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How to Determine the Obviousness of Chemical Compounds in Patent Applications
Introduction
A patentable invention is an invention that is “novel” under
35 U.S.C.A. § 102, “useful” under 35 U.S.C.A. § 101, and “nonobvious” under 35 U.S.C.A. § 103. Section 103(a) of
the Patent Act sets forth the parameter of the obviousness requirement:
A patent may not be obtained though the invention is not
identically disclosed or described as set forth in Section 102 of this title,
if the differences between the subject matter sought to be patented and the
prior art must not be such that the subject matter as a whole would have been
obvious at the time the invention was made to a person having ordinary skill in
the art to which said subject matter pertains.
In Graham v. John
Deere Co., 383 U.S. 1, 17 (1966), the United States
Supreme Court interpreted this language to mean that the
ultimate determination on the issue of obviousness is treated as a question of
law but is based on factual inquires that include (1) the scope and content of
the prior art; (2) the differences between the prior art and the claimed
invention; (3) the level of skill in the art; and (4) the objective evidence of
non-obviousness.
To obtain a patent on a new chemical compound, the compound
must meet the nonobviousness requirement at the time it is invented. Special issues, however, arise with chemical patents
because unlike electrical and mechanical sciences, chemistry is an
unpredictable art. Minor changes in structures can
dramatically affect a compound's properties. Thus, it is inherently difficult
for a court to determine the obviousness of a claimed compound with a similar
structure to that of a prior art.
The extent of the challenge to determine the obviousness of
chemical compounds can be illustrated by the issues faced by the court in Yamanouchi
Pharmaceutical Co. v. Danbury Pharmacal, 231 F.3d 1339 (Fed. Cir.
2000). In Yamanouchi, the dispute centered on whether one skilled in
the art would have considered it obvious to make the drug Famotidine by (1)
combining the polar tail from lead compound 44 with the modified heterocycle
from Tiotidine to form an intermediate compound, and (2) substituting the
carbamoyl group in the intermediate compound with a sulfamoyl group to create
Famotidine as shown below in Scheme 1.
It was well known that both Tiotidine and Tagamet were prior compounds, of
which Tagamet was a successful drug in market place while Tiotidine failed in
preclinical trials due to its high toxicity. Both compounds, however, showed
high efficacy as inhibitors of gastric acid secretion.
Scheme 1
The court in Yamanouchi upheld the patent against an
assertion of obviousness. Id. at 1345. The court explained, “For a
chemical compound, a prima facie case of obviousness requires a showing of
‘structural similarity between claimed and prior art subject matter … where the
prior art gives reason or motivation to make the claimed compositions.’” Id. at 1343 (quoting In re Dillon,
919 F.3d 688, 692 (Fed. Cir. 1990)). Even though the claimed compound failed
the test of structural similarity, the
Yamanouchi court invalidated a prima facie case of obviousness based on
a lack of motivation to combine the prior art to make the claimed
invention with similar biological function to that of the prior art.
A.
Structural similarity
Structural similarity
between chemical compounds has effectively created a unique and troublesome
area of patent law. In re Jones, 958 F.2d 347, 350 (Fed. Cir.
1992). In determining the obviousness of a traditional chemical compound,
courts previously focused on the similarity between the structures of a claimed
compound and that of a compound disclosed in the prior art. In
re Hass, 141 F.2d 122 (C.C.P.A 1944); In re Henze, 181 F.2d 196
(C.C.P.A. 1950).
General formula: A—(CH2)n—B
Prior art compound: A—CH2—B
(n=1)
Claimed compound: A—CH2—CH2—B
(n=2)
Scheme
2
In Hass, the
claimed compound was a homolog of a prior art compound (Scheme 2). See Hass,
141 F.2d at 125. There was only one more carbon unit in the claimed compound
than that in the prior art. The Court of Claims and Patent Appeals held that
the claimed compound was not patentable unless it revealed “some nonobvious or
unexpected beneficial properties not possessed by the homologous compound
disclosed in the prior art.” Id. The general principle behind the
court’s decision was that chemical and physical properties vary only slightly
between members of a homologous series. Id. The Henze case
transformed this principle into a presumption that was rebuttable if the
applicant showed “that the claimed compound possesses unobvious or unexpected
beneficial properties not actually possessed by the prior art homologues.” In
re Henze, 181 F.2d at 201. Clearly both courts perceived chemical structure
and chemical properties as two different considerations. Therefore, for
structurally similar chemical homologues, a new compound was deemed prima facie
obvious because a chemist could expect or predict that the new chemical compound
would have the same properties in a given system as did a similar prior art
compound.
B.
Inseparable structure and its properties
After section 103 was
enacted, courts gradually moved to a more holistic view of chemical compounds
that considered chemical properties in addition to chemical structures. In re Papesch, 315 F.2d 381 (C.C.P.A. 1971). In Papesch,
an applicant claimed a family of compounds including representative compound
2,4,6-triethylpyrazolo(4,3-d)-4,5,6,7-tetrahydropyrimidine-5,7-dione (ethyl =
CH2CH3), which was admittedly “structurally obvious” in light of a claimed
compound 2,4,6-trimethylpyrazolo(4,3-d)-4,5,6.7-tetrahydropyrimidine-5,7-dione
(methyl = CH3) as shown in Scheme 3. Id. at 384.
Scheme
3
Comparative tests of the trimethyl compound and the
applicant’s triethyl compound showed that the latter was an active
anti-inflammatory agent while the prior art compound was completely inactive
for that utility. The Papesch court stated that
the properties of compounds were relevant to obviousness, emphasizing that the invention as a whole was a compound
with its own properties. Id. at 390. Additionally, the court found that
proof of non-obvious or unexpectedly advantageous properties not shared by the
prior art compound may rebut a prima facie case of obviousness. Id. at 391.
A compound and all of its properties are inseparable; they
are one and the same thing …. But a formula is not a compound and while it may
serve in a claim to identity what is being patented, as the metes and bounds of
a deed identify a plot of land, the thing that is patented is not the formula
but the compound identified by it. And the patentability of the thing does not
depend on the similarity of its formula to that of another compound but of the
similarity of the former compound to the latter. There is no basis in law for
ignoring any property in making such a comparison.
Id. Thus the court generously encouraged
chemical patent applications as long as a claimed invention could demonstrate
new properties even though the claimed compound shared a similar structure with
a prior art compound. The Papesch court, however, did not deal with the
requirements for establishing a prima facie case of obviousness. The court only
held that, for cases with a presumption of obviousness, an examiner had to
consider both the properties of the
invention and the structural
similarity. Id.
C. Structures, properties and
motivation
In re Dillon was the first
case to discuss the “motivation” argument, and it
established the standard for an examiner's evidentiary burden to show prima
facie obviousness in chemical composition cases. In re
Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990). Dillon’s patent claimed
compositions containing tetra-orthoesters useful as fuel additives to reduce
soot emissions during fuel combustion. Id. at 690. In rejecting the
application, the court pointed to several earlier patents, and one of which
contained tri-orthoesters that was also used as fuel additives, but to obtain a
different benefit: dewatering. Id. at 694.
The dewatering compounds of tri-orthoesters were
structurally similar to the soot-reducing compounds of tetra-orthoester in
Dillon’s fuel. Id. Dillon argued that, although her additives were
structurally similar to additives in previously patented compositions, her
additives had a different use. Id. The court noted that the prior art
neither taught nor suggested Dillon’s method of reducing emissions. In re
Dillon, 919 F.2d at 692. The
court held, however, that neither what the prior art taught nor the suggested
properties of the claimed compound would determine prima facie obviousness. Id.
at 695. Consequently, for purposes of establishing a prima facie case of
obviousness, it did not matter that the earlier patents had failed to indicate
that Dillon’s additives would reduce soot. Instead the Dillon court
created a new test for prima facie obviousness: prima facie obviousness arises where the prior art suggests or
motivates the selection of the structurally similar claimed
composition. Id. at 693.
Thus, Dillon’s structurally similar compounds were prima
facie obvious because the prior art provided Dillon with motivation to make
them. Therefore, Dillon required that the prior art suggest the
structurally similar claimed compound for prima facie obviousness to arise. See
Id. at 694. Rather than suggest the utility of the claimed compound,
however, the prior art need only motivate one to make the claimed
compound. In other words, a prima facie case is made if both
structural similarity and some motivation to make the claimed
composition are present.
Id.
Once a prima facie case has been established, the applicant
has an opportunity to rebut that case in a timely manner. Dillon
indicated three methods of rebuttal: (1) a comparison of test data showing that
the claimed compositions possess unexpectedly improved properties or properties
that the prior art does not have . . .
, (2) that the prior art is so deficient that there is no
motivation to make what otherwise appear to be obvious changes . . . , or (3)
any other argument or presentation of evidence that is pertinent." Id. n re Dillon, 919
F.2d at 692-93.
Upon rebutting a prima facie case, where the claimed composition has both expected and unexpected properties, a "balancing" or "relative significance" test is applied: if the unexpected properties, on balance, are of greater significance than the prior art's expected properties, then the claimed invention may be nonobvious. Id. at 692. The balancing test attempts to differentiate between the unexpected properties resulting from minor chemical manipulations of the prior art compound and the expected and desirable properties from these minor manipulations. Warner-Jenkinson co. v. Allied Chem. Corp., 477 F. Supp. 371, 388 (S.D.N.Y. 1979). Absent motivation, a change in the chemical structure that may be "obvious-to-try" is not necessarily an obvious change. Hybritech Inc. v. Monoclonal Antibodies, Inc. 802 F.2d.1367 (Fed. Cir. 1986). In other words, a prior art compound must teach toward or suggest adding a substitution, combination, or modification where the end result would be useful. See United States v. Adams, 383 U.S. 39 (1966); W.L. Gore & Associates Inc. v. Garlock, Inc., 721 F.2d 1540 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984).
D. Reasonable expectation of success
The Dillon court essentially
solved the problem regarding a claimed compound and a prior art compound with
different properties. The court in Yamanouchi Pharmaceutical Co. v. Danbury
Pharmacal, 231 F.3d 1339 (Fed. Cir. 2000), however, had to deal with a case
that a claimed compound and a prior art shared the same properties with
arguably similar structures: the
claimed compound was a second-generation compound of the prior art.
In Yamanouchi, Danbury filed
an Abbreviated New Drug Application (ANDA) with the Food and Drug
Administration seeking approval to market generic Famotidine. Id. at 1342. Danbury made a paragraph IV
certification that claim 4 of U.S. Patent No. 4,283,408 (the ’408 patent) was
invalid. Id. At the heart of validity dispute was whether one skilled in
the art would have considered it obvious to select lead compound 44 from
Yamanouchi’s U.S. Patent No. 4,252,819 and Tiotidine from the ’378 patent to
use as leads for making Famotidine. Id. at 1343. These compounds,
respectively, are three and eleven times more active than Cimetidine (Tagamet),
a benchmark compound at the time of invention (Scheme 1). Id. The
polar tail from lead compound 44 was combined with the substituted heterocycle
from Tiotidine, thus creating the intermediate compound. Thereafter a
bioisosteric substitution of the carbamoyl group (CONH2) in the
intermediate compound with a sulfamoyl group (SO2NH2)
resulted in a new, successful compound -- Famotidine. Id. at 1344.
The Yamanouchi court found that there was not
sufficient motivation for one of ordinary skill in the art at the time of
invention to take any one of the following steps, let alone the entire complex
combination: (1) selecting lead compound 44 as a starting
compound, (2) combining the polar tail from lead compound 44 with the
substituted heterocycle from Tiodine, and (3) substituting the carbamoyl group
in the intermediate compound with a sulfamoyl group to create Famotidine. Yamanouchi
Pharmaceutical Co. 231
F.3d Id. at
1345.
In
addition, the court stated that the prior art offered
no suggestion to pursue the particular order of manipulating parts of the
compounds, and any deviation in the order of combination would have taught away
from Famotidine. Id. The court
further stated that if the sulfamoyl group were substituted for the carbamyl
group on lead compound 44 without attaching the substituted hererocycle from
Tiotidine, the evidence showed that the resulting compound would have 1/100 times
the activity of Cimetidine. So the
court concluded that there was no evidence suggesting what might have led an
ordinary artisan in this field to follow the precise steps that produced a
remarkable invention. Id.
Furthermore, the Yamanouchi court stated that to show obviousness, the level of motivation must be coupled with a “reasonable expectation of success”: the ordinary medicinal chemist would have expected Famotidine to have the “most desirable combination of pharmacological properties” that it possessed. The court also concluded that there was no evidence suggesting what might have led an ordinary artisan in this field to “follow the precise steps” that produced the claimed invention. Id.
E. Flaws in the Yamanouchi court’s
arguments
1. The test of “reasonable
expectation of success” might not be applicable to chemical compounds
The test of “reasonable expectation of success” was
established in In re O'Farrell, 853 F.2d 894 (Fed. Cir. 1988), a landmark biotechnology case. In contrast to the Yamanouchi
court, which was asked to determine the obviousness of a new chemical
compound, the O’Farrell court faced the obviousness question of a novel
genetic engineering method for the synthesis of protein.
Due to the fact that a process rather than a product was
under review, the O’Farrell court correctly employed a different test
than that of the Dillon court. The O’Farrell court, however,
failed to clarify this distinction: “For obviousness under Section 103, all
that is required is a reasonable expectation of success.” Id. Thus it
seemed that, with respect to prima facie
obviousness, the O’Farrell court’s test of “reasonable expectation of
success” represented a subtle divergence from that of the prior chemical case
law precedent established in Dillon.
Considering that the invention at issue had been clearly suggested in
prior art references, the court focused on whether the applicant had a
reasonable chance to succeed in carrying out the invention. The court concluded that the inventions were
patently obvious, and hence unpatentable, when the inventor had a reasonable
expectation of success in his endeavor even though such an expectation of
success did not have to be absolute. Id.
As established in O’Farrell, a prima facie
obviousness case is made if a reasonable expectation of success is present. The
O’Farrell court arrived at this test not by analyzing compositions of
chemical compounds, but by examining the methodology
used to isolate the claimed composition. So the application of the reasonable
expectation of success to measure the level of motivation might not be
appropriate in a chemical compound patent litigation case.
A process or methodology development is similar to
electrical or mechanical science, which is predictable, as the use or
combination of any components, and the invention as a whole, are readily
discernable. Chemistry, on the other hand, is predominantly an unpredictable
art. Small changes in bonding or adding
an atom or a molecule to a chemical structure could have dramatic macroscopic
and microscopic effects. For example, in biochemistry the change of a double
bond between two atoms to a single bond transforms an unsaturated fat to a
saturated one, and the property of which would be completely different and
affect people’s lives in different ways. As another example in catalytic
chemistry, minor changes in a chemical catalyst may produce different types of
products. Studiengesellschaft Lohle Mbh v. Eastman Kodak Co, 616 F.2d
1315, 1341 (Fed. Cir. 1980). Thus due to the unpredictability of potentially
active chemical compounds, the test of “reasonable expectation of success”
becomes inapplicable to the determination of the obviousness of chemical
compounds in patent applications.
2. “The
precise steps to follow” argument from the Yamanouchi court
The Yamanouchi court also
stated that the prior art offered no suggestion to pursue the particular order
of manipulating parts of the compounds, and any deviation in the order of
combination would have taught away from Famotidine. Yamanouchi Pharmaceutical
Co, 231 F.3d at 1345. The court further argued that if the sulfamoyl group
were substituted for the carbamyl group on lead compound 44 without attaching
the substituted heterocycle from Tiotidine, the evidence showed that the
resulting compound would have 1/100 times the activity of Cimetidine. Therefore
the court concluded that there was no evidence suggesting what might have led
an ordinary artisan in this field to “follow the precise steps” that produced a
remarkable invention. Id.
Here the court’s finding was
arguably persuasive to recognize the nonobviousness of a specific chemical
compound. Yet iIt
failed to consider the fact that one specific chemical compound could be
prepared by designing different routes, so it is not necessary to pursue the
exact order or particular steps to synthesize that compound.
F. The Proposal: the
use of objective evidence of nonobviousness in chemical patent prosecution
Objective evidence of nonobviousness has often been
described as addressing secondary considerations. Such evidence is important and must be
considered before a court may find a patent claim invalid for obviousness. In
re Rouffet, 149 F.3d at 1355. Many courts have gradually realized the
importance of objective evidence of nonobviousness in patent prosecution. For
example, the Federal Circuit reversed a district court for failing to consider
objective evidence of nonobviousness in Demaco corp . v. F.Von Langsdorff
Licensing Ltd., 851 F.2d 1387, 1391 (Fed. Cir. 1988). The Federal Circuit has also stated that
objective evidence must be considered before a conclusion on obviousness was
reached, and it “was not merely ‘icing on the cake.’” See Hybritech Inc. v.
Monoclonal Antibodies, Inc, 802 F.2d 1367, 1380 (Fed. Cir. 1980). Of
course, objective evidence requires the establishment of a nexus between the
evidence and the merits of the claimed invention. Demaco Corp., 851 F.2d
at 1392.
1.
Commercial success
Commercial success has been
listed as the first convincing argument among objective evidence. In Yamanouchi,
the court could use the success of Famotidine to defeat any case of
obviousness.
Famotidine, an H2
receptor antagonist useful for treating peptic ulcer, has been extremely
successful. In 1996, for example, prescription sales of Famotidine in the
United States alone reached over 690 million dollars. Yamanouchi, 231
F.3d at 1341. This is a strong evidence of commercial success, especially in a
field with other patented competitors. Among companies who tried and failed to
develop second generation drugs similar to Famotidine were Bristol-Myers,
Merck, Glaxo, Pfizer, and ICI. Their research identified millions of potential
candidate compounds, but none turned out to be safe, effective, and successful
drugs. Id.
In the meantime many generic drug
manufacturers have great interest in offering their own version of the drug.
For example, Danbury Pharmacal, Inc., filed an Abbreviated New Drug Application
with the FDA seeking approval to market generic Famotidine. To make a paragraph
IV certification under the Hatch-Waxman Act, Danbury claimed that one of
Yamanouchi’s patent was invalid, resulting in the Yamanouchi case.
2. Unexpected results
The Federal Circuit has recognized
that unexpected superior results from an invention tend to support a finding
that the invention was not obvious to a person of ordinary skills in the art. In
re Baxter Travenol Labs, 952 F.2d 388, 392 (Fed. Cir. 1991). The principle
may apply most often to the less predictable fields, such as chemistry, where
minor changes in a product would yield substantially different results. In
re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997). This principle is
especially appropriate for medicinal chemistry, because the biological effects
of a new compound are often too complex to predict with any accuracy.
3.
Long-felt need and failure of others
The failure
of others to develop alternatives to the invention may also be an evidence of
nonobviousness. Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). The
first successful H2 receptor antagonist was Cimetidine (Tagamet), which was
approved by the FDA in 1977, and has remained a commercial product so far. A
proposed competing drug, Cimedine, however, turned out to cause some negative
side effects, such as interference with liver enzymes that caused the buildup
of certain drugs to toxic levels, as well as impotence and breast swelling in
men when administered in high doses. In
addition, it was very inconvenient to administer Cimedine, which had to be
taken four times a day. More evidence showed that, after the discovery and
initial success of Cimetididne, many major pharmaceutical companies all over
the world tried to develop improved compounds for the next generation—compounds
that would be more effective than Cimetidine and have fewer side effects. So
far, Famotidine has been the best one as
a second-generation H2 antagonist.
G. Conclusion
Chemical compounds present special issues that arise from the unpredictable nature of chemistry. A question of obviousness of chemical compounds could be answered if all the following has been considered: (1) a claimed compound and a prior art compound are sufficiently structurally similar; (2) the compounds and all of its properties are inseparable and must be considered as a whole in determining obviousness; (3) any suggestion or motivation is disclosed in the prior art to make the new compound; and (4) objective evidence demonstrates the level of motivation showing a “reasonable expectation of success.”