Microsoft word - 4_taroli - sstlr, vol. 21, fall 2009 - final
SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER OBVIOUS FALLACY: IMPROVING THE STANDARD OF OBVIOUSNESS FOR CHEMICAL COMPOUNDS TO MORE ACCURATELY REFLECT COMMON PRACTICE IN THE ART INTRODUCTION
Patent protection for newly discovered chemical compounds is one of the most important
priorities for a successful pharmaceutical company. In order to obtain a patent, a chemical
compound must be nonobvious at the time of its invention.2 As compared with obviousness
evaluations in chemical cases, application of the law of obviousness to inventions in the
electrical and mechanical sciences is fairly straightforward. Obviousness in the chemical arts has
been difficult to determine in light of chemistry’s inherent unpredictability. The properties of a
chemical compound can be dramatically altered with only slight structural changes. Courts have
attempted to address this difficulty by further defining the law of chemical obviousness to
include subtests relating to structural similarity and motivation to make the claimed composition.
However, these tests have failed at simplifying the obviousness test for chemical compounds,
1 J.D./M.S. Candidate, Syracuse University College of Law, 2010; Form & Accuracy Editor, Syracuse Science and Technology Law Reporter. The author would like to thank Professor Lisa A. Dolak for her guidance and assistance in writing this note and her family, Mom, Dad, Daniel, and Eric, for all of their unconditional love and support. 2 35 U.S.C. § 103(a) (2004) (“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 are such that the subject matter as a whole would have been obvious at the time the invention was made to person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.”).
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particularly in light of the significant increase in combinatorial chemistry techniques in the
pharmaceutical industry. Due to the enormous costs associated with drug research and
discovery, the law of obviousness of chemical compounds needs to be further defined to provide
pharmaceutical companies with sufficient notice as to whether their newly created compounds
will be refused patent protection due to obviousness in view of the prior art.
BACKGROUND
The patent laws were enacted to prevent publicly available information from being
confiscated and monopolized.3 When a patent is obtained, the inventor receives the right to
exclude others, and the public obtains the benefit of the disclosure.4 Three important
requirements to obtain a patent on an invention are utility,5 novelty,6 and nonobviousness.7 The
novelty and utility requirements can typically be readily satisfied for chemical compound
inventions, as an invention only needs to be minimally useful and comparatively minor structural
changes can render an invention novel.8 Consequently, nonobviousness frequently becomes the
critical element in ultimately determining chemical patentability.9
3 See 60 AM. JUR. 2D Patents § 6 (2009). 4 60 AM. JUR. 2D Patents § 2 (2009). 5 See 35 U.S.C. § 101 (1952). 6 See 35 U.S.C. § 102 (2002). 7 See 35 U.S.C. § 103 (2004). 8 ROBERT PATRICK MERGES & JOHN FITZGERALD DUFFY, PATENT LAW AND POLICY: CASES AND MATERIALS 612 (4th ed. 2007). 9 Id.
SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER I. The Law of Obviousness Generally
The law of obviousness is codified in Title 35 of the United States Code (“U.S.C.”).
Under § 103 (a) of the U.S.C., “patent may not be obtained though the invention is not
identically disclosed or described [in the prior art], if the differences between the subject matter
sought to be patented and the prior art are 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.”10 The nonobviousness requirement can be described as the
“nontriviality” condition; in other words, an invention does not deserve patent protection
although it may be new and useful if it embodies only a trivial modification of the prior art.
Obviousness is a legal question based on fundamental factual determinations.11
In order to understand obviousness, it is crucial to define a person of ordinary skill in the
art. The Manual of Patent Examining Procedure describes five factors that can be used to
determine the level of ordinary skill in the art: (1) the type of problems encountered in the art,
(2) prior art solutions to the problems, (3) rapidity with which innovations are made, (4)
sophistication of the technology, and (5) the educational level of active workers in the field.12
The person of ordinary skill in the art is a hypothetical person and does not necessarily embody
the level of skill of the inventor himself.13
10 35 U.S.C. § 103(a) (2008). 11 See Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997). 12 MANUAL OF PATENT EXAMINING PROCEDURE § 2141.03 (8th ed. 2001); See, e.g.,In re GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986); Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). 13 See Cool-Fin Elec. Corp. v. Int’l Elec. Research Corp., 491 F.2d 660, 662 n.7 (9th Cir. 1974).
SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER A. Development of the Law of Obviousness 1. The Graham Factors
The Supreme Court in 1966 set forth several factors that can be used to determine
obviousness in view of the prior art.14 In Graham v. John Deere Co., the Court held a patent on
a “Clamp for Vibrating Shank Plows,” which included a combination of old mechanical elements
designed to absorb shock from plow shanks as they moved through rocky soil in order to prevent
damage to the plow, as invalid for obviousness.15 The Court held that the scope and content of
the prior art, the level of ordinary skill in the art, the differences between the claimed invention
and the prior art, and objective evidence of nonobviousness should be used to determine
nonobviousness.16 Objective evidence of nonobviousness may include commercial success,
long-felt but unresolved needs, and the failure of others.17 However, the Court emphasized that
the obviousness inquiry is clearly fact-specific and an analysis including all of these factors was
Graham provided additional considerations to determine nonobviousness, it did
not construct bright-line rules for the nonobviousness requirement. Accordingly, an invention
does not need to be completely predicted by prior art to be considered obvious.19 In fact, the
14 See Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17 (1966) (holding that objective evidence of nonobviousness can be used to determine nonobviousness). 15 Id. at 18. 16 Id. at 17. 17 Id. 18 Id. 19 In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988) (stating that obviousness does not involve absolute predictability but only a reasonable probability of success).
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Federal Circuit in In re O’Farrell noted that “[o]bviousness does not require absolute
predictability of success.”20 Obviousness only requires a reasonable expectation of success.21 2. The Teaching, Suggestion or Motivation Test
In order to examine whether there was a reasonable expectation of success with regard to
a particular invention, courts have applied the Teaching, Suggestion, or Motivation test (“TSM
test”).22 A teaching, suggestion, or motivation means there was some reason or suggestion to
combine known elements in the prior art to form the claimed invention.23 In In re Kahn, the
Court of Appeals explained that an analysis of the TSM test involves examining the combined
teachings, knowledge of one of ordinary skill in the art, and the nature of the problem to be
solved as a whole.24 By looking at these factors together, the court can determine what would
have been suggested to those of ordinary skill in the art at the time that the invention was made.25
Additionally, the teaching, suggestion, or motivation does not need to be found explicitly in the
prior art, but it may be inferred by looking at the prior art as a whole.26
20 O’Farrell, 853 F.2d at 903. 21 Id. 22 Winner Int’l Royalty Corp. v. Wang, 202 F.3d. 1340, 1348 (Fed. Cir. 2000) (noting that the teaching, suggestion, or motivation test attempts to locate some reason that would have motivated one skilled in the art to modify the prior art to create the new invention). However, the teaching, suggestion, or motivation test was changed in KSR (see infra note 67). 23 Winner Int’l Royalty Corp., 202 F.3d. at 1348. 24 SeeIn re Kahn, 441 F.3d 977 (Fed. Cir. 2006). 25 Id. at986 (holding that the teaching, suggestion, or motivation to modify the prior art may be inferred from viewing the prior art as a whole). 26 Id. SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER 3. Teaching Away
Although an invention merely combines known elements, a patentee may overcome an
assertion of obviousness by showing that the prior art teaches away from combining the known
elements.27 In United States v. Adams, the Supreme Court held that a patent for a water activated
battery, which operated on an open circuit comprising two electrodes, one of magnesium and one
of cuprous chloride, was nonobvious even though it simply combined previously known
elements in the prior art.28 The Court emphasized that a person of ordinary skill in the art would
have thought that the batteries, which operated on an open circuit and heated in normal use, were
not practical. And, water activated batteries were successful only when combined with
electrolytes detrimental to the use of magnesium.29 These accepted principles would have
strongly discouraged the person of ordinary skill in the art from attempting to create this
particular battery.30 Therefore, the discovery of a successful means of combining known
elements is more likely to be considered nonobvious when the prior art teaches away from their
27 United States v. Adams, 383 U.S. 39, 51 (1966) (indicating that when the prior art teaches away from combining known elements, the resulting combination is more likely to be nonobvious). 28 Id. at 42, 48. 29 Id. at 51-52. 30 Id. at 52. 31 Id.SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER 4. Unexpected Results
An inventor may also demonstrate that an invention which merely combines known
elements in the prior art is nonobvious by providing evidence of “unexpected results.”32
According to In re Soni, an inventor may “show that the claimed invention exhibits some
superior property or advantage that a person of ordinary skill in the relevant art would have
found surprising or unexpected.”33 Therefore, an invention may be held to be nonobvious if the
inventor can show that the invention exhibits properties that would have been unanticipated at
the time of invention by a person with ordinary skill in the art.34 Unexpected results must be
established with factual data; a mere contention or conclusory statement that the invention
exhibits unanticipated and superior properties is not enough to overcome a finding of
II. Obviousness of Chemical Compounds A. Obviousness Pre-KSR
The above-described principles apply generally to obviousness determinations.
However, it is complicated to establish obviousness in the chemical arts due to chemistry’s
intrinsic unpredictability. In many circumstances, a small and seemingly insignificant change in
a chemical structure may generate a compound with remarkably different properties. The
Graham factors and the TSM test have proved insufficient at providing a workable formula for
32 In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (holding that evidence of “unexpected results” may provide evidence that an invention is nonobvious). 33 Id. 34 Id. 35 Id. at 752.
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determining chemical obviousness. Accordingly, courts have attempted to normalize the
obviousness standard for chemical compounds by further delineating the requirements. Some of
the earliest precedent regarding the obviousness of chemical compounds derives from two early
seminal cases: In re Hass and Application of Henze.36 The resulting principle of law derived
from these two cases is conventionally known as the Hass-Henze Doctrine.37
1. The Hass-Henze Doctrine In re Hass involved an appeal to the Court of Customs and Patent Appeals, predicated on
the Board of Patent Appeals’ rejection of Hass’ patent application.38 In his patent application,
Hass claimed a genus of compounds which included a homologue,39 2–nitro–2–pentene, of a
compound previously disclosed in the prior art.40 The Board rejected Hass’ claims because there
was no critical difference between the properties of the prior art compound and Hass’ claimed
homologue.41 Hass argued that it was not necessary to establish any material difference in the
properties of the claimed homologue and the prior art compound because the claimed homologue
36 In re Hass, 141 F.2d 122 (C.C.P.A. 1944); Application of Henze, 181 F.2d 196 (C.C.P.A. 1950). 37 See Helmuth C. Wegner, Prima Facie Obviousness of Chemical Compounds, 6 AIPLA Q. J. 271 (1978) (discussing the evolution of the Hass-Henze doctrine, which was named after In re Hass and the Application of Henze). 38 Hass, 141 F.2d at 122.
39 “The term homologue is used to describe a compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etc.” International Union of Pure and Applied Chemists, Glossary of Terms Used in Medicinal Chemistry (1998), available at http://www.chem.qmul.ac.uk/iupac/medchem/ah.html#a9 (last visited Jan. 15, 2009).
40 Hass, 141 F.2d at 122-23 (holding that novelty alone does not cause a chemical compound to be patentable over the prior art). 41 Id. at 123.SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER
was novel.42 The court disagreed with Hass’ argument because novelty alone, without non-
obviousness, does not render a compound patentable over the prior art.43 A person skilled in the
art would have been motivated to make the claimed homologue since:
It is well understood by chemists that the members of a homologous series of chemical compounds possess the same principal characteristics; that generally the chemical and physical properties of the individual members vary gradually from member to member; and that knowledge of the properties and chemical behavior of one of the members of the series suggests to the chemist the properties and chemical behavior of the other members of the series.44
Consequently, the decision of the board was accordingly affirmed.45
A few years later, the Court of Customs and Patent Appeals decided the Henze case on
similar grounds. The Board of Patent Appeals held that Henze’s claimed compound, 5–
isopropoxymethyl–5–phenylhydrantoin, was obvious in view of prior art containing the
homologue, 5–ethoxymethyl–5–phenylhydratoin.46 The prior art stated that 5–ethoxymethyl–5–
phenylhydratoin caused convulsions at moderate doses, and the range between an effectual and
lethal dose was too narrow for 5–ethoxymethyl–5–phenylhydratoin to be commercially viable.47
Conversely, the compound 5–isopropoxymethyl–5–phenylhydrantoin was shown to have been
42 Hass, 141 F.2d at 123. 43 Id. at 125. 44 Id. (citing Holeman & Walker, Textbook of Organic Chemistry, 5th ed., 1920. 41-42; Paul Karrer, Organic Chemistry, 1938, 23). 45 Id. at 126. 46 Henze, 181 F.2d at 198 (holding that an invention must show that a prior art did not have the same properties as the claimed compound). 47 Id. at 200.
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successful as an anticonvulsant with low toxicity.48 Henze’s 5–isopropoxymethyl–5–
phenylhydrantoin was rejected as obvious in view of the prior art containing 5–ethoxymethyl–5–
phenylhydratoin, even though the prior art made no mention of 5–ethoxymethyl–5–
phenylhydratoin’s anticonvulsant properties at any level other at moderate levels.49
The court held that Henze failed to show that 5–isopropoxymethyl–5–phenylhydrantoin
possessed unexpected and advantageous properties not found in the prior art compound 5–
ethoxymethyl–5–phenylhydratoin.50 Henze attempted to assert that it would be sufficient to
prove that 5–isopropoxymethyl–5–phenylhydrantoin had properties which were not known to be
properties possessed by 5–ethoxymethyl–5–phenylhydratoin.51 The court rejected this rationale,
stating that Henze made no showing that 5–ethoxymethyl–5–phenylhydratoin would not exhibit
similar anticonvulsant properties under the same dosage conditions.52 It was necessary that
Henze prove that the prior art compound does not exhibit the same properties of the claimed
compound under the same conditions.53 Again, the assumption underlying this decision is that a
chemist skilled in the art would know that homologues typically possess similar properties, and
the applicant has the burden of showing that a homologue possesses unexpected properties which
make it patentable over the prior art.54 Essentially, the Hass-Henze Doctrine indicates that if an
48 Henze, 181 F.2d at 200.49 Id. 50 Id. at 201. 51 Id. at 200. 52 Id. at 202. 53 Henze, 181 F.2d at 202. 54 Id. at 201.
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examiner finds a compound in the prior art that is close enough to the claimed compound such
that it would motivate a person skilled in the art to make the claimed compound (e.g., a
homologue), then the claimed compound is assumed to be obvious unless evidence is provided
which shows that the claimed compound possessed unexpected properties.55
2. Structural Similarity
The Hass-Henze Doctrine was considered good law until Henze was explicitly overruled
in Application of Stemniski.In Stemniski, the Court held that an inventor does not need to prove
that a prior art homologue to the claimed compound with no disclosed utility possesses
properties that are materially different from the claimed compound at issue in order to render the
claimed compound patentable over the prior art.56 Although this portion of the Henze decision
was overruled, courts continued to use a “structural similarity” test to address the issue of
obviousness as shown in In re Dillon.57 In this case, the Court of Appeals held that obviousness
could be shown by “structural similarity between claimed and prior art subject matter, proved by
combining references or otherwise, where the prior art gives reason or motivation to make the
claimed compositions.”58 An obviousness rejection based on structural similarity and function
means that there was sufficient motivation for a person of ordinary skill in the art to create the
55 Harold C. Wegner, POST-KSRCHEMICAL OBVIOUSNESS IN LIGHT OF PFIZER V. APOTEX8(2007), available at http://www.patenthawk.com/blog_docs/070613_PostKSRChemical Obviousness.pdf (last visited Jan. 14, 2009). 56 Applicationof Stemniski, 444 F.2d 581, 587 (C.C.P.A. 1971). 57 In re Dillon, 919 F.2d 688 (Fed. Cir. 1990) (noting that a compound may be rejected as obvious in view of the prior art if the claimed compound is structurally similar to the prior art compound and there was motivation to modify the prior art to achieve the claimed compound). 58 Id. at 692.
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new compound with the expectation that the new compound would exhibit properties similar to
that of a prior art compound because of their structurally similarity.59
3. Unexpected Properties
Courts also continued to recognize that obviousness based on structural similarity
between a new compound and a prior art compound may be overcome by a showing that the new
compound exhibited unexpected properties.60 In Application of Papesch, the inventor claimed a
family of compounds which included the compound 2,4,6-triethylpyrazolo(4,3-d)-4,5,6,7-
tetrahydropyrimidine-5,7-dione.61 It was undisputed that this compound was obvious due to
structural similarity in light of a prior art compound 2,4,6-trimethylpyrazolo(4,3-d)-4,5,6,7-
tetrahydropyrimidine-5,7-dione, since these two compounds differ only in that the prior art
compound has three methyl groups where the claimed compound has three ethyl groups.62
However, the inventor provided test results that demonstrated that the claimed triethyl compound
was an active anti-inflammatory agent, whereas the prior art trimethyl compound did not exhibit
any anti-inflammatory properties.63 A close similarity in structure alone does not render a
compound obvious.64 The Court held that the properties of compounds may and should be taken
59 Dillon, 919 F.2d at 692 60 Application of Papesch, 315 F.2d 381 (C.C.P.A. 1963) (stating that a compound may not be held obvious if the inventor can provide evidence that the claimed compound possessed unexpected properties). 61 Id. 62 Id. 63 Id. at 383. 64 Id. at 391.
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into account when analyzing obviousness.65 A compound’s structure and its physical, chemical,
and biological properties cannot be separated; thus, when proving obviousness, a chemical
compound must be considered as a whole.66
B. Flexible Teaching, Suggestion, or Motivation Test in KSR
In 2007, the Supreme Court made a decision that would significantly affect the
obviousness standard for all inventions in KSR Int’l Co. v. Teleflex, Inc.KSR concerned a patent
for an “Adjustable Pedal Assembly with Electric Throttle Control” which was licensed to
Teleflex.67 The claimed invention included an electronic sensor placed on the pivot point of an
adjustable accelerator pedal.68 The sensor detected the position of the pedal and sent this
information to a computer which controlled the amount of fuel injected into the engine.69
Teleflex claimed that KSR infringed the patent when KSR developed an adjustable mechanical
pedal with a modular sensor for Ford Motor Company.70 KSR argued that the Teleflex patent
was obvious in light of the relevant prior art.71 The District Court granted summary judgment for
KSR because there was little difference between the prior art and the claimed invention.72
65 Papesch, 315 F.2d at 391. 66 Id. 67 KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 399 (2007) (holding that the “teaching, suggestion, or motivation” (TSM) test should be flexibly applied, not as “rigid and mandatory formulas”). 68 Id. at 399. 69 Id. at 398. 70 Id. at 399. 71 Id. 72 KSR, 550 U.S. at 399-400.
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Additionally, the District Court found that the relevant prior art satisfied the Teaching
Suggestion or Motivation (TSM) test, and the claimed invention would have been obvious to a
person of ordinary skill in the art.73 The Court of Appeals reversed the district court’s decision,
stating that the district court did not apply the TSM test strictly enough.74 The Court of appeals
noted that “the District Court’s recourse to the nature of the problem to be solved was
insufficient because, unless the prior art references addressed the precise problem that the
patentee was trying to solve, the problem would not motivate an inventor to look at those
The Supreme Court reversed the decision of the Court of Appeals, agreeing with the District
Court that the claimed invention would have been obvious to one of ordinary skill in the art. 76
The Supreme Court stated that the Court of Appeals applied the TSM test too rigidly, and
criticized the Court of Appeals for indicating the District Court had not applied the TSM test
strictly enough.77 The Supreme Court disapproved of the Court of Appeal’s assertion that the
prior art must necessarily include a discussion of the exact problem the invention was created to
address.78 The Court of Appeals thought the District Court incorrectly stated that the nature of
the problem to be solved satisfied the TSM test.79 The Court of Appeals indicated that unless the
73 KSR, 550 U.S. at 399-400. 74 Id. 75 Id. 76 Id. 77 Id. at 415. 78 KSR, 550 U.S. at 420. 79 Id. at 400.
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prior art references addressed the specific problem that the inventor was attempting to solve, the
inventor would not be motivated to consider those references.80 The Supreme Court disagreed,
stating “[w]e begin by rejecting the rigid approach of the Court of Appeals. Throughout this
Court’s engagement with the question of obviousness, our cases have set forth an expansive and
flexible approach inconsistent with the way the Court of Appeals applied its TSM test here.”81
In deciding the KSR case, the Supreme Court did not substantially change the TSM test.
In fact, the Supreme Court commended the introduction of the TSM test into the obviousness
inquiry. The Supreme Court noted, “[w]hen it first established the requirement of demonstrating
a teaching, suggestion, or motivation to combine known elements in order to show that the
combination is obvious, the Court of Customs and Patent Appeals captured a helpful insight.”82
The Supreme Court repeatedly cautioned against the use of a rigid, pedantic application of the
TSM test that the Court of Appeals recommended.83 The Supreme Court noted:
Helpful insights, however, need not become rigid and mandatory formulas; and when it is so applied, the TSM test is incompatible with our precedents. The obviousness analysis cannot be confined by a formalistic conception of the words teaching, suggestion, and motivation, or by overemphasis on the importance of published articles and the explicit content of issued patents. The diversity of inventive pursuits and of modern technology counsels against limiting the analysis in this way.84
80 KSR, 550 U.S. at 400. 81 Id. at 415. 82 Id. at 418. 83 Id. at 419. 84 Id. SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER C. Obviousness of Chemical Compounds Post-KSR
As a result of KSR, determining the obviousness of chemical compounds became
increasingly uncertain. It has been speculated that the flexible TSM test supported by the Court
in KSR would strengthen the ability of generic drug companies to challenge the validity of some
pharmaceutical patents.85 Although many pharmaceutical patents held by major drug companies
involve the invention of innovative new drug compounds, many patents simply cover the
homologues, salts, metabolites, or new formulas of prior art compounds including time-release
capsules, new combinations of old drugs, and larger doses which can be taken less frequently.86
These patents are a critical part of the innovation companies’ strategy for prohibiting generic
drug companies from making minor changes to the innovative new patented drugs and claiming
them as their own.87 It has been argued that KSR’s flexible TSM test will easily allow generic
drug companies to prove that the homologues, salts, metabolites, and new formulas would have
been obvious at the time they were made.88
In addition to the problem of easing the way for generic drug companies to prove that
patented compounds were obvious, it has been argued that KSR essentially changed the long-
standing rigid approach of evaluating the obviousness of chemical compounds to a new flexible
approach inconsistent with the prior case law. Under the so-called “old rigid approach,” patent
examiners would be required to find structural similarity between the claimed compound and a
85 Rebecca Eisenberg, Pharma’s Nonobvious Problem, 12 LEWIS & CLARK L. REV. 375, 377 (2008). 86 Id. 87 Id. 88 Id. SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER
prior art compound.89 This approach frequently allowed claimed compounds which are not
structurally similar to the prior art to automatically be considered nonobvious, even if there may
have been some motivation in the prior art to make the claimed compound.90 For example, in the
case of In re Deuel, the Court of Appeals indicated that a DNA sequence encoding a polypeptide
was nonobvious over prior art which disclosed a partial amino acid sequence.91 Even though the
prior art provided sufficient motivation for a person skilled in the art to clone the DNA sequence,
the partial amino acid sequence was not “structurally similar” to the claimed DNA sequence.92
Ultimately, the court held that the DNA sequence was nonobvious.93 In the absence of a rigid
formula of structural similarity, the Court of Appeals would have been able to find the DNA
sequence obvious since there was explicit motivation to make the partial amino acid sequence in
the prior art. Therefore, it has been argued that the flexible TSM formula articulated in KSR is a
On the other hand, it has been suggested that the KSR decision did not substantially
change the obviousness inquiry with regard to chemical compounds.94 It is contended that by
89 Eisenberg, supra note 85.90 Id. 91 In re Deuel, 51 F.3d 1552, 1556 (Fed. Cir. 1995) (holding that motivation to combine the prior art does not render a compound obvious without structural similarity. If the case had been decided using the flexible teaching, suggestion, or motivation test in KSR, the court may have reached a different result given that the structural similarity test need not be rigidly applied). 92 Id. at 1557. 93 Id. at 1559. 94 See generally Jonathan M. Spenner, Obvious-to-Try: Obviousness of Chemical Enantiomers in View of the Pre- and Post-KSR Analysis, 90 J. PAT. & TRADEMARK OFF. SOC’Y 475 (2008) (arguing that the KSR decision may have been a mere anomaly).
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rejecting the Court of Appeals’ rigid application of the TSM test, the Supreme Court was simply
instructing the Court of Appeals to follow its own precedent.95 Prior to KSR, a flexible TSM test
was employed to determine the obviousness of chemical compounds.96 For example, in the case
of Forest Labs., Inc. v. Ivax Pharms., Inc., the Court of Appeals held that a claimed enantiomer97
was nonobvious over the disclosure of the racemic mixture98 found in the prior art.99 The Court
held that an inventor would not have been motivated to attempt a difficult racemate separation
rather than simply try to discover a new compound and the claimed enantiomer was
nonobvious.100 Consequently, the Court failed to make the rigid assumption that enantiomers
which were separated from the racemic mixture were obvious over the prior art.101
D. Eisai v. Dr. Reddy’s: Active Site Substitution is “Per Se” Nonobvious
There were clearly conflicting opinions regarding the affects of KSR on the obviousness
in pharmaceutical cases. In 2008, however, the Court of Appeals had a chance to directly
95 Spenner, supra note 94,at 514. 96 Id. 97 Enantiomers are molecules having “the same conductivity but differ[ing] in the arrangement of atoms in space . . . that are nonsuperposable mirror images of each other.” ERIC V. ANSLYN & DENNIS A. DOUGHERTY, MODERN PHYSICAL ORGANIC CHEMISTRY 299 (John Murdzek ed., University Science 2006). 98 A racemic mixture is “a 50:50 mixture of enantiomers.” ANSLYN & DOUGHERTY, supra note 97, at 300. 99 See Forest Labs., Inc. v. Ivax Pharms., Inc., 501 F.3d 1263, 1265-66 (Fed. Cir. 2007) (noting that enantiomers separated from a racemic mixture known in the art are not necessarily obvious). 100 Id. at 1267. 101 Id. SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER
address this question in Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.102 Eisai had a patent (“the ‘552
Patent”) on rabeprazole, the active ingredient in Aciphex, shown to be an effective drug for
treating ulcers.103 In order to be able to manufacture a generic version of Aciphex before the end
of the patent term, Dr. Reddy’s Laboratories (“Dr. Reddy’s”) and Teva Pharmaceuticals
(“Teva”) filed Abbreviated New Drug Applications (“ANDA”) under the Hatch-Waxman Act.104
As a result, Eisai filed suit against Dr. Reddy’s and Teva for patent infringement since the filing
of an ANDA is a legally recognized form of patent infringement.105 At the trial court, Dr.
Reddy’s and Teva were found to infringe the ‘522 Patent, and they appealed the court’s
judgment.106 Specifically, Teva asserted that the ‘552 Patent was invalid for obviousness over a
European patent and a United States patent (“the ‘431 Patent”) claiming, as well as an article
describing, the ulcer-treating compound lansoprazole.107
The chemical formulas of lansoprazole (R-OCH2CF3) and rabeprazole (R-
OCH2CH2CH2OCH3), where the R-core structure is identical in both molecules, differ only in
one substituent group, the trifluoroethoxy substituent (-OCH2CF3) for lansoprazole compared to
the methoxypropoxy substituent (-OCH2CH2CH2OCH3) for rabeprazole.108 Lansoprazole was
102 See Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1362 (Fed. Cir. 2008) (holding that the claimed compound was nonobvious in view of the prior art because the claimed compound was modified at the particular substituent which activated the prior art compound). 103 Id. at 1356. 104 Id. 105 Id. (citing Glaxo Group Ltd. v. Apotex, Inc., 376 F.3d 1339, 1344 (Fed. Cir. 2004)). 106 Id. at 1356. 107 Eisai, 533 F.3d at 1356-57. 108 Id. at 1357.
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known to possess qualities, including a low molecular weight and lipophilicity, which a person
skilled in the art of drug discovery would recognize as positive characteristics for a potential
drug candidate.109 Additionally, lansoprazole was determined to be twenty times more effective
than another compound of similar structure, omeprazole, in treating ulcers.110
about the affect of KSR on the determination of obviousness of
chemical compounds, the Court explained:
The Supreme Court’s analysis in KSR thus relies on several assumptions about the prior art landscape. First, KSR assumes a starting reference point or points in the art, prior to the time of invention, from which a skilled artisan might identify a problem and pursue potential solutions. Second, KSR presupposes that the record up to the time of invention would give some reasons, available within the knowledge of one of skill in the art, to make particular modifications to achieve the claimed compound. Third, the Supreme Court’s analysis in KSR presumes that the record before the time of invention would supply some reasons for narrowing the prior art universe to a “finite number of identified, predictable solutions.” In Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc., 520 F.3d 1358, 1364 (Fed. Cir. 2008), this court further explained that this “easily traversed, small and finite number of alternatives . . . might support an inference of obviousness.” To the extent an art is unpredictable, as the chemical arts often are, KSR’s focus on these “identified, predictable solutions” may present a difficult hurdle because potential solutions are less likely to be genuinely predictable.111
The Court noted that the KSR decision did not significantly change the obviousness inquiry with
The Court began its obvious inquiry by identifying lansoprazole as the lead compound
109 Eisai, 533 F.3d at 1358. 110 Id.
111 Id. at 1359. 112 Id. at 1358.
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since the data presented indicated that lansoprazole would make a good starting candidate for
anti-ulcer drugs.113 The Court then attempted to discover some motivation in the prior art for a
person skilled in the art to modify lansoprazole to achieve rabeprazole.114 The prior art European
patent containing lansoprazole indicated that lansoprazole’s fluorinated substituent gave the
compound its increased lipophilicity, which made it a particularly favorable drug candidate.115
Additionally, Teva’s expert witness at trial provided testimony that fluorinated-substituted
groups increase lipophilicity.116 The Court pointed out that lansoprazole’s advantageous
property, namely its increased lipophilicity, could be attributed to the fluorinated substituent.117
Consequently, the Court reasoned that a person skilled in the chemical arts would not have
considered the elimination or alteration of the same substituent group which gave lansoprazole
its beneficial properties to be an identifiable, predictable solution.118 Although lansoprazole and
rabeprazole were structurally similar, the trial court’s determination of nonobviousness was
affirmed on appeal due to the lack of motivation for a person skilled in the art to modify
lansoprazole at the activating substituent group.119
III. Compounds Modified at the Active Site Should Be Considered “Ad Hoc”
While it is certainly debatable whether the Court of Appeals in Eisai reached the correct
113 Eisai, 533 F.3d at 1358. 114 Id.115 Id. 116 Id. 117 Id. 118 Eisai, 533 F.3d at 1358.119 Id.SYRACUSE SCIENCE & TECHNOLOGY LAW REPORTER
conclusion regarding the obviousness of rabeprazole in view of lansoprazole, its reasoning for
the ultimate conclusion of nonobviousness is troublesome. The Court indicated that there was no
evidence in the record that would motivate a person skilled in the chemical arts to modify the
fluorinated substituent group of lansoprazole when that exact group gave the compound its
superior properties in comparison to other compounds with the same core structure. Essentially,
the argument suggested that chemists skilled in the art, after realizing the effectiveness of a
compound following the successful addition of a particular substituent group in a given location,
would not further attempt to modify that compound at the same location to improve its efficacy.
The logical conclusion which flows from that argument is that a novel compound which is
known to possess favorable properties as a drug candidate for a specific human condition will
never be obvious in view of a structurally similar prior art compound used for treating that same
condition if the novel compound was synthesized solely by altering the activating substituent
site. In other words, altering a compound at the location of the particular activating substituent
can never be obvious. This represents a fundamental misconception of the drug discovery
process. The danger underlying the Eisai decision is not the ultimate conclusion of
nonobviousness but rather the reasoning behind that decision.
Although chemists regularly synthesize a drug candidate compound with a core structure
not previously known to possess therapeutic properties, they will often begin with a core
structure which is known to successfully treat a given condition and then subsequently alter the
substituent groups.120 By altering the substituent groups of a compound selected for
120 See ALFRED BURGER, A GUIDE TO THE CHEMICAL BASIS OF DRUG DESIGN, 15 (Wiley-Interscience, Inc. 1983) (“The pattern of accidental or semiplanned drug discovery followed by systematic variation of the ‘lead’ has been repeated time and again.”); 1 C.J. CAVALLITO, MEDICINAL CHEMISTRY 233 (Alfred Burger ed., Wiley-Interscience, Inc. 1957) (“New drug discovery may be considered broadly in terms of two kinds of investigational activities,
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experimentation due to some desirable properties, chemists strive to increase the efficacy and
decrease the toxicity of the compound.121 Even if the addition of a particular substituent group
increased the therapeutic properties of the compound, chemists will frequently replace this group
with other substituent groups which can be reasonably expected to possess the similar or
increased advantageous properties at the exact same location. In order to determine what types
of substituent groups would be expected to possess the same advantageous properties, chemists
will look at structure-activity relationships.122 Chemists may substitute substituent groups
possessing many of the same properties, such as molecular weight, polarity, stereochemical
arrangement, and reactivity, since similar substituent groups would likely behave with
comparable biological activity.123 Chemists skilled in the art thoughtfully select particular
substituent groups expected to produce a similar or enhanced resulting efficacy to substitute at
‘exploration’ and ‘exploitation’ of leads . . . the latter [involves] the assessment, improvement, and extension of the lead. It is largely in the latter area that rational approaches to drug design have been productive.”); Id. at 236 (“In molecules with a variety of potential bonding interacting moieties it is useful, when possible, to eliminate individual bonding components sequentially and observe the effects on activity.”). 121 BURGER, supra note 120, at 86 (“The purpose of molecular modification is usually to seek subtle changes in the compound that should not alter some properties but change others in order to improve potency, selectivity, duration of action, and reduce toxicity”). 122 See generally G. A. Patani & E. J. LaVoie, Bioisosterism: A Rational Approach in Drug Design, 96 CHEM. REV. 3147-76 (1996). 123 BURGER, supra note 120, at 86 (“Bioisosteric replacement is the principal guide followed by medicinal chemists in developing analogs of a ‘lead’ compound . . . [t]he parameters being changed are molecular size, steric shape (bond angles, hybridization), electron distribution, lipid solubility ( = hydrophobicity), water solubility, the pKa, the chemical reactivity to cell components and metabolizing enzymes, and the capacity to undergo hydrogen bonding (receptor interactions). [If similar properties predominate], the overall properties of the two compounds may be adequately similar.”).
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Many examples illustrate this strategy, including research performed on paclitaxel.125 In
its naturally-occurring form, paclitaxel can be used as an anticancer drug.126 Even after years of
its successful use in chemotherapy treatments, researchers continued to modify the peripheral
substituent groups which gave paclitaxel its advantageous properties in an effort to improve its
efficacy and decrease its toxicity.127 Although paclitaxel was already known to work for its
intended purpose, researchers continued to attempt to improve its effectiveness by modifying its
Another example which illustrates how chemists modify substituent groups on a core
molecule to achieve new or enhanced properties involves a group of statins, which are
cholesterol-lowering drugs.129 One of these statins, Mevacor, is a naturally occurring compound
which can be isolated from the bacterium Aspergillius terreus.130 Researchers attached one
124 See 1 ALFRED BURGER, MEDICINAL CHEMISTRY 72-73 (Alfred Burger ed., Wiley-Interscience, Inc. 1957) (“The search for structural analogs for ‘lead’ compounds . . . can be rationalized by gradually substituting one atom or group of atoms in the parents compound for another with a similar electronic and steric configuration.”). 125 See generally W.S. Fang & X.T. Liang, Recent Progress in Structure Activity Relationship and Mechanistic Studies of Taxol Analogues, 5 MINI REVIEWS IN MEDICINAL CHEMISTRY 1 (2005). 126 Id. 127 Id. 128 This is not to suggest that any substituent group substituted at an activating site would necessarily be obvious to one skilled in the art.
129 Rebecca M. Wilson & Samuel J. Danishefsky, Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis Connection, 71 J. ORG. CHEM. 8329, 8332 (2006).
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additional methyl group to Mevacor, which produced the new separately patentable molecule
Zocor.131 Another statin, compactin, is also a naturally occurring compound isolated from the
bacterium Penicilliumbrevicompactin.132 By adding a hydroxyl group to compactin and opening
the ring on the core, chemists synthesized the new compound Pravachol, which was
subsequently patented by Bristol-Myers Squib.133 In both of these situations, the two pairs of
molecules differed from each other by one substituent group while the core remained the same.
In addition to these specific examples, it is crucial to note that it is common practice for
chemists to begin with a known compound and modify the substituent groups when synthesizing
new compounds. For example, researchers at Hoffman-La Roche, Inc. fabricated a collection of
forty-five benzodiazepines.134 In order to create this collection, the researchers maintained the
core benzodiazepine structure and varied the substituent groups.135 Then, the newly created
compounds were tested for acute toxicities and screened for sedative, muscle-relaxant, taming,
and anticonvulsant effects.136 Two patented drugs resulted from such molecular modification
programs focused on benzodiazepines: flurazapem and nitrazepam, both used to treat
insomnia.137 This case presents a clear model of the general practice in the chemical arts of
131 Wilson & Danishefsky, supra note 129. 132 Id. 133 Id.See generally Bristol-Myers Squib, Pravachol, www.pravachol.com (last visited Feb. 28, 2009). 134 See L. H. Sternbach, et al., Quinazolines and 1,4-Benzodiazepines. XXV. Structure-Activity Relationships of Aminoalkyl-Substituted 1,4-Benzodiazepin-2-ones, 8 J. MED. CHEM. 815 (1965). 135 Id. 136 Id. at 819. 137 BURGER, supra note 120, at 133.
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modifying substituent groups on the core of a compound in order to synthesize a new compound.
One of the best classic examples of the use of molecular modification of known
compounds to arrive at potentially useful therapeutic agents involves the sulfanilamides.138 The
antihyperglycemic and diuretic properties of known sulfanilamides prompted investigators to
create and test over two thousand analogs.139 One product of the research was the discovery of
acetazolamide, which has been proven clinically useful for treating glaucoma.140 Therefore,
since the obviousness determination would depend on the particular substituent substitution
made as shown in the previous examples, it is clear that an ad hoc analysis of a claimed
compound in view of the prior art is necessary to more accurately determine the obviousness
standard for chemical compounds. In sum, the emphasis should be placed on what substitution
was made, not the location of such substitution on the compound.
IV. Proposed Two-Part Test for Obviousness of Chemical Compounds
In order to improve the standard of obviousness for chemical compounds to more
accurately reflect synthesis techniques in the art, the following two-part test should be employed:
(1) was the particular substitution obvious to a person skilled in the art?; and (2) if so, did the
A. Whether the Particular Substitution Was Obvious to One Skilled in the Art
I propose that a factual inquiry into what specific substitution was made and the
reasoning for that specific substitution at the activating site would be required to ultimately
determine if a novel compound is truly nonobvious. For example, a substitution involving two
138 BURGER, supra note 120, at 80. 139 Id. 140 Id.
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substituents with similar polarity and molecular weight would more likely be held obvious
compared to the substitution of a strong polar substituent for a nonpolar substituent. There is no
evidence that the Eisai court even considered whether lansprazole’s trifluoroethoxy substituent (-
OCH2CF3) and rabeprazole’s methoxypropoxy substituent (-OCH2CH2CH2OCH3) would be
expected to possess similar properties and, consequently, cause similar or enhanced antiulcer
capabilities.141 Following this type of inquiry, the Eisai court would have been better equipped
to determine rabeprazole’s potential obviousness.
B. Whether There Were Unexpected Results
Even if a particular substitution may have been considered obvious to one of ordinary
skill in the art, an appropriate standard for determining the obviousness of chemical compounds
must include a consideration of unexpected results. The doctrine of unexpected results has long
been a part of the obviousness inquiry. In In re May, the invention encompassed the acid
addition salts of certain levo and alpha-levo isomers of N-methyl benzomorphan.142 May
attempted to rebut the presumption of obviousness by showing that claimed compounds
possessed pain-relieving properties similar to morphine, but they did not have the adverse side
effects of morphine, for example, addictiveness.143 The court determined that the nonaddictive
property of the N-methyl benzomorphans would have been totally unexpected to a person skilled
in the art.144 Due to this unexpected property, the court held that the N-methyl benzomorphans
141 See generally Eisai, 533 F.3d 1353. 142In re May, 574 F.2d 1082, 1084 (C.C.P.A. 1978) (stating that evidence of unexpected properties may refute a determination of obviousness). 143 Id. 144 Id. at 1092.
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would not have been obvious to one skilled in the art.145
Accordingly, the standard for determining obviousness of chemical compounds should
also allow for a compound which was synthesized by obvious substitutions to a prior art
compound to be patented when there is a showing of unexpected results. Pharmaceutical
companies should not be barred from patenting a compound with clearly new or significantly
enhanced therapeutic properties simply because an obvious
substitution was made to the prior art compound.146
C. Proposed Two-Part Test Would Lead to Increased Efficiency
By employing a test of chemical obviousness which allows a fact-specific inquiry into the
particular substitution and reasoning, the standard of obviousness for a novel chemical
compound would become more practicable. Chemists skilled in the art are capable of predicting,
within the limits of chemistry’s uncertainty, whether certain substituent groups substituted on a
core molecule could reasonably lead to expected results. This would result in a more efficient
allocation of monetary resources, because chemists would spend more time and money pursuing
the development of compounds which are less likely to be held obvious. The expansion of drug
development involving compounds, which would be nonobvious under my proposed standard,
would potentially lead to the discovery of truly innovative, not merely trivially different, drugs.
Additionally, a more clearly defined obviousness standard for chemical compounds
would allow pharmaceutical companies to pursue the most economically viable, potential drug
candidates. In 2004, United States pharmaceutical companies alone spent approximately $98
145 May, 574 F.2d at 1093. 146 ALFRED BURGER, MEDICINAL CHEMISTRY 64 (Alfred Burger ed., Wiley-Interscience, Inc. 1957) (“An added bonus of molecular modification may be the discovery of an unrelated pharmacological side effect that could be of interest in another context.”).
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billion on drug research and development; this represents approximately 0.85 percent of the
United States gross domestic product (GDP).147 This enormous amount of money spent on drug
research should be spent striving to attack new and unsolved problems in medicinal chemistry
rather than making minimal changes to compounds which have already been shown to work for a
specified purpose. The Constitution of the United States gives Congress the power to “promote
the progress of science and useful arts, by securing for limited times to authors and inventors the
exclusive right to their respective writings and discoveries.”148 The most important word in this
clause is progress. By more efficiently allocating the money spent on pursuing drug research,
the United States could be at the forefront of progressive drug exploration, targeting key diseases
like cancer, AIDS, autism, and many others.
In addition, the widespread use of combinatorial chemistry149 significantly increases the
discovery rate of new chemical compounds that can be reasonably synthesized and tested for
pharmacological activity. Combinatorial chemistry is relatively new methodology developed by
chemists to decrease the time and monetary costs required to produce effective new drug
compounds. Chemists use combinatorial chemistry to generate a library of molecules that can be
examined resourcefully at the same time. Through creating increasingly diverse chemical
147 Samuel C. Silverstein, M.D., What does economic research tell us about the economic benefits of investments in medical and health research and training? 2 (2005), available at http://www.asbmb.org/uploadedFiles/Advocacy/Economic%20Benefits%20of%20Research%20Investments%20(Silverstein,%20SC).pdf (last visited Jan. 16, 2009). 148 U.S. CONST. art 1, § 8, cl. 8. 149 For a detailed description of combinatorial chemistry techniques, see E. V. Gordeeva et al., COMPASS program – An Original Semi-Empirical Approach to Computer-Assisted Synthesis, 48 TETRAHEDRON 3789 (1992); X. D. Xiang et al., A Combinatorial Approach to Materials Discovery, 268 SCIENCE 1738 (1995); Miklos Feher & Jonathan M. Schmidt, Property Distribution: Differences Between Drugs, Natural Products, and Molecules from Combinatorial Chemistry, 43 J. CHEM. INF. COMPUT. SCI. 218 (2003).
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compound libraries, pharmaceutical companies can enhance the probability of identifying novel
compounds with important medicinal and economic value. With these techniques, the patent
office and the courts should anticipate an increase in the number of chemical compound patents
whose ultimate patentability will depend on the nonobviousness requirement. Therefore, a more
well-defined and accurate obviousness standard for chemical compounds based on actual
practice in the art will decrease the burden placed on patent examiners and the court system who
are frequently left to toil with a vague and impracticable chemical obviousness standard.
CONCLUSION
The law of obviousness has been constantly evolving since its statutory enactment in
1952. While this law has been an effective tool in eliminating trivial improvements on
inventions in the electrical and mechanical sciences, the law of obviousness has failed to provide
the chemical arts with a clear standard to determine whether chemical compounds will be held
The current standard for assessing the obviousness of a chemical compound has two
parts: (1) identification of a prior art compound with a structure similar to the claimed
compound and (2) motivation for a person skilled in the art to modify the prior art compound to
achieve the claimed compound. KSR, which struck down the rigid TSM test employed by the
Court of Appeals, raised questions as to whether it would be essentially the same or easier for
generic drug companies to show that patented chemical compounds would have been obvious at
the time of their discovery. When the Court of Appeals had the chance to specifically address
this issue in the Eisai case, the court failed to more clearly delineate the obviousness standard for
chemical compounds. Additionally, the Court’s reasoning for holding the claimed compound in
Eisai to be nonobvious is inconsistent with generally accepted drug discovery principles. An
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inquiry into the motivation for making a substituent substation on the core of a molecule known
to have therapeutic properties must necessarily include an investigation of the particular
substitution made and the reason for that substitution, not merely an analysis of the location of
that substitution on the compound’s core.
Chemistry is an intrinsically volatile art; consequently, an unambiguous obviousness
standard has been difficult to outline. The Eisai court’s decision has set the stage for trivial
substitutions to known compounds to be held nonobvious. Due to the enormous amount of
money spent on pharmaceutical research and development in the United States, the development
of a more well-defined obviousness standard is necessary to allow pharmaceutical companies to
put the most time and money into economically practical areas to promote the progress of the