Petition for Writ of Certiorari — Bristol-Myers Squibb Co. v. Zenith Laboratories, Inc.
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‘Supreme Court, y
FILED -S.
No. 94 494 SEP 1 4 1994
OFFICE OF THE CLERK
IN THE
Supreme Court of the United States
OCTOBER TERM, 1994
BRISTOL-MYERS SQUIBB COMPANY,
‘ Petitioner,
ZENITH LABORATORIES, INC.,
Respondent.
Petition for a Writ of Certiorari to the
United States Court of Appeals
for the Federal Circuit
PETITION FOR A WRIT OF CERTIORARI
H. BARTOW FARR, III
(Counsel of Record)
RICHARD G. TARANTO
FARR & TARANTO
2445 M Street, NW
Washington, DC 20037
(202) 775-0184
S. LESLIE MISROCK
BRIAN D. CocGcio
STEVEN I. WALLACH
KENT H. CHENG
PENNIE & EDMONDS
1155 Avenue of the Americas
New York, NY 10036
hearse MRR
WILSON - EPes PRINTING Co., INC. - 789-0096 - WASHINGTON, D.C. 20001
QUESTIONS PRESENTED
1. Whether proof of literal infringement of a patent for
a new composition of matter (e.g., a chemical compound )
requires examination of each item of information in the
patent claim, even when that information consists of
scientifically redundant, overinclusive “fingerprint” data
included for evidentiary identification of the patented
composition, rather than restrictive conditions that pre-
cisely define and limit the patented aspects of the com-
position.
2. Whether a valid patent lacks protection against
infringement under the doctrine of equivalents except to
the extent the invention performs a function not previ-
ously performed by any prior art.
(i)
ii
RULE 29.1 STATEMENT
Petitioner Bristol-Myers Squibb Company has no parent
company. Its non-wholly owned subsidiaries are the fol-
lowing: Laboratoires UPSA; Nyagen; RCS Realty Cor-
poration; Sino American Shanghai Squibb Pharma Ltd.;
Squibb Nigeria Limited; UPSA Investissements; 2309
Realty Corporation; Bristol-Myers Lion Ltd.; Bristol-
Myers Squibb G.M.B.H.; P.T. Squibb Indonesia; Squibb
of Bangladesh Limited; Synbiotics Limited; Mead John-
son.
TABLE OF CONTENTS
Page
QUESTIONS PRESENTED ..........--:.<00se-<s2c0ss--<s0s:-0--sse000- i
DE I I ois ne cceetcnicinnersenpnbesnsnacanncnsseeers ii
po i eg a |: iv
i 0 cncahonovminanansentanqueoesmmevenen 1
ic enadciantininnkeomnbonnninoenannee 1
STATUTORY PROVISIONS INVOLVED .................... 2
ae NE RE an oe 3
a ceniensemuiancinees Seeds 3
B. District Court Proceedings .....................-------0e0-s--- 7
C. The Court of Appeals Decision ............................-- 9
REASONS FOR GRANTING THE PETITION ............ 12
I. THE FEDERAL CIRCUIT ERRONEOUSLY
LIMITED THE SCOPE OF PROTECTION
AGAINST LITERAL INFRINGEMENT FOR
VALID PATENTS FOR NEW COMPOSI-
TIONS OF MATTER SUCH AS CHEMICAL
RINE Sati bendabacncicckcnsdnsyadsctesscecreunsntthlenerets epee 13
Il. THE FEDERAL CIRCUIT ERRONEOUSLY
LIMITED PROTECTION AGAINST _IN-
FRINGEMENT UNDER THE DOCTRINE OF
EQUIVALENTS TO PATENTS FOR INVEN-
TIONS THAT PERFORM NEW FUNCTIONS.. 20
I ohiticiicnnsccterintirieienenccencstilinsiaenovennsitenayentareseeerene 26
(iii)
iv
TABLE OF AUTHORITIES
Cases Page
Bristol-Myers Co. v. U.S. Int'l Trade Comm’n, 15
USPQ24 1266. (Fed. Cir. 1969} .............................. 4, 6,14
Carman Indus., Inc. v. Wahl, 724 F.2d 932 (Fed.
SE) BRE SES Deena mre cicpens oat AE SSS Ne NOOEL 21, 22
Connell v. Sears, Roebuck & Co., 722 F.2d 1542
i Sp a RRR ene oar tyra: CIR Ae re 21
Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
851 F.2d 1387 (Fed. Cir.), cert. denied, 488 U.S.
| SURE rename MTN ern aS Co ST ee 23, 24
Fromberg, Inc. v. Thornhill, 315 F.2d 407 (5th
Ee + | Cay SOS Ger CO EL WS. Fc re RE 15
Georgia-Pacific Corp. v. United States Plywood
Corp., 258 F.2d 124 (2d Cir.), cert. denied, 358
iis, a a i 19
Graver Tank & Mfg. Co. v. Linde Air Prods. Co.,
Son UF. Gb. Cees adi i ee 7, 20, 21, 25
Gray v. James, 10 F. Cas. 1015 (C.C.D. Pa. 1817).. 21
Hewlett-Packard Co. v. Bausch & Lomb, Inc., 909
Fie Sk Cr a Be teen 23
In re Casey, 370 F.2d 576 (Ct. Cust. Pat. App.
ys ARERR ERE RET DE Nee eR tres A SET ed ON CM ee OO Ae AT OR 23
In re Certain Crystalline Cefadroxil Monohydrate,
15 USPOSd 1960) (ies Bee voces... 6, 15
In re Cofer, 354 F.2d 664 (Ct. Cust. Pat. App.
}) | Een eC LS iS Le ie, Slorseee nee nemenee 23
In re Grose, 592 F.2d 1161 (Ct. Cust. Pat. App.
DOT caciasec seis ee ce annette 16, 17,18
In re Papesch, 315 F.2d 381 (Ct. Cust. Pat. App.
QI icici ac ace ttrrrentersnctee ton 16
In re Spada, 911 F.2d 705 (Fed. Cir. 1990) -........... 9, 24
Intervet America, Inc. v. Kee-Vet Labs., Inc., 887
P20 oOo (red. Cat Be oe... 15, 21
Leeds & Northrup Co. v. Doble Eng’g Co., 159 F.2d
66d Cink Ce Fer aes. 21
Lerner v. Child Guidance Prods., Inc., 547 F.2d 29
Ca Ca FI ka octets cersesecenyas 21
Morley Sewing-Machine Co. v. Lancaster, 129 U.S.
DUE CED vaccine cicn 23
v
TABLE OF AUTHORITIES—Continued
Page
National Hollow Brake-Beam Co. v. Interchange-
able Brake-Beam Co., 106 F. 693 (8th Cir.
bs Qentererad Mm Seer reek dant oR TO RES eo ee Te 25
Odiorne v. Winkley, 18 F. Cas. 581 (C.C.D. Mass.
cg Senn ania hit sees tem denies et ea 21
Potts v. Creager, 155 U.S. 597 ( RN hi 24
Radio Corp. of America v. Radio E'ng’g Lab., Inc.,
ee Sree CE ee ek 24
Read Corp. v. Portec, Ltd., 970 F.2d 816 (Fed. Cir.
OD Carico deere et 22
Roberts v. Ryer, 91 U.S. 150 (1875) ............... 24
Sanitary Refrigerator Co. v. Winters, 280 U.S. 30
5 USAGI AIRS Pade tne ne ME, SI nanan 21
Schriber-Schroth Co. v. Cleveland Trust Co., 305
ee Oe I 14
Smith v. Snow, 294 U.S. 1 (1935) ............... 16
Spectra Corp. v. Lutz, 839 F.2d 1579 (Fed. Cir.
bg RE SEP TEMG Tac diet NUR NE) Ee a 20, 21
SKI Intl v. Matsushita Elec. Corp., 715 F.2d 1107
o£ Ee, LEE meee 16, 25
Topliff v. Topliff, 145 U.S. 156 (1892) 19
Union Paper-Bag Machine Co. v. Murphy, 97 U.S.
pS ee te ae mage Fd ice ee 15, 21
Westinghouse v. Boyden Power Brake Co., 170
ai ak Sw} 23, 25
Wilson Sporting Goods Co. v. David Geoffrey &
Assoc., 904 F.2d 677 (Fed. Cir.), cert. denied,
A ris SO ee eS 22
Winans v. Denmead, 56 U.S. (15 How.) 330
ig ERRORPEE Cine sR LGe Tate RR ene See SOS el ee 21
Ziegler v. Phillips Petroleum Co., 483 F.2d 858
(Sth Cir.), cert. denied, 414 U.S. 1079 (1973) .... 22, 25
Statutes
EE RES TST CRE Sel ee 2
REET REIS I SRG nT a 7
tgp Ae ec 16
week 2, 22
oo
vi
TABLE OF AUTHORITIES—Continued
Page
SES Rae Tere Ae ee ee Oot ae 22
§ 108 ........ 22
| ROE te ass 2,19
| Tes ee ce Sel Re ss EE 2, 22
(_ EEERIDE EN RPRROCREE CRE Ane eS see 8, 9, 10, 22
Rules and Regulations
Pas Bic MOI TD dachicctiictsicasatchinccsndetehiaasec Dhlaiteeaaninn talents ; 16
FER TREE Ae eT CO a 16
ARSE EEA RCE MENDEL. Fe 16
er a ba ee i ec eins 19
Other Authorities
L. Azaroff & M. Buerger, The Powder Method in
X-Ray Crystallography (1958) ................-.-..-------- 6
R. Faber, Landis on Mechanics of Patent Claim
Pi By. Re 18
P. Giannelli & E. Imwinkelried, Scientific Evidence
CORO ack caades DORE RT ae OTRO oes) a 14
E. Lipscomb, Walker on Patents (8d ed. 1987)...... 25
A. Miller & M. Davis, Intellectual Property: Pat-
ents, Trademarks, and Copyright in a Nutshell
eR RR aa Se ee 25
P. Rosenberg, Patent Law Fundamentals (2d ed.
EE ERR. cet SAE TSS 1 A Pe 23
E. Thomas, Chemical Inventions and Chemical Pat-
ents (Ausiander 66. 1966) —................................. 19
United States Pharmacopeia 23 (1994) .................. 6, 8,15
IN THE
Supreme Court of the United States
OCTOBER TERM, 1994
No. 94-
BRISTOL-MYERS SQUIBB COMPANY,
Petitioner,
Vv.
ZENITH LABORATORIES, INC.,
Respondent.
Petition for a Writ of Certiorari to the
United States Court of Appeals
for the Federal Circuit
PETITION FOR A WRIT OF CERTIORARI
Bristol-Myers Squibb Company hereby petitions for a
writ of certiorari to review the judgment of the United
States Court of Appeals for the Federal Circuit in this
case.
OPINIONS BELOW
The opinion of the court of appeals (Pet. App. 1a-17a)
is reported at 19 F.3d 1418. The opinions of the district
court (Pet. App. 18a-74a, 75a-78a) are reported at 24
USPQ2d 1652 (D.N.J. 1992).
JURISDICTION
The court of appeals entered judgment on March 24,
1994. Pet. App. la. A timely petition for rehearing was
denied on May 26, 1994. Pet. App. 79a-80a. On July
2
28, 1994, Chief Justice Rehnquist extended the time for
filing a petition to and including September 14, 1994.
Pet. App. 81a. This Court has jurisdiction under 28
U.S.C. § 1254.
STATUTORY PROVISIONS INVOLVED
Statutory provisions involved in the case include the
following:
35 U.S.C. § 101. Inventions patentable
Whoever invents or discovers any new and useful
process, machine, manufacture, or composition of
matter, or any new and useful improvement thereof,
may obtain a patent therefor, subject to the condi-
tions and requirements of this title.
35 U.S.C. § 112. Specification
The specification shall contain a written description
of the invention, and of the manner and process of
making and using it, in such full, clear, concise, and
exact terms as to enable any person skilled in the art
to which it pertains, or with which it is most nearly
connected, to make and use the same, and shall set
forth the best mode contemplated by the inventor of
carrying out his invention.
The specification shall conclude with one or more
claims particularly pointing out and distinctly claim-
ing the subject matter which the applicant regards as
his invention.
* * * *
35 U.S.C. § 154. Contents and term of patent
Every patent shall contain . . . 2 grant to the
patentee, . .. for the term of seventeen years, .. . of
3
the right to exclude others from making, using, or
selling the invention throughout the United States,
and, if the invention is a process, of the right to ex-
clude others from using or selling throughout the
United States, or importing into the United States,
products made by that process, referring to the spec-
ification for the particulars thereof... .
35 U.S.C. § 271. Infringement of patent
(a) Except as otherwise provided in this title.
whoever without authority makes, uses or sells any
patented invention, within the United States during
the term of the patent therefor, infringes the patent.
(b) Whoever actively induces infringement of a
patent shall be liable as an infringer.
* * * *
STATEMENT
The Federal Circuit in this case adopted restrictive new
positions on two important and recurring aspects of patent
law: the treatment of overinclusive scientific information
set forth in patent claims to identify a patented new
chemical compound or other composition of matter; and
the meaning of the established doctrine of equivalents as
a means of ensuring realistic protection against infringe-
ment commensurate with the full extent of a patent’s
validity. The Federal Circuit’s rulings establish limita-
tions on the scope of patent protection that are sharply
out of keeping with well-settled principles of patent law.
Petitioner asks this Court to grant the petition to review
and to correct these rulings.
A. Background
In 1970, the Patent and Trademark Office issued a
patent for a new antibiotic chemical compound called
4
“cefadroxil,” which is effective against bacteria that are
resistant to penicillin.’ Bristol-Myers (the owner of the
patent) recognized that cefadroxil in its original form
could not easily be used for actual delivery of medicine to
patients (or even for preliminary clinical studies) because
there was no sufficiently pure or stable form of the drug.
See Bristol-Myers Co. v. U.S. Int'l Trade Comm’n, 15
USPQ2d 1258, 1259, 1260 (Fed. Cir. 1989). Bristol-
Myers scientists therefore set to work trying to produce
a usable form of cefadroxil. These efforts ultimately were
rewarded with the creation of a new crystal form of
cefadroxil, the “Bouzard monohydrate,” consisting of one
water molecule for each cefadroxil molecule and named
after one of the inventors, Bristol-Myers chemist Daniel
Bouzard. See id. at 1259-60; Pet. App. 19a n.2. Bristol-
Myers marketed this new drug as DURICEF.
In 1985, the Patent and Trademark Office issued a
patent for this new compound—No. 4,504,657, the ’657
patent. Pet. App. 2a-3a. Pursuant to 35 U.S.C. § 112,
the patent contains a lengthy “specification” that describes
the new crystal and how it is made and then concludes
with a single “claim” that identifies the new crystal with
x-ray diffraction data—‘“a technique,” as the district court
observed (Pet. App. 49a), “that in essence takes the
‘fingerprint’ of a crystalline compound.” The claim states:
We claim:
1. Crystalline 7-[D-a-amino-g-(p-hydroxyphenyl-
) acetamido] -3-methy]-3-cephem-4-carboxylic acid
monohydrate exhibiting essentially the following x-ray
diffraction properties:
1This was patent No. 3,489,752, referred to by the last three
digits—the ’752 patent. That patent expired in 1987. See Pet.
App. 2a.
Relative
Line Spacing d(A) Intensity
1 8.84 100
2 7.88 40
3 7.27 42
4 6.89 15
5 6.08 70
6 5.56 5
7 5.35 63
8 4.98 38
9 4.73 26
10 4.43 18
11 4.10 61
12 3.95 5
13 3.79 70
14 3.66 5
15 3.55 12
16 3.45 74
17 3.30 11
18 3.18 14
19 3.09 16
20 3.03 29
21 2.93 8
22 2.85 26
23 2.76 19
24 2.67 9
25 2.59 28
26 2.51 12
27 2.46 13
28 2.41 2
29 2.35 12
30 2.30 2
31 2.20 15
32 2.17 11
33 2.12 7
34 2.05 4
35 1.99 4
36 1.95 14
37 1.90 10
6
U.S. Patent No. 4,504,657, cols. 18-20 (Def. Ex. 1, Ct.
App. JA 507-08). The table gives the results of directing
x-rays at the crystalline powder, detecting the reflections
of the x-rays from various angles (like photographing it
from various angles), and recording the location and
intensity of those reflections.”
The validity of this patent was soon tested and con-
firmed. When several companies sought to import the
identical patented crystal into the United States, Bristol-
Myers sued for injunctive relief from the International
Trade Commission (1 ‘C). The ITC denied preliminary
relief, doubting the validity of the ‘657 patent, but the
Federal Circuit reversed, rejecting the ITC’s basis for
questioning the validity of the patent. Bristol-Myers Co.
v. U.S. Int'l Trade Comm'n, 15 USPQ2d 1258 (Fed. Cir.
1989). In so holding, the Federal Circuit made clear that
the invention claimed was the crystal itself, with the
diffraction pattern supplying information to identify this
unique crystal: “The product is claimed in the '657
patent as a specific crystalline cefadroxil monohydrate,
identified by its X-ray powder diffraction pattern, an ac-
cepted ‘fingerprint’ for crystal structure.” Jd. at 1260.
See id. at 1260 (“new chemical structure”); id. at 1262
(“patentability of a new chemical structure”) .*
2 The “spacing d(A)” in the table stands for the location of the
x-ray reflections from the crystal powder, which depend on the
shape and size of the crystal lattice (unit cell); the “relative in-
tensity” of the reflections depends on the arrangement of the atoms
within the lattice. “The combination of the unit cell and the
arrangement of atoms in it comprises the crystal structure itself.
Therefore, the locations and relative intensities of the reflections
of a crystal are characteristics of the crystal structure.” L. Azaroff
_& M. Buerger, The Powder Method in X-Ray Crystallography 11
(1958) ; see also United States Pharmacopeia 23 at 1843-44 (1994)
(describing x-ray powder diffraction method and showing diffraction
patterns).
3The ITC subsequently held the patent valid. In re Certain
Crystalline Cefadroxil Monohydrate, 15 USPQ2d 1263 (ITC 1990).
7
B. District Court Proceedings
In 1988, respondent Zenith acquired from a Spanish
company the right to distribute a compound it called
“cefadroxil DC.” Although Zenith’s compound differs
structurally from Bristol-Myers’ Bouzard monohydrate in
that it contains one-half of a molecule of water (a hemi-
hydrate) for each molecule of cefadroxil, Zenith sought
and obtained approval from the Food and Drug Admin-
istration to sell its drug as a generic equivalent of Bristol-
Myers’ already-approved Bouzard monohydrate. See Pet.
App. 3a, 19a n.2. Zenith subsequently brought this suit
against Bristol-Myers in the United States District Court
for the District of New Jersey, seeking, under 28 U.S.C.
§ 1338, a declaratory judgment that cefadroxil DC did
not infringe Bristol-Myers’ '657 patent. See Pet. App. 4a,
19a.*
Bristol-Myers responded that Zenith’s compound in-
fringed its patent because cefadroxil DC does its medicinal
work by actually converting into the patented Bouzard
monohydrate in vivo—that is, in the patient’s stomach.
Zenith’s compound, therefore, induces literal infringement
in violation of 35 U.S.C. §271(b) and also infringes
Bristol-Myers’ patent under the established “doctrine of
equivalents,” which asks whether an accused product per-
forms substantially the same function in substantially the
same way to produce substantially the same result as the
patented product. See Pet. App. 5a, 15a, 19a; Graver
Tank & Mfg. Co. v. Linde Air Prods. Co., 339 U.S. 605,
609 (1950). Bristol-Myers relied on a host of prior
precedents, not questioned by the Federal Circuit here,
concluding that infringement may be found where an
accused product converts ia vivo or in situ into a pat-
ented product. Pet. App. 15a-16a, 61a-62a.
4 Earlier, Bristol-Myers had commenced an infringement action
against Zenith’s Spanish supplier, but that action was withdrawn
when the Spanish company ceased manufacturing cefadroxil DC.
Pet. App. 4a.
8
The district court held a six-day bench trial in which
“(t]he primary factual issue . . . was whether cefadroxil
DC converted in vivo to the Bouzard monohydrate.” Pet.
App. 20a.° Scientific witnesses on both sides testified
about their experiments addressed to that factual ques-
tion. Jd. at 20a-44a. Most critical for present purposes
was the testimony of Dr. Harry Brittain, particularly
about his x-ray diffraction analysis. Jd. at 48a-5la.° That
testimony, and the district court’s findings on the point
(id. at 50a-5la), proceeded in two steps. First, Dr.
Brittain showed that a sample of Bristol-Myers’ product
(DURICEF) was in fact the compound described in the
patent: he took x-ray diffraction readings of DURICEF
and matched them (21 of 22 lines, or angles) with the
diffraction figures set out in the patent. 7d. at 50a. Sec-
ond, he then used the graph form of the diffraction read-
ings for DURICEF (a diffraction pattern) as a “refer-
ence pattern” to compare with the diffraction pattern pro-
duced by certain wetted versions of Zenith’s compound
designed to simulate in vivo conditions, and he found that
those patterns matched as well. Jd. at 50a-5la. Zenith
concentrated on attacking the second step by questioning
whether the discovered conversion occurred in conditions
that truly corresponded with stomach conditions. Jd. at
51a-58a. Zenith did not dispute the scientific adequacy of
Dr. Brittain’s first step.’
5 The district court had initially “granted summary judgment in
Zenith’s favor on the issue of in vivo conversion” but immediately
vacated its order and proceeded to trial. Pet. App. 19a.
6 Dr. Brittain conducted ‘a host of other experiments as well to
determine whether cefadroxil DC converts into the Bouzard mono-
hydrate. See Pet. App. 30a-41a.
7 Dr. Brittain’s generation of a “reference pattern” on his equip-
ment was in accord with the recommended practice of the source
establishing official FDA standards: “If a reference material (e.g.,
USP Reference Standard) is available, it is preferable to generate
a primary reference pattern on the same equipment used for run-
ning the unknown sample, and under the same conditions.” United
States Pharmacopeia 28 at 1844.
9
The district court found Bristol-Myers’ “powerful
proofs” to “greatly outweigh” Zenith’s evidence and thus
found that cefadroxil DC does in fact convert into the
patented compound in vivo. Id. at 58a; see id. at 47a
(“The Court finds that Bristol presented by far the more
compelling case on the issue of conversion.”); id. at 57a
(Bristol-Myers’ evidence is “simply better supported and
vastly more credible”). Based on that finding, the court
held that Zenith’s “proposed sales of cefadroxil DC would
constitute inducement of infringement under 35 U.S.C.
§ 271(b).” Pet. App. 66a (footnote omitted); id. at 66a-
73a.° The district court entered judgment declaring
Zenith’s sale of cefadroxil DC an act of infringement and
directing that Zenith could not sell cefadroxil DC until
the date on which Bristol-Myers’ patent will expire (in
2002). Id. at 73a-78a.
C. The Court of Appeals Decision.
The Federal Circuit reversed. Pet. App. la-18a. At the
outset, the court rejected Zenith’s argument that the “657
patent was itself limited to pre-ingested Bouzard mono-
hydrate and thus, in Zenith’s view, excluded Bouzard
crystals that form in a patient’s stomach after ingestion of
cefadroxil DC. Id. at 6a-8a. Although Zenith contended
that the scope of the patent was restricted by the Bouzard
monohydrate’s function of facilitating the manufacture of
cefadroxil in usable form, the court made clear that this
function was not an aspect of the patent: “The '657
claim is a claim for a compound. Its patentability thus
derives from the structure of the claimed compound in
relation to prior compounds. See In re Spada, 911 F.2d
8 Although unnecessary to its ultimate holding, the district court
rejected Bristol-Myers’ alternative argument that Zenith was liable
for infringement under the doctrine of equivalents. The court
found “prosecution history estoppel” based on its view that Bristol-
Myers had predicated its patent solely on the enhanced manufac-
turing properties of its invention, properties that Zenith would not
use in producing the cefadroxil monohydrate in vivo. Id. at 64a-66a.
10
705, 708, 15 USPQ2d 1655, 1657 (Fed. Cir. 1990).
The relevance to patentability of the properties or char-
acteristics exhibited by the compound is limited to assess-
ing the significance of the structural distinctions of the
claimed compound over the prior art.” Pet. App. 7a-8a.
Having construed the 657 patent to cover any Bouzard
monohydrate crystals that form in vivo, the court of ap-
peals nevertheless overturned the district court’s finding
that there was literal infringement in vivo, explaining that
there was an “absence of evidence comparing the ’657
claim with the cefadroxil DC after ingestion.” Pet. App.
12a.° This holding in no way questioned the district
court’s finding that ingested cefadroxil DC converts to
DURICEF (based on a comparison of their diffraction
patterns); nor did it question the scientific adequacy of
the finding that DURICEF was the same as the compound
described in the patent (based on matching of 21 of 22
diffraction lines set forth in the ‘657 patent and shown by
the “reference pattern” produced by DURICEF). Rather,
the court’s holding was that proof of infringement re-
quires, as a matter of law, a matching of the accused
product and its diffraction pattern with the full set of
diffraction data included in the patent claim. Id. at 11a-
12a.” Explaining that “the claim is drafted in terms of
x-ray diffraction lines,” which therefore “set{] the metes
and bounds of the invention,” the court found a “failure
® The court of appeals thus held simply that there was no proof
that literal infringement occurred after ingestion. The court left
unimpaired the district court’s holding that, if literal infringement
occurs in vivo, Zenith is liable for inducement under 35 U.S.C.
§ 271(b). The court of appeals’ holding on this point, accordingly,
is a holding entirely about the requirements for proving literal
infringement.
10 The court observed that something less than complete identity
might be satisfactory, given the patent claim’s use of the term
“essentially exhibiting,” but that the law “does not permit ignoring
a substantial number of lines altogether,” as the scientific evidence
did in focusing on 22 of the 37 diffraction lines. Jd. at 11la-12a.
11
of proof” because of the “improper comparison.” Id. at
lla, 12a.
Turning from the issue of literal infringement, the Fed-
eral Circuit next held that a judgment of infringement
could not rest on the doctrine of equivalents. Pet. App.
13a-17a. The court began by rejecting the district court’s
reasoning on this point—which relied on “prosecution
history estoppel” based on Bristol-Myers’ assertion of its
invention’s manufacturing benefits (see note 8, supra)—
because “[t]here is nothing in the record indicating that
the statements about manufacturing benefits played any
role in the procurement of the ‘657 patent.” Jd. at 13a;
see id. at 13a-15a. But the court of appeals immediately
returned to the manufacturing benefits of the Bouzard
monohydrate in giving its own reason for holding that
“the doctrine of equivalents is inapplicable ... as a mat-
ter of law.” Id. at 15a.
The court ruled that, for purposes of determining
whether the accused product performs substantially the
same “function” as the patented invention, the only func-
tion that counts is a new function—one that the patented
invention was the first to perform. Jd. (“the primary, if
not the only, function of the Bouzard crystal form of the
drug as compared to other forms is to facilitate pre-
ingestion manufacturing”) (emphasis added); id. at n.9
(“the function cannot be described more broadly, i.e. as
the delivery of therapeutic value to the patient, for that
is the function attributable to cefadroxil per se, which is
prior art in relation to Bouzard monohydrate”). Based
on that proposition of law, the Federal Circuit ruled that
“there can be no infringement under the doctrine of
equivalents” in this case. Jd. at 15a. With the focus re-
stricted to new functions, it was irrelevant that Zenith’s
compound necessarily performs the same function of de-
livering medicine to patients as does Bristol-Myers’ com-
pound: the only relevant function was “facilitating en-
capsulation” for manufacturing (a function that the Fed-
eral Circuit had just concluded played no role in the
12
issuance of the patent), and that function was one Zenith’s
compound could not perform after ingestion. 7d. at 15a,
17a.
The full Federal Circuit subsequently denied a sugges-
tion for rehearing en banc. Judge Newman voted to re-
hear the case en banc. Pet. App. 79a-80a.
REASONS FOR GRANTING THE PETITION
The Federal Circuit rested its ruling in this case on
two conclusions that, conflicting with a number of funda-
mental and previously clear principles of patent law, cre-
ate substantial confusion about and improperly curtail
the scope of patent protection. The court restricted the
scope of literal infringement by equating mere identifying
data (like diffraction patterns or fingerprints) with the
articles that such data identify, thereby deliberately
turning a blind eye to indisputable scientific evidence
about how to determine when a unique chemical com-
pound or other composition of matter is present. The
court then restricted the scope of infringement under the
doctrine of equivalents by limiting protection to patented
inventions that perform a new function, thereby discon-
necting the scope of infringement protection from the
scope of patent validity and effectively stripping a whole
range of valid patents of the essential protection to which
they have long been entitled.
Each of the court’s rulings is on its face broadly ap-
plicable and incompatible with otherwise-established prin-
ciples of patent law. Where no intercircuit conflict is pos-
sible because of the exclusive jurisdiction of the Federal
Circuit over matters of patent law, the resulting uncer-
tainty about legal issues as fundamental as those pre-
sented here is more than enough to call for this Court’s
review. The Court should grant the petition to address
these issues and restore the proper understanding of iden-
tifying data in patent claims and the proper concordance
between infringement protection and patent validity.
a
13
I. THE FEDERAL CIRCUIT ERRONEOUSLY LIM-
ITED THE SCOPE OF PROTECTION AGAINST
LITERAL INFRINGEMENT FOR VALID PATENTS
FOR NEW COMPOSITIONS OF MATTER SUCH AS
CHEMICAL COMPOUNDS.
The court of appeals in this case held that it was error
for a court, addressing a charge of infringement, “to
compare . . . the accused product with the patentee’s
commercial embodiment or other version of the product
or process,” even if, as a scientific matter, the commercial
product is exactly the same as the patented article. Pet.
App. lla. Thus, despite the fact that Bristol-Myers es-
tablished to a scientific certainty that its product was the
same as the compound identified in the patent, and fur-
ther established that Zenith’s compound (cefadroxil DC
in vivo) was the same as that product, the court of ap-
peals nonetheless reversed the district court’s finding of
infringement, holding that as a matter of law the accused
product has to be directly compared to the full set of
identifying data in the patent. Jd. at 1la-12a. If this rule
of law were to stand, it would mean that a patent holder,
to prove infringement, would have to compare the infring-
ing product to each and every piece of identifying data
in the patent claim even when a far less burdensome
comparison would irrefutably establish that the two com-
pounds were identical. There is simply no sound basis
for engrafting this requirement onto the structure of ex-
isting patent law.
The Federal Circuit’s ruling fundamentally confuses
two different types of patent claims and imposes a new
limitation on a type of patent claim where it does not
belong. Where the full set of limitations set forth in a
patent claim restrictively defines what is new about the
invention—as when a new machine is built and the claim
precisely specifies the novel aspects of it—then it is un-
doubtedly correct that each of those limitations must be
“read on” an accused product to establish literal infringe-
ment. But where the data in the claim serve merely to
14
identify or describe what is concededly a new invention,
and such data are in scientific terms more than necessary
(overinclusive, excessive) for that purpose, then the Fed-
eral Circuit’s rule is erroneous. In that circumstance,
which is a common one—e.g., when a never-before-created
chemical compound or other composition of matter is the
patented invention and the patent claim simply gives
scientists the tell-tale signs to determine if what they have
produced is the new compound or composition—the
court’s rule mistakenly equates the object patented with
information that is only of evidentiary significance in de-
termining when that object has been found.
This error is the equivalent of requiring, as a matter of
law, a matching of every ridge, whorl, loop, and other
characteristic of a detailed fingerprint to prove that an
“accused” finger is the same as a known finger—even
though the science of fingerprint identification establishes
the indisputable sufficiency of far less information. See
P. Giannelli & E. Imwinkelried, Scientific Evidence § 16-7
(1986). When there is no question about what the ob-
ject of identification is (e.g., a finger of a particular per-
son), it is a scientific question how much of a particular
form of evidence (e.g., fingerprint information) is suffi-
cient to establish the identification. And when there is
more such evidence than is scientifically necessary to es-
tablish the identification, it is senseless to ignore the
redundant character of the data and require jot-by-jot
scrutiny of every item.
The x-ray diffraction data in a patent like ’657 are, as
the district court and Federal Circuit both recognized, just
like “fingerprint” evidence. Pet. App. 49a; Bristol-Myers
Co. v. ITC, 15 USPQ2d at 1260. It does not restrict and
define the patented aspects of a physical object, but
merely supplies data for identifying the object that is
patented—namely, the chemical compound itself. Indeed,
the Federal Circuit, both in its opinion on the validity of
the ’657 patent and elsewhere in its opinion under review
here, expressly recognized that the thing patented was the
os
15
crystal structure itself (the Bouzard monohydrate). Pet.
App. 7a (“The ’657 claim is a claim for a compound.”);
page 6, supra (quoting validity opinion). It is there-
fore fundamentally a factual scientific question how much
diffraction data (or, in a different case, other types of
data) are needed to answer the central question of in-
fringement analysis—whether the accused product and
the patented product are “the same.” Union Paper-Bag
Machine Co. v. Murphy, 97 U.S. 120, 125 (1878). See
Fromberg, Inc. v. Thornhill, 315 F.2d 407, 411 (Sth
Cir. 1963); Intervet America, Inc. v. Kee-Vet Labs., Inc.,
887 F.2d 1050, 1053 (Fed. Cir. 1989) (“infringement is
a question of fact”).
Yet the Federal Circuit did not question—what is in-
deed beyond dispute—that as a scientific matter 37 dif-
fraction lines are grossly overinclusive, or redundant, for
identification purposes." The court nevertheless treated
11 For example, the United States Pharmacopeia 23, which sets
forth official FDA standards, states that “[i]dentification of crystal-
line materials can be accomplished by comparison of X-ray powder
diffraction patterns obtained for known materials with those of the
unknown” and “[i]t is generally sufficient [to establish identity] to
scan past the ten strongest reflections” in a diffracticn pattern.
Id. at 1844 (footnote omitted). Zenith’s own experts testified to the
scientific sufficiency, for identification purposes, of looking at
“maybe 15 or 20” lines (Ct. App. JA 2075 (Dr. Pfeiffer) ) or even
three lines if they are strong enough (Ct. App. JA 2918 (Dr.
Greenblatt) ). The 21 lines relied on in this case by Bristol-Myers’
expert and the district court included the strongest, most significant
lines.
Beyond that, there was no serious dispute as a scientific factual
matter that DURICEF was the same as the invention described in
the ‘657 patent. Zenith’s expert Dr. Greenblatt so testified in her
deposition. Ct. App. JA 1567, 1570-71. An FDA report submitted
by Zenith stated that the diffraction pattern for Bristol-Myers’
product “agrees with the data presented by the Bouzard patent.”
Ct. App. JA 237. The ITC stated in its opinion upholding the valid-
ity of the ‘657 patent that Bristol-Myers’ “commercially successful
product .. . is the invention claimed in the ‘657 patent.” In re
16
the diffraction data as if each element of it imposed an
additional limitation on the protected invention. That
treatment, which is scientifically incorrect, necessarily es-
tablishes what Zenith described as “a ruling of law...
as a matter of claim interpretation” (Response to Reh’g
Pet’n at 5) that the patented invention in this common
situation is not the chemical itself, but each and every
piece of identifying data. The Federal Circuit’s ruling is
thus contrary to the court’s own prior recognition in this
very case. More basically, it violates the cardinal prin-
ciple that patent claims should be construed “in the light
. . . of scientific fact.” Smith v. Snow, 294 U.S. 1, 14
(1935).”
The Federal Circuit’s new treatment of chemical pat-
ents and diffraction data is, in fact, flatly inconsistent
with the (otherwise-binding) precedent of its predecessor
court. In In re Papesch, 315 F.2d 381, 391 (Ct. Cust.
Pat. App. 1963), the court stressed the very distinction
the Federal Circuit here ignored: “a formula is not a
compound and while it may serve in a claim to identify
what is being patented, as the metes and bounds of a
deed identify a plot of land, the thing that is patented is
not the formula but the compound identified by it.” More
specifically, in In re Grose, 592 F.2d 1161 (Ct. Cust.
Pat. App. 1979), the court discussed “[t]he significance
of differences in X-ray diffraction data” where a patent
claim for a chemical compound (a “zeolite”), using lan-
guage materially indistinguishable from the claim here,
Certain Crystalline Cefadroxil Monohydrate, 15 USPQ2d at 1270.
And Zenith’s amended complaint (at {| 30) described Bristol-Myers’
product as “covered by the ’657 patent.” Ct. App. JA 202.
12To the extent that the Federal Circuit was establishing a
special evidentiary rule—one that disregards scientific standards
of evidentiary sufficiency—it plainly has no authority to depart
from the Federal Rules of Evidence that govern all cases in district
courts. See Fed. R. Evid. 101, 1101, 1102; 28 U.S.C. § 2072; SRI
Int’l v. Matsushita Elec. Corp., 775 F.2d 1107, 1116 (Fed. Cir.
1985).
17
“followed the apparently universal practice in this art of ©
‘fingerprinting’ the crystal structure of their zeolite through
a characteristic X-ray powder diffraction pattern.” /d. at
1165.* In comparing the claimed crystal with another,
the court stated:
X-ray powder diffraction data are merely an ana-
lytical tool for identifying polycrystalline materials
according to differences in crystal structure. The
ultimate question, in ascertaining whether a particu-
lar zeolite is a different species from those of like
chemical composition, is whether it has the same
crystal structure. Appellants are claiming a crystal
structure. Thus, we are concerned not with whether
there are differences in d-spacing values and relative
intensities, but with whether such differences support
a conclusion that [the two compounds] have different
crystal structures.
Id. at 1165-66 (footnote omitted). That approach to
construing a claim for a compound that recites diffraction
data, and to comparing the compound with another
chemical compound, respects sound science. The Federal
Circuit ruling in this case is fundamentally inconsistent
with that approach.
The ruling below not only is incorrect but also will
have harmful consequences. Owners (or future seekers)
of patents for chemical compounds or other compositions
of matter will now be limited, or at a minimum have to
guess which authority will govern, in their efforts to se-
cure protection against infringement for their inventions.
This impairment—with the inevitable waste and difficul-
ties in having to prove infringement through efforts to
match every bit of scientifically redundant data in a pa-
13 The patent claim stated that a particular compound had “an
X-ray powder diffraction pattern containing at least those d-spacings
set forth” in a table included in the claim. 592 F.2d at 1162 (em-
phasis added).
18
tent claim “—will immediately affect a large number of
chemical patents. With respect to the use of diffraction
data alone, which is a standard procedure (see In re
Grose, 592 F.2d at 1165), the decision affects the ap-
proximately 400 unexpired patents for chemical com-
pounds that recite diffraction data.** And the principle
adopted by the Federal Circuit applies not just to diffrac-
tion data but equally to any other form of scientific
“fingerprint” data.”®
The Federal Circuit’s ruling also produces immediate
uncertainty for claimants seeking new patents. If patent
owners are to be penalized for overinclusive identifying
data in their patent claims, they will spend needless re-
sources attempting to predict not only what language the
Patent and Trademark Office will accept but also what
data will simultaneously serve the two essential purposes
of the patent claim: to be inclusive enough to identify
the invention and thus afford protection against infringe-
ment, while not being so overinclusive as to make en-
forcing the patent over its 17-year life wastefully expen-
sive (through, e.g., compelled redundancy of scientific
proof) or perhaps impossible. The drafting of claims is
14 Here, for example, present-day accepted methodology for x-ray
diffraction analysis would not produce the full set of 37 diffraction
readings included in the ‘657 claim. Given the undisputed scientific
adequacy of the diffraction-pattern matching produced by current
equipment, it would be purely wasteful of the time and resources
of scientists, inventors, and courts (and in other cases perhaps
impossible) to insist on examination of even concededly redundant
data in the patent.
15 A computer search on Dialog discloses roughly that number
of patents using diffraction data issued during the past 17 years
(the term of patents).
16 For chemical compounds alone, such data include infrared
spectra, nuclear magnetic resonance spectra, data about solubility
and melting points, and “elemental analysis” information. See, e.g.,
R. Faber, Landis on Mechanics of Patent Claim Drafting § 52 (3d
ed. 1990).
19
already difficult and costly ; a judicial refusal to accept
scientific reality in reading and applying claim language
for infringement purposes senselessly adds new difficulties
and costs, and thus unjustifiably weakens the meaningful
economic protection that patent law is designed to afford
inventors.
The Federal Circuit’s ruling harms persons other than
the patent owner as well. If patent claimants are penal-
ized for overinclusion of information in their claims, they
must seek to reduce the information supplied to the bare
minimum that will suffice for protection—e.g., to give
the minimal amount of diffraction data needed for iden-
tification. The inevitable result of holding back informa-
tion is to make it more difficult for the public to identify
the patented invention. But that result is squarely con-
trary to the basic purpose of the requirement of written
descriptions in patents: to provide as much information
as possible for the public to be able to identify the in-
vention, both to avoid infringement during the term of
the patent and to reproduce the invention once the patent
has expired. See 35 U.S.C. § 112; 37 C.F.R. $1.71;
Schriber-Schroth Co. v. Cleveland Trust Co., 305 U.S. 47,
57 (1938). The Federal Circuit’s rule—as applied to the
range of cases where the patented invention is a new
chemical compound or other composition of matter and
the information set forth in the claim serves redundantly
17 See Topliff v. Topliff, 145 U.S. 156, 171 (1892) (“The specifica-
tion and claims of a patent, particularly if the invention be at all
complicated, constitute one of the most difficult legal instruments to
draw with accuracy.”); Georgia-Pacific Corp. v. United States
Plywood Corp., 258 F.2d 124, 136 (2d Cir.), cert. denied, 358 U.S.
884 (1958) (“the policy of the patent statute contemplates granting
protection to valid inventions, and this policy would be defeated if
protection were to be accorded only to those patents which were
capable of precise definition”; inventions “cannot always be de-
scribed in terms of exact measurements, symbols and formulae’) ;
E. Thomas, Chemical Inventions and Chemical Patents §9 (Aus-
lander ed. 1964) (a chemical invention presents a special “difficulty
of interpreting and describing something invisible”).
20
to identify, but not to restrict, the invention—would thus
perversely penalize patent claimants for oversupplying in-
formation: it “would foster concealment rather than dis-
closure of inventions, which is one of the primary pur-
poses of the patent system.” Graver Tank, 339 USS. at
607. This topsy-turvy result should not stand.
II. THE FEDERAL CIRCUIT ERRONEOUSLY LIM-
ITED PROTECTION AGAINST INFRINGEMENT
UNDER THE DOCTRINE OF EQUIVALENTS TO
PATENTS FOR INVENTIONS THAT PERFORM
NEW FUNCTIONS.
In holding the doctrine of equivalents inapplicable here,
the Federal Circuit ruled simply that the doctrine’s thres-
hold requirement (that the patented product and the ac-
cused product perform substantially the same “function” )
is limited to new functions of the invention—those it
performs “as compared to” those performed by “prior
art.” Pet. App. 15a & n.9. Under that ruling, a per-
fectly valid patent for an invention that does not perform
any new function has no protection against infringement
under the doctrine of equivalents. This startling result is
contrary to established precedents and principles of patent
law.
Most specifically, this Court and the Federal Circuit
itself, in applying the doctrine of equivalents, have iden-
tified the “function” of a patented invention in terms
making clear that it need not be one never before per-
formed by prior art. For example, in Graver Tank, this
Court identified “welding” as the function for purposes of
the longstanding function/way/result test. 339 U.S. at
611.'* In Spectra Corp. v. Lutz, 839 F.2d 1579 (Fed.
~18"The trial judge found on the evidence before him that the
Lincolnweld flux [the accused product] and the composition of the
patent in suit are substantially identical in operation [way] and in
result. He found also that Lincolnweld is in all respects equivalent
to Unionmelt [the patented product] for welding purposes [fwne-
Ort. He
21
Cir. 1988), the court identified the function as “dyeing.”
Id. at 1582 (“The function (dyeing) and the result
(dyed material) are broadly the same.”). Plainly,
neither function was original to the patented inventions
at issue. Similarly, in Carman Indus., Inc. v. Wahl, 724
F.2d 932 (Fed. Cir. 1983), the court made explicit that
the invention’s function (“to promote the flow from the
[storage] bin or hopper of solids that have poor flow
characteristics”) was far from new: the court described
the “[p]rior art approaches to” performing the same func-
tion. Id. at 934 (“Prior art approaches to the problem
of promoting the flow of difficult-to-handle solids involve
the use of sweep arms, screw conveyors, or like ele-
ments.”). The Federal Circuit’s ruiing in the present case
is flatly inconsistent with those standard applications of
the doctrine of equivalents.
More broadly, the Federal Circuit’s ruling, by stripping
a large class of valid patents of an important protection
against infringement, violates the bedrock principle that
protection against infringement should be commensurate
with the validity of the patent. For example, the Federal
Circuit has recognized that “claims must be given the
same construction when considering infringement as when
considering validity.” Intervet America, 887 F.2d at
1053; see Connell v. Sears, Roebuck & Co., 722 F.2d
1542, 1554 (Fed. Cir. 1983); Lerner v. Child Guidance
Prods., Inc., 547 F.2d 29, 31 (2d Cir. 1976); Leeds &
Northrup Co. v. Doble Eng’g Co., 159 F.2d 644 (1st Cir.
tion].” 339 U.S. at 611; see also Union Paper-Bag Machine Co. v.
Murphy, 97 U.S. at 126 (“cutting” function).
The doctrine of equivalents, with its function/way/result test,
traces its lineage well back into the nineteenth century. See
Graver Tank, 339 U.S. at 608-09, citing, e.g., Sanitary Refrigerator
Co. v. Winters, 280 U.S. 30 (1929), Westinghouse v. Boyden Power
Brake Co., 170 U.S. 537 (1898), Union Paper-Bag Machine Co. v.
Murphy, supra, Winans v. Denmead, 56 U.S. (15 How.) 330 (1854) ;
Gray v. James, 10 F. Cas. 1015, 1016 (C.C.D. Pa. 1817) (No. 5718)
(Washington, J.) ; Odiorne v. Winkley, 18 F. Cas. 581, 582 (C.C.D.
Mass. 1814) (No. 10,432) (Story, J.).
22
1947). It is equally well recognized that the doctrine of
equivalents is to be applied in light of prior art precisely
to ensure that the realistic protection afforded by the doc-
trine reaches no farther than, but as far as, what is
claimed as new—=i.eg., patentable—in the patented inven-
tion. See Wilson Sporting Goods Co. v. David Geoffrey
& Assoc., 904 F.2d 677, 684 (Fed. Cir.), cert. denied,
498 U.S. 992 (1990); Read Corp. v. Portec, Inc., 970
F.2d 816, 822 n.2 (Fed. Cir. 1992) (“Equivalency to
limitations of the claim must be the focus of the [doc-
trine of equivalents] inquiry.”); Carman Indus., 724 F.2d
at 937 n.5. See also Ziegler v. Phillips Petroleum Co.,
483 F.2d 858, 869 (Sth Cir.), cert. denied, 414 US.
1079 (1973) (“The nature of the invention determines
the breadth of its protection under the doctrine of equiva-
lents. Because the doctrine rests on equitable considera-
tions, the principle has developed that an inventor, with
respect to his patent, is entitled to a range of equivalents
commensurate with the scope of his invention.” (citing
cases) ). The law could hardly be otherwise: the value
of a valid patent is the right it gives the owner to pre-
clude others from infringement. 35 U.S.C. § 154 (patent
gives owner “the right to exclude others from making,
using, or selling the invention”), § 271(a) (infringement
occurs when anyone “without authority makes, uses or
sells any patented invention”).
Yet it is beyond dispute that an invention need not
perform a new function to be validly patentable. The
requirements of utility, novelty, and nonobviousness (35
U.S.C. $$ 101, 102, 103) do not, as a matter of plain
English or common sense, incorporate a demand that the
use of the invention be a new one: a different apparatus
or compound that performs the same function as an
existing one (like a new medicine for an ailment currently
treated by an existing drug) can be useful, novel, and
nonobvious. That, indeed, is why “pioneer patents”—for
inventions that perform “a function never before per-
formed”—are recognized as only one special subtype, not
23
the universe, of valid patents. Westinghouse v. Boyden
Power Brake Co., 170 U.S. 537, 561-62 (1898); see
Morley Sewing-Machine Co. v. Lancaster, 129 U.S. 263,
273 (1889).
Not surprisingly, the Federal Circuit and its predecessor
court have repeatedly recognized that it is a mistake to re-
quire a new invention to perform a new function (or
operation). The Court of Customs and Patent Appeals
specifically held that “whether a given chemical compound
or composition has the same usefulness” as a prior prod-
uct (though potentially relevant as an evidentiary matter
to the issue of obviousness) is mot a requirement for
patent validity. In re Cofer, 354 F.2d 664, 667 (1966).
More recently, the Federal Circuit stressed that “there is
no requirement . . . that [the patent owner] show ‘opera-
tional differences’ of the claimed device over the prior art.
. . [A]pparatus claims cover what a device is, not
what a device does. An invention need not operate dif-
ferently than the prior art to be patentable, but need only
be different.” Hewlett-Packard Co. v. Bausch & Lomb,
Inc., 909 F.2d 1464, 1468 (1990) (footnote omitted ).”
The Federal Circuit has even recognized that a patent, to
be valid, need not perform an old function in an improved
manner. Demaco Corp. v. F. Von Langsdorff Licensing
Ltd., 851 F.2d 1387, 1390, cert. denied, 488 U.S. 956
(1988): see In re Casey, 370 F.2d 576, 580 (Ct. Cust.
19 Patents fall into two groups: those where what is patented is
an apparatus, machine, device, composition of matter, or other
physical object; those where what is patented is a process or other
physical operation. See P. Rosenberg, Patent Law Fundamentals
§ 6.01[2], at 6-25 (2d ed. 1994). The Federal Circuit’s reference
to “apparatus claims” in Hewlett-Packard distinguishes “process
claims,” where it is the function performed that is the subject of
the patent. The patent at issue here, as the Federal Circuit itself
observed in rejecting Zenith’s effort to restrict it to manufacturing
properties, is for a physical object, like the apparatus claim in
Hewlett-Packard, not for a process.
20 “The patent statute does not require that a patentable inven-
tion be superior to all prior devices. Custom Accessories, Inc. v.
24
Pat. App. 1967). In this very case, moreover, the Fed-
eral Circuit recognized in another portion of its opinion
that a new compound need not perform a new operation
or function to be patentable: “Its patentability thus de-
rives from the structure of the claimed compound in rela-
tion to prior compounds,” not from its “properties.” Pet.
App. 7a-8a (citing In re Spada, 911 F.2d 705, 708 (Fed.
Cir. 1990)).
The Federal Circuit’s new view of the doctrine of
equivalents necessarily casts aside this well-established
law. Unless the Federal Circuit meant sub silentio to
introduce a new condition on issuance of a valid patent
(namely, that the invention perform a new function)—
which it could not properly do—the ruling below neces-
sarily severs the scope of protection against infringement
from the scope of patent validity, depriving a class of in-
disputably valid patents of full protection against infringe-
ment. The decision thus dramatically curtails the realistic
protection to which all valid patents have long been en-
titled and throws into confusion the continuing validity of
long-settled principles of patent law.”
Jeffrey-Allan Industries, Inc., 807 F.2d 955, 960 n.12, 1 USPQ2d
1196, 1199 n.12 (Fed. Cir. 1986) (‘Finding that an invention is an
“improvement” is not a prerequisite to patentability’); G. Rich,
Principles of Patentability, 28 Geo.Wash.L.Rev. 393, reprinted in
42 J.Pat.Off.Soc’y 75 (1960) (discussing ‘the unsound notion that
to be patentable an invention must be better than the prior art’).”
851 F.2d at 1390.
21 The Federal Circuit’s holding disregards another, closely re-
lated, well-established principle of patent law: that the owner of a
non-process patent (like the “composition of matter” patent here)
is entitled to a monopoly on every use of the invention during the
term of the patent. See Potts v. Creager, 155 U.S. 597, 606 (1895)
(“Doubtless a patentee is entitled to every use of which his in-
vention is susceptible, whether such use be known or unknown to
him.”) ; Radio Corp. of America v. Radio Eng’g Lab., Inc., 293 U.S.
1, 14 (1934); Roberts v. Ryer, 91 U.S. 150, 157 (1875) (“The
inventor of a machine is entitled to all the uses to which it can be
put, no matter whether he had conceived the idea of the use or
>i el sat ata bts dts Syne Ale called tee
25
The protection stripped from a large range of inven-
tions is of dramatic significance. Many and perhaps most
patents involve inventions that perform old functions:
again, that is what makes pioneer patents distinctive.”
And the doctrine of equivalents, far from being a minor ap-
pendage to the guarantee against literal infringement, is
so fundamental to patent law that it has been described as
stating “[t]he critical test in any infringement suit.” A.
Miller & M. Davis, Intellectual Property: Patents, Trade-
marks, and Copyright in a Nutshell 124 (2d ed. 1990);
see id. at 126. Indeed, this Court has said that, without
the “wholesome realism” of the protection furnished by
the doctrine of equivalents, a patent would be a “hollow
and useless thing.” Graver Tank, 339 U.S. at 608, 607.
Because “minor deviations in the structure of almost any
invention could be devised to elude the reach of the
patent’s protection, . . . a patent would be virtually worth-
less if it did not protect against devices which incorporate
unimportant variations of the patented device.” Ziegler,
483 }.2d at 868; see Graver Tank, 339 U.S. at 607
(“Outright and forthright duplication is a dull and very
rare type of infringement. To prohibit no other would
place the inventor at the mercy of verbalism and would
be subordinating substance to form.”).
The Federal Circuit’s ruling is anything but the sort of
finetuning of patent-law principles, or settling of rules
where clarity is as important as content, that this Court
should leave to that court for final determination. Rather,
the ruling destroys a fundamentally important protection
not.”); SRI Int’l, 775 F.2d at 1123. In this case, the Federal
Circuit, while recognizing the validity of the ‘657 patent, denied
Bristol-Myers the right to control one use of that very invention—
as medicine in vivo.
22 Most patents are not pioneer patents and hence do not perform
“a function never before performed” (Westinghouse, 170 U.S. at
561-62). See National Hollow Brake-Beam Co. v. Interchangeable
Brake-Beam Co., 106 F. 693, 710-11 (8th Cir. 1901); 6. E.
Lipscomb, Walker on Patents § 22:41, at 557-58 (3d ed. 1987).
26
for a significant class of valid patents. This Court should
grant the petition to review and reverse the Federal Cir-
cuit’s ruling.
CONCLUSION
The petition for a writ of certiorari should be granted.
Respectfully submitted,
H. BARTOW FArR, III
(Counsel of Record)
RICHARD G. TARANTO
FARR & TARANTO
2445 M Street, NW
Washington, DC 20037
(202) 775-0184
S. LESLIE MISROCK
BRIAN D. CoGGIo
STEVEN I. WALLACH
KENT H. CHENG
PENNIE & EDMONDS
1155 Avenue of the Americas
Dated: September 14, 1994 New York, NY 10036
APPENDICES
la
APPENDIX A
UNITED STATES COURT OF APPEALS
FOR THE FEDERAL CIRCUIT
92-1527
ZENITH LABORATORIES, INC.,
Plaintiff-A ppellant,
Vv.
BRISTOL-MYERS SQUIBB COMPANY,
Defendant-A ppellee.
Appealed from U.S. District Court
for the District of New Jersey
Judge Wolin
Decided: March 24, 1994 [corrected March 31, 1994]
Before PLAGER, CLEVENGER, and SCHALL, Circuit
Judges.
PLAGER, Circuit Judge.
The question in this declaratory judgment action is
whether a drug compound, which in its manufactured
state does not infringe the patent in suit, becomes in-
fringing as a result of transitory chemical changes that
occur in vivo, that is, as a result of ingestion by the
patient. There are fact issues—what changes actually
occur when the drug is ingested, and how do we know;
2a
there are legal issues—does a compound that changes in
the human body into the patented product on its way to
becoming the active ingredient in the drug (the original
patent on the active ingredient having earlier expired)
literally infringe, infringe under the doctrine of equiva-
lents, or infringe by inducement.
The District Court for the District of New Jersey,
Civil Action No. 91-3423, entered judgment, following a
bench trial, that plaintiff/appellant Zenith Laboratories,
Inc.’s (Zenith) commercial sale of cefadroxil DC induces
infringement of U.S. Patent 4,504,657 (the ’657- patent),*
the patent at issue. Zenith Lab. Inc. v. Bristol-Myers
Squibb Co., 24 USPQ2d 1652 (D.N.J. 1992) (Zenith
II). The ’657 patent is owned by Bristol-Myers Squibb
Co. (Bristol). For the reasons set forth, we reverse.
BACKGROUND
The chemical compound cefadroxil, an antibiotic of
the cephalosporin family effective against bacteria that
are resistant to penicillin, was described and claimed in
United States Patent No. 3,489,752 (the ’752 patent),
which issued in 1970; the owner was Bristol. The claims
of the ’752 patent covered any and all forms of cefa-
droxil—they described the chemical compound per se.
The ’752 patent expired in 1987.
In the meantime, Bristol set to work to find a com-
mercially useful crystalline form of the compound that
would overcome problems related to manufacture of the
product so that it would be usable by humans. The task
of developing a commercial production process was as-
signed to certain of Bristol’s chemists. They developed
what became known as the Bouzard monohydrate, named
after one of the discoverers—a new crystalline form of
cefadroxil. Unlike prior forms of cefadroxil, Bouzard
1That patent issued March 12, 1985, and thus will expire on
March 12, 2002.
3a
monohydrate possesses certain characteristics in its pre-
ingested, powdered form, related to bulk density, solu-
bility, and stability (manufacturing-related characteris-
tics), which make it particularly suitable for packaging
into capsules.
The Bouzard monohydrate was the subject of the single
claim in the ‘657 patent:
1. Crystalline 7 - [D-a-amino-«-(p-hydroxyphenyl-)
acetamido]-3-methyl-3-cephem-4-carboxylic acid mon-
ohydrate exhibiting essentially the following x-ray
diffraction properties: [a 37-line table of relative
intensities exhibited by Bouzard monohydrate at
various scan angles].
In July 1988, Zenith, the plaintiff in this declaratory
judgment action, contracted with a Spanish company,
Gema, S.A. of Barcelona (Gema), to become the exclu-
sive United States distributor of the form of cefadroxil
manufactured by Gema and known as cefadroxil DC.
Cefadroxil DC is a hemihydrate form of cefadroxil
and thus differs structurally from Bouzard monohydrate.”
Zenith and Gema then undertook to obtain approval from
the Food and Drug Administration (FDA) for commer-
cial marketing in the United States of cefadroxil DC.
Pursuant to FDA regulations, Zenith and Gema sought
abbreviated approval on the grounds that cefadroxil DC
was bioequivalent to a form of cefadroxil monohydrate
(other than Bouzard monohydrate) which had already
been approved by the FDA for commercial sale. In Octo-
ber 1990, the FDA granted approval.*
2The difference is the number of water molecules which are
paired with each cefadroxil molecule.
8The record suggests that the FDA subsequently reconsidered
and rescinded this approval after Bristol filed with the FDA a
citizens petition seeking to block approval on the grounds cefa-
droxil DC was a hemihydrate and thus not bioequivalent to cefa-
droxil monohydrate. The record does not indicate whether the
FDA thereafter approved Zenith’s application.
———
4a
In June 1991, after learning of Zenith’s and Gema’s
efforts to obtain FDA approval, Bristol filed suit against
Gema (and Gema’s affiliates) in the District Court for
the District of Maryland, Civil Action No. HAR 91-1765
(the Maryland action), alleging infringement of the ’657
patent. Subsequently, when Gema announced it was
abandoning its plans to manufacture cefadroxil DC, that
Suit was dismissed upon stipulation of the parties.
Zenith then, in August 1991, filed the present declara-
tory judgment action against Bristol in the District Court
for the District of New Jersey. Zenith’s complaint con-
tained four counts. In count one, Zenith sought a decla-
ration that cefadroxil DC does not infringe the ’657
patent, and in count two, a declaration that Bristol is
equitably estopped from asserting that cefadroxil DC in-
fringes the ‘657 patent. In count three, Zenith alleged
that Bristol, by initiating the Maryland action, violated
a consent decree previously entered in settlement of prior
litigation between the parties; and in count four, that
Bristol had engaged in unfair competition. (Zenith subse-
quently added a fifth and still pending count alleging that
Bristol had committed antitrust violations. )
Bristol then moved to dismiss counts one and two, and
for summary judgment on counts three and four. Zenith
filed cross-motions for summary judgment on these counts.
On December 12, 1991, the trial court granted Bristol’s
motion to dismiss count three (concerning the prior con-
sent decree) on the ground that the count was moot in
view of the previous dismissal of the Maryland action.
Zenith Lab. Inc. v. Bristol-Myers Squibb Co., 24 USPQ
2d 1641, 1651 (D.N.J. 1991) (Zenith 1). As to Zenith’s
motion for summary judgment on count one (the infringe-
ment count), the court stayed that motion pending an
oral hearing. 7d. at 1648. The court denied all other
motions. Jd. at 1648, 1650-51.
At the hearing on the infringement count, Bristol con-
ceded that cefadroxil DC, being a hemihydrate, did not
5a
literally infringe the ’657 patent in its pre-ingested form.
Bristol nevertheless argued that Zenith was liable under
the patent on two grounds; Zenith’s product infringed
under the doctrine of equivalents; and Zenith’s product
converted into the patented compound in the patient's
stomach, and thus the sale of cefadroxil DC would induce
infringement of the ‘657 patent under 35 U.S.C. § 271(b)
(1988). The trial court concluded that summary judg-
ment was appropriate since Bristol had not raised a
genuine factual dispute on these issues; and on March 4,
1992, the court granted Zenith’s motion for summary
judgment on count one.
However, subsequently, on April 16, 1992, upon Bris-
tol’s motion for reconsideration, the court vacated its
March 4, 1992 decision. The court denied Zenith’s mo-
tion for summary judgment on count one on the basis
that Bristol, through two declarations submitted with its
motion for reconsideration, had demonstrated a genuine
dispute on the in vivo conversion issue. Consequently, it
ordered that that count be severed from the remaining
counts and tried separately.
From May 26, 1992 through June 5, 1992, the court
conducted a bench trial on count one. Following the
trial, the court rejected Bristol’s theory of infringement
under the doctrine of equivalents. It found that Bristol,
through prosecution history estoppel, had relinquished
coverage of cefadroxil DC. However, the court found
that cefadroxil DC converts to Bouzard monohydrate in
the patient’s stomach. Since an act of literal infringement
thus occurs in the patient’s stomach as a result of ingestion
of cefadroxil DC, the court concluded that Zenith’s sale
of cefadroxil DC would induce infringement of the ‘657
patent.
On August 6, 1992, the court, in accordance with its
findings and conclusions, entered judgment for Bristol.
Zenith II, 24 USPQ2d 1652. The court, pursuant to 35
U.S.C. § 271(e)(4) (A) (1988), ordered that the effec-
———E—EE——
6a
tive date of any approval by the FDA of cefadroxil DC
for commercial distribution and sale by Zenith could be
no earlier than March 12, 2002, the expiration date of
the ‘657 patent. Jd. at 1676. It subsequently certified the
finality of that judgment pursuant to Rule 54(b) of the
Federal Rules of Civil Procedure. Zenith then filed this
appeal.
DISCUSSION
Zenith presents five separate grounds on which the
judgment of the trial court should be reversed. First, the
claim of the ‘657 patent, properly construed, does not
cover Bouzard crystals which might form momentarily in
a patient’s stomach. Second, even assuming conversion
in vivo is within the scope of the claim, there was a
failure of proof as to whether any crystals, formed in the
stomach from ingested cefadroxil DC, literally infringe the
‘657 patent. Third, even if such crystals formed, there
would be no infringing “use” within the meaning of 35
U.S.C. § 271(a) (1988). Fourth, the doctrine of equiva-
lents, applied in reverse, precludes a judgment of literal
infringement. And fifth, the court erroneously declined to
grant summary judgment that Bristol was equitably es-
topped from asserting that cefadroxil DC infringed the
Bouzard patent.
1.
We begin with claim construction: whether the claim
of the ’657 patent, properly construed, covers Bouzard
crystals which might form momentarily in a patient’s
stomach. Zenith argues that, due to statements made by
Bristol during the ’657 prosecution, the ‘657 claim is
limited to the pre-ingested, powdered form of Bouzard
monohydrate. In those statements Bristol particularly
emphasized the superior manufacturing-related benefits of
the pre-ingested form of Bouzard monohydrate in relation
to prior forms of cefadroxil. Bristol, it is argued, thus
relinquished coverage of any forms of cefadroxil DC that
do not exhibit these manufacturing-related characteristics
=<
ee ee ee
Ja
—that would obviously include any Bouzard monohydrate
formed in a patient’s stomach.
Zenith has a point. Prosecution history serves as a
limit on the scope of claims by excluding any interpreta-
tion of the claim language that would permit the patentee
to assert a meaning for the claim that was disclaimed or
disavowed during prosecution in order to obtain claim
allowance. Standard Oil Co. v. American Cyanamid Co.,
114 F.2d 448, 452, 227 USPQ 293, 296 (Fed. Cir.
1985). The prosecution history in this case is replete
with arguments by Bristol that the importance of this
invention was the discovery of a way to manufacture the
known compound so as to make it commercially available
for medical treatment.
The difficulty with Zenith’s argument, however, is in
the nature of the’sole claim in the patent. The claim as
written and allowed simply describes a compound having
specified chemical properties. The question before us
is not one of validity: whether the claim would be pat-
entable over the prior art if the suggested restriction were
not applicable. The question here is one of infringement:
whether there is anything in the claim as issued that limits
it to the pre-ingested form, keeping in mind the principle
that it is improper to read a limitation into a claim
“wholly apart from any need to interpret what the pat-
entee meant by particular words or phrases in the claim.”
E.I. Du Pont de Nemours & Co. v. Phillips Petroleum
Co., 849 F.2d 1430, 1433, 7 USPQ2d 1129, 1131 (Fed.
Cir.), cert. denied, 488 U.S. 986 (1988).
Zenith nonetheless argues that the term “properties” in
the claim is the vehicle for incorporating its proposed
restriction into the claim. But that term plainly refers to
x-ray diffraction properties. X-ray diffraction properties
have nothing to do with the manufacturing benefits which
Bristol highlighted.
Zenith’s argument suffers from additional infirmities.
The ’657 claim is a claim for a compound. Its patentabil-
8a
ity thus derives from the structure of the claimed com-
pound in relation to prior compounds. See In re Spada,
911 F.2d 705, 708, 15 USPQ2d 1655, 1657 (Fed. Cir.
1990). The relevance to patentability of the properties or
characteristics exhibited by the compound is limited to
assessing the significance of the structural distinctions of
the claimed compound over the prior art. Second, as we
later note in more detail, it is not at all clear that the
statements concerning these characteristics played a de-
terminative or even significant role in the Patent and
Trademark Office’s (PTO’s) decision to grant the patent.
We conclude, therefore, that while the claim as issued is
limited to the crystalline form of cefadroxil exhibiting the
specified x-ray diffraction pattern, it is not limited to the
compound in its pre-ingested form with the manufacturing
characteristics which Bristol emphasized during prosecu-
tion.*
y
We turn next to the question of whether Bouzard mono-
hydrate is actually found in the stomach of patients who
ingest cefadroxil DC. One answer is that no one knows—
the scientific fact appears to be that there is no known
way to actually sample the contents of patients’ stomachs
at the precise moment and conduct the x-ray diffraction
analyses required to ascertain if all 37 lines described in
the patent are present. ;
For its proof Bristol offered instead the testimony of its
principal scientific witness, Dr. Harry Brittain, who de-
scribed various studies and experiments simulating the
environment of the human stomach which were conducted
under his auspices; Zenith countered with the testimony
of its principal scientific witness, Dr. Martha Greenblatt.
The trial judge, after hearing all the evidence, concluded
4The trial court apparently reached the same conclusion: “use
of converted Bouzard monohydrate by a patient who ingests cefa-
droxil DC is an infringing use.” (But see note 6 regarding the
significance of the term ‘use.’)
9a
that the Bouzard monohydrate in fact does inevitably
form in the patient’s stomach after ingestion of cefadroxil
DC. In deciding this issue, the court specifically resolved
the conflicting testimony presented by Dr. Brittain and
Dr. Greenblatt:
[T]he Court finds that Brittain has established by a
preponderance of evidence, well within his range of
expertise, that cefadroxil DC in fact converts in vivo
to Bouzard monohydrate.
The strength of Brittain’s experiments and results
is their totality. Piece by piece, Brittain built an im-
pressive collection of data. The results of each series
of experiments strengthen the results of each other
set of experimental results. The total effect of the
experiments is to prove with sufficient certainty the
fact of conversion in vivo.
* * * *
[A]lthough she may have significant expertise in
fields of inquiry unrelated to the issues in this case,
Greenblatt demonstrated little understanding of the
problem at issue in this case or the reason for her
procedures and thus played no role in the design of
her experiments, . . ., was lax in her methodology,
particularly in the recording of her procedures and
observations, and in fact did not even participate in
the second series of experiments. The Court finds
that Brittain’s . . . results are simply better supported
and vastly more credible. According, those findings
are adopted by the Court.
Zenith I], 24 USPQ2d at 1664, 1668.
Courts of law are not the optimal fora for trying ques-
tions of scientific truth; even less are appellate courts
equipped to choose among conflicting scientific theories.
Judges are dependent on the quality and strength of the
scientific evidence brought before them. The trial judge
who hears the witnesses and does the initial assessment of
ee
10a
the evidence deserves considerable latitude in eventually
choosing sides based on what is ultimately an educated
guess—that is what judging is about.
However, in determining whether a claim in a patent
has been infringed, the scientific theories utilized must
establish the presence of the limitations recited in the
claim. In this case, Dr. Brittain based his scientific con-
clusions on three kinds of tests—visual observation (ob-
tained through optical microscopy), birefringence com-
parison, and x-ray diffraction pattern comparison. The
trial judge explained:
Brittain first established indisputably through photo-
micrography that cefadroxil DC crystals are much
smaller than Bouzard monohydrate crystals, and are
much different in shape. He also established that
cefadroxil DC crystals exhibit a much weaker bi-
refringence than do crystals of Bouzard monohydrate,
which are highly birefringent. Thus, through micro-
scopy, Brittain could determine with a high degree
of certainty whether a sample of wetted cefadroxil
DC had changed its crystalline form, and could con-
clude to a lesser extent that the form to which it
had changed was Bouzard monohydrate. Although
changes in the physical properties of shape, size and
birefringence of the cefadroxil DC crystals could be
conclusively determined through microscopy, Brittain
could not determine by observation clone that the
larger, more birefringent crystals were necessarily
Bouzard. To determine conversion to Bouzard with
great certainty, Brittain ran x-ray powder diffraction
patterns, a technique that in essence takes the “finger-
print” of a crystalline compound. Through x-ray dif-
fraction analysis, Brittain determined with much
greater confidence that all of the conversions sus-
pected after optical examination had in fact been
to Bouzard monohydrate. (Emphasis added).
Id. at 1665.
lla
The key piece of evidence, then, was the x-ray diffraction
pattern analysis. This is also what the claim in the patent
requires. The first two kinds of tests are only inferen-
tially relevant given that the claim is drafted in terms of
x-ray diffraction lines. Thus they cannot substitute for
a proper comparison of those lines.
And here a major problem arises. In order to establish
its case, Bristol had to show that the accused compound
infringed the claim contained in the patent.© This re-
quired Bristol to show that the diffraction pattern of
cefadroxil DC following its conversion in vivo displayed
the same diffraction pattern as that of the claimed com-
pound. The district court, instead of requiring the com-
parison of the accused compound following conversion to
be made with the lines specified in the claim, allowed
Bristol to make the comparison with the diffraction pat-
tern exhibited by a sample (the reference pattern) of a
material considered by Bristol to be the patented com-
pound.
As we have repeatedly said, it is error for a court to
compare in its infringement analysis the accused product
or process with the patentee’s commercial embodiment or
other version of the product or process; the only proper
comparison is with the claims of the patent. E.g., Martin
v. Barber, 755 F.2d 1564, 1567, 225 USPQ2d 233, 235
(Fed. Cir. 1985).
The difficulty was compounded. The x-ray diffraction
pattern exhibited by Bristol’s sample (the reference pat-
tern) consisted of a table of only 30 lines of relative
intensities. Of this total, the court only compared 22
lines to corresponding lines recited in the claim. Zenith
II, 24 USPQ2d at 1665. Based on its comparison, the
court concluded the two were sufficiently similar to per-
5 A finding that a claim is infringed is a necessary prerequisite
to a finding that there has been an act constituting inducement to
infringe under § 271(b). See Met-Coil Sys. Corp. v. Korners Un-
limited, Inc., 803 F.2d 684, 687, 231 USPQ 474, 477 (Fed. Cir.
1986).
12a
mit Bristol to use the reference pattern in its infringe-
ment analysis. In fact, the number of lines recited in the
claim is 37. Thus, 15 of the lines recited in the claim
(representing about 40% of the total) were not consid-
ered by the court in its comparison. Although the term
“essentially” recited in the claim permits some leeway in
the exactness of the comparison with the specified 37°
lines of the claim, it does not permit ignoring a substan-
tial number of lines altogether. It is the claim that sets
the metes and bounds of the invention entitled to the
protection of the patent system.
On the basis of this evidence the trial court concluded
that when cefadroxil DC is ingested Bouzard monohy-
drate is created in a patient’s stomach, that that con-
stitutes an infringing use, and that therefore the sale of
cefadroxil DC by Zenith would constitute inducement of
infringement under 35 U.S.C. § 271(b). Since the find-
ing of infringement was based on testimony which incor-
porated an improper comparison, and since that com-
parison was an essential element in the conclusion that
infringement occurred, the conclusion that Zenith by sell-
ing cefadroxil DC would engage in inducement of in-
fringement is insupportable. Zenith is correct that there
was a failure of proof as to whether any crystals, assumed
to form in the stomach from ingested cefadroxil DC, lit-
erally infringe the ’657 claim. In the absence of evidence
comparing the “657 claim with the cefadroxil DC after
ingestion Bristol has failed to establish any infringing
use and therefore we must reverse the district court’s con-
clusion that Zenith’s sale of cefadroxil DC induces in-
fringement of the ’657 patent.®
6 As noted previously, Zenith offered three other grounds on
which the judgment of the trial court could be reversed: an inci-
dental conversion to Bouzard crystals does not “use” the claimed
compound; the reverse doctrine of equivalents forecloses literal
infringement by conversion; and equitable estoppel. In view of our
disposition of the appeal we need not address these other grounds
for reversal.
13a
3.
On the question of infringement under the doctrine of
equivalents, the trial court decided for Zenith, finding
that Bristol, through statements it made during the “657
prosecution, was estopped via prosecution history estoppel
from asserting that cefadroxil DC infringed under the
doctrine of equivalents. According to Bristol, this was
error, because the statements relied on by the district
court do not support a finding that there was an estoppel;
thus the doctrine of equivalents, properly applied, pro-
vides an alternative ground on which the judgment for
Bristol could be affirmed.
Bristol’s point has merit. The essence of prosecution
history estoppel is that a patentee should not be able to
obtain, through litigation, coverage of subject matter re-
linquished during prosecution. See Loctite Corp. v. Ultra-
seal Ltd., 781 F.2d 861, 870, 228 USPQ 90, 96 (Fed.
Cir. 1985). The legal standard for determining what sub-
ject matter was relinquished is an objective one, meas-
ured from the vantage point of what a competitor was
reasonably entitled to conclude, from the prosecution his-
tory, that the applicant gave up to procure issuance of
the patent. See Prodyne Enters., Inc. v. Julie Pomerantz,
Inc., 743 F.2d 1581, 1583, 223 USPQ 477, 478 (Fed.
Cir. 1984); Kinzenbaw v. Deere & Co., 741 F.2d 383,
389, 222 USPQ 929, 933 (Fed. Cir. 1984), cert. denied,
470 U.S. 1004 (1985). Here, we do not believe a com-
petitor would have been reasonably justified in concluding
that Bristol, through the statements in question, gave up
coverage of those forms of Bouzard monohydrate other
than the pre-ingested form.
There is nothing in the record indicating that the state-
ments about manufacturing benefits played any role in the
procurement of the ‘657 patent. As noted earlier, in these
statements Bristol argued the superior manufacturing-
related characteristics exhibited by Bouzard monohydrate
in relation to prior forms of cefadroxil. Yet, these prior
14a
forms of cefadroxil were never asserted as prior art by
the examiner, and the examiner expressly indicated that
Bristol’s assertions were not a factor in determining pat-
entability. Moreover, according to the examiner’s state-
ment of reasons for allowance, the sole basis upon which
allowance was challenged, and upon which the ’657 pat-
ent was eventually issued, was related to a single prior
art reference, Garbrecht, U.S. Patent No. 3,781,282," and
Bristol’s successful showing that the claimed compound
was not inherent in that reference. There is no indication
the examiner ever relied on the statements regarding
manufacturing-related characteristics in allowing the pat-
ent to issue.*
Zenith asserts that the statements in question fore-
stalled an obviousness rejection of the claim on the basis
of the prior forms of cefadroxil. That, however, is at
best highly speculative; it is unpersuasive in view of the
examiner’s statement of reasons for allowance. Thus, the
7 According to MPEP § 1302.14:
One of the primary purposes of [a statement of reasons for
allowance] is to improve the quality and reliability of issued
patents by providing a complete file history which should
clearly reflect, as much as is reasonably possible, the reasons
why the application was allowed. Such information facilitates
evaluation of the scope and strength of a patent by the patentee
and the public and may help avoid or simplify litigation of a
patent.
The absence of any reference to the manufacturing related char-
acteristics in the statement of reasons for allowance supports our
conclusion that the examiner did not rely on such characteristics in
issuing the patent.
8 Although actual reliance by the examiner need not be shown,
if an estoppel is to rest upon argument made during the examina-
tion process, the circumstances must be such as to permit the infer-
ence that such reliance in fact occurred. A showing that the con-
duct in question played a material role in the issuance of the patent
usually suffices. See Mannesmann Demag Corp. v. Engineered Metal
Prod., 793 F.2d 1279, 1285, 280 USPQ2d 45, 48 (Fed. Cir. 1986).
I srs actin AN ar Te
15a
court’s conclusion, that the statements in question gave
rise to prosecution history estoppel, is insupportable.
However, any error in the court's application of pros-
ecution history estoppel was harmless; the court’s conclu-
sion that the doctrine of equivalents is inapplicable to this
case is correct as a matter of law. To prove infringe-
ment under the doctrine of equivalents, Bristol bore the
burden of showing that cefadroxil DC was the equivalent
of Bouzard monohydrate. See Corning Glass Works v.
Sumitomo Elec., U.S.A., Inc., 868 F.2d 1251, 1259, 9
USPQ2d 1962, 1967 (Fed. Cir. 1989). A necessary
part of the function/way ‘result equivalency analysis is the
function of the substituted element as seen in the context
of the patent, the prosecution history, and the prior art.
Graver Tank & Mfg. Co. v. Linde Air Products Co., 339
U.S. 605, 609 (1950), reh’g denied, 340 U.S. 845
(1950).
In view of Bristol’s numerous statements in the prosecu-
tion history regarding the superior manufacturing-related
benefits of the Bouzard crystal in relation to the prior
forms of cefadroxil, it is clear that the primary, if not the
only, function of the Bouzard crystal form of the drug
as compared to other forms is to facilitate pre-ingestion
manufacturing. No other intended function is described
or suggested. Since any unanticipated production of the
Bouzard crystal in the patient's stomach as a result of
ingesting cefadroxil DC does not even remotely perform
that function, the “function” part of the function/way/
result test of equivalency is not met. As a matter of law,
there can be no infringement under the doctrine of
equivalents.
Bristol cites a number of cases to demonstrate that the
doctrine of equivalents has been applied to find infringe-
It is self-evident that the function cannot be described more
broadly, i.e. as the delivery of therapeutic value to the patient, for
that is the function attributable to cefadroxil per se, which is prior
art in relation to Bouzard monohydrate.
16a
ment in situations involving in situ or in vivo conversions.
However, these cases do not support Bristol’s argument.
In two, Broadview Chemical Corp. v. Loctite Corp., 159
USPQ 80 (D. Conn. 1968), aff'd in relevant part, 406
F.2d 538, 160 USPQ 449 (2d Cir.), cert. denied, 394
U.S. 976 (1969) and Studiengesellschaft Kohle, M.b.H.
v. Dart Industries, Inc., 549 F. Supp. 716, 216 USPQ
381 (D.Del. 1982), aff'd, 726 F.2d 724, 220 USPQ 841
(Fed. Cir. 1984), the doctrine of equivalents was not
the issue in the case.”® In the others, Atlas Powder Co.
v. E.I. DuPont de Nemours & Co., 588 F. Supp. 1455,
221 USPQ 426 (N.D. Tex. 1983, aff'd, 750 F.2d 1569,
224 USPQ 409 (Fed. Cir. 1984); Chemical Cleaning
Corp. v. Dow Chemical Co., 379 F.2d 294, 155 USPQ
49 (Sth Cir. 1967), cert. denied, 389 U.S. 1040 (1968);
Ortho Pharmaceutical Corp. v. Smith, 18 USPQ2d 1977
(E.D. Pa. 1990), aff'd, 959 F.2d 936, 22 USPQ2d 1119
(Fed. Cir. 1992); and Beecham Group Ltd. v. Bristol
Lab. Ltd., [1978] R.P.C. 153 (House of Lords 1977),
the substituted compound or ingredient converted in vivo
or in situ to the compound or ingredient called for by
the claim, and performed the same function as that of the
claim. The infringer was thus using the equivalent ele-
10 In Broadview, the claimed ingredient was found to be present
in the accused product independently of the purportedly substituted
ingredient. 406 F.2d at 541-42, 160 USPQ at 451. Thus, that
product literally infringed. Equivalence between the two ingredi-
ents was not an issue in the case. In Studiengesellschaft, although
it was unclear whether the trial judge had made findings on the
doctrine of equivalents issue, we concluded on appeal that any
such findings were inappropriate and unnecessary insofar as the
court’s judgement was sustainable on the basis of literal infringe-
ment. 726 F.2d at 728, 220 USPQ at 843.
11J[n Atlas Powder, it was found that the substituted compound—
an oil-in-water emulsifier—converted in situ to the claimed com-
pound—a water-in-oil emulsifier—which in turn performed its
intended function—forming an emulsion between oil and water.
588 F. Supp. at 1472, 221 USPQ at 440, aff’d, 750 F.2d at 1581, 224
USPQ at 417. In Chemical Cleaning, it was determined that the
substituted compound—monomethylolthiourea—disassociated in up-
| |
17a
ment to perform the same function as the claimed com-
pound, a typical case for doctrine of equivalents appli-
cation.
Even assuming that cefadroxil DC converts in vivo
to Bouzard monohydrate in measurable amounts, that par-
ticular crystalline form does not perform the function of
facilitating encapsulation. On the record before us, the
trial court was correct in his judgment that Bristol had
failed to establish infringement under the doctrine of
equivalents.
CONCLUSION
For the reasons given, the judgment of the trial court
in favor of Bristol on count one is reversed.
REVERSED
eration to form the claimed compound—thiourea—which in turn
performed its intended function—acting as a sequestering agent
for copper. 379 F.2d at 296, 155 USPQ at 49. In Ortho, it was
found that the substituted compound—norgestimate—converted in
vivo to the claimed compounds—norgestral and norgestral ace-
tate—which in turn performed their intended function—contra-
ception. 18 USPQ2d at 1985-86, aff'd, 959 F.2d at 939, 22 USPQ2d
at 1122. Finally, in Beecham, it was determined that the substi-
tuted compound—hetacillin—converted in vivo to the claimed com-
pound—ampicillin—-which in turn performed its intended function
—acting as an antibiotic. [1978] R.P.C. at 167, 182-83, 202.
18a
APPENDIX B
DISTRICT COURT
D. NEW JERSEY
No. 91-3423
ZENITH LABORATORIES INC.
V.
BRISTOL-MYERS SQUIBB Co.
Decided July 21, 1992
Wolin, J.
Bristol-Myers Squibb Company (“Bristol”), a Dela-
ware corporation, is the owner of United States Patent
No. 4,504,657 (“the ‘657 patent”), issued on March 12,
1985. The ’657 patent includes a single claim for a spe-
cific crystalline form of cefadroxil monohydrate (herein-
after “Bouzard monohydrate”). Cefadroxil is a ceph-
alosporin antibiotic compound that has a number of
medical uses. Bristol previously owned the now-expired
1The patent claim reads:
We claim:
1. Crystalline 7-[D-c-amino-a- (p- hydroxypheny) I- aceta-
mido] -3-methyl-3 -cephem-4- carboxylic acid monohydrate ex-
hibiting essentially the following x-ray diffraction properties:
[followed by a table of numbers corresponding to the x-ray
diffraction characteristics of the Bouzard monohydrate]
(United States Patent No. 4,504,657 at page 18, lines 65-69).
cli angina Mt ae Nt
19a
United States Patent No. 3,489,752, which issued on
January 13, 1970 and claimed all forms of cefadroxil.
This action was filed by Zenith Laboratories, Inc.
(“Zenith”), a New Jersey corporation, against Bristol on
August 5, 1991. Among other claims for relief, Zenith
seeks a declaration that “cefadroxil DC”, a hemihydrate
form of cefadroxil for which Zenith has obtained Food
and Drug Administration (“FDA”) approval to market in
finished dosage form as a generic equivalent of cefadroxil
monohydrate, does not infringe the ’657 patent.? Although
Bristol does not contend that cefadroxil DC infringes the
‘657 patent in its manufactured, pre-ingested state, it
does contend that after ingestion, the drug “converts” to
the Bouzard monohydrate inside the body, or “in vivo,”
and that such conversion renders cefadroxil DC an in-
fringing compound under the docirine of equivalents, or
alternatively, that sales of cefadroxil DC by Zenith would
constitute inducement of infringement of the ’657 patent.
In an Opinion dated February 21, 1992, the Court
granted summary judgment in Zenith’s favor on the issue
of in vivo conversion, and found that Zenith was entitled
to a declaration that cefadroxil DC does not infringe the
‘657 patent. An Order reflecting this ruling was filed on
March 4, 1992. On motion for reconsideration, in an
Opinion and Order dated April 13, 1992, the Court
vacated its March 4, 1992 Order, motivated in substantial
part by the uncommon manner and speed by which the
record was created for the motion, and by how early in
the proceedings the motion was brought. Recognizing the
immediacy of the rights at stake, the Court set down the
issue of infringement for trial on an accelerated basis
following expedited discovery.
2A hemihydrate is a crystal form containing two molecules of
water for each molecule of a chemical compound. A monohydrate
contains one water molecule for each molecule of the chemical com-
pound.
_—— SE ~~--~--~r—Seststt
20a
The issue of infringement was tried to the Court be-
tween May 26, 1992 and June 5, 1992, during which six
days of evidence was received. The primary factual issue
at trial was whether cefadroxil DC converted in vivo to
the Bouzard monohydrate. Set forth below is a summary
of the testimony at trial, and the Court’s findings of fact
and conclusions of law as required by Federal Rule of
Civil Procedure 52(a). Based on these findings and con-
clusions, a judgment will be entered in Bristol’s favor.
I. THE EVIDENCE AT TRIAL
The evidence at trial consisted for the most part of
expert testimony presented by both parties. Both parties’
experts conducted a number of experiments to investigate
whether cefadroxil DC converts in vivo to the Bouzard
monohydrate. These experts were presented as witnesses
to explain their theories of conversion, experimental meth-
odologies, test results, and conclusions based on those
results. Additional experts were presented to provide
foundations for assumptions made by some of the experts
who conducted experimental studies, or to rebut the as-
sumptions, methodologies, theories, or conclusions of other
expert witnesses. The Court will summarize each party’s
case in the order presented at trial.
A. Zenith’s Direct Case
C. David Smith
Zenith’s first witness was C. David Smith, its vice-
president of quality assurance. Mr. Smith testified as to
the status of Zenith’s FDA application, and as to the
formulation for Zenith’s cefadroxil DC capsules. He testi-
fied that the capsules contain, in addition to the cefadroxil
material, lactose, sodium starch glycolate and magnesium
stearate. (Tr. 17)*° These nonactive ingredients, known
as “excipients”, are included in the capsules for different
purposes. Lactose is used as a filler. Sodium starch
3 “Tr, ____” refers to the trial transcript at the page indicated.
2la
glycolate swells greatly when exposed to water, and is
included as a disintegrant to break apart the capsule. (Tr.
18) Magnesium stearate is a lubricant useful in machin-
ing the capsules. (/d.)
Edwin C. Rothstein
Zenith next presented the testimony of Edwin C. Roth-
stein, president of Leberco Testing, Inc. (“Leberco”), an
independent testing laboratory located in New Jersey.
Leberco was retained by Zenith to perform dissolution
and solubility tests on cefadroxil DC and the Bouzard
monohydrate, both in their formulated and bulk forms.
1. Dissolution Tests
Rothstein testified that Leberco technicians conducted
dissolution tests in which they recorded the rates at which
500 milligram capsules of cefadroxil DC and Bouzard
monohydrate dissolved into simulated gastric juice. (Tr.
39) The tests were performed by placing 500 milligram
capsules in a dissolution basket rotated at 100 revolutions
per minute (“rpm”) in 900 milligrams of simulated gastric
juice without enzymes. (PX 21)* The percentage of ma-
terial dissolved into the dissolution media was measured
and recorded at intervals of 3, 5, 7.5, 10 and 20 minutes.
(Id.) Six runs were performed and averaged on each sub-
stance. From the results of this experiment, Rothstein
concluded that between three and five minutes, cefadroxil
DC had a higher dissolution rate than the Bouzard mono-
hydrate. (Tr. 40) He also concluded that cefadroxil DC
had a higher total solubility than Bouzard monohydrate.
(Id.) The same tests were run using 1000 milligram
tablets. (Id.) Rothstein concluded that the results of this
experiment were essentially the same as with the first test.
(Tr. 40-41; PX 22)
4“PxX ” refers to plaintiff's exhibit numbered as indi-
cated. Likewise, “DX ” refers to the indicated defendant’s
exhibit.
22a.
Rothstein testified that Leberco performed an addi-
tional experiment designed to determine whether the dis-
solution rates observed were affected in any way by any
difference between the Zenith gelatin capsule and the
Bristol gelatin capsule. The experiment consisted of com-
paring the dissolution rate of 350 milligrams of cefadroxil
DC in a Zenith capsule with the dissolution rate of 350
milligrams of cefadroxil DC in a Bristol capsule. (PX
23) From the measured results of this test, Rothstein con-
cluded that the gelatin capsule shell had no effect on
the dissolution rates of the two cefadroxil materials. (Tr.
41)
One further dissolution experiment was conducted by
Leberco. A comparison was made of the dissolution of
capsules of cefadroxil DC and Bouzard monohydrate in
30 milliliters of simulated gastric juice at 37° C in a dis-
solution basket rotated at three rpm. (PX 24) Rothstein
testified that the dissolution test could not be performed
due to the small quantity of fluid used. (Tr. 42) There-
fore, only visual observations could be made. (Jd.) Roth-
stein testified that after three minutes, the Zenith capsule
had released most of its contents, but that the Bristol
capsule still contained most of its contents. (/d.)
2. Solubility and Bulk Density Tesis
Rothstein testified that Leberco technicians performed
solubility tests on cefadroxil DC and Bouzard mono-
hydrate. Solubility is a measure of the quantity of a given
material that can be dissolved in a given solvent at a given
temperature and pressure in a given volume. (Tr. 46)
Rothstein testified that five grams of a material was placed
in 100 milliliters of deionized water that was maintained
at a specific temperature and intermittently agitated for
ten hours. Undissolved materials were then filtered, and
the clear filtrate was then spectrophotometrically analyzed:
to determine its cefadroxil content. (Jd.) This was done
for each cefadroxil material at three temperatures: 4°C,
23a
room temperature (between 23°C and 25°C) and 50°C.
(Id.) From the test results obtained (see PX 25, 26),
Rothstein concluded cefadroxil DC is “clearly more solu-
ble” than the Bouzard monohydrate under the conditions
utilized. (Tr. 43)
Leberco also measured the bulk densities of cefadroxil
DC and Bouzard monohydrate. (PX 25) From the tests,
Rothstein concluded that cefadroxil DC has a bulk density
considerably lower than that of Bouzard monohydrate.
Dr. Martha Greenblatt
The testimony of Dr. Martha Greenblatt was offered
into evidence on Zenith’s direct case through deposition
transcript. Greenblatt was deposed by Zenith de bene
esse on May 21, 1992. The transcript was accepted into
evidence without objection. On Zenith’s rebuttal case,
Greenblatt testified in court.
Greenblatt is a professor at Rutgers University in New
Jersey who teaches solid state chemistry, and is an expert
in x-ray crystallography. (Deposition Tr. 5) She was
asked to perform an experiment that was intended to
determine whether, at the time a capsule of cefadroxil
DC bursts in simulated gastric acid, cefadroxil DC has
already converted to Bouzard monohydrate. This was ac-
complished by Greenblatt placing a Zenith capsule in
simulated gastric acid until the capsule breached, and at
the moment that cefadroxil began to pour out of the cap-
sule, she froze the material in liquid nitrogen. (Dep. 11)
This experiment was repeated. She then freeze-dried the
frozen samples, and recorded the x-ray powder diffraction
patterns of two samples. (Dep. 15-16; PX 31)
In the first experiment, Greenblatt placed a Zenith
capsule in a dissolution basket that was then immersed
in 100 milliliters of simulated gastric acid maintained at
37°C and rotated at six rpm. At one minute, 54 seconds,
Greenblatt observed that the capsule had burst, and re-
24a
moved the basket from the beaker and placed it into the
liquid nitrogen within five seconds. A second experiment
was performed in which Greenblatt observed a burst in
the capsule at approximately two minutes. Both frozen-
samples were placed in a freeze-drier overnight.
The next day, 20 hours after the samples were frozen
(Tr. 894), x-ray diffraction patterns of the samples were
recorded and designated Z1 and Z2. (PX 31) These pat-
terns were compared to “standard” patterns made from
samples of cefadroxil DC and Bristol’s Bouzard monohy-
drate.’ According to Greenblatt, the patterns for Z1 and
Z2 were “identical” to the standard cefadroxil DC pat-
tern. (Dep. 17) From the comparison, Greenblatt con-
cluded that the cefadroxil DC samples she placed in acid
and freeze-dried had not undergone any structural change
in their crystal form. (Dep. 22)
Dr. Ralph R. Pfeiffer
Dr. Pfeiffer is a consultant at Purdue School of Phar-
macy in the solid state drug chemistry group. (Tr. 65)
He also does consulting and teaches seminars on poly-
morph formation and solvate formation, most recently
for the F.D.A. (Tr. 66) He has extensive experience, in-
cluding 30 years at Eli Lilly Company, in x-ray powder
diffraction analysis, in the identification of polymorphs
and solvates of drugs, and in other areas related to crystal
formation and behavior. (Tr. 66) Pfeiffer was offered as
an expert in x-ray powder diffraction analysis, crystal
theory and the behavior of oral drug dosages in the hu-
man body.
Pfeiffer testified as to his comparison of x-ray diffrac-
tion patterns of cefadroxil DC and a prior art form of
cefadroxil known as “Gottstein” cefadroxil. (Tr. 71-2)
For the Gottstein pattern, Pfeiffer relied on the pattern
attached to the declaration of Timothy Marr, which was
5 Greenblatt verified that the patterns obtained from bulk cefa-
droxil DC and formulated DC with excipients were identical.
25a
filed with the United States Patent and Trademark Of-
fice in 1982. (Tr. 71; PX 33) Zenith also offered the
declaration of David Whitehead, which was also filed with
the United States Patent and Trademark Office, in which
Whitehead declared that the Gottstein material utilized by
Mar had not changed in the eleven years since it was first
prepared. (PX 37) Pfeiffer used one of Dr. Greenblatt’s
patterns as representative of cefadroxil DC. (Tr. 71) He
concluded, after comparing the patterns, that cefadroxil
DC and Gottstein cefadroxil “are of the same crystal
structure.” (Tr. 72) Based on this conclusion, Pfeiffer
also concluded that the structure-dependent properties of
both materials—including equilibrium solubility, melting
point and density—would be the same. (Tr. 82-83)
Pfeiffer further opined that if one material converted to
the Bouzard monohydrate when exposed to an aqueous
environment, so would the other. (Tr. 83)
Dr. Pfeiffer testified that in his opinion, it was unlikely
that cefadroxil DC could convert in vivo to the Bouzard
monohydrate. (Tr. 83-84) He believed that a number of
conditions existed in tre stomach that would preclude
the dissolution and recrystallizatton processes that would
be required for conversion. (Tr. 84) Specifically, he be-
lieved that cefadroxil DC would dissolve very quickly in
the stomach and prevent the creation of a super-saturated
environment needed for recrystallization. (Tr. 88-89) In
addition, Pfeiffer believed that the mixing action of the
stomach would tend to disperse any super-saturated region
that might otherwise form. (Tr. 89)
Dr. Pfeiffer testified further as to the conditions that
he believed were necessary for conversion to occur. In
addition to the super-saturated solution, he testified that
nucleation must occur. (Tr. 89) Conditions that could
produce nucleation include evaporation, cooling of the
solution, and inducement of mechanical stress. (Tr. 90)
Recrystallization could also occur if nuclei were already
present. (Tr. 90) Pfeiffer opined that none of these con-
ditions are present in the stomach. (Tr. 91)
SER ee eT
as
|
26a
Pfeiffer testified as to the conclusions that he drew
from the tests performed by Leberco, introduced through
Dr. Rothstein. He concluded from the results of the
equilibrium solubility tests performed by Leberco that
cefadroxil DC did not convert to Bouzard monohydrate
because at the end of ten hours in simulated gastric acid,
different amounts of the two material dissolved into iden-
tical volumes of the fluid. To Pfeiffer, this indicated that
no conversion occurred because if it had, equal amounts
of material would have dissolved. (Tr. 92) This is true
even though, in their dissolved states, cefadroxil DC and
Bouzard monohydrate are identical—they are simply the
compound cefadroxil. (Tr. 92)
On one-last topic, Pfeiffer opined that Dr. Greenblatt’s
experiments minimized the chance that changes would
occur in cefadroxil DC after it had been removed from
the dissolution medium. (Tr. 93) He further agreed with
her conclusion that no conversion had occurred. (Tr. 93)
B. Bristol’s Case
Dr. Howard Goldin
Bristol’s first witness, Dr. Goldin, is a Board-certified
doctor of internal medicine and gastroenterology. (Tr.
246) He was offered as an expert on the conditions that
exist inside the human stomach. Goldin was asked to
provide a protocol for simulating stomach conditions,
which could be used in in vitro experiments intended to
determine whether cefadroxil DC converted in vivo to the
Bouzard monohydrate. (Tr. 253) According to Goldin,
ethical constraints precluded actual in vivo experiments
from being conducted for this purpose. (Tr. 253)
The protocol provided by Goldin consisted of the use
of 30 milliliters of actual gastric juice maintained at body
temperature (37°C) and gently agitated at three rpm.
(Tr. 254, 264) Goldin also recommended that simulated
gastric juice (a 0.1 solution of hydrochloric acid) could be
EAI MARE IRN Rp eo
27a
used. (Tr. 255) The stirring rate was chosen as an
approximation of the agitation that occurs in the stomach.
Goldin testified that for the most part, the stomach is in
a flaccid state, with only intermittent gentle waves that
“barely agitate the contents of the stomach.” (Tr. 265)
For only approximately five out of every 90 to 120 min-
utes are there- vigorous contractions in the stomach. (Tr.
265) An in vitro stirring rate of 100 rpm, in Dr. Goldin’s
opinion “far exceed[s] the physiologic spectrum of the
human stomach.” (Tr. 270)
Samples of actual gastric juice provided to Bristol for
experimentation uses by Dr. Goldin were obtained from
Goldin’s patients during a routine suction of the contents
in preparation for an endoscopic examination. (Tr. 265-
66) The patients had all fasted prior to the examination.
(Tr. 265) Most of the gastric acid obtained had a pH
of between one and two. (Tr. 266) The average volume
of acid suctioned from the patients was 30 milliliters. (Tr.
267) Essentially all of a stomach’s contents are removed
by the suctioning. (Tr. 267) The pH of gastric acid in
a non-fasting patient is generally higher (less acidic) due
to neutralization by the ingested solids or liquids. (Tr.
266)
Goldin opined that experiments utilizing his specified
conditions would simulate in vivo conditions. (Tr. 270)
He further opined that he did not believe that much of a
difference would be observed if gastric acid from non-
fasting patients were used, even if it consisted of a greater
volume of fluid. (Tr. 274-75) Goldin opined that a vol-
ume of gastric acid between 30 and 240 milliliters was
within the physiologic range of the human stomach. (Tr.
278) He also opined that a stirring rate between three
and ten rpm would also be within that range, but that 25
rpm would fall outside of the range. (Tr. 281-82)
Goldin ultimately concluded that he would expect con-
version to occur in vivo if it occurred in vitro under the
conditions that he specified. (Tr. 284-85)
28a
Dr. Robert J. Levine
The testimony of Dr. Levine was offered into evidence
by Bristol through deposition transcript. Levine was
deposed by Bristol de bene esse on May 11, 1992. The
transcript was accepted into evidence without objection as
defendant’s exhibit 20. (Tr. 317-18)
Levine is a professor of medicine at Yale University
School of Medicine in Connecticut, specializing in medical
ethics. (Dep. 5) His previous experience included serving
as chief of the clinical pharmacology section at Yale Uni-
versity School of Medicine. (Dep. 11) He has reviewed
more than 5,600 proposals to do medical research on
human subjects. (Dep. 13) In Levine’s opinion, no insti-
tutional review board would approve research on human
subjects solely to defend a patent. (Dep. 14-15) He
further opined that he did not believe that an in vivo
experiment could be designed to test whether cefadroxil
DC converts to Bouzard monohydrate that would not be
subject to the same criticisms to which the in vitro experi-
ments have been subjected. (Dep. 15)
Dr. Gerond V. Lake-Bakaar
Dr. Lake-Bakaar is a } sician who, like Dr. Goldin,
specializes in internal medicine and gastroenterology. (Tr.
318-19) He teaches medicine at the State University of
New York at Stony Brook. (Tr. 319) Bristol offered
Lake-Bakaar as an expert in gastroenterology. (Tr. 320)
Lake-Bakaar testified that he conducts research in gas-
troenterology and has on a number of occasions designed
in vitro studies that were intended to simulate in vivo con-
ditions, (Tr. 320, 326), and that such tests are frequently
relied on by gastroenterologists to predict in vivo results,
(Tr. 327). In his opinion, the in vitro conditions em-
ployed by Dr. Harry Brittain, a witness for Bristol dis-
cussed infra, of 30 milliliters of 0.1 N HCl maintained at
37°C with gentle agitation, closely simulates conditions
29a
in the human stomach. (Tr. 332-33) In his experience,
Dr. Lake-Bakaar has encountered varying volumes of
gastric acid in patients, ranging between 20 and 80 milli-
liters. (Tr. 333) He also opined that mixing rates between
three rpm and 100 rpm covered a range that exceeded the
range of agitation that he believes occurs in the human
stomach. (Tr. 336) In his opinion, 10 rpm is the
average rate of mixing in the human stomach, to the
extent it can be quantified in those terms. (Tr. 336, 369-
70) Lake-Bakaar further opined that little difference
exists between the gastric juice of fasted and non-fasted
patients. (Tr. 337)
Dr. Lake-Bakaar testified that, in his opinion, Dr. Brit-
tain’s failure to account for emptying and replenishment
of stomach juices does not affect the validity of his simula-
tions, because the emptying rate of the human stomach is
sufficiently slow such that it would be minimal over the
short time interval that elapsed before Brittain observed
conversion in his experiments. (Tr. 334-35). Lake-
Bakaar estimated that in five minutes, the human stomach
replaces approximately five percent of its gastric acid.
(Tr. 334). This rate remains constant without regard to
whether additional fluid has been ingested. (Tr. 358-59)
He further opined that Brittain’s failure to take into
account absorption of materials through the stomach wall
did not affect the validity of his simulation, because, with
the exception of extremely acidic compounds, such absorp-
tion is minimal. (Tr. 335) He also testified that he did
not believe “sink” conditions existed in the human stomach.
(Tr. 337) In his understanding, “sink” conditions exist
when the concentration of a solvent is altered by, for
example, emptying and replacement. (Tr. 337-38)
For his final conclusion, Lake-Bakaar opined that, if
conversion actually occurs under the range of conditions
observed by Dr. Brittain in his in vitro experiments, he
believes that conversion would also occur in vivo. (Tr.
339-40)
30a
Dr. Harry G. Brittain
Dr. Brittain has a doctorate in chemistry, has done
extensive post-doctoral fellowship work, taught chemistry
at several colleges, and has, since 1985, worked for Bristol
or one [of] its predecessor corporations. Brittain was of-
fered as an expert in physical-chemistry, x-ray powder
diffraction analysis and optical microscopy. (Tr. 384)
As part of his job responsibilities at Bristol, Dr. Brittain
examines, compares and analyzes x-ray powder diffraction
patterns on a regular basis. (Tr. 630-31) Relying on the
conditions specified by Drs. Goldin and Lake-Bakaar, Dr.
Brittain conducted numerous experiments that were de-
signed to determine whether cefadroxil DC converts to
Bouzard monohydrate in vivo after ingestion. He designed
all of his own experiments. (Tr. 495) The conditions
and results of these experiments are summarized in tables
received into evidence as defendant’s exhibits 42a-d.
1. Brittain’s Theory of the Conversion Mechanism
Dr. Brittain testified that he believes conversion occurs
because cefadroxil DC, when wetted, partially dissoives
and forms a saturated layer around the undissolved ma-
terial, and then recrystallizes as the Bouzard monohydrate.
(Tr. 510) He opined that when liquid enters a cefadroxil
DC capsule, a micro-environment of saturation is created
that allows partial dissolution of cefadroxil DC crystals
that act as nuclei for the formation of Bouzard mono-
hydrate crystals. (Tr. 629, 806) He does not believe that
the beaker in which he conducted his experiments had
any effect on the conversion because he believes that con-
version occurs inside of the capsule. (Tr. 510)
2. Initial Experiments
The first experiments undertaken by Brittain to investi-
gate conversion are summarized in defendant’s exhibit.
By placing a range of weights of cefadroxil DC in a series
of test tubes with one milliliter of water and observing in
3la
which tubes all of the drug dissolved, Brittain determined
that the equilibrium solubility of cefadroxil DC was ap-
proximately between 10.1 and 16.3 milligrams per milli-
liter. (Tr. 390; DX 17) This was considered consistent
by Brittain with his understanding that cefadroxil DC has
an equilibrium solubility of 12 milligrams per milliliter.
(DX 17)
Brittain also observed that the fine cefadroxil DC povw-
der that he placed in the test tubes turned granular in
appearance after being in contact with the water for one
minute. (Tr. 390; DX 17) Upon examination by optical
microscope at 400 magnification, Brittain observed that
the granular solids in the solution had a significantly dif-
ferent appearance from the unwetted cefadroxil DC. The
initial cefadroxil DC consisted of small needle-shaped
crystals, but the wetted cefadroxil consisted of much larger
rhombic crystals. (Tr. 396-97; DX 17) The larger rhom-
bic crystals are characteristics, in Brittain’s opinion, of
crystals of Bouzard monohydrate. (Tr. 400)
A significant difference was also observed between the
birefringence of both samples. The wetted sample was
significantly birefringent, but the unwetted sample was
only slightly birefringent. (DX 17) The phenomenon of
birefringence is the degree to which the indices of refrac-
tion in a given material scatters light passed through the
material. By passing polarized light through a substance
and then observing the substance through a second polar-
‘zer rotated 90° from the initial polarizer, the relative
degree to which light is scattered as it passes through
different substances can be observed as varying intensities
of brightness. (Tr. 383) Birefringence can be a useful
test for identifying crystals, or comparing whether two
substances are the same crystal. (Tr. 383) If the same
crystals are present, they will have the same birefringent
characteristics. According to Brittain, the birefringence of
cefadroxil DC is “extremely weak”. (Tr. 401)
32a
3. Second Series of Experiments
The next series of experiments performed by Dr. Brit-
tain is summarized in defendant’s exhibits 14 and 18, but
is described in greater detail in Brittain’s laboratory note-
book, offered into evidence as defendant’s exhibit 16.
In that experiment, he initially photomicrographed dry
cefadroxil DC to reconfirm its particle size and shape as
small needles, and verified that it exhibited weak bire-
fringence. (Tr. 405) He also ran an x-ray powder
diffraction analysis of a sample of dry cefadroxil DC
that he possessed, to obtain a diffraction pattern for use
as a reference in his future experimentation. (Tr. 406-
07) He also obtained an x-ray diffraction pattern for
Bouzard monohydrate. (Tr. 410)
For this experiment, Brittain placed a dry 10 milligram
sample of cefadroxil DC on a microscope slide, wetted
it with water, and observed it under a microscope. (Tr.
411-12; DX 14) He observed that the cefadroxil material
transformed from very small crystals to large block-like
crystals. (Tr. 412) In a second experiment, Brittain
placed 100 milligrams of cefadroxil DC on a slide, and
wetted it with 0.1 N HC1 solution. (Tr. 413) He ob-
served the same phenomena as in the prior experiment,
except that the crystal faces appeared better formed, and
the birefringence was more distinctive. (Tr. 413) The
transformation of the crystals occurred within 30 seconds
of being wetted. (DX 14) The sample remained in the
solution for five minutes before it was removed and sub-
jected to x-ray diffraction analysis. When the x-ray
powder diffraction pattern obtained from the wetted
cefadroxil DC was compared to the reference patterns,
Brittain observed that the pattern for the wetted cefadroxil
was equivalent to the reference pattern for Bouzard
monohydrate. (Tr. 415)
A third experiment in this series was performed to de-
termine whether cefadroxil DC converted to Bouzard
monohydrate within a capsule immersed in fluid. In two
separate runs, handfilled capsules of cefadroxil DC were
33a
placed respectively in 250 milliliters of water and in 250
milliliters of 0.1 N HC1 solution and allowed to sit for
respectively four and ten minutes, and were then removed,
sliced open, and examined under the microscope for crys-
tal shape and size, and for birefringence. (Tr. 416-18,
423: DX 16) These visual tests confirmed that the ma-
terial had converted to Bouzard monohydrate. (/d.) X-ray
diffraction analysis further confirmed that conversion had
occurred. (Tr. 418, 424, 425)
4. Dissolution Experiments
In a series of dissolution experiments, Dr. Brittain
utilized the in vivo conditions specified by Dr. Goldin,
in an attempt to determine with more certainty whethe=
conversion would occur in the human stomach. Those
conditions consisted of 30 milliliters of simulated gastric
juice maintained at 37°C and stirred at three rpm.
In the first experiment, approximately 300 milligrams
of cefadroxil DC was placed in a clear capsule and low-
ered into a dissolution kettle that contained 30 milliliters
of simulated gastric juice stirred at three rpm for a period
of eight minutes. (Tr. 438) Optical microscopy was per-
formed on the capsule, which revealed to Brittain, con-
sistent with previous experiments, that the crystals had
changed from small needles to large monohydrate crystals,
and that the birefringence had also increased significantly.
(Tr. 439) The same conditions were repeated and the
same results were obtained. (Tr. 441-42) X-ray powder
diffraction patterns were not run because the x-ray unit
was not operating on that day. (Tr. 442)
Brittain later ran many other dissolution experiments,
using varied condition of temperature, volume dissolu-
tion medium, and stirring rate. Tests were performed on
handfilled capsules containing between 300 and 500
milligrams of cefadroxil DC, as well as on actual formu-
lated Zenith cefadroxil DC 500 milligram capsules in-
cluding excipients. Capsules were immersed in media
34a
maintained at 37°C and at 25°C. Dissolution media vol-
umes were varied between 30 and 900 milliliters. Both
simulated gastric juice and actual gastric acid provided
by Dr. Goldin were used as dissolution media, with pHs
ranging between 1 and 6.5. Stirring rates were varied
between zero and 100 rpm. Brittain testified at length
during trial as to the conditions of these experiments.
His laboratory notebook provides a contemporaneous rec-
ord of the details of these experiments. (DX 16) The re-
sults of these experiments are summarized in table form
in defendant’s exhibits 42a-42c. For all of these experi-
ments, similar tests were performed to reach uniform re-
sults. Optical microscopy observation of crystal size and
birefringence, together with x-ray powder diffraction
analyses, uniformly indicated to Dr. Brittain that conver-
sion of cefadroxil DC to Bouzard monohydrate occurred
under all of the varied experiment conditions. Brittain
concluded that the pH of the dissolution medium had little
or no effect on whether conversion would occur. (Tr.
533) He also concluded that the volume of the dissolu-
tion medium and stirring rate had little or no effect on
whether conversion would occur. (Tr. 540-41)
5. Protonation Experiment
One of the claims raised by Zenith on motion for sum-
mary judgment was that cefadroxil DC wetted with acid
could not recrystallize once dissolved, because the cefa-
droxil would become protonated as it reacted with the
acid. Protonation occurs when a compound binds with
free hydrogen ions as the acid reacts with the compound.
(Tr. 468) To test this assertion, Brittain ran fourier trans-
form infrared reflectance (“FTIR”) analyses of the ma-
terial he believed was converted cefadroxil and of un-
wetted Bouzard material, to obtain FTIR spectra. (Tr.
466-67) FTIR analysis is commonly used to determine
whether a material has protonated. (Tr. 467) Brittain
concluded from a comparison of the two spectra that the
cefadroxil DC material had converted to the Bouzard
monohydrate, and that it was not protonated. (Tr. 467)
ew tes ‘ets
35a
6. Light Scattering Experiments
Although he did not believe that removing cefadroxil
from the dissolution medium had any effect on the con-
version process, Dr. Brittain designed a light-scattering
experiment with which he could investigate whether con-
version could be observed without removing a sample
from the dissolution medium. (Tr. 548)
The apparatus used to conduct the light-scattering ex-
periments consisted of a laser light source that was passed
through a square cuvette containing three milliliters of
liquid. (Tr. 550-52) On an adjacent side of the cuvette
was a photomultiplier tube that received the light passing
through the cuvette at a right angle to the laser source,
and converted it to an electrical current that varied in
proportion to the intensity of the scattered light. (Tr.
552) The electrical current was then converted to a
voltage output that also varied in proportion to the scat-
tered light intensity, which was amplified and displayed on
an output device. (Tr. 552)
To isolate the laser light passing through the cuvette,
and to minimize the effect of changes in ambient light
levels, the laser light source was pulsed at a chosen fre-
quency. Through use of a lock-in implifier, which ampli-
fied only the converted voltage signal with the same fre-
quency as the pulsed laser source, the final displayed out-
put, as recorded on a strip chart recorder, measured es-
sentially just light that had originated from the laser light
source. (Tr. 553) This apparatus was designed and built
by Dr. Brittain.
To validate the system, Brittain mixed twenty milli-
grams of microcrystalline cellulose, a water insoluble sub-
stance, with water in a cuvette. (Tr. 554) The mixture
was alternatively stirred with a magnetic stirrer, then
allowed to settle, while the laser source passed through
the cuvette. (Tr. 554-55) The output recorded on the
36a
strip chart recorder showed changes in negative voltage
that varied from a lesser negative voltage when the ma-
terial was completely settled, to a maximum negative
voltage when the stirring occurred. (Tr. 555) This
indicated that the apparatus measured changes in the in-
tensity of light scattered from the original laser source.
(Tr. 555) When more particles are suspended in solu-
tion, more light is scattered.
Brittain then used the apparatus to determine whether
changes in light could be detected as the cefadroxil DC
was mixed in simulated gastric juice. To separate the
possible effect on the test that dissolution, as opposed to
conversion, would have on the light-scattering measure-
ment, Brittain started with a filtered saturated solution of
cefadroxil DC, because no further dissolution could occur
if the saturated solution was held at a constant tempera-
ture. (Tr. 557) In the first series of runs, he added 25
milligrams of Bouzard monohydrate to the saturated solu-
tion, which was mixed vigorously while the scattered light
intensity was measured by the light-scattering apparatus.
(Tr. 558-59) Three strip chart traces were obtained in
three separate runs, which revealed a fairly constant nega-
tive output. (Tr. 539) The materials in the cuvettes were
examined by microscopy to verify that the Bouzard ma-
terial was still present. (Tr. 561).
In the next series of runs of the experiment, Brittain
replicated the conditions used in the first series, except
that he used cefadroxil DC instead of Bouzard monohy-
drate. (Tr. 562) This experiment was also run and re-
corded three different times. (Tr. 563) The curves plotted
in all three runs were essentially the same. (Tr. 568)
They show a sharp arc-shaped decrease in negative volt-
age output through most of the first minute of the experi-
ment, and then a gradual steady increase in negative volt-
age intensity through the remainder of the experiment.
(DX 16, pages 148-49) Dr. Brittain believed that the
initial decrease in intensity was due to dissolution of the
cefadroxil DC crystals, which resulted in less scattering
— vee ee ee eee
37a
of the laser signal because fewer solid particles were pres-
ent to scatter the light. (Tr. 565) He also believed that
the later increase in the scattered light intensity was con-
sistent with conversion, because it indicated that some
physical change had occurred in the tube at the approxi-
mate time that he had observed conversion in his other
experiments. (Tr. 566-67, 569)
Another experiment was conducted in which Brittain
used the same conditions of solution and stirring as used
in the light-scattering experiment, but instead of measur-
ing light intensity with the light scattering apparatus, he
took a series of nine photomicrographs -of material ex-
tracted out of the cuvette at different time intervals dur-
ing a four minute period. (DX 16, pages 150-53) Bire-
fringence was also examined. (Tr. 573) Brittain observed
very small Bouzard crystals in the first photograph taken
at 14 seconds. (Tr. 573) In each successive photograph,
he observed larger and more crystals up until approxi-
mately two minutes, after which the appearance did not
change significantly. (Tr. 575) From this, he concluded
that evaporation did not play any role in conversion, be-
cause if the material converted only due to evaporation
on the slide, each photograph would look the same. (Tr.
575) Brittain related these results to the light-scattering
measurements by observing that the Bouzard crystals only
began to aggregate at approximately one minute, the
time at which the light scattering intensity began to in-
crease. (Tr. 576) He opined that the aggregation of
crystals at one minute was consistent with the change in
light-scattering intensity that was observed beginning at
that time interval. (Tr. 576)
Brittain conducted another series of light-scattering ex-
periments in which he re-ran the first two series of experi-
ments except that instead of using a saturated cefadroxil
solution as the dissolution medium, he used only simulated
gastric juice, in which he placed a greater quantity of
cefadroxil material. (Tr. 577) This was done so that he
could determine whether conversion occurred in an un-
saturated solution. (Tr. 579-80)
38a
When Brittain recorded the light scattering intensities
of the Bouzard material, he plotted a different tracing
from that obtained in the first series of experiments. In-
stead of a constant light-scattering intensity, he recorded
a pattern that began as a maximum negative voltage and
gradually decreased to a constant intensity value. (Tr.
580) Brittain opined that the initial maximum scattered
light intensity was consistent with the fact that none of the
cefadroxil had yet dissolved, and that the gradual decrease
in intensity represented the dissolution of the Bouzard
monohydrate until it reached an equilibrium, at which
point the light scattering intensity remained constant. (Tr.
580; DX 16, pages 155-56)
In the next experiment, Brittain plotted scattered light
intensities over time for light passed through simulated
gastric juice in which he placed cefadroxil DC. The
scattered light intensity curves he obtained in these experi-
ments were more complex than in the other light scatter-
ing experiments. The initial intensity was not as great as
the initial intensity of the Bouzard material suspended in
the gastric juice. Brittain believed that this was consistent
with the fact that cefradoxil DC crystals are smaller than
Bouzard crystals, and hence would not refract as much
light. (Tr. 581) Over the first minute, the scattered light
intensity decreased, consistent with dissolution of the cefa-
droxil DC crystals into the gastric juice. (Tr. 581) At
approximately one minute and eighteen seconds, however,
the scattered light intensity increased steadily, surpassing
the initial intensity, until the four and one-half minute
mark, at which point the intensity remained relatively
constant, decreasing only slightly. (Tr. 581) Brittain
concluded from the fact that the final intensity was
greater tham the initial intensity that a definite change had
occurred m the physical characteristics of the cefadroxil
DC. (Tr. 581-82) This was consistent with his observa-
tions in other experiments that conversion to Bouzard had
occurred. (Tr. 582) Brittain conducted microscopy ex-
periments similar to those run in connection with the
39a
first set of light-scattering experiments, in which he repro-
duced the conditions of the light scattering experiment
this time cefadroxil DC in simulated gastric juice—and
took a series of microphotographs to record visual and
birefringence changes in the crystals over time. (Tr. 587-
88) Brittain observed that as early as 12 seconds into the
experiment, Bouzard crystals were evident. (Tr. 588)
From the strength of the birefringence of the crystals, and
from the depth of the crystals, Brittain opined that evap-
oration could not have been the cause of the formation
of the crystals. (Tr. 589)
7. Sealed System Experiments
A further set of experiments was performed in an at-
tempt to minimize the effects that evaporation could have
on cefadroxil solution observed microscopically. Brittain
observed cefadroxil DC in simulated gastric juice placed
in the well of a thick miscroscope slide over which he
had placed a slide cover that was sealed with nail polish.
(Tr. 593) This experiment was a standard laboratory
technique for creating a sealed system that can be ob-
served by microscope. (Tr. 593) Photomicrographs were
taken at approximately two, four, six and eight minutes.
(Tr. 594; DX 37) In each successive photograph, dis-
tinctive large triangular crystals believed by Brittain to
be Bouzard crystals can be seen in greater quantity. (DX
37; Tr. 595)
Brittain conducted a second type of sealed system ex-
periment, in which he filled test tubes that could be
sealed by screwing on a threaded cap with cefadroxil DC
in approximately 23 milliliters of water or simulated gas-
tric juice. (Tr. 600-02) The goal of this experiment was
to determine whether cefadroxil DC converted in a larger
quantity of fluid in a sealed environment. (Tr. 601)
Samples were maintained in a bath at 37°C and allowed
to equilibrate for one half hour. (Tr. 601-02) Samples
were then examined by microscopy and x-ray powder
40a
diffration. Again, Brittain concluded that Bouzard crys-
tals had formed. (Tr. 603, 605) These results were
believed consistent with the sealed slide tests, and caused
Brittain to conclude that evaporation played no role in
the conversion of cefadroxil DC to Bouzard monohy-
drate. (Tr. 605)
8. Freeze-Drying Experiments
Brittain simulated the freeze-drying experiments of Dr.
Greenblatt, with minor variations. He placed a Zenith
cefadroxil DC capsule in 30 milliliters of simulated gas-
tric juice maintained at 37°C and stirred at 10 rpm. (Tr.
606-07) At approximately two and three quarters min-
utes, instead of Dr. Greenblatt’s one and three quarters
minutes. Brittain removed the capsule from the dissolu-
tion apparatus and, within five to ten seconds, as op-
posed to Dr. Greenblatt’s approximately five seconds,
plunged the sample into liquid nitrogen. (Tr. 607) Dr.
Brittain opined that the five second difference had no
scientific significance. (Tr. 618)
After five minutes in the nitrogen, Brittain removed
the sample and place it in a freeze-drying (“lyophiliza-
tion”) apparatus that he had constructed himself. (Tr.
608) The following day, he removed the contents and
conducted microscopy and x-ray powder diffraction anal-
yses of the sample. (Tr. 613) From these tests, Brittain
concluded that the samples he observed contained Bou-
zard monohydrate. (Tr. 613)
Brittain conducted another experiment in which he
replicated the dissolution and sample removal aspects of
Dr. Greenblatt’s experiment, removing the sample at one
and three quarters minutes. (Tr. 619) He then sliced
the capsule and performed microscopy and x-ray powder
diffraction analyses of the contents. Brittain first ob-
served that the contents of the capsule did not appear
sufficiently wetted, in his opinion, for conversion to occur.
(Tr. 620) The results of his microscopy examination
“a
ied
3
:
3
tsi
mat
4la
was that although some Bouzard crystals were present,
the bulk of the sample was cefadroxil DC with weak bire-
fringence. (Tr. 612) Likewise, the x-ray powder diffrac-
tion analysis yielded a pattern that signified to Brittain
a mix of cefadroxil DC and Bouzard crystals. (Tr. 621-
22) Brittain concluded that if a sample of cefadroxil DC
is not sufficiently wetted, no conversion will occur. (Tr.
622-23)
9. Gottstein Comparison
To rebut Dr. Pfeiffer’s testimony, Dr. Brittain made
an independent comparison of the Gottstein and Zenith
cefadroxil DC x-ray powder diffraction patterns. (Tr.
642) He concluded that the two patterns were on the
border between being considered by him “similar” or
“equivalent”. (Tr. 642) From this, he did not believe
that he could conclude that Gottstein would convert to
Bouzard monohydrate. (Tr. 644-45)
Brittain recorded an x-ray diffraction pattern of a com-
pound represented to him by Bristol to be Gottstein cefa-
droxil. When he compared the pattern obtained from
the Bristol sample to the Marr pattern relied on by Dr.
Pfeiffer, Brittain found that 21 of 24 peaks matched,
and concluded that the patterns were equivalent. (Tr.
819-20) He then wetted 200 milligrams of the substance
he believed was Gottstein cefadroxil and, after eight
minutes, recorded another x-ray powder diffraction pat-
tern. (Tr. 821) Brittain concluded from the second x-ray
pattern that the Gottstein material had not changed, and
that no Bouzard monohydrate could be detected. (Tr.
822) After another fifteen minutes had elapsed, which
would have allowed evaporation to have occurred, he ran
another powder pattern, which again remained un-
changed. (Tr. 822-23) Yet another x-ray powder pattern
was made after one hour had elapsed, with similar re-
sults. (Tr. 823) From this Britain concluded that Gott-
stein cefadroxil does not convert to Bouzard monohy-
drate when wetted. (Tr. 824)
42a
C. Zenith’s Rebuttal Case
Dr. Martha Greenblatt
Greenblatt was presented as a live witness on Zenith’s
rebuttal case. She testified that at the time of her initial
experiments and deposition, she had not considered
whether leaving the capsules in the simulated gastric acid
for a longer period of time would have had any impact
on the results of her tests. (Tr. 846) Since it was brought
to her attention, Greenblatt had formed the opinion that
leaving the capsules immersed for a longer period of time
would not have changed her results, because the capsules
had already opened and she ‘believed that the capsules’
contents had already been wetted. (Tr. 847) To verify
this opinion, Greenblatt instructed a graduate student
to conduct a further experiment in which he replicated
her earlier experiments except that he increased the length
of time in which the capsule remained in the gastric fluid
before they were removed, from approximately two min-
utes to almost three minutes. (Tr. 864-65; PX 46) Green-
blatt concluded that the results of this experiment were
no different than the results of her earlier experiments—
no conversion could be detected from the x-ray powder
patterns. (Tr. 865)
Dr. Anthony P. Simonelli
Dr. Simonelli, the last witness to testify at trial, is a
professor emeritus at the University of Connecticut. (Tr.
929) Dr. Simonelli performed no experiments of his own
that were introduced at trial, but only gave his expert
opinions based on the experiments of others. He was
offered as an expert in biopharmaceutics, which is the
study of how formulations of drugs interact with a bio-
logical environment/system (otherwise known as a body,
be it human or other animal), and how changes in drug
formulations affect their absorption by the biological sys-
tem. (Tr. 929-30) Simonelli was also offered as an ex-
43a
pert in the identification and analysis of polymorphic and
solvate transformation in solid state and heterogeneous
systems, and in the fields of nucleation and crystal growth,
and x-ray diffraction analysis and optical microscopy
(Tr. 931-33, 935)
Simonelli testified at length about the nucleation process
that must precede any recrystallization of dissolved cefa-
droxil DC. He differed substantially with the theories of
Dr. Brittain. Simonelli opined that Dr. Brittain’s ex-
periments did not prove that conversion occurred in the
dissolution beaker. (Tr. 958) He instead believed that
the recrystallization occurred on the microscope slide
after a sample was removed from the beaker, because
the conditions for nucleation and crystal growth are “fan-
tastically higher on the slide than they are in the beaker,”
due to the greater saturation on the slide, (Tr. 959),
and the cooling effect of evaporation, which aids precip-
itation of solids from a solution, (Tr. 980-81). Simonelli
testified that Brittain’s slide observations would not be
representative of in vivo conditions, because evaporation
and cooling, factors present on the slide that he believed
greatly enhance crystal growth, are not present in the
human stomach. (Tr. 981) He also believed that the
stirring motion present in the stomach would diminish
the possibility of nucleation and crystal growth. (Tr.
981) Simonelli further opined that other factors present
in the stomach but not on a slide that might inhibit
nucleation and crystal growth include the dissolved gela-
tin capsule, (Tr. 982-83), excipients, (Tr. 984), and
the presence of macromolecules such as proteins and en-
zymes, (Tr. 1008, 1018).
Simonelli believed that Brittain’s sealed system experi-
ments are not conclusive because they at most eliminate
only one factor as a possible explanation for the conver-
sion: evaporation. (Tr. 986) He was at a loss to explain
the difference in results between Dr. Brittain’s and Dr.
Greenblatt’s second freeze-drying test results. He postu-
44a
lated that the difference in time it took Brittain to re-
move the sample from the dissolution beaker and plunge
it in the liquid nitrogen—at most five seconds—may ac-
count for the difference. (Tr. 987-88)
Simonelli opined that Brittain’s light-scattering experi-
ments also did not establish that conversion occurred
in solution as opposed to on the slide, but were merely
inconclusive. (Tr. 993, 995) He further opined that
“sink” conditions present in the stomach would also in-
hibit nucleation and crystal growth. (Tr. 1012) Accord-
ing to Simonelli, sink conditions exist when the concen-
tration of a compound is negligible in the bulk of a dis-
solution medium and is high near the surface of the
compound being dissolved. (Tr. 1013-15) He believed
that Dr. Lake-Bakaar was wrong in concluding that the
rapidity of the conversion would counteract the sink
effect, because he believes that the speed of the conver-
sion does not affect the action of the sink conditions in
preventing a localized supersaturation zone. (Tr. 1015-
17) Simonelli conceded that the speed of the reaction is
not unimportant, but, all else being equal, the presence
of sink versus non-sink conditions would impact on the
likelihood of nucleation and crystal growth. (Tr. 1017)
In general, Simonelli concluded that Brittain’s experi-
ments did not sufficiently simulate in vivo conditions to
be indicative of nucleation and crystal growth in the
human stomach. (Tr. 1008-09) He did not disagree with
the conditions in the human stomach specified by Drs.
Goldin and Lake-Bakaar, but disagreed that the beaker
experiments of Dr. Brittain adequately accounted for
other factors present in the stomach that would adversely
affect the likelihood of conversion. (Tr. 1018-19)
Il. FINDINGS OF FACT
The central fact issue that the Court must determine
is whether the cefadroxil DC in Zenith’s formulated cap-
sules converts to Bouzard mpnohydrate in vivo. This
45a
one issue was the focus of much scientific theorizing and
experimentation, and has resulted in a trial record that
contains a number of theories and abundance of data.
A subsidiary issue that Zenith asserts circumscribes the
breadth of the claim in the ’657 patent is whether “Gott-
stein” cefadroxil is in fact cefadroxil DC, and whether
Gottstein cefadroxil converts in vivo to the Bouzard mon-
ohydrate. This issue accounted for a minor portion of
the evidence presented at trial.
A. In Vivo Conversion
Zenith’s position on the conversion of cefadroxil DC
into Bouzard monohydrate rests on the results it obtained
from several experiments, and on expert opinion testi-
mony that attempted to refute the results obtained by
Bristol from its experiments. Zenith had three sets of
experiments conducted to support its position that con-
version does not occur.
First, Dr. Rothstein supervised an experiment to mea-
sure and compare the dissolution rates of cefadroxil DC
and Bouzard monohydrate. Second, Dr. Rothstein super-
vised an experiment to measure and compare the equilib-
rium solubility and bulk density of those two compounds.
Both the dissolution rates and equilibrium solubilities,
as well as initial bulk densities, were found by Rothstein
to be different for both compounds. In reliance on this
data, Zenith expert Dr. Pfeiffer opined that conversion
did not occur. His theory was that if cefadroxil DC first
converted to Bouzard monohydrate before dissolving, the
equilibrium solubility for the two materials would be
identical, because in essence the same material would be
dissolving into the dissolution medium.
POSTE
The third set of experiments offered into evidence by
Zenith were the freeze-drying experiments of Dr. Green-
blatt. Greenblatt conducted two sets of experiments, dif-
fering only in the time at which the dissolving capsule
was removed from the dissolution vat and frozen in liquid
ii aie
46a
nitrogen. The first set of experiments, with the shorter
dissolution period, was offered into evidence on Zenith’s
direct case through deposition transcript with exhibits.
The second set of experiments was offered into evidence
on Zenith’s rebuttal case through Greenblatt’s live testi-
mony and exhibits. The results obtained by Greenblatt
were the [ ] same for both experiments: no conversion
occurred.
Bristol’s position with respect to Zenith’s experiments
is that they were scientifically inaccurate and otherwise
flawed. Bristol’s position on the conversion of cefadroxil
DC into Bouzard monohydrate rests on the results it ob-
tained from a number of experiments conducted by Dr.
Brittain, and on expert opinion testimony that laid a
foundation for some of the assumptions made by Brit-
tain in attempting to simulate in vivo conditions. Drs.
Levine and Goldin were offered as experts to support
Bristol’s position that actual in vivo experiments could
not be conducted due to medical ethics constraints, and
that no satisfactory in vivo experiment could be designed
to test the conversion hypothesis that would be any more
probative of the issue than are in in vitro experiments
of Dr. Brittain. Drs. Goldin and Lake-Bakaar were
offered as experts in gastroenterology to lay the founda-
tion for the conditions utilized by Dr. Brittain to simulate
conditions inside the human stomach.
The bulk of Bistol’s evidence consists of the numerous
experiments conducted by Dr. Brittain to verify that
cefadroxil DC converts to Bouzard monohydrate. Brit-
tain designed and conducted a variety of experiments to
test different aspects of the conversion issue, all of which
confirmed in his opinion that conversion would in fact
occur in vivo. Zenith’s position with respect to Bristol’s
experiments is that they at best prove that conversion
occurs on a microscope slide under conditions different
from those present in the human stomach. Zenith’s ex-
perts opined that Bristol did not even prove that conver-
sion occurs in a dissolution beaker, much less in vivo.
‘47a
The Court finds that Bristol presented by far the more
compelling case on the issue of conversion.
1. Use of In Vitro Experiments
The opinions of Drs. Levine and Goldin that, given
the nature of the experiments which would be required,
in vivo experimentation could not be justified under med-
ical ethics constraints merely to prove patent infringe-
ment, stands unrefuted by Zenith. Both doctors were
adequately qualified to give this opinion and were credible
witnesses. Therefore, the Court finds that Bristol’s use of
in vitro experiments to establish in vivo events is in prin-
ciple a valid methodology. Cross v. lizuka, 753 F.2d
1040, 1050 [224 USPQ 739] (Fed. Cir. 1985); Nelson
v. Bowler, 626 F.2d 853, 856 [206 USPQ 881]
(C.C.P.A. 1980).
2. Validity of Brittain’s Simulated In Vivo Condi-
tions
The conditions prescribed by Drs. Goldin and Lake-
Bakaar to simulate conditions in the human stomach, i.e.,
30 milliliters of simulated or actual gastric juice main-
tained at 37°C and stirred at three to ten rpm, were also
unrefuted by Zenith. Further substantialy unrefuted was
Dr. Lake-Bakaar’s opinion that the emptying rate of the
stomach and the secretion rate of additional gastric juice
are sufficiently slow in comparison to the rate at which
Brittain believed conversion occurred such that failure to
account for those factors would not constitute a flaw in
Brittain’s experiments. Both doctors were adequately
qualified to give these opinions and were credible wit-
nesses. Therefore, to the extent Bristol established the oc-
currence of conversion under these conditions that was
not attributable to some other condition present in the in
vitro experiment that is not present in vivo, it has proved
that in vivo conversion also would occur.
48a
3. Brittain’s Experiments
Dr. Brittain spent far more time on the witness stand
during this trial than did any other witness. Over the
course of nearly three full days of testimony, the Court
had the opportunity to observe and listen to Brittain at
great length. The Court’s impression of Dr. Brittain is
that he is a talented research chemist, who possesses a
significant ability to thoroughly understand a problem and,
through his broad knowledge of laboratory instrumenta-
tion, design multiple experiments to test many aspects of
that problem. He was also, for the most part, a very
credible witness.
Dr. Brittain’s explanation of the reason that conversion
occurs, and the process by which it @oours, however,
seemed to be somewhat beyond the scope of his expertise.
On this point, Zenith’s Dr. Simonelli seemed more knowl-
edgeable. In fact, though, the Court does not believe
~ that any witness presented in this case has anything more
than a superficial understanding of the “mechanism” or
“pathway” by which conversion occurs. At issue in this
case, however, is not “why” conversion occurs, but only
“whether” it occurs. Thus, although Dr. Brittain’s ex-
planation of the conversion process seemed beyond the
ken of his expertise and was somewhat lacking in credi-
bility, the Court finds that Brittain has established by a
preponderance of evidence, well within his range of ex-
pertise, that cefadroxil DC in fact converts in vivo to
Bouzard monohydrate.
The strength of Brittain’s experiments and results is
their totality. Piece by piece, Brittain built an impressive
collection of data. The results of each series of experi-
ments strengthen the results of each other set of experi-
mental results. The total effect of the experiments is to
prove with sufficient certainty the fact of conversion in
vivo.
In support of its motion for summary judgment, Zenith
submitted expert affidavits that concluded that the pro-
49a
tonation of cefadroxil DC molecules dissolved in gastric
acid would prevent recrystallization of dissolved cefadroxil
DC. At trial, Bristol introduced testimony and test re-
sults by Brittain to refute this claim. Those experiments
tested for protonation, and the results indicated that pro-
tonation did not occur. Zenith offered no evidence at
trial to refute this evidence. Accordingly, the Court finds
that protonation plays no role in inhibiting conversion.
The largest number of experiments conducted by Brit-
tain were the dissolution experiments in which he placed
both bulk powder or formulated capsules in varied
amounts of water or simulated or actual gastric juice and
later tested the samples for conversion. The dissolution
medium volume and stirring rate conditions employed en-
compassed and exceeded the wide range of possible condi-
tions in vivo. Through the use of three tests—visual ob-
servation, birefringence comparison and x-ray diffraction
pattern comparison—Brittain concluded uniformly that
under any of the conditions used, he detected conversion.
Brittain first established indisputably through photo-
micrography that cefadroxil DC crystals are much smaller
than Bouzard monohydrate crystals, and are much dif-
ferent in shape. He also established that cefadroxil DC
crystals exhibit a much weaker birefringence than do
crystals of Bouzard monohydrate, which are highly bire-
fringent. Thus, through microscopy, Brittain could de-
termine with a high degree of certainty whether a sample
of wetted cefadroxil DC had changed its crystalling form,
and could conclude to a lesser extent that the form to
which it had changed was Bouzard monohydrate. Al-
though changes in the physical properties of shape, size
and birefringence of the cefadroxil DC erystals could be
conclusively determined through microscopy, Britain could
not determine by observation alone that the larger, more
birefringent crystals were necessarily Bouzard. To deter-
mine conversion to Bouzard with great certainty, Brittain
ran x-ray powder diffraction patterns, a technique that in
essence takes the “fingerprint” of a crystalline compound.
50a
Through x-ray diffraction analysis, Brittain determined
with much greater confidence that all of the conversions
suspected after optical examination had in fact been to
Bouzard monohydrate.
Zenith contends that Brittain failed to establish that
any of the x-ray diffraction patterns, including his Bouzard
monohydrate reference pattern, conform to the x-ray dif-
fraction pattern that forms the claim of the ’657 patent.
The Court disagrees, with respect to the reference pattern,
Bristol has put into evidence numerical tables represent-
ing both the patent pattern and Brittain’s reference pat-
tern. (DX 1; DX 16 at 19) According to Zenith’s own
expert, Dr. Pfeiffer, differences of 0.2 or less are insig-
nificant in comparing x-ray diffraction patterns. (Tr. 233)
According to Dr. Brittain, whose expertise on X-ray
powder diffraction pattern analysis the Court accepts,
patterns with at least a 95% match of peaks are “iden-
tical” compounds. (Tr. 633). Using Dr. Pfeiffer’s mar-
gin of error, a simple comparison of the tables reveals
that 21 out of 22 peaks in the patent pattern are matched
by peaks in Brittain’s reference pattern. Although Pfeiffer
would find a “match” even with a variation of up to 0.2,
most of the matches have differences of less than 0.05.
In fact, only one match even approaches, but does not
exceed 0.1. Thus, there are 21 clear matches out of 22
peaks in the patent pattern. The ratio of 21/22 exceeds
the 95% peak matches Brit[t]ain would require to con-
clude that two compounds are identical. The Court thus
concludes that Zenith’s claim that Brittain’s reference pat-
tern is not of the same compound claimed in the ’657
patent is without any merit.
The Court further finds credible Brittain’s conclusions
that the patterns obtained from wetted cefadroxil samples
recovered from his experiments are equivalent to the refer-
ence pattern for Bouzard monohydrate. Dr. Brittain’s ex-
pertise with the analysis and comparison of x-ray diffrac-
tion patterns was amply demonstrated, and the Court ac-
cordingly adopts Brittain’s conclusions. Zenith’s assertion
S5la
that the comparison are inconclusive because Brittain con-
cluded only that the patterns were “equivalent” and not
“identical” is rejected by the Court. Although under
Brittain’s rating system “identical” is the higher rating,
the Court accepts Brittain’s opinion that a finding of
“equivalance” is sufficient to support his conclusion that
conversion had occurred. The standard of proof in this
case is not the “beyond a reasonable doubt” standard.
The Court finds that Brittain’s laboratory procedures
for the dissolution experiments were consistent, well-
documented and highly credible. Zenith has not with any
force directly refuted the results of Brittain’s microscopy
and x-ray diffraction tests. Zenith’s criticisms of Brittain’s
results are based on contentions that the conversion oc-
curred not in the dissolution beaker, but on the micro-
scope slide, under conditions greatly different from ac-
tual in vivo conditions. Alternatively, Zenth contends that
even if conversion does occur in the beaker, the beaker
conditions are significantly different from in vivo condi-
tions. The Court finds these contentions also without
merit.
A major basis for Zenith’s contention that conversion
occurs on a slide and not in a beaker or the stomach is
that on the slide, a much more saturated solution ex-
ists, which Dr. Simonelli opined was much more conducive
to nucleation and crystal growth. The Court finds that
Bristol demonstrated with a high degree of certainty that
conversion occurs inside of an ingested capsule, and that
the environment inside of a capsule penetrated by gastric
liquid would be of a similar or greater saturation level
to that existing on a slide. Thus, the Court finds that
Zenith’s distinction between beaker and slide conversion
is meaningless to the extent it is based on differences in
saturation levels. To the extent that the beaker/slide ar-
gument is premised on conditions present on a slide that
are not also present inside of a capsule ingested in vivo,
it has adequately been overcome by Bristol’s affirmative
proofs.
52a
Zenith, through Drs. Simonelli and Pfeiffer, posited
that several material differences exist between the condi-
tions present on a slide and those present in vivo, which
impact greatly on the question of in vivo conversion.
First, both Pfeiffer and Simonelli identified evaporation
and cooling as two factors present on a slide but not in
the stomach. They opined that evaporation is conducive
of cooling, which is conducive of precipitation of crystals
out of solution. As will be discussed below, Brittain con-
ducted experiments that refuted the significance of either
of these factors.
Simonelli and Pfeiffer further opined that the stirring
action and replenishment of fluids in the stomach would
adversely affect the occurrence of nucleation and crystal
growth. Dr. Simonelli assumed that conversion occurs
after the cefadroxil DC leaves the capsule, because the
“dynamic situation” he discussed was based on the move-
ment of the capsule contents as they poured out of the
capsule. (Tr. 981) Dr. Pfeiffer’s opinion was similarly
flawed. Because the Court finds that conversion occurs
inside of an ingested capsule, it finds that stomach agita-
tion as an inhibitor of conversion is of minimal signifi-
cance, and opinions relying on it are not entitled to much,
if any, weight. Further, the Court finds that Simonelli’s
suggestion that the replenishment of fluids in the stomach
is similarly without credibility. Dr. Lake-Bakaar’s testi-
mony as to the extremely slow rate of stomach emptying
and replenishment was highly credible and stands unre-
futed. The Court therefore finds Simonelli’s opinion as
to this factor to be lacking in credibility.
Other factors identified by Simonelli as existing in the
stomach but not on a slide include the presence of gelatin,
excipients and macromolecules such as food particles, pro-
teins and enzymes. The Court finds this testimony to be
worthy of no weight.
First, on cross-examination, Simonelli conceded that
macromolecules such as food particles or proteins could
it
53a
enhance nucleation and crystal growth, as well as in-
hibit them. (Tr. 1026-27) Second, excipients were pres-
ent on the slide as well as in vivo in those dissolution ex-
periments conducted by Brittain that used Zenith capsules.
Dr. Simonelli’s attempted explanation of why excipients
would have a lesser impact on a slide than they would in
a capsule, (Tr. 984), seemed contrived and lacked credi-
bility. Third, macromolecules of the variety identified by
Simonelli were present on the slide in those dissolution
experiments conducted by Brittain that used actual gastric
juice. Last, Simonelli’s testimony that dissolved gelatin
may inhibit nucleation and crystal growth, though prob-
ably true in the abstract, does little to refute the results
of Brittain’s experiments. According to Simonelli, Brit-
tain’s experiments failed to account for the presence of
gelatin because his samples were taken from the inside
of the capsule. (Tr. 983) Because the Court finds that
conversion occurs inside the capsule, it finds Simonelli’s
criticism to lack merit.
Yet another factor Simonelli identified as present in
the stomach but n
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