United States Court of Appeals
for the Federal Circuit
__________________________
PROMETHEUS LABORATORIES, INC.,
Plaintiff-Appellant,
v.
MAYO COLLABORATIVE SERVICES (DOING
MAYO MEDICAL LABORATORIES) AND
BUSINESS AS
MAYO CLINIC ROCHESTER,
Defendants-Appellees.
__________________________
2008-1403
__________________________
On Remand from the Supreme Court of the United
States.
____________________________
Decided: December 17, 2010
____________________________
RICHARD P. BRESS, Latham & Watkins LLP, of Wash-
ington, DC, argued for plaintiff-appellant. With him on
the brief were J. SCOTT BALLENGER, ALEXANDER MALTAS,
and GABRIEL K. BELL. Of counsel was F.T. ALEXANDRA
MAHANEY, Wilson, Sonsini, Goodrich & Rosati, of San
Diego, California.
JONATHAN E. SINGER, Fish & Richardson P.C., of Min-
neapolis, Minnesota, argued for defendants-appellees.
With him on the brief were DEANNA J. REICHEL and JOHN
PROMETHEUS LAB v. MAYO COLLABORATIVE 2
A. DRAGSETH. Of counsel were TIMOTHY S. BISHOP and
STEPHEN M. SHAPIRO, Mayer Brown, LLP, of Chicago,
Illinois.
CHRISTOPHER M. HOLMAN, University of Missouri-
Kansas City School of Law, of Kansas City, Missouri, for
amicus curiae Christopher M. Holman, et al.
JENNIFER GORDON, Baker Botts L.L.P., of New York,
New York, for amicus curiae Novartis Corporation.
JAY Z. ZHANG, Myriad Genetics, Inc., of Salt Lake
City, Utah, for amicus curiae Myriad Genetics, Inc. With
him on the brief was BENJAMIN G. JACKSON.
EDWARD R. REINES, Weil Gotshal & Manges, LLP, of
Redwood Shores, California, for amicus curiae American
Intellectual Property Law Association. With him on the
brief were JILL J. HO; and TERESA STANEK REA, American
Intellectual Property Law Association, of Arlington,
Virginia.
KATHERINE J. STRANDBURG, DePaul University Col-
lege of Law, of Chicago, Illinois, for amici curiae The
American College of Medical Genetics, et al.
ROY T. ENGLERT, JR., Robbins, Russell, Englert,
Orseck, Untereiner & Sauber LLP, of Washington, DC, for
amici curiae Arup Laboratories, Inc., et al. With him on
the brief was DANIEL R. WALFISH.
JEFFREY P. KUSHAN, Sidley Austin LLP, of Washing-
ton, DC, for amicus curiae Biotechnology Industry Or-
ganization. With him on the brief were PAUL J. ZEGGER
3 PROMETHEUS LAB v. MAYO COLLABORATIVE
and PETER S. CHOI. Of counsel on the brief was HANS
SAUER, Biotechnology Industry Organization, of Washing-
ton, DC. Of counsel was DAVID L. FITZGERALD, of McLean,
Virginia.
__________________________
Before RADER, Chief Judge, LOURIE and BRYSON, Circuit
Judges.
LOURIE, Circuit Judge.
This case returns to this court on remand from the
Supreme Court for further consideration in light of the
Court’s decision in Bilski v. Kappos, 561 U.S. -- , 130 S.
Ct. 3218 (2010). In Prometheus Laboratories, Inc. v. Mayo
Collaborative Services, 581 F.3d 1336 (Fed. Cir. 2009), we
decided an appeal by Prometheus Laboratories, Inc.
(“Prometheus”) from a final judgment of the United States
District Court for the Southern District of California
granting summary judgment of invalidity of U.S. Patents
6,355,623 (“the ’623 patent”) and 6,680,302 (“the ’302
patent”) under 35 U.S.C. § 101. We held that the district
court erred as a matter of law in finding Prometheus’s
asserted medical treatment claims to be drawn to non-
statutory subject matter under this court’s machine-or-
transformation test, which we had held in In re Bilski,
545 F.3d 943 (Fed. Cir. 2008), to be the definitive test for
determining the patentability of a process under § 101.
Following our decision in this case, the Supreme Court
held that the machine-or-transformation test, although “a
useful and important clue,” was not the sole test for
determining the patent eligibility of process claims.
Bilski, 130 S. Ct. at 3226-27. Based on that decision, the
Court vacated and remanded our Prometheus decision.
Mayo Collaborative Servs. v. Prometheus Labs., Inc., 130
S. Ct. 3543 (2010) (“GVR Order”). On remand, we again
hold that Prometheus’s asserted method claims are drawn
PROMETHEUS LAB v. MAYO COLLABORATIVE 4
to statutory subject matter, and we again reverse the
district court’s grant of summary judgment of invalidity
under § 101.
BACKGROUND
Prometheus is the sole and exclusive licensee of the
’623 and ’302 patents, which claim methods for determin-
ing the optimal dosage of thiopurine drugs used to treat
gastrointestinal and non-gastrointestinal autoimmune
diseases. These drugs include 6-mercaptopurine (“6-MP”)
and azathiopurine (“AZA”), a pro-drug that upon admini-
stration to a patient converts to 6-MP, both of which are
used to treat inflammatory bowel diseases (“IBD”) such as
Crohn’s disease and ulcerative colitis. 6-MP is broken
down by the body into various 6-MP metabolites, includ-
ing 6-methylmercaptopurine (“6-MMP”) and 6-
thioguanine (“6-TG”) and their nucleotides. 1
Although drugs such as 6-MP and AZA have been
used for years to treat autoimmune diseases, non-
responsiveness and drug toxicity may complicate treat-
ment in some patients. Accordingly, the patents claim
methods that seek to optimize therapeutic efficacy while
minimizing toxic side effects. As written, the claimed
methods typically include two separately lettered steps:
(a) “administering” a drug that provides 6-TG to a subject,
and (b) “determining” the levels of the drug’s metabolites,
6-TG and/or 6-MMP, in the subject. See, e.g., ’623 patent
claim 1. The measured metabolite levels are then com-
pared to pre-determined metabolite levels, “wherein” the
measured metabolite levels “indicate a need” to increase
or decrease the level of drug to be administered so as to
minimize toxicity and maximize treatment efficacy. See,
e.g., id. In particular, according to the patents, a 6-TG
1 For the purposes of this opinion, “6-TG” encom-
passes 6-thioguanine nucleotides.
5 PROMETHEUS LAB v. MAYO COLLABORATIVE
level greater than about 400 picomole (“pmol”) per 800
million red blood cells or a 6-MMP level greater than
about 7,000 pmol per 800 million red blood cells indicates
that a downward adjustment in drug dosage may be
required to avoid toxic side effects. See id. col.20 ll.22, 54.
Conversely, according to the patents, a 6-TG level of less
than about 230 pmol per 800 million red blood cells indi-
cates a need to increase the dosage to ensure therapeutic
efficacy. See id. col.20 ll.18-19.
Claim 1 of the ’623 patent is representative of the in-
dependent claims asserted by Prometheus in this case:
1. A method of optimizing therapeutic efficacy for
treatment of an immune-mediated gastrointesti-
nal disorder, comprising:
(a) administering a drug providing 6-
thioguanine to a subject having said im-
mune-mediated gastrointestinal disorder;
and
(b) determining the level of 6-thioguanine in
said subject having said immune-mediated
gastrointestinal disorder,
wherein the level of 6-thioguanine less than
about 230 pmol per 8x108 red blood cells
indicates a need to increase the amount of
said drug subsequently administered to
said subject and
wherein the level of 6-thioguanine greater than
about 400 pmol per 8x108 red blood cells
indicates a need to decrease the amount of
said drug subsequently administered to
said subject.
’623 patent claim 1 (emphases added). Claim 1 of the ’302
patent is substantially the same, with the addition of
PROMETHEUS LAB v. MAYO COLLABORATIVE 6
determining 6-MMP levels in addition to 6-TG levels.
Claim 46 of the ’623 patent dispenses with the “adminis-
tering” step and claims only the “determining” step:
46. A method of optimizing therapeutic efficacy
and reducing toxicity associated with treatment of
an immune-mediated gastrointestinal disorder,
comprising:
(a) determining the level of 6-thioguanine or 6-
methylmercaptopurine in a subject admin-
istered a drug selected from the group con-
sisting of 6-mercaptopurine,
azathiop[u]rine, 6-thioguanine, and 6-
methyl-mercaptoriboside, said subject hav-
ing said immune-mediated gastrointestinal
disorder,
wherein the level of 6-thioguanine less than
about 230 pmol per 8x108 red blood cells
indicates a need to increase the[] amount of
said drug subsequently administered to
said subject, and
wherein the level of 6-thioguanine greater
than about 400 pmol per 8x108 red blood
cells or a level of 6-methylmercaptopurine
greater than about 7000 pmol per 8x108
red blood cells indicates a need to decrease
the amount of said drug subsequently ad-
ministered to said subject.
’623 patent claim 46 (emphases added).
Prometheus marketed a PROMETHEUS Thiopurine
Metabolites test (formerly known as the PRO-PredictRx®
Metabolites test) that used the technology covered by the
patents in suit. Mayo Collaborative Services and Mayo
Clinic Rochester (collectively, “Mayo”) formerly purchased
7 PROMETHEUS LAB v. MAYO COLLABORATIVE
and used Prometheus’s test, but in 2004, Mayo announced
that it intended to begin using internally at its clinics and
selling to other hospitals its own test. Mayo’s test meas-
ured the same metabolites as Prometheus’s test, but
Mayo’s test used different levels to determine toxicity of 6-
TG and 6-MMP.
On June 15, 2004, Prometheus sued Mayo for in-
fringement of the ’623 and ’302 patents. Prometheus
asserted independent claims 1, 7, 22, 25, and 46 of the
’623 patent and independent claim 1 of the ’302 patent.
Prometheus also asserted several dependent claims that
require either that the measurement of the metabolites be
performed using high pressure liquid chromatography, see
’623 patent claims 6, 14, 24, 30, and 53, or that the thio-
purine drug used be one of four specified drugs, see id.
claims 32, 33, 35, and 36. Mayo rescinded its announce-
ment shortly after Prometheus filed suit, and has yet to
launch its test.
On November 22, 2005, the district court held on
cross-motions for summary judgment that Mayo’s test
literally infringed claim 7 of the ’623 patent. Prometheus
Labs., Inc. v. Mayo Collaborative Servs., No. 04-CV-1200,
slip op. at 23 (S.D. Cal. Nov. 22, 2005) (Dkt. No. 227). In
its opinion, the court construed “indicates a need” to mean
“a warning that an adjustment in dosage may be re-
quired.” Id. at 18. This construction did not require
doctors to adjust drug dosage if the metabolite level
reached the specified levels; rather, the court found the
two “wherein” phrases to mean “that when the identified
metabolites reach the specified level, the doctor is warned
or notified that a dosage adjustment may be required, if
the doctor believes that is the proper procedure.” Id. at
17-18.
PROMETHEUS LAB v. MAYO COLLABORATIVE 8
On January 29, 2007, Mayo filed a motion for sum-
mary judgment of invalidity, arguing that the patents in
suit are invalid because they claim subject matter unpat-
entable under 35 U.S.C. § 101. Specifically, Mayo con-
tended that the patents impermissibly claim natural
phenomena—the correlations between, on the one hand,
thiopurine drug metabolite levels and, on the other hand,
efficacy and toxicity—and that the claims wholly preempt
use of the natural phenomena.
On March 28, 2008, the district court granted Mayo’s
motion for summary judgment of invalidity under § 101.
Prometheus Labs., Inc. v. Mayo Collaborative Servs., No.
04-CV-1200, 2008 WL 878910 (S.D. Cal. Mar. 28, 2008)
(“Invalidity Opinion”). First, the court found that the
patents only claimed the correlations between certain
thiopurine drug metabolite levels and therapeutic efficacy
and toxicity. The court reasoned that, as construed in the
November 2005 summary judgment order, the claims
have three steps: (1) administering the drug to a subject,
(2) determining metabolite levels, and (3) being warned
that an adjustment in dosage may be required. The court
stated that the fact that the inventors framed the claims
as treatment methods does not render the claims patent-
eligible subject matter. Rather, the court found that the
“‘administering’ and ‘determining’ steps are merely neces-
sary data-gathering steps for any use of the correlations”
and that “as construed, the final step—the ‘warning’ step
(i.e., the ‘wherein’ clause)—is only a mental step.” The
court noted that the warning step does not require any
actual change in dosage and that “it is the metabolite
levels themselves that ‘warn’ the doctor that an adjust-
ment in dosage may be required.” Id. With this under-
standing of the claims, the court concluded that the
claims recited the correlations between particular concen-
9 PROMETHEUS LAB v. MAYO COLLABORATIVE
trations of 6-TG and 6-MMP and therapeutic efficacy or
toxicity in patients taking AZA drugs. Id. at *6.
Second, the district court found that those correla-
tions were natural phenomena, not patent-eligible inven-
tions because the correlations resulted from a natural
body process. The court stated that the inventors did not
“invent” the claimed correlation; rather, “6-TG and 6-
MMP are products of the natural metabolizing of thio-
purine drugs, and the inventors merely observed the
relationship between these naturally produced metabo-
lites and therapeutic efficacy and toxicity.” Id. at *7.
Finally, the court determined that “[b]ecause the claims
cover the correlations themselves, it follows that the
claims ‘wholly pre-empt’ the correlations.” Id. at *11.
Thus, the court concluded that there was no genuine issue
of material fact to be resolved as to whether the patents
in suit were directed to statutory subject matter and
found by clear and convincing evidence that the claims
were invalid under § 101. Id. at *14. On May 16, 2008,
the district court entered final judgment, and Prometheus
timely appealed.
On appeal, we reversed and upheld the asserted
claims’ validity under what was at the time this court’s
“definitive test” for determining whether a process is
patentable subject matter under § 101: the machine-or-
transformation test. Prometheus, 581 F.3d at 1342.
Under the machine-or-transformation test, a claimed
process is patent eligible if it (1) is tied to a particular
machine or apparatus, or (2) transforms a particular
article into a different state or thing. Id. (quoting Bilski,
545 F.3d at 954). We held that both the “administering”
and “determining” steps were transformative and not
merely data-gathering steps under the second prong of
the test, and as such the claims did not wholly preempt
PROMETHEUS LAB v. MAYO COLLABORATIVE 10
the use of the recited correlations between metabolite
levels and drug efficacy or toxicity. Id. at 1345-49.
Following our decision in Prometheus, the Supreme
Court issued a decision rejecting the machine-or-
transformation test as the sole, definitive test for deter-
mining the patent eligibility of a process under § 101.
Bilski, 130 S. Ct. at 3226-27. Instead, the Court declined
to adopt any categorical rules outside the well-established
exceptions for laws of nature, physical phenomena, and
abstract ideas, and resolved the case based on its deci-
sions in Gottschalk v. Benson, 409 U.S. 63 (1972), Parker
v. Flook, 437 U.S. 584 (1978), and Diamond v. Diehr, 450
U.S. 175 (1981), holding that Bilski’s claims to methods of
hedging risk are not patentable processes because they
attempt to patent abstract ideas. Id. at 3226, 3229-30.
The Court did not, however, reject the machine-or-
transformation test, but rather characterized the test as
“a useful and important clue, an investigative tool, for
determining whether some claimed inventions are proc-
esses under § 101.” Id. at 3227.
The Court then granted Mayo’s petition for certiorari,
vacated our decision holding Prometheus’s method of
treatment claims to cover patent-eligible subject matter
under the machine-or-transformation test, and remanded
the case for consideration in light of the Court’s Bilski
decision. On September 1, 2010, we requested that the
parties simultaneously submit briefs, without further oral
argument, to address the effect of the Supreme Court’s
decision in Bilski on the disposition of this case. In view
of this additional briefing and the Supreme Court’s guid-
ance in Bilski, we again hold that Prometheus’s method
claims recite patentable subject matter under § 101.
11 PROMETHEUS LAB v. MAYO COLLABORATIVE
DISCUSSION
We review the district court’s grant of summary
judgment de novo. AT&T Corp. v. Excel Commc’ns, 172
F.3d 1352, 1355 (Fed. Cir. 1999). Summary judgment is
appropriate if there are no genuine issues of material fact
and the moving party is entitled to judgment as a matter
of law. Fed. R. Civ. P. 56(c). Whether a patent claim is
directed to statutory subject matter is a question of law
that we review de novo. AT&T, 172 F.3d at 1355.
I.
The issue again before us is whether Prometheus’s
method claims meet the requirements of § 101. The text
of the statute provides that:
Whoever invents or discovers any new and useful
process, machine, manufacture, or composition of
matter, or any new and useful improvement
thereof, may obtain a patent thereof, subject to
the conditions and requirements of this title.
35 U.S.C. § 101. The Supreme Court has consistently
construed § 101 broadly. Most recently, in Bilski, the
Court stated that by choosing expansive terms to specify
four independent patent-eligible categories of inventions
or discoveries—processes, machines, manufactures, and
compositions of matter—and by modifying those terms
with the comprehensive “any,” Congress plainly contem-
plated that § 101 would be given wide scope. 130 S. Ct. at
3225 (quoting Diamond v. Chakrabarty, 447 U.S. 303, 308
(1980)). “Congress took this permissive approach to
patent eligibility to ensure that ‘ingenuity should receive
a liberal encouragement.’” Id. (quoting 5 Writings of
Thomas Jefferson 75-76 (H. Washington ed. 1871)).
Yet, it is equally well-established that § 101, while
broad, is not unlimited. “The Court’s precedents provide
PROMETHEUS LAB v. MAYO COLLABORATIVE 12
three specific exceptions to § 101’s broad patent-eligibility
principles: ‘laws of nature, physical phenomena, and
abstract ideas.’” Id. (quoting Chakrabarty, 447 U.S. at
309). Although not compelled by the statutory text, the
Court has held that “these exceptions have defined the
reach of the statute as a matter of statutory stare decisis
going back 150 years,” id. (citing Le Roy v. Tatham, 55
U.S. (14 How.) 156, 174-75 (1853)), and “[t]he concepts
covered by these exceptions are ‘part of the storehouse of
knowledge of all men . . . free to all men and reserved
exclusively to none,’” id. (quoting Funk Bros. Seed Co. v.
Kalo Inoculant Co., 333 U.S. 127, 130 (1948)); see also
Benson, 409 U.S. at 67 (“Phenomena of nature, though
just discovered, mental processes, and abstract intellec-
tual concepts are not patentable, as they are the basic
tools of scientific and technological work.”).
The Supreme Court has also established that while a
law of nature, natural phenomenon, or abstract idea
cannot be patented, “an application of a law of nature or
mathematical formula to a known structure or process
may well be deserving of patent protection.” Bilski, 130 S.
Ct. at 3230 (quoting Diehr, 450 U.S. at 188). In making
this determination, the Court has made clear that a claim
must be considered as a whole; it is “inappropriate to
dissect the claims into old and new elements and then to
ignore the presence of the old elements in the analysis.”
Id. (quoting Diehr, 450 U.S. at 188). Nonetheless, a
scientific principle cannot be made patentable by limiting
its use to a particular technological environment or by
adding insignificant post-solution activity. Diehr, 450
U.S. at 191-92.
In light of the Supreme Court’s decision in Bilski, pat-
ent eligibility in this case turns on whether Prometheus’s
asserted claims are drawn to a natural phenomenon, the
patenting of which would entirely preempt its use as in
13 PROMETHEUS LAB v. MAYO COLLABORATIVE
Benson or Flook, or whether the claims are drawn only to
a particular application of that phenomenon as in Diehr.
Bilski, 130 S. Ct. at 3230. We conclude they are drawn to
the latter.
II.
We turn to the parties’ arguments on remand. Pro-
metheus argues that neither the Supreme Court’s Bilski
decision nor the Court’s GVR Order compels a different
outcome on remand, and therefore we should again re-
verse the district court’s judgment of invalidity under
§ 101. Regarding Bilski, Prometheus contends that the
Court held only that patents that do not satisfy the ma-
chine-or-transformation test are not necessarily unpat-
entable and did not overrule the long-established view
that claims that satisfy the machine-or-transformation
test, like Prometheus’s, necessarily satisfy § 101. But
regardless, Prometheus argues, its asserted claims not
only satisfy the machine-or-transformation test, but also
are not drawn to mere abstractions. Specifically, Prome-
theus argues that its asserted claims involve a particular
transformation of a patient’s body and bodily sample and
use particular machines to determine metabolite concen-
trations in a bodily sample (e.g., via high pressure liquid
chromatography), thus satisfying either prong of the
machine-or-transformation test. Prometheus further
argues that its claims also involve an application of a law
of nature, not the law itself, because they recite specific
means of treating specific diseases using specific drugs,
and therefore do not preempt the abstract idea of calibrat-
ing drug dosages to treat disease.
Mayo argues that the Supreme Court in Bilski reaf-
firmed that preemption is the controlling standard for
§ 101 under the Court’s Benson, Flook, and Diehr prece-
dents and made clear that while a machine-or-
PROMETHEUS LAB v. MAYO COLLABORATIVE 14
transformation test may inform the analysis, that test is
not outcome determinative. And, according to Mayo,
under the governing preemption standard, Prometheus’s
claims are invalid because they preempt all practical use
of naturally occurring correlations between metabolite
levels and drug efficacy and any machine or transforma-
tion present in the claims is merely insignificant post-
solution activity. Mayo also asserts that the carefully
considered opinion of three Justices—allegedly cited
approvingly by five Justices in Bilski—rejected Prome-
theus’s machine-or-transformation argument for nearly
identical claims in Laboratory Corp. of America Holdings,
Inc. v. Metabolite Laboratories, Inc., 548 U.S. 124, 138-39
(2006), concluding that the claims do not cover a process
for transforming a bodily sample, but rather merely
instruct the user to obtain test results and think about
them. Finally, Mayo claims that the Supreme Court’s
decision to GVR our earlier decision in this case indicates
that a different analysis is required of us on remand.
We disagree with Mayo. We do not think that either
the Supreme Court’s GVR Order or the Court’s Bilski
decision dictates a wholly different analysis or a different
result on remand. In our pre-Bilski decision in this case,
we held not only that Prometheus’s asserted claims recite
transformative “administering” and “determining” steps,
but also that Prometheus’s claims are drawn not to a law
of nature, but to a particular application of naturally
occurring correlations, and accordingly do not preempt all
uses of the recited correlations between metabolite levels
and drug efficacy or toxicity. The Supreme Court’s deci-
sion in Bilski did not undermine our preemption analysis
of Prometheus’s claims and it rejected the machine-or-
transformation test only as a definitive test. The Court
merely stated that “[t]he Court of Appeals incorrectly
concluded that this Court has endorsed the machine-or-
15 PROMETHEUS LAB v. MAYO COLLABORATIVE
transformation test as the exclusive test.” 130 S. Ct. at
3226 (emphasis added). The Court stated that it had
previously noted in Benson, 409 U.S. at 70, that
“[t]ransformation and reduction of an article ‘to a differ-
ent state or thing’ is the clue to the patentability of a
process claim that does not include particular machines.”
Id. at 3227. Thus, the Court did not disavow the ma-
chine-or-transformation test. And, as applied to the
present claims, the “useful and important clue, an inves-
tigative tool,” leads to a clear and compelling conclusion,
viz., that the present claims pass muster under § 101.
They do not encompass laws of nature or preempt natural
correlations.
III.
As before, we again hold that Prometheus’s asserted
method claims recite a patent-eligible application of
naturally occurring correlations between metabolite levels
and efficacy or toxicity, and thus do not wholly preempt
all uses of the recited correlations. As discussed below,
the claims recite specific treatment steps, not just the
correlations themselves. And the steps involve a particu-
lar application of the natural correlations: the treatment
of a specific disease by administering specific drugs and
measuring specific metabolites. As such, and contrary to
Mayo’s assertions, the claims do not preempt all uses of
the natural correlations; they utilize them in a series of
specific steps. See Diehr, 450 U.S. at 187 (“Their process
admittedly employs a well-known mathematical equation,
but they do not seek to preempt the use of that equation.
Rather, they seek only to foreclose from others the use of
that equation in conjunction with all of the other steps in
their claimed process.”). The inventive nature of the
claimed methods stems not from preemption of all use of
these natural processes, but from the application of a
natural phenomenon in a series of steps comprising
PROMETHEUS LAB v. MAYO COLLABORATIVE 16
particular methods of treatment. Other drugs might be
administered to optimize the therapeutic efficacy of the
claimed treatment.
We similarly reaffirm that the treatment methods
claimed in Prometheus’s patents in suit satisfy the trans-
formation prong of the machine-or-transformation test, as
they “transform an article into a different state or thing,”
and this transformation is “central to the purpose of the
claimed process.” See Bilski, 545 F.3d at 962. The trans-
formation is of the human body and of its components
following the administration of a specific class of drugs
and the various chemical and physical changes of the
drugs’ metabolites that enable their concentrations to be
determined. We thus have no need to separately deter-
mine whether the claims also satisfy the machine prong of
the test.
Contrary to the district court and Mayo’s arguments
on remand, we do not view the disputed claims as merely
claiming natural correlations and data-gathering steps. 2
2 Mayo, as did the district court, points to the opin-
ion of three Justices dissenting from the dismissal of the
grant of certiorari in Lab. Corp., 548 U.S. 124 (Breyer, J.,
dissenting from dismissal of certiorari as improvidently
granted). See Invalidity Opinion, 2008 WL 878910, at *8
(discussing the dissent in Lab. Corp. at length and finding
Justice Breyer’s reasoning persuasive). Again, with
respect, we decline to discuss a dissent; it is not control-
ling law, and it involved different claims from the ones at
issue here. Mayo further claims that five Justices in two
concurrences cited Lab. Corp. with approval in Bilski, but
such citations fail to transform a dissent into controlling
law. Moreover, one concurrence cites Lab. Corp. for the
proposition that “too much patent protection can impede
rather than ‘promote the Progress of . . . useful Arts,’” in
arguing for a categorical rule that business method pat-
ents do not qualify as patent-eligible processes under
17 PROMETHEUS LAB v. MAYO COLLABORATIVE
The asserted claims are in effect claims to methods of
treatment, which are always transformative when one of
a defined group of drugs is administered to the body to
ameliorate the effects of an undesired condition. More
specifically, Prometheus here claimed methods for opti-
mizing efficacy and reducing toxicity of treatment regimes
for gastrointestinal and non-gastrointestinal autoimmune
diseases that utilize drugs providing 6-TG by administer-
ing a drug to a subject. The invention’s purpose to treat
the human body is made clear in the specification and the
preambles of the asserted claims. See ’623 patent col.2
ll.16-19 (“The present invention provides a method of
optimizing therapeutic efficacy of 6-mercaptopurine drug
treatment of an immune-mediated gastrointestinal disor-
der.”); see, e.g., id. claim 1 (“A method of optimizing
therapeutic efficacy for treatment of an immune-mediated
gastrointestinal disorder, comprising . . .”); id. claim 7 (“A
method of reducing toxicity associated with treatment of
an immune-mediated gastrointestinal disorder, compris-
ing . . .”); id. claim 22 (“A method of optimizing therapeu-
tic efficacy of treatment of a non-IBD autoimmune
disease, comprising . . .”).
When administering a drug such as AZA or 6-MP, the
human body necessarily undergoes a transformation. The
drugs do not pass through the body untouched without
affecting it. In fact, the transformation that occurs, viz.,
the effect on the body after metabolizing the artificially
administered drugs, is the entire purpose of administer-
ing these drugs: the drugs are administered to provide 6-
TG, which is thought to be the drugs’ active metabolite in
the treatment of disease, to a subject. See ’623 patent
col.1 ll.49-51. The fact that the change of the adminis-
§ 101. Bilski, 130 S. Ct. at 3255 (Stevens, J., concurring).
But this case does not involve business method patents.
PROMETHEUS LAB v. MAYO COLLABORATIVE 18
tered drug into its metabolites relies on natural processes
does not disqualify the administering step from the realm
of patentability. As Prometheus points out, quite literally
every transformation of physical matter can be described
as occurring according to natural processes and natural
law. Transformations operate by natural principles. The
transformation here, however, is the result of the physical
administration of a drug to a subject to transform—i.e.,
treat—the subject, which is itself not a natural process.
“It is virtually self-evident that a process for a chemical or
physical transformation of physical objects or substances
is patent-eligible subject matter.” Bilski, 545 F.3d at 962.
The administering step, therefore, is not merely data-
gathering but a significant transformative element of
Prometheus’s claimed methods of treatment that is “suffi-
ciently definite to confine the patent monopoly within
rather definite bounds.” Benson, 409 U.S. at 70.
Not all of the asserted claims, however, contain the
administering step. That omission, which occurs in
claims 46 and 53 of the ’623 patent, does not diminish the
patentability of the claimed methods because we also hold
that the determining step, which is present in each of the
asserted claims, is transformative and central to the
claimed methods. Determining the levels of 6-TG or 6-
MMP in a subject necessarily involves a transformation.
Some form of manipulation, such as the high pressure
liquid chromatography method specified in several of the
asserted dependent claims or some other modification of
the substances to be measured, is necessary to extract the
metabolites from a bodily sample and determine their
concentration. As stated by Prometheus’s expert, “at the
end of the process, the human blood sample is no longer
human blood; human tissue is no longer human tissue.”
Decl. of Dr. Yves Théorêt ¶ 6, Prometheus Labs., Inc. v.
Mayo Collaborative Servs., No. 04-CV-1200 (S.D. Cal.
19 PROMETHEUS LAB v. MAYO COLLABORATIVE
Mar. 29, 2007) (Dkt. No. 528-3). That is clearly a trans-
formation. In fact, Mayo does not dispute that determin-
ing metabolite levels in the clinical samples taken from
patients is transformative, but argues that this transfor-
mation is merely a necessary data-gathering step for use
of the correlations. On the contrary, this transformation
is central to the purpose of the claims, since the determin-
ing step is, like the administering step, a significant part
of the claimed method. Measuring the levels of 6-TG and
6-MMP is what enables possible adjustments to thio-
purine drug dosage to be detected for optimizing efficacy
or reducing toxicity during a course of treatment. The
determining step, by working a chemical and physical
transformation on physical substances, likewise suffi-
ciently confines the patent monopoly, as required by the
machine-or-transformation test.
A further requirement for patent-eligibility is ensur-
ing that the involvement of the transformation in Prome-
theus’s claimed process is “not merely insignificant extra-
solution activity.” Flook, 437 U.S. at 590. As made clear
from the discussion above, the administering and deter-
mining steps are transformative and are central to the
claims rather than merely insignificant extra-solution
activity.
The crucial error the district court made in reaching
the opposite conclusion was failing to recognize that the
first two steps of the asserted claims are not merely data-
gathering steps. See Invalidity Opinion, 2008 WL
878910, at *6 (finding that “the ‘administering’ and ‘de-
termining’ steps are merely necessary data-gathering
steps for any use of the correlations”). While it is true
that the administering and determining steps gather
useful data, it is also clear that the presence of those two
steps in the claimed processes is not “merely” for the
purpose of gathering data. Instead, the administering
PROMETHEUS LAB v. MAYO COLLABORATIVE 20
and determining steps are part of a treatment protocol,
and they are transformative. As explained above, the
administering step provides thiopurine drugs for the
purpose of treating disease, and the determining step
measures the drugs’ metabolite levels for the purpose of
assessing the drugs’ dosage during the course of treat-
ment.
Given the integral involvement of the administering
and determining steps in Prometheus’s therapeutic meth-
ods, this case is easily distinguishable from prior cases
that found asserted method claims to be unpatentable for
claiming data-gathering steps and a fundamental princi-
ple. Perhaps the case that offers the closest comparison is
In re Grams, 888 F.2d 835 (Fed. Cir. 1989), but the as-
serted claims found unpatentable in that case are readily
distinguished from those in the instant action. In Grams,
the applicant claimed a process that involved (1) perform-
ing a clinical test on individuals and (2) based on the data
from that test, determining if an abnormality existed and
determining possible causes of any abnormality by using
an algorithm. We found that this process was not drawn
to patentable subject matter because the essence of the
claimed process was the mathematical algorithm, rather
than any transformation of the tested individuals. 888
F.2d at 839-41. More specifically, the Grams process was
unpatentable because “it was merely an algorithm com-
bined with a data-gathering step,” i.e., performing a
clinical test. Bilski, 545 F.3d at 963. The claims did not
require the performing of clinical tests on individuals that
were transformative—and thus rendering the entire
process patentable subject matter—because the tests were
just to “obtain data.” Grams, 888 F.2d at 840. The patent
and thus the court focused only on the algorithm rather
than the clinical tests purported to be covered by the
claims.
21 PROMETHEUS LAB v. MAYO COLLABORATIVE
Here, unlike the clinical test recited in Grams, the
administering and determining steps in Prometheus’s
claimed methods are not “merely” data-gathering steps or
“insignificant extra-solution activity”; they are part of
treatment regimes for various diseases using thiopurine
drugs. See Bilski, 545 F.3d at 963 (discussing Grams). As
a result, the administering and determining steps are not
insignificant extra-solution activity, and the claims are
therefore not drawn merely to correlations between
metabolite levels and toxicity or efficacy.
We agree with the district court that the final
“wherein” clauses are mental steps and thus not patent-
eligible per se. However, although they alone are not
patent-eligible, the claims are not simply to the mental
steps. A subsequent mental step does not, by itself,
negate the transformative nature of prior steps. Thus,
when viewed in the proper context, the final step of pro-
viding a warning based on the results of the prior steps
does not detract from the patentability of Prometheus’s
claimed methods as a whole. The data that the adminis-
tering and determining steps provide for use in the men-
tal steps are obtained by steps well within the realm of
patentable subject matter; the addition of the mental
steps to the claimed methods thus does not remove the
prior two steps from that realm. No claim in the Prome-
theus patents claims only mental steps. Therefore, con-
trary to Mayo’s assertions, a physician who only evaluates
the result of the claimed methods, without carrying out
the administering and/or determining steps that are
present in all the claims, cannot infringe any claim that
requires such steps.
This analysis is consistent with In re Abele, 684 F.2d
902 (CCPA 1982). In Abele, a method claim called for the
use of X-ray attenuation data, which necessarily involved
production, detection, and display with a CAT scan. The
PROMETHEUS LAB v. MAYO COLLABORATIVE 22
method also called for use of an algorithm. We found that
the claim was patentable because removal of the algo-
rithm still left all the steps of a CAT scan in the claim;
thus, the production and detection could not be considered
“mere antecedent steps to obtain values for solving the
algorithm. . . . We view the production, detection, and
display steps as manifestly statutory subject matter, and
are not swayed from this conclusion by the presence of an
algorithm in the claimed method.” Id. at 908. In the
instant case, the presence of mental steps similarly does
not detract from the patentability of the administering
and determining steps.
As we explained in Bilski,
[I]t is inappropriate to determine the patent eligi-
bility of a claim as a whole based on whether se-
lected limitations constitute patent-eligible
subject matter. After all, even though a funda-
mental principle itself is not patent-eligible, proc-
esses incorporating a fundamental principle may
be patent-eligible. Thus, it is irrelevant that any
individual step or limitation of such processes by
itself would be unpatentable under § 101.
545 F.3d at 958 (citations omitted). Such is the case here.
Although the wherein clauses describe the mental proc-
esses used to determine the need to change the dosage
levels of the drugs, each asserted claim as a whole is
drawn to patentable subject matter. Although a physi-
cian is not required to make any upward or downward
adjustment in dosage during the “warning” step, the prior
steps provide useful information for possible dosage
adjustments to the method of treatment using thiopurine
drugs for a particular subject. Viewing the treatment
methods as a whole, Prometheus has claimed therapeutic
methods that determine the optimal dosage level for a
23 PROMETHEUS LAB v. MAYO COLLABORATIVE
course of treatment. In other words, when asked the
critical question, “What did the applicant invent?,”
Grams, 888 F.2d at 839 (citation omitted), the answer is a
series of transformative steps that optimizes efficacy and
reduces toxicity of a method of treatment for particular
diseases using particular drugs.
In light of the foregoing analysis, we hold that Prome-
theus’s asserted method claims satisfy the preemption
test as well as the transformation prong of the machine-
or-transformation test.
CONCLUSION
For the foregoing reasons, we reverse the judgment of
the district court and remand to the court with instruc-
tions to deny Mayo’s motion for summary judgment that
the asserted claims are invalid under § 101.
REVERSED and REMANDED