Cabilly et al.v.Boss et al.

Board of Patent Appeals and Interferences

Aug 13, 1998

06672265 (B.P.A.I. Aug. 13, 1998)

Application 08/205,419, filed June 10, 1988. According benefit of Application1
06/483,457, filed April 8, 1983, now patent No. 4,816,567, issued March 28, 1989.
Assignee for Genentech, Inc., South San Francisco, CA, A California Corporation.
Application 06/672,265, filed November 14, 1984, now Patent No. 4,816,397,2
issued March 28, 1989. Accorded benefit of PCT application, PCT/GB84/00094, filed
March 23, 1984 and UK application No. 83/08235, filed March 25, 1983. Assignee for
Celltech Limited, Berkshire SL1 4DY, U.K., A British Company.
1
THIS OPINION WAS NOT WRITTEN FOR PUBLICATION
The opinion in support of the decision being entered today (1) was not written for
publication in a law journal and (2) is not binding precedent of the Board.

Paper No. 57
UNITED STATES PATENT AND TRADEMARK OFFICE
__________
BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________
SHMUEL CABILLY, HERBERT L. HEYNEKER,
WILLIAM E. HOLMES, ARTHUR D. RIGGS
and RONALD B. WETZEL
Junior party1
v.
MICHAEL A. BOSS, JOHN H. KENTEN,
JOHN S. EMTAGE and CLIVE R. WOOD
Senior party2
__________
Patent Interference No. 102,572
___________
Interference No. 102,572
APJ Schafer has been substituted for APJ Pellman who has retired. In re Bose,3
772 F.2d 866, 868-869, 227 USPQ 1, 2-4 (Fed. Cir. 1985).
2
Before RONALD H. SMITH, DOWNEY and SCHAFER, Administrative Patent Judges.3
DOWNEY, Administrative Patent Judge.
FINAL DECISION
The interference concerns a two step process for producing either an
immunoglobulin (Ig) molecule or an immunologically functional Ig fragment comprising at
least the variable domains of the Ig heavy and light chains in a single host cell.
The subject matter at issue is defined by a single count, which count is identical to
claim 1 of the Boss et al. patent. The count reads as follows:
Count 1
A process for producing an Ig molecule or an immunologically functional Ig
fragment comprising at least the variable domains of the Ig heavy and light
chains, in a single host cell, comprising the steps of:
(i) transforming said single host cell with a first DNA sequence encoding at
least the variable domain of the Ig heavy chain and a second DNA sequence
encoding at least the variable domain of the Ig light chain, and
(ii) independently expressing said first DNA sequence and said second
DNA sequence so that said Ig heavy and light chains are produced as
separate molecules in said transformed single host cell.
Boss et al. claims 1-18 and Cabilly et al. claims 101-120 correspond to the count.
During the preliminary motion stage of this proceeding, the administrative patent
Interference No. 102,572
3
judge (APJ), granted the Boss et al. motion for benefit of the March 25, 1983 and March
23, 1984, filing dates of their United Kingdom application, No. 83/08235 and PCT
application, PCT/GB84/00094, respectively. With the granting of the motion for benefit,
party Boss et al. became senior party in this interference.
Boss et al. took no testimony and thus stand on their March 25, 1983, filing date
accorded them during the motion period.
Junior party Cabilly et al. raise the following issues in their brief (Brief, page 3):
(1) does the record establish that Cabilly et al. actually reduced to practice the
invention of the count prior to the March 25, 1983, effective filing date accorded Boss et
al., and if not, then,
(2) does the record establish that Cabilly et al. conceived of the invention of the
count prior to the March 25, 1983, filing date accorded Boss et al. and proceeded with
reasonable diligence to either an actual or constructive reduction to practice (April 8,
1983) from a time prior to conception of Boss et al. (March 25, 1983).
In addition, we have before us, a Cabilly et al. motion, pursuant to 37 CFR § 1.635,
to have certain Cabilly et al. pages, 224-231 attached to exhibit 8 and page 993 attached
to Exhibit 20, entered into the record (Paper No. 49). The motion stands opposed (Paper
No. 50); and a reply was filed (Paper No. 51).
The following issues have not been raised by the parties:
(1) a question of no interference-in-fact;
Interference No. 102,572
The record and exhibits will be referred to as CR and CX followed by the4
appropriate number.
4
(2) a question of separate patentability of any claim(s);
(3) a question of whether Cabilly et al. claims are unpatentable. Boss et al. filed a
motion for judgment against Cabilly et al. claims during the motion stage, which motion
was denied; Boss et al. do not seek review of this motion at final hearing; and
(4) a question of whether Cabilly et al. rely upon attorney diligence for their priority
case. Cabilly et al. allege priority based on conception coupled with reasonable diligence
to filing of their application. Cabilly et al. could have but did not offer any evidence relating
to attorney diligence in preparing and filing the Cabilly et al. patent application during the
critical period.
Cabilly et al. filed a record (CR) consisting of exhibits 1-20 (CX) and the4
declarations of coinventors: Arthur D. Riggs, Ph.D, (Riggs) and Shmuel Cabilly (Cabilly),
employees of City of Hope; William E. Holmes (Holmes) and Ronald B. Wetzel, Ph.D.,
(Wetzel), employees of Genentech, Inc.; and corroborators Paul J.
Interference No. 102,572
The Carter testimony was submitted in response to the Boss et al.5
motion for judgment; as noted the motion is not being reviewed at final hearing and thus
the Carter testimony is not relevant to the issues before us and has not
been considered in rendering this decision.
5
Carter, Ph.D (Carter) , Michael B. Mumford (Mumford), L. Jeanne Perry (Perry), Michael5
W. Rey (Rey), all employees of Genentech and John E. Shively, Ph.D., (Shively), an
employee of City of Hope. Boss et al. did not cross examine any of the witnesses.
Both parties filed briefs and appeared through counsel at final hearing.
I.
Cabilly et al. motion to correct the record
With their reply brief, Cabilly et al. filed a motion to have entered into the record
certain pages which were referred to and relied upon in various declarations but were
omitted from the record when it was filed and served upon Boss et al. The omission was
first realized when Boss et al. noted, in their brief, that the pages were not in the Cabilly et
al. record.
The motion is granted. In view of the fact that Cabilly et al. referred to CX-8, pages
224-231 in the Wetzel and Perry declarations and CX-20, page 993 in the declaration, we
find the failure to file these pages with their respective exhibits an oversight on the part of
Cabilly et al.
Interference No. 102,572
6
The Boss et al. arguments are without merit. It is true that the present rules do not
require Boss et al. to notify Cabilly et al. of the oversight. As a matter of courtesy, Boss et
al. could have notified Cabilly et al. of the omission when the exhibits were served. We find
no prejudice to Boss et al. by entering the omitted exhibits into the record.
II.
Background:
Immunoglobulins (Ig), also called antibodies, are protein molecules produced in
vertebrates by B cells in response to foreign antigenic agents. (Boss et al. patent, column
1, lines 60-64, Cabilly et al. specification, page 1). The basic structure of all
immunoglobulin molecules is a unit consisting of two identical light (L) polypeptide chains
of molecular weight of approximately 23,000 daltons and two identical heavy (H)
polypeptide chains of molecular weight 53,000-70,000 daltons, shaped to form a Y:
Each H and L chain is held together by disulfide bonds to form a monomer, and the two
Interference No. 102,572
7
monomers are linked by disulfide bonds to form the basic dimeric structure of the molecule
(Cabilly et al. specification, page 5). There are five classes or types of H chains, gamma,
mu, alpha, delta, or epsilon which characterize an individual Ig as an IgG, IgM, IgA, IgD or
IgE, respectively; and two classes of L chains, kappa (6) and lambda (8) (Cabilly et al.
specification, page 5). Each antibody chain contains a variable region (V) and a constant
region. The variable region is about 100 amino acids in length and is specific for the
antigen which elicited it. (Cabilly et al. specification, page 6). The constant region does
not take part in the binding of any antigenic determinant but does serve to link the antibody
to other participants in the immune defenses, e.g. to fix complement, and thus makes an
antibody bifunctional. The variable region of the H and L chain interact closely and when
correctly folded form a three dimensional site at each branch of the Y for binding to a
particular portion or epitope of the specific antigen which elicited the antibody(Cabilly et al.
specification, page 5-6, and Boss et al. patent, column 1, line 60-column 2, line 47).
Kohler and Milstein developed a technique that made it possible to produce
monoclonal antibodies, i.e., homogenous antibodies of a single class and single
specificity, by the use of hybridoma technology. Monoclonal antibodies are produced in
Interference No. 102,572
8
a laboratory by a hybridoma cell line, created by injecting the mouse with antigen,
harvesting its spleen cells and fusing the same with cells from an immortal cancer cell line.
Monoclonal antibodies are specific to one antigen which may have multiple determinants
or epitopes. Antibodies have the ability to detect and bind to antigens. The strength of
the antibody-antigen binding is referred to as specificity and is quantatively measured by
an affinity value.
III.
THE COUNT
It is well-settled that, absent ambiguity, a count in an interference is to be given the
broadest reasonable interpretation that the language of the count permits without resort to
either party’s disclosure. DeGeorge v. Bernier, 768 F.2d 1318, 1322, 226 USPQ 758,
761 (Fed. Cir. 1985); Fontijn v. Okamoto, 518 F.2d 610, 618, 186 USPQ 97, 103-104
(CCPA 1975); Lamont v. Berguer, 7 USPQ2d 1580, 1582 (Bd. Pat. App.
& Int. 1988). We find the count is clear and unambiguous.
Accordingly, we construe the count as being directed to a two step process for the
production of either an Ig molecule or an immunologically functional Ig fragment encoding
at least the variable domains of the Ig heavy and light chains. The first step comprises
transforming a single host cell (e.g., E.coli) with first and second DNA sequences
encoding at least the variable regions of both the heavy chain and light chain and the
second step comprises expressing, in the transformed host cell, the respective heavy and
Interference No. 102,572
Inclusion bodies are also known as refractile bodies. They are insoluble particles6
which require cell lysis and solubilization in denaturant to permit recovery. (Cabilly et al.
specification, page 23, lines 18-21).
9
light chains as separate molecules.
The count is broad enough to include adding a single plasmid or vector containing
both the DNA sequences encoding for at least the variable regions of the heavy and light
chains to the host cell or by adding two plasmids to the host cell each containing said DNA
sequences individually. The count does not require that the expression step directly result
in the production in the host cell of an Ig molecule or an immunological functional fragment
of Ig containing at least the variable regions of the heavy and light chains. If the process
results in the production of inclusion bodies, then in order to show that a useful product6
was produced it would be necessary to reassociate or refold after extraction of the
inclusion bodies and denaturing its contents. Hence, while the count does not set forth any
additional steps it is clear that the count does not exclude other process steps because the
count utilizes the open-ended term “comprising “. In re Baxter, 656 F.2d 679, 686-687, 210
USPQ 795, 802-803 (CCPA 1981).
IV.
THE PARTIES BRIEFS
The requirements for the parties briefs are set forth in 37 CFR § 1.656(b). In
particular, 37 CFR § 1.656(b)(4) requires:
[a]n argument, which may be preceded by a summary, which shall contain
Interference No. 102,572
Dr. Herbert Heyneker, a coinventor of the Cabilly et al. application, is said to be a7
senior scientist from Genentech; he did not testify in this proceeding.
10
the contentions of the party with respect to the issues to be decided, and the
reasons therefor, with citations to the cases, statutes, other authorities, and
part of the record relied on. (Emphasis added)
Conclusions of fact and law made without appropriate citation to the record or citation of
authority will be taken as attorney argument. Compare Ex parte McCullough, 7 USPQ2d
1889, 1891 (Bd. Pat. App. & Int. 1988); Ex parte Myer, 6 USPQ2d 1966, 1968 (Bd. Pat.
App. & Int. 1988); In re Mehta, 347 F.2d 859, 863-864, 146 USPQ 284, 286 (CCPA
1965). Attorney argument cannot take the place of evidence lacking in the record.
Meitzner v. Mindick, 549 F.2d 775, 782, 193 USPQ2d 17, 22 (CCPA), cert. denied, 434
U.S. 854 (1977).
V.
The Cabilly et al. Case for Priority (as set forth in their brief):
(1) Coinventor Riggs testified that during the period of July 1980 through
September 1980 he was at Genentech on sabbatical from City of Hope. It was his
intention to explore the possibility of producing antibodies in bacteria. According to Riggs,
after returning to City of Hope, he submitted a proposal (CX-2) to Genentech on October
5, 1981, which was based in part on conversations he had with Dr. Heyneker and Cabilly. 7
Riggs contended that he proposed the use of a single bacterial strain for coexpression of
the heavy and light chain genes. Riggs, ¶ 3. Riggs stated that he discussed this project
Interference No. 102,572
Carcinoembryonic antigen (CEA) is an antigen unique to humans and is found8
mainly in intestinal tumors. (CX-2, page 2).
11
with Shively who was involved in the study of human anti-CEA antibodies and that he8
requested and received from Shively, on
or about February, 1981, a mouse hybridoma cell line, CEA.66-E3, said to express anti-
CEA antibodies. Riggs, ¶¶ 3-5 (CR-15-16).
(2) Shively testified that he had conversations with Riggs regarding the project and
that upon request from Riggs he supplied Riggs with the cells requested on or about
February, 1981. Shively, ¶ 5 (CR-17).
(3) Cabilly, a post doctoral fellow in Riggs' laboratory at City of Hope, testified that
in September 1981, he received CEA.66-E3 cells from Shively and that he used these
cells to extract total RNA. The polyA mRNA was purified from the total RNA by using an
oligo-dT cellulose column. Following the isolation of the mRNA, Cabilly testified that he
gave a sample of it to Holmes at Genentech for the preparation of an E. coli colony cDNA
library. Cabilly ¶ 4 (CR-39).
(4) Coinventor Holmes testified that on July 12, 1982 he began working on the
project to express antibodies directed against human CEA in E. coli. Holmes, ¶ 3.
Holmes testified that he received a sample of polyA mRNA from City of Hope and
prepared cDNA which was incorporated into plasmids to make a E. coli colony library.
Holmes, ¶ 4. He testified that he inoculated colonies into microliter plates and the cultures
Interference No. 102,572
Restriction digestion is a process involving the use of enzymes which recognize9
different DNA sequences and cleave the DNA backbone at the site recognized forming
either blunt or stick ends.
SDS-PAGE stands for sodium dodecylsulfate-polyacrylamide gel10
electrophoresis which is a technique which separates various species of proteins or
polynucleotides of different sizes in an electric field.
12
therefrom were stamped onto agar plates and allowed to grow. Holmes, ¶ 5 (CR-29).
(5) Rey, a research assistant at Genentech reporting to Heyneker, testified that he
began work on the project in July 1982 when he received microliter dishes with cultures
containing cDNA from the hybridoma cell line CEA.66-E3. He transferred these cultures to
agar plates and allowed them to grow and later transferred the colonies to nitrocellulose
filters, layered them onto agar plates and allowed them to grow. Once grown, he lysed the
colonies on the filters and treated them for subsequent probing. Rey, ¶ 3 (CR-33).
(6) Holmes used oligonucleotides from the Organic Chemistry Department at
Genentech to prepare light and heavy chain oligonucleotide probes to hybridize with the
filters. After exposure to X-ray film, he picked several colonies which hybridized to the light
or heavy chain oligonucleotide probes, characterized the colonies by Pst restriction
endonuclease digestion and fractionation by [sodium dodecylsulfate(SDS)] 9
polyacrylamide [gel] electrophoresis (PAGE) . Several colonies which hybridized to the10
heavy chain probe were also digested with both PstI and NcoI and analyzed by PAGE.
Holmes subcloned these DNA sequences into M13 vectors. Holmes, ¶ 6, ¶ 7 (CR-30).
(7) Rey testified that he assisted in the sequencing of the heavy chain cDNA by
Interference No. 102,572
The Cabilly et al. brief (page 11) alleges that the “filling in” was done with DNA11
polymerase I large fragment . No one testified as to how the filling in was done. Meitzner,
549 F.2d at 782, 193 USPQ at 22.
13
subcloning DNA into M13 vectors, preparing single-stranded template and carrying out the
sequencing reactions. Rey also testified that he assisted in the sequencing of the heavy
and light chain cDNA's. Rey, ¶ 4 (CR-33).
(8) Holmes testified that he and Heyneker analyzed the sequences and found that
the entire coding region of the light chain was found in the cDNA insert of pK17G4 and that
portions of the nucleotide sequence of the heavy chain were found in two isolated
plasmids: pGamma298 and pGamma11. Holmes, ¶ 7.
(9) Holmes indicated that the plasmid, pKCEAInt 2, for direct expression of the anti-
CEA light chain gene was prepared from five DNA fragments, 1-5. According to Holmes,
fragment 1 was prepared by digesting pHGH207-1* with EcoRI, filling in and digesting11
with BamHI. Following purification of this fragment, Holmes stated that he treated the DNA
with bacterial alkaline phosphatase (BAP). The large fragment (fragment 1) was purified
by PAGE. Holmes, ¶ 8 (CR-30). For fragment 2, Holmes testified that he digested
pK17G4 DNA with PstI, purified the fragment by PAGE, digested with AvaII and isolated
the 333 bp PstI-AvaII fragment by PAGE; he used the PstI-AvaII fragment and an
oligonucleotide primer in a primer repair reaction to introduce the initiation codon to the
light chain gene. Following the primer repair, Rey sequenced a PstI to AvaII DNA fragment
of the light chain. Rey, ¶ 5 (CR-34). Holmes indicated that he and Heyneker analyzed the
Interference No. 102,572
The Cabilly et al. brief (page 11, first paragraph) alleges that this analysis and12
isolation of pKCEAInt1 was done on or about October 30, 1982. No one testified as to
this date. id.
14
sequencing results . Holmes, ¶ 9 (CR-30). The fragment was purified by PAGE, cleaved
with Sau3A and the 182 bp fragment isolated by PAGE (fragment 2). Holmes, ¶ 9 .
Thereafter, fragments 1 and 2 were ligated together and the ligation reaction transformed
into E. coli. The resultant transformants were analyzed by restriction digestion and
sequencing to confirm the construction of pKCEAInt1. Holmes, ¶ 10. To prepare12
fragment 3, Holmes testified that he digested pK17G4 DNA with PstI and purified the
fragment by PAGE. This fragment was partially digested with AvaII, filled in and purified by
PAGE. This fragment was subsequently digested with HpaII and the 497 bp fragment
isolated by PAGE (fragment 3). Holmes, ¶ 11 (CR-31). For fragment 4, Holmes testified
that he digested the plasmid pKCEAInt1 with AvaI, filled in and digested with XbaI. The
large fragment was treated with BAP and isolated by PAGE (fragment 4). Holmes, ¶ 12.
The small fragment was digested with HpaII and the 169 bp fragment isolated by PAGE
(fragment 5). Holmes, ¶ 12 (CR-31). Fragments 3, 4 and 5 were ligated and the ligation
reaction transformed into E.coli. Resultant transformants were analyzed by restriction
digestion to confirm the construction of pKCEAInt2. Holmes, ¶ 13 (CR-31).
(10) Cabilly testified that he modified plasmid pKCEAtrp207-1* by cleaving out the
PstI-PvuI fragment from the ampicillin resistance gene, filling it in and relegating the blunt
ends to yield plasmid pKCEAtrp207-1*delta which is resistant to tetracycline but sensitive
Interference No. 102,572
15
to ampicillin. Cabilly ¶ 5 (CR-39).
(11) According to Holmes, six fragments, A-F, had to be isolated to make the heavy
chain expression plasmid, pGammaCEAInt2. To make the first fragment, Holmes
digested pHGH207-1* with AvaI, filled in, digested with BamHI, treated with BAP and
purified the large fragment by PAGE (fragment A). Holmes, ¶ 14. He digested
pGamma11 with PstI, the fragment was purified by PAGE, digested with AvaII, filled in,
and digested with TaqI. The 375 bp fragment was isolated by PAGE (fragment B).
Holmes, ¶ 15. He digested pGamma298 with TaqI, BamHI, and isolated the 496 bp
fragment by PAGE (fragment C). Holmes, ¶ 16. Holmes ligated fragments A, B and C and
transformed the ligation reaction into E. coli. The resultant transformants were analyzed by
restriction digestion to confirm the construction of pGammaCEAInt1. Holmes, ¶17 (CR-
31). Holmes used a 15 nucleotide DNA primer in a primer repair reaction to introduce the
initiation codon into an AluI to RsaI fragment of pGamma 298 (fragment D). Holmes, ¶ 18
(CR-31). He digested pGamma298 with PstI, BamHI, HpaII and purified the fragment by
PAGE (Fragment E). Holmes, ¶ 18 (CR-31). He digested pGammaCEAInt1 with EcoRI,
filled in, and digested with BamHI. The then treated this fragment with BAP and purified
the fragment by PAGE (Fragment F). Holmes, ¶ 18. He then ligated fragments D, E and F
and transformed the ligation reaction into E. coli. The plasmid, pGammaCEAInt2 was
said to be confirmed by restriction analysis and sequencing. Holmes, ¶ 18 (CR-31).
(12) Holmes stated that he prepared the expression plasmid pGammaCEAtrp207-
Interference No. 102,572
The Cabilly et al. brief (page 13) argues that this work was done by December 8,13
1982. This argument is also not supported by any testimony. id.
The Cabilly et al. brief (page 14, sec. 4) alleges that the Western Blot used14
rabbit anti-mouse primary antibodies and I-labeled protein A. This is attorney argument.125
16
1* when he digested plasmid pBR322(Xap) with EcoRI, filled in, digested with PstI, and
purified by PAGE. He isolated a 1543 bp fragment by treating pGammaCEAInt2 with PstI
followed by BamHI and purification by PAGE. He also isolated a 869 bp fragment from
pGammaCEAInt2 by digestion with AvaI, filling in, cleaving with BamHI and subsequent
PAGE purification. He then ligated these fragments, transformed the ligation reaction into
E. coli and analyzed the resultant colonies by restriction analysis to confirm
pGammaCEAtrp207-1*. Holmes, ¶ 1913
(CR-31-32).
(13) Accordingly to Cabilly he transformed competent E. coli cells with
pKCEAtrp207-1*delta and retransformed the successful E.coli cells with
pGammaCEAInt2 which confers resistance to ampicillin but not to tetracycline.
Cabilly, ¶ 6 (CR-39-40). He grew the cotransformed cells in minimal media containing
ampicillin and tetracycline and induced the cultures with indoleacrylic acid (IAA) to make
refractile body preparations. Cabilly testified that he gave a sample to Jeanne Perry for
SDS-PAGE analysis. Cabilly indicated that he analyzed several samples by SDS-PAGE;
subsequently these were silver stained or subjected to Western blot using anti-mouse IgG
for the identification of light and heavy chain protein. Cabilly, ¶ 7 (CR-14
Interference No. 102,572
id.
The Cabilly et al. brief (page 14) alleges that this analysis was performed on or15
about January 22, 1983. No one testified as to this date for the analysis. id.
17
40).
(14) Perry indicated that the first sample she analyzed from a "cotransformed
refractile body preparation" was supplied to her by Cabilly. She analyzed this sample by
PAGE. Perry, ¶ 12 (CR-26).
(15) Cabilly testified that he also constructed pGammaCEAFABtrp207-1*, a
plasmid vector for the direct expression of the FAB fragment of the heavy chain gene.
(CR-40). Accordingly to Cabilly, he digested pBR322 with HindIII, filled in, digested with
PstI and treated with BAP. He isolated the vector fragment by PAGE (fragment I). Cabilly,
¶ 9. Cabilly indicates that he received a sample of pGammaCEAtrp207-1* from Holmes,
he digested this plasmid with BamHI and PstI and isolated the fragment by PAGE
(fragment II). Another sample of this plasmid was digested with NcoI and NdeI, he isolated
the 260 bp DNA by PAGE. He used a 13 bp oligonucleotide primer in a primer repair
reaction in order to introduce a termination codon. The fragment was then digested with
BamHI, the 179 bp fragment isolated by PAGE, filled in (fragment III). Fragments I, II and III
were ligated and transformed into E. coli. Cabilly, ¶ 9. These transformants were said to
be analyzed by Rey, Holmes and Cabilly by restriction cleavage analysis and
sequencing. Cabilly, ¶ 9, Holmes, ¶ 20 and Rey, ¶ 7 (CR-40-41).15
Interference No. 102,572
The Cabilly et al. brief (page 16) alleges that the fermentations occurred on Feb.16
8, 1983. Rey did not give any specific run dates for these fermentations. id.
18
(16) Cabilly testified that he conducted a refolding experiment with the material
from the cotransformed heavy and light chain E. coli cells. He grew the cotransformants,
lysed them by sonication, solubilized the pellet with guanidine hydrochloride and incubated
this material overnight at room temperature. He then, dialyzed the reaction mixture against
urea buffer at room temperature followed by dialysis into phosphate buffered saline (PBS).
Cabilly testified that he performed an assay to detect active anti-CEA antibody. He
indicated that he found the heavy chain and light chain protein had recombined to yield
antigen binding activity significantly higher than background. Cabilly, ¶ 8 (CR-40).
(17) Mumford, an employee of Genentech, was responsible for microbial
fermentation optimization of gene products. Mumford, ¶ 2 (CR-35) . The record shows that
on three occasions between December 13, 1982 to March 25, 1983, he or someone in his
lab received and recorded receipt of labeled microbial samples. Mumford, ¶¶ 5-7 (CR-
36). Of specific interest is the receipt on February 2, 1983 of W3110/p10 and W3110/p62 2
from Heyneker's laboratory. Mumford, ¶ 7. Mumford recorded:
[T]hese two organisms are E. coli strains, which had been co-transformed
with two plasmids for the co-expression of heavy and light chain of an anti-
CEA antibody. These samples were used to prepare the DMSO stocks
1246-31 and 1246-32, respectively. (¶ 7) (CR-36)
(18) Fermentations were run on these two stock solutions. Thereafter, on16
February 14, 1983, Mumford recorded the fermentations in CX-18. Mumford, ¶ 13
Interference No. 102,572
Other than referring to January, 1983, Perry, in her testimony, does not set forth17
any date for the work she did or observed.
19
(CR-38).
(19) Coinventor Wetzel, a senior scientist at Genentech, testified that he had some
success in folding other recombinant proteins and his help was enlisted on the project.
Wetzel, ¶ 5 (CR 19-20). He and Perry, a research associate in his lab, began working on
the project in January, 1983. Wetzel, ¶ 6 (CR-20) , and Perry, ¶ 2
(CR-21-22 ). Initially they attempted to isolate and purify the heavy and light chains
produced in two different E. coli strains from cell pastes received by Mumford. Wetzel, ¶7
(CR-20).
(20) Perry testified that their strategy to refold the heavy and light chains from17
singly transformed bacteria was to first purify the refractile bodies from the bacteria,
solubilize the protein in denaturant, followed by sulfitolysis. The chains would then be
further purified by S300 gel filtration chromatography and possibly DEAE ion-exchange
chromatography. The plan was to then reconstitute the antibodies by folding the heavy
chain first, adding it to the light chain, allowing both chains to fold together and then oxidize
the disulfide bonds. Perry, ¶ 3 (CR-22). She testified that they tried this strategy and
found a loss of heavy chain protein after the removal of the denaturant by dialysis into
native buffer. In order to alleviate proteolysis, they tried adding PMSF, EDTA, EGTA, and
altering pH and temperature. Protease was found to be inactivated by addition of PMSF,
Interference No. 102,572
The Cabilly et al. brief (page 19, last 5 lines-page 20, line 1) lists a number of18
conditions not identified by Perry in her testimony. id.
20
Perry, ¶ 7 (CR-23-24), and protease could be removed by DEAE ion exchange
chromatography. Perry, ¶ 8 (CR-24).
(21) The strategy to reconstitute immunoglobulin chains also included the
comparison of the refolding results of heavy and light chains from the anti-CEA antibodies
produced from hybridoma cells. Perry, ¶ 10. The antibodies were said to be supplied by
Cabilly. Optimal conditions were determined and used. Perry, ¶ 10.18
(22) Perry stated that later they found that they could isolate the heavy and light
chains from both single and cotransformed bacteria by guanidine solubilization of refractile
body preparations without any further purification by column chromatography. These
samples could then be used directly in the refolding reactions. The final conditions
involved a mixture of sulfitolized heavy chain and an extract of light chain cells. The chains
were reconstituted using the same conditions as the optimal conditions for the
reconstitution of antibody chains produced in hybridoma cells. Perry, ¶ 11 (CR-26) .
(23) Wetzel testified that he recorded in his notebook the results of a Western blot
of SDS-PAGE run by Perry. He testified that from the blot they noted production of heavy
and light chain protein product in the co-transformed E.coli cells and that they were able to
estimate the level of expression (%) from cell paste from Mumford. Wetzel testified that the
results were used to calculate the theoretical maximum possible yield which were in turn
Interference No. 102,572
21
used to calculate % yield. Wetzel, ¶ 9 (CR-25).
(24) Perry testified that she performed a refolding experiment on the cotransformed
cell paste received from Mumford. The paste was sonicated and centrifuged to isolate the
refractile bodies. Perry analyzed the refractile body preparations by SDS-PAGE. The
sample was resuspended in urea, dialyzed, and then assayed. Later Perry analyzed
another reconstitution experiment from denaturant solubilized refractile body preparations
of cotransformed cells. Perry found that the heavy and light chains were insoluble, and that
dialysis into urea was necessary to obtain activity. She stated “[T]he reconstitution of
cotransformed cell extracts utilizing the optimal conditions for the reconstitution of
hybridoma cell produced antibody chains was significantly higher than the background”.
Perry, ¶ 13 (CR26-27).
(25) Wetzel testified that he and Perry , between March 18, and March 24, 1983,
performed an experiment in which CEA-binding activity was generated after refolding. He
testified that the results showed a refolding yield of 0.76% starting from a cotransformed
cellular extract and a yield of 0.32% starting from a mixture of a heavy chain S-sulfonate
and the urea-solubilize crude extract of light chain producing cells. The value of 1580 ng/ml
in the cotransformed refolding reaction was significantly higher than the background levels
of apparent activity obtained from controls of either heavy chain alone (441ng/ml) or light
chain alone (108ng/ml); these latter values are said to arise from the non-specific binding
to CEA in the assay. Wetzel concluded that this data shows “that heavy and light chain
Interference No. 102,572
22
recombine in the refolding reaction to generate antigen binding activity”. Wetzel, ¶ 11 (CR-
20A).
VI.
The Boss et al. position
Boss et al. argue that Cabilly et al. have not established (A) prior conception or (B)
an actual reduction to practice of the subject matter of the count. Boss et al. argue that the
Cabilly et al. record is deficient because (1) there is no corroborated evidence of the
preparation and identification of the starting DNA sequences, the expression plasmids,
and the end product produced or verified dates for these activities; (2) there is no
corroboration of the inventor’s work; (3) the exhibits are unauthenticated as to author,
content and date and are mostly illegible, and not sufficiently explained; and (4) binding
activity does not establish a practical utility for the unidentified end product . Boss et al.
assert that the Cabilly et al. case for priority falls within the doctrine of simultaneous
conception and reduction to practice, citing Smith v. Bousquet, 111 F.2d 157, 160, 45
USPQ 347, 348 (CCPA 1940); Alpert v. Slatin, 305 F.2d 891, 894, 134 USPQ 296, 299
(CCPA 1962); Amgen Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 1217, 18
USPQ2d 1016, 1021 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991); and Colbert v.
Lofdahl, 21 USPQ2d 1068, 1071 (Bd. Pat. App. & Int. 1991).
VII.
BURDEN OF PROOF
Interference No. 102,572
37 CFR § 1.657(b), as now amended, states that: [I]n an interference involving19
copending applications or involving a patent and an application having an effective filing
date on or before the date the patent issued, a junior party shall have the burden of
establishing priority by a preponderance of the evidence.
23
Cabilly et al. as the junior party, whose application was copending with the Boss et
al. patent, bears the burden of proving their case for priority by a preponderance of the
evidence. Bosies v. Benedict, 27 F.3d 539, 541-542, 30 USPQ2d 1862, 1864 (Fed. Cir.
1994); See also Peeler v. Miller, 535 F.2d 647, 651 n.5, 190 USPQ 117, 120 n.5 (CCPA
1976); Linkow v. Linkow, 517 F.2d 1370, 1373, 186 USPQ 223, 225 (CCPA 1975);
Frilette v. Kimberlin, 412 F.2d 1390, 1391, 162 USPQ 148, 149 (CCPA 1969) cert.
denied, 396 U.S. 1002 (1970). See also 37 CFR § 1.657(b)[1995].19
REDUCTION TO PRACTICE
The issue of reduction to practice is a question of law. Hybritech, Inc. v. Monoclonal
Antibodies, Inc., 802 F.2d 1367, 1376, 231 USPQ 81, 87 (Fed. Cir. 1986), cert. denied,
480 U.S. 947 (1987). To establish a reduction to practice of a method count, a party must
show that each step of the method was performed. Szekely v. Metcalf, 455 F.2d 1393,
1396, 173 USPQ 116, 119 (CCPA 1972) . All limitations of the count have to be satisfied.
Id. Such performance may be made by the inventor or someone on his behalf. A party
must show that the method produced the product of the count. Blicke v. Treves, 241 F.2d
718, 720-721, 112 USPQ 472, 475 (CCPA 1957). Where the objective of the process is
to produce a product having particular properties, the product must be tested to show that
it has the desired properties, and that the product is satisfactory for its intended purpose,
Interference No. 102,572
24
which in some cases requires testing of the product. Birmingham v. Randall, 171 F.2d
957, 958-959, 80 USPQ 371, 372 (CCPA 1948). Whether a product must be tested in
order to establish a reduction to practice, and if so, what tests are necessary is a question
which must be decided on the basis of the facts of the particular case involved. Blicke,
241 F.2d at 720-21, 112 USPQ at 475. The character of testing varies with the character
of invention and the problem it solves. Scott v. Finney, 34 F.3d 1058, 1061-1062, 32
USPQ2d 1115, 1118 (Fed. Cir. 1994). Complex inventions require laboratory tests that
“accurately duplicate actual working condition in practical use” Id. When complex
inventions are involved, a correlation between the test conditions and actual use conditions
must be shown Id. When reviewing the sufficiency of evidence for reduction to practice a
“reasonableness” standard is applied. Holmwood v. Sugavanam, 948 F.2d 1236, 1238,
20 USPQ2d 1712, 1714 (Fed. Cir. 1991). Lastly, there must be an appreciation of the
existence of an embodiment of the invention and the operability of the embodiment. Estee
Lauder v. L’Oreal, 129 F.3d 588, 595-595, 44 USPQ2d 1610, 1615 (Fed. Cir. 1997);
Silvestri v. Grant, 496 F.2d 593, 597, 181 USPQ 706, 706 (CCPA 1974), cert. denied,
420 U.S. 928 (1975); Heard v. Burton, 333 F.2d 239, 243, 142 USPQ 97, 100 (CCPA
1964). See also, D. Chisum Int. Law & Practice §10.06[2](1995).
The reduction to practice must be corroborated in point of time. An inventor must
provide independent corroborating evidence in addition to his own statements and
documents. Hahn v. Wong, 892 F.2d 1028, 1032, 13 USPQ2d 1313, 1317 (Fed. Cir.
Interference No. 102,572
25
1989); Lacotte v. Thomas, 758 F.2d 611, 613, 225 USPQ 633, 634 (Fed. Cir. 1985). Such
evidence “may consist of testimony of a witness, other than an inventor, to the actual
reduction to practice or it may consist of evidence of surrounding facts and circumstances
independent of information received from the inventor” (our emphasis). Hahn, 892 F.2d at
1032-33, 13 USPQ2d at 1317; Reese v. Hurst, 661 F.2d 1222, 1225, 211 USPQ 936,
940 (CCPA 1981) . The purpose of the rule requiring corroboration is to prevent fraud.
Berry v Webb, 412 F.2d 261, 267, 162 USPQ 170, 174 (CCPA 1969). A rule of reason
applies to determine whether the inventor's testimony has been sufficiently corroborated.
Price v. Symsek, 988 F.2d 1187, 1192, 26 USPQ2d 1031, 1036-1037 (Fed. Cir. 1993).
The “rule of reason” involves an examination, analysis and evaluation of the record as a
whole to the end that a reasoned determination as to the credibility of the inventor’s story
may be reached. Berges v. Gottstein, 618 F.2d 771, 776, 205 USPQ 691, 695 (CCPA
1980); Mann v. Werner , 347 F.2d 636, 640, 146 USPQ 199, 202 (CCPA 1965). There
is no single formula that must be followed in proving corroboration. Whether an actual
reduction to practice has been corroborated must be decided on the facts of each
particular case. Berges, 618 F.2d at 776, 205 USPQ at 695. Nonetheless, adoption of
the “rule of reason” has not dispensed with the requirement that corroborative evidence
must not depend solely from the inventor himself but must be independent of information
received from the inventor. Coleman v. Dines, 754 F.2d 353, 359, 224 USPQ 857, 862
(Fed. Cir. 1985); Reese v. Hurst, 661 F.2d 1222, 1225, 211 USPQ 936, 940 (CCPA
Interference No. 102,572
Extrinsic evidence of authenticity as a condition precedent to admissibility is not20
required for self-authenticating evidence. See FRE 902.
26
1981); Mikus. Wachtel , 542 F.2d 1157, 1159, 191 USPQ 571, 573 (CCPA 1976). Thus
where, as here, the process is carried out by the inventors, there must be corroborated
evidence that all the limitations as to materials, properties, steps and results required by
the count were present in the work performed. Land v. Regan, 342 F.2d 92, 101, 144
USPQ 661, 669 (CCPA 1965) ; Vandenberg v. Reynolds, 268 F.2d 744, 747, 122 USPQ
381, 383 (CCPA 1959).
VIII.
OPINION ON PRIORITY
We find that based on the record before us, Cabilly et al. have not proved, by a
preponderance of evidence, an actual reduction to practice of the invention in issue prior to
March 25, 1983.
A. Exhibits
As noted previously, Boss et al. have challenged the Cabilly et al. exhibits on the
basis of lack of authentication as to author, date, and content.
Authentication is defined as “genuineness” and is said to be established, when it is
proved to be the thing it is supposed or represented to be. Rivise & Caesar, 1940, Vol IV,
§563, page 2418; see also FRE 901. An exhibit may be authenticated by oral testimony
of a witness but not by the uncorroborated testimony of the party on whose behalf it is
offered in evidence. Hence, a witness must properly identify the exhibit as to what it is20
Interference No. 102,572
Amoss v. McKinley, 195 USPQ 452, 453-454 (Bd. Pat. Int. 1977). The extent to21
which an exhibit is explained depends on the simplicity or complexity of the subject matter
as well as technical background of tribunal hearing the case. Rivise and Caesar Vol. III, §
435, page 1891. Herein, because of the complexity and the terminology used in the
biotechnical arena, it is most imperative that a witness’ explanation as to authorship and
content of a document be sufficiently clear and detailed as to the specific entries in the
exhibits relied upon by a witness in order for the Board to make a proper analysis of the
record. It is not sufficient to provide a bare allegation that certain work was done citing
certain pages of notes or notebooks attached to the affidavit or declaration. It is not the
burden of the Board to try to read the exhibits and to correlate allegations made in the
testimony with specific entries. Amoss, citing Gipstein v. Contois, 191 USPQ 688, 690
(Bd. Pat. Int. 1975); and Golota v. Strom, 489 F.2d 1287, 1292-1293, 180 USPQ 396,
400-401 (Bd. Pat. Int. 1975); Triplett v. Steinmayer, 129 F.2d 869, 871-872, 54 USPQ
409, 411-412 (CCPA 1942); Chandler v. Mock, 150 F.2d 563, 567-568, 66 USPQ 209,
213-214 (CCPA 1945); Teel v. Cotton, 151 USPQ 428, 430-431 (Bd. Pat. Int. 1966);
Popoff v. Orchin, 144 USPQ 762, 763 (Bd. Pat. Int. 1963); and In re Borkowski, 505 F.2d
713, 194 USPQ 29 (CCPA 1974).
C.F.R. § 1.671(f) states that “[T[he significance of documentary and other exhibits22
shall be discussed with particularity by a witness during oral deposition or in an affidavit.”
See Notice of Final Rule at 48447, col. 3, 1050 Off. Gaz. Pat. Office at 416, in 1984 the
rules were amended to require the particularized explanation of material in non-self
authenticating documents. The commentary explained that “[B]y providing in the rules that
documentary evidence must be explained, the PTO hopes to save both
parties and the Board considerable difficulty in presenting and evaluating evidence.”
27
as well as to explain the witness’ relationship to the document in question. In addition,
authenticity of an exhibit must be established both as to subject matter (content) and time.
Rivise & Caesar, Vol IV, § 563, page 2418.
Documents do not speak for themselves. They must be explained even if they contain a21
label and a date. Further, 37 C.F.R. § 1.671(f) requires a witness to explain the entries22
on the various pages of the notebooks/exhibits. This explanation provides the opponent
Interference No. 102,572
Notebooks are not self-authenticating. FRE 902.23
Where a party submits a handwritten exhibit, the Board should not be expected to24
decipher it. If the exhibit is a handwritten document, a typed copy of the document should
be provided on a separate piece of paper and attached to the exhibit. Cf. Latimer v.
Wetmore, 231 USPQ 131 (Bd. Pat. App. & Int. 1985).
28
party and the Board a basis to determine whether the witness’ testimony is supported by
contemporaneous documentation or whether a party is relying upon the witness’ oral
testimony.
While the record index, page v, refers to CX-20 as Cabilly’s notebook, Cabilly 23
himself provides no testimony regarding the identity of the exhibit, the specific entries in
the exhibit or any date the work was done except for his initial statement of when he
received the cells. No other declarant identifies this exhibit. Our review of CX-20 shows
that it consists of a series of loose-leaf pages that are unsigned and unwitnessed. The
entries on the pages are either pasted in or handwritten and are difficult to read and24
understand because of legibility as well as the extensive use of abbreviations and
acronyms. While a few pages appear to bear dates, the dates on the pages are not in
chronological order. (See for example Feb. 8, 83 (Bates page 991) and Jan. 21, 83
(Bates Page 998). We find CX-20 unauthenticated and of no probative value.
The record index, pages iv and v, identifies CX-11 and CX-13 as Holmes’
notebook and CX-12 as Wetzel’s notebook. Wetzel does not identify CX-12 as his
notebook and makes no mention of this exhibit in his declaration. Holmes parenthetically
refers to CX-11, 12 and 13 in his declaration but never identifies these documents as his
Interference No. 102,572
29
notebooks. Our review of CX-11 shows it to be a notebook No. 1446 issued to Holmes
consisting of unwitnessed pages with mostly illegible handwritten entries, abbreviations
and acronyms, along with a number of attachments. Our review of CX-12 and CX-13
shows them to consist of spiral bound notebooks containing a series of pages of mostly
illegible handwritten entries containing deletions, abbreviations and acronyms, and with a
number of attachments. The pages are unsigned and unwitnessed. The dates that do
appear on various pages of CX-12 are not in chronological order. CX-11, 12 and 13 are
non-probative.
CX-6 is identified by Wetzel as one of three notebooks (CX-6, CX-8 and CX-9) that
he reviewed in reconstructing the work he and Perry did on this project. Our review of the
CX-6 shows it to be a notebook issued to Wetzel, and consists of handwritten entries,
mostly illegible, unsigned, unwitnessed and undated except for Bate page Nos. 64 and 87.
CX-2 is identified by Riggs as a proposal he wrote. CX-2 and CX-6 have been identified
as to author. However, questions as to content and date as well as corroboration remain.
Both Perry and Rey indicate that it was their practice to date their notebooks and
then parenthetically refer to CX-8 and CX-15, respectively. Perry does not identify CX-9
as her notebook. Mumford testifies that he or someone under his supervision recorded
receipt of cultures and fermentations of the same into CX-17 and CX-18. Even assuming
arguendo that CX’s-8, 9, 15, 17 and 18 have been adequately identified as the
corroborator’s notebooks, the issue of whether these exhibits have been adequately
Interference No. 102,572
30
explained as to content and date remain.
Cabilly et al. allege that the parties had a stipulation that in the event that verification
of information such as the dating of notebooks was necessary, the original would be
furnished. (Reply brief, page 9) Contrary thereto, the stipulation (Record, vi-ix) does not
reflect any agreement with respect to dates on the exhibits.
Cabilly et al. also allege that Boss et al. failed to cross-examine the witnesses.
However, we will draw no adverse inference from Boss et al.’s failure to cross-examine
because it is fundamental that after the junior party has made its case-in-chief that if a
senior party upon examination thereof is of the opinion that the record made by the junior
party is not sufficient to establish priority, there is no compulsion upon senior party to
present any evidence whatsoever. Senior party has the right to stand on its position that
junior party has failed to make his case. Teter v. Kearlby, 169 F.2d 808, 814, 79 USPQ
65, 70 (CCPA 1948); and Cf. Boises v. Benedict, 27 F.3d at 541-542, 30 USPQ2d at
1864 (Fed. Cir. 1994); citing Linkow, 517 F.2d at 1373, 186 USPQ at 225.
B. Essential Limitations of the Count
In the Cabilly et al. proofs, Cabilly et al. focus upon the production of an IgG
molecule containing the heavy (Gamma) chain and light chain of CEA.66-E3 antibody. In
order for Cabilly et al. to prove priority based upon an actual reduction to practice of the
process count, Cabilly et al. must prove by a preponderance of the evidence that they
carried out each step of the process and that the process actually results in the production
Interference No. 102,572
31
of an IgG molecule comprising the heavy and light chain of the CEA.66-E3 antibody, and
that such product is useful.
We find that Cabilly et al. have failed to show the essential elements of the count, to
wit: (1) the first and second DNA sequences of the heavy and light chain of CEA.66-E3
antibody, and (2) that the separate molecules expressed contain the heavy and light chain
of CEA.66-E3 antibody. In addition, Cabilly et al. have failed to show production of the
IgG molecule of CEA.66-E3 antibody and that such product is useful.
Cabilly et al. argue that the heavy and light chains of the anti-CEA antibody were
cloned and sequenced by the end of October, 1982, citing CR-30 and CR-33. In support
of this argument, Cabilly et al. rely upon Holmes’ testimony that Rey sequenced both the
light chain and heavy chain DNA inserts. Holmes’ testimony requires corroboration. A
review of Rey’s testimony indicates that he only assisted in sequencing of the heavy and
light chain cDNA’s. Rey has not explained what he meant by “assisted”, what the results
were from such alleged sequencing and when such work was done. CX-15 contains
various attachments as well as handwritten entries which are not at all legible. This
notebook, CX-15, as best that we can review it, does not appear to contain DNA
sequences for the heavy and light chain of CEA.66-E3 antibody. Rey’s parenthetical
reference to certain pages of CX-15 in his declaration are deemed insufficient to explain
the entries on the pages or when this work was done. In our view, Rey’s testimony, some
nine years after the alleged activities, and his alleged notebook are insufficient to identify
Interference No. 102,572
The Cabilly et al. Brief (page 10, sec. 3) alleges that the work on the light chain25
was done on or about October 28, 1982 and for the heavy chain on or about October 18,
1982. This is an unsupported allegation. Meitzner, 549 F.2d at 782, 193 USPQ at 22.
32
or corroborate the identity of the DNA sequences encoding for the heavy and light chain of
CEA.66-E3. Corroboration must consist of factual evidence as to what was done, not of
broad generalizations or conclusions. Murphy v. Eiseman, 166 USPQ 149, 150-151 (Bd.
Pat. Int. 1970); Azar v. Burns, 188 USPQ 601, 605 (Bd. Pat. Int. 1975).
Cabilly et al. contend that the heavy and light chain sequences were confirmed by
Holmes and Rey (Brief, page 24) . The Cabilly et al. contention that Rey confirmed the
sequences is unsupported by Rey. Holmes testified that he and Heyneker analyzed the
sequences. This testimony requires corroboration and none is offered.25
On this record, Cabilly et al. point to no evidence which identifies the first and
second DNA sequences encoding the heavy and light chains of CEA.66-E3 antibody and
thus such argument is but attorney argument. Meitzner, 549 F.2d at 782, 193 USPQ at 22.
As to the separate molecules expressed, Cabilly et al. argue that Perry analyzed by
SDS-PAGE the cotransformed cell culture she received. While it is true that Perry testified
that she analyzed a sample supplied to her by Cabilly, this record does not establish that
the sample was labeled, how it was transferred between City of Hope and Genentech,
what the results of the run were with respect to the unlabeled sample and the meaning, if
any, of such results. Perry reference to CX-8, pages 149-151 for contemporaneous
documentation is deemed inadequate in view of the fact that the entries on the pages and
Interference No. 102,572
Mumford actually stated: [T]he products that were expected from these26
fermentation runs were both the light and heavy chain of an anti-CEA antibody. SDS-
PAGE shows protein expression from the time course samples. I recorded that the
fermentation run No. GGLH-1 was harvested and that the 80 grams of wet biomass paste
was given to Dr. Ron Wetzel. Fermentation GGLH-1 demonstrated refractile bodies upon
microscopic analysis. (¶ 13). (CR-38).
Mumford’s entry in his notebook No. 18, at page 31 (Bates 730) actually appears27
to contradict the Cabilly et al. arguments. Mumford states (as best that we can read the
(continued...)
33
time of work are not fully explained. These pages are illegible and also contain
unexplained attachments.
Cabilly et al., in their brief, page 16, argue that the SDS-PAGE gel run by Mumford
showed that each of these transformants, GGLH-1 and GGLH-2, was expressing both
heavy and light chains. (our emphasis). They also argue in their reply brief, page 17, that
Mumford testified that:
“Analysis by SDS-polyacrylamide gel electrophoresis (PAGE) show[ed] a
band in the 55kD region which is the expected molecular weight of the heavy
chain product,” (Mumford, CR-37,¶10) “ SDS-PAGE analysis indicated
product expression at the 23.5kD molecular weight range which was
expected for light chain product,” (Mumford, CR37-38, ¶12) and then finally
that SDS-PAGE showed that the cotransformed cells expressed both the
heavy and light chain of the antiCEA-antibody.(our emphasis)
Initially we note that this record never identifies the origin of GGLH-1 and GGLH-2,
that is, who made them, the process used to make them, and what DNA they contained.
Contrary to the Cabilly et al. arguments, Mumford never testified that the SDS-PAGE gel
of GGLH-1 and GGLH-2 showed expression of both the heavy and light chain(our
emphasis). Mumford testified to an expectation and not to what he actually found. The26 27
Interference No. 102,572
(...continued)27
entry): “[T]he gels are shown on [the] following pages. No real strong product bands could
be seen on either gel. It is possible that trace metal contamination would have occurred in
the new fermentors due to condensation pick-up during sterilization.”
34
analysis of the cultures noted by Mumford at CR-37, ¶ 10 and at CR-37-38, ¶ 12 are those
of the heavy chain or light chain transformed cells and are not of cotransformed cells.
SDS-PAGE of refractile body preparations does not and cannot identify and verify
the production of the intended product because the refractile body preparations made by
E.coli require lysis and solubilization to permit recovery and then refolding of the
recovered heavy and light chains. Cabilly et al. offered no evidence to identify and verify
the refolded product as the intended protein product of the count.
A demonstration of binding activity in an assay does not establish that all of the
steps of the process have been performed and that the intended product was produced.
No declarant asserted that a conclusion as to the chemical composition or structure could
be drawn from the binding activity data. Schendel v. Curtis, 83 F.3d 1399, 1403-1404, 38
USPQ2d 1743, 1747 (Fed. Cir. 1996); Colbert, 21 USPQ2d at 1071. Because the
intended product has not been identified and verified there can be no appreciation of the
existence or operability of the intended product.
While the question of utility is actually moot, we add the following comments for
completeness. Herein, the count does not set forth a particular utility for the intended
product of the count. Evidence of substantial utility for any purpose is sufficient to prove
Interference No. 102,572
35
reduction to practice. Cabilly et al. have chosen to rely upon a difference between an
assay value of an alleged reformed product and an antigen and the background values of
the heavy and light chain individually. Cabilly et al. conclude that such data shows
recombination and utility. Cabilly et al. urge that binding activity to the antigen which binds
the known hybridoma antibody is sufficient to prove the utility of the recombinantly
produced antibodies.
We disagree with Cabilly et al. that such testing establishes practical utility.
This record does not identify the antigen used in the binding assay and its
relationship to the original source of immunoglobulin cDNA.
Cabilly et al. have provided no testimony which explains how a comparison of an
assay value of an allegedly reformed antibody of CEA.66-E3 bound to an unidentified
antigen and the background values of the individual unfolded chains is indicative of
practical utility. Practical utility is a shorthand way of attributing “real world” value to the
claimed subject matter. In other words, one skilled in the art can use a claimed discovery
in a manner which provides some immediate benefit to the public. Nelson v. Bowler, 626
F.2d 853, 856, 206 USPQ 881, 883 (CCPA 1980). We acknowledge that assays, in
general, are useful for immunological diagnostic testing to detect or quantitate antigens or
antibodies in solution. Antibodies and antigens bind; how they bind, that is, how
complementary the antibody and antigen are to one another and the strength of the bond
between the antibody and antigen is determinative of the specificity of the antibody-antigen
Interference No. 102,572
36
reaction If in an assay, an antibody is used to detect the presence of or quantity of the
antigen which elicited the initial response of the antibody-producing cell used in producing
the hybridoma cell line, practical utility may be shown because the antibody and antigen
which elicited it have a unique relationship and the specificity and sensitivity of that
relationship would be known and used as a control. Where an antigen other that which
elicited the antibody is used, binding may occur, however such binding, that is, cross-
reactivity is not indicative of practical utility but may lead to false positives in diagnostic
testing. Thus, any assay to be reliable requires investigation of the sensitivity and
specificity of the antibody-antigen reaction. On this record, we are unable to conclude that
the testing is adequate since neither a correlation between the test conditions and actual
use conditions is established nor is the sensitivity and specificity of the recombinantly
produced antibody with regard to any antigen and the reformed product and same antigen
established.
Cabilly et al. allege that the authenticity and identity of the cell line from which the
known anti-CEA antibodies and recombinant Ig molecules were derived was attested to by
Shively and his reference to Cabilly et al. CX-4. We do not find this argument persuasive.
Shively provided no specific testimony with respect to CX-4 other than to provide a
statement that a mouse hybridoma cell line was generated, CEA.66-E3, which secretes
antibodies directed against human carcinoembryonic antigen and to parenthetically refer
to CX-4 in that statement. Our review of CX-4 shows it to be an article entitled
Interference No. 102,572
Cabilly et al., in their brief (page 9), argue that the CEA.66-E3 cell line prepared28
by Shively and given to Riggs in February 1981, was produced by polyethylene glycol
(PEG) fusion of cells from a myeloma cell line Sp2/0-Ag 14 with
splenocytes from female BALB/c mice which had been immunized with CEA, at a ratio of
1:3, citing Shively CR-17 and CX-4.
37
“Monoclonal Antibodies for Carcinoembryonic Antigen and Related Antigens as a Model
System: A Systematic Approach for the Determination of Epitope Specificities of
Monoclonal Antibodies,” authored by several persons including Shively, published in May,
1983, after the date accorded to Boss et al. The significance of this document with
respect to the cells made and given to Riggs in February 1981 has never been explained.
Moreover and contrary to Cabilly et al. allegations (brief, page 9 and reply brief page 12)28
, no one gave detailed testimony explaining exactly how the cell line, CEA.66-E3, was
prepared, how the antibodies produced therefrom were characterized, and what, if any,
epitope specificity the antibody has. Statements in the brief cannot take the place of
evidence in the record. Meitzner, 549 F.2d at 782, 193 USPQ at 22.
In addition to not having established all the steps of the process, the production and
appreciation of the intended product and the usefulness of the same, we find after a
reasoned examination, analysis and evaluation of all the pertinent evidence relied upon by
Cabilly et al. that the work allegedly done by inventors stands uncorroborated.
Cabilly alleges that he received the cell line, CEA.66-E3, from Shively in
September of 1981 and extracted the mRNA therefrom. Cabilly’s oral testimony regarding
the obtention of the cell line is not confirmed by Shively.
Interference No. 102,572
38
While Cabilly indicates that he sent the mRNA to Holmes, Holmes’ testimony
indicates that the mRNA was from an unnamed source at City of Hope. And while Cabilly
et al. would have us accept that Holmes received the cell line from Cabilly based on
Cabilly’s testimony, it is well settled that joint inventors cannot be corroborators. Kendall v.
Dickinson, 195 USPQ 605, 614 (Bd. Pat. Int. 1975). It should be noted that the record
never establishes that these inventors were working in the same laboratory; note that City
of Hope is said to be in Duarte, California, and Genentech in San Francisco, California.
Moreover, here, as well as throughout this record, samples made are not labeled and no
chain of transfer of the samples between the declarants is ever established. id.
Holmes testifies that he prepared an E.coli cDNA library. Cabilly et al. (RB-13)
alleges that Holmes gave the cells on agar plates to Rey. Rey is identified as a research
assistant at Genentech who reported to Heyneker not Holmes. There is no testimony that
the cultures received were labeled and Rey never testified when he got or from whom he
got the cultures or to whom he gave the filters. Moreover, Rey never testified that he
analyzed the cultures and thus there is no independent corroboration as to the content of
the cultures.
Holmes alleges that he received from the Genentech lab oligonucleotides which he
used to prepare light and heavy chain oligonucleotide probes to hybridize with the filters.
On this record, the oligonucleotides are not identified. Holmes did not testify as to how he
Interference No. 102,572
Prior to 1983, there were only three approaches to designing oligonucleotide29
probes to screen libraries. Amgen Inc. v. Chugai Pharmaceutical Co., 13 USPQ2d 1737
(D. Mass. 1989) .
39
designed the probes. And no one corroborated the oligonucleotide request, what the29
actual request was, and the making of such probes and the transfer of such probes to
Holmes. Cabilly et al. argue that it is irrelevant that Holmes (1) did not identify from whom
in the lab he received oligonucleotides and (2) did not examine the sequence of
oligonucleotides he received because he used the oligonucleotides for its intended
purpose and sequenced the resulting clones. We disagree. Holmes testimony requires
corroboration. Corroboration may be by a witness or by
Interference No. 102,572
Cabilly et al. alleged that the DNA sequence encoding various Ig heavy and light30
chains were known by 1981. (CS Brief, p. 2) There is no evidnce in this record to support
this allegation. Meitzner, 549 F.2d at 782, 193 USPQ at 22.
40
circumstantial evidence independent of the inventor. We find neither. The count requires
the use of specific DNA encoding an Ig molecule [herein CEA.66-E3 antibody] These
sequences are material limitations in the count. The question is how one obtains and
verifies such materials. In order to isolate a gene of interest from a cDNA library, the30
library is first denatured and then screened with a probe which may bind or hybridize under
specific conditions with a complementary strand. In addition, the probe must not bind with
identical portions of a gene for other proteins thereby resulting in the retrieval of a gene
other than the one of interest. Thus, the identity of the DNA sequence that complexes with
the probe and forms the hybridized product is directly related to the identity of the
oligonucleotides used as probes and to the conditions used. Holmes also alleges that he
sequenced the resulting clones. Such allegation stands uncorroborated. There is no
evidence of record to indicate that the first and second DNA molecules used were ever
obtained, identified and verified.
Cabilly et al., in their brief (page 24), asserts that the expression plasmids for the
heavy and light chains, pKCEAtrp207-1*delta and pGammaCEAInt2, respectively, were
constructed by Cabilly and Holmes and confirmed with the assistance of Rey by about
December, 8, 1982. Reduction to practice must be completely corroborated in point of
Interference No. 102,572
41
time. Neither inventors Cabilly and Holmes nor corroborator Rey testified to when the
alleged constructions and confirmations were done. Meitzner, 549 F.2d at 782, 193
USPQ at 22. Cabilly’s and Holmes’ testimony with respect to the making and confirming
the constructs requires corroboration. Holmes indicates that he made pGammaCEAInt2,
an expression plasmid said to contain the heavy chain of CEA.66-E3 antibody. He does
not indicate what he did with this expression plasmid after making it. Cabilly et al. in their
brief, allege that his work was done on or about December 2, 1982. This allegation is
unsupported. The process involved a series of complex steps. See Cabilly et al. case, ¶
11, supra. Cabilly indicates that he made pKCEAtrp207-1*delta, an expression plasmid
said to contain the light chain of CEA.66-E3 antibody, by initially modifying pKCEAtrp207-
1.* Cabilly et al., in their brief, have not presented any citation to the record or argument
as to who made pKCEAtrp207-1,* how it was made, what DNA sequence it contained or
how Cabilly got it.
Rey’s limited testimony that he sequenced a fragment of the light chain following a
primer repair reaction (Cabilly et al. case, ¶ 9, supra, Rey ¶ 5, CR-34) does not and can
not corroborate the making or confirmation of both of these two expression plasmids or the
identity of the first and second DNA sequence of the count. Hence, Holmes’ and Cabilly’s
testimony with respect to the making and confirmation of the expression plasmids said to
contain the heavy and light chain of CEA.66-E3 antibody stands uncorroborated. An
inventor’s statements are self-serving and have no corroborative value. The record before
Interference No. 102,572
The Cabilly et al. brief (page 17) alleges that the SDS-PAGE was run on January31
21, 1983. Perry did not provide any date for this run.
42
us does not show or confirm the structure of the expression plasmids.
Cabilly testified that he cotransformed E.coli with pKCEAtrp207-1*delta and
pGammaCEAInt2 and expressed refractile bodies. Cabilly et al. allege in their brief (page
14, sec. 4) that this work was done on or about January 21, 1983. Cabilly did not provide
any dates with respect to this work. Therefore, the Cabilly et al. allegation as to when this
work was done is but attorney argument. Id. Cabilly’s testimony requires corroboration.
For corroboration, Cabilly et al. allege that Perry received a sample of
cotransformants from Cabilly and that she analyzed these transformants by SDS-PAGE. 31
While it is true that Perry testified that she received a sample from Cabilly neither Cabilly
nor Perry testified as to the label on the sample and the chain of transfer between the City
of Hope and Genentech. SDS-PAGE analysis by Perry was performed on an unlabeled
and unidentified sample. Perry’s testimony, in our view is insufficient to corroborate
Cabilly’s alleged work, since she did not have first-hand knowledge of how the sample was
made or whether it was made according to the process recited in the count. Her analysis
by SDS-PAGE of such sample would not establish how the sample was made or whether
it was produced by the process of the count and produced the intended Ig molecule of
CEA.66-E3. It would appear that she derived all of her information with respect to the
sample from Cabilly. The burden is on Cabilly et al. to prove that information was not
Interference No. 102,572
43
derived from the inventor. Zoiss v. Nix, 185 USPQ 419, 421-422 (Bd. Pat. Int. 1974).
Further, since SDS-PAGE is but a technique to separate proteins or nucleotides by size
and the sample allegedly contained refractile bodies, neither Perry nor any other witness
explained the results of this run, what such analysis would establish or how one would know
from the data of the run that the process of the count had been successfully performed and
the intended product made.
Cabilly et al. also allege that Mumford received these cotransformed cells on
February 2, 1983. This allegation is not corroborated by Mumford. Mumford testified that
he received from Heyneker’s lab, on February 2, 1983, samples labeled
W3110/ p10 and W3110/p6 said to contain the heavy and light chain of CEA.66-E32 2
antibody. There is no indication in this record that Cabilly labeled his sample(s) as
W3110/ p10 and W3110/p6 and transmitted them from City of Hope to Mumford at2 2
Genentech. Mumford provides no first hand knowledge as to who made these samples,
whether the samples were made according to the process of the count, and whether the
samples contained the separate molecules of the heavy and light chain of CEA.66-E3
antibody. Id. Mumford’s testimony (CR-36, ¶ 7, and ¶ 17 of case in chief) identifying
these two organisms as E.coli strains that had been cotransformed with two plasmids for
coexpression of heavy and light chain of an anti-CEA antibody is not independent of the
inventor. Hahn, 892 F.2d at 1032, 13 USPQ2d at 1317; Reese, 661 F.2d at 1225, 211
USPQ at 940.
Interference No. 102,572
44
Cabilly indicates that he refolded the material obtained from the refractile bodies
and assayed the refolded protein in an assay to detect active anti-CEA antibody. Cabilly
et al. brief (page 21) alleges that this was done on February 8, 1983. There is no
testimony with regard to the date of this work. Meitzner, 549 F.2d at 782, 193 USPQ at
22. There is no testimony or evidence to corroborate the Cabilly’s testimony regard this
testing. Cabilly et al. allege that the assay demonstrated effective refolding of the heavy
and light chains which produced antibody that bound antigen at a level significantly higher
than background. However, the testimony of an inventor is not by itself effective to prove
reduction to practice in the absence of corroboration. White v. Habenstein, 219 USPQ
1213, 1217 (Bd. Pat. Int. 1983). Cabilly’s testimony stands uncorroborated and does not
establish that Cabilly et al. identified a product of the count or its usefulness.
Cabilly et al. urge that we need look no further than the Wetzel and Perry tests
demonstrating immunological activity for the refolded antibody to determine that Cabilly et
al. have proven actual reduction to practice. We disagree. There is no testimony that a
demonstration of binding activity of an unidentified product would establish an actual
reduction to practice of the process of the count. Without explaining the entries on pages
87-88 of CX-6, Wetzel testified that he and Perry conducted an experiment in which “CEA-
binding activity was generated after refolding” and that they found refolding yield
percentages and binding levels. He concluded that “the data shows that the heavy chain
and light chain recombine in the refolding reaction to generate antigen binding activity.
Interference No. 102,572
45
(CR-20A, ¶ 11, see also ¶ 25, supra, in Cabilly et al. case). However, he did not explain
exactly what sample was tested, how it was tested, and what antigen was used. Further he
did not explain how this test and the results of such test establish practical utility. Further,
Wetzel’s testimony and documentation are self-serving and require corroboration.
Perry does not identify the sample tested, the test performed, the results of any
testing or when the tests were performed. Corroboration must be independent of the
inventor and must be to point in time. She simply states at various places that “samples”
were assayed. (CR-27, ¶ 13). She also did not explain how this testing established a
practical utility. Further, Perry does not corroborate Wetzels’ testimony regarding
refolding yield percentages, the value of the refolding process and the levels of chains
allegedly expressed in the transformations.
Cabilly et al. argue that they have shown that there was a well defined “network” of
researchers involved in this project, who maintained reasonable records of their activities
and who worked together to achieve an actual reduction to practice of the invention. We
do not find the Cabilly et al. argument persuasive. As noted, supra, not all of the
researchers were employed by Genentech nor did they maintain reasonable records. The
researchers did not label their samples nor provide a chain of custody for transferring the
samples between the two companies in different cities. In addition, we cannot conclude
that Cabilly et al. maintained reasonable records because of the lack of authentication and
explanation of the exhibits.
Interference No. 102,572
Even assuming arguendo that Cabilly et al. relied upon this testimony and made32
such an argument in their brief, such testimony would not be deemed sufficient to establish
an actual reduction to practice as now alleged because an inventor’s testimony and
documentation are self-serving and have no corroborative value. Moreover, while Rey
testified that he analyzed the transformant pGammaCEAFABtrp207-1*, there is no
corroborating evidence of record with respect to Cabilly’s alleged work on any
cotransformation involving pGammaCEAFABtrp207-1*. There is no evidence proferred to
establish (1) what Rey found upon sequencing the heavy chain transformant, (2) whether
Rey sequenced a light chain transformant; (3) whether Rey analyzed a cotransformant
containing plasmid(s) containing the heavy and light chains of CEA.66-E3 antibody; and
(continued...)
46
Lastly, Cabilly et al. argue in their reply brief (page 16) that Cabilly testified that he
ligated fragments I, II and III and transformed them into E.coli and that he later
retransformed these cells to get cotransformed cells potentially expressing both the heavy
and light chains; that Rey corroborates this testimony because he analyzed these
transformants by restriction analysis and sequencing before Boss et al.’ March 25, 1983
filing date. Cabilly et al. in their brief set forth their scenario for priority and included the
work of Cabilly et al. in ligating fragments I, II and III to prepare pGammaCEAFABtrp207-
1* (identified by Cabilly et al. as a plasmid vector for the direct expression of the FAB
fragment of the heavy chain gene) (see ¶ 15, Cabilly et al. case). However, they did not rely
upon Cabilly’s testimony that he later retransfomed these cells potentially expressing both
heavy and light chains. Moreover, there are no argument’s in the Cabilly et al. brief
directed to the work of Cabilly et al. in the preparation of pGammaCEAFABtrp207-1*
transforming these into E.coli nor to the cotransformation of this heavy chain with a light
chain. Hence, both of these new arguments are not entitled to any consideration.32
Interference No. 102,572
(...continued)
(4) what the DNA sequence analysis results of the individual transformants were, what
product was produced on expression, what product was produced after refolding, and
whether there was utility testing for the product.
47
II.
Conception
We find that the Cabilly et al. record does not establish a complete conception of
the count in issue prior to the March 25, 1983, date accorded to Boss et al. Without an
earlier conception than the date accorded Boss et al., the issue of reasonable diligence by
the inventors to a reduction to practice is moot and the evidence relating to diligence has
not been considered herein.
. Conception is a question of law. Kridl v. McCormick, 105 F.3d 1446, 1449, 41
USPQ2d 1686, 1688-1689 (Fed. Cir. 1997); Bosies v. Benedict, 27 F.3d at 542, 30
USPQ2d at 1864; and Fiers v. Revel, 984 F.2d 1164, 1168-1169, 25 USPQ2d 1601,
1604 (Fed. Cir. 1993). Conception is defined as the formation “in the mind of the inventor
of a definite and permanent idea of the complete and operative invention, as it is hereafter
to be applied in practice.” Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d at
1376, 231 USPQ at 87-88 (Fed. Cir. 1986), cert. denied, 480 U.S. 947 (1987) ( citing 1
Robinson on Patents 532 (1890), Coleman, 754 F.2d at 359, 224 USPQ at 862; (quoting
Gunter v. Stream, 573 F.2d 77, 80, 197 USPQ 482, 484 (CCPA 1978)). By this definition,
conception consists of two parts, the idea and the means to carry out the idea.
Interference No. 102,572
48
Conception must include every feature or limitation in the count, and every limitation must
have been known to the inventor at the time of the alleged conception. Coleman, 754 F.2d
at 359, 224 USPQ at 862. Conception of an inventive process involves proof of mental
possession of the steps of an operative process and, if necessary, of means to carry it out
to such a degree that nothing remains but routine skill for effectuation thereof. Alpert v.
Slatin, 305 F.2d 891, 894, 134 USPQ 296, 299 (CCPA 1962). Since, conception takes
place in the mind of the inventor, additionally there must be disclosure to and corroboration
by a third party. For it is well settled that the inventor’s testimony standing alone, is
insufficient to prove conception Price, 988 F.2d at 1193-1194, 26 USPQ2d at 1036. In
evaluating whether there is conception, a rule of reason is applied, the rule does not
however dispense with the requirement of some evidence of independent corroboration.
Coleman, 754 F.2d 360, 224 USPQ at 862.
For conception, Cabilly et al. rely upon Riggs’ testimony, on CX-2 and also upon
discussions that Riggs is said to have had with Shively regarding the strategy for bacterial
expression of immunogloblins.
The conception analysis necessarily turns on the inventor’s ability to describe his
invention with particularity. Burroughs Wellcome Co. v. Barr Laboratories, Inc., 40 F.3d
1223, 1227-1228, 32 USPQ2d 1915, 1919 (Fed. Cir. 1994). Coinventor Riggs, in his
testimony, testified that he formulated a proposal which suggested that a “single bacterial
strain could be constructed which contained both heavy and light chain genes for co-
Interference No. 102,572
49
expression...”; and submitted the proposal to Genentech on October 5, 1981 (citing CX-2
and Bates page 922). While Riggs’, in his testimony identifies CX-2 as a proposal he
formulated and forwarded to Genentech on October 5, 1981, his testimony is insufficient
to establish a complete conception since he does not explain what specific passage(s) of
Bates page 922 support his conclusory statement or how any part of Bates page 922
“contains all the elements of Count 1" as alleged in their brief. (CB-24, first paragraph)
Amoss, 195 USPQ at 453-454. Exhibits do not speak for themselves. We find no
explanation as to how the statement “a single bacterial strain could be constructed which
contained both heavy and light chain genes for co-expression” satisfies the terms of the
count and shows that every limitation of the count was known by the inventor at the time of
the alleged conception. Coleman, 754 F.2d at 359, 224 USPQ at 862. Each express
limitation of the count is considered material and cannot be disregarded. Schur v. Muller,
372 F.2d 546, 551, 152 USPQ 605, 609 (CCPA 1967). The count requires employing a
first and second DNA sequence encoding for at least the variable regions of the heavy and
light chain of an Ig molecule. In addition, the process requires the production of specific
product. There is no evidence in this record that establishes that the inventors were in
possession of the DNA encoding for the heavy and light chains of the IgG antibody
produced by CEA.66-E3 cell line or any other antibody and the means for producing an
active antibody product. Hence, the idea is not so clearly defined in the inventor's mind
that only ordinary skill would be necessary to reduce the invention to practice, without
Interference No. 102,572
50
extensive research or experimentation. Burroughs, 40 F.3d at 1230, 32 USPQ2d 1921.
Riggs’ testimony and exhibit are also deficient, in that there is no corroboration
independent of the inventor. Herein, no third party testified regarding receipt of CX-2.
For conception, Cabilly et al. also rely upon a conversation between Riggs and
Shively as to the Riggs’ proposal. We also do not find Riggs’ testimony that he discussed
the proposed project with Shively and Shively’s testimony that he recalled having some
conversations “regarding the cotransformation of E.coli with plasmids containing heavy
and light chain genes “ sufficient to establish corroborated conception of the count in this
interference. There is no testimony as to when and where this conversation took place,
who was present, and exactly what the conversation was and how such alleged
conversations satisfy all the limitations of the count. The testimony by both of these
witnesses regarding the alleged conversation is conclusory and it fails to explain how
Riggs’ discussion and corroborator's Shively’s vague recollection of some earlier
conversations establish a complete conception of the subject matter of the count. We find
Riggs' and Shively's oral testimony, given some nine years after an alleged conversation,
unsupported by any contemporaneous documentation or physical evidence, unreliable and
of little probative value.
Boss et al. urges in his brief, that this case is one which comes under the doctrine
of conception and simultaneous reduction to practice because of the unpredictability of the
technology. Smith, 111 F.2d at 160, 45 USPQ at 348; Alpert, 305 F.2d at 894, 134
Interference No. 102,572
51
USPQ at 299; Amgen, 927 F.2d at 1217, 18 USPQ2d at 1021; and Colbert, 21 USPQ2d
at 1071. If after the claimed conception date extensive research was found necessary
before achieving minimum satisfactory performance obviously the mental embodiment of
that date was a mere hope or expectation, a statement of a problem, but not an inventive
conception Alpert, supra.
We agree with Boss et al. that on the record before us, this case is one where
conception and reduction to practice must be concurrent. The record shows that by March
25, 1983 it was known, at least theoretically, that the recombinant DNA approach may be
applied to the production of any heterologous polypeptide or protein in a suitable host cell,
provided that appropriate DNA coding sequences can be identified and used to transform
the host cell. And that indeed a number of heterologous protein were produced by
bacteria however all of these were single chain polypeptides or proteins. (Boss et al.
patent col. 1, lines 15-65) Thus the construction of plasmids, the transformation of cells and
expression of single chain genes in a single cell were routine. However, there is no
evidence that immunoglobulins, multiple chains proteins, had been produced by
recombinant DNA techniques from a single host cell prior to March 25, 1983. (See Boss
et al. patent, column 1).
Rather the evidence of record establishes that Riggs had but a research plan. He
testified that he intended “to explore the possibility of producing antibodies in bacteria.”
and suggested that “a single bacterial strain could be constructed which contained both
Interference No. 102,572
The Cabilly et al. specification (pages 24-25) supports this view in indicating that33
attempts to reconstitute active antibodies from native IgG had been largely unsuccessful.
52
heavy and light chain genes for co-expression” (emphasis added) (CR-15, ¶ 3). The
written proposal indicates that Cabilly et al. would construct a strain carrying both heavy
and light chain genes and “try to get in vivo assembly of active antibody” (emphasis added)
(CX-2, Bates No. 922). In addition, Wetzel testified (CR-20, ¶ 4-5) that a major hurdle as
to expression of immunoglobulin in E.coli was expected to be in the folding of the protein. 33
Riggs' and Wetzel’s testimony as well as CX-2 provide a clear indication that the
contemplated process was not a complete idea of the process of the subject matter of the
count which would allow the skilled worker to carry out the process of the count in issue.
Herein, the evidence indicates that Cabilly et al. had but a hope or wish to produce active
antibodies in bacteria; and, there is no supporting evidence to establish the development
of the means to accomplish that result or evidence of a disclosure to a third party of a
complete conception. Conception is not the perception or realization of the desirability of
producing a certain result; rather it is the perception or realization of the means by which
the result can be produced. Rivise & Caesar Vol. I, § 110, page 317. Accordingly, Cabilly
et al. were unable to establish conception until Cabilly et al. reduced the invention to
practice through a successful experiment.
Cabilly et al. continually argue that they established conception when the genes
encoding the Ig heavy and light chains were isolated and sequenced by Holmes and Rey
Interference No. 102,572
53
by the end of October 1982. There is no evidence in this record that the DNA sequences
encoding of the Ig heavy and light chains of CEA.66-E3 or any other immunoglobulin DNA
were known at any time before the Boss et al. filing date.
Decision
In view of the foregoing, judgment is entered against Shmuel Cabilly et al., Herbert
L. Heyneker, William E. Holmes, Arthur D. Riggs, and Ronald B. Wetzel, the junior party,
who are not entitled to a patent containing claims 101 through 120 corresponding to the
count.
On this record, judgment is entered in favor of Michael A. Boss et al., John K.
Kenten, John S. Emtage and Clive R. Wood, the senior party, who are entitled to their
Interference No. 102,572
54
patent containing claims 1 through 18 corresponding to the count
RONALD H. SMITH )
Administrative Patent Judge )
)
)
) BOARD OF PATENT
MARY F. DOWNEY )
Administrative Patent Judge ) APPEALS AND
)
) INTERFERENCES
)
RICHARD E. SCHAFER )
Administrative Patent Judge )
Interference No. 102,572
55
Francis A. Paintin
Woodcock, Washburn, Kurtz, Mackiewicz
& Norris
One Liberty Place - 46th Floor
Philadelphia, PA 19103
R. Danny Huntington
Burns, Doane, Swecker & Mathis
P. O. Box 1404
Alexandria, VA 22313-1404
7/6/98