Ex Parte Harbeck et al

Patent Trial and Appeal Board

Jan 31, 2018

10504287 (P.T.A.B. Jan. 31, 2018)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
10/504,287 06/28/2005 Nadia Harbeck 10011/002631-US2 6831
76808 7590 02/02/2018
T ,p.asnn F.llis FT P
EXAMINER
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte NADIA HARBECK, MANFRED SCHMITT,
JOHN FOEKENS, and RONALD ERNEST KATES1
Appeal 2016-007051
Application 10/504,287
Technology Center 1600
Before ULRIKE W. JENKS, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims directed
to a method of evaluating treatment protocols for breast cancer patients. The
Examiner rejects the claims as directed to patent ineligible subject matter,
indefiniteness, anticipation, and obviousness. We have jurisdiction under
35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellants, the Real Party in Interest is Sekisui Diagnostics,
LLC. Appeal Br. 3.
Appeal 2016-007051
Application 10/504,287
STATEMENT OF THE CASE
Claims 54—57, 65—67, 69, 112—114, and 121—154 are on appeal, and
can be found in the Claims Appendix of the Appeal Brief. Claim 54 is
representative of the claims on appeal, and reads as follows:
54. A method for determining whether to administer an
aggressive treatment or non-aggressive treatment having the
highest demonstrated overall survival to a subpopulation of
patient with primary breast cancer, said patient having primary
tumor tissue, said method comprising:
(a) measuring the level of uPA [(urokinase plasminogen
activator)] and the level of PAI-1 [(plasminogen activator
inhibitor -1)] in said primary tumor tissue or a sample of said
primary tumor tissue of said patient;
(b) classifying said patient as low risk if the level of uPA
is lower than a uPA cut-off value of at least the 55th percentile
and at most the 75th percentile of normalized or analogous uPA
levels in a randomized population of breast cancer patients and
the level of PAI-1 is lower than a cut-off value of at least the
61st percentile and at most the 81st percentile of normalized or
analogous PAI-1 levels in a randomized population of breast
cancer patients, or as high risk if either the level of uPA is
higher than the uPA cut-off value or the level of PAI-1 is higher
than the PAI-1 cut-off value;
(c) if said patient is classified as low risk in step (b),
administering an aggressive treatment regimen if said
aggressive treatment results in a higher expected benefit than
non-aggressive treatment in a comparable population of low
risk breast cancer patients; and
(d) if said patient is classified as high risk in step (b),
administering a non-aggressive treatment regimen if said non-
aggressive treatment results in a higher expected benefit than
aggressive treatment in a comparable population of high risk
breast cancer patients.
Appeal Br. 29-30 (Claims Appendix).
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Appellants request review of the following grounds of rejection made
by the Examiner:
I claims 54—57, 65—67, 69, 112—114, and 121—154 under 35 U.S.C.
§ 101, as being directed to patent ineligible subject matter;
II. claims 54—57, 65—67, 69, 112—114, and 121—154 under pre-AIA
35 U.S.C. § 112, second paragraph, as being indefinite;
III claims 54, 56, 57, 65—67, 69, 139-146, 152, and 153 under pre-AIA
35 U.S.C. § 102(b) as being anticipated by Janicke;2
IV. claims 54—57, 65—67, 69, 139—146, 152, and 153 under pre-AIA
35 U.S.C. § 103(a) as unpatentable over Foekens3 in view Janicke;
V. claims 54—57, 65—67, 69, 121—146, 152, and 153 under pre-AIA
35 U.S.C. §103(a) as unpatentable over Foekens in view Janicke and
further in view of Bastholm4 and Dublin;5 and
VI. claims 54—57, 65—67, 69, 139—146, 152, and 153 under pre-AIA
35 U.S.C. §103(a) as unpatentable over Harbeck6 in view Janicke;
2 Janicke et al., Randomized Adjuvant Chemotherapy Trial in High-Risk,
Lymph Node-Negative Breast Cancer Patients Identified by Urokinase-Type
Plasminogen Activator and Plasminogen Activator Inhibitor Type 1, 93 J.
Nat’l Cancer Inst. 913-920 (2001)(“Janicke”).
3 Foekens et al., The Urokinase System of Plasminogen Activation and
Prognosis in 2780 Breast Cancer Patients, 60 Cancer Research Res. 636—
647 (2000)(“Foekens”).
4 Bastholm et al., Confocal fluorescence microscopy of urokinase
plasminogen activator receptor and cathepsin Din human MDA-MB-231
breast cancer cells migrating in reconstituted basement membrane, 69
Biotech Histochem 61—7 (1994)(“Bastholm”).
5 Dublin et al., Immunohistochemical Expression of uPA, uPAR, andPAl-1
in Breast Carcinoma, Fibroblastic Expression Has Strong Associations with
Tumor Pathology, 157 Am. J. Pathology 1219-1227 (2000)(“Dublin”).
6 Harbeck et al., Risk-group discrimination in node-negative breast cancer
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VII. claims 54—57, 65—67, 69, 112—114, and 121—154 under pre-AIA
35 U.S.C. § 103(a) as unpatentable over Harbeck in view Bastholm
and Dublin.
I Patent Ineligible Subject Matter
To determine whether a claim is invalid under § 101, we employ the
two-step Alice framework. In step one, we ask whether the claims are
directed to a patent ineligible concept, such as an abstract idea, natural
phenomena, or law of nature. Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347,
2350, (2014); Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566
U.S. 66, 75—77 (2012); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d
1371, 1375 (Fed. Cir. 2015). In step two, we examine the elements of the
claims to determine whether they contain an inventive concept sufficient to
transform the claimed naturally occurring phenomena into a patent-eligible
invention. Alice, 134 S.Ct. at 2350; Mayo, 566 U.S. at 75—77. While
method claims, as we have here, are generally eligible subject matter,
method claims that are directed only to natural phenomena are directed to a
patent ineligible concept. Ariosa, 788 F.3d at 1376.
Alice Step One
Claim 54 of the instant application is directed to a method for
determining whether to provide aggressive or non-aggressive treatment to a
patient with primary breast cancer based on the level of uPA and PAI-1
found in the tumor tissue of the patient. The process involves measuring the
level of uPA and PAI-1 in the sample and classifying the sample by
using invasion and proliferation markers: 6-year median follow-up, 80 Brit.
J. Cancer 419-426 (1999)(“Harbeck”).
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assigning a value based on where the particular sample sits in comparison to
a randomized population. That process is directed to both a law of nature
and an abstract idea. In particular, the law of nature/natural phenomenon is
the level of uP A and PAI-1 in the tumor tissue of the patient that classifies a
patient’s risk factor. See Ans. 3. These compounds naturally occur in
primary breast cancer tumor tissue. The relation between levels of uPA and
PAI-1 is a consequence of the tumor etiology — a natural process. See Ans. 3
(“The ‘natural phenomenon’ is: levels of uPA and PAI-1 classify breast
cancer patients as high-risk or low-risk” (emphasis removed)); see Mayo,
566 U.S. at 77 (“The relation is a consequence of the ways in which
thiopurine compounds are metabolized by the body—entirely natural
processes”).
In addition, the recited steps of measuring and classifying are steps
that involve categorizing and/or analyzing information. All that is achieved
by these process steps is that they measure a relationship between two
concentration levels of enzymes in the tumor tissue, namely the levels of
uPA and PAI-1, and this relationship is a patent-ineligible abstract idea. Our
reviewing Court has explained that “[information as such is an intangible”
and “that collecting information, including when limited to particular
content (which does not change its character as information),” analyzing it,
and presenting the results of the collection and analysis without more are
patent ineligible abstract concepts. See, e.g., Electric Power Group, LLC v.
Alstom S.A., 830 F.3d 1350, 1353—54 (Fed. Cir. 2016). Because the claims
are directed to an abstract idea/natural law, we turn to the second step of the
Alice framework.
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Alice Step Two
In Alice step two, we examine the elements of the claims to determine
whether they contain an inventive concept sufficient to transform the
claimed naturally occurring phenomena into a patent-eligible application.
Alice, 134 S.Ct. at 2350 (quoting Mayo, 566 U.S. at 71—72). We must
consider the elements of the claims both individually and as an ordered
combination to determine whether additional elements transform the nature
of the claims into a patent-eligible concept. Ariosa, 788 F.3d at 1375.
The Examiner explains:
[The rjecited active steps of the claims impose no meaningful
limit on the scope of the natural phenomenon, implicate a
relevant pre-existing audience (see Janicke et al (JNCI, 2001,
93: 913-920), in particular), and are recited at a high level of
generality such that substantially all routine methods of
measuring levels of uPA and PAI-1 in breast cancer tissue to
determine prognosis and/or predict treatment response followed
by administering a treatment (or not administering a treatment)
would conventionally and routinely perform such steps.
Ans. 3. We agree with the Examiner’s findings.
Claim 54 broadly covers any treatment based on the law of nature:
either an aggressive treatment or a non-aggressive treatment. In other
words, the treatment step tells doctors to engage in well-understood activity.
The Supreme Court in Mayo explained with respect to a method for
measuring metabolites in the bloodstream in order to calibrate the
appropriate dosage of thiopurine drugs in the treatment of autoimmune
diseases that “[sjimply appending conventional steps, specified at a high
level of generality,” was not enough to supply an inventive concept. Mayo,
566 U.S. at 82.
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The method starts and ends with naturally occurring phenomena with
no meaningful non-routine steps in between. The claim does not recite any
new laboratory technique for detecting the relationship of uPA, PAI-1 and
the patient’s level of risk. The steps of measuring, classifying, and applying
treatment to one group of patients over another group is found in the prior
art. See Janicke, 918, Fig. 3 (showing that applying standard chemotherapy
program to high risk patients improves survival). The additional step recited
in the claim “such as administering (or not administering) a treatment ‘if’
said treatment somehow results (or does not result) in an expected benefit
impose no meaningful limit on the performance of the claimed invention
because the claims do not recite under which circumstances which treatment
results (or does not result) in an expected benefit.” Ans. 3^4.
We conclude that the practice of the method claims does not result in
an inventive concept that transforms the abstract idea/natural phenomena of
obtaining levels of uPA and PAI-1 in breast cancer tissue. Mayo and Ariosa
make clear that transforming claims that are directed to a law of nature
requires more than simply stating the law of nature while adding the words
“apply it.” Mayo, 566 U.S. at 72; Ariosa, 788 F.3d at 1377.
In Ariosa, the challenged claims involved a method that was a general
instruction to doctors to apply routine, conventional techniques when
seeking to detect paternally inherited cell-free fetal DNA in the blood serum
of a pregnant woman. Ariosa, 788 F.3d at 1377. The same is generally true
here. The claims contain steps that require measuring uPA and PAI-1 levels
in a tumor tissue sample, and based on those levels determining what
treatment protocol to apply. Appellants cannot purport to have invented
measuring the uPA and PAI-1 levels (see Spec. 6 and 78, ELISA assay) or
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sorting the patients based on these values into high and low risk groups for
determining disease free survival. See Spec. 78; see Janicke; see Foeken;
see Dublin, see Harbeck. No specific element is identified as inventive in
the Specification.
In Cleveland Clinic, the claims were directed to a multistep method
for observing the myeloperoxidase (MPO) activity and correlating it to
cardiovascular disease. Cleveland Clinic Foundation v. True Health
Diagnostics LLC, 859 F.3d 1352, 1362 (Fed. Cir. 2017). Cleveland Clinic
did not invent the methods of detecting MPO nor did they “derive new
statistical methods to arrive at the predetermined or control levels of MPO
that would indicate a patient’s risk of cardiovascular disease.” Id. at 1362.
As in Cleveland Clinic, the claims here identify risk groups based on uPA
and PAI-1 levels using conventional methods and “compare those values to
predetermined or control values derived from conventional statistical
methods.” Id. The claims as a whole do not sufficiently transform the
natural existence of uPA and PAI-1 levels in a tumor tissue sample and their
correlation with survival risk levels into a patentable invention.
We also find unpersuasive, Appellants’ contention that because the
evaluating step implements a specific method using “these markers in the
present case is not to identify breast cancer patients generally, but to identify
a specific subpopulation of breast cancer patients suitable for treatment of
recurrence of the cancer not appreciated in the art.” Appeal Br. 9. As
already discussed, these steps are routine and conventional. Furthermore,
the subpopulation is identified as simply that group of patients that have
either low risk based on these measured factors but that would nevertheless
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benefit from receiving aggressive treatment just like the high risk patient
group benefits from aggressive treatment.
The Examiner explains that,
[b]y taking other factors (in addition to uPA and PAI-1 levels)
into consideration wherein said other factors are predictive of
response to various treatments, it would be considered
conventional and routine in the art to administer (or not
administer) aggressive treatment to patients having uPA and
PAI-1 levels below cutoff values and not administer (or
administer) aggressive treatment to patients having uPA and
PAI-1 levels above cut-off values based on said other factors.
Ans. 20. The position that other factors can be considered when placing
patients into high and low risk groups is also supported in the art. See
Harbeck.
Appellants contend that in addition to measuring the level of uPA and
the level of PAI-1 in the primary tumor tissue the present claims provide a
“specific treatment regimen (steps c and d) based on the results of the cancer
classification in step b (the alleged ‘natural phenomenon’). . . . [Tjhese
additional steps amount to more than simply diagnosing (here, ‘classifying’)
the patient, and ‘instructing a doctor to generically ‘treat it’.’” Reply Br. 6
(citing USPTO Example 29, Claim 6, page 15).
We are not persuaded. The USPTO guidance makes clear that claim 6
of Example 29, relied on by Appellants in their arguments, “is eligible
because it recites additional limitations that when considered as a
combination are a meaningful way of applying the exception that is more
than a mere instruction to ‘apply’ the exception.” See USPTO Subject
Matter Eligibility Examples- Life Sciences p. 15. In the USPTO example,
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the specificity of the treatment was not itself sufficient to render the claims
patent eligible. Id. (
This claim further recites an additional element of
administering an effective amount of anti-TNF antibodies to the
diagnosed patient (step d). Prior to applicant’s invention, and at
the time the application was filed, however, administering these
antibodies to treat a patient diagnosed with julitis was well-
understood, routine and conventional activity engaged in by
doctors in the field. Further, it is well established that the mere
physical or tangible nature of additional elements such as the
obtaining, detecting, and administering steps does not
automatically confer eligibility on a claim directed to an
exception (see, e.g., Alice Corp., 134 S.Ct. at 2358-59).)
It is the detection of JUL-1 in the plasma sample to determine if a patient has
Julitis, a process which, though carried out by conventional methods, was
not previously known in the prior art, in combination with the use of “anti-
TNF antibodies” for treatment of JUL-1, i.e., “steps a, b and d,” “that adds
meaningful limits on the use of the exception” and makes the treatment in
the JUL-1 identified population patent eligible. Id. 9—11, 15. This is not the
case with respect to the present claims because the claims do not recite using
a previously unknown method of measuring uPA and PAI-1 in primary
tumor tissue in order to classify patients who are then provided with a
known “specific” treatment. Not only is the measuring method recited at a
high level of generality, the treatment is not even “specific.” For example
claim 54 recites “(d) if said patient is classified as high risk in step (b),
administering a non-aggressive treatment regimen if said non-aggressive
treatment results in a higher expected benefit than aggressive treatment in a
comparable population of high risk breast cancer patients.” The
Specification, however, does not specify which “high risk” patients benefit
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from non-aggressive treatment as compared to other treatments. Indeed, the
Specification lists “adjuvant endocrine therapy” such as “anti-estrogens,
aromatase inhibitors, gestagens” as both aggressive and non-aggressive
treatments. See Spec. 7. With the same treatments parameters described as
both aggressive and non-aggressive at the same time in the Specification, the
treatment protocols using these therapies is thereby not specific. Because no
specific treatment protocol is applied to an identified population the claims
do not even recite a meaningful way of applying the patent ineligible
concept.
Following Supreme Court and Federal Circuit precedent we are
constrained to conclude that all of the claims on appeal are directed to patent
ineligible subject matter. We therefore affirm the Examiner’s rejection of
the claims under 35 U.S.C. § 101, as being directed to patent ineligible
subject matter.
II. Indefiniteness
The Examiner rejects claims 54—57, 65—67, 69, 112—114, and
121—154 as indefinite because “[t]he claims do not distinctly point-out the
metes and-bounds of the claims’ cut-off values.” Ans. 4—5; Final Act. 3.
The Examiner rejects claims 54—57, 121—126, 139-142, and 152 as
indefinite because the claims do not specify under what conditions a
particular treatment regime would result in the “highest expected benefit.”
Ans. 5—7; Final Act. 5.
The Examiner rejects claims 65—67, 69, 127—132, 143—146, and 153
as indefinite because the claims do not specify under what conditions a
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particular adjuvant treatment regime would result in the “highest expected
benefit.” Ans. 7—8; Final Act. 7.
The Examiner rejects claims 112—114, 133—138, 147—151, and 154 as
indefinite because the claims do not specify under what conditions a
particular aggressive or non-aggressive treatment regime would result in the
“highest expected benefit.” Ans. 8—9; Final Act. 7.
Findings of Fact
FF1. The Specification provides that “[hjigh risk subjects are
identified by high levels of both uPA and PAI-1, a high level of
uPA and a low level of PAI-1, or a low level of uPA and a high
level of PAI-1 as determined by cut-off values for these
indicators.” Spec. 5. “Conversely, a low level of uPA and a
low level of PAI-1 correspond to levels that are lower than the
cut-off value set for the indicator. A patient is classified as low
risk if both the uPA and PAI-1 levels are low, i.e., below the
cut-off value.” Spec. 28.
FF2. The Specification provides that mRNA levels can be measured by any
means but RT-PCR is the preferred amplification. Spec. 5. “[A] high
level of uPA or mRNA encoding uPA corresponds to levels above a
cut-off value of at least about the 55th percentile and no more than
about the 75th percentile of normalized (i.e., adjusted for differences
in measured values due to differences in assay methods) uPA levels or
levels of mRNA encoding uPA for a randomized group of patients
using any assay.” Spec. 6.
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FF3. The Specification provides if evaluating protein levels by ELISA “a
high level of uPA is defined as above a cut-off value of at least about
2.4 ng uPA/mg protein and no more than about 4 ng uPA/mg protein.”
Spec. 6. “[A] high level of PAI-1 is defined as above a cut-off value
of at least about 11 ng/mg protein and no more than about 19 ng PAI-
1/mg protein.” Spec. 6.
Cut-Off Values of Percentiles
The Examiner rejects claims 54—57, 65—67, 69, 112—114, and
121—154 as indefinite because “[t]he claims do not distinctly point-out the
metes and-bounds of the claims’ cut-off values.” Final Act. 3. “While
calculations can be performed in the art to determine the percentile of where
a particular patient falls in a population, the claims are defined by absolute
cut-off values that vary depending [on] specific subjects used to determine
the cut-off values and therefore it is unclear what would or would not be
considered ‘at least the 55th percentile and at most the 75th percentile ... at
least the 61st percentile and at most the 81st percentile.’” Final Act. 4.
According to the Examiner, “the claims do not distinctly point-out whether
cut-off values of 14 ng/ml and 3 ng/ml (taught in prior art cited below)
infringe on the claims if patented.” Ans. 5.
Appellants contend that “the percentile is measured within a
randomized population of breast cancer patients. There is no requirement
for the claims to recite absolute ng/mg values as cut-off values.” Appeal
Br. 10. “[A]ll that is required is routine calculation to determine the
percentile of where a particular patient falls in the population.” Appeal Br.
10.
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The percentage cut off values are best illustrated by Appellants figure
as shown in the Appeal Brief.
m
75%
High £
ftisk j
\
]----- ^
j Law
m?x
81%
n%
See Appeal Br. 4. This figure is a graphical depiction of high risk and low
risk ranges for uPa and PAI-1. In this figure two percentile values are
depicted for uPA, 55% and 75% and two percentile values for PAI-1 are
depicted, 61% and 81%. Low risk boundary for uPA is anything below
75%, while high risk boundary is anything above 55%. This is consistent
with the claim language that defines the uPA cut-off for low risk as being at
least 55% and at most 75% and high risk as being a level of uPA higher than
the uPA cut-off value. In other words high risk for uPA can be above 55%.
The problem is that for uPA levels there is a band between 55—75% that is
identified in the claim as being both high and low risk at the same time. The
percent values set out for PAI-1 has the same issue in that there is a band
Highf
«
< Low
* &5X
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that is identified in the claims as meeting both high and low risk values at
the same time. Thus, whether these percentages are presented as measured
values in, for example, ng/mg based on a particular assay type (e.g. ELISA),
or some other value based on another assay, we agree with the Examiner that
“the meets-and-bounds” of the claims are nebulously defined. Ans. 4—5.
Because values between 55—75% for uPA as claimed can be both low risk or
high risk, an ordinary artisan would not know into which category to place a
patient that falls into this band and thereby would not be able to assess what
treatment protocol to administer. A similar problem arises with the PAI-1
levels as recited in the claims.
Appellants contend that “[tjhere is no requirement for the claims to
recite absolute ng/mg values as cut-off values. In a population of
randomized population of breast cancer patients, all that is required is
routine calculation to determine the percentile of where a particular patient
falls in the population.” Appeal Br. 10. In other words, Appellants’position
is that anyone practicing this method should evaluate their own cohort of
breast cancer patients using their own methods to then determine where a
particular patient’s uPA and PAI-1 levels fall in the larger population of
breast cancer patients.
We are not persuaded by Appellants’ contentions. In Forest
Laboratories, the claims were directed to a pharmaceutical composition that
required a particular dissolution profile. Forest Labs., Inc. v. leva Pharms.
USA, Inc. (non-precedential) 2017 WL 6311688 (Dec. 11, 2017). One of
ordinary skill in the art would understand that “different human
pharmacokinetic studies produce widely varying concentration profiles for
particular formulations.” Id. at 5. Neither the specification nor the claims in
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Forest tied the dissolution profile to a particular study design. As explained
in Forest:
In these circumstances, the district court’s indefiniteness ruling
is supported by precedents that hold claims indefinite in
particular circumstances where the claims require measured
quantities (absolute or relative), different techniques for such
measurements are known in the art and some produce
infringing results and others not, the intrinsic evidence does not
adequately specify the technique or techniques to use, and
extrinsic evidence does not show that a relevant skilled artisan
would know what technique or techniques to
use. See, e.g., Dow Chem. Co. v. Nova Chems. Corp. (Canada),
803 F.3d 620, 633-35 (Fed. Cir.), reh’g denied, 809 F.3d 1223
(Fed. Cir. 2015); HoneywellInt7, Inc. v. Int’l Trade Comm’n,
341 F.3d 1332, 1339-A2 (Fed. Cir. 2003).
Id.
The examples and tables presented in the Specification rely on
collected data from numerous patients. See Spec. 72—74, (table 3 listing
results from 761 patients). We understand that claiming cut off values in
percentages would allow for the application of later discovered measuring
technologies; however, the problem with using percentage cut off values of
“normalized or analogous uPA (PAI-1) levels in a randomized population”
is that the size of the population can have a significant effect upon where the
normalized (or analogous) level lies in the spectrum of interest. Similar to
Forest, the Specification does not require a particular test (or study design)
in order to derive the values required in the claim, nor does the Specification
establish the requisite size of the randomized population. For example, a
population of 2 or 10 patients would meet the claimed requirements. But
calculating averages from such small numbers will not necessarily represent
a larger population of, e.g., 100, 1000, or more patients. Because there is no
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limitation on the size of the randomized population set out in the
Specification the percentage cut off can be arbitrarily high or low and
thereby we agree with the Examiner’s conclusion that the claims are not
clear.
On this record we agree with the Examiner that the claims do not
sufficiently establish the meets and bounds of what is encompassed by high
or low risk based on a “percentage cut off value” as claimed. Accordingly,
we affirm the Examiner’s rejection that these claims are indefinite.
Expected Benefit
The Examiner rejects claims 54—57, 121—126, 139-142, and 152 as
indefinite because the claims do not specify under what conditions a
particular treatment regime would result in a “higher expected benefit.”
Ans. 5—7; Final Act. 5—7. Similar rejections are made by the Examiner for
claims 65-67, 69, 112-114, 127-138, 143-151, 153, and 154. See Ans. 7-9;
Final Act. 7—9.
Appellants contend that “the expected benefit of the aggressive and
nonaggressive treatments is measured within a population of a randomized
population of breast cancer patients. One of skill in the art would
understand the meaning of the expected benefit of a treatment as measured
via average or means in a particular patient population.” Appeal Br. 11.
Figure 4 of the Specification, reproduced below, shows the different
survival curves for patient groups depending on their uPA and PAI-1 status.
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FIG. 4, reproduced above, is a line graph that shows the “[prognostic
impact of the four different combinations of uP A and P AI-1 on disease-free
survival (DFS) in node-negative breast cancer (no adjuvant systemic
therapy).” Spec. 25.
We understand that the purpose of the claimed method is to only
administer medicine to a patient population (and in a way) in which the
medicine will be effective — because if the medicine is not effective there is
no point in administering medicine to the patient. However, the problem
here is that neither the claims nor the Specification provide information that
establishes under which circumstances specific treatment protocols will
provide a “higher expected benefit” to the patient.
Section 112(b) requires the Specification to “conclude with one or
more claims particularly pointing out and distinctly claiming the subject
matter which the inventor or a joint inventor regards as the invention.” As
our reviewing court has explained, § 112(b) requires the claims “to be cast in
clear—as opposed to ambiguous, vague, indefinite—terms.” In re Packard,
751 F.3d 1307, 1313 (Fed. Cir. 2014). The rationale for requiring such
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“reasonable precision” in claim language is because “[i]t is the claims that
notify the public of what is within the protections of the patent, and what is
not.” Id.; see Ex parte McAward, Appeal No. 2015-006416 at 4—12
(precedential)(PTAB Aug. 25 2017)(discussing standard of indefmiteness
applied in proceedings at PTO). The claims, here, are not clear because at
best they describe a general desire to achieve a particular result but do not
provide the ordinary artisan the instructions on how to implement a strategy
to achieve said result.
In Dow, the claims recited a “slope strain hardening coefficient” and
were held to be indefinite. Dow Chem. Co. v. Nova Chems. Corp., 803 F.3d
620, 631 (Fed. Cir. 2015). There were four known methods to determine a
slope strain hardening coefficient, and there was “no question that each of
these four methods may produce different results, i.e., a different slope.” Id.
at 633. “Neither the patent claims nor the specification here discusses the
four methods or provides any guidance as to which method should be used
or even whether the possible universe of methods is limited to these four
methods.” Id. at 634. This is similar to the situation we have here, neither
the Specification nor the claims
specifically point-out (i) under which circumstances an
aggressive treatment regimen for low risk patients results in a
higher expected benefit than non-aggressive treatment in a
comparable population of low risk breast cancer patients and
(ii) under which circumstances a non-aggressive treatment
regimen for high risk breast cancer patients results in a higher
expected benefit than aggressive treatment in a comparable
population of high risk breast cancer patients.
Ans. 25. This uncertainty is further compounded because the Specification
lists several treatments as being both aggressive and non-aggressive
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treatments. For example anti-estrogens (e.g., tamoxifen therapy), aromatase
inhibitors, gestagens are described in the Specification as being both
aggressive and non-aggressive treatments. See below FF5 & FF6.
Another problem with the claims is that there are three groups of
patients contemplated: those that fall (1) above the lowest cut off, or (2)
below the highest cut off value, and (3) those that are both above the lower
cut off value and below the upper cut off value for either uPA or P AI-1.
Again, neither the claims nor the Specification provide guidance on when to
apply a particular treatment protocol to achieve the “higher expected
benefit” that is claimed. Thereby the claims do not notify the public with
reasonable precision what falls within the scope of the claim. See Packard,
751 F.3d at 1313; see Ex Parte McAward, Appeal No. 2015-006416 at 11.
Based on this record, we agree with the Examiner that the claims do
not sufficiently establish the meets and bounds of what is encompassed by
“a higher expected benefit” as claimed. Accordingly, we affirm the
Examiner’s rejection that these claims relying on this limitation are
indefinite.
III. Anticipation by Janicke
The Examiner finds that Janicke teaches measuring uPA and PAI-1
levels to classify patients into high and low risk groups and then apply
treatment therapies. See Final Act. 11; see Ans. 9-10. As disused above in
the indefmiteness rejection {see II.) claiming percentile values is flexible
because “[depending on the ‘randomized population’ used to determine
cutoff values, percentiles of [these] various values would” change. Final
Act. 11; Ans. 10. In other words, depending on the size of the group tested
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the cut off values as measured by RNA or protein levels will vary depending
on the size of the group tested. The larger the group tested, the more
accurate the cut off level is expected to reflect the population.
Appellants do not contest that “Janicke’s teaching is simple: if a
patient is above the cut-off value, aggressive treatment is administered and if
a patient is below the cut-off value, non-aggressive treatment or no treatment
is administered.” Appeal Br. 14. Appellants contend that their claims are
more sophisticated and flexible than the regimen taught in Janicke. Id.
The issue is: Does the preponderance of evidence of record support
the Examiner’s position that Janicke anticipates the claims by establishing
that certain treatments provide “a higher expected benefit” to a particular
patient population?
Findings of Fact
FF4. The Specification provides that “[h]igh level uPA is defined as above
3ng uPA/mg protein in primary tumor tissue extracts measured by
EFISA. High level PAI-1 is defined as above 14ng PAI-l/mg
protein.” Spec. 64. When measured by
EFISA, a high level of uPA is defined as above a cut-off
value of at least about 2.4 ng uPA/mg protein and no
more than about 4 ng uPA/mg protein. In specific
embodiments, a high level of uPA is defined as above a
cut-off value of at least about 2.6, 2.8, 3.0, 3.2, 3.2, 3.4,
3.6, or 3.8 ng uPA/mg protein. In a preferred
embodiment, a high level of uPA is defined as above a
cutoff value of at least about 3 ng uPA/mg protein. In a
specific embodiment, a high level of PAI-1 is defined as
above a cut-off value of at least about 11 ng/mg protein
and no more than about 19 ng PAI-1/mg protein.
Spec. 6; see Final Act. 12—13.
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FF5. The Specification provides:
Non-aggressive post-surgery treatment regimens
are treatment regimens that have less significant side-
effects. These treatment regimens may include, but are
not limited to, non-treatment, radiation therapy and
adjuvant endocrine therapy, such as, anti-estrogens (e.g.,
tamoxifen therapy), aromatase inhibitors, gestagens,
immunotherapy, and tumorbiological therapy, e.g.
HERCEPTIN®, anti-uPA therapies, including anti-uPA
and anti-PAI- 1 monoclonal antibodies, and uPA (and
uPA receptor) and PAI-1 peptides and small molecule
inhibitors.
Spec. 7.
FF6. The Specification provides:
Aggressive post-surgery treatment regimens are
treatment regimens that have significant side-effects.
These treatment regimens may include, but are not
limited to, chemotherapy, adjuvant chemotherapy,
adjuvant CMF chemotherapy, adjuvant non-CMF
chemotherapy, adjuvant anthracyclin-containing
chemotherapy, and adjuvant taxane-containing
chemotherapy, and may include adjuvant endocrine
therapy, including for example, anti-estrogens, aromatase
inhibitors, gestagens, and also includes radiation therapy,
or gene therapy. Although these treatment regimens are
usually selected for high risk patients, certain aggressive
treatments may be very effective even in low risk
patients.
Spec. 7.
FF7. Janicke teaches that “levels of urokinase-type plasminogen activator
(uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the
primary tumor are predictive of disease recurrence.” Janicke
Abstract. “Patients with high levels of uPA and/or PAI-1 in their
primary tumors, determined by enzyme linked immunosorbent assay
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(ELISA), had statistically significant shorter disease-free survival
(DFS) and overall survival rates than patients with low tumor levels.”
Janicke 913.
FF8. Janicke teaches that “[ujsing uPA and PAI-1,... to classify about half
of the patients with lymph node-negative breast cancer as low risk, for
whom adjuvant chemotherapy may be avoided, and half as high risk,
who appear to benefit from adjuvant chemotherapy.” Janicke
Abstract. “The cutoff for uPA was 3 ng/mg of protein, and the cutoff
for PAI-1 was 14 ng/mg of protein. High-risk patients with lymph
node-negative breast cancer (uPA levels >3 ng/mg of protein and/or
PAI-1 levels >14 ng/mg of protein).” Id. at 914. “[Hjigh risk
patients, defined by high tumor levels of uPA and/or PAI-1, appear to
benefit from adjuvant chemotherapy.” Id. at 919.
FF9. Janicke teaches testing 374 patients for uPA and PAI-1 levels and
assigning them into various groups. “The benefit of adjuvant CMF in
the high-risk group was assessed as DFS in the following two
populations: The intention-to-treat population contained 182 patients.
(study arm B1 orB2; . . .).” Id. 914—915
High-risk patients with lymph node-negative breast
cancer (uPA levels >3 ng/mg of protein and/or PAI-1
levels >14 ng/mg of protein) were randomly assigned
either to six courses of CMF (study arm B1 [(a standard
chemotherapy regimen (CMF) was selected for systemic
adjuvant treatment)]) or to observation only (study arm
B2). High-risk patients who refused randomization were
followed-up and analyzed separately (study arm B3).
Patients with low tumor levels of uPA and PAI-1 (uPA
levels < 3 ng/mg of protein and PAI-1 levels <14 ng/mg
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of protein) did not receive systemic adjuvant therapy but
received observation only (study arm A).
Id. 915, see Fig. IB.
Analysis
Appellants contend “that the percentile cut-off values of a
randomized population of breast cancer patients in the claims under appeal is
not the same as the absolute unit measurement in ng/mg cut-off values of a
node-negative breast cancer patients as taught in Janicke. For this reason
alone, Janicke does not anticipate the claims under appeal.” Appeal Br.
12-13.
Anticipation requires a showing that each limitation of a claim is
found in a single reference, either expressly or inherently. Perricone v.
Medicis Pharm. Corp., 432 F.3d 1368, 1369 (Fed.Cir.2005). Disclosure of a
species will anticipate a genus. See Titanium Metals Corp. of America v.
Banner, 778 F.2d 775, 782 (1985), citing In re Petering, 301 F.2d 676, 682,
(1962).
In order to compare the disclosure in Janicke with the claims, the
Examiner reasonably consulted the Specification to determine if the values
disclosed in Janicke’s reference fall within the scope of the claim. See FF4.
In other words, Janicke presents cut off values as measured in ng/mg of
protein to place patients into high and low risk groups after measuring the
protein levels of uPA and PAI-1 in their tumor tissue. FF7 and FF8. Here
the cut off value(s) as measured by ELISA in Janicke is/are the same as the
value(s) disclosed in the Specification as being high risk or low risk.
Compare FF8 (“High-risk patients with lymph node-negative breast cancer
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(uPA levels >3 ng/mg of protein and/or PAI-1 levels >14 ng/mg of
protein)”) with FF1 (“[h]igh level uPA is defined as above 3ng uPA/mg
protein in primary tumor tissue extracts measured by ELISA. High level
PAI- 1 is defined as above 14ng PAI-l/mg protein”). Here, the Examiner
has established that the measured ng/mg protein level is equivalent to the
claimed percentage value. Thus, we are not persuaded by Appellants’
contention that Janicke’s absolute unit measurement cut-off values do not
meet the percentage cut off values as claimed.
Janicke sorts patients into high and low risk groups. “The cutoff for
uPA was 3 ng/mg of protein [in Janicke], and the cutoff for PAI-1 was 14
ng/mg of protein. High-risk patients with lymph node-negative breast
cancer (uPA levels >3 ng/mg of protein and/or PAI-1 levels >14 ng/mg of
protein).” FF8. Janicke teaches that high risk patients are sorted into two
treatment groups, those that receive six courses of chemotherapy and those
that received no treatment. FF9 (“high risk patients in “study arm B1 [(a
standard chemotherapy regimen (CMF) was selected for systemic adjuvant
treatment)] or to observation only (study arm B2)”). The Specification
defines that non-aggressive treatment includes “non-treatment.” FF5.
Thus, Janicke teaches administering either aggressive treatment or
non-treatment therapy to high risk patients, but does not disclose
administering aggressive treatment to low risk patients. FF9 (“Patients with
low tumor levels of uPA and PAI-1 (uPA levels < 3 ng/mg of protein and
PAI-1 levels <14 ng/mg of protein) did not receive systemic adjuvant
therapy but received observation only (study arm A)”). In Janicke, the
administration of non-treatment to the high risk patients resulted in a higher
probability of recurrent disease and, therefore, this treatment protocol would
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not meet a “higher expected benefit” limitation required by claim 54. See
Janicke 918, Fig. 3.
Applying “adjuvant chemotherapy for these low-risk patients
[identified by Janicke] may be overtreatment, [only] high risk patients,
defined by high tumor levels of uPA and/or PAI-1, appear to benefit from
adjuvant chemotherapy.” Janicke 919. At best Janicke suggests that
applying therapy to the low risk patient group may be overtreatment and is
not shown to be beneficial because there is no net survival gain by this
treatment protocol. Thus, administering aggressive treatment to the low risk
patient population does not result in a higher expected benefit as required by
the claim.
Because Janicke does not meet the limitations as recited in either step
(c) or (d) of claim 54 we reverse this rejection that relies on Janicke for
teaching these limitations. See Perricone, 432 F.3d at 1369.
Accordingly, we revere the rejection of claim 54 and any dependents
as anticipated by Janicke.
III.—V. Obviousness over Foekens and Janicke
The Examiner rejected claims 54—57, 65—67, 69, 139-146, 152, and
153 under pre-AIA 35 U.S.C. § 103(a) as unpatentable over Foekens in view
Janicke; and additionally rejected 121—138 under pre-AIA 35 U.S.C.
§103 (a) as unpatentable over Foekens, Janicke, and further in view of
Bastholm and Dublin. Because both of these rejections rely on the
combination of Foekens and Janicke we will discuss these rejections
together.
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The Examiner finds that “Janicke et al teaches patients with levels of
uPA and PAI-1 above the cut-off values are to be treated with adjuvant
chemotherapy and patients with levels of uPA and PAI-1 below the cut-off
values should avoid adjuvant chemotherapy.” Ans. 12—13. The Examiner
finds that Foekens “further teaches said patient as having 0, 1—3, or >3
lymph nodes affected” and having tumor sizes ranging from less than 2 cm
to greater than 5 cm. Ans. 15. The Examiner acknowledges that Foekens
“does not specifically teach when to administer or not administer adjuvant
therapy. However, these deficiencies are made up in the teachings of
Janicke.” Ans. 15. The Examiner concludes that the combined references
teach administering adjuvant chemotherapy therapy to patients having high
uPA and PAI-1 levels and not administering such therapy to patients having
low levels of uPA and PAI-1 levels. See Ans. 15.
Appellants contend that the combination of Foekens and Janicke fails
to teach all recited claim elements. “Janicke does not or suggest selecting a
treatment regimen based on its expected benefit in a comparable population
of breast cancer patients.” Appeal Br. 15. Foekens likewise does not
suggest this type of treatment regime. Appeal Br. 14 (“Examiner explicitly
states that Foekens fails to teach when to administer or not to administer
adjuvant therapy”); Ans. 15.
We find that on this record Appellants have the better position. Even
if we are not entirely clear on what constitutes “higher expected benefits” as
claimed (see above II. Indefinites), we find that neither Janicke nor Foekens
teach administering aggressive treatment to patients that have low levels of
both uPA and PAI-1, indeed Janicke would suggest that such treatment is
overtreatment. “Although adjuvant chemotherapy for these low-risk patients
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may be overtreatment, high risk patients, defined by high tumor levels of
uPA and/or PAI-1, appear to benefit from adjuvant chemotherapy.” Janicke
919. Additionally, the application of non-treatment to high risk patients has
not been shown to be beneficial in these references. The Examiner has not
articulated any other rationale to explain why aggressive treatment in a low
risk patient group would be obvious based on the teachings of the references.
A rejection for obviousness must include “articulated reasoning with some
rational underpinning to support the legal conclusion.” KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441 F.3d 977,
988 (Fed. Cir. 2006)).
As the Examiner has not directed us to adequate support to establish
that the combination of references discloses the limitations of steps (c) or (d)
as recited in claim 54, we reverse each rejection that relies on the
combination of Foekens and Jenicke.
VI. Obviousness over Harbeck and Janicke
The Examiner rejected claims 54—57, 65—67, 69, 139-146, 152, and
153 as unpatentable over Harbeck and Janicke. The Examiner
acknowledges that Harbeck “does not specifically teach when to administer
or not administer adjuvant therapy.” Ans. 15. Nevertheless, the Examiner
finds that based on the combined references it would be obvious to “treat
patients identified by Harbeck . . . with elevated levels of uPA and PAI-1
(high risk group) with adjuvant chemotherapy and not treat patients
identified by Harbeck . . . with low levels of uPA and PAI-1 (low risk
group) with adjuvant chemotherapy because Janicke . . . teaches patients
with elevated levels of uPA and PAI-1 are to be treated with adjuvant
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chemotherapy and patients with low levels of uPA and PAI-1 should avoid
adjuvant chemotherapy.” Ans. 32—33.
Appellants contend that the combination of Harbeck and Janicke fails
to teach all the claim elements recited in claim 54. See Appeal Br. 16.
Specifically, “Harbeck does not teach situations when an aggressive
treatment has a higher expected benefit than non-aggressive treatment in a
comparable population.” Appeal Br. 16.
We find that on this record Appellants have the better position. Even
though we agree with the Examiner that the combined references teach
administering aggressive therapy to high risk patients, the claims require the
alternative, i.e. treatment of the high risk group with non-aggressive therapy
if that is more beneficial. The Examiner has not, however, articulated why,
based on the teachings of these references, it would be obvious to treat high
risk patients with a non-aggressive treatment regime. As the Examiner has
not articulated any rationale explaining how the combination of references
discloses either limitation of steps (c) or (d) as recited in claim 54, we
reverse the rejection that relies on the combination of Harbeck and Jenicke.
VII. Obviousness over Harbeck, Bastholm, and Dublin
According to the Examiner, Harbeck teaches measuring uPA and
PAI-1 levels using ELISA and determining high and low risk patients, but
does not specify when to administer particular therapies and relies on
Bastholm and Dublin to teach these limitations. Ans. 16.
Appellants contend that Harbeck does not teach when to administer
adjuvant therapy and neither does the Bastholm or Dublin. Appeal Br. 17.
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We find that on this record Appellants have the better position. The
Examiner has not articulated why, based on these references teachings, it
would be obvious to treat high risk patients with a non-aggressive treatment
regime. As the Examiner has not articulated any rationale explaining how
the combination of references discloses either limitation of steps (c) or (d) as
recited in claim 54, we reverse the rejection that relies on the combination of
Harbeck, Balstom, and Dublin.
SUMMARY
We affirm the rejection of claims 54—57, 65—67, 69, 112—114, and
121—154 under 35 U.S.C. § 101 as being directed to patent ineligible subject
matter.
We affirm the rejection the rejection of claims 54—57, 65—67, 69, 112—
114, and 121—154 under 35 U.S.C. § 112, second paragraph, as being
indefinite.
We reverse the rejection of claims 54, 56, 57, 65—67, 69, 139-146,
152, and 153 as anticipated by Janicke.
We reverse the rejection of claims 54—57, 65—67, 69, 139-146, 152,
and 153 as unpatentable over Foekens and Janicke.
We reverse the rejection of claims 54—57, 65—67, 69, 121—146, 152,
and 153 as unpatentable over Foekens, Janicke, Bastholm, and Dublin.
We reverse the rejection of claims 54—57, 65—67, 69, 139-146, 152,
and 153 as unpatentable over Harbeck and Janicke.
We reverse the rejection of claims 54—57, 65—67, 69, 112—114, and
121—154 as unpatentable over Harbeck, Bastholm, and Dublin.
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
AFFIRMED
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