Capon v. Eshhar v. Dudas

United States Court of Appeals for the Federal Circuit
03-1480, -1481
(Interference No. 103,887)
DANIEL J. CAPON, ARTHUR WEISS, BRIAN A. IRVING,
MARGO R. ROBERTS, and KRISZTINA ZSEBO,
Appellants,
v.
ZELIG ESHHAR, DANIEL SCHINDLER, TOVA WAKS,
and GIDEON GROSS,
Cross-Appellants,
v.
JON DUDAS, Director of the Patent and Trademark Office,
Intervenor.
Steven B. Kelber, Piper Rudnick, LLP, of Washington, DC, argued for appellants.
Roger L. Browdy, Browdy and Neimark, P.L.L.C., of Washington, DC, argued for
cross-appellants.
Mary L. Kelly, Associate Solicitor, Office of the Solicitor, United States Patent and
Trademark Office, of Arlington, Virginia, argued for intervenor. With her on the brief
were John M. Whealan, Solicitor and Stephen Walsh, Associate Solicitor.
Appealed from: United States Patent and Trademark Office Board of Patent Appeals
and Interferences
United States Court of Appeals for the Federal Circuit
03-1480, -1481
(Interference No. 103,887)
DANIEL J. CAPON, ARTHUR WEISS, BRIAN A. IRVING,
MARGO R. ROBERTS, and KRISZTINA ZSEBO,
Appellants,
v.
ZELIG ESHHAR, DANIEL SCHINDLER, TOVA WAKS,
and GIDEON GROSS,
Cross-Appellants,
v.
JON DUDAS,
Director of the Patent and Trademark Office,
Intervenor.
__________________________
DECIDED: August 12, 2005
__________________________
Before NEWMAN, MAYER,* and GAJARSA, Circuit Judges.
NEWMAN, Circuit Judge.
Both of the parties to a patent interference proceeding have appealed the decision of
the Board of Patent Appeals and Interferences of the United States Patent and Trademark
Office, wherein the Board held that the specification of neither party met the written
description requirement of the patent statute. Capon v. Eshhar, Interf. No. 103,887
____________________
* Haldane Robert Mayer vacated the position of Chief Judge on December 24,
2004.
(Bd. Pat. App. & Interf. Mar. 26, 2003). The Board dissolved the interference and cancelled
all of the claims of both parties corresponding to the interference count. With this ruling,
the Board terminated the proceeding and did not reach the question of priority of invention.
We conclude that the Board erred in its application of the law of written description. The
decision is vacated and the case is remanded to the Board for further proceedings.
BACKGROUND
Daniel J. Capon, Arthur Weiss, Brian A. Irving, Margo R. Roberts, and Krisztina
Zsebo (collectively "Capon") and Zelig Eshhar, Daniel Schindler, Tova Waks, and Gideon
Gross (collectively "Eshhar") were the parties to an interference proceeding between
Capon's United States Patent No. 6,407,221 ("the '221 patent") entitled "Chimeric Chains
for Receptor-Associated Signal Transduction Pathways" and Eshhar's patent application
Serial No. 08/084,994 ("the '994 application") entitled "Chimeric Receptor Genes and Cells
Transformed Therewith." Capon's Patent No. 5,359,046 ("the '046 patent"), parent of the
'221 patent, was also included in the interference but was held expired for non-payment of
a maintenance fee. The PTO included the '046 patent in its decision and in its argument of
this appeal.1
A patent interference is an administrative proceeding pursuant to 35 U.S.C. ''102(g)
and 135(a), conducted for the purpose of determining which of competing applicants is the
first inventor of common subject matter. An interference is instituted after the separate
1 Although Capon is designated as appellant and Eshhar as cross-appellant,
both appealed the Board's decision. See Fed. R. App. P. 28(h). The Director of the PTO
intervened to support the Board, and has fully participated in this appeal.
03-1480, -1481 2
patent applications have been examined and found to contain patentable subject matter.
Capon's patents had been examined and had issued before this interference was instituted,
and Eshhar's application had been examined and allowed but a patent had not yet issued.
During an interference proceeding the Board is authorized to determine not only
priority of invention but also to redetermine patentability. 35 U.S.C. '6(b). The question of
patentability of the claims of both parties was raised sua sponte by an administrative patent
judge during the preliminary proceedings. Thereafter the Board conducted an inter partes
proceeding limited to this question, receiving evidence and argument. The Board then
invalidated all of the claims that had been designated as corresponding to the count of the
interference, viz., all of the claims of the Capon '221 patent, claims 5-8 of the Capon '046
patent, and claims 1-7, 9-20, and 23 of the Eshhar '994 application.
In accordance with the Administrative Procedure Act, the law as interpreted and
applied by the agency receives plenary review on appeal, and the agency's factual findings
are reviewed to determine whether they were arbitrary, capricious, or unsupported by
substantial evidence in the administrative record. See 5 U.S.C. §706(2); Dickinson v.
Zurko, 527 U.S. 150, 164-65 (1999); In re Gartside, 203 F.3d 1305, 1315 (Fed. Cir. 2000).
The Invention
A chimeric gene is an artificial gene that combines segments of DNA in a way that
does not occur in nature. The '221 patent and '994 application are directed to the
production of chimeric genes designed to enhance the immune response by providing cells
with specific cell-surface antibodies in a form that can penetrate diseased sites, such as
solid tumors, that were not previously reachable. The parties explain that their invention is
03-1480, -1481 3
a way of endowing immune cells with antibody-type specificity, by combining known
antigen-binding-domain producing DNA and known lymphocyte-receptor-protein producing
DNA into a unitary gene that can express a unitary polypeptide chain. Eshhar summarized
the problem to which the invention is directed:
Antigen-specific effector lymphocytes, such as tumor-specific T cells, are
very rare, individual-specific, limited in their recognition spectrum and difficult
to obtain against most malignancies. Antibodies, on the other hand, are
readily obtainable, more easily derived, have wider spectrum and are not
individual-specific. The major problem of applying specific antibodies for
cancer immunotherapy lies in the inability of sufficient amounts of monoclonal
antibodies (mAb) to reach large areas within solid tumors.
Technical Paper Explaining Eshhar's Invention, at 6.
The inventions of Capon and Eshhar are the chimeric DNA that encodes single-
chain chimeric proteins for expression on the surface of cells of the immune system, plus
expression vectors and cells transformed by the chimeric DNA. The experts for both
parties explain that the invention combines selected DNA segments that are both
endogenous and nonendogenous to a cell of the immune system, whereby the
nonendogenous segment encodes the single-chain variable ("scFv") domain of an
antibody, and the endogenous segment encodes cytoplasmic, transmembrane, and
extracellular domains of a lymphocyte signaling protein. They explain that the scFv domain
combines the heavy and light variable ("Fv") domains of a natural antibody, and thus has
the same specificity as a natural antibody. Linking this single chain domain to a lymphocyte
signaling protein creates a chimeric scFv-receptor ("scFvR") gene which, upon transfection
into a cell of the immune system, combines the specificity of an antibody with the tissue
penetration, cytokine production, and target-cell destruction capability of a lymphocyte.
03-1480, -1481 4
The parties point to the therapeutic potential if tumors can be infiltrated with
specifically designed immune cells of appropriate anti-tumor specificity.
The Eshhar Claims
The Board held unpatentable the following claims of Eshhar's '994 application; these
were all of the ‘994 claims that had been designated as corresponding to the count of the
interference. Eshhar's claim 1 was the designated count.
1. A chimeric gene comprising
a first gene segment encoding a single-chain Fv domain (scFv) of a
specific antibody and
a second gene segment encoding partially or entirely the
transmembrane and cytoplasmic, and optionally the extracellular, domains of
an endogenous protein
wherein said endogenous protein is expressed on the surface of cells
of the immune system and triggers activation and/or proliferation of said cells,
which chimeric gene, upon transfection to said cells of the immune
system, expresses said scFv domain and said domains of said endogenous
protein in one single chain on the surface of the transfected cells such that
the transfected cells are triggered to activate and/or proliferate and have
MHC nonrestricted antibody-type specificity when said expressed scFV
domain binds to its antigen.
2. A chimeric gene according to claim 1 wherein the second gene segment
further comprises partially or entirely the extracellular domain of said
endogenous protein.
3. A chimeric gene according to claim 1 wherein the first gene segment
encodes the scFv domain of an antibody against tumor cells.
4. A chimeric gene according to claim 1 wherein the first gene segment
encodes the scFv domain of an antibody against virus infected cells.
5. A chimeric gene according to claim 4 wherein the virus is HIV.
6. A chimeric gene according to claim 1 wherein the second gene segment
encodes a lymphocyte receptor chain.
7. A chimeric gene according to claim 6 wherein the second gene segment
encodes a chain of the T cell receptor.
03-1480, -1481 5
9. A chimeric gene according to claim 7 wherein the second gene segment
encodes the α, β, γ, or δ chain of the antigen-specific T cell receptor.
10. A chimeric gene according to claim 1 wherein the second gene segment
encodes a polypeptide of the TCR/CD3 complex.
11. A chimeric gene according to claim 10 wherein the second gene
segment encodes the zeta or eta isoform chain.
12. A chimeric gene according to claim 1 wherein the second gene segment
encodes a subunit of the Fc receptor or IL-2 receptor.
13. A chimeric gene according to claim 12 wherein the second gene
segment encodes a common subunit of IgE and IgG binding Fc receptors.
14. A chimeric gene according to claim 13 wherein said subunit is the
gamma subunit.
15. A chimeric gene according to claim 13 wherein the second gene
segment encodes the CD16α chain of the FcγRIII or FcγRII.
16. A chimeric gene according to claim 12 wherein the second gene
segment encodes the α or β subunit of the IL-2 receptor.
17. An expression vector comprising a chimeric gene according to claim 1.
18. A cell of the immune system endowed with antibody specificity
transformed with an expression vector according to claim 17.
19. A cell of the immune system endowed with antibody specificity
comprising a chimeric gene according to claim 1.
20. A cell if the immune system according to claim 19 selected from the
group consisting of a natural killer cell, a lymphokine activated killer cell, a
cytotoxic T cell, a helper T cell and a subtype thereof.
23. A chimeric gene according to claim 1 wherein said endogenous protein is
a lymphocyte receptor chain, a polypeptide of the TCR/CD3 complex, or a
subunit of the Fc or IL-2 receptor.
The Board did not discuss the claims separately, and held that the specification
failed to satisfy the written description requirement as to all of these claims.
03-1480, -1481 6
The Capon Claims
Claims 1-10, all of the claims of the '221 patent, were held unpatentable on written
description grounds. Claims 1-6 are directed to the chimeric DNA, claims 7, 8, and 10 to
the corresponding cell comprising the DNA, and claim 9 to the chimeric protein:
1. A chimeric DNA encoding a membrane bound protein, said chimeric
DNA comprising in reading frame:
DNA encoding a signal sequence which directs said membrane bound
protein to the surface membrane;
DNA encoding a non-MHC restricted extracellular binding domain
which is obtained from a single chain antibody that binds specifically to at
least one ligand, wherein said at least one ligand is a protein on the surface
of a cell or a viral protein;
DNA encoding a transmembrane domain which is obtained from a
protein selected from the group consisting of CD4, CD8, immunoglobulin, the
CD3 zeta chain, the CD3 gamma chain, the CD3 delta chain and the CD3
epsilon chain; and
DNA encoding a cytoplasmic signal-transducing domain of a protein
that activates an intracellular messenger system which is obtained from CD3
zeta,
wherein said extracellular domain and said cytoplasmic domain are
not naturally joined together, and said cytoplasmic domain is not naturally
joined to an extracellular ligand-binding domain, and when said chimeric DNA
is expressed as a membrane bound protein in a host cell under conditions
suitable for expression, said membrane bound protein initiates signaling in
said host cell when said extracellular domain binds said at least one ligand.
2. The DNA of claim 1, wherein said single-chain antibody recognizes an
antigen selected from the group consisting of viral antigens and tumor cell
associated antigens.
3. The DNA of claim 2 wherein said single-chain antibody is specific for the
HIV env glycoprotein.
4. The DNA of claim 1, wherein said transmembrane domain is naturally
joined to said cytoplasmic domain.
5. An expression cassette comprising a transcriptional initiation region, the
DNA of claim 1 under the transcriptional control of said transcriptional
initiation region, and a transcriptional termination region.
03-1480, -1481 7
6. A retroviral RNA or DNA construct comprising the expression cassette of
claim 5.
7. A cell comprising the DNA of claim 1.
8. The cell of claim 7, wherein said cell is a human cell.
9. A chimeric protein comprising in the N-terminal to C-terminal direction:
a non-MHC restricted extracellular binding domain which is obtained
from a single chain antibody that binds specifically to at least one ligand,
wherein said at least one ligand is a protein on the surface of a cell or a viral
protein;
a transmembrane domain which is obtained from a protein selected
from the group consisting CD4, CD8, immunoglobulin, the CD3 zeta chain,
the CD3 gamma chain, the CD3 delta chain and the CD3 epsilon chain; and
a cytoplasmic signal-transducing domain of a protein that activates an
intracellular messenger system which is obtained from CD3 zeta,
wherein said extracellular domain and said cytoplasmic domain are
not naturally joined together, and said cytoplasmic domain is not naturally
joined to an extracellular ligand-binding domain, and when said chimeric
protein is expressed as a membrane bound protein in a host cell under
conditions suitable for expression, said membrane bound protein initiates
signaling in said host cell when said extracellular domain binds said at least
one ligand.
10. A mammalian cell comprising as a surface membrane protein, the
protein of claim 9.
In addition, claims 5, 6, 7, and 8 of Capon's '046 patent were held unpatentable. These
claims are directed to chimeric DNA sequences where the encoded extracellular domain is
a single-chain antibody containing ligand binding activity.
The Board Decision
The Board presumed enablement by the specifications of the '221 patent and '994
application of the full scope of their claims, and based its decision solely on the ground of
03-1480, -1481 8
failure of written description. The Board held that neither party's specification provides the
requisite description of the full scope of the chimeric DNA or encoded proteins, by
reference to knowledge in the art of the "structure, formula, chemical name, or physical
properties" of the DNA or the proteins. In the Board's words:
We are led by controlling precedent to understand that the full scope of novel
chimeric DNA the parties claim is not described in their specifications under
35 U.S.C. '112, first paragraph, by reference to contemporary and/or prior
knowledge in the art of the structure, formula, chemical name, or physical
properties of many protein domains, and/or DNA sequences which encode
many protein domains, which comprise single-chain proteins and/or DNA
constructs made in accordance with the plans, schemes, and examples
thereof the parties disclose.
Bd. op. at 4. As controlling precedent the Board cited Regents of the University of
California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997); Fiers v. Revel Co., 984 F.2d
1164 (Fed. Cir. 1993); Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200 (Fed. Cir.
1991); and Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316 (Fed. Cir. 2002). The
Board summarized its holding as follows:
Here, both Eshhar and Capon claim novel genetic material described in
terms of the functional characteristics of the protein it encodes. Their
specifications do not satisfy the written description requirement because
persons having ordinary skill in the art would not have been able to visualize
and recognize the identity of the claimed genetic material without considering
additional knowledge in the art, performing additional experimentation, and
testing to confirm results.
Bd. op. at 89.
DISCUSSION
Eshhar and Capon challenge both the Board's interpretation of precedent and the
Board's ruling that their descriptions are inadequate. Both parties explain that their
03-1480, -1481 9
chimeric genes are produced by selecting and combining known heavy- and light-chain
immune-related DNA segments, using known DNA-linking procedures. The specifications
of both parties describe procedures for identifying and obtaining the desired immune-
related DNA segments and linking them into the desired chimeric genes. Both parties point
to their specific examples of chimeric DNA prepared using identified known procedures,
along with citation to the scientific literature as to every step of the preparative method.
The parties presented expert witnesses who placed the invention in the context of
prior knowledge and explained how the descriptive text would be understood by persons of
skill in the field of the invention. The witnesses explained that the principle of forming
chimeric genes from selected segments of DNA was known, as well as their methods of
identifying, selecting, and combining the desired segments of DNA. Dr. Eshhar presented
an expert statement wherein he explained that the prior art contains extensive knowledge
of the nucleotide structure of the various immune-related segments of DNA; he stated that
over 785 mouse antibody DNA light chains and 1,327 mouse antibody DNA heavy chains
were known and published as early as 1991. Similarly Capon's expert Dr. Desiderio
discussed the prior art, also citing scientific literature:
The linker sequences disclosed in the '221 patent (col. 24, lines 4 and 43)
used to artificially join a heavy and light chain nucleic acid sequence and
permit functional association of the two ligand binding regions were published
by 1990, as were the methods for obtaining the mature sequences of the
desired heavy and light chains for constructing a SAb (Exhibit 47, Batra et al.,
J., Biol. Chem., 1990; Exhibit 48, Bird et al., Science, 1988; Exhibit 50,
Huston et al., PNAS, 1988; Exhibit 51, Chaudhary, PNAS, 1990, Exhibit 56,
Morrison et al., Science, 1985; Exhibit 53, Sharon et al., Nature 1984).
Desiderio declaration at 4 ¶11.
03-1480, -1481 10
Both parties stated that persons experienced in this field would readily know the
structure of a chimeric gene made of a first segment of DNA encoding the single-chain
variable region of an antibody, and a second segment of DNA encoding an endogenous
protein. They testified that re-analysis to confirm these structures would not be needed in
order to know the DNA structure of the chimeric gene, and that the Board's requirement
that the specification must reproduce the "structure, formula, chemical name, or physical
properties" of these DNA combinations had been overtaken by the state of the science.
They stated that where the structure and properties of the DNA components were known,
reanalysis was not required.
Eshhar's specification contains the nucleotide sequences of sixteen different
receptor primers and four different scFv primers from which chimeric genes encoding
scFvR may be obtained, while Capon's specification cites literature sources of such
information. Eshhar's specification shows the production of chimeric genes encoding
scFvR using primers, as listed in Eshhar's Table I. Capon stated that natural genes are
isolated and joined using conventional methods, such as the polymerase chain reaction or
cloning by primer repair. Capon, like Eshhar, discussed various known procedures for
identifying, obtaining, and linking DNA segments, accompanied by experimental examples.
The Board did not dispute that persons in this field of science could determine the
structure or formula of the linked DNA from the known structure or formula of the
components.
The Board stated that "controlling precedent" required inclusion in the specification
of the complete nucleotide sequence of "at least one" chimeric gene. Bd. op. at 4. The
Board also objected that the claims were broader than the specific examples. Eshhar and
03-1480, -1481 11
Capon each responds by pointing to the scientific completeness and depth of their
descriptive texts, as well as to their illustrative examples. The Board did not relate any of
the claims, broad or narrow, to the examples, but invalidated all of the claims without
analysis of their scope and the relation of claim scope to the details of the specifications.
Eshhar and Capon both argue that they have set forth an invention whose scope is
fully and fairly described, for the nucleotide sequences of the DNA in chimeric combination
is readily understood to contain the nucleotide sequences of the DNA components. Eshhar
points to the general and specific description in his specification of known immune-related
DNA segments, including the examples of their linking. Capon points similarly to his
description of selecting DNA segments that are known to express immune-related proteins,
and stresses the existing knowledge of these segments and their nucleotide sequences, as
well as the known procedures for selecting and combining DNA segments, as cited in the
specification.
Both parties argue that the Board misconstrued precedent, and that precedent does
not establish a per se rule requiring nucleotide-by-nucleotide re-analysis when the structure
of the component DNA segments is already known, or readily determined by known
procedures.
The Statutory Requirement
The required content of the patent specification is set forth in Section 112 of Title 35:
'112 &1. The specification shall contain a written description of the
invention, and of the manner and process of making and using it, in such full,
03-1480, -1481 12
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 "written description" requirement implements the principle that a patent must describe
the technology that is sought to be patented; the requirement serves both to satisfy the
inventor's obligation to disclose the technologic knowledge upon which the patent is based,
and to demonstrate that the patentee was in possession of the invention that is claimed.
See Enzo Biochem, 296 F.3d at 1330 (the written description requirement "is the quid pro
quo of the patent system; the public must receive meaningful disclosure in exchange for
being excluded from practicing the invention for a limited period of time"); Reiffin v.
Microsoft Corp., 214 F.3d 1342, 1345-46 (Fed. Cir. 2000) (the purpose of the written
description requirement "is to ensure that the scope of the right to exclude . . . does not
overreach the scope of the inventor's contribution to the field of art as described in the
patent specification"); In re Barker, 559 F.2d 588, 592 n.4 (CCPA 1977) (the goal of the
written description requirement is "to clearly convey the information that an applicant has
invented the subject matter which is claimed"). The written description requirement thus
satisfies the policy premises of the law, whereby the inventor's technical/scientific advance
is added to the body of knowledge, as consideration for the grant of patent exclusivity.
The descriptive text needed to meet these requirements varies with the nature and
scope of the invention at issue, and with the scientific and technologic knowledge already in
existence. The law must be applied to each invention that enters the patent process, for
each patented advance is novel in relation to the state of the science. Since the law is
applied to each invention in view of the state of relevant knowledge, its application will vary
03-1480, -1481 13
with differences in the state of knowledge in the field and differences in the predictability of
the science.
For the chimeric genes of the Capon and Eshhar inventions, the law must take
cognizance of the scientific facts. The Board erred in refusing to consider the state of the
scientific knowledge, as explained by both parties, and in declining to consider the separate
scope of each of the claims. None of the cases to which the Board attributes the
requirement of total DNA re-analysis, i.e., Regents v. Lilly, Fiers v. Revel, Amgen, or Enzo
Biochem, require a re-description of what was already known. In Lilly, 119 F.3d at 1567,
the cDNA for human insulin had never been characterized. Similarly in Fiers, 984 F.2d at
1171, much of the DNA sought to be claimed was of unknown structure, whereby this court
viewed the breadth of the claims as embracing a "wish" or research "plan." In Amgen, 927
F.2d at 1206, the court explained that a novel gene was not adequately characterized by its
biological function alone because such a description would represent a mere "wish to know
the identity" of the novel material. In Enzo Biochem, 296 F.3d at 1326, this court reaffirmed
that deposit of a physical sample may replace words when description is beyond present
scientific capability. In Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1332
(Fed. Cir. 2003) the court explained further that the written description requirement may be
satisfied "if in the knowledge of the art the disclosed function is sufficiently correlated to a
particular, known structure." These evolving principles were applied in Noelle v. Lederman,
355 F.3d 1343, 1349 (Fed. Cir. 2004), where the court affirmed that the human antibody
there at issue was not adequately described by the structure and function of the mouse
antigen; and in University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 925-26 (Fed.
03-1480, -1481 14
Cir. 2004), where the court affirmed that the description of the COX-2 enzyme did not serve
to describe unknown compounds capable of selectively inhibiting the enzyme.
The "written description" requirement must be applied in the context of the particular
invention and the state of the knowledge. The Board's rule that the nucleotide sequences
of the chimeric genes must be fully presented, although the nucleotide sequences of the
component DNA are known, is an inappropriate generalization. When the prior art includes
the nucleotide information, precedent does not set a per se rule that the information must
be determined afresh. Both parties state that a person experienced in the field of this
invention would know that these known DNA segments would retain their DNA sequences
when linked by known methods. Both parties explain that their invention is not in
discovering which DNA segments are related to the immune response, for that is in the
prior art, but in the novel combination of the DNA segments to achieve a novel result.
The "written description" requirement states that the patentee must describe the
invention; it does not state that every invention must be described in the same way. As
each field evolves, the balance also evolves between what is known and what is added by
each inventive contribution. Both Eshhar and Capon explain that this invention does not
concern the discovery of gene function or structure, as in Lilly. The chimeric genes here at
issue are prepared from known DNA sequences of known function. The Board's
requirement that these sequences must be analyzed and reported in the specification does
not add descriptive substance. The Board erred in holding that the specifications do not
meet the written description requirement because they do not reiterate the structure or
formula or chemical name for the nucleotide sequences of the claimed chimeric genes.
Claim Scope
03-1480, -1481 15
There remains the question of whether the specifications adequately support the
breadth of all of the claims that are presented. The Director argues that it cannot be known
whether all of the permutations and combinations covered by the claims will be effective for
the intended purpose, and that the claims are too broad because they may include
inoperative species. The inventors say that they have provided an adequate description
and exemplification of their invention as would be understood by persons in the field of the
invention. They state that biological properties typically vary, and that their specifications
provide for evaluation of the effectiveness of their chimeric combinations.
It is well recognized that in the "unpredictable" fields of science, it is appropriate to
recognize the variability in the science in determining the scope of the coverage to which
the inventor is entitled. Such a decision usually focuses on the exemplification in the
specification. See, e.g., Enzo Biochem, 296 F.3d at 1327-28 (remanding for district court to
determine "[w]hether the disclosure provided by the three deposits in this case, coupled
with the skill of the art, describes the genera of claims 1-3 and 5"); Lilly, 119 F.3d at 1569(genus not described where "a representative number of cDNAs, defined by nucleotide
sequence, falling within the scope of the genus" had not been provided); In re Gostelli, 872
F.2d 1008, 1012 (Fed. Cir. 1989) (two chemical compounds were insufficient description of
subgenus); In re Smith, 458 F.2d 1389, 1394-95 (CCPA 1972) (disclosure of genus and
one species was not sufficient description of intermediate subgenus); In re Grimme, 274
F.2d 949, 952 (CCPA 1960) (disclosure of single example and statement of scope sufficient
disclosure of subgenus).
Precedent illustrates that the determination of what is needed to support generic
claims to biological subject matter depends on a variety of factors, such as the existing
03-1480, -1481 16
knowledge in the particular field, the extent and content of the prior art, the maturity of the
science or technology, the predictability of the aspect at issue, and other considerations
appropriate to the subject matter. See, e.g., In re Wallach, 378 F.3d 1330, 1333-34 (Fed.
Cir. 2004) (an amino acid sequence supports "the entire genus of DNA sequences" that
can encode the amino acid sequence because "the state of the art has developed" such
that it is a routine matter to convert one to the other); University of Rochester, 358 F.3d at
925 (considering whether the patent disclosed the compounds necessary to practice the
claimed method, given the state of technology); Singh v. Brake, 317 F.3d 1334, 1343 (Fed.
Cir. 2002) (affirming adequacy of disclosure by distinguishing precedent in which the
selection of a particular species within the claimed genus had involved "highly
unpredictable results").
It is not necessary that every permutation within a generally operable invention be
effective in order for an inventor to obtain a generic claim, provided that the effect is
sufficiently demonstrated to characterize a generic invention. See In re Angstadt, 537 F.2d
498, 504 (CCPA 1976) ("The examples, both operative and inoperative, are the best
guidance this art permits, as far as we can conclude from the record"). While the Board is
correct that a generic invention requires adequate support, the sufficiency of the support
must be determined in the particular case. Both Eshhar and Capon present not only
general teachings of how to select and recombine the DNA, but also specific examples of
the production of specified chimeric genes. For example, Eshhar points out that in
Example 1 of his specification the FcRγ chain was used, which chain was amplified from a
human cDNA clone, using the procedure of Kuster, H. et al., J. Biol. Chem., 265:6448-6451
(1990), which is cited in the specification and reports the complete sequence of the FcRγ
03-1480, -1481 17
chain. Eshhar's Example 1 also explains the source of the genes that provide the heavy
and light chains of the single chain antibody, citing the PhD thesis of Gideon Gross, a co-
inventor, which cites a reference providing the complete sequence of the Sp6 light chain
gene used to construct the single-chain antibody. Eshhar states that the structure of the
Sp6 heavy chain antibody was well known to those of skill in the art and readily accessible
on the internet in a database as entry EMBL:MMSP6718. Example 5 at page 54 of the
Eshhar specification cites Ravetch et al., J. Exp. Med., 170:481-497 (1989) for the method
of producing the CD16α DNA clone that was PCR amplified; this reference published the
complete DNA sequence of the CD16α chain, as discussed in paragraph 43 of the Eshhar
Declaration. Example 3 of the Eshhar specification uses the DNA of the monoclonal anti-
HER2 antibody and states that the N29 hybridoma that produces this antibody was
deposited with the Collection Nationale de Cultures de Microorganismes, Institut Pasteur,
Paris, on August 19, 1992, under Deposit No. CNCM I-1262. It is incorrect to criticize the
methods, examples, and referenced prior art of the Eshhar specification as but "a few PCR
primers and probes," as does the Director's brief.
Capon's Example 3 provides a detailed description of the creation and expression of
single chain antibody fused with T-cell receptor zeta chain, referring to published vectors
and procedures. Capon, like Eshhar, describes gene segments and their ligation to form
chimeric genes. Although Capon includes fewer specific examples in his specification than
does Eshhar, both parties used standard systems of description and identification, as well
as known procedures for selecting, isolating, and linking known DNA segments. Indeed,
the Board's repeated observation that the full scope of all of the claims appears to be
"enabled" cannot be reconciled with the Board's objection that only a "general plan" to
03-1480, -1481 18
combine unidentified DNA is presented. See In re Wands, 858 F.2d 731, 736-37 (Fed. Cir.
1988) (experimentation to practice invention must not be "undue" for invention to be
considered enabled).
The PTO points out that for biochemical processes relating to gene modification,
protein expression, and immune response, success is not assured. However, generic
inventions are not thereby invalid. Precedent distinguishes among generic inventions that
are adequately supported, those that are merely a "wish" or "plan," the words of Fiers v.
Revel, 984 F.2d at 1171, and those in between, as illustrated by Noelle v. Lederman, 355
F.3d at 1350; the facts of the specific case must be evaluated. The Board did not discuss
the generic concept that both Capon and Eshhar described -- the concept of selecting and
combining a gene sequence encoding the variable domain of an antibody and a sequence
encoding a lymphocyte activation protein, into a single DNA sequence which, upon
expression, allows for immune responses that do not occur in nature. The record does not
show this concept to be in the prior art, and includes experimental verification as well as
potential variability in the concept.
Whether the inventors demonstrated sufficient generality to support the scope of
some or all of their claims, must be determined claim by claim. The Board did not discuss
the evidence with respect to the generality of the invention and the significance of the
specific examples, instead simply rejecting all the claims for lack of a complete chimeric
DNA sequence. As we have discussed, that reasoning is inapt for this case. The Board's
position that the patents at issue were merely an "invitation to experiment" did not
distinguish among the parties' broad and narrow claims, and further concerns enablement
more than written description. See Adang v. Fischhoff, 286 F.3d 1346, 1355 (Fed. Cir.
03-1480, -1481 19
2002) (enablement involves assessment of whether one of skill in the art could make and
use the invention without undue experimentation); In re Wright, 999 F.2d 1557, 1561 (Fed.
Cir. 1993) (same). Although the legal criteria of enablement and written description are
related and are often met by the same disclosure, they serve discrete legal requirements.
The predictability or unpredictability of the science is relevant to deciding how much
experimental support is required to adequately describe the scope of an invention. Our
predecessor court summarized in In re Storrs, 245 F.2d 474, 478 (CCPA 1957) that "[i]t
must be borne in mind that, while it is necessary that an applicant for a patent give to the
public a complete and adequate disclosure in return for the patent grant, the certainty
required of the disclosure is not greater than that which is reasonable, having due regard to
the subject matter involved." This aspect may warrant exploration on remand.
In summary, the Board erred in ruling that '112 imposes a per se rule requiring
recitation in the specification of the nucleotide sequence of claimed DNA, when that
sequence is already known in the field. However, the Board did not explore the support for
each of the claims of both parties, in view of the specific examples and general teachings in
the specifications and the known science, with application of precedent guiding review of
the scope of claims.
We remand for appropriate further proceedings.
VACATED AND REMANDED
03-1480, -1481 20