United States Court of Appeals for the Federal Circuit
06-1329
TAKEDA CHEMICAL INDUSTRIES, LTD.
and TAKEDA PHARMACEUTICALS NORTH AMERICA, INC.,
Plaintiffs-Appellees,
v.
ALPHAPHARM PTY., LTD.
and GENPHARM, INC.,
Defendants-Appellants.
David G. Conlin, Edwards Angell Palmer & Dodge LLP, of Boston, Massachusetts,
argued for plaintiffs-appellees. With him on the brief were Barbara L. Moore, Kathleen B.
Carr, and Adam P. Samansky; and Anthony J. Viola, of New York, New York. Of counsel
on the brief was Mark Chao, Takeda Pharmaceuticals North America, Inc., of
Lincolnshire, Illinois.
Kevin F. Murphy, Frommer Lawrence & Haug LLP, of New York, New York, argued
for defendants-appellants. With him on the brief were Edgar H. Haug and Jeffrey A.
Hovden.
Appealed from: United States District Court for the Southern District of New York
Judge Denise Cote
United States Court of Appeals for the Federal Circuit
06-1329
TAKEDA CHEMICAL INDUSTRIES, LTD. and TAKEDA
PHARMACEUTICALS NORTH AMERICA, INC.,
Plaintiffs-Appellees,
v.
ALPHAPHARM PTY., LTD. and GENPHARM, INC.,
Defendants-Appellants.
_____________________
DECIDED: June 28, 2007
_____________________
Before LOURIE, BRYSON, and DYK, Circuit Judges.
Opinion for the court filed by Circuit Judge LOURIE. Concurring opinion filed by Circuit
Judge DYK.
LOURIE, Circuit Judge.
Alphapharm Pty., Ltd. and Genpharm, Inc. (collectively “Alphapharm”) appeal
from the decision of the United States District Court for the Southern District of New
York, following a bench trial, that U.S. Patent 4,687,777 was not shown to be invalid
under 35 U.S.C. § 103. Takeda Chem. Indus., Ltd. v. Mylan Labs., 417 F. Supp. 2d 341
(S.D.N.Y. 2006). Because we conclude that the district court did not err in determining
that the claimed compounds would not have been obvious in light of the prior art, and
hence that the patent has not been shown to be invalid, we affirm.
BACKGROUND
Diabetes is a disease that is characterized by the body’s inability to regulate
blood sugar. It is generally caused by inadequate levels of insulin—a hormone
produced in the pancreas. Insulin allows blood sugar or glucose, which is derived from
food, to enter into the body’s cells and be converted into energy. There are two types of
diabetes, known as Type 1 and Type 2. In Type 1 diabetes, the pancreas fails to
produce insulin, and individuals suffering from this type of diabetes must regularly
receive insulin from an external source. In contrast, Type 2 diabetic individuals produce
insulin. However, their bodies are unable to effectively use the insulin that is produced.
This is also referred to as insulin resistance. As a result, glucose is unable to enter the
cells, thereby depriving the body of its main source of energy. Type 2 diabetes is the
most common form of diabetes—affecting over 90% of diabetic individuals.
In the 1990s, a class of drugs known as thiazolidinediones (“TZDs”) was
introduced on the market as a treatment for Type 2 diabetes. Takeda Chemical
Industries, Ltd., and Takeda Pharmaceuticals North America, Inc. (collectively “Takeda”)
first invented certain TZDs in the 1970s. Takeda’s research revealed that TZDs acted
as insulin sensitizers, i.e., compounds that ameliorate insulin resistance. Although the
function of TZDs was not completely understood, TZDs appeared to lower blood
glucose levels by binding to a molecule in the nucleus of the cell known as PPAR-
gamma, which activates insulin receptors and stimulates the production of glucose
transporters. Takeda, 417 F. Supp. 2d at 348-49. The transporters then travel to the
cellular surface and enable glucose to enter the cell from the bloodstream. Id.
Takeda developed the drug ACTOS®, which is used to control blood sugar in
patients who suffer from Type 2 diabetes. ACTOS® has enjoyed substantial commercial
06-1329 2
success since its launch in 1999. By 2003, it held 47% of the TZD market, and gross
sales for that year exceeded $1.7 billion. Id. at 386. The active ingredient in ACTOS®
is the TZD compound pioglitazone, a compound claimed in the patent in suit.
Takeda owns U.S. Patent 4,687,777 (the “’777 patent”) entitled
“Thiazolidinedione Derivatives, Useful As Antidiabetic Agents.” The patent is directed to
“compounds which can be practically used as antidiabetic agents having a broad safety
margin between pharmacological effect and toxicity or unfavorable side reactions.” ’777
patent col.1 ll.34-37. The asserted claims are claims 1, 2, and 5. Claim 1 claims a
genus of compounds. Claim 5 claims pharmaceutical compositions containing that
genus of compounds. Those claims read as follows:
1. A compound of the formula:
or a pharmacologically acceptable salt thereof.
5. An antidiabetic composition which consists essentially of a
compound of the formula:
or a pharmacologically acceptable salt thereof, in association with a
pharmacologically acceptable carrier, excipient or diluent.
06-1329 3
Id., claims 1 & 5.
For purposes of this appeal, the critical portion of the compound structure is the
left moiety of the molecule, namely, the ethyl-substituted pyridyl ring. 1 That chemical
structure, which has an ethyl substituent (C2H5) pictorially drawn to the center of the
pyridyl ring, indicates that the structure covers four possible compounds, viz.,
compounds with an ethyl substituent located at the four available positions on the
pyridyl ring. Takeda, 417 F. Supp. 2d at 360. The formula includes the 3-ethyl
compound, 4-ethyl compound, 5-ethyl compound (pioglitazone), and 6-ethyl compound.
Claim 2 of the ’777 patent covers the single compound pioglitazone. That claim,
which depends from claim 1, reads:
2. A compound as claimed in claim 1, wherein the compound is 5-{4-
[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione.
’777 patent, claim 2. Pioglitazone is referred to as the 5-ethyl compound because the
ethyl substituent is attached to the 5-position on the pyridyl ring. That portion of the
compound is depicted as:
Alphapharm, a generic drug manufacturer, filed an Abbreviated New Drug
Application (“ANDA”) pursuant to the Hatch-Waxman Act seeking U.S. Food and Drug
Administration (“FDA”) approval under 21 U.S.C. § 355(j) et seq. to manufacture and
sell a generic version of pioglitazone. Alphapharm filed a Paragraph IV certification with
1
Pyridine is a “six-membered carbon-containing ring with one carbon replaced
by a nitrogen.” Takeda, 417 F. Supp. 2d at 351.
06-1329 4
its ANDA pursuant to § 505(j)(2)(B)(ii), asserting that the ’777 patent is invalid as
obvious under 35 U.S.C. § 103. In response, Takeda sued Alphapharm, along with
three other generic drug manufacturers who also sought FDA approval to market
generic pioglitazone, alleging that the defendants have infringed or will infringe the ’777
patent.
On January 17, 2006, the district court commenced a bench trial solely on the
issues of validity and enforceability of the ’777 patent. Alphapharm advanced its
invalidity argument, asserting that the claimed compounds would have been obvious at
the time of the alleged invention. Alphapharm’s obviousness contention rested entirely
on a prior art TZD compound that is referenced in Table 1 of the ’777 patent as
compound b. The left moiety of compound b consists of a pyridyl ring with a methyl
(CH3) group attached to the 6-position of the ring. That portion of its chemical structure
is illustrated as follows:
Alphapharm asserted that the claimed compounds would have been obvious over
compound b.
The district court found that Alphapharm failed to prove by clear and convincing
evidence that the asserted claims were invalid as obvious under 35 U.S.C. § 103. The
court first concluded that there was no motivation in the prior art to select compound b
as the lead compound for antidiabetic research, and that the prior art taught away from
its use. As such, the court concluded that Alphapharm failed to make a prima facie
06-1329 5
case of obviousness. The court continued its analysis and found that even if
Alphapharm succeeded in making a prima facie showing, Takeda would still prevail
because any prima facie case of obviousness was rebutted by the unexpected results of
pioglitazone’s nontoxicity. The court then rendered judgment in favor of Takeda. The
district court also held that the ’777 patent had not been procured though inequitable
conduct. That decision has been separately appealed and has been affirmed in a
decision issued today.
Alphapharm timely appealed. We have jurisdiction pursuant to 28 U.S.C.
§ 1295(a)(1).
DISCUSSION
A. Standard of Review
In this appeal, we are presented with one issue, namely, whether the asserted
claims of the ’777 patent would have been obvious under 35 U.S.C. § 103 at the time
the invention was made. An invention is not patentable, inter alia, “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.” 35 U.S.C. § 103(a). Because a patent is
presumed to be valid, 35 U.S.C. § 282, the evidentiary burden to show facts supporting
a conclusion of invalidity, which rests on the accused infringer, is one of clear and
convincing evidence. AK Steel Corp. v. Sollac & Ugine, 344 F.3d 1234, 1238-39 (Fed.
Cir. 2003). Whether an invention would have been obvious under 35 U.S.C. § 103 is a
“question of law, reviewed de novo, based upon underlying factual questions which are
06-1329 6
reviewed for clear error following a bench trial.” Alza Corp. v. Mylan Labs., Inc., 464
F.3d 1286, 1289 (Fed. Cir. 2006).
B. Obviousness
Alphapharm raises three main arguments in support of its contention that the
claims would have been obvious. First, Alphapharm asserts that the district court
misapplied the law, particularly the law governing obviousness in the context of
structurally similar chemical compounds. According to Alphapharm, the record
established that compound b was the most effective antidiabetic compound in the prior
art, and thus the court erred by failing to apply a presumption that one of ordinary skill in
the art would have been motivated to make the claimed compounds. Alphapharm
asserts that such a conclusion is mandated by our case law, including our en banc
decision in In re Dillon, 919 F.2d 688 (Fed. Cir. 1990). Second, Alphapharm argues that
the court erred in determining the scope and content of the prior art, in particular,
whether to include the prosecution history of the prior ’779 patent. Lastly, Alphapharm
assigns error to numerous legal and factual determinations and certain evidentiary
rulings that the court made during the course of the trial.
Takeda responds that the district court correctly determined that Alphapharm
failed to prove by clear and convincing evidence that the asserted claims are invalid as
obvious. Takeda contends that there was overwhelming evidence presented at trial to
support the court’s conclusion that no motivation existed in the prior art for one of
ordinary skill in the art to select compound b as a lead compound, and even if there
was, that the unexpected results of pioglitazone’s improved toxicity would have rebutted
any prima facie showing of obviousness. Takeda further argues that all of
06-1329 7
Alphapharm’s remaining challenges to the district court’s legal and factual rulings are
simply without merit.
We agree with Takeda that the district court did not err in concluding that the
asserted claims of the ’777 patent would not have been obvious. The Supreme Court
recently addressed the issue of obviousness in KSR International Co. v. Teleflex Inc.,
127 S. Ct. 1727 (2007). The Court stated that the Graham v. John Deere Co. of Kansas
City, 383 U.S. 1 (1966), factors still control an obviousness inquiry. Those factors are:
1) “the scope and content of the prior art”; 2) the “differences between the prior art and
the claims”; 3) “the level of ordinary skill in the pertinent art”; and 4) objective evidence
of nonobviousness. KSR, 127 S. Ct. at 1734 (quoting Graham, 383 U.S. at 17-18).
In a thorough and well-reasoned opinion, albeit rendered before KSR was
decided by the Supreme Court, the district court made extensive findings of fact and
conclusions of law as to the four Graham factors. Alphapharm’s arguments challenge
the court’s determinations with respect to certain of these factors, which we now
address.
1. Differences Between the Prior Art and the Claims
a. Selection of Compound b as Lead Compound
Alphapharm’s first argument challenges the court’s determination with regard to
the “differences between the prior art and the claims.” Alphapharm contends that the
court erred as a matter of law in holding that the ethyl-substituted TZDs were
nonobvious in light of the closest prior art compound, compound b, by misapplying the
law relating to obviousness of chemical compounds.
06-1329 8
We disagree. Our case law concerning prima facie obviousness of structurally
similar compounds is well-established. We have held that “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,
creates a prima facie case of obviousness.” Dillon, 919 F.2d at 692. In addition to
structural similarity between the compounds, a prima facie case of obviousness also
requires a showing of “adequate support in the prior art” for the change in structure. In
re Grabiak, 769 F.2d 729, 731-32 (Fed. Cir. 1985).
We elaborated on this requirement in the case of In re Deuel, 51 F.3d 1552, 1558
(Fed. Cir. 1995), where we stated that “[n]ormally a prima facie case of obviousness is
based upon structural similarity, i.e., an established structural relationship between a
prior art compound and the claimed compound.” That is so because close or
established “[s]tructural relationships may provide the requisite motivation or suggestion
to modify known compounds to obtain new compounds.” Id. A known compound may
suggest its homolog, analog, or isomer because such compounds “often have similar
properties and therefore chemists of ordinary skill would ordinarily contemplate making
them to try to obtain compounds with improved properties.” Id. We clarified, however,
that in order to find a prima facie case of unpatentability in such instances, a showing
that the “prior art would have suggested making the specific molecular modifications
necessary to achieve the claimed invention” was also required. Id. (citing In re Jones,
958 F.2d 347 (Fed. Cir. 1992); Dillon, 919 F.2d 688; Grabiak, 769 F.2d 729; In re Lalu,
747 F.2d 703 (Fed. Cir. 1984)).
06-1329 9
That test for prima facie obviousness for chemical compounds is consistent with
the legal principles enunciated in KSR. 2 While the KSR Court rejected a rigid
application of the teaching, suggestion, or motivation (“TSM”) test in an obviousness
inquiry, the Court acknowledged the importance of identifying “a reason that would have
prompted a person of ordinary skill in the relevant field to combine the elements in the
way the claimed new invention does” in an obviousness determination. KSR, 127 S. Ct.
at 1731. Moreover, the Court indicated that there is “no necessary inconsistency
between the idea underlying the TSM test and the Graham analysis.” Id. As long as
the test is not applied as a “rigid and mandatory” formula, that test can provide “helpful
insight” to an obviousness inquiry. Id. Thus, in cases involving new chemical
compounds, it remains necessary to identify some reason that would have led a chemist
to modify a known compound in a particular manner to establish prima facie
obviousness of a new claimed compound.
We agree with Takeda and the district court that Alphapharm failed to make that
showing here. Alphapharm argues that the prior art would have led one of ordinary skill
in the art to select compound b as a lead compound. By “lead compound,” we
understand Alphapharm to refer to a compound in the prior art that would be most
promising to modify in order to improve upon its antidiabetic activity and obtain a
2
We note that the Supreme Court in its KSR opinion referred to the issue as
whether claimed subject matter “was” or “was not” obvious. Since 35 U.S.C. § 103 uses
the language “would have been obvious,” and the Supreme Court in KSR did consider
the particular time at which obviousness is determined, we consider that the Court did
not in KSR reject the standard statutory formulation of the inquiry whether the claimed
subject matter “would have been obvious at the time the invention was made.” 35
U.S.C. § 103. Hence, we will continue to use the statutory “would have been” language.
06-1329 10
compound with better activity. 3 Upon selecting that compound for antidiabetic research,
Alphapharm asserts that one of ordinary skill in the art would have made two obvious
chemical changes: first, homologation, i.e., replacing the methyl group with an ethyl
group, which would have resulted in a 6-ethyl compound; and second, “ring-walking,” or
moving the ethyl substituent to another position on the ring, the 5-position, thereby
leading to the discovery of pioglitazone. Thus, Alphapharm’s obviousness argument
clearly depends on a preliminary finding that one of ordinary skill in the art would have
selected compound b as a lead compound.
The district court found, however, that one of ordinary skill in the art would not
have selected compound b as the lead compound. In reaching its determination, the
court first considered Takeda’s U.S. Patent 4,287,200 (the “’200 patent”), which was
issued on September 1, 1981, and its prosecution history. The court found that the ’200
patent “discloses hundreds of millions of TZD compounds.” 4 Takeda, 417 F. Supp. 2d
at 378. The patent specifically identified fifty-four compounds, including compound b,
that were synthesized according to the procedures described in the patent, but did not
disclose experimental data or test results for any of those compounds. The prosecution
history, however, disclosed test results for nine specific compounds, including
compound b. That information was provided to the examiner in response to a rejection
3
The parties do not dispute that compound b was the closest prior art
compound. Thus, the legal question is whether or not the claimed subject matter would
have been obvious over that compound. We will, however, use Alphapharm’s
terminology of “lead compound” in this opinion, deciding the appeal as it has been
argued.
4
Three divisional applications derive from the ’200 patent. Those applications
matured into U.S. Patent 4,340,605, U.S. Patent 4,438,141, and U.S. Patent No.
4,444,779 (the “’779 Patent”). The ’779 patent is of particular relevance in this appeal
and is discussed below. Takeda, 417 F. Supp. 2d at 378.
06-1329 11
in order to show that the claimed compounds of the ’200 patent were superior to the
known compounds that were disclosed in a cited reference. The court, however, found
nothing in the ’200 patent, or in its file history, to suggest to one of ordinary skill in the
art that those nine compounds, out of the hundreds of millions of compounds covered
by the patent application, were the best performing compounds as antidiabetics, and
hence targets for modification to seek improved properties. Id. at 375.
The court next considered an article that was published the following year in
1982 by T. Sodha et al. entitled “Studies on Antidiabetic Agents. II. Synthesis of 5-[4-(1-
Methylcyclohexylmethoxy)-benzyl]thiazolidine-2,4-dione (ADD-3878) and Its
Derivatives” (“Sodha II”). The Sodha II reference disclosed data relating to
hypoglycemic activity and plasma triglyceride lowering activity for 101 TZD compounds.
Those compounds did not include pioglitazone, but included compound b. Significantly,
Sodha II identified three specific compounds that were deemed most favorable in terms
of toxicity and activity. Notably, compound b was not identified as one of the three most
favorable compounds. On the contrary, compound b, was singled out as causing
“considerable increases in body weight and brown fat weight.”
The court also considered Takeda’s ’779 patent. That patent covers a subset of
compounds originally included in the ’200 patent application, namely, TZD compounds
“where the pyridyl or thiazolyl groups may be substituted.” Id. at 353. The broadest
claim of the ’779 patent covers over one million compounds. Id. at 378. Compound b
was specifically claimed in claim 4 of the patent. The court noted that a preliminary
amendment in the prosecution history of the patent contained a statement that “the
06-1329 12
compounds in which these heterocyclic rings are substituted have become important,
especially [compound b].” Id.
Based on the prior art as a whole, however, the court found that a person of
ordinary skill in the art would not have selected compound b as a lead compound for
antidiabetic treatment. Although the prosecution history of the ’779 patent included the
statement that characterized compound b as “especially important,” the court found that
any suggestion to select compound b was essentially negated by the disclosure of the
Sodha II reference. The court reasoned that one of ordinary skill in the art would not
have chosen compound b, notwithstanding the statement in the ’779 patent prosecution
history, “given the more exhaustive and reliable scientific analysis presented by Sodha
II, which taught away from compound b, and the evidence from all of the TZD patents
that Takeda filed contemporaneously with the ’779 [p]atent showing that there were
many promising, broad avenues for further research.” Id. at 380.
The court found that the three compounds that the Sodha II reference identified
as “most favorable” and “valuable for the treatment of maturity-onset diabetes,” not
compound b, would have served as the best “starting point for further investigation” to a
person of ordinary skill in the art. Id. at 376. Because diabetes is a chronic disease and
thus would require long term treatment, the court reasoned that researchers would have
been dissuaded from selecting a lead compound that exhibited negative effects, such
as toxicity, or other adverse side effects, especially one that causes “considerable
increases in body weight and brown fat weight.” Id. at 376-77. Thus, the court
determined that the prior art did not suggest to one of ordinary skill in the art that
06-1329 13
compound b would be the best candidate as the lead compound for antidiabetic
research.
Admissions from Alphapharm witnesses further buttressed the court’s
conclusion. Dr. Rosenberg, head of Alphapharm’s intellectual property department,
testified as a 30(b)(6) witness on behalf of Alphapharm. In discussing Sodha II, Dr.
Rosenberg admitted that there was nothing in the article that would recommend that a
person of ordinary skill in the art choose compound b over other compounds in the
article that had the same efficacy rating. Dr. Rosenberg, acknowledging that compound
b had the negative side effects of increased body weight and brown fat, also admitted
that a compound with such side effects would “presumably not” be a suitable candidate
compound for treatment of Type II diabetes. Alphapharm’s expert, Dr. Mosberg,
concurred in that view at his deposition when he admitted that a medicinal chemist
would find such side effects “undesirable.”
Moreover, another Alphapharm 30(b)(6) witness, Barry Spencer, testified at his
deposition that in reviewing the prior art, one of ordinary skill in the art would have
chosen three compounds in Sodha II as lead compounds for research, not solely
compound b. In addition, Takeda’s witness, Dr. Morton, testified that at the time Sodha
II was published, it was known that obesity contributed to insulin resistance and Type 2
diabetes. Thus, one of ordinary skill in the art would have concluded that Sodha II
taught away from pyridyl compounds because it associated adverse side effects with
compound b.
We do not accept Alphapharm’s assertion that KSR, as well as another case
recently decided by this court, Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir.
06-1329 14
2007), mandates reversal. Relying on KSR, Alphapharm argues that the claimed
compounds would have been obvious because the prior art compound fell within “the
objective reach of the claim,” and the evidence demonstrated that using the techniques
of homologation and ring-walking would have been “obvious to try.” Additionally,
Alphapharm argues that our holding in Pfizer, where we found obvious certain claims
covering a particular acid-addition salt, directly supports its position.
We disagree. The KSR Court recognized that “[w]hen there is a design need or
market pressure to solve a problem and there are a finite number of identified,
predictable solutions, a person of ordinary skill has good reason to pursue the known
options within his or her technical grasp.” KSR, 127 S. Ct. at 1732. In such
circumstances, “the fact that a combination was obvious to try might show that it was
obvious under § 103.” Id. That is not the case here. Rather than identify predictable
solutions for antidiabetic treatment, the prior art disclosed a broad selection of
compounds any one of which could have been selected as a lead compound for further
investigation. Significantly, the closest prior art compound (compound b, the 6-methyl)
exhibited negative properties that would have directed one of ordinary skill in the art
away from that compound. Thus, this case fails to present the type of situation
contemplated by the Court when it stated that an invention may be deemed obvious if it
was “obvious to try.” The evidence showed that it was not obvious to try.
Similarly, Alphapharm’s reliance on Pfizer fares no better. In Pfizer, we held that
certain claims covering the besylate salt of amlodipine would have been obvious. The
prior art included a reference, referred to as the Berge reference, that disclosed a genus
of pharmaceutically acceptable anions that could be used to form pharmaceutically
06-1329 15
acceptable acid addition salts, as well as other publications that disclosed the chemical
characteristics of the besylate salt. Pfizer, 480 F.3d at 1363. Noting that our conclusion
was based on the “particularized facts of this case,” we found that the prior art provided
“ample motivation to narrow the genus of 53 pharmaceutically-acceptable anions
disclosed by Berge to a few, including benzene sulphonate.” Id. at 1363, 1367. Here,
the court found nothing in the prior art to narrow the possibilities of a lead compound to
compound b. In contrast, the court found that one of ordinary skill in the art would have
chosen one of the many compounds disclosed in Sodha II, of which there were over
ninety, that “did not disclose the existence of toxicity or side effects, and to engage in
research to increase the efficacy and confirm the absence of toxicity of those
compounds, rather than to choose as a starting point a compound with identified
adverse effects.” Thus, Pfizer does not control this case.
Based on the record before us, we conclude that the district court’s fact-findings
were not clearly erroneous and were supported by evidence in the record. Moreover,
we reject the assertion that the court failed to correctly apply the law relating to prima
facie obviousness of chemical compounds. Because Alphapharm’s obviousness
argument rested entirely on the court making a preliminary finding that the prior art
would have led to the selection of compound b as the lead compound, and Alphapharm
failed to prove that assertion, the court did not commit reversible error by failing to apply
a presumption of motivation. We thus conclude that the court did not err in holding that
Alphapharm failed to establish a prima facie case of obviousness. See Eli Lilly & Co. v.
Zenith Goldline Pharms., 471 F.3d 1369 (Fed. Cir. 2006) (affirming the district court’s
06-1329 16
finding of nonobviousness upon concluding, in part, that the prior art compound would
not have been chosen as a lead compound).
b. Choice of the Claimed Compounds
Even if Alphapharm had established that preliminary finding, and we have
concluded that it did not, the record demonstrates that Alphapharm’s obviousness
argument fails on a second ground. The district court found nothing in the prior art to
suggest making the specific molecular modifications to compound b that are necessary
to achieve the claimed compounds. In reaching that conclusion, the court first found
that the process of modifying lead compounds was not routine at the time of the
invention. Takeda, 417 F. Supp. 2d at 380. Dr. Mosberg opined that the steps of
homologation and ring-walking were “routine steps in the drug optimization process,”
but the court found that testimony unavailing in light of the contrary, more credible,
testimony offered by Takeda’s experts. Id. at 381. In addition, the court relied on Dr.
Rosenberg’s admission that a person of ordinary skill in the art would “look at a host of
substituents, such as chlorides, halides and others, not just methyls” in modifying the
pyridyl ring. Id.
Pioglitazone differs from compound b in two respects, and one would have to
both homologate the methyl group of compound b and move the resulting ethyl group to
the 5-position on the pyridyl ring in order to obtain pioglitazone. With regard to
homologation, the court found nothing in the prior art to provide a reasonable
expectation that adding a methyl group to compound b would reduce or eliminate its
toxicity. Based on the test results of the numerous compounds disclosed in Sodha II,
the court concluded that “homologation had no tendency to decrease unwanted side
06-1329 17
effects” and thus researchers would have been inclined “to focus research efforts
elsewhere.” Id. at 383. Indeed, several other compounds exhibited similar or better
potency than compound b, and one compound in particular, compound 99, that had no
identified problems differed significantly from compound b in structure. Id. at 376 n.51.
Moreover, Dr. Mosberg agreed with Takeda’s expert, Dr. Danishefsky, that the
biological activities of various substituents were “unpredictable” based on the disclosure
of Sodha II. Id. at 384-85. The court also found nothing in the ’200 and ’779 patents to
suggest to one of ordinary skill in the art that homologation would bring about a
reasonable expectation of success.
As for ring-walking, the court found that there was no reasonable expectation in
the art that changing the positions of a substituent on a pyridyl ring would result in
beneficial changes. Dr. Mosberg opined that the process of ring-walking was “known”
to Takeda, but the court found that testimony inapt as it failed to support a reasonable
expectation to one of ordinary skill in the art that performing that chemical change would
cause a compound to be more efficacious or less toxic. Id. at 382. Moreover, Dr.
Mosberg relied on the efficacy data of phenyl compounds in Sodha II, but the court
found those data insufficient to show that the same effects would occur in pyridyl
compounds.
Alphapharm relies on In re Wilder, 563 F.2d 457 (CCPA 1977), for the
proposition that differences in a chemical compound’s properties, resulting from a small
change made to the molecule, are reasonably expected to vary by degree and thus are
insufficient to rebut a prima facie case of obviousness. In Wilder, our predecessor court
affirmed the Board’s holding that a claimed compound, which was discovered to be
06-1329 18
useful as a rubber antidegradant and was also shown to be nontoxic to human skin,
would have been obvious in light of its homolog and isomer that were disclosed in the
prior art. The evidence showed that the homolog was similarly nontoxic to the human
skin, whereas the isomer was toxic. The court held that “one who claims a compound,
per se, which is structurally similar to a prior art compound must rebut the presumed
expectation that the structurally similar compounds have similar properties.” Id. at 460.
While recognizing that the difference between the isomer’s toxicity and the nontoxicity of
the homolog and claimed compound “indicate[d] some degree of unpredictability,” the
court found that the appellant failed to “point out a single actual difference in properties
between the claimed compound and the homologue,” and thus failed to rebut the
presumption. Wilder, 563 F.2d at 460.
We would note that since our Wilder decision, we have cautioned “that
generalization should be avoided insofar as specific chemical structures are alleged to
be prima facie obvious one from the other,” Grabiak, 769 F.2d at 731. In addition to this
caution, the facts of the present case differ significantly from the facts of Wilder. Here,
the court found that pioglitazone exhibited unexpectedly superior properties over the
prior art compound b. Takeda, 417 F. Supp. 2d at 385. The court considered a report
entitled “Preliminary Studies on Toxicological Effects of Ciglitazone-Related Compounds
in the Rats” that was presented in February 1984 by Dr. Takeshi Fujita, then-Chief
Scientist of Takeda’s Biology Research Lab and co-inventor of the ’777 patent. That
report contained results of preliminary toxicity studies that involved selected
compounds, including pioglitazone and compound b. Compound b was shown to be
“toxic to the liver, heart and erythrocytes, among other things,” whereas pioglitazone
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was “comparatively potent” and “showed no statistically significant toxicity.” Id. at 356-
57. During the following months, Takeda performed additional toxicity studies on fifty
compounds that had been already synthesized and researched by Takeda, including
pioglitazone. The compounds were tested for potency and toxicity. The results were
presented in another report by Fujita entitled “Pharmacological and Toxicological
Studies of Ciglitazone and Its Analogues.” Pioglitazone was shown to be the only
compound that exhibited no toxicity, although many of the other compounds were found
to be more potent. Id. at 358.
Thus, the court found that there was no reasonable expectation that pioglitazone
would possess the desirable property of nontoxicity, particularly in light of the toxicity of
compound b. The court’s characterization of pioglitazone’s unexpected results is not
clearly erroneous. As such, Wilder does not aid Alphapharm because, unlike the
homolog and claimed compound in Wilder that shared similar properties, pioglitazone
was shown to differ significantly from compound b, of which it was not a homolog, in
terms of toxicity. Consequently, Takeda rebutted any presumed expectation that
compound b and pioglitazone would share similar properties.
Alphapharm also points to a statement Takeda made during the prosecution of
the ’779 patent as evidence that there was a reasonable expectation that making
changes to the pyridyl region of compound b would lead to “better toxicity than the prior
art.” During prosecution of the ’779 patent, in response to an enablement rejection,
Takeda stated that “there should be no reason in the instant case for the Examiner to
doubt that the claimed compounds having the specified substituent would function as a
hypolipidemic and hypoglycemic agent as specified in the instant disclosure.” That
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statement, however, indicates only that changes to the left moiety of a lead compound
would create compounds with the same properties as the compounds of the prior art; it
does not represent that lower toxicity would result. And even if the statement did so
represent, it does not refer to any specific substituent at any specific position of TZD’s
left moiety as particularly promising. As the court correctly noted, the compounds
disclosed in the ’779 patent included a variety of substituents, including lower alkyls,
halogens, and hydroxyl groups, attached to a pyridyl or thiazolyl group. As discussed
supra, the district court found that the claims encompassed over one million
compounds. Thus, we disagree with Alphapharm that that statement provided a
reasonable expectation to one of ordinary skill in the art that performing the specific
steps of replacing the methyl group of the 6-methyl compound with an ethyl group, and
moving that substituent to the 5-position of the ring, would have provided a broad safety
margin, particularly in light of the district court’s substantiated findings to the contrary.
We thus conclude that Alphapharm’s challenges fail to identify grounds for
reversible error. The court properly considered the teachings of the prior art and made
credibility determinations regarding the witnesses at trial. We do not see any error in
the district court’s determination that one of ordinary skill in the art would not have been
prompted to modify compound b, using the steps of homologation and ring-walking, to
synthesize the claimed compounds. Because the court’s conclusions are not clearly
erroneous and are supported by the record evidence, we find no basis to disturb them.
The court properly concluded that Alphapharm did not make out a prima facie
case of obviousness because Alphapharm failed to adduce evidence that compound b
would have been selected as the lead compound and, even if that preliminary showing
06-1329 21
had been made, it failed to show that there existed a reason, based on what was known
at the time of the invention, to perform the chemical modifications necessary to achieve
the claimed compounds.
In light of our conclusion that Alphapharm failed to prove that the claimed
compounds would have been prima facie obvious, we need not consider any objective
indicia of nonobviousness. 5
2. Scope and Content of the Prior Art
Alphapharm also assigns error to the district court’s determination regarding the
scope and content of the prior art. Alphapharm asserts that the court excluded the
prosecution history of the ’779 patent from the scope of the prior art after wrongly
concluding that it was not accessible to the public. Takeda responds that the court
clearly considered the ’779 patent prosecution history, which was admitted into
evidence on the first day of testimony. Takeda urges that the court’s consideration of
the prosecution history is apparent based on its extensive analysis of the ’779 patent
and the file history that appears in the court’s opinion.
We agree with Takeda that the district court did not err in its consideration of the
scope of the prior art. As discussed above, the court considered the prosecution
history, and even expressly considered one of the key statements in the prosecution
history upon which Alphapharm relies in support of its position that compound b would
have been chosen as the lead compound. Takeda, 417 F. Supp. 2d at 378. In
5
The concurrence, while agreeing that the question of the “overbreadth” of
claims 1 and 5 has been waived, states further that the 6-ethyl compound, which is
within the scope of claims 1 and 5, has not been shown to possess unexpected results
sufficient to overcome a prima facie case of obviousness, and hence claims 1 and 5 are
likely invalid as obvious. Since waiver is sufficient to answer the point being raised, no
further comment need be made concerning its substance.
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considering the prosecution history of the ’779 patent, the court noted that Takeda filed
a preliminary amendment on March 15, 1983, in which its prosecuting attorney stated
that “the compounds in which these heterocyclic rings are substituted have become
important, especially [the 6-methyl compound].” Id. The court rejected Alphapharm’s
assertion that that statement supported the conclusion that compound b would have
been selected as a lead compound. Rather, the court found that viewing the prior art as
a whole, the prior art showed “that Takeda was actively conducting research in many
directions, and had not narrowed its focus to compound b.” Id. at 379. Thus, while the
district court may have incorrectly implied that prosecution histories are not accessible
to the public, see id. at n.59, see also Custom Accessories, Inc. v. Jeffrey-Allan Indus.,
807 F.2d 955 (Fed. Cir. 1986) (“[t]he person of ordinary skill is a hypothetical person
who is presumed to be aware of all the pertinent prior art”), the court nonetheless
considered the prosecution history of the ’779 patent in its obviousness analysis and
accorded proper weight to the statements contained therein. Thus, any error committed
by the court in this regard was harmless error.
We have considered Alphapharm’s remaining arguments and find none that
warrant reversal of the district court’s decision.
CONCLUSION
We affirm the district court’s determination that claims 1, 2, and 5 of the ’777
patent have not been shown to have been obvious and hence invalid.
AFFIRMED
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United States Court of Appeals for the Federal Circuit
06-1329
TAKEDA CHEMICAL INDUSTRIES, LTD. and TAKEDA
PHARMACEUTICALS NORTH AMERICA, INC.,
Plaintiffs-Appellees,
v.
ALPHAPHARM PTY., LTD. and GENPHARM, INC.,
Defendants-Appellants.
DYK, Circuit Judge, concurring.
I join the opinion of the court insofar as it upholds the district court judgment
based on a determination that a claim to pioglitazone (the 5-ethyl compound) would be
non-obvious over the prior art. The problem is that only one of the three claims involved
here—claim 2—is limited to pioglitazone. In my view, the breadth of the other two
claims, claims 1 and 5 of U.S. Patent No. 4,867,777 (“’777 patent”)—which are also
referenced in the judgment—renders them likely invalid.
All of the compounds claimed in claims 1, 2 and 5 were included in generic
claims in the prior art U.S. Patent No. 4,287,200 (“’200 patent”). Unfortunately our law
concerning when a species is patentable over a genus claimed in the prior art is less
than clear. It is, of course, well established that a claim to a genus does not necessarily
render invalid a later claim to a species within that genus. See Eli Lilly & Co. v. Bd. of
Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir. 2003). In my view a species
should be patentable over a genus claimed in the prior art only if unexpected results
have been established. Our case law recognizes the vital importance of a finding of
unexpected results, both in this context and in the closely related context where a prior
art patent discloses a numerical range and the patentee seeks to claim a subset of that
range. See Application of Petering, 301 F.2d 676, 683 (C.C.P.A. 1962) (species found
patentable when genus claimed in prior art because unexpected properties of the
species were shown); see also Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed.
Cir. 2007) (relying on lack of unexpected results in determining that species claim was
obvious in view of prior art genus claim); In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir.
1990) (when applicant claims a subset of a range disclosed in a prior art patent, the
applicant must generally show that “the claimed range achieves unexpected results
relative to the prior art range.”).
While the 5-ethyl compound (pioglitazone) is within the scope of the ’200 patent,
there is clear evidence, as the majority correctly finds, of unexpected results regarding
that compound, and therefore its validity is not in question on this ground. However, at
oral argument the patentee admitted that the prior art ’200 patent also generically
covers the 6-ethyl compound, which is within the scope of claims 1 and 5 of the ’777
patent, and admitted that there is no evidence of unexpected results for the 6-ethyl
compound. Under such circumstances, I believe that the 6-ethyl is likely obvious, and
consequently claims 1 and 5 are likely invalid for obviousness. However, the argument
as to the overbreadth of claims 1 and 5 has been waived, because it was not raised in
the opening brief. In any event, as a practical matter, the judgment finding that the
appellants’ filing of the ANDA for pioglitazone is an infringement and barring the making
of pioglitazone is supported by the finding that claim 2 standing alone is not invalid and
is infringed.
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