Boris Kovatchev et al.Download PDFPatent Trials and Appeals BoardJun 2, 20212020004849 (P.T.A.B. Jun. 2, 2021) Copy Citation 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): eofficeaction@appcoll.com patents@potomaclaw.com vdeluca@potomaclaw.com 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. Appeal 2020-004849 Application 13/380,839 2 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”). Appeal 2020-004849 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). Appeal 2020-004849 Application 13/380,839 4 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. Appeal 2020-004849 Application 13/380,839 5 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 Appeal 2020-004849 Application 13/380,839 6 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: Appeal 2020-004849 Application 13/380,839 7 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 Appeal 2020-004849 Application 13/380,839 8 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 Appeal 2020-004849 Application 13/380,839 9 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. Appeal 2020-004849 Application 13/380,839 10 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 Copy with citationCopy as parenthetical citation