from the United States District Court for the Northern
District of California in No. 3:14-cv-03228-EDL, Magistrate
Judge Elizabeth D. Laporte.
Stephen S. Rabinowitz, Hughes Hubbard & Reed LLP, New
York, NY, argued for plaintiff-appellant. Also represented by
James W. Dabney, Mitchell Epner, Patrice Polyxene Jean, David
E. Lansky, Lynn M. Russo.
R. Puknys, Finnegan, Henderson, Farabow, Garrett &
Dunner, LLP, Palo Alto, CA, argued for defendant-appellee.
Also represented by Michael Paul Barker; Grant L. Kim, Wesley
Ellsworth Overson, Morrison & Foerster LLP, San
O'Malley, Reyna, and Hughes, Circuit Judges.
Roche Molecular Systems, Inc. ("Roche") owns U.S.
Patent No. 5, 643, 723 ("the '723 patent"),
titled "Detection of a Genetic Locus Encoding Resistance
to Rifampin in Microbacterial Cultures and in Clinical
Specimens." The United States District Court for the
Northern District of California found that the asserted
claims of the '723 patent are directed to
patent-ineligible subject matter and are therefore invalid
under 35 U.S.C. § 101. Roche appeals from a grant of
summary judgment of invalidity. We affirm.
'723 patent is directed to methods for detecting the
pathogenic bacterium Mycobacterium tuberculosis ("M.
tuberculosis" or "MTB"). '723 patent col.
2 ll. 50-54. MTB infection is a major cause of tuberculosis.
Id. col. 1 ll. 13-30. In 1994, before the priority
date of the '723 patent, the general method of MTB
detection in a tuberculosis patient was known as sputum
examination by the acid-fast bacilli smear. For this test, a
biological sample taken from a patient is subjected to cell
culture in a process that can take three to eight weeks.
Id. col. 2 ll. 9- 11. This test has limitations: it
can identify the presence of bacterial cells in a biological
sample, but cannot identify the cells as MTB. There is a need
to know whether the MTB from a patient is resistant to
antibiotics. The standard of care for MTB treatment at the
time involved a regimen of antibiotics, with rifampin being a
first-line anti-tuberculosis drug. Id. col. 1 ll.
31-33. Tuberculosis outbreaks, however, still resulted
because of delays in diagnosis and reporting of
rifampin-resistant tuberculosis due to the inability to
rapidly identify MTB strains that are resistant to rifampin
and put a patient on an appropriate alternative therapy.
Id. col. 1 ll. 61-65.
to the '723 patent, scientists in the field had been
working on diagnostic tests for faster detection of MTB,
particularly rifampin-resistant MTB strains. Id.
col. 2 ll. 18-46. It was speculated that "[g]enotypic
detection of multi-drug resistant MTB [strains] directly from
clinical specimens is theoretically the fastest and most
direct step toward determining effective therapy for
patients." Id. col. 2 ll. 39-42. It was known
in the art that rifampin has a unique site of action on a
particular gene that encodes the β subunit of bacterial
RNA polymerase ("the rpoB gene").
Id. col. 1 ll. 31-42. The rpoB gene is
present in MTB and other bacterial species, and its
deoxyribonucleic acid ("DNA") sequences were known
to be highly conserved, with little variation from one
bacterial species to another. In 1994, single site mutations
in the rpoB gene that confer rifampin resistance in
some bacteria, such as Escherichia coli ("E.
coli"), were well characterized, making rpoB a
prime candidate for studying rifampin resistance in MTB.
Id. col. 1 ll. 42-52.
inventors of the '723 patent-scientists from Roche and
the Mayo Foundation for Medical Education and Research
("Mayo")-sequenced the rpoB gene from
various bacteria species, including MTB, obtained from a
commercial vendor. Id. col. 8 ll. 1-3 and col. 8 l.
15-col. 9 l. 20. After comparing rpoB DNA sequences
across different species, the inventors discovered that the
rpoB gene in MTB contains eleven
"position-specific 'signature nucleotides'"
(i.e., naturally occurring single nucleotide mutations) that
are only present in MTB but not in other bacteria.
Id. col. 2 l. 60-col. 3 l. 2. In other words, these
naturally occurring signature nucleotides are like
fingerprints of MTB: if an investigator detects one of the
eleven signature nucleotides from a biological sample, she
knows the sample contains MTB, and vice versa. These
signature nucleotides, therefore, could be used to identify
MTB using genetic testing, which is both faster and more
accurate than the traditional MTB detection methods.
Id. col. 2 ll. 9-31.
on these eleven MTB-specific signature nucleotides, the Roche
inventors devised a diagnostic test that could (1) identify
whether or not a biological sample contains MTB, and (2) if
MTB is present, predict whether that MTB is a strain that is
resistant to rifampin treatment. The diagnostic test of the
'723 patent involves subjecting DNA extracted from a
biological sample taken from a patient (e.g., a tissue or
fluid sample) to amplification by polymerase chain reaction
("PCR") using a short, single-stranded nucleotide
sequence (a "primer") that can hybridize (i.e.,
bind) to at least one of the eleven position-specific
signature nucleotides in the MTB rpoB gene.
a method of amplifying DNA exponentially. See Roche,
2017 WL 6311568, at *2. In PCR, a pair of primers effectively
"flanks," or marks the start and finish of, the DNA
segment-e.g., the rpoB gene or a portion of it-to be
copied. Strands of DNA are then replicated between the primer
pair by a DNA polymerase. This process is repeated until a
sufficient number of copies of the desired DNA segment are
generated. These copies, known as "amplification
product," make it possible to detect whether a specific
type of DNA is present. Id. It is undisputed that by
the time of the invention in 1994, PCR had become a
well-understood, routine, and conventional technique.
PCR is performed, the presence of DNA amplification product
in sufficient copies from the reaction indicates that MTB is
present in the biological sample. The absence of DNA
amplification product (i.e., below the detection limit using
standard assays) indicates that MTB is absent from the
biological sample. The amplified rpoB DNA segment
from the PCR can, in turn, be tested for the presence of
known genetic mutations associated with rifampin resistance.
Thus, the '723 patent represents an improvement over the
traditional sputum examination method for detecting MTB, as
its genetics-based diagnostic method is faster and more
'723 patent provides two types of claims: (1)
com-position-of-matter claims for the primers used in the
PCR, which could hybridize to the rpoB gene of MTB
at a site that includes at least one of the eleven signature
nucleotides ("the primer claims"); and (2) process
claims for methods for detecting MTB that include amplifying
target sequences by PCR and detecting amplification products,
which, if present, indicate the presence of MTB ("the
1-13 are the method claims. Claim 1, the sole independent
method claim, recites:
1. A method for detecting Mycobacterium tuberculosis in a
biological sample suspected of containing M. tuberculosis
(a) subjecting DNA from the biological sample to polymerase
chain reaction [PCR] using a plurality of primers under
reaction conditions sufficient to simplify a portion of a M.
tuberculosis rpoB [gene] to produce an amplification product,
wherein the plurality of primers comprises at least one
primer that hybridizes under hybridizing conditions to the
amplified portion of the [gene] at a site comprising at least
one position-specific M. tuberculosis signature nucleotide
selected, with reference to FIG. 3 (SEQ ID NO: 1), from the
a G at nucleotide position 2312,
a T at nucleotide position 2313,
an A at nucleotide position 2373,
a G at nucleotide position 2374,
an A at nucleotide position 2378,
a G at nucleotide position 2408,
a T at nucleotide position 2409,
an A at nucleotide position 2426,
a G at nucleotide position 2441, an A at nucleotide position
a T at nucleotide position 2465; and
(b) detecting the presence or absence of an amplification
product, wherein the presence of an amplification product is
indicative of the presence of M. tuberculosis in the
biological sample and wherein the absence of the
amplification product is indicative of the absence of M.
tuberculosis in the biological sample.
'723 patent col. 25 l. 57-col. 27 l. 6. Dependent claims
2- 13 add various limitations to claim 1 concerning PCR, PCR
analysis, and primer preparation details.
17-20 are the primer claims. Independent claim 17 is
representative and recites:
17. A primer having 14-50 nucleotides that hybridizes under
hybridizing conditions to an M. tuberculosis rpoB [gene] at a
site comprising at least one position-specific M.
tuberculosis signature nucleotide selected, with reference to
FIG. 3 (SEQ ID NO: 1), from the group consisting of [the same
11 nucleotides at the positions disclosed in claim 1].
Id. col. 28 ll. 14-31. Dependent claims 18-20 each
add further limitations.Id. col. 28 ll. 32-46.
Dependent claim 20, for example, discloses full DNA sequences