Boris Kovatchev et al.

Patent Trials and Appeals Board

Jun 2, 2021

2020004849 (P.T.A.B. Jun. 2, 2021)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
13/380,839 02/10/2012 Boris P. Kovatchev 2646-0005US01 9421
134006 7590 06/02/2021
Potomac Law Group, PLLC (UVA)
8229 Boone Blvd
Suite 430
Vienna, VA 22182
EXAMINER
ARCHER, MARIE
ART UNIT PAPER NUMBER
1631
NOTIFICATION DATE DELIVERY MODE
06/02/2021 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte BORIS P. KOVATCHEV, CLAUDIO COBELLI,
and CHIARA DALLA MAN,

___________

Appeal 2020-004849
Application 13/380,839
Technology Center 1600

____________

Before JEFFREY N. FREDMAN, RYAN H. FLAX, and
TIMOTHY G. MAJORS, Administrative Patent Judges.

MAJORS, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal under 35 U.S.C. § 134(a) involving
claims to a system that simulates a glucose-insulin metabolic system of a
Type 2 diabetic subject that comprises, among other features, an electronic
database of virtual subjects. We have jurisdiction under 35 U.S.C. § 6.
We REVERSE.

1 “Appellant” refers to “applicant” as defined in 37 C.F.R. § 1.42(a).
Appellant identifies University of Virginia Patent Foundation of
Charlottesville, Virginia as the real party-in-interest. Appeal Br. 1.
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Application 13/380,839
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STATEMENT OF THE CASE
“Over 20 million people in the United States alone have Type 2
Diabetes Mellitus (T2DM) – a complex derangement of the glucose-insulin
metabolic system, which results in an increased insulin resistance and
inappropriate insulin secretion.” Spec. 1.2 Given the prevalence of T2DM,
the Specification explains that “it is essential to investigate the mechanisms
of glucose-insulin system derangement and drug pharmacodynamics, with
properly designed experimental trials,” yet such trials may not be possible,
cost-effective, or even ethical to conduct on T2DM subjects in vivo. Id.
According to the Specification, “[w]hile simulators of diabetes exist,
most are based on general population models” and, thus, their “capabilities
are generally limited to prediction of population averages that would be
observed during clinical trials.” Id. at 2. The Specification discloses that an
“in silico simulation environment could offer an alternative tool to test
different treatment strategies,” and “in silico modeling could produce
credible pre-clinical results that could be substituted for certain animal
trials” yielding “results in a fraction of the time required for animal trials.”
Id. at 1–2. In furtherance of these objectives, the simulator system of the
present invention makes use of, among other things, a population of “virtual
subjects” with T2DM and prediabetes. Id. at 2–3 (“[A] simulator of T2DM
should be equipped with a ‘cohort’ of in silico ‘subjects’ that spans
sufficiently well the observed inter-person variability of key metabolic

2 The Specification explains that T2DM does not appear suddenly and that
subjects “usually move from a healthy state to a diabetic state passing
through an intermediate phase, called prediabetes.” Spec. 1 (“[I]ndividuals
with impaired fasting glucose (IFG) have a 20–30% chance of developing
diabetes over the following 5–10 years”).
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Application 13/380,839
3
parameters in the general population of people with T2DM.”); see also id. at
11–13 (describing generation of virtual subjects for the simulator).3
Claims 1–32 are on appeal. Claim 1 is illustrative:
1. An electronic system that simulates a glucose-insulin
metabolic system of a T2DM or prediabetic subject, comprising:
a subsystem that models dynamic glucose concentration in
a T2DM or prediabetic subject, including
an electronic module that models endogenous
glucose production (EGP(t)) of a T2DM or prediabetic
subject,
an electronic module that models meal glucose rate
of appearance (Ra(t)) of a T2DM or prediabetic subject,
an electronic module that models glucose utilization (U(t))
of a T2DM or prediabetic subject,
an electronic module that models renal excretion of
glucose (E(t)) of a T2DM or prediabetic subject;
a subsystem that models dynamic insulin concentration in
said T2DM or prediabetic subject, including
an electronic module that models insulin secretion
(S(t)) of a T2DM or prediabetic subject;
an electronic database containing a population of virtual
T2DM or prediabetic subjects representative of the T2DM and
prediabetic population, each virtual subject having a plurality of
metabolic parameters with values encompassing a distribution of
parameters observed in vivo across the population of T2DM or
prediabetic subjects; and
a processor that calculates an effect of variation of at least
one metabolic parameter value on the glucose-insulin metabolic

3 The Specification discloses that “the present invention extends the
simulation of T1DM [Type 1 diabetes mellitus] to T2DM” but
“emphasize[s] that due to profound physiological differences between
T1DM and T2DM, the mathematical model and simulated ‘subjects’ with
T2DM are very different from the model and simulated ‘population’ of
T1DM.” Spec. 2; see also id. (citing references related to other simulators).
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system of a virtual T2DM or prediabetic subject by inputting said
plurality of metabolic parameter values of said T2DM or
prediabetic subject into said glucose concentration and insulin
concentration subsystems and varying at least one of said
metabolic parameter values to determine its effect on the
glucose-insulin metabolic system of said T2DM or prediabetic
subject.
Appeal Br. 11. The other independent claim, claim 18, contains similar
limitations to claim 1’s system, but is related to a computer-executable
program product. Id. at 15–16.
Appellant seeks review of the Examiner’s rejection of claims 1–32
under 35 U.S.C. § 103 for obviousness over Brahznik4 in view of Dalla
Man5 and Magni.6 Adv. Act. 1–3; Ans. 4–10.7
ANALYSIS
The Examiner “bears the initial burden . . . of presenting a prima facie
case of unpatentability.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir.
1992). Considering the record before us, we conclude that the Examiner has

4 Brahznik et al., US 2009/0070088 A1, published Mar. 12, 2009.
5 C. Dalla Man et al., Meal Simulation Model of the Glucose-Insulin System,
54 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING 10, 1740–1749
(2007).
6 L. Magni, Ph.D., et al., Model Predictive Control of Type 1 Diabetes: An in
Silico Trial, 1 J. OF DIABETES SCIENCE AND TECHNOLOGY 6, 804–812
(2007).
7 We focus on the rejection as described in the Advisory Action dated June
11, 2019, and Examiner’s Answer dated April 13, 2020, because the
Examiner allowed amendment of the claims after the February 27, 2019,
Final Rejection. See Adv. Act. 1–2 (indicating that the proposed amendment
“will be entered, and an explanation of how the new or amended claims
would be rejected is provided below or appended [in the Advisory Action]”).
Other claim rejections under § 112 were withdrawn. Adv. Act. 2.
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not met the burden of showing prima facie unpatentability of the pending
claims under § 103. We explain below.
We focus on claim 1. The Examiner finds that claim 1 would have
been obvious over Brahznik, in further combination with Dalla Man and
Magni. Adv. Act. 3; Ans. 4–8. According to the Examiner, “Brahznik’s
model enables a researcher to simulate the dynamics of the biological state
associated with type 2 diabetes,” “Man provides an embodiment where the
same model and events are applied to a database for extending the model to
type 2 diabetes,” and Magni “teaches a database containing a population of
virtual T2DM or prediabetic subjects, each virtual subject having a plurality
of metabolic parameters with values within a range of values derived from in
vivo T2DM or prediabetic subjects.” Adv. Act. 3.
More specifically, turning to claim 1’s limitations, the Examiner finds
that Brahznik teaches an electronic system that simulates a glucose-insulin
metabolic system” using mathematical models. Ans. 5. The Examiner
further finds that Brahznik’s system includes a computer subsystem with
modules that model most of the physiological parameters of the subsystems
recited in claim 1. Id. For example, the Examiner finds that Brahznik
teaches a subsystem that models dynamic insulin concentration in a T2DM
subject, including modeling for insulin secretion (S(t)). Id. at 5–6 (citing
Brahznik ¶ 35). Moreover, the Examiner finds that Brahznik teaches a
processing module that calculates effects of a variation of metabolic
parameter values by inputting varied metabolic parameter values (e.g.,
through “manipulation of the model equations and their associated
parameters”). Id. at 6 (citing Brahznik ¶¶ 19, 116, and Fig. 6).
The Examiner finds, however, that Brahznik does not teach “an
electronic module that models endogenous glucose production (EGP(t)),” or
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the electronic database containing a population of virtual T2DM or
prediabetic subjects having the features claimed. Id. The Examiner turns
first to Dalla Man. According to the Examiner, Dalla Man teaches an
electronic system that simulates a glucose-insulin metabolic system
comprising a module that models endogenous glucose production. Id. The
Examiner also finds Dalla Man further teaches a population of virtual T2DM
or prediabetic subjects. Id. at 7 (citing a “database was obtained in 14 type 2
diabetic subjects” at Dalla Man, 1740).
Because the Examiner finds that Brahznik and Man “do not teach a
database containing a population of virtual T2DM or prediabetic subjects,
each virtual subject having a plurality of metabolic parameters with values
within a range of values derived from in vivo T2DM or prediabetic
subjects,” the Examiner turns to Magni. Id. According to the Examiner,
Magni “teach[es] a database containing a population of virtual T2DM or
prediabetic subjects, each virtual subject having a plurality of metabolic
parameters with values within a range of values derived from in vivo T2DM
or prediabetic subjects.” Id. (citing Magni, 807).
From the above, the Examiner concludes the ordinarily skilled artisan
would have combined and modified the art’s teachings so that the subject
matter of claim 1 would have been obvious. Id. at 7–8. More specifically,
the Examiner reasons that it would have been obvious “to combine an
electronic module that models endogenous glucose production (EGP(t)), as
taught by [Dalla] Man, with the teachings of Brahznik because EGP is a
clinical means to quantify the glucose utilization and renal excretion, useful
in identification of patients susceptible to hypoglycemia and type 2
diabetes.” Id. at 7. Then, turning to Magni, the Examiner reasons:
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it would have been prima facie obvious to one of ordinary skill
in the art to combine an electronic database containing a
population of virtual T2DM or prediabetic subjects, each virtual
subject having a plurality of metabolic parameters with values
within a range of values derived from in vivo T2DM or
prediabetic subjects, as taught by Magni, with Brahznik in view
of Man, because with an electronic database containing a
population of virtual T2DM or prediabetic subjects, each virtual
subject having a plurality of metabolic parameters with values
within a range of values derived from in vivo T2DM or
prediabetic subjects would provide a data set of similar patients,
and enable a more precise extrapolation and prediction of clinical
outcomes for the patients; thereby increasing the efficiency and
the accuracy of the combined invention.
Id. at 7–8.
Appellant makes three primary arguments. Appeal Br. 5–10. We
focus here on the first of Appellant’s arguments. Id. at 6–8; Reply Br. 2–4.
Appellant contends that the Examiner’s finding that Magni discloses the
database of the system as claimed is incorrect. Appeal Br. 6–7. According
to Appellant, “Magni uses parameters from healthy subjects, and then
simply alters those parameters based on average assumptions” to “obtain
parameter joint distributions in [theoretical] T1DM” subjects. Id. Thus,
Appellant contends, “Magni does not relate to T2DM or prediabetic
subjects” and “Magni nowhere describes or suggests a database containing a
population of virtual T2DM or prediabetic subjects representative of the
T2DM and prediabetic population, each virtual subject having a plurality of
metabolic parameters with values encompassing a distribution of parameters
observed in vivo across the population of T2DM or prediabetic subjects.”
Id.; Reply Br. 2–3 (“The Examiner’s Answer has failed to refute this
assertion of fact” and “the Answer has confirmed and implicitly agrees with
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Appellant’s explanation that Magni nowhere describes or suggests a
database” as claimed.).
For the reasons below, we conclude that the Examiner has not, on this
record, shown that claim 1 would have been prima facie obvious.
As an initial matter, we note that the Examiner’s mapping of Magni to
relevant claim elements—the pivotal database limitation with its various
features—uses claim language from an older, pre-amendment version of
claim 1. The Examiner finds that Brahznik and Dalla Man do not teach “a
database containing a population of virtual T2DM or prediabetic subjects,
each virtual subject having a plurality of metabolic parameters with values
within a range of values derived from in vivo T2DM or prediabetic
subjects,” but that deficiency is allegedly remedied by Magni’s teachings.
Ans. 7. That quoted content is not, however, what pending claim 1 recites as
the database limitation, which is: “an electronic database containing a
population of virtual T2DM or prediabetic subjects representative of the
T2DM and prediabetic population, each virtual subject having a plurality of
metabolic parameters with values encompassing a distribution of parameters
observed in vivo across the population of T2DM or prediabetic subjects.”
Compare Appeal Br. 11 (present claim 1), with Claims dated Mar. 9, 2015
(old version of claim 1).8 This leaves the record unclear as to how Magni
teaches the features of the system that are actually claimed in claim 1 and
allegedly missing in Brahznik and Dalla Man.9

8 The old version of claim 1 was considered in the prior appeal to the Board.
Ex parte Kovatchev, Appeal 2017-003243 at 2 (PTAB Dec. 8, 2017)
(affirming the then-pending rejection for obviousness).
9 Although the Examiner cites a database containing an alleged “population
of virtual T2DM” subjects in Dalla Man (Ans. 7), it is not clear, and the
Examiner does not sufficiently explain that Dalla Man, indeed, discloses a
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Second, we agree with Appellant that Magni does not describe T2DM
or prediabetic subjects, much less describe a database of virtual T2DM
subjects comprising the other database features claimed. Appeal Br. 6–7.
The Examiner’s initial assertion to the contrary—that Magni “teach[es] a
database containing a population of virtual T2DM or prediabetic subjects” is
not accurate. Indeed, the Examiner does not dispute this point in response to
Appellant’s argument, there describing Magni as “identify[ing] parameters
in healthy subjects wherein corresponding parameters in diabetic patients are
altered.” Ans. 11; Reply 4 (“[I]n contradistinction to the claimed invention,
Magni uses parameters from healthy subjects, and then simply alters those
parameters based on average assumptions. The Answer does not dispute this
fact but instead acknowledges and confirms it.”). The Examiner’s further
counterpoint that “one cannot show nonobviousness by attacking references
individually where the rejections are based on combinations of references,”
while a correct statement of the legal principle, fails to deal persuasively
with Appellant’s argument. Ans. 10–11. As discussed above, the present
record lacks a sufficiently clear and cohesive explanation of where the art
teaches the database of virtual T2DM subjects with the limitations actually
claimed, or how precisely the art would have been combined and modified
to arrive at that subject matter.

database of “virtual” subjects as claimed. See Dalla Man, 1740 (describing a
database that appears to include data from 204 actual normal subjects or,
alternatively, data from 14 actual Type 2 diabetic subjects). In any event,
the Examiner’s modification of the art does not purport to combine Dalla
Man’s database with Brahznik to satisfy the claimed database and virtual
subject limitations. To the contrary, the Examiner proposes modifying
Brahznik with Dalla Man’s module that models endogenous glucose
production (EGP(t)), and turns to Magni for the database and virtual subject
limitations. Ans. 7.
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The Examiner’s fallback reliance on the Board’s affirmance of the
obviousness rejection in an earlier appeal is misplaced. Ans. 11. The
claims, including the database limitation, were amended since the time of the
prior appeal. Reply Br. 4 (“[T]he prior decision was not based on the
subject matter as now claimed, which pending claims were substantively
amended taking into account the Board’s reasoning and findings.”). And,
relatedly, the argument Appellant makes now that Magni fails to teach the
database with the particular features claimed was not part of the prior appeal.
See Dec. 2, 2015, Appeal Brief, 10 (arguing, in the prior appeal, that Dalla
Man and Brahznik are “conceptually inapposite and cannot be combined”
and that “no purpose” would be served by combining Magni and Brahznik).
For the above reasons, we conclude the Examiner has not met the
burden to show that claim 1 would have been obvious over Brahznik, Dalla
Man, and Magni. The rejection of independent claim 18 fails for the same
reasons. Ans. 5–8 (addressing claim 1 and 18 together). So too, the burden
has not been met on dependent claims 1–17 and 19–32. In re Fritch, 972
F.2d 1260, 1266 (Fed. Cir. 1992) (“[D]ependent claims are nonobvious if the
independent claims from which they depend are nonobvious.”).
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–32 103 Brahznik, Dalla
Man, Magni
1–32

REVERSED