reflected by many
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Appendix A
documented reports of promising compounds that failed
either for lack of efficacy or toxic side-effects, the FDA, in
late 1989, approved clozapine with careful blood-monitoring.
Id. at 832.
Until discovery of olanzapine, researchers attributed the
efficacy of clozapine and typical antipsychotics to their
“neuroleptic substituent”-an electron-withdrawing group
considered important to the antipsychotic activity of the
compounds. /d. Halogen-a fluorine (F) or chlorine (Cl) atom-
is such an electron withdrawing group. /d. at 832, 850.
Olanzapine does
not have a halogen
atom, i.e. a fluorine
(F) or chlorine (C1) J
atom. Instead, it has a so
hydrogen atom (H),
which is not an 3
electron withdrawing Olanzapine
(or electronegative)
group. /d. at 850.
Reak
The prior art to olanzapine includes ethyl flumezapine
and flumezapine, both disclosed in U.S. Patent No. 4,115,574
(°574 patent) that issued in 1978. The prior art also includes
ethyl olanzapine (a.k.a. Compound ’222). Ethyl flumezapine
caused widespread blood problems in dogs. /d. at 847.
Flumezapine caused extra-pyramidal symptoms (EPS) and
an increase in liver enzymes and a muscle enzyme called
creatine phosphokinase (CPK). Ethyl olanzapine caused a
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Appendix A
significant increase in cholesterol] in female beagle dogs. /d.
Thus, the prior art to olanzapine had significant detrimental
side effects.
Olanzapine
differs structurally yor
from flumezapine, by —~
substitution of a
hydrogen atom (H) for
the fluorine atom (F) 4
in flumezapine at the
7-position of the Flumezapine
benzene ring. 7d.
Olanzapine
differs structurally CH,
from ethyl pm—N
flumezapine by "il
replacement of the 2
fluorine atom (F) and
ethyl group (CH,CH,) t CHCH,
in ethyl flumezapine
with a hydrogen atom
(H) and methy! group Ethyl Flumezapine
(CH,) respectively. /d.
>
8a
Appendix A
Olanzapine
differs structurally <<
from its ethyl analog, eng
Compound °222
(ethyl olanzapine), by Le @
Ze CHLH,
replacement of the
ethyl group (CH,CH,)
with a methyl group
(CH,) at the 2- Ethyl Olanzapine
position of the (Compound ‘222)
thiophene ring. /d.
Cal
I
The trial court found that the defendants did not prove
by clear and convincing evidence that claims 1, 2, 3, 7, 8,
and 15 of the ’382 patent were invalid as anticipated under
35 U.S.C. § 102. Findings of Fact and Conclusions of Law,
364 F.Supp.2d at 922-23. The primary reference the
defendants cited for anticipation of these claims is an article
entitled“4-Piperazinyl-10H-thieno[2,3-5][1,5]
benzodiazepines as Potential Neuroleptics” from the Journal
of Medicinal Chemistry in 1980 ( Chakrabarti 1980a ). Jiban
K. Chakrabarti, Linda Horsman, et al., 4-Piperazinyl-10H-
thieno[{2,3-b] [1,5]benzodiazepines as Potential
Neuroleptics, 23 J. Med. Chem. 8 (1980).
Anticipation is a question of fact, including whether or
not an element is inherent in the prior art. See In re Schreiber,
128 F.3d 1473, 1477 (Fed.Cir.1997). Therefore, this court
reviews a finding of anticipation under the clearly erroneous
standard. Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342,
1346 (Fed.Cir. 1999). To anticipate, a prior art reference must
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Appendix A
place the inventive compound or composition in the
possession of the public. Jn re Brown, 51 C.C.P.A. 1254,
329 F.2d 1006, 1011 (1964). Thus, the prior art reference
must disclose each and every feature of the claimed invention,
either explicitly or inherently. Glaxo Inc. v. Novopharm Ltd.,
52 F.3d 1043, 1047 (Fed.Cir.1995).
Pointing to Jn re Petering, 49 C.C.P.A. 993, 301 F.2d
676 (1962) and Jn re Schaumann, 572 F.2d 312
(C.C.P.A.1987), IVAX asserts that Chakrabarti 1980a
anticipated claim | of the 2382 patent because it identified
compounds from the same family of compounds
(thienobenzodiazepines). Indeed, in Petering, the Board of
Patent Appeals affirmed the examiner’s rejection of claims
1, 2,4, 5, 7, and 10-12 of the patent applicant’s application
on “isoalloxazines.” 301 F.2d at 677. However, in contrast
to this case, the prior art in Petering did more than make a
broad generic disclosure. In Petering, the prior art disclosed
a limited number of specific preferences from a specifically
defined group of isoalloxazines. /d. As a result, Petering
actually disclosed to one skilled in the art a limited class of
only “some 20 compounds,” including “6, 7-dimethyl-9-
(Bmonohydroxyethy])-isoalloxazine.” Schaumann, 572 F.2d
at 315 (citing Petering, 301 F.2d at 682).
Similarly, the prior art in Schaumann disclosed 14
compounds, later further narrowed to 7, considering express
preferences. Additionally, the structural formula of this prior
art contained but a single variable. 572 F.2d at 314. Thus, in
Schaumann, the prior art patent embraced a very limited
number of closely related compounds and specifically
described the claimed compound. 572 F.2d at 316. Thus,
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Appendix A
unlike this case, the prior art in both Petering and Schaumann
expressly spelled out a definite and limited class of
compounds that enabled a person of ordinary skill in the art
to at once envisage each member of this limited class.
Schaumann, 572 F.2d at 315; Petering, 301 F.2d at 681-82.
By contrast, the number of compounds actually disclosed
by Chakrabarti 1980a numbers in the millions (including
all proposed alternative substituents). Chakrabarti 1980a
examined forty-five specific compounds (as opposed to a
genus of compounds) in the 4-piperazinyl-10H-thieno
[2,3-b] [1,5]benzodiazepine family and fourteen
analogous 5-piperazinyl-substituted 4H-thieno[2,3-b][1,4]
benzodiazepines, which were created to compare activity.
Findings of Fact and Conclusions of Law, 364 F.Supp.2d at
848. Indeed, Chakrabarti 1980a listed several preferred
compounds and substituents, none of which resemble
olanzapine:
for R-a methyl, hydroxyethyl, or hydroxypropyl;
for Rl-a fluorine, chlorine, or 7, 8, di-fluoro /no
hydrogen]; and
for R2-a methyl, 2-ethyl, or 2-isopropyl group.
Id. at 848. Five of the preferred individual compounds (9,
12, 17, 29, and 34) are more potent than clozapine (scoring
a3 CAR' or higher) and have clozapine-like effect. For those
1. Conditioned Avoidance Response (CAR): The CAR test
evaluates the inhibition of a behavioral response in rats. The CAR
(Cont'd)
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Appendix A
five preferred compounds, the Chakrabarti 1980a authors
expressed a preference for specific, complete compounds
without any variation of the individual substituents on those
molecules. Chakrabarti 1980a also always expressed a
preference for halogen-containing compounds (fluorine or
chlorine), not hydrogen. /d. at 832-33. Furthermore,
compounds 9, 12, 17, and 29 all have fluorine at the 7-
position of the benzene ring. And though Compound 34 does
have hydrogen at the 7-position of the benzene ring, it has a
hydroxyethyl on its piperazine ring, unlike olanzapine. /d.
In sum, Chakrabarti 1980a discloses nothing close to the
claimed invention.
Chakrabarti 1980a does provide a general structural
formula with possible substituents of “R,” “R1,” and “R2,”
but it does not define them at all. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 900. No possible
combination of those preferred substituents would lead to
the components that make up olanzapine, because each would
contain a fluorine or a chlorine. To make olanzapine from
Chakrabarti 1980a, one would have to depart from the
teaching of the article and recombine the components of the
specific illustrative compounds with hindsight. Thus,
Chakrabarti 1980a does not anticipate because: (1) the article
prefers complete compounds, not individual substituents, (2)
the article discloses no generic disclosure encompassing
olanzapine or even stating that substituents on different
compounds were interchangeable, and (3) the article does
(Cont'd)
test was the only measure of potential antipsychotic activity, and if
the compound did not achieve a CAR score of three or four at a dose
of less than 30 mg/kg, it was not considered active.
12a
Appendix A
not suggest transforming unpreferred compound 7? into a
preferred can pound.Thus,Chakrabarti 1980a did not place
olanzapine in the possession of the public. Therefore, this
court detects no clear error in the trial court’s finding of no
anticipation.
Il
The trial court found that the defendants did not prove
by clear and convincing evidence that claims 1, 2, 3, 7, 8,
and 15 of the °382 patent were invalid as obvious under
35 U.S.C. § 103. Findings of Fact and Conclusions of Law,
364 F.Supp.2d at 922-23. On appeal, IVAX argues that the
district court erred by erecting “a threshold requirement that
defendants establish a teaching or incentive to treat the closest
prior art (i.e., Compound °222) as a ‘lead compound.’” IVAX
also charges that the district court disregarded (1) the
structural characteristic of olanzapine as the adjacent
homolog of Compound °222, (2) the suggestions to delete
fluorine from the prior art compound flumezapine, and (3)
the observation that Compound °222 and flumezapine
“bracket” olanzapine.
This court reviews obviousness without deference as a
legal conclusion with underlying factual determinations
which are reviewed for clear error. Medichem, S.A. v. Rolabo,
S.L., 437 F.3d 1157, 1164 (Fed.Cir.2006). The factual
underpinnings are: (1) the scope and content of the prior art,
2. Furthermore, compound 7 (like compound °222) lacks the
electron withdrawing “neuroleptic substituent” believed at that time
to be necessary for antipsychotic efficacy.
l3a
Appendix A
(2) the differences between the prior art and the claimed
invention at the time of invention, (3) the level of ordinary
skill in the art, and (4) the objective indicia of
nonobviousness. See Graham vy. John Deere Co., 383 U.S.
1, 17, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966); Panduit Corp. v.
Dennison Mjg., 810 F.2d 1561, 1566-67 (Fed.Cir. 1987). For
a chemical compound, a prima facie case of obviousness
requires “structural similarity between claimed and prior art
subject matter ... where the prior art gives reason or
motivation to make the claimed compositions.” Jn re Dillon,
919 F.2d 688, 692 (Fed.Cir.1990) (en banc). “[A] reasonable
expectation of success, not absolute predictability” supports
a conclusion of obviousness. /n re Longi, 759 F.2d 887, 896
(Fed.Cir.1985).
For the following reasons, the district court did not err
in reaching its conclusion. As succinctly stated by the district
court:
175. In light of the general state of the art,
including the teachings of the °574 patent and
Chakrabarti 1980a, Chakrabarti 1982, and
Chakrabarti 1989, one of ordinary skill in the art
would have expected that replacing the fluorine
atom with a hydrogen atom would produce a
compound without sufficient antipsychotic
activity. Nichols Tr. 2776:5-11.
176. While Chakrabarti 1980a suggests that
a chlorine atom in place of the fluorine atom
would also enhance the compound’s activity, it
does not specifically suggest that the same result
l4a
Appendix A
could be obtained with a hydrogen atom. Nichols
Tr. 2779: 17-24; TX 3465 at 879, col. 2. Nor does
anything in Sullivan and Franklin suggest the
desirability of using a hydrogen atom at this
position. Nichols 2776:5-11; TX 3161; Findings
of Fact § IV. B.I.d. /fone were looking to replace
the fluorine, one would replace the fluorine with
other electronegative groups, not hydrogen. TX
1315 at 3172; LaVoie Tr. 1572:12-1573:18.
Indeed, the art as a whole teaches directly away
from using hydrogen because it is not an electron-
withdrawing substituent.
Findings of Fact and Conclusions of Law, 364 F.Supp.2d at
850 (emphases added). Though the °574 patent disclosed
Compound °222, the patent expressed a preference for
halogen containing compounds and specifically those with a
halogenated substituent on the benzene ring in a location
analogous to the chlorine in clozapine. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 845. These teachings
do not suggest or make obvious, among other things,
olanzapine’s hydrogen component. The prior art references
at the time of this invention taught away from using a non-
halogenated compound as a substituent in the benzene ring,
exactly where olanzapine has a hydrogen atom.
Furthermore, the trial court found that a person of
ordinary skill in the art would not have chosen Compound
°222 as the beginning compound because it contained a
hydrogen atom instead of a halogen atom, which again is
not a preferred substituent. Findings of Fact and Conclusions
of Law, 364 F.Supp.2d at 849-50. In addition, the prior art
15a
Appendix A
supplied no motivation to change the 2-ethyl in Compound
°222 to a 2-methyl. The prior art would have instead
suggested modification by adding a halogen atom-to supply
the neuroleptic substituent as a trigger for antipsychotic
activity. Jd. The district court found that, at the relevant time,
a person with ordinary skill in the art would not have expected
any reasonable chance of success with other clozapine-like
compounds. /d. at 850-52.
And though olanzapine is also the adjacent homolog of
Compound ’222, patentability for a chemical compound does
not depend only on structural similarity. Comm’r of Patents
v. Deutsche Gold-und-Silber-Scheideanstalt Vormals
Roessler, 397 F.2d 656 (D.C.Cir. 1968). This court will not
ignore a relevant property of a compound in the obviousness
calculus. Jn re Lalu, 747 F.2d 703 (Fed.Cir.1984). When
claimed properties differ from the prior art, those differences,
if unexpected and significant, may lead to nonobviousness.
In re Mehta, 52 C.C.P.A. 1615, 347 F.2d 859 (1965); In re
Grabiak, 769 F.2d 729 (Fed.Cir.1985). In this case, the trial
court noted some structural similarity of olanzapine and the
prior art, but also accounted for the unexpected beneficial
properties in olanzapine.
This case is similar in many respects to Yamanouchi
Pharm. Co., Ltd. v. Danbury Pharmacal, Inc., 231 F.3d 1339,
1344 (Fed.Cir.2000). In Yamanouchi, this court held that the
ANDA filer did not show obviousness of the famotidine
compound:
[The ANDA filer} did not show sufficient
motivation for one of ordinary skill in the art at
l6a
Appendix A
the time of invention to take any one of the
following steps, let alone the entire complex
combination: (1) selecting example 44 as a lead
compound, (2) combining the polar tail from
example 44 with the substituted heterocycle from
tiotidine, and (3) substituting the carbamoyl
(CONH2) group in the intermediate compound
with a sulfamoyl group (SO2NH2) to create
famotidine.
Id. Likewise, in this case, the defendants have not shown
that a person ordinarily skilled in this art would have selected
Compound ’222 as a lead compound because it contained
hydrogen rather than fluorine or chlorine. At the time of
invention, the state of the art would have directed the person
of ordinary skill in the art away from unfluorinated
compounds like Compound ’222. After all, the primary
example of the state of the art at that time, the °574 patent,
did not provide any biological data for compound °222,
suggested a preference for halogen-containing compounds,
and identified a fluorine-containing compound, ethyl
flumezapine, as “particularly active.” Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 904. Moreover, as the
trial court detailed, Chakrabarti 1980a expressly taught that
the addition of a fluorine or chlorine enhanced anti-psychotic
activity. It also taught that the unfluorinated Compound ’222
was less active than the benchmark compound, clozapine.
Id. Thus, rather than providing the requisite motivation, the
prior art taught away from selecting Compound °222 as a
lead compound for further development.
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Appendix A
Nevertheless, citing to an article entitled “Jn Vitro
Thiomethylation: Studies with Flumezapine,” written by H.R.
Sullivan and R.B. Franklin (S & F article), I1VAX argues that
removal of fluorine from flumezapine would have resuited
in a default to a hydrogen atom. H.R. Sullivan and R.B.
Franklin, Jn Vitro Thiomethylation: Studies with
Flumezapine, 13 Drug & Metabolism Disposition 276 (1985).
To the contrary, however, the S & F article says nothing
whatsoever about removal of fluorine. Specifically, the article
discusses the metabolism of flumezapine in dogs that
produces methylthio metabolite. Jd. The S & F article does
not state that flumezapine is toxic or that the methylthio
metabolite could be avoided by replacement of fluorine with
hydrogen. As noted by the district court, the S & F article
“does not teach that replacing the fluorine with a hydrogen
atom would stop the formation of the methylthio metabolite.
Indeed, acetaminophen (Tylenol ®), a non-fluorinated
compound, also forms methylthio meiabolite.” Findings of
Fact and Conclusions of Law, 364 F.Supp.2d at 846-47. The
trial court correctly concluded that nothing in the S & F article
suggested “that a hydrogen atom in place of the fluorine atom
. .. would be desirable . . . or that to make such a substitution
would avoid the formation of the methylthio metabolite.”
Id.
Beyond the nonobvious selection step, the prior art also
did not suggest any of the other modifications necessary to
reach olanzapine. Thus, even if the S & F article taught what
IVAX claims, the skilled artisan would still need to combine
those teachings with compound 34 in Chakrabarti 1980a to
reach olanzapine. As taught by Yamanouchi Pharm. Co. and
other precedent, mere identification in the prior art of each
18a
Appendix A
component of a composition does not show that the
combination as a whole lacks the necessary attributes for
patentability, i.e. is obvious. Jn re Kahn, 441 F.3d 977, 986
(Fed.Cir.2006) (citing Jn re Rouffet, 149 F.3d 1350, 1355
(Fed.Cir.1998)). Rather, to establish a prima facie case of
obviousness based on a combination of elements in the prior
art, the law requires a motivation to select the references
and to combine them in the particular claimed manner to
reach the claimed invention. /d. In conclusion, because
flumezapine caused EPS in two patients, elevations in CPK
and a variety of liver enzymes in a number of patients,
substantial evidence supports the trial court’s conclusion that
the S & F article would not have led a person of ordinary
skill in the art to believe that flumezapine could be
successfully modified with a hydrogen atom. The district
court correctly concluded that nothing in the S & F article
and Chakrabarti 1980a made the combination reached in
olanzapine obvious.
Nonetheless, [VAX also cites to /n re Payne, 606 F.2d
303 (C.C.P.A 1979) to argue that Compound °222 and
flumezapine “bracket,” and thereby make olanzapine prima
facie obvious. To the contrary, Payne did not feature prior
art that taught away from making the structural alterations
as in this case. In this case, the prior art would have directed
one of skill away from making flumezapine and ethyl-
olanzapine (Compound °222). The “bracket” notion from
Payne simply characterized the structural similarity in that
case, which this court has noted does not control this case.
Furthermore, Lilly overcame any prima facie case of
obviousness. Among other things, Lilly proved extensive
19a
Appendix A
secondary considerations to rebut obviousness. The trial court
found the evidence clearly established four of the five
proffered secondary considerations. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 852-74, 905-12. Lilly
established (1) a long-felt and unmet need; (2) failure of
others; (3) industry acclaim; and (4) unexpected results. /d.
The record shows a long-felt need for a safer, less toxic, and
more effective clozapine-like drug; a decade (or more) of
failure to find a replacement for clozapine; a reasonable
amount of commercial success for olanzapine; and a number
of awards for olanzapine as indicators of industry acclaim.
Id. at 852-53. Specifically, the trial court noted a “long-felt
but unsolved need for a safe atypical antipsychotic from 1975
until 1990,” as well as extensive evidence supporting the
other objective criteria. /d. at 832-34, 906. The trial court
also discussed the unexpected differences between the closest
analog, Compound °222 and olanzapine, most of which
focused on olanzapine not raising cholesterol levels in dogs,
and a comparison of some humans tests with other similar
drugs that raised CPK. /d. at 853-73. In sum, these objective
criteria buttressed the trial court’s conclusion of
nonobviousness.
Il]
The trial court concluded that Lilly’s clinical trials of
olanzapine were not a public, but an experimental, use that
negated any section 102 bar. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 913-14. Under section
102, a person is entitled to a patent, unless “the invention
was... .in public use. . . in this country, more than one year
prior to the date of the application for patent in the United
20a
Appendix A
States.” 35 U.S.C. § 102(b) (2000). Public use includes “any
[public] use of [the claimed] invention by a person other
than the inventor who is under no limitation, restriction or
obligation of secrecy to the inventor.” /n re Smith, 714 F.2d
1127, 1134 (Fed.Cir.1983) (citing Egbert v. Lippmann, 104
U.S. 333, 336, 26 L.Ed. 755 (1881)).
In considering whether a particular use was “public”
within the meaning of section 102(b), this court considers
the policies underlying the bar. Jone Bros., Inc. v. Sysco
Corp., 28 F.3d 1192, 1198 (Fed.Cir.1994), cert. denied, 514
U.S. 1015, 115 S.Ct. 1356, 131 L.Ed.2d 214 (1995). In
assessing this case, the trial court found that Lilly personnel
conducted the HGAA, HGAB, and HGAC Phase I clinical
trials of olanzapine in the Lilly clinic. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 912-13. In all three
stages, Lilly restricted access to the facility and provided
full-time security. Jd. Lilly closely monitored and confined
the movements of the volunteers, who were healthy and not
suffering from schizophrenia, for the duration of the study.
Id. Visitors to the volunteers did not interrupt the control or
confidentiality of the study. /d. Moreover, as the trial court
noted, the clinical trials did not use the drugs to treat
schizophrenic patients, but merely to test the safety and
efficacy of the drug. Findings of Fact and Conclusions of
Law, 364 F.Supp.2d at 913.
Beyond this convincing record evidence, the
experimental character of these tests negated any statutory
bar. Even a use that occurs in the open may not invoke a bar
when undertaken to experiment on or with the claimed
invention. 7P Labs., Inc. v. Prof 'l Positioners, Inc., 724 F.2d
2la
Appendix A
965, 971 (Fed.Cir. 1984), cert. denied, 469 U.S. 826, 105 S.Ct.
108, 83 L.Ed.2d 51 (1984). In the words of the Supreme
Court, “[t]he use of an invention by the inventor himself, or
of any other person under his direction, by way of experiment,
and in order to bring the invention to perfection, has never
been regarded as [a public] use.” City of Elizabeth v. Am.
Nicholson Pavement Co., 97 U.S. 126, 134, 24 L.Ed. 1000
(1877). Several indicia may show the negating experimental
character of a use, including (1) the length of the test period,
(2) any confidentiality agreement, (3) any records of testing,
(4) any monitoring and control of the test results, (5) the
number of tests, and /6) the length of the test period in relation
to tests of similar inventions. 7P Labs., 724 F.2d at 971-72;
see also Inre Brigance, 792 F.2d 1103, 1108 (Fed.Cir.1986).
In this case, Lilly tailored its tests to their experimental drug
safety and efficacy purpose, adequately monitored for results,
and maintained confidentiality throughout the duration of
the study. The trial court did not err in finding no public use.
IV
DRL argues that the district court erred in not finding
inequitable conduct because if it had looked at the totality of
the circumstances, the evidence would have shown that Lilly
intentionally made per se material statements that misled the
examiner. “Inequitable conduct occurs when a patentee
breaches his or her duty to the United States Patent and
Trademark Office (PTO) of ‘candor, good faith, and
honesty.’ ” Warner-Lambert Co. v. Teva Pharms. USA, Inc.,
418 F.3d 1326, 1342 (Fed.Cir.2005) (quoting Molins PLC v.
Textron) Inc., 48 F.3d 1172, 1178 (Fed.Cir.1995)). Inequitable
conduct includes affirmative misrepresentations of material
22a
Appendix A
facts, non-disclosure of material information, or submission
of false material information, coupled with an intent to
deceive. See Nobelpharma AB v. Implant Innovations, Inc.,
141 F.3d 1059, 1068-71 (Fed.Cir.1998) (citing Molins, 48
F.3d at 1178). To assess inequitable conduct, the trial court
must determine whether the withheld reference meets a
threshold level of materiality. Dayco Prods., Inc. v. Total
Containment, Inc., 329 F.3d 1358, 1362-63 (Fed.Cir.2003)
(quoting Purdue Pharma L.P. v. Boehringer Ingelheim
GMBH, 237 F.3d 1359, 1366 (Fed.Cir.2001)). Then, the trial
court must also determine whether the evidence shows a
threshold level of intent to mislead the PTO. See Halliburton
Co. v. Schlumberger Tech. Corp., 925 F.2d 1435, 1439
(Fed.Cir.1991). After finding the threshold levels of
materiality and intent, the trial court then balances those
factors. See Molins, 48 F.3d at 1178.
Gross negligence alone is insufficient to justify an
inference of intent to deceive the PTO. See Kingsdown Med.
Consultants, Ltd. v. Hollister, Inc., 863 F.2d 867, 876
(Fed.Cir. 1988); FMC Corp. v. Manitowoc Co., 835 F.2d 1411,
1415 n. 9 (Fed.Cir.1987). In a case involving an omission of
a material reference to the PTO, the record must contain clear
and convincing evidence that the applicant made a deliberate
decision to withhold a known material reference. See Molins,
48 F.3d at 1181. Beyond that, the applicant must have
withheld the material subject matter with the intent to
deceive. Ferring B.V. v. Barr Labs., Inc., 437 F.3d 1181, 1190
(Fed.Cir.2006). “Intent to deceive cannot be inferred simply
from the decision to withhold the reference where the reasons
given for the withholding are plausible.” Dayco Prods., 329
F.3d at 1368.
23a
Appendix A
Before the Swedish Board, Lilly noted idiosyncratic
blood toxicity problems in isolated dogs at 10 mg/kg, and
DRL claims Lilly’s failure to mention this to the PTO is
inequitable conduct. However, the PTO had questions only
about blood cholesterol levels. Before the Swedish Board,
Lilly never commented about cholesterol levels. Indeed,
Lilly’s statements to the Swedish Board about the
idiosyncratic blood toxicity resulted from Lilly’s desire to
conduct human clinical studies of olanzapine in Scandinavia.
Findings of Fact and Conclusions of Law, 364 F.Supp.2d at
875-76. Before allowing human clinical studies, the Swedish
Board required Lilly to respond to concerns about the toxic
effects of olanzapine on blood cells and bone marrow in dogs
during the D07290 Dog Study. /d. at 919-20. Lilly replied
that these findings of hematoxicity “were believed not to have
clinical relevance to humans since the effects occurred at
large multiples of the clinical dose.” /d. at 875-76. These
statements to the Swedish Board discounted the results of
the blood studies by reference to idiosyncratic hematoxicity,
not cholesterol problems. Thus, Lilly did not fail to disclose
information or contradict its later patentability arguments.
Furthermore, contrary to DRL’s argument, Dr. David
Scruby’s declaration did not create a “false” impression that
ihe D07290 Dog Study cholesterol findings could be
extrapolated to humans. Dr. Scruby had been a staff physician
at Lilly since 1983. Findings of Fact and Conclusions of
Law, 364 F.Supp.2d at 882. This court acknowledges that
Rohm & Haas, Co. v. Crystal Chem. Co., 722 F.2d 1556,
1571 (Fed.Cir.1983) states: “[T]here is no room to argue that
submission of false affidavits is not material.” In this case,
24a
Appendix A
however, the record shows that Dr. Scruby’s affidavit was
not false.
Dr. Scruby’s affidavit could only be considered false if
read to suggest that Dr. Scruby was telling the examiner to
extrapolate point-by-point to humans olanzapine’s improved
cholesterol levels in dogs as compared to Compound ’222.
Dr. Scruby’s affidavit does not suggest such an extrapolation
of the benefits of olanzapine from dogs to humans. Dr.
Scruby, in fact, separates into different paragraphs his
discussions of olanzapine’s benefits for cholesterol levels in
humans and the effects of Compound °222 for dogs.
Furthermore, he expressly relies on the declarations of Dr.
Jeffrey Means and Dr. James Symanowski as “the basis for
my clinical statements concerning the dog toxicology
studies.” Dr. Means is a pharmacologist and toxicologist;
and Dr. Symanowski is a statistician. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 837-38.
Dr. Scruby’s affidavit appears in the prosecution history
as a Response After Final (Response) for the following
propositions: (1) that “cholesterol is recognized as a factor
in coronary artery disease;” (2) that the Framingham Study
“indicated that a 1% reduction in the cholesterol level results
in a 2% reduction in coronary artery disease;” and (3) that
“there is overwhelming evidence in the literature that serum
cholesterol in excess of 240 mg/dL is a significant contributor
to the genesis of atherosclerosis.” These statements are not
false. The trial court did not err in discerning no clear and
convincing evidence that Dr. Scruby misrepresented or
withheld information from the PTO with an intent to deceive.
Id. at 883-84.
25a
Appendix A
Lilly’s Response did not intentionally blur the
distinctions between humans and dogs. Rather, Lilly’s
Response expressly replied to the examiner’s request for
human clinical comparisons of olanzapine and Compound
222 by stating:
Applicants maintain that the Examiner’s request
for human clinical comparison of olanzapine and
compound ’222 is inappropriate .... In light of
serious consequences associated with artificially
altering the balance of cholesterol synthesis,
Applicants assert that human clinical trials with
'222 would be unethical and well as
unreasonable.
Response, at p. 11 (emphases added). Lilly made clear that it
based none of its statements about the effects of either
olanzapine or Compound °222 on human testing.
Furthermore, the examiner also understood that the
cholesterol data was based on the D07290 Dog Study because
he asked ahout those results without any reference to
cholesterol benefits for humans. Findings of Fact and
Conclusions of Law, 364 F.Supp.2d at 882.
In addition, on a separate inequitable conduct question,
the trial court concluded that Lilly did not omit material
subject matter from its Information Disclosure Statement in
April 1991, which did not disclose the °574 patent and
Chakrabarti 1980a. Id. at 917. The trial court also found no
clear and convincing evidence that Lilly withheld
Chakrabarti 1980a or the °574 patent with an intent to
deceive the PTO. /d. at 917. The trial court noted that Lilly
26a
Appendix A
did disclose U.S. Patent No. 4,115,568 (°568 patent) to the
PTO, and specifically explained that “[t]he reference fails to
disclose the compound which is now claimed, but does
describe the adjacent homologue [Compound ’222].” /d. at
894. It also noted that the technical disclosures of the °574
and °568 patents are identical and each discloses the genus
of compounds that generically includes olanzapine.
Moreover, Lilly cited the British counterpart of the °574 and
°568 patents in the olanzapine patent application. In addition,
the examiner found and relied on Chakrabarti 1980a during
prosecution. As a result, the trial court did not err in its
conclusion that nondisclosure of Chakrabarti 1980a or the
°574 patent was neither a material omission nor done with
an intent to deceive.
Vv
In conclusion, this court affirms the trial court on
anticipation, obviousness, and public use questions. Because
the parties do not dispute the facts, this court also affirms
the trial court's legal conclusions on inequitable conduct
finding no abuse of discretion therein.
COSTS
Each party shall bear its own costs.
AFFIRMED.
27a
APPENDIX B — FINDINGS OF FACT AND
CONCLUSIONS OF LAW OF THE UNITED STATES
DISTRICT COURT FOR THE SOUTHERN DISTRICT
OF INDIANA, INDIANAPOLIS DIVISION
DATED APRIL 14, 2005
UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF INDIANA
INDIANAPOLIS DIVISION
1:01-cv-443-RLY-VSS
ELI LILLY AND COMPANY and
LILLY INDUSTRIES LTD.,
Plaintiffs,
VS.
ZENITH GOLDLINE PHARMACEUTICALS, INC.,
DR. REDDY’S LABORATORIES, LTD., and
TEVA PHARMACEUTICALS USA, INC.,
Defendants.
FINDINGS OF FACT AND CONCLUSIONS OF LAW
[Table of Contents intentionally omitted]
Plaintiffs, Eli Lilly and Company and Lilly Industries
Ltd., filed suit against the Defendants, Zenith Goldline
Pharmaceuticals, Inc., Dr. Reddy’s Laboratories, Ltd., and
Teva Pharmaceuticals USA, Inc. (collectively “Defendants”),
for infringement of United States Patent No. 5,229,382 (*“382
patent”). The parties tried this case before the court from
28a
Appendix B
January 26, 2004, through February 12, 2004. Following the
trial, the parties filed proposed findings of fact and
conclusions of law, and responses thereto. The parties also
filed post-trial briefs, which the court found helpful given
the breadth and complexity of the disputed issues. The
majority of the relevant briefing was submitted by May 12,
2004, with final submissions filed in February 2005.
Being duly advised, the court finds that Defendants have
failed to prove by clear and convincing evidence that the
°382 patent is invalid, as anticipated under 35 U.S.C. § 102,
as obvious under 35 U.S.C. § 103, under the doctrine of
double patenting, or as barred by prior public use under
35 U.S.C. § 102. The court further finds that Defendanis have
failed to prove by clear and convincing evidence that the
°382 patent is unenforceable due to inequitable conduct.
The court now issues its findings of fact and conclusions
of law pursuant to Federal Rule of Civil Procedure 52(a):
FINDINGS OF FACT'
I. The Parties
1. Eli Lilly and Company is an Indiana corporation engaged
in the business of research, development, manufacture,
1. Citations to the trial transcript will be “[witness name] Tr.”
followed by “[transcript page: line];” citations to the deposition
testimony submitted by the parties will be “[witness name] Dep.”
followed by “[dep. page: line]”; citations to the trial exhibits will be
“TX” followed by the exhibit number; citations to the file history of
referenced patents will be “FH” followed by the page number; and
citations to Lilly’s demonstrative exhibits will be “LD” followed by
the exhibit number.
29a
Appendix B
and sale of pharmaceutical products throughout the
world.
Lilly Industries Ltd., located in England, is a subsidiary
of Eli Lilly and Company (the Plaintiffs are hereinafter
collectively and individually “Lilly”).
Zenith Goldline Pharmaceuticals, Inc. (“Zenith”) is a
Florida corporation having its corporate offices and
principal place of business at 4400 Biscayne Boulevard,
Miami, Florida 33137. Zenith’s Amended Answer to
Complaint for Patent Infringement, Affirmative Defenses
and Counterclaims, filed August 7, 2002, P 3.
Dr. Reddy’s Laboratories, Ltd. (“DRL”) is a public
limited liability corporation having its principal place
of business at 7-1-27 Ameerpet, Hyderabad 500 016,
India. DRL’s Amended Answer and Counterclaim, filed
July 29, 2002, P 3.
Teva Pharmaceuticals USA, Inc. (“Teva”) is a Delaware
corporation with its principal place of business at 650
Cathill Road, Sellersville, Pennsylvania. Answer of
Defendant Teva Pharmaceuticals USA, Inc., filed on
March 18, 2003, P 3.
On July 20, 1993, the United States Patent and Trademark
Office (“PTO”) issued the 382 patent which is entitled
*2-Methyl-Thieno-Benzodiazepine.” The °382 patent
was assigned to, and is owned by, Lilly. TX 1000; TX
1360.
10.
11.
30a
Appendix B
The °382 patent claims, inter alia, the chemical
compound known as olanzapine and methods of using
olanzapine to treat schizophrenia. TX 1000, col. 12,
claims 1, 2, 3, 7, 8, and 15.
Olanzapine, sold by Lilly under the trademark
ZYPREXA(R) (“Zyprexa”), was approved by the
United States Food and Drug Administration (“FDA”)
in late 1996. Paul Tr. 139:16-19.
Zenith, DRL, and Teva filed Abbreviated New Drug
Applications (“ANDAs”) under the Drug Price
Competition and Patent Term Restoration Act of 1984,
98 Stat. 1585 (popularly known as the Hatch-Waxman
Act), seeking approval to market generic copies of
Lilly’s olanzapine products prior to the expiration of
the °382 patent.
Pursuant to 21 U.S.C. § 355(j)(2)(B)(ii), Zenith, DRL,
and Teva sent letters to Lilly to notify it that they had
filed ANDAs for olanzapine in various dosages.
Lilly filed suit against Zenith, DRL, and Teva alleging
infringement of the °382 patent under 35 U.S.C.
§ 271(e)(2)(A). The court consolidated Lilly’s suits
against Zenith, DRL, and Teva into this single action.
See e.g., Entries of February 15, 2002: April 11, 2002;
November 1, 2002; and March 14, 2003.
Lilly seeks an order (1) prohibiting FDA approval of
the Defendants’ generic olanzapine products prior to
the expiration of the °382 patent, in accordance with
3la
Appendix B
35 U.S.C. § 271(e)(4)(A); and (2) enjoining the
Defendants from the commercial manufacture, use,
offer to sell, sale, or importation of their olanzapine
products, in accordance with 35 U.S.C. § 271(e)(4)(B).
Complaint, filed April 2, 2001, Prayer for Relief.
13. After the commencement of the suit, Zenith and DRL
14.
stipulated that “if the Court finds the *382 patent valid
and enforceable, then their actions constitute
infringement.” Entry, December 2, 2003 at 2. The
parties further stipulated that the only method-of-use
claims to be tried in this case are claims 7 and 8 of the
°382 patent relating to the treatment of schizophrenia.
Stipulation and Order entered on ‘uly 31, 2003 at p. 3.
Therefore, the issues before the court are the validity
and enforceability of claims 1, 2, 3, 7, 8, and 15 of the
°382 patent.
Teva did not participate in the trial but agreed to be
bound by the decision of the court herein. Entry on Joint
Stipulation and Staying Actions. July 16, 2003.
II. Background in the Relevant Field Prior to the
15.
Prosecution of the ’382 Patent
A. Schizophrenia
Schizophrenia is a chronic, debilitating mental illness
that appeers during late adolescence or early adulthood
and essentially lasts the lifetime of the patient. Paul Tr.
109:17-119:1.
16.
17.
18.
32a
Appendix B
Some of the symptoms of schizophrenia include, but
are not limited to, “positive” symptoms and “negative”
symptoms. “Positive” symptoms include hallucinations,
delusions, and thought disorders. See, e.g., video clip
at TX 1446.1. “Negative symptoms” include loss of
emotional and mental functioning, loss of motivation,
loss of normal emotional response to other people,
slowness of thinking, memory deficits, changes in
speech (speaking in a dull monotone), and difficulties
with cognition, sustained attention, decision-making,
and mental flexibility. Paul Tr. 108:2-25, 109:1-16;
Schulz Tr. 2972:1-5.
B. Early Drug Treatment — Typical Antipsychotic
Drugs
Prior to the discovery of antipsychotic medications in
the 1950s, most schizophrenic patients were isolated
from society and kept in large asylums. Paul Tr. 110:10-
19. This pattern of lifetime institutionalization for
schizophrenic patients began to change in 1952 with
the introduction of chloropromazine and continued
through the later introduction of haloperidol in the
1960s. TX 1398 at 746; Paul Tr. 111:2-9. These early
antipsychotic medications (known as “typical”
antipsychotics) showed substantial reduction of positive
symptoms and allowed a number of patients to leave
institutional settings. TX 1398 at 746; Paul Tr. 111:12-
112: 4.
However, the typical antipsychotic medications did
little to treat the symptoms of schizophrenia and also
19.
20.
33a
Appendix B
induced a number of “sometimes severe and intolerable
neurological side effects.” TX 1398 at 746; Paul Tr.
112:8-13. Such side effects associated with so-called
extrapyramidal symptoms or “EPS” led to gross
movement disorders, such as disfiguring tremors,
stiffness, tics, and writhing. A particularly severe form
of EPS, called “tardive dyskinesia,” persisted even after
medications were withdrawn. Paul Tr. 113:22-114:1.
In addition, patients experienced elevation of the
hormone prolactin that led to breast engorgement and.
milk production in both male and female patients. Paul
Tr. 112:5-115:12.
C. Clozapine: The First Atypical Antipsychotic
In the late 1960s and early 1970s, it became apparent
that a drug called “clozapine” could treat the psychotic
symptoms without EPS or prolactin elevation, causing
it to be recognized as the first “atypical” antipsychotic:
Paul Tr. 116:6-117:2; Nichols Tr. 2743:9-13.
In 1975, clozapine was withdrawn from the market in
many countries because it was found to cause an often
fatal blood disorder called “agranulocytosis” in
approximately one percent of patients. This effect, and
resulting withdrawal of the drug from the market,
prompted people in the pharmaceutical industry to start
looking for a drug like clozapine, but without the same
side effect profile. Nichols Tr. 2743:14-2744:9; Paul
Tr. 131:8-11; Schulz Tr. 3004:15-20.
21.
34a
Appendix B
D. The Search for a Safe, Atypical Antipsychotic Drug
The general failure for many years to find a clozapine
replacement was reflected in the scientific literature.
TX 1356, Nichols Tr. 2750:17-2752:2. The literature
contains many reports of promising compounds which
failed either for lack of efficacy or because of toxic
side effects. TX 1356; TX 1383; TX 1593; TX 1594;
TX 1595; Nichols Tr. 2751:5-2769:24; see also
Tupper Tr. 242:22-243:10, 246:9-247:8; TX 1595
(summarizing various scientific publications that
reported the efforts of major pharmaceutical companies
to find safe and effective antipsychotic medications).
In late 1989, the FDA approved clozapine for limited
use in the United States notwithstanding its adverse side
effects, as a therapy of last resort to be used only with
careful blood monitoring. Paul Tr. 117:25-118:13.
In 1991, the New England Journal of Medicine reported
that, “despite the extensive developmental effort in this
area, no alternative to clozapine has been identified that
has clinical antipsychotic efficacy and no
extrapyramidal neurologic side effects, but has a low
risk of inducing other important toxic effects (bone
marrow suppression or seizures).” TX 1398 at 747.
Clozapine and certain other “typical” antipsychotics on
the market such as chlorpromazine and haloperidol, had
a “neuroleptic substituent,” an electron withdrawing
group believed to be important for antipsychotic
activity. The most common neuroleptic substituent has
25.
26.
27.
35a
Appendix B
a halogen atom: The term “halogen” refers to either a
fluorine or a chlorine atom. Tupper Tr. 414:9-418:18,
487:13-488:1.
E. Lilly’s Attempts to Discover a Safe, Atypical
Antipsychotic Drug
In the late 1970s and early 1980s, Lilly produced a novel
class of compounds called thienobenzodiazepines.
Tupper Tr. 428:23-429:25. Thienobenzodiazepines are
tricyclic compounds having “thieno,” “benzo,” and
“diazepine” rings fused together.
In 1975, Lilly filed a patent application related to these
compounds. In 1978, the PTO issued two patents, U.S.
Patent No. 4,115,568 (“the 568 patent”), TX 1408, and
U.S. Patent No. 4,115,574 (“the 574 patent”), TX 3129,
having identical technical disclosures, but different
claims. Tupper Tr. 429:16-20, 431:4-19. Dr. Jiban
Chakrabarti (“Dr. Chakrabarti”) and Dr. David Tupper
(“Dr. Tupper”) are listed as the named inventors on the
568 patent and the 574 patent. TX 1408; TX 3129.
The 568 and 574 patents described the members of this
class of new compounds as “useful in the treatment of
. .. certain kinds of psychotic conditions. . .” TX 3129,
col. 13,11. 62-66; TX 1408, col. 14, 11. 41-42.
The 574 patent identifies the characteristics of the most
preferred class of compounds within this family. TX
3129, col. 4,11. 27-29. From this most preferred class,
the patent identifies one particularly active compound
29.
30.
. o
36a
Appendix B
as 2-ethyl-7-fluoro-10-(4'-methyl-1'-piperazinyl)-4H-
thieno[2,3-b][1,5]benzodiazepine, known throughout
this trial as “ethyl flumezapine.” Tupper Tr. 431:20-
432:8.
Lilly, like many others in the field, modeled its lead
candidates after clozapine, having a halogen atom in
the molecule. Nichols Tr. 2751:5-2757:14; TX 1356 at
806; Tupper Tr. 413:21-414:9, 503:20-21; Pullar Tr.
200:20-201:3. Clozapine has a chlorine atom (Cl) at a
position analogous to the fluorine atom (F) in ethyl
flumezapine.
Other than the broad genus claimed in claim 1, Lilly’s
574 patent claimed only compounds with a halogen.
TX 3129, col. 39, claims 2-7; Tupper Tr. 433:5-14;
Nichols Tr. 2749:5-9.
Beginning in the fall of 1974, Lilly made a compound
like ethyl flumezapine, but without the fluorine atom,
which corresponds to ethyl olanzapine, a compound
otherwise known as “compound 222”. Tupper Tr.
426:23-427:10; TX 1205.
From the very earliest tests of the ethy] flumezapine
and compound 222 molecules, it was apparent that the
fluorine-containing molecule (ethyl flumezapine) was
much more active in tests believed to be relevant to
potential antipsychotic activity than the molecule
without the fluorine (compound 222). Tupper Tr. 428:9-
15.
33.
34.
33.
37a
Appendix B
After a year and a half of preclinical development work
aimed at taking ethyl flumezapine into human clinical
trials, disaster struck. In a six-month toxicology study
with dogs, conducted at 4, 8, and 12 mg/kg using three
dogs of each sex at each dose level, blood disorders,
reminiscent of the potentially fatal blood disorder seen
with clozapine in humans, were seen in dogs at all dose
levels. TX 1035; TX 3421; Pullar Tr. 175:14-176:23.
In particular, the toxicology tests in dogs showed
widespread neutropenias in all dose groups and one
anemia. Neutropenia is a reduction of white blood cells.
Some of the dogs had reductions as much as 75% of
their normal value. TX 3421; Emmerson Tr. 542:6-21.
In an effort to find a compound in the class free of this
problem, Lilly conducted a comparative toxicology test
between ethyl flumezapine and a closely related
compound called “flumezapine.” TX 1003; Pullar Tr.
177:23-178:14. The difference between ethyl
flurnezapine and flumezapine is that in the two position
on the thiophene ring where ethyl flumezapine has an
ethyl group (-CH[2]-CH[3]), flumezapine has a methyl
group (-CH[3]). Pullar Tr. 178:1-7.
During the comparative dog study, two of the ethyl
flumezapine-treated dogs, but none of the flumezapine-
treated dogs, developed blood problems. Pullar Tr.
180:11-19; TX 1003, 1004. As a result, Lilly terminated
the development of ethyl flumezapine and commenced
the development of flumezapine in early 1978 under
the guidance of Dr. Jan Pullar (“Dr. Pullar”). Pullar Tr.
180:23-181:1; Hotten Dep. 71:12-72:10.
36.
37.
38.
38a
Appendix B
Lilly spent the next four years developing flumezapine
through preclinical testing and initial safety testing in
normal human volunteers. Pullar Tr. 185:20-188:12; TX
1008; TX 1010. Among other tests, Lilly conducted a
six-month dog study of flumezapine, Emmerson Tr.
544:23-545:24; TX 1005, and a safety trial in normal
human volunteers. TX 1010 at ZYP 177 1715-19. Then,
in the spring of 1982, during the first trial of
flumezapine in actual schizophrenic patients,
administered at and below therapeutic doses, several
patients experienced elevations in the muscle enzyme
creatinine phosphokinase (or “CPK’”) and in a variety
of liver enzymes. Pullar Tr. 188:13-189:14, 195:15-
198:16; TX 1015 at ZYP 177 1998-99; Hotten Dep.
70:14-71:11.
The findings were reported by telephone to the FDA.
TX 3259. That afternoon, Dr. Paul Leber in the Division
of Neuropharmacology Drug Products at the FDA,
halted U.S. clinical testing when he “advised that
patients be withdrawn from the drug as soon as
possible.” TX 3260.
Similarly, the British regulatory authority “expressed
surprise at the magnitude of the increases in liver
enzymes and especially the levels of CPK,” noting that
they “had not experienced anything similar.” TX 1615.
After Lilly informed the agency of these results, the
agency withdrew the United Kingdom (“U.K.”)
authorization for clinical testing, and Lilly terminated
the flumezapine clinical trials. Pullar Tr. 190:20-194:11:
TX 1042.
a9:
40.
41.
39a
Appendix B
Neither the failure of the flumezapine clinical trials nor
the reasons for it (muscle or liver enzyme elevations)
were publicly reported. Reith Tr. 927:9-11; Nichols Tr.
2776:18-2777:3; TX 1356 at 809.
F. The Discovery of Olanzapine
After the failure of flumezapine in clinical trials, a team
led by Dr. Tupper at Lilly created another group of
compounds in the same series in an effort to find another
compound that could be developed as a clozapine
replacement and that would not meet the same fate in
the clinic as flumezapine. Tupper Tr. 441:23-443:2,
446:2-447:17; TX 1229-40.
The cause of flumezapine’s toxicity was unknown.
Tupper Tr. 443:3-20. Speculation abounded inside Lilly
regarding possible causes, including reactions involving
the “piperazine nitrogen” and the fluorine atom.
The distal piperazine nitrogen is demethylated
and the nitrogen and adjacent carbon oxidised
as with other N-methylpiperazinyl compounds.
If this is the source of the toxicity it is unlikely
that it can be reduced without losing the
neuroleptic activity. The 7-fluorine is replaced
by hydroxy and methylthio groups... . whether
the source of this toxicity is the reduction in
glutathione levels, a metabolic intermediate or
the methylthio metabolite itself is at present,
unknown. The hydroxylation metabolic
pathway could also be implicated.
TX 3657 at ZY 80 94.
43.
44,
45.
40a
Appendix B
Compounds with ethyl groups (like ethyl flumezapine
and ethyl olanzapine (compound 222)) were not
considered for further development because the ethyl
group was believed by some at Lilly to produce
agranulocytosis in dogs. TX 3657 at ZY 80 94; Tupper
Tr. 443:6-444:20; Hotten Dep. 79:6-80:8, 81:11-19.
Several fluorinated and unfluorinated alternatives were
made and tested, including the compound known as
olanzapine (then known simply as “LY 170053”). Hotten
Dep. 42:5-16, 43:20-44:8, 45:1-17. Olanzapine was first
synthesized in the U.K. by Terrence Hotten (“Mr.
Hotten’’), a research chemist at Lilly, on April 29, 1982.
Tupper Tr. 446:2-14; TX 1229.
Olanzapine differs from flumezapine by having a
hydrogen atom (conventionally not shown on structural
diagrams) where flumezapine has a fluorine atom.
Pullar Tr. 199:16-24; Hotten Dep. at 42:21-43:6. A
number of people doubted that olanzapine would work
because it lacked the halogen atom then known to be
important to the activity of clozapine and believed to
be important for activity in this series of compounds as
well. Pullar Tr. 200:20-201:3; Tupper Tr. 451:7-20.
Indeed, olanzapine was believed, based on a variety of
preclinical tests, to be only about half as potent as
flumezapine. Pullar Tr. 201:10-18; Tye Dep. 71:21-
72:21, 75:21-76:12; TX 3657 at ZY 80 100-101,103
(comparing two compounds).
In 1983, Lilly began by testing olanzapine in dogs —
first in a three-month study and later in a one-year study.
46.
47.
4la
Appendix B
Emmerson Tr. 546:23-547-6, 552:14-17. During each
of the studies, one dog developed a blood problem.
Emmerson Tr. 546:19-24, 552:18-553:7. After
extensive testing, Lilly determined that the effect in
dogs appeared to be an immune response and
“idiosyncratic” in nature, meaning it occurred due to
the unusual sensitivity in individual dogs. Emmerson
Tr. 549:22-550:23, 554:18-555:15. Only then did Lilly
determine that it might cautiously proceed with human
trials of olanzapine. Emmerson Tr. 550:14-551:8,
555:6-15.
In 1986 and 1987, Lilly conducted Phase | clinical trials
of olanzapine in healthy human volunteers in
Indianapolis, Indiana. Goldberg Tr. 307:9-21; TX 3741;
TX 3742; TX 3744. At the conclusion of these trials,
Lilly proceeded to the litmus test of olanzapine — a
clinical trial to test the compound’s efficacy in actual
schizophrenic patients. Goldberg Tr. 326:25-327:20.
These clinical trials took place in the U.K. TX 1058;
TX 1064.
Toward the end of 1989, the clinical trials were
promising. In the first test of the drug in actual
schizophrenic patients, olanzapine appeared to be a safe
and effective, atypical antipsychotic drug having a more
favorable side effect profile than typical antipsychotics
in terms of EPS and not producing the blood disorders
in patients. Goldberg Tr. 335:19-20, 344:14-22, 345:6-
9; TX 1063; TX 1064 at ZYP 520 983-84.
48.
49.
50.
4
42a
Appendix B
On January 18, 1990, the olanzapine project team
reported the success of the clinical trial to Lilly’s
Research Management Staff (“RMS”), and the RMS
agreed to “product commitment.” TX 1063 at ZYP 449
1132. After the project team report, the project was
referred to with words like “AAA priority” and the
“Manhattan Project” (in reference to the scientific push
to develop the atom bomb), TX 3532, and Lilly
scientists made plans for expanded clinical trials on
the compound. Goldberg Tr. 338:21-340:7; TX 1063
at ZY 449 1128.
In the fall of 1990, Lilly conducted another comparative
dog toxicology study prior to filing a patent application
with the PTO. The study was designated D07290, and
is known throughout this litigation as the “D07290 Dog
Study” or “D07290 Study.”
The purpose of the D07290 Study was to determine
over the course of a chronic treatment period whether
there was a difference in the toxicity profile between
olanzapine and compound 222. Symanowski Tr. 664:4-
665:13, 668:24-669:4, 2077:9-18; TX 3439 at ZYP 187
713, Item 4.
At the conclusion of the D07290 Study, Lilly claimed
that the results of the study showed that olanzapine was
unexpectedly superior to compound °222 in that
olanzapine did not cause a significant elevation in
average mean cholesterol versus compound °222.
TX 1001.1 at FH 17-18.
52.
Il
53.
54.
a0.
56.
43a
Appendix B
The D07290 Dog Study is at the heart of this case and is
discussed at length in this opinion.
. Prosecution History of the ’382 Patent
A. The 143 Patent Application
On April 23, 1991, Lilly filed U.S. Application Serial No.
690,143 (“the 143 application”). TX 1000, col. 1, 11. 4-5.
Lilly had previously filed a patent application in the U.K.
on April 25,1990, and perfected the priority date. Pursuant
to 35 U.S.C. § 119, Lilly is entitled to the April 25, 1990
date for purposes of determining the relevant scope and
content of the prior art. Killworth Tr. 769:15-770:16,
TX 1000.
As part of the 143 patent application, Lilly was required
to fill out an Information Disclosure Statement (“IDS”’)
to inform the Patent Examiner (“Examiner”) of the most
closely related prior art. In Lilly’s IDS, Charles Ashbrook
(“Mr. Ashbrook”), Assistant General Patent Counsel at
Lilly, represented that the most closely related prior art
was the matter claimed in the 568 patent. TX 1001.1 at
FH 44-45.
Though the patent applicants did not cite the Examiner to
either the 574 patent or Chakrabarti et al., 4-Piperazinyl-
10H-thieno[{2,3-b][1,5]benzodiazepines as Potential
Neuroleptics, J. MED. CHEM. 23:878-84 (1980)
(“Chakrabarti 1980a’’), the Examiner performed a search
of the prior art, found those references, and cited them in
the Office Action. TX 1001.1 at FH 48-53.
oY.
58.
59.
44a
Appendix B
In the 1991 IDS, Lilly told the Examiner that compound
222, described in the 568 patent, is the adjacent
homolog to olanzapine, but that olanzapine is patentable
over the disclosure in the 568 patent because of the
“surprising biological differences of the 2-methy]
derivative (olanzapine) over the 2-ethyl derivative
(compound 222).” TX 1001.1 at FH 44.
Also in the 1991 IDS, the patent applicants told the
Examiner that flumezapine, which is the 7-fluoro
derivative of olanzapine, “caused significant adverse
effects. when administered to humans” and that
olanzapine “has an unexpectedly superior therapeutic
profile.” TX 1001.1 at 45.
In the 143 application, the applicants represented that:
“In dog toxicity studies with a closely analogous
compound 2-ethyl-10-(4-methy!-1-piperazinyl)-4H-
thieno[2,3-b][1,5] benzodiazepine [compound 222], at
a dosage of 8 mg/kg, it was observed that four out of
eight dogs showed a significant rise in cholesterol
levels, whereas the compound of the invention did not
show any rise in cholesterol levels.” TX 1001.1 at FH
17-18. This text corresponds to col. 3, 11. 29-36 of the
°382 patent, TX 1000, co!. 3,11. 29-36, and is a
reference to the D07290 Dog Study. Plaintiffs’ Reply
to Amended Answer to Complaint for Patent
Infringement, Affirmative Defenses, And
Counterclaims of Zenith Goldline Pharmaceuticals, Inc.
(filed September 20, 2002) (“Lilly’s Reply”), P 19.
60.
61.
62.
63.
45a
Appendix B
In the 143 application, Lilly stated that seventeen
patients received flumezapine before the clinical trial
was terminated after consultation with the FDA because
of an unacceptably high incidence of raised enzyme
levels in the treated patients. Specifically, “creatinine
phosphokinase (CPK) and the liver enzymes, serum
glutamate oxalacetic transmaninase (SGOT) and serum
glutamate pyruvate transaminase (SGPT), estimated in
the blood samples from the patients, were substantially
in excess of normal values, indicating the possibility
of toxicity.” TX 1001.1 at FH 15. With respect to
olanzapine, Lilly stated only that “there is a low
incidence of only mild and transient elevation of liver
enzymes in patients treated with therapeutic doses, and
plasme levels of ... CPK are lower than with
flumezapine, indicating a lower adverse effect on
muscular tissue.” TX 1001.1 at FH 17.
The Examiner reviewed the claims for compliance with
the enablement requirement of 35 U.S.C. § 112, the
definiteness requirements of 35 U.S.C. § 112, for
novelty under 35 U.S.C. § 102, for nonobviousness
under 35 U.S.C. § 103, and for obviousness-type double
patenting. TX 1001.1 at FH 49-51, 53; Killworth Tr.
778:10-24, 779:5-21, 781:13-19.
On November 25, 1991, the Examiner issued an Office
Action with respect to the °143 application rejecting
all of the claims. TX 1001.1 at FH 48-53.
In evaluating novelty, the Examiner rejected Lilly’s
claims under 35 U.S.C. § 102(b) as being “anticipated”
64.
46a
Appendix B
by the 574 patent, citing a portion of the text of the 574
patent that was shared by the 568 patent cited by Mr.
Ashbrook in his IDS. Killworth 778:20-779:3; TX 1001.1
at FH 50.
The Examiner rejected all of the claims under 35 U.S.C.
§ 103 as obvious over the 574 patent in view of
Chakrabarti 1980a. TX 1001.1 at FH 51-53. The
Examiner stated that “it would have been obvious to one
with ordinary skill in the art toreplace the 2-ethyl
substituent on the homologous species [compound 222]
taught in [the 574 patent] with the 2-methy] substituent in
order to obtain the instant compound [olanzapine] because
[Chakrabarti 1980a] specifically suggests to one with
ordinary skill in the art that this type of substituent is
preferably [sic] to increase [central nervous system]
activity.” TX 1001.1 at FH 51-52.
65. The Examiner considered the description of the unexpected
66.
cholesterol results in the application to be “insufficient”
because “1) no controls were run, 2) there is no evidence
that such data is statistically significant and 3) that such
data is necessarily showing a significant beneficial effect
to the patient.” TX 1001.1 at FH 52; Killworth Tr. 780:10-
17.
Finally, the Examiner rejected Lilly’s claims under the
judicially created doctrine of “obviousness-type double
patenting” as being unpatentable over the claims of the
574 patent in view of Chakrabarti 1980a for the same
reasons that the claims were alleged to be obvious from
the vext of the 574 patent in view of Chakrabarti 1980a
under 35 U.S.C. § 103. TX 1001.1 at FH 53; Killworth
Tr. 781:13-782:12.
67.
68.
69.
70.
71.
47a
Appendix B
B. The 348 Continuation Application
Lilly responded to the Office Action on May 22, 1992, by
filing a file wrapper continuation application to extend
the time period for response to the rejection. TX 1001.1
at FH 98-100; Killworth Tr. 782:16-783:13. This
application was assigned the application serial number
890,348 (the “348 application”). TX 1001.1 at FH 98.
The 348 application contained the same disclosure,
including the claims, as the 143 application. In accordance
with standard PTO procedure, the 348 application was
assigned to the same Examiner who had examined the
143 application. Killworth Tr. 782:16-783:25; TX 1001.1
at FH 98-100.
On September 11, 1992, the Examiner issued another
Office Action rejecting the claims for the same reasons
set forth in the prior Office Action in the 143 application.
Killworth Tr. 784:1-22; TX 1001.1 at FH 102.
On December 10, 1992, three representatives of Lilly
conducted a personal interview with the Examiner in the
348 application. The Lilly representatives were Macharri
Vorndran-Jones (““Ms. Vorndran-Jones”) and Joseph Jones
(“Mr. Jones”) from Lilly’s legal department, and Dr. James
Emmerson (“Dr. Emmerson”), a Lilly toxicologist.
TX 1001.1 at FH 109-10.
At the interview, Lilly presented eight declarations of
Lilly employees to the Examiner extensively describing
the results of comparative tests of olanzapine and
73.
74.
48a
Appendix B
compound 222, including the D07290 Dog Study.
TX 1001.1 at FH 125-54.
These declarations were submitted by Dr. Nicholas Tye
(“Dr. Tye”), Dr. Pullar, Dr. Nicholas Moore (“Dr.
Moore”), Dr. Jeffrey Means (“Dr. Means”), Dr.
Emmerson, Dr. David Wong (“Dr. Wong”), Dr. David
Scruby (“Dr. Scruby”), and Dr. James Symanowski
(“Dr. Symanowski’). TX 1001.1 at FH 125-27 (Tye),
FH 128-30 (Pullar), FH 131-34 (Moore), FH 135-39
(Means), FH 140-42 (Emmerson), FH 143-45 (Wong),
FH 146-48 (Scruby), FH 149-54 (Symanowski). Dr.
Tye, Dr. Pullar, and Dr. Moore are pharmacologists;
Dr. Means is a pharmacologist and toxicologist; Dr.
Emmerson, as stated earlier, is a toxicologist; Dr. Wong
is a biochemist; Dr. Scruby is a Lilly physician; and
Dr. Symanowski is a statistician.
All declarations were submitted under 37 C.F.R. § 1.132
and all declarants swore that the statements made
therein were true. TX 1001.1 at FH 125-54.
Dr. Moore’s declaration analyzed the results of
behavioral tests in which animals were administered
olanzapine or compound 222. TX 1001.1 at FH 131-
34. Dr. Moore concluded that in the conditioned
avoidance response (“CAR”) test, olanzapine was more
active. TX 1001.1 at 132. He also concluded that out
of the four tests he conducted — the apomorphine-
induced climbing and hypothermia tests in mice, the
CAR test in rats, the catalepsy-induction in rats, and
the locomotor activity in rats — “both compounds have
49a
Appendix B
very similar dopamine antagonist activity in vivo.*”
TX 1001.1 at 134.
75. Dr. Pullar presented the results of in vitro testing of
olanzapine and compound 222 using binding assay
tests. The results were presented in two tables showing
the respective IC[{50] values for each compound in each
of the tests. No argument was made that the compounds
could be differentiated based on the results of these
tests. TX 1001.1 at FH 128-30.
76. Dr. Tye’s declaration discussed his examination of the
data set out by Dr. Moore and Dr. Pullar and his views
on the D07290 Dog Study carried out by Dr. Means
and the results thereof. TX 1001.1 at FH 124-27. Dr.
Tye concluded that: (1) the data of Dr. Moore and Dr.
Pullar suggested “little difference in the properties of
[olanzapine and compound 222]”; (2) the data from the
dog toxicology study “showed significantly increased
levels of cholesterol in the case of [compound 222],”
(3) raised cholesterol levels resulting from compound
222 are a serious disadvantage because cholesterol is a
factor in coronary heart disease in humans, and
(4) olanzapine “is clearly and significantly superior to
[compound 222] so far as it has been shown in the
toxicity study by Dr. Means to lack any tendency to
raise cholesterol levels.” TX 1001.1 at FH 126.
2. As used in this case, the term “in vivo” refers to the results
observed in animals, and the term “in vitro” refers to the results
observed in a laboratory.
ii
78.
79.
50a
Appendix B
Dr. Wong’s declaration evaluated data obtained from
radioligand and binding studies of olanzapine and
compound 222. TX 1001.1 at FH 143-45. In part, Dr.
Wong concluded that “both olanzapine and [compound]
222 can produce functional responses at 5-HT[1C] and
5-HT[2] receptors.” TX 1001.1 at FH 145.
Dr. Emmerson oversaw the Lilly D07290 Dog Study.
He stated in his declaration that he believed that
“olanzapine displayed an unexpected and significant
superior toxicological benefit over compound 222” with
respect to the elevation of serum cholesterol in female
dogs dosed with 8 mg/kg of compound 222 compared
with dogs similarly dosed with olanzapine and the
control dogs. TX 1001.1 at FH 142. Dr. Emmerson
believed that this toxicological benefit was a critical
property to consider in the safety analysis of the two
compounds and that he “would not recommend the
clinical development of a compound which significantly
increases the serum cholesterol levels in dogs when
there is a compound with similar activity which does
not affect serum cholesterol levels.” TX 1001.1 at FH
142.
Dr. Means was the study director for Lilly’s D07290
Dog Study. His declaration summarized the design,
conduct, and findings of the study. TX 1001.1 at FH
134-39.
a. Dr. Means stated that “suprisingly serum
cholesterol levels in females of the 8 mg/
kg-°222 treatment group were significantly
Sla
Appendix B
increased when compared to the cholesterol
levels of females in either the 8 mg/kg-
olanzapine treatment group or the control
group.” TX 1001.1 at FH 137.
b. Dr. Means also stated that “no significant
differences in serum cholesterol levels were
detected among the olanzapine treatment
and control groups.” TX 1001.1 at FH 137.
c. Dr. Means concluded that “the toxicity of
olanzapine and compound 222 in beagle
dogs is similar in many respects,” but that
“an unexpected difference between
olanzapine and compound 222 was the
significant increase of serum cholesterol
coicentrations with time in female dogs
given 8 mg/kg/day of compound 222
compared to the cholesterol values in female
dogs given 8 mg/kg/day [of] olanzapine and
compared to the cholesterol values in female
control dogs.” TX 1001.1 at FH 139.
80. Dr. Scruby stated that he reviewed Dr. Means’ and Dr.
Symanowski’s declarations, and that those declarations
provided the basis for Dr. Scruby’s clinical statements
concerning the gog toxicology studies. TX 1001.1 at
FH 146-48.
a. In his declaration, Dr. Scruby discussed his
knowledge of the risk associated with
elevated total cholesterol in humans and
81.
52a
Appendix B
stated that “any factor which leads to an
increase in serum lipids [] can have a
significant deleterious effect on [cornary
artery disease and the progression of
atherosclerosis].” TX 1001.1 at FH 147-48.
Dr. Scruby concluded that based on the
findings of the study in which the serum
cholesterol female dogs treated with
compound 222 after 60 days averaged
nearly 260mg/dl and “in view of the
overwhelming evidence in the literature that
serum cholesterol in excess of 240 mg/dl is
a significant contributor to the genesis of
atherosclerosis,” he believed that “the
significant elevation of serum cholesterol
observed in female dogs treated with the
222 compound could provide a marked
clinical difference in the pathogenesis of
coronary artery disease.” TX 1001.1 at FH
148.
Dr. Symanowski’s declaration summarized the
statistical tests used in the D07290 Study. TX 1001.1
at FH 149-54. He reported that cholesterol levels in
8 mg/kg compound 222 female dogs were noticeably
elevated after day 25 of treatment and that statistical
analysis indicated that these levels increased
significantly over time when compared to both the
8 mg/kg olanzapine female dogs and the control group,
whereas none of the olanzapine-treated groups were
statistically significantly different from control.
\
82.
83.
84.
53a
Appendix B
TX 1001.1 at FH 150-51. He presented three graphs
illustrating mean cholesterol levels over time. Figure |
presented the group mean cholesterol values throughout
the study for all of the groups of female dogs. TX 1001.1
at FH 152. Figure 2 presented the same information
for the groups of male dogs. TX 1001.1 at FH 153. The
data presented by Dr. Symanowski showed no
significant difference between olanzapine and
compound 222 with respect to cholesterol in male or
low-dose female dogs. Figure 3 illustrated the mean
values plus and minus one standard error for the
cholesterol levels in female dogs dosed with 8 mg/kg
of compound 222 and olanzapine, as well as the female
control group. TX 1001.1 at FH 154.
Following the interview, the Examiner prepared a short,
handwritten summary of the interview indicating that
the Lilly representatives and the Examiner discussed
the declarations. TX 1001.1 at FH 109. The Examiner
reported in his summary that while “the reviewed data
looked sufficient pending final review and analysis of
the complete set of data,” an agreement was not reached
as to patentability. TX 1001.1 at FH 109.
Following the interview, the patent applicants presented
to the PTO a document entitled “Response After Final.”
TX 1001.1 at FH 112-24.
In the Response After Final, the patent applicants argued
that “olanzapine exhibits the significant beneficial
property of preserving the natural balance of cholesterol
85.
86.
87.
88.
54a
Appendix B
synthesis in the treatment of schizophrenia and
schizophreniform disorders.” TX 1001.1 at FH 119-20.
In the Response After Final, the patent applicants also
argued that Lilly’s “probative evidence of olanzapine’s
superiority in one or more properties is sufficient to
overcome the prima facie obviousness rejection.” TX
1001.1 at FH 120.
To overcome a prima facie obviousness rejection, a
patent applicant can respond to the rejection or the
applicant can attempt to overcome the rejection by filing
declaratory evidence. Sofocleous Tr. 959:15-960:6;
Killworth Tr. 789:4-16.
While Lilly did not acquiesce to the Examiner’s
determination that the claims were prima facie obvious,
it did not advance specific argument to challenge this
finding. TX 1001.1 at FH 117, 124 (indicating Lilly’s
intent not to admit prima facie obviousness); Vorndran-
Jones Tr. 1611:3-7; Killworth Tr. 789:4-790:2;
Sofocleous Tr. 789:15-22.
In the Response After Final, Lilly made several
significant statements.
a. “Dr. Means’ Declaration demonstrates that the
blood cholesterol levels of female dogs treated
with the °222 derivative were significantly elevated
when compared to the blood cholesterol levels of
dogs treated with the 2-methyl (olanzapine)
compound.” TX 1001.1 at FH 120-21.
89.
90.
55a
Appendix B
b. “No significant increase in cholesterol levels was
observed in either the olanzapine treated dogs or
the control dogs.” TX 1001.1 at FH 120.
c. “Valid controls were included in the study as
substantiated by Dr. Means’, Dr. Emmerson’s, and
Dr. Symanowski’s Declarations.” TX 1001.1 at FH
121.
d. “Statistically significant elevated blood cholesterol
levels occurred in the °222 treated dogs, as
demonstrated by Dr. Symanowski’s Declaration.”
TX 1001.1 at 121.
e. “Dr. Tye declares that pharmacologically there is
little difference. between olanzapine and °222;
however, he states that olanzapine is clearly and
significantly superior to the °222 compound based
on olanzapine’s toxicological benefit.” TX 1001.1
at FH 122.
On December 17, 1992, the Examiner issued a Notice
of Allowability of all of the pending claims of the °382
patent, meaning that he had determined that the
requirements for patentability had been met and that
all previous rejections were withdrawn. TX 1001.1 at
FH 156.
The Examiner noted that the Notice of Allowability was
in response to “Amendment B [Lilly’s Response After
Final] and the declarations filed 12/10/92.” TX 1001.1
at FH 156; Killworth Tr. 792:16, 793:16.
91.
——,
IV.
92.
93.
94.
95.
56a
Appendix B
On July 20, 1993, the PTO issued the ’382 patent. TX
1000; TX 1360. The named inventors are Dr.
Chakrabarti, Dr. Tupper, and Mr. Hotten.
The Validity of the ’382 Patent
A. Anticipation
1. Anticipation by Chakrabarti 1980a
Defendants argue the claims of the °382 patent are
anticipated by Chakrabarti 1980a. One of the authors
of that scientific article is Dr. Chakrabarti of Lilly.
TX3465.
The Chakrabarti 1980a publication describes several
variations of the 4-piperazinyl-10H-thieno[2,3-
b][1,5]benzodiazepine family of compounds and
examines specifically three areas on the structure of
the family of molecules. TX 3465; Reith Tr. 820:14-
821:10; 827:18-828:3.
All compounds examined in Chakrabarti 1980a had a
common structural nucleus with different substitutions
at three places: the piperazine ring, the benzene ring,
and the thiophene ring. TX 3465; Reith Tr. 827:18-
828:3. The authors labeled these three areas for
substitution “R”, “R[1]”, and “R[2]”. TX 3465.
Only particular substituents for each disclosed
compound are listed in a table. TX 3465 at 880-82.
96.
97.
98.
99.
57a
Appendix B
In total the authors examined forty-five specific
compounds (as opposed to a genus of compounds) in
the 4-piperazinyl-10H-thieno[2,3-b][1,5]benzo
diazepine family and 14 analogous 5-piperazinyl-
substituted 4H-thieno[2,3-b][1,4]benzodiazepines,
created “to compare the activity.” TX 3465 at 879, 880-
82. Significantly, olanzapine was not one of the
compounds the authors examined. TX 3465; Reith Tr.
828:7-9.
To arrive at their conclusions about which compounds
were preferred, the authors tested the compounds by
using three different animal behavioral tests: the mouse
hypothermia test, the CAR test, and the rat catalepsy
(“CAT”) test. TX 3465; Reith Tr. 821:16-826:5. Of
these, the tests of special interest were the CAR and
the CAT test. Pullar Tr. 254:4-11.
The CAR test evaluates the inhibition of a behavioral
response in rats. Reith Tr. 822:19-823:13. In this test,
inhibition is expressed on a scale from zero to five
where a score of zero reflects minor inhibition, and a
score of five represents severe inhibition. Reith Tr.
823:8-13.
The CAR test was the only measure of potential
antipsychotic activity, and if the compound did not
achieve a CAR score of three or four at a dose of less
than 30 mg/kg, it was not considered active. Nichols
Tr. 2768:16-2769:11.
100.
101.
102.
103.
58a
Appendix B
A “good score” in the CAR test — a three or four —
indicates a desirable blockade of dopamine receptors.
Reith Tr. 823:22-24; Pullar Tr. 222:25-223:1.
Clozapine, the benchmark compound, had a CAR
score of three. LaVoie Tr. 1568:11-15.
The CAT test evaluates cataleptic behavior in rats
following administration of a compound. The scores
in this test reflect group scores, with a group
consisting of eight animals. The higher the score the
more catalepsy observed in the group. Reith Tr. 824:8-
825:16.
Generally, for purposes of determining whether a
compound has the potential to be an effective atypical
antipsychotic, a scientist would like to see a
“separation of activity” — i.e., a good score on the
CAR test at a dose that would not get a high score on
the CAT test. Reith Tr. 826:6-23; Pullar Tr. 254:4-15.
However, a separation between the CAR and CAT
scores only came into play if the first condition — a
good CAR score — was met. Moore Dep. 82:5-22,
83:9-84:6, 86:5-14. The separation of activity between
the CAR and CAT scores was thought to be relevant
to the potential absence of EPS at an active or
potentially therapeutic dose. The separation, by itself,
is not a measure of activity. Moore Dep. 83:9-84:6,
86:5-14.
104.
105.
106.
107.
59a
Appendix B
Chakrabarti 1980a identified five specific
compounds (9, 12, 17, 29, and 34) that were “found
to be more potent than clozapine and show similar, if
less marked, separation of activity in [the CAR and
CAT] tests.” TX 3465 at 878, 883.
The five preferred compounds had a CAR score of
three or better. LaVoie Tr. 1568:16-18.
With respect to these five preferred compounds, the
authors expressed a preference for specific, complete
compounds; they did not express a preference for a
genus of compounds having any and all con -inations
of the individual substituents on those molecules.
Nichols Tr. 2779:2-8 (“[A] preferred compound
would have a combination of different substituents
that would lead it to have optimal activity. Removing
one or more of those substituents would destroy that
preference. So the compound would be taken as a
whole.”); LaVoie Tr. 1567:11-19.
Four of the five preferred compounds (9, 12, 17, and
29) have a fluorine at the 7-position of the benzene
ring (compound 29 contains two fluorine atoms, one
at the 7-position and one at the 8-position). Tupper
Tr. 437:4-11; Nichols Tr. 2749:9-18, 2780:2-9; TX
3465 at 880-81. The fifth, compound 34, does not
contain a fluorine on the benzene ring, but contains a
hydroxyethyl group on the piperazine ring. Tupper
Tr. 437:12-16; Nichols Tr. 2749:9-18, 2780:11-19; TX
3465 at 881. These two components were generally
recognized at the time of the publication of
60a
Appendix B
Chakrabarti 1980a to enhance antipsychotic activity.
LaVoie Tr. 1564:6-1565:4; Nichols Tr. 2785:18-
2787:22; TX 3123 at 396-97. Olanzapine does not
include either of these substituents. Reith Tr. 902:5-
8; LaVoie Tr. 1564:16-18.
108. The authors did not list compound 6, the freebase of
compound °222, as a preferred compound. TX 3465.
Compound 6 had a CAR score of two. TX 3465 at
880; LaVoie Tr. 1568:11-15.
109. In addition to the preferred compounds, the authors
discussed the authors’ preferred substituents. Reith
Tr. 897:6-12. For example, the authors expressed a
preference for position 7 by stating that “the
substitution of the phenyl ring with a halogen atom
(Cl, F) at position 7 enhanced the activity” and that
the “7,8-difluoro compound (29) retained good
activity.” TX 3465 at 879, col. 2. The text never states
a preference for a hydrogen at position 7, as is required
for olanzapine. In addition, the authors mentioned
three specific substituent groups thought to be helpful:
three R groups (methyl, hydroxyethyl, and
hydroxypropyl), three R[1] substitutions (7-F, 7-Cl,
7,8-di-F, explained above), and three R[2] groups (2-
methyl, 2-ethyl, and 2-isopropyl).. TX 3465 at 879.
No possible combination of these preferred
substituents, i.e., a preferred R with a preferred R{1]
and a preferred R2, would generate olanzapine
3. R corresponds to the piperazine ring at the upper right of the
molecule, R[ 1] to position 7, and R[2] to position 2. See TX 3465 at
880, figure labeled “1-45"; Reith Tr. 831:2-3, 853:5-18, 840:23-25.
110.
111.
112.
6la
Appendix B
because all of these combinations contain a fluorine
(F) or a chlorine (Cl) atom at position 7 where
olanzapine has only a hydrogen. Reith Tr. 897:16-
898:21; LaVoie Tr. 1566:2-12; Nichols Tr. 2777:4-
2778:6; TX 3465 at 879.
Because none of the forty-five specific compounds
disclosed in Chakrabarti 1980a include olanzapine,
none of the five preferred compounds disclosed in
Chakrabarti 1980a include olanzapine, and none of
the preferred substituents include a hydrogen at
position 7 as is required for olanzapine, the court finds
Chakrabarti 1980a does not describe olanzapine.
The court further finds that one of ordinary skill in
the art, applying the preferences expressed in
Chakrabarti 1980a, would not envision olanzapine.
The composition and method claims of the °382 patent
are directed to dosage forms containing specified
amounts of olanzapine (e.g.. claim 15) and methods
of treating patients suffering from schizophrenia with
specified doses of olanzapine (e.g., claim 8). Such
dosage forms and methods are not described in
Chakrabarti 1980a for any of the compounds
disclosed in that article. See Findings of Fact # # 183-
84.
113.
114.
115.
116.
62a
Appendix B
2. Anticipation by Schauzu
DRL also argues that olanzapine is described as
compound 11 in a scientific article entitled Schauzu,
H.G. and Mager, P.P., A Free-Wilson Study of 4-
Piperazinyl-10H-thienobenzodiazepine Analogues,
38 DIE PHARMAZIE 562 (1983) (“Schauzu”).
The biological data in Schauzu comes from
Chakrabarti, J.K., et al., Effects of Conformationally
Restricted 4-Piperazinyl-10H-thienobenzodiazepine
Neuroleptics on Central Dopaminergic and
Cholinergic Systems, J. MED. CHEM. 1133(1982)
(“Chakrabarti 1982”). Nichols Tr. 2793:20-2794:9;
LaVoie Tr. 1506:9-18; Reith Tr. 902:9-20.
The compounds disclosed in Chakrabarti 1982 were
fluorinated piperazine compounds. This means that
the compounds had a fluorine in the 7-position and
two nitrogens in the top ring (the piperazine ring).
Nichols Tr. 2793:7-16.
The structure drawn in Schauzu is not a fluorinated
piperazine compound because it is missing both a
fluorine atom at the 7-position and one of the nitrogen
atoms in the top ring. Nichols Tr. 2792:22-2795:19.
Thus, the structure drawn in Schauzu is a piperidine
compound — not a piperazine as the title of the article
otherwise sets forth. LaVoie Tr. 1532:5-19; Nichols
Tr. 2789:3-23.
117.
118.
119.
120.
121.
122.
63a
Appendix B
A piperidine compound has one nitrogen in the top
ring (the piperidine ring), whereas a piperazine
compound, as noted above, includes a second
nitrogen” substituent in the top ring (the piperazine
ring). Nichols Tr. 2789:16-2790:1; LaVoie Tr.
1500:16-1501:10.
Schauzu was abstracted by both Chemical Abstracts
and Beilstein as disclosing piperidine compounds.
Nichols Tr. 2791:10-2792:18; LaVoie Tr. 1532:3-
1535517.
Olanzapine is a piperazine compound. Nichols Tr.
2795:12-16.
The structure drawn in Schauzu does not include
olanzapine since the structure does not include a
second nitrogen in the top ring. Nichols Tr. 2792:22-
2795:19.
The biological data from Chakrabarti 1982 does not
include olanzapine because olanzapine is an
unflourinated piperazine compound. Nichols Tr.
2789:24-2790:1, 2795:12-16.
In order to find that olanzapine is described as
compound 11 in Schauzu, one with ordinary skill in
the art would have to mentally insert a nitrogen atom
into the structure depicted in Schauzu, thereby
converting it into a piperazine compound (in this case,
olanzapine), yet ignore the fact that the biological data
reported in the Schauzu article was from Chakrabarti
EZa.
64a
Appendix B
1982, which discussed only fluorinated compounds.
Compare LaVoie Tr. 1500:20-1501:2, 1504:4-1507:5,
with Nichols Tr. 2793:20-2794:9, 2789:16-2790:1;
Reith Tr. 902:9-20.
Olanzapine is not described as compound 11 in
Schauzu. Nichols Tr. 2789:3-5.
. Obviousness
Lilly contends the discovery of olanzapine and its
unique properties represent a nonobvious selection
invention within the broad genus of compounds
disclosed in the °574 and °568 patent. In other words,
the °382 patent, which specifically claims olanzapine,
is a “species” falling within the broad “genus” claimed
in the °574 patent. Defendants contend that the claims
of the °382 patent are obvious under 35 U.S.C. § 103
over the disclosure of olanzapine in the °574 patent
in combination with Chakrabarti 1980a. They also
contend the claims of the °382 patent are obvious over
the disclosure of flumezapine in the °574 patent in
combination with Chakrabarti 1980a and the Sullivan
and Franklin article discussed infra., Findings of Fact
§ IV.B.1.d.
125.
126.
127.
6Sa
Appendix B
1. The Scope and Content of the Prior Art
a. Clozapine and Clozapine-Like
Molecules
The prior art included numerous failures to find a safe,
atypical antipsychotic drug. See Findings of Fact
§ I1.D.
As mentioned, clozapine, the first atypical
antipsychotic, was withdrawn from the market in
1975. Thus, the challenge was to find a clozapine-
like molecule that produced the benefits of clozapine
without the adverse side effects. Nichols Tr. 2743:14-
2744:9; Paul Tr. 131:8-11; Schulz Tr. 3004:15-20.
The prior art confirmed that small structural changes
in clozapine-like molecules led to unpredictable
changes in properties. Changing the position of the
chlorine atom in clozapine changed it from an atypical
antipsychotic to a typical antipsychotic. TX 3465 at
878 (“[Clozapine’s] 2-chloroisomer HF-2046 behaves
like a classical neuroleptic. . .”); Nichols Tr. 2796:16-
2797:3; LaVoie Tr. 1543:23-1544:11; LD 45; LD 94.
Changing the ring structure of clozapine led to
variable and unpredictable toxicities. Tilozepine
caused seizures. TX 1356, compound 3; TX 1365 at
col. 12, claim 12; TX 3772 at 394 (tilozapine (NT
104-252) clinical trials terminated); Nichols Tr.
2752:15-2754:11; LaVoie Tr. 1547:11-15, 1549:24-
1551:3, 1552:115-19. Fluperlapine caused
agranulocytosis in a some patients. TX 1356 at 809,
128.
66a
Appendix B
compound 2; TX 1387 at 155; Nichols Tr. 2745:18-
2747:9, 2751:13-2752:14; LD 87. Removal of the
halogen atom from clozapine and fluperlapine
(yielding perlapine) destroyed antipsychotic activity.
TX 1317 at 712, col. 2; TX 3124, compound Ic;
Tupper Tr. 420:1-14; Nichols Tr. 2744:22-2745:17,
2747:10-2748:10; LaVoie Tr. 1545:8-18; LD 142; LD
143.
b. The ’574 Patent
As noted, the °574 patent, issued on September 19,
1978, describes a family of chemical compounds of
thieno[1, 5]benzodiazepines that have useful central
nervous system (“CNS”) activity. TX 3129 (abstract);
Reith Tr. 848:10-15. The unique properties of these
compounds render them particularly “useful in the
treatment of mild anxiety states and certain kinds of
psychotic conditions such as schizophrenia and acute
mania.” TX 3129, col. 13:62-66; Reith Tr. 853:12-
20; Nichols Tr. 2839:19-2840:1.
The text of the 574 patent was written in 1975.
The first compound specifically mentioned in the °574
patent is ethyl flumezapine, which is the sole
compound identified as “particularly active.” The
chemical name of that compound is 2-ethyl-7-fluoro-
10-(4'-methyl-1'-piperaziny])-4H-thieno[2,3-
b][1.5]benzodiazepine. TX 3129, col. 4:30-34. Ethyl]
flumezapine has a fluorine atom on the benzene ring.
This fluorinated compound is the only compound that
131.
bd.
133.
134.
67a
Appendix B
the °574 patent specification describes in actual
examples of pharmaceutical formulations. TX 3129,
Examples 37-40, col. 37, 1.62 — col. 39, 1.12; Tupper
Tr. 431:20-432:22; Nichols Tr. 2749:5-9.
The specification identifies about one hundred other
compounds as examples of the compounds of the
invention, including flumezapine and compound °222.
See TX 3129, col. 4-6, 15-37. No biological data is
reported, however, for any of the compounds and no
specific compound, other than ethyl flumezapine, is
identified as being particularly active. TX 3129.
While the °574 patent claims unhalogenated
compounds among the millions of compounds
described in claim 1, the patent expresses a preference
for halogen-containing compounds and specifically
those with a halogenated substituent on the benzene
ring in a location analogous to the chlorine in
clozapine. TX 3129, col. 4:30-33, col. 39:42-62;
Tupper Tr. 433:5-14; Nichols Tr. 2749:5-9.
In fact, the patent contains six claims defining specific
compounds each containing a fluorine or a chlorine
atom. Tupper Tr. 433:5-14; Nichols Tr. 2749:5-9; TX
3129, claims 2-7, col. 39:42-62.
Olanzapine is one of the millions of compounds
within the scope of claim | of the °574 patent. TX
3129, col. 39:15-40; Reith Tr. 850:3-851:2; Hotten
Dep. 160:10-22.
135.
136.
137.
138.
139.
68a
Appendix B
c. The Chakrabarti Articles
The Chakrabarti publications also express a
preference for halogen-containing compounds.
Chakrabarti 1980a, previously discussed in Findings
of Fact § IV.A.1, is also central to the obviousness
inquiry.
(1) Chakrabarti 1980a
Chakrabarti 1980a reports on the in vivo behavior
and toxicity testing of some individual compounds
within the generic family of the
thienobenzodiazepines. TX 3465.
The authors expressed a preference for a halogen
substituent at the 7-position of the phenyl ring. Tupper
Tr. 434:12-435:3; TX 3465 at 879; Finding of Fact #
109.
The five preferred compounds identified by the
authors (compounds 9, 12, 17, 29, and 34) have CAR
scores equal to or better than clozapine’s score of
three. Tupper Tr. 436:1-437:3; TX 3465 at 880-82.
Compounds 9, 12, 17, and 29 have a fluorine at the
7-position, and compound 34 has a hydroxyethyl
piperazine group on the piperazine ring. TX 3465;
Nichols Tr. 2780:6-18; Findings of Fact # # 105, 107.
The authors also report that “[a] short alkyl
substitution ({methyl], ethyl, isopropyl]) at position 2
of the thiophene ring seems to increase the activity.”
140.
141.
69a
Appendix B
TX 3465 at 879, col. 2. The authors compare the effect
of a short alkyl substitution at position 2 versus a t-
buty! substitution, a 2-hydrogen substitution, or other
higher alkyl substitution. TX 3465 at 879, col. 2;
Tupper Tr. 486:2-25. The only series of data that
allows for each of these comparisons is based on
results from fluorinated compounds. Tupper Tr.
435:10-25.
(2) Chakrabarti 1982
In Chakrabarti 1982 the authors further confirmed
the belief that neuroleptic substituents, such as
fluorine atoms, were necessary for good antipsychotic
activity. Each of the twelve thienobenzodiazepines
described contains a fluorine atom at the 7-position.
Reith Tr. 916:2-16; Nichols Tr. 2749: 18-24; TX 3131
at 1135. The article specifically identifies fluorinated
compounds “2 and 9” (flumezapine and ethyl
flumezapine) as having “potent. . . activity.” TX 3131
at 1137; Nichols Tr. 2749:18-24.
(3) Chakrabarti 1989
In J. K. Chakrabarti et al., Synthesis and
Pharmacological Evaluation of a Series of 4-
Piperazinylpyrazolo [3,4-b]-and-[4,3-b][1,5]
benzodiazapines as Potential Anxiolytics, J. MED.
CHEM. 2573 (1989) (“Chakrabarti 1989”), the
authors reflected the ultimate preference for a fluorine
substitution in this class of molecules by reporting
that the fluorinated compound flumezapine “was
142.
143.
144.
70a
Appendix B
chosen as a candidate for clinical trial.” Reith Tr.
922:25-923:3:; Nichols Tr. 2749:25-2750:3; TX 3132
at 2574.
d. The Sullivan and Franklin Article
Sullivan and Franklin, /n Vitro Thiomethylation,
DRUG, METABOLISM, AND DISPOSITION 276
(1985) (“Sullivan and Franklin”), reports a study in
which flumezapine was administered to dogs and rats.
The study found that a methylthio metabolite arose
from the metabolism of flumezapine in the test
animals. Nichols Tr. 2774:20-2775:10, 2843:23-
2844:3; TX 3161.
There is some toxicity associated with compounds
that are metabolized via methylthio metabolites. TX
3161; Nichols Tr. 2844:8-13. Sullivan and Franklin
does not teach that the methylthio metabolic product
is toxic. Reith Tr. 928:13-16; Nichols Tr. 2775:12-
18. In addition, the article does not specifically state
that flumezapine is toxic. Reith Tr. 927:9-11; Nichols
Tr. 2775:11-13.
The article describes that during the metabolism of
flumezapine, the fluorine at the 7-position is replaced
by a methylthio group. Thus, one with ordinary skill
in the art may have been motivated, based on the
resulting potential toxicity from the metabolic process
as described in the article, to consider developing a
compound without the fluorine atom. Reith Tr.
858:22-859:6. There is, however, nothing in the article
145.
146.
147.
148.
T7la
Appendix B
to suggest that a hydrogen atom in place of the
fluorine atom at the 7-position (yielding olanzapine)
would be desirable, Nichols Tr. 2776:5-11, or that to
make such a substitution would avoid the formation
of the methylthio metabolite. Reith Tr. 929:11-18.
The article does not teach that replacing the fluorine
with a hydrogen would stop the formation of the
methylthio metabolite. Indeed, acetaminophen
(Tylenol(R)), a non-fluorinated compound, also forms
a methylthio metabolite. Reith Tr. 928:17-928:21;
Nichols Tr. 2776:5-11.
2. Ordinary Skill in the Art
A person of ordinary skill in the art in this case would
be a scientist with a Ph.D. in medicinal chemistry,
pharmacology, or a similar discipline. Reith Tr.
819:23-820:6; Nichols 2850:25-2851:4; LaVoie
1527:22-1528:1.
Lilly’s expert, Dr. David Nichols (“Dr. Nichols”), is
personally familiar with the search for a safe, atypical
antipsychotic, the relevant scope and content of the
prior art, and the capabilities of a person of ordinary
skill in the art. The court qualified him as an expert
in medicinal chemistry. Nichols Tr. 2737:13-14.
Dr. Nichols obtained a Ph.D. in medicinal chemistry
from the University of Iowa in 1973. Nichols Tr.
2733:25-2734:2; TX 3764.1. Dr. Nichols worked in
the 1980s on developing antipsychotic compounds
with an atypical activity profile; that is, active
149.
150.
72a
Appendix B
antipsychotics, but with few side effects. Nichols Tr.
2735:13-2736:17. Dr. Nichols has taught the subject
of antipsychotics for many years, including during
the time period of the prior art at issue in this case.
Nichols Tr. 2734:8-21. Dr. Nichols also has personal
experience with the behavioral tests and other
screening tests relied upon in Chakrabarti 1980a.
Nichols Tr. 2735:25-2736:7. The focus of Dr. Nichols’
research, however, has been hallucinogens and
doparnine receptors. Nichols Tr. 2812:24-2813:6.
The court qualified Zenith’s expert, Dr. Maarten Reith
(“Dr. Reith”), as an expert in the field of molecular
pharmacology and neuropharmacology. Reith Tr.
815:25-816:16. Dr. Reith has extensive experience
with respect to dopamine and serotonin receptors, TX
3170, the specific areas of the brain at which the
effects of antipsychotics are observed. TX 1000, col.
2:45-57; col. 7:6-59. Further, Dr. Reith demonstrated
substantial knowledge of the tests used in Chakrabarti
1980a, as well as those reported in the declarations
of Lilly’s scientists. See e.g., Reith Tr. 821:16-827:17,
865:1-866:24.
3. The Differences Between the Claimed
Invention and the Prior Art
Structurally, olanzapine differs from clozapine in that
olanzapine has a methyl-substituted thiophene ring
in place of the benzene ring in clozapine. Olanzapine
also has a hydrogen in place of the chlorine on its
benzene ring. See e.g., LD 52; LD 80. Clozapine
caused agranulocytosis in humans. Paul Tr. 117:3-24.
151.
152.
133.
154.
73a
Appendix B
Olanzapine differs structurally from ethyl
flumezapine by replacement of the fluorine and ethy]
group in ethyl flumezapine with a hydrogen and
methyl group respectively. See e.g., LD 48; LD S52.
Ethyl flumezapine caused widespread blood problems
in dogs; olanzapine did not. Nichols Tr. 2798:4-
2800:25.
Olanzapine differs structurally from flumezapine,
described as the lone clinical trial candidate out of
this series of compounds, by substituting a hydrogen
atom for the fluorine atom in flumezapine at the 7-
position of the benzene ring. See e.g., LD 49; LD 52;
Nichols Tr. 2801:1-2802:11.
Olanzapine differs structurally from its ethyl analog,
compound °222, by replacement of the ethyl group
with a methy! group at the 2-position of the thiophene
ring. See e.g., LD 50; LD 52. In Lilly’s D07290 Study,
compound 222 caused a significant increase in
cholesterol in female beagle dogs; olanzapine did not.
TX 1001.1 at FH 149-54; McGrath Dep. 85:13-89:12.
4. Motivation Provided By the Prior Art to
Make Olanzapine
a. Compound 222 as the Beginning
Compound
The 574 patent specifically names over one hundred
compounds, including compound °222. TX 3129, col.
4-6, 15-37, Example 26(a). The patentees did not
155.
156.
157.
74a
Appendix B
differentiate compound °222 from the other
exemplary compounds in the way that they did with
ethyl flumezapine. TX 3129, col. 4:30-34.
Compound:’222 is not halogenated and, therefore,
does not satisfy the preference expressed in the 574
patent itself, in Chakrabarti 1980a, Chakrabarti
1982, or Chakrabarti 1989. Nichols Tr. 2748:11-
2750:9, 1772:18-1773:2; Reith Tr. 898:12-899:10,
914:7-915:4, 916:2-16, 922:9-923:3; LaVoie Tr.
1566:5-12.
(1) Compound ’222’s Activity
Chakrabarti 1980a did not provide specific
motivation to use compound °222 as a starting point
for further research. In fact, the article reported that
compound °222, corresponding to compound 6 in
Table I, did not have the minimum CAR score of three
required for a suitable atypical antipsychotic agent
and thus was not considered a preferred compound.
Pullar Tr. 227:1-22; LaVoie Tr. 1568:11-1569:3;TX
3465 at 880-82.
(2) Hydrogen as a Preferred
Substituent
Chakrabarti 1980a also did not provide specific
motivation to substitute a hydrogen in the 7-position.
One skilled in the art would not have recognized from
compounds 6, 34, and 36 in Chakrabarti 1980a that
a hydrogen in the 7-position was a desirable
substituent.
158.
159.
160.
75a
Appendix B
(a) Compound 6
}
Chakrabarti 1980a reported that compound 6 had a
CAR score of two at 10 mg/kg. LaVoie Tr. 1568:11-
1569:3; Pullar Tr. 227:1-22; Tupper Tr. 437:22-438:2;
Nichols Tr. 2772:18-2773:2; TX 3465 at 880-81.
A better CAR score for compound 6 could not be
achieved by increasing the dose, since higher doses
would cause the test animal to completely stop
responding to the test stimuli due to muscular
incoordination. Pullar Tr. 223:8-224:2. Dr. Pullar
explained that increasing the dose caused the test
animals to completely stop responding to the test —-
a distinctly negative outcome. These results, based
on tests with the compound administered orally, were
corroborated with other results using intraperitoneal
(IP) administration. Increasing the dose in both cases
could not increase the activity of compound 6 above
the substandard CAR score of two. Pullar Tr. 224:18-
228:3; TX 3470.
The evidence does not support the argument that a
person of ordinary skill in the art would presume that
compound 6’s corresponding free base (compound
°222) would be more active. The difference between
a maleate salt and a free base is just their physical
forms, with salts typically being used for ease of
handling. It is the same molecule in both forms.
Tupper Tr. 504:20-505:8. As Dr. Tupper explained,
the form (salt or free base) does not fundamentally
change the pharmacological action. Tupper Tr. 505:5-
161.
162.
76a
Appendix B
8. There are some differences in the way the body
processes the salt of a compound versus its free base
due to the varying size of the particles. But if
administered to achieve equal concentrations in the
blood, the free base and maleate salt should produce
the same results, and one would expect the same
activity between the two forms. Nichols Tr. 2883:10-
16; Tupper Tr. 505:11-17. Indeed, prior to trial, Dr.
Reith made no distinction between compound 6 and
its free base (compound 222) and actually treated
them interchangeably. Reith Tr. 909:8-20.
Accordingly, one of ordinary skill in the art would
not have understood from a close reading of
Chakrabarti 1980a that compound 6 was a preferred
compound, and hence, that a hydrogen in the 7-
position would have been preferred.
(b) Compound 36
Chakrabarti 1980a reported that compounds 34, 35,
and 36 “retained good activity.” TX 3465 at 879, col.
2 (“However, compounds (34-36) ... retain good
activity.”). The statement regarding the activity of
compounds 34-36 was made in the context of
comparing the compounds, in which each had a
hydroxyethyl! or hydroxypropy! on the piperazine ring
(and which had good activity), to compounds 31-33
having other substituents on that ring (and which were
less active or inactive). Nichols Tr. 2830:18-2831:14;
TX 3465 at 879.
163.
164.
165.
166.
77a
Appendix B
Compound 36 received a CAR score of two at a dose
of 10 mg/kg, and a CAT score of two at a dose of
12.5 mg/kg. As stated previously, a CAR score of two
was not preferred. Pullar Tr. 227:1 22, 255:12-256:13.
Dr. Tupper testified that because of the manner in
which the test was scored, a reported CAR score of
two encompassed a broad range of activity ranging
from a 31% to 50% block of the conditioned
avoidance response. Pullar Tr. 229:12-230:14; TX
3465 at 882 n.d. Only the authors knew where in that
score range each compound fell, and there is no way
for the reader to second guess the judgment of the
authors as to which compounds were “good” and
which were not. Pullar Tr. 294:15-24; Nichols Tr.
2778:12-22; LaVoie Tr. 1561:17-25.
Therefore, the fact that the authors stated that
compound 36 “retained good activity” with a CAR
score of two can at most be interpreted as a reference
to a compound at the high end of the “two” range
approaching a 50% block. It cannot be taken as a
statement that all compounds with a reported CAR
score of two (with activities as low as 31%) were
good, active compounds when the remaining text of
the article indicated that they were not.
One of ordinary skill in the art would not have
understood from a reading of Chakrabarti 1980a that
compound 36 was a preferred compound. The fact
that the authors’ stated that compound 36 “retained
good activity,” read in its proper context, is not
evidence to the contrary.
167.
168.
169.
78a
Appendix B
(c) Compound 34
Compound 34 is singled out by the authors as a
preferred compound. TX 3465. This compound, like
olanzapine, has a hydrogen substituent at the R1 or
7-position, but, unlike olanzapine, also has a
hydroxyethyl] piperazine group on the piperazine ring.
Such hydroxyethyl piperazine groups were known to
enhance the activity of antipsychotic drugs. LaVoie
Tr. 1564:24-1565:4, 1567:11-22; Nichols Tr. 2779:25-
2786:22 (“There was a recognition in the art that a
hydroxyethyl had special properties . .. In general,
the compounds were more potent. They usually had
better brain penetration. . .”).
The identification of five preferred compounds by
Chakrabarti 1980a, each of which had either a
fluorine or a hyroxyethyl piperazine substituent, could
not rationally be read by a person actually skilled in
this field to be an expression of preference for
compounds like olanzapine that have neither a
fluorine atom nor a hydroxyethyl piperazine group.
Nichols Tr. 2786:12-2788:8; Reith Tr. 901:15-902:8.
Nothing in Chakrabarti 1980a provides motivation
for a person with ordinary skill in the art to begin
with compound °222 over one of the compounds the
authors endorse as preferred. Nichols Tr. 2272:22-
23, 2273:1-12.
170.
171.
79a
Appendix B
b. Changing the 2-methyl in Compound
°222 to a 2-ethyl
One skilled in the art would not have been motivated
to modify compound ’222 by changing the ethyl group
to a methyl group at the 2-position of the thiophene
ring because there is no suggestion in the °574 patent
or any other prior art that such a modification would
have increased activity and decreased unwanted side
effects. Reith Tr. 915:20-916:1; LaVoie Tr. 1562:1-
6; Nichols Tr. 2772:18-2774:7. Even if a person of
ordinary skill in the art were motivated to begin with
compound 222, he would modify it by adding a
halogen atom to give it the neuroleptic substituent
believed at the time to be required for antipsychotic
activity. Nichols Tr. 2773:13-19.
Although Chakrabarti 1980a reports that “[a] short
alkyl substitution ({methyl, ethyl, isopropyl]) at
position 2 of the thiophene ring seems to increase the
activity,” TX 346S at 879, col. 2, the article does not
state that any particular short alkyl group will provide
better results than any other short alkyl group. Reith
Tr. 915:20-916:1; LaVoie Tr. 1574:2-4; Nichols Tr.
2273:20-2274:7.
The only compounds for which data is given allowing
comparison of hydrogen at the 2-position with all of
the “short alkyl” substitutions at the 2-position (as
well as the longer alkyls, e.g., “bulky t-Bu group”) as
described in the text are compounds 8 through 21 —
all of which have a fluorine at the 7-position of the
173.
174.
175.
80a
Appendix B
benzene ring. Tupper Tr. 435:20-25; Reith Tr. 915:5-
19; LaVoie Tr. 1574:2-9; TX 3465 at 880-81.
Compounds 6 and 7, neither of which is identified as
preferred, provide an isolated example of a
comparison between a short alkyl substitution and a
t-butyl substitution in unfluorinated compounds.
Tupper Tr. 487:1-7.
Regardless of this one comparison, the paragraph in
Chakrabarti 1980a in which this preferred substituent
is revealed states a preference for short alkyl groups
in the context of a fluorinated series of compounds;
thus the article does not generally provide mc tivation
or guidance relating to the effect of such substitution
on fundamentally different unfluorinated molecules.
Reith Tr. 915:5-19; Nichols Tr. 2772:18-2774:7.
c. Replacing the Fluorine Atom in
Flumezapine with a Hydrogen Atom
Defendants contend that one of ordinary skill in the
art would have been motivated to replace the fluorine
atom in flumezapine with a hydrogen atom in the 7-
position of the benzene ring to arrive at olanzapine.
In light of the general state of the art, including the
teachings of the °574 patent and Chakrabarti 1980a,
Chakrabarti 1982, and Chakrabarti 1989, one of
ordinary skill in the art would have expected that
replacing the fluorine atom with a hydrogen atom
would produce a compound without sufficient
antipsychotic activity. Nichols Tr. 2776:5-11.
176.
177.
8la
Appendix B
While Chakrabarti 1980a suggests that a chlorine
atom in place of the fluorine atom would also enhance
the compound’s activity, it does not specifically
suggest that the same result could be obtained with a
hydrogen atom. Nichols Tr. 2779:17-24; TX 3465 at
879, col. 2. Nor does anything in Sullivan and
Franklin suggest the desirability of using a hydrogen
atom at this position. Nichols 2776:5-11; TX 3161;
Findings of Fact § IV.B.1.d. If one were looking to
replace the fluorine, one would replace the fluorine
with other electronegative groups, not hydrogen. TX
1315 at 3172; LaVoie Tr. 1572:12-1573:18. Indeed,
the art as a whole teaches directly away from using
hydrogen because it is not an electron-withdrawing
substituent. Nichols Tr. 2773:3-12.
Moreover, the 1990 publication, Davis et al., Chloro-
Substituted, Sterically Hindered 5,11 Dicarbo
Analogues of Clozapine as Potential Chiral
Antipsychotic Agents, J. MED. CHEM, 809 (1990),
proposed that the possible toxicity of candidates that
were being investigated as safe alternatives to
clozapine (including flumezapine) might be due to
the presence of so-called “hetero atoms” — nitrogens
and sulfurs — in the three-ring system of those
compounds. Nichols Tr. 2757:21-2758:10; TX 1356
at 809. Those hetero atoms have nothing to do with
the fluorine atom, and if those hetero atoms were
removed, one would not obtain olanzapine. Nichols
Tr. 2757:21-2758:16; TX 1356.
178.
82a
Appendix B
5. Reasonable Expectation of Success
By April 1990, a person with ordinary skill in the art
knew facts that would have foreclosed a reasonable
expectation of success with other clozapine-like
compounds. These include: (1) the first known
atypical antipsychotic drug, clozapine, was known to
interact with a large number of receptors in the brain,
including dopamine receptors, serotonin receptors,
and cholinergic receptors, Paul Tr. 121:20-122:8,
LaVoie Tr. 1541:24-1542:8, Nichols Tr. 2763:6-
2765:10; (2) it was not known through what
combination of these or other receptors clozapine
exerted its atypical antipsychotic action, Nichols Tr.
2763:6-16; (3) it was not known why clozapine caused
agranulocytosis in humans, Paul Tr. 121:14-17,
Nichols Tr. 2769:13-17; (4) many compounds
identified in patents and publications during the 1970s
and 1980s as potential antipsychotic drugs had failed
in clinical trials due to lack of efficacy, lack of
atypicality, and/or an array of adverse side effects,
Nichols Tr. 2751:1-2757:14; TX 1356; (5) small
structural changes in clozapine-like molecules yielded
great and unpredictable changes in properties, Pentel
Tr. 1926:25-1927:9; Nichols Tr. 2796:6-2804:14; and
(6) many researchers made a large number of
compounds over a long period of time in an effort to
find a safe, atypical antipsychotic drug and failed.
Nichols Tr. 2743:14-2744:17, 2751:1-4; TX 1397 at
ZY 19 66.
179.
180.
181.
83a
Appendix B
In 1990, a skilled artisan would have believed that a
halogen atom on clozapine was important for its
antipsychotic activity, that the particularly active
members of the thienobenzodiazepine family had a
halogen, and that the only member of that family of
compounds to be advanced to clinical trials,
flumezapine, had a halogen atom. Nichols Tr.
2748:11-2750:9, 2772:18-2773:2; Reith Tr. 916:2-16;
LaVoie Tr. 1566:5-12; TX 3129; TX 3131; TX 3132;
TX 3465. A person of ordinary skill in the art would
not likely assume that the halogen substituent widely
used on this class of compounds could be eliminated
without adverse effect. Nichols Tr. 2774:8-19.
In 1990, a skilled artisan would not have reasonably
expected, based on the data from the animal tests,
that any of the compounds identified in Chakrabarti
1980a would be effective antipsychotics. The animal
behavioral tests reported in Chakrabarti 1980a were
only indicators of potential antipsychotic activity.
Reith Tr. 929:22-930:17; Nichols Tr. 2768:16-
2769:11.
Moreover, these animal tests were not indicative of a
compound being a safe, atypical antipsychotic, which
was the goal of researchers after the toxicity of
clozapine was recognized in patients. Pullar Tr.
173:21-174:12; TX 1031 at ZYP 506 1725; Reith Tr.
930:5-932:12; Nichols Tr. 2768:16-2769:24; Tupper
Tr. 457:20-458:2. Indeed, the two most preferred
compounds identified as showing good activity in the
Chakrabarti prior art, flumezapine and ethyl
182.
183.
84a
Appendix B
flumezapine, turned out to be toxic. Pullar Tr. 180:2-
181:8, 188:13-189:14. Thus, there would have been
no reasonable basis from Chakrabarti 1980a to expect
that new compounds such as olanzapine would have
been safe, atypical antipsychotics.
In light of these facts, at the time olanzapine was
developed, there could have been no reasonable
expectation of success that an unhalogenated
compound structurally similar to compound °222
would succeed as a safe and effective atypical
antipsychotic.
6. Composition and Method Claims
Claims 2, 3, 7, 8, and 15 are the composition and
method claims of the °382 patent. TX 1000.
a. Claim 1 claims the compound olanzapine. TX
1000, col. 12.
b. Claims 2, 3, and 15 claim “pharmaceutical
compositions” of the compound claimed in claim
1. TX 1000, col. 12.
c. Claim 7 claims a method for treating an animal
suffering from or susceptible to schizophrenia
using the compound claimed in claim 1. TX 1000,
col. 12.
184.
85a
Appendix B
d. Claim 8 claims “[a] method of claim 7 wherein
the effective amount is from 0.1 to 20 mg per
day” of the compound claimed in claim 1. TX
1000, col. 12.
The °574 patent, the Chakrabarti publications, and
the Sullivan and Franklin article do not teach or
suggest either the use of olanzapine in amounts less
than 20 mg/day to treat schizophrenia or the dosage
forms for such treatment. Dr. Reith and Dr. LaVoie
did not offer any trial testimony that the references
teach or suggest what an “effective amount” of
olanzapine would be to treat a human suffering from
or susceptible to schizophrenia. Dr. Reith agreed that
the °574 patent refers to doses in the range of 0.1 to
20 mg/kg/day, equivalent to between 7 and 1400 mg/
day for a 70 kilogram (150 pound) person, and that
the °574 patent provides no guidance as to where in
that range one should treat an actual schizophrenic
patient with olanzapine. Reith Tr. 905:8-906:3.
Similarly, Dr. LaVoie conceded on cross-examination
that the °574 patent referred to 0.1 to 20 mg/kg/day
while the °382 patent referred to 0.1 to 20 mg/day, a
70-fold difference for a 70 kilogram (150 pound)
person. LaVoie Tr. 1574:23-1575:9.
185.
186.
187.
188.
86a
Appendix B
7. Secondary Considerations
a. Long-Felt Need
Beginning at least as early as 1975, there was a long-
felt need for a safe, atypical antipsychotic drug that
remained unsatisfied at the time Lilly filed the
olanzapine patent application in 1990. Nichols Tr.
2751:1-4, 2808:5; Schultz Tr. 2971:8-2972:17; TX
1397 at ZY 19 66 (“The medical need for better
antipsychotic drugs in terms of increased efficacy and
fewer unwanted effects is great”).
Numerous investigators, including scientists at Lilly,
tried but failed to develop a safe, atypical
antipsychotic drug between 1975 and 1990. Nichols
Tr. 2751:1-12; Schulz Tr. 2971:8-2972:17; TX 1356;
TX 1397 at ZY 19 46-48, 54-58, 66.
Risperidone (marketed and sold by Jansen
Pharmaceuticals as Risperdal) is an atypical
antipsychotic. It was first prescribed to schizophrenic
patients in February 1994. Olanzapine (marketed as
Zyprexa) was first prescribed in October 1996. Schulz
Tr. 2987:15-17, 2988: 15-17; Kinon Tr. 2526:24-
2527:2; TX 1590; LD 113.
Risperidone and olanzapine are prescribed by doctors
more than any other atypical antipsychotic on the
market. See TX 1590. Risperidone, however, is
prescribed more often than olanzapine. TX 1590 at
189.
190.
191.
192.
193.
87a
Appendix B
ZYP 528 16; LD 113; Paul Tr. 150:13-151:2; see also
Finding of Fact # 193.
There is no evidence in the record to establish when
the risperidone patent application was filed.
Because risperidone was not prescribed or otherwise
available to schizophrenic patients at the time the ’382
patent was filed, olanzapine met the long-felt but
unsolved need for a safe, atypical antipsychotic.
b. Failure of Others
As reflected in the court’s previous findings, there
was a failure by others to develop a safe, atypical
antipsychotic drug prior to the filing of the olanzapine
patent application in the U.K. See Findings of Fact
§ II.D.
c. Commercial Success
Since late 1996, when olanzapine was approved for
use, it has captured significant market share in terms
of the number of prescriptions written for
antipsychotic medications. TX 1590.
In 2001, olanzapine accounted for more than 25% of
all antipsychotic prescriptions written, and
risperidone accounted for more than 29% of all
antipsychotic prescriptic » vritten. TX 1590.
194.
195.
196.
197.
198.
88a
Appendix B
In 2001, olanzapines’ U.S. sales were $ 2.18 billion,
representing one third of Lilly’s revenues for that year.
TX 1597; Paul Tr. 139:6-8.
Lilly also spent a substantial portion of its revenue
on marketing and administrative costs. Between 1996-
2001, Lilly spent more on marketing and
administrative costs than on research and
development. Paul Tr. 148:5-149:3.
The evidence of the commercial success of olanzapine
does not weigh in favor of either Lilly or the
Defendants.
d. Industry Acclaim
Olanzapine has received substantial industry acclaim
in the form of the Prix Galien Award in 1997, and
Queens Award for Enterprise in 2000, and the
Pharmaceutical Manufacturer’s Association
Discoverer’s Award in 2000. In addition, testimonials
from treating doctors and patients provide objective
evidence of olanzapine’s nonobviousness. Trial Tr.
2730:12-2731:15 (stating the February 10, 2004
Stipulation regarding awards received for the
discovery of olanzapine); Paul Tr. 142:4-143:8;
Schulz Tr. 2973: 10-2974:2.
Although the inventor of risperidone received the Prix
Galien Award in 1996, Trial Tr. 2730:24-25, that fact
does not vitiate the industry acclaim held by
olanzapine.
199.
200.
89a
Appendix B
e. Unexpected Differences Between
Compound 222 and Olanzapine — The
Dog Studies
(1) Basic Principles of Toxicology
Drug development relies heavily on animal testing to
try to find drugs that will be safe for human use.
Testing first directly on human subjects was, and still
is, unethical and unheard of in modern drug
development. Instead, testing in animals always
precedes human clinical studies. The genetic make-
up, organ systems, and biochemistry in other
mammals are sufficiently similar to those in humans
that one can study adverse effects of drugs in
laboratory animals. Dr. Shayne Gad (“Dr. Gad”),
Zenith’s expert in toxicology, testified, “it is a
fundamental hypothesis of toxicology that adverse
effects caused by chemical entities in animals are
generally the same as those induced by those entities
in humans. . .” Gad Tr. 1753:9-13. Thus, the field of
toxicology relates generally to the testing of drugs in
animals in an effort to identify toxic risks for humans.
Emmerson Tr. 512:17-20; Gad Tr. 1754:1-12.
Toxicity testing 1s done in order to identify the
potential toxic effects of drug candidates under
development. Gad Tr. 1754:1-6, 1756:1-12. Such
testing is done at doses chosen to elicit any toxic
effects, that is, at or near the “maximum tolerated
dose” or “MTD.” Maximum tolerated dose means the
highest dose an animal can receive consistent with
201.
bho
to
90a
Appendix B
living and general good health. Emmerson Tr. 539:4-
8. The MTD and fractions thereof are appropriate
doses for pharmaceutical toxicology testing so that
the full range of potential toxicities can be observed.
Emmerson Tr. 539:10-14; Kanter Tr. 2102:9-2103:4.
Indeed, if a compound is not tested at or near the
MTD, an “important adverse finding that is attributed
to treatment with the compound” can be missed.
Emmerson Tr. 539:22-25. This is because humans are
generally more sensitive to the toxic effects of drugs
than a homogeneous population of laboratory animals.
Emmerson Tr. 526:4-13, 539:15-25.
(2) Lilly’s and Defendants’ Dog
Toxicology Studies
(a) Lilly’s D07290 Dog Study
The D07290 Dog Study was a toxicology study
conducted by Lilly at the request of Lilly’s patent
department. Emmerson Tr. 568:3-7.
The D07290 Dog Study compared five groups of
beagle dogs: a control group that received a placebo,
a group that received 4/mg/kg/day of olanzapine, a
group that received 4 mg/kg/day of compound °222,
a group that received 8 mg/kg/day of olanzapine, and
a group that received 8 mg/kg/day of compound °222.
Each group consisted of eight dogs, four males and
four females. TX 1164 at ZY 622 340.
204.
205.
206.
9la
Appendix B
Drug administration to dogs commenced on
September 25, 1990, and ended on April 2, 1991. TX
1164 at ZY 622 340.
At the conclusion of the D07290 Study, Lilly claimed
that the four females in the high-dose compound °222
group showed a statistically significant increase in
group average (mean) cholesterol over time as
compared to female control animals and the high-dose
female dogs given olanzapine. See TX 1001.1 at FH
150-51, 154.
(b) Zenith’s Dog Study — The
MPI Study
Zenith commissioned a dog toxicology study, which
was conducted at MPI Research, Inc. (“MPI”), for
purposes of this litigation (the “MPI Study” or “Zenith
Study”). The Zenith Study, like the Lilly Study, lasted
six months. Drug administration to dogs lasted from
May 3, 2002, to November 4, 2002. TX 1188 at ZG
001604.
The Zenith Study was an expanded comparison of
olanzapine and compound °222 in female beagle dogs
at a dose of 8 mg/kg/day. TX 1188 at ZG 001608.
Included in the Zenith Study were measurements of
progesterone in order to evaluate the estrous state of
the female dogs. TX 1188 at ZG 001613. Zenith’s
Study design thus allowed consideration of the estrous
cycle in individual animals and permitted study of
the possible effect of the drug on that cycle as well as
207.
208.
92a
Appendix B
the relation of that cycle to the levels of cholesterol
that were observed. Nachreiner Tr. 1099:6-25. The
Zenith Study was conducted according to GLP
guidelines. TX 1188 at ZG 001603.
In the Zenith Study, there were fifteen female dogs
assigned to each of three groups. Group 1 was a
nontreated control group. Group 2 was a group in
which each dog was given 8 mg/kg/day of °222. Group
3 was a group in which each dog was given 8 mg/kg/
day of olanzapine. TX 1188 at ZG 001608. The dogs
were assigned to the groups based on body weight
and cholesterol levels, but not based on pretest estrous
state. TX 1188 at ZG 001606. Blood samples for
cholesterol analysis were taken before the test began,
twice within the first week after dosing started, and
then at monthly intervals. TX 1188 at ZG 1611-12.
Before administering the test compounds, Zenith
divided the dogs into three test groups that all had
the same average cholesterol level, excluding in the
process any dog with a cholesterol level above 175
mg/dl. Nachreiner Tr. 1111:2-6; Goldenthal Dep.
131:8-15. The dogs in the Lilly D07290 Study were
not preselected to have cholesterol levels under 175
mg/dl. Nachreiner Tr. 1111:7-9. The difference
between the average cholesterol values of the
untreated dogs in the Zenith Study and the untreated
dogs in Lilly’s D07290 Study was approximately 40
mg/dl. Nachreiner Tr. 1112:8-11.
209.
210.
93a
Appendix B
The numerical magnitude of the increase in
cholesterol caused by compound 222 in both the
D07290 and Zenith Studies was about 40 mg/dl.
Thisted Tr. 3108:5-3109:6. When the effect of
progesterone (estrus) is filtered out, the magnitude
of the estimated difference is about the same, 1.e.,
about 40 mg/dl. Thisted Tr. 3093:25-3095:3; Gibbons
Tr. 2221:10-22, 2269:8-11. The numerical difference
in mean cholesterol levels, 40 mg/dl, and the fact that
the mean cholesterol was shifted upward by one
standard deviation, are both good measures of effect
magnitude. Thisted Tr. 3122:3-9.
The Zenith Study also purported to measure the
fractions of total cholesterol carried as HDL and LDL.
Beginning with the week two bleeding, and at every
subsequent time point, the mean LDL cholesterol
values for the compound °222-treated dogs were
statistically significantly higher than those for the
olanzapine-treated dogs and the control dogs.
Nachreiner Tr. 1118:12-1119:3; Goldenthal Dep.
265:1-11. Over the course of six months, the
compound 222-treated dogs experienced an 18 point
increase in HDL and a 22.6 point increase in LDL.
Scanu Tr. 1277:13-1279:6, 1309:12-14. In these dogs,
the percentage of LDL increased six times more than
the percentage of HDL. Scanu Tr. 1309:5-11.
In short, the results of Zenith’s MPI Study confirmed
the findings of the D07290 Study that cholesterol in
the female high-dose compound °222 group was
significantly greater than in the olanzapine and control
94a
Appendix B
groups, whereas the olanzapine group did not differ
significantly from the control group.
(c) DRL’s Dog Study — The
Calvert Study
Unlike the Lilly and Zenith toxicology studies, the
study commissioned by DRL and conducted by
Calvert Preclinical Services, Inc. (the “Calvert
Study”) lasted only sixty days — from April 2, 2002,
to July 2, 2002. Gayheart-Walsten Dep. 83:16-18; TX
1180 at DRL-IN 055560, 055563. The only clinical
chemistry variable studied was cholesterol. TX 1180
at DRL-IN 055560. There were ten female beagle
dogs in each of four groups: (1) a control group, (2) a
group given 8 mg/kg/day of compound 222, (3) a
group given 8 mg/kg/day of olanzapine, and (4) a
group of untreated dogs that were offered double
rations of food. The researchers gave the dogs in
Group 4 double the normal ration of food to see if
doing so would have an effect on cholesterol
concentrations. TX 1180 at DRL-IN 055560, 055566-
67.
While the Calvert Study is fundamentally too short
to compare to the longer Lilly and Zenith Studies,
Rebar Tr. 2318:22-2319:2, the observed effects on
cholesterol are consistent with those in the longer
studies. Thisted Tr. 3124:20-3126:9. For example,
there was a rapid increase in cholesterol
concentrations in the compound 222-treated group.
Thisted Tr. 3125:24-25. The mean cholesterol values
214.
215.
216.
217.
95a
Appendix B
in the compound °222-treated dogs were greater than
in the olanzapine-treated dogs at all time points.
Kanter Tr. 2162:22-2163:5; Gayheart-Walsten Dep.
102:5-17. In addition, the cholesterol levels of the
control dogs rose over the course of the Calvert Study.
Thisted Tr. 3126:1-3.
The cholesterol concentrations did not increase in the
group of dogs offered double rations of food.
Gayheart-Walsten Dep. 103:13-20, 104:8-105:12;
Kanter Tr. 2160:16-18.
(3) Criticisms of Lilly’s Dog Study
Evidence
Defendants attack the D07290 Study on numerous
grounds and assert that the data and the conclusions
drawn therefrom by Lilly scientists are seriously
confounded.
(a) The Dog as a Model
The dog is an appropriate species in which to test for
potential toxic effects in humans, including effects
on total cholesterol. Emmerson Tr. 525:4-18; see, e.g.,
TX 1272; TX 1278; TX 3072 at DRL IN 055565; TX
3087.
By 1990, the beagle dog had emerged as the large
mammal of choice for toxicology testing of new drug
candidates. Emmerson Tr. 572:3-19; Means Tr.
1998:9-18. The dog, while not perfectly predictive,
218.
4
96a
Appendix B
is reasonably predictive of toxic effects in humans.
Gad Tr. 1754:1-6; Kanter Tr. 2105:8-20, 2120:16-22;
Means Tr. 1998:24-1999:7. A wealth of expert
testimony and literature supports the finding that the
dog is an acceptable toxicity model for humans. The
writings of Zenith’s expert toxicologist, Dr. Gad,
teach “that the dog is currently the first choice
nonrodent model for toxicity studies ...” Gad Tr.
1758:1-4.
The dog model was widely used by Lilly in a variety
of studies early in the development work leading to
the discovery of olanzapine. These studies, conducted
and reviewed over a period of years, provided the
basis for making decisions to terminate or advance
testing of drug candidates such as olanzapine. See
Emmerson Tr. 542:6-21, 543:10-13, 545:17-546:5,
546:22-547:1.
(b) Total Cholesterol as a Tested
Parameter
Over the years, a standard battery of observations and
measurements seeking to detect the toxic effects of
drugs in dogs has been developed. As technology and
measurement methods improved, this standard battery
grew. By 1990, the standard battery included
measurement of total cholesterol. Gad Tr. 1758:5-13;
TX 3107 at 121; Emmerson Tr. 536:16-23. The design
of the D07290 Dog Study, therefore, included a
measurement of total cholesterol as part of the then
220.
221.
97a
Appendix B
standard battery of dog toxicology tests. Emmerson
Tr. 535:16-536:25.
In this regard, the laboratory retained by DRL to
conduct DRL’s Calvert Study for this litigation
reported that “the beagle dog is an acceptable species
to study the effects of compounds and diet on total
cholesterol, triglycerides, HDL, LDL, and VLDL.”
TX 3072 at 11. Similar conclusions have been drawn
in the literature. A 1997 article in the journal
Atherosclerosis states in reference to the beagle dog,
“this animal model has been successfully used to
demonstrate the effect of statins [cholesterol lowering
drugs] on cholesterol. . .” and that “this animal model
has good predictive power for hypocholesterolemic
effects in man.” TX 3087 at 203; Scanu Tr. 1286:20-
1288:10; Davidson Tr. 2919:2-14.
Both dogs and humans can experience elevations in
total cholesterol concentrations as the result of similar
metabolic effects and abnormalities. Scanu Tr.
1260: 1 1-1263:24; Gad Ir. 1810:16-22. Examples of
hypercholesterolemias (elevation of serum cholesterol
concentrations) in both dogs and humans with
common etiologies include the ingestion of high-fat
diets, cholestasis, hypothyroidism, diabetes mellitus,
pancreatitis, hyperadrenocorticism, and nephrotic
syndrome. Bauer Tr. 2665:23-2668:15; TX 1347.
There is a known and reported nexus between dog
studies and humans with regard to total cholesterol.
Dr. Michael Davidson (“Dr. Davidson”), Lilly’s expert
223.
98a
Appendix B
in cardiology, cholesterol, and cardiovascular disease,
Davidson Tr. 2891:13-14, 2897:25-2898:5, testified
that he has been involved in human clinical trials for
statin drugs, including Mevacor, Zocor, Pravacol,
Lipitor, and Crestor. Davidson Tr. 2893:17-2894:5.
Dr. Davidson testified that the experimental statins
were tested in dogs before they were tested in people.
Davidson Tr. 2919:2-21. Indeed, the dogs proved to
be a reasonable predictor of cholesterol effects in
humans in that statins decrease cholesterol in both
dogs and humans. Davidson Tr. 2918:12-15, 2919:2-
21. Moreover, there are a number of articles regarding
statin research that show that the dog is used by large,
established pharmaceutical companies as an
appropriate model to indicate whether drugs may
lower cholesterol! in people. See, e.g., Scanu Tr.
1286:20-1293:10; TX 1272, 1273, 1275, 1278, 3087.
Dr. Davidson further testified that rapamycin, a.k.a.
Rapamune, a drug that prevents transplant rejection
in organ transplant patients, raised cholesterol in both
dogs and humans. Davidson 2926:1-5, 2927:12-14
(humans), 2928:16 (dogs); see also Scanu 1253:18-
25 (humans); TX 1353 (humans).
Dr. John Bauer (“Dr. Bauer”), Lilly’s expert in lipids
and lipoproteins in dogs as well as comparative
studies in humans and dogs, Bauer Tr. 2655:10-12,
testified that “observations of total blood cholesterol
or total serum cholesterol [in dogs] using the terms
equally are a useful predictive index for the response
of total blood cholesterol in humans.” Bauer Tr.
2655:15-2659:4. This opinion is implicit in many of
224.
225.
99a
Appendix B
his writings and is explicitly stated in an article he
wrote in 1996. Bauer Tr. 2655:25-2657:16; TX 1347.
Dr. Bauer summarized three reasons for his opinion
that dogs are good models to predict cholesterol
effects in humans: (1) the many similarities in
cholesterol metabolism in humans and dogs; (2) the
similar effects in cholesterol in humans and dogs
caused by diseases; and (3) the considerable literature
on the effects of experimental compounds on
cholesterol in dogs and humans, showing that
cholesterol reductions or elevations seen in dogs were
also seen in humans. Bauer Tr. 2658:2-2659:4.
There are recognized differences in the way
cholesterol is metabolized in dogs and humans.
Humans carry most of their cholesterol in LDL, the
so-called “bad cholesterol,” while dogs carry most
of their cholesterol in HDL, the so-called “good
cholesterol.” Scanu Tr. 1210:6-17; Bauer Tr. 2708:18-
22. Consequently, when total cholesterol is elevated
in dogs, the resulting increase in HDL cholesterol does
not usually form atherosclerotic plaque in dogs. In
contrast, when total cholesterol is elevated in humans,
it is carried primarily as LDL, thereby increasing
atherogenic risk in humans. Bauer Tr. 2667:5-12,
2721:5-12.
Because dogs are resistant to elevated cholesterol
while humans are not, Dr. Bauer opined that if an
experimental compound elevated cholesterol levels
in dogs, then he would expect either an equal or
greater increase in humans. Bauer Tr. 2675:13-
226.
Pt
100a
Appendix B
2676:17, 2678:4-7, 2678:18-2679:12. His opinion,
although not supported by a published study or
subjected to peer review, was based on his
extensive experience studying comparative
hypercholesterolemia in both species. Bauer Tr.
2703:15-2704:25. Thus, Dr. Bauer’s expression of this
untested theory does not diminish his credibility as a
witness in his area of expertise — lipids and
lipoproteins in dogs and comparative studies in
humans and dogs.
One of the articles which Dr. Bauer cited in his expert
report is an article entitled “SR-12813 lowers plasma
cholesterol in beagle dogs by decreasing cholesterol
biosynthesis.” TX 3087. That article reports that the
mechanism by which a statin drug works and the
metabolic pathway through which it proceeds is
known in both dogs and humans. TX 3087; Bauer
2694: 12-2695:23. The mechanism by which a dog’s
cholesterol is raised is unknown. Bauer Tr. 2698:1-5.
Despite this fact, this article remains consistent with
the fact that there are similarities between the
cholesterol metabolism in dogs and humans which
render the dog a good predictive model for humans.
Dr. Bauer’s opinion is supported by a chapter he co-
wrote in The Clinical Chemistry of Laboratory
Animals, TX 3779, which concluded that dogs remain
a good model for predicting total cholesterol effects
in humans. Bauer Tr. 2652:3-2654:3, 2656: 25-
2657:16.
229.
10la
Appendix B
Dr. Angelo Scanu (“Dr. Scanu”), Zenith’s expert in
lipoproteins, testified that in his experience in
lipoprotein metabolism, his review of the D07290
Study, and his review of published literature in the
area of lipoprotein metabolism, the dog is not a good
animal model for predicting cholesterol results in
human patients. The principle reason cited for his
opinion is the fact that cholesterol is metabolized in
a strikingly different manner in dogs as opposed to
humans. Scanu Tr. 1200:14-1201:2.
Contrary to Dr. Scanu’s opinion, the evidence
demonstrates that this metabolic difference does not
prevent the dog from being a good model for
predicting total cholesterol results in humans. Bauer
Tr. 2655:15-2659:4. Although differences exist
between humans and dogs as to the manner in which
total cholesterol elevations are metabolically
transferred and disposed of, these differences are
“downstream” from the causes of cholesterol
elevations and, therefore, secondary to them. Bauer
Tr. 2659:5-2665:18. For example, when dogs are fed
high-fat diets, the hypercholesterolemic response in
dogs is to partition excess cholesterol into HDL
fractions, whereas humans partition the excess
cholesterol into LDL fractions. Scanu Tr. 1273:11-
1274:16. In either event, however, both dogs and
humans experience an elevation in total cholesterol.
Bauer Tr. 2676:18-2679:14; see also Finding of Fact
#221.
230.
tN
ty
102a
Appendix B
(c) Randomization
In a well-designed experiment, animals are randomly
assigned to treatment groups to remove systematic
effects (aside from the treatment being studied),
known and unknown, that could affect the outcomes
being measured. A purpose of randomization is to
ensure that subjective judgments play no role in which
animals are assigned to which treatment groups. This
eliminates a source of bias that otherwise could
systematically favor one treatment group over others
for reasons unrelated to the treatment itself. Thisted
Tr. 3082:15-3083:1.
Lilly’s design of a dog study using forty dogs
randomly assigned by body weight is common in
standard toxicology studies, and consistent with
Lilly’s standard operating procedure. Emmerson Tr.
§71:22-572:2; Gad Tr. 1765:15-21; Gayheart-Walsten
Dep. 127:7-128:9. There are a variety of physiological
variations that might exist among dogs. The general
purpose of random assignment based on body weight
of dogs amongst the treatment groups is to balance
out whatever variations may exist. Gad Tr. 1765:18-
21, 1766:6-9.
At the start of the D07290 Study, there was one dog
in the compound °222 group that weighed more than
the others. The dog was not obese, and her weight
was within the protocol guidelines. There is no
evidence that the size of a dog affects its cholesterol
233.
234.
103a
Appendix B
levels. Rebar Tr. 2333:3-21; TX 1164 at ZY 622 607
(body weight 5-12 kg), 688-97.
There was no reason that the dogs in the D07290
Study should have been randomized based on their
estrous stage because (1) it was not common practice
to examine female dogs for their estrous stage prior
to standard toxicology tests, see, e.g., Goldenthal Dep.
164:7-9 (stating that MPI has never randomized by
estrous state prior to a study); (2) it was a common
practice to randomize dogs based on body weight
prior to standard toxicology tests; and (3) Lilly did
not know at the outset that it would find a result that
may be affected by the estrous stage. Gad Tr. 1764:8-
15, 5:15-1766:9; Emmerson Tr. 571:22-572:2, 580:4-
581:22. Even Zenith did not randomize by estrous
state in conducting its dog study, even though it knew
that cholesterol results would be very important.
Goldenthal Dep. 162:15-166:13, 168:6-8.
(d) The Length of the Study
The length of the D07290 Study was “long enough to
recognize a biological [sic] significant effect,” Rebar
Tr. 2316:21-2317:1, i.e, to study the chronic effects
of drug candidates and determine their suitability for
repeated-dose studies in humans. Gad Tr. 1757:15-
25; Rebar Tr. 2333:22-2334:20. Such preclinical six-
month studies had been done at Lilly for both ethy]
flumezapine and flumezapine. Emmerson Tr. 543:10-
13, 544:23-545:4.
235.
236.
437.
104a
Appendix B
(e) The Number of Dogs and
Analysis by Sex
The forty dogs that Lilly used in conducting the
D07290 Study were an appropriate number of dogs
to use. Rebar Tr. 2316:13-16, 2331:3-12, 2331:24-
2332:14.
It is standard practice in the scientific community to
test toxicity in both male and female dogs and to
analyze the results separately by sex. Gad Tr. 1767:3-
8; see also Pentel Tr. 1914:6-10, 1916:17-1918:11
(agreeing this is common and appropriate); Emmerson
Tr. 535:6-11. Indeed, it is required by the FDA.
Davidson Tr. 2938:20-2939:14.
Lilly used four dogs per sex per group in dog studies
submitted to and accepted by the FDA. Emmerson
Tr. 535:2-5, 547:15-18, 569:8-10; TX 1005 at ZYP
177 734; TX 1086 at ZYP 661 721; TX 1087 at ZYP
661 1010. Lilly submitted to the FDA a three-month
olanzapine study done in 1983, two one-year
olanzapine studies (done in 1984 and 1993), and the
D07290 Study, that all used four dogs per sex group.
Emmerson Tr. 547:15-18, 553:10-11. Lilly also used
the same number of dogs in its preclinical testing of
flumezapine, which the FDA approved for initial
safety and efficacy testing in humans. TX 1005; TX
3421. Four dogs per sex treatment group is a common
number of animals to use. Gayheart-Walsten Dep.
35:3-6; Spainhour Dep. 85:8-13; Selim Dep. 19:20-
20:22. This sample size was appropriate to perform
238.
105a
Appendix B
statistical analysis and achieve statistically significant
results. Thisted Tr. 3061:16-3062:7; Symanowski Tr.
708:2-10.
(f) The Dosage Used
At the time of the design for the D07290 Study, there
existed considerable experience at Lilly’s laboratories
with the effects of chronic administration of
olanzapine and related compounds in dogs. See
Engelhardt Dep. 34:3-11 (stating that the dosage for
the D07290 Study was selected based on a previous
comparison of flumezapine and ethy] flumezapine).
As explained above, toxicology testing is traditionally
done at or near the MTD, i.e., at higher than
therapeutic doses, because the science of toxicology
accepts effects in dogs at doses greater than the human
therapeutic dose to be reliable indicators of human
toxic risk. Gad Tr. 1768:18-1769:5. Comparable
toxicology studies done with ethyl! flumezapine,
flumezapine, and olanzapine prior to actual human
testing of those compounds were done at 4, 8, and 12
mg/kg for ethyl flumezapine; at 1, 2, 4, 8, and 12 mg/
kg for flumezapine; and at 2, 5, and 10 mg/kg for
olanzapine. See TX 1002; TX 1003; TX 1004; TX
1005; TX 1040; TX 1041; see also LD 22. Thus, the
evidence establishes that the 4 and 8 mg/kg doses of
compound 222 and olanzapine selected for use in the
D07290 Dog Study were well within the objectively
reasonable range of preclinical toxicology doses for
compounds of this type. Emmerson Tr. 569:4-7; Gad
Tr. 1779:24-1780:4; Kanter Tr. 2165:16-2166:18.
239.
241.
106a
Appendix B
A one-week pilot study of 8 mg/kg of compound °222
confirmed that the dogs could tolerate 8 mg/kg of
compound °222 and that therefore, it was appropriate
to proceed with 8 mg/kg of compound °222 as the
high dose in the D07290 Dog Study. TX 1164 at ZY
622 344; Emmerson Tr. 569:11-570:1.
(g) The Use of Equal Doses of
Olanzapine and Compound
222
It was appropriate for Lilly to use equal doses of
olanzapine and compound °222 in the Lilly D07290
Dog Study. First, the available in vitro and in vivo
pharmacological data for compound °222 and
olanzapine suggested that they would be relatively
equally active. See TX 1001.1 at FH 125-34, FH 143-
45; Tye Dep. 169:17-170:2, 170:24-171:11, 171:13-
20 (and errata). Second, one of the objectives of the
D07290 Dog Study was to test the hypothesis that
these compounds were so similar in structure that they
would have essentially the same properties. Nichols
Tr. 2860:13-17. The reasonable way to achieve this
objective was to test the compounds at equal doses.
Killworth Tr. 3022:5-3023:12.
Defendants assert the dose for compound °222 was
inappropriate as too great a multiple of the human
therapeutic dose, and that therefore, the cholesterol
results observed in the D07290 Study have no
practical relevance. Gad Tr. 1712:2-1713:4; Pentel Tr.
1893:12-17. However, there is no evidence of a
242.
107a
Appendix B
therapeutic dose or safety margin for compound 222
because compound 222 has never been tested in
humans. Pentel Tr. 1910:6-10. Moreover, Defendants’
experts admitted that dosing the dogs at 4 and 8 mg/
kg of compound 222 was reasonable given the fact
that olanzapine had been tested at 2, 5, and 10 mg/
kg. Gad Tr. 1779:24-1780:4; Kanter Tr. 2165:16-
2166:18; LaVoie Tr. 1574:19-1575:16.
(h) How the Study Was
Conducted
i) Good Laboratory
Practices Were Followed
The D07290 Dog Study was carefully conducted in
accordance with its protocol and with the FDA’s GLP
guidelines. 21 C.F.R. § 58; Emmerson Tr. 570:2-4.
Lilly maintained complete records. Data reports and
logs show careful observation of the dogs and
comprehensive consideration of the health of the
animals. The D07290 Dog Study was actually
reported to the FDA in connection with Lilly’s request
for approval to market olanzapine. Emmerson Tr.
570:15-24; TX 1164.
ii) Double Rations
After observing significant weight loss during
D07290 in Dogs 240584 and 242547, two of the
female high-dose compound °222 dogs, Lilly
researchers gave them double rations of food. Dog
245.
246.
108a
Appendix B
240584 ate her double ration of food 75% of the time.
Nachreiner Tr. 1057:2-6, 1057:24-1058:11; TX 3437
at ZY 622 685. Dog 242547 ate her double rations
every day of the study but one. Nachreiner Tr. 1057:9-
14, 1058:12-22; TX 3437 at ZY 622 687.
It is standard toxicology practice to offer increased
food rations to dogs to help them maintain their body
weight and complete the study. Emmerson Tr. 579:23-
580:22; TX 1179 at ZYP 570 152; see also Goldenthal
Dep. 111:17-112:17 (testifying that MPI generally
gives the dogs in studies as much food as they want
and then measures the amount they eat); TX 3195.
After the double feeding began for these dogs, their
cholesterol increased and never came back down to
the point it was at before they were double-fed.
Emmerson Tr. 613:23-614:4; Symanowski Tr. 734:16-
20; Nachreiner Tr. 1060:5-1061:2, 1063:10-21,
1065:4-9.
Both dogs regained weight but were continued on
double rations throughout the remainder of the
D07290 Study. Nachreiner Tr. 1059:16-24.
Dr. Bauer testified that feeding dogs increased
amounts of Purina 5007 dry dog food, the food offered
to the dogs in the D07290 Study in order to maintain
their normal body weight, “would have no effect on
their blood or total serum cholesterol” because
that particular type of dry extruded dog food
is one that contains only modest amounts of
248.
249.
109a
Appendix B
its total calories from fat. And feeding —
simply feeding larger or increased amounts,
even double amounts, of that type of dog food
that’s very low in its total calories from fat to
a dog in order to maintain its normal body
weight will not cause an elevation in total
blood cholesterol . . . if one wanted to do that
by diet, it would take feeding a diet which
had a much greater percentage of its total
calories from fat in order to elevate the
cholesterol in the dog. It’s not a question of
feeding more of a low or moderate fat diet;
it’s a question of feeding a diet which contains
higher amounts of the total calories from fat.
Bauer Tr. 2682:19-2683:16.
The two dogs offered double rations had the lowest
cholesterol levels in their group. Symanowski Tr.
706:18-707:8.
A similar finding was noted in DRL’s Calvert Study.
Thisted Tr. 3161:1-9 (testifying that the cholesterol
levels in the group of dogs offered double rations of
food did not increase); see also Findings of Fact
§ IV.B.7.e(2)(c).
Dr. Ronald Thisted (“Dr. Thisted”), Lilly’s expert
statistician, performed a robustness check removing
the two dogs offered double rations, and found that
the results remained statistically significant, Thisted
Tr. 3085:4-24, as did Dr. Robert Gibbons (“Dr.
ari.
232.
110a
Appendix B
Gibbons”), Zenith’s expert statistician, using a
different method. Gibbons Tr. 2218:24-2220:7; TX
3236 at ZG 13034, 13037; Thisted Tr. 3085:25-
3086:8.
Although offering double rations to two of the dogs
in the D07290 Study caused a difference in the
treatment of some of the tested animals which is not
ideal, see Thisted Tr. 3083:2-3, the evidence
establishes that the offer of double rations alone did
not confound the results of the D07290 Study.
(i) The Results of Lilly’s and
Zenith’s Studies
i) Statistics Experts for All
of the Parties Found a
Statistically Significant
Cholesterol! Increase in
the Compound ’222-
Treated Dogs
The statisticians for each of the parties analyzed the
data from the D07290 Study and found the cholesterol
effect associated with compound °222 was statistically
significant over the course of a chronic treatment
period. Dr. Symanowski’s original repeated measures
analysis showed that for cholesterol in the female dogs
at the 8 mg/kg/day dose level (a) there was a
difference over time between olanzapine and
compound °222 that was highly statistically
significant, with a p-value of 0.001, (b) there was also
253.
Illa
Appendix B
a difference over time between compound 222 and
the untreated (control) group that was statistically
significant (p 0.001), and (c) there was no statistically
significant difference between the olanzapine and
control groups. TX 1001.1 at FH 149-54; Thisted Tr.
3079:4-15; Symanowski Tr. 644:12-645:10, 653:17-
654:9. The results of Dr. Symanowski’s statistical
analysis of the D07290 Study have been
independently confirmed by both Lilly’s statistics
expert, Dr. Thisted, and by the Defendants’ experts
using a variety of methods. Thisted Tr. 3079:16-
3082:11, 3085:5-3089:12; LD 391. Dr. McDougall,
DRL’s expert, replicated Dr. Symanowski’s repeated
measures analysis and obtained the same results.
Thisted Tr. 3080:15-16. Zenith’s expert, Dr. Gibbons,
used the mixed effect regression method and also
found that the high-dose compound °222-treated
female group showed a statistically significant
increase in mean cholesterol over time compared to
both the olanzapine and control groups, but no
statistically significant difference between olanzapine
and control. Thisted Tr. 3080:17-22; Gibbons Tr.
2214:14-18, 2215:10-2218:22, 2236:4-14; TX 3236
at ZG 12909; LD 391.
Dr. Thisted and Dr. Gibbons each analyzed the
D07290 data with different modern techniques that
allowed them to include both protocol and
nonprotocol measurements for all of the dogs. They
still found a statistically significant effect of
compound °222 in the female high-dose group.
Thisted Tr. 3080:23-3082:1; Gibbons Tr. 2216:19-
254.
}12a
Appendix B
2217:1, 2218:18-22. They also found statistical
significance when they excluded data for the two dogs
from the compound °222 group that received extra
rations. Thisted Tr. 3085:4-24; Gibbons Tr. 2218:24-
2219:24.
The results of Zenith’s MPI Study confirmed the
findings of Lilly’s D07290 Study which showed that
cholesterol in the female high-dose compound °222
group was significantly greater than in the olanzapine
and control groups, whereas the olanzapine group did
not differ significantly from the control group. The
statistical significance of the results of the MPI Study
were found using several different statistical tests.
Thisted Tr. 3089:13-3097:19; LD 17; LD 131; LD
381(b); LD 390. Dr. Gibbons confirmed these results
as did Dr. Thisted using the GEE analysis. Thisted
Tr. 3089:21-3090:12; Gibbons Tr. 2204:3-13. Dr.
Thisted also looked at the last four months of the MPI
Study, when cholesterol levels stabilized, and found
a highly statistically significant difference between
compound °222 and both olanzapine and control
during that period. Thisted Tr. 3090:13-3092:3; LD
17. MPI’s own data tables of the study results show a
difference between compound °222 and olanzapine
throughout the study (using a statistical test called a
t-test), and that compound °222 was statistically
significantly greater than control at months two, four,
and five (using Dunnett’s test). TX 3076; Thisted Tr.
3092:11-3093:4. When the effect of estrus on
cholesterol levels in the control group is taken into
account, the difference between compound °222 and
£20.
li3a
Appendix B
control was statistically significant at the three-and
six-month time points as well. Thisted Tr. 3095:4-
3097:19; LD 381(b). Over the last three months of
the MPI Study, the difference between the mean
cholesterol values in the compound ’222 group and
the olanzapine group was about 40 mg/dl, a result
also seen in the Lilly D07290 Study. Thisted Tr.
3108:5-3109:6; Gibbons Tr. 2269:8-11.
Furthermore, the availability of progesterone
measurements in the MPI Study makes it possible to
separately evaluate the effects of drug treatment and
progesterone on cholesterol. Based on the method of
evaluating the progesterone effect set forth by Dr.
Raymond Nachreiner (“Dr. Nachreiner”), Zenith’s
expert in veterinarian endocrinology and reproductive
physiology, and based on his own study of the graphs
of the individual dogs, Dr. Thisted performed an
analysis of the MPI Study data and found that when
progesterone effects on cholesterol are filtered out,
there is still a highly significant increase in cholesterol
in dogs given compound °222. Thisted Tr. 3093:5-
3094:12, 3161:16-22. In particular, Dr. Thisted found
that the estimated magnitude of the cholesterol
elevation, about 40 mg/dl, is about the same whether
or not the effect of progesterone is taken into account.
Thisted Tr. 3093:5-3094:12. The statistical model that
he used, correcting cholesterol for the effects of
elevated progesterone one month earlier, was a model
proposed by Dr. Nachreiner. Thisted Tr. 3161:16-22.
256.
114a
Appendix B
Dr. Gibbons performed a similar analysis using a
different method and also found that after the effect
of the estrous cycle on cholesterol was filtered out
mathematically, a statistically significant effect of
compound 222 remains, with the magnitude of 41 mg/
dl. Gibbons Tr. 2220:11-2221:22, 2269:8-11; Thisted
Tr. 3094:13-3095:3, 3161:23-3162:4. In addition, he
found no statistically significant difference between
the olanzapine and control groups. Gibbons Tr.
2221:23-2222:7.
Although the shorter DRL Study did not achieve a
statistically significant difference between the
compound ’222-treated dogs and the other groups at
the p 0.05 level, the results are not inconsistent with
the results of the six-month D07290 and Zenith
Studies. Thisted Tr. 3124:20-3126:9: LD 117. All
three studies exhibit the same pattern in the first two
months, as is shown in LD 117, with a rapid rise in
cholesterol in the compound °222-treated dogs and a
lesser increase in the olanzapine dogs when compared
to the control group. Kanter Tr. 2138:5-16, 2161:20-
2163:5. There is no way to tell whether the cholesterol
levels in the compound 222-treated dogs in the DRL
Study would have stabilized after two months at a
significantly higher level than those in the olanzapine
and control groups, as was seen in Lilly’s D07290
Study and Zenith’s Study. Thisted Tr. 3124:20-3126:9.
258.
259.
115a
Appendix B
ii) The Repeated Measures
Analysis Was Appropriate
The technique
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