By Kevin E. Noonan —

Christopher M. Holman, Associate Professor of Law
at the University of Missouri-Kansas City (and proprietor of Holman's Biotech
IP Blog), has filed an amicus brief in support of
neither party in Ariad Pharmaceuticals, Inc. v. Eli Lilly
& Co.  While not arguing on
behalf of either party, Ariad would benefit if the Federal Circuit adopts Professor
Holman's position:  he not only
advocates that there is no separate written description requirement in 35
U.S.C. § 112, first paragraph, but asserts that the requirement is
differentially (and improperly) applied to biotechnology inventions.

The brief begins by arguing that the Federal Circuit "established
a novel interpretation of the written description requirement" in Regents of the University of California v.
Eli Lilly & Co.  His
argument is not only that this requirement was new (and unnecessary), but that
the Court has applied it in a manner "that is essentially redundant to the
enablement requirement" and that acts as a super-enablement requirement
for biotechnology claims reciting protein and DNA subject matter.  Citing Enzo Biochem, Inc. v. GenProbe Inc., he argues that the Court has applied the
requirement in an arbitrary and inconsistent manner that lacks any basis in
science and can, in some instances, preclude adequate patent protection for
biotechnology inventions.  The
enablement requirement, grounded in the "objective" considerations
exemplified by the factors enunciated in In
re Wands, is the proper method for assessing whether the specification
describes the invention sufficiently, according to Professor Holman.

His argument falters somewhat when he discusses the
requirement that at least one species must be disclosed to support a claim, as
opposed to the necessity under the written description requirement for "something
more" as interpreted under the Lilly
precedent.  The problem with this
argument is that while priority of invention requires merely that the
specification teaches how to make and use "at least one" species
falling within the scope of the claim (Hahn
v. Wong, 892 F.2 1028
(Fed. Cir. 1989)), enablement requires a claim to be supported by a specification
that enables the skilled person in the art to make and use the claimed
invention throughout its scope (M.P.E.P. § 2164.08; In re Wright, 999 F.2d 1557 (Fed. Cir. 1993)).  He illustrates what he considers to be
a major inconsistency in the Court's written description jurisprudence by
contrasting the Court's decisions in Noelle
v. Lederman (for proteins) and Falkner
v. Inglis (for DNA species) with the strict interpretation of the Lilly decision.  In Noelle, the Court upheld the validity of claims
to antibodies where the specification describes only their cognate antigens, while in Falkner, the Court upheld the validity of
claims directed to virus species having non-specific deletion mutations
resulting in an observable phenotype.  These cases are inconsistent with Lilly,
according to Professor Holman, in that Lilly
requires "super-enablement" disclosure of human insulin while Noelle and Falkner permit patenting of undisclosed proteins (antibodies in Noelle) or DNAs (viruses in Falkner).

This argument misses the reasoning behind the
seeming inconsistency.  In
both Noelle and Falkner, the patentees were claiming species that could be reliably
produced by one having skill in the art, wherein the impediment to producing
the invention was overcome by the patentees.  (For example, in Noelle, the Court required there to be a novel antigen disclosed in the specification in
order for generic antibody claims to be patentable.)  In Lilly, on the
other hand, the patentees were claiming a species — human insulin DNA — that they
neither possessed, conceived, nor described.  In Lilly,
permitting the patentee to bootstrap its cloning of the rat insulin gene to
support a claim for human insulin would violate several long-standing
principles, priority of invention being but one of them.

Professor Holman also cites the Enzo debacle, and makes an interesting
argument.  He posits that Enzo I was a literal reading of the Lilly precedent, and as a consequence,
reversal of the initial panel decision in Enzo
II was a repudiation of the "super-enablement" written
description requirement enunciated in Lilly.  Another way of viewing the situation is
that Enzo I was an
over-interpretation of the Lilly
precedent, ignoring the portion of that decision that said (emphasis added):

Thus, as we have previously held, a cDNA is not
defined or described by the mere name "cDNA," even if accompanied by
the name of the protein that it encodes, but requires a kind of specificity
usually achieved by means of the recitation of the sequence of nucleotides that
make up the DNA . . . .  A description of a genus of cDNAs may be achieved by
means of a recitation of a representative number of cDNAs, defined by
nucleotide sequence, falling within the scope of the genus or of a recitation
of structural features common to the members of the genus, which features
constitute a substantial portion of the genus . . . .  This is analogous to
enablement of a genus under § 112, P 1, by showing the enablement of a
representative number of species within the genus.  We will not speculate
in what other ways a broad genus of genetic material may be properly described,
but it is clear to us, as it was to the district court, that the claimed genera
of vertebrate and mammal cDNA are not described by the general language of the '525
patent's written description supported only by the specific nucleotide
sequence of rat insulin.

Considering this language, the decision in Enzo I was in error not for applying the
Lilly test properly, but for
disregarding the fact that a deposit satisfies both the written description and the enablement requirements because
it places the public in possession of the claimed embodiment directly.

Another case Professor Holman cites as evidence of
the error of the Lilly decision is In re Wallach, where the applicant had
disclosed an enabling method for producing protein embodiments of the claimed
invention (which the Court found to be patentable) but did not disclose the
nucleic acid encoding the protein (claims to which were unpatentable for
failure to satisfy the written description requirement).  According to Professor Holman, the Court's
decision in In re Kubin points out
the error in the Wallach
decision.  In Kubin, the Court held that claims to a DNA encoding a known protein
were obvious, in view of the routine nature of cloning methods in the art and
the existence of both the known protein and a probe (a monoclonal antibody)
specific for the protein.  The Court held that the Supreme Court in KSR International Co. v. Teleflex Inc. had repudiated the Federal Circuit's earlier
jurisprudence on the question of the obviousness of a nucleic acid encoding a
known protein as set forth in In re Deuel.  That jurisprudence was based on
traditional rubrics of chemical obviousness, wherein invalidating prior art
disclosed a compound having a structure sufficiently related to the claimed
structure to render the latter obvious.  Spurred on by its interpretation of KSR,
the Kubin panel instead determined
that the claimed nucleic acid was obvious substantially because it satisfied
the enablement standard — that it could be obtained from the prior art without
undue experimentation.

The connection between the chemical obviousness
cases and written description is made by Professor Holman by way of a quotation from Lilly, citing In re Deuel and In re Bell to
the effect that if a chemical structure must be disclosed in the prior art to
render a nucleic acid obvious, "a
fortiori, a description that does not render a claimed invention obvious
does not sufficiently describe that invention for purposes of §112, ¶1."  For Professor Holman, the intervening Kubin decision destroys this rationale,
since for the Kubin court, a prior art
description no longer requires disclosure of a chemical structure to render a
nucleic acid claim obvious.  This
argument fails to consider two relevant facts, however.  First, even the Patent Office conceded
that the factual underpinnings in Kubin
were vastly different from the facts in Deuel,
and that the obviousness of the Kubin claims was directly related to those
differences (including the existence of a specific antibody probe, advances in
the level of skill in the art, and a non-prior art example of cloning the mouse
homolog using a combination of the antibody probe and routine methods in the
art).  Second, the written
description and obviousness prohibitions are not competitive but
complementary:  the concept of
obviousness precludes patenting for an invention that does not sufficiently "promote
the progress" of the relevant art, while the written description
requirement, as applied under the Lilly
precedent, does not permit a patentee to claim what the patentee has not actually
obtained.  The fact that it could have been obtained is deemed
insufficient.

The brief castigates the Federal Circuit for
inconsistencies in applying the written description requirement, and as a
consequence asserts that this has prevented the Patent Office from arriving at
proper standards for assessing the patentability of biotechnology claims.  Professor Holman discusses the Written
Description Training Materials promulgated in March 2008 in this regard and
contrasts the treatment of nucleic acid claims in Wallach with antibody claims (under the Noelle case precedent; Example 13), with regard to the "billions"
of variants in the (appropriately-named) variable region and the laxity with
which the Office applies the written description requirement (essentially
providing no barrier to patentability despite the complete absence of a
description of any actually-produced antibody).  Correctly, he characterizes this treatment as being
inconsistent and rejects the policy reasons for these differences as discussed
above and enunciated by the Office.  He argues that the existence of variable regions in antibodies provides
just as much uncertainty as the sequence of an unknown nucleic acid, and
permitting antibodies to be patented with little or no disclosure of structure
provides the basis for the inconsistency.  This basis, of course, is (ironically) rooted in the enablement
requirement, because antibodies inherently select just those (generally
unknown) sequences that specifically bind their cognate antigen by the way they
are produced.  This specificity is
not inherently a part of cloning methods used to produce nucleic acids, thus
raising the heightened description requirement for such claims.

The Carnegie-Mellon University
v. Hoffman-LaRoche Inc. case is also discussed in the brief with regard to how
the written description requirement is inconsistently applied.  In this portion of the brief, Professor Holman makes an
interesting argument that turns on their heads traditional rationales against
broad variant nucleic acid claims.  He asserts, based on several scientific treatises, that it is "generally
possible to substantially alter a protein's structure without necessarily
destroying its function.  For
example, in some cases 50% or more of the amino acids in a protein can be
altered while still maintaining function."  He then acknowledges the more conventional bases for
requiring actual written descriptions of such functional variants, because "a
single amino acid change can sometimes result in loss of function," citing
his own scientific work.  He also
correctly identifies the latter situation as the basis for requiring a priori "some level [of]
disclosure of the structure-function relationship" that would permit the
skilled worker to appreciate "which variants" will retain function.  This he properly characterizes as an "impossible"
standard.  Given the very large
number of variants for even a small (300 amino acid) protein (10²²⁶),
this results in claims that cannot properly protect their inventions, since it
is relatively easy for an infringer to produce a (presumably non-infringing)
functional amino acid sequence variant.

To illustrate, he contrasts the court's decisions
in Capon v. Esshar (regarding
recombinant antibodies) and Carnegie-Mellon
(regarding DNA polymerase I enzymes).  In Capon, the Court held that
a description of "well-known" sequences encoding alternative
antigen-binding portions of proteins expressed at the surface of an immune
system cell that triggers proliferation thereof was not necessary to satisfy
the written description requirement.  In contrast, the Court in Carnegie-Mellon
invalidated claims to recombinant constructs for producing bacterial DNA
polymerases because the specification disclosed only the polymerase from E. coli, and only two other bacterial DNA
polymerases were known in the art at the time the invention was made.  For Professor Holman, the
existence of "thousands" of mouse antibody-derived antigen-binding
species in the art has but "superficial appeal" as a rationale, in
view of the great amino acid sequence variability in antibodies, and the
structural similarity of bacterial polymerases.  He maintains that polymerases being enzymes all have substantially the same
function, and makes the reasonable presumption that this function is dictated by
structure (conferred by the protein's amino acid sequence) and thus "there
is a relatively strict correlation between structure and function in the class
of bacterial DNA polymerase I proteins."  This he contrasts with the recognized hypervariability of
antigen-binding portions of antibodies as further examples of the inconsistent
application of the written description requirement.

Professor Holman returns to the PTO Training
Materials with regard to Examples 11A and 11B, which he evocatively characterizes
as "junk science."  Specifically, he raises the apparent paradox between what the Office
considers unpatentable (Example 11A) and patentable (Example 11B) claims to
amino acid sequence variants, based on disclosure of structure-function
relationships of the variants in the supporting specification.  The claims in both examples recite a
nucleic acid encoding an amino acid sequence 85% identical to the disclosed
sequence.  The difference in the
patentability of the claims is that the specification supporting the claim in
Example 11A provides no evidence of any structure-function relationship, while
the specification supporting the claim in Example 11B discloses a deletion
variant that identifies two domains "critical" for the protein's
function.  The "Catch-22"
nature of these examples has been discussed on Patent Docs previously (see "An Analysis of the New Written Description Training Materials – DNA Hybridization & Percent Identity" and "Docs at BIO: 'Gotcha' Games Continue at USPTO"); here,
Professor Holman asserts that "[t]he PTO's analysis fails to recognize the
complex and unpredictable relationship between protein structure and function,
and thus fails to comport with scientific reality."  (Of course, the irony is that these
examples are an attempt, however flawed, to do just what Professor Holman
contends that they do not do.)  The
basis for Professor Holman's contention is that the general tendency of non-conservative
substitutions to be more likely than not to result in loss-of-function is "anything
but hard and fast rules," because while the scientific literature is
replete with examples consistent with Patent Office assumptions, it is also the
case that there are several examples to the contrary, e.g., where mutations at one site can correct or compensate for
mutations at another, spatially-distinct site, or where a conservative
substitution results in a greater loss of function than a non-conservative one (citing
several scientific references including one of his own).  "The bottom line," according
to Professor Holman, is that the deletion studies in Example 11B of the
Training Materials are "but the slightest tip of the iceberg, and [do] not
identify regions of the protein that could or could not be altered without a
loss of function."  Finally,
he correctly notes that the "patentable" claim of Example 11B is not
limited to conservative substitutions or mutations outside the identified
functional domains, and thus are likely to include non-described, inoperative
embodiments.

In the penultimate portion of the brief, Professor
Holman discusses the history of the development of the written description
requirement, from the "simultaneous conception and reduction to practice"
concept announced by the court in Amgen Inc.
v. Chugai Pharmaceutical Co., to the decision in Fiers
v. Revel that a nucleic acid claim must be supported by an actual
description of the claimed nucleic acid in order to show possession, and
finally to the Lilly decision.  (He also mentions In re Smythe, but dismisses it as being "not even a chemical
case.")  He asserts that the Court has "never articulated a rational justification" for the
written description requirement as it has been applied to "some"
nucleic acid and protein inventions.  In conjunction with the argument (discussed above) that the Court's Kubin decision rebuts the legal basis
for the Lilly decision, he also
attacks the basic premise of that decision:  according to Professor Holman, a claim to a "gene that
controls blood sugar" would be a functional definition, while a claim to "human
insulin" is not, since the latter "describes" a "specific
gene that was known to exist at the time of the patent application."  While this is true, the argument
appears to miss the point that while the gene existed, the patentee did not
know or disclose its structure.

Finally, Professor Holman argues that the
enablement requirement is sufficient to ensure "adequate disclosure across
all technologies."  He
notes instances where the enablement requirement has been used to "police"
the scope of biotechnology claims, and asserts that the "well-developed"
body of enablement case law is more suited to the task than the Court's written
description jurisprudence.  (He
doesn't mention that, as a question of law, such consistency should be more
likely than for questions of fact, such as whether the written description
requirement is met.)  He consigns
the outcomes of "the Amgen–Fiers–Lilly trilogy" to being appropriate under the "unpredictability
of cloning technology at the time," but says this is no longer warranted
in view of the technology having become "conventional and relatively
predictable," citing Kubin and
argues:

Just as in Kubin
this Court chose to discard the strict requirement of structural disclosure in
the obviousness determination arguably required by Bell and Deuel, it should
do away with LWD [Lilly written description] and its irrational focus on
structure, and employ the more adaptable and appropriate enablement requirement
to assess adequate disclosure of biotechnological and other inventions.

Professor Holman cites almost as many law reviews
and opinions of other legal scholars as he does Federal Circuit and CCPA
precedent in support of his arguments.  Noticeably missing from the citation list, however, are the cases cited
in Lilly to support its formulation
of the written description requirement, including In re Wilder, 736 F.2d 1516 (Fed. Cir. 1984); In re Robins, 429 F.2d 452 (CCPA 1970); In re Grimme, 274 F.2d 949 (CCPA 1960); In re Angstadt, 537 F.2d 498 (CCPA 1976) and In re Gosteli, 872 F.2d 1008 (Fed. Cir. 1989).  This deficiency may compromise the
persuasiveness of Professor Holman's otherwise thought-provoking brief.

For additional information regarding this topic, please see:
• "Lilly Files Principal Brief for Ariad v. Lilly Rehearing En Banc," November 16, 2009
• "Next Up: Ariad v. Lilly Rehearing En Banc," November 10, 2009
• "Federal Circuit Grants En Banc Review in Ariad v. Lilly," August 21, 2009
• "Ariad Files Petition for Rhearing in Ariad v. Lilly," June 3, 2009
• "Ariad Decision Voids Attempt to Use Broad Claiming to Avoid the Written Description Requirement," April 14, 2009
• "Ariad Pharmaceuticals, Inc. v. Eli Lilly and Co. (Fed. Cir. 2009)," April 6, 2009