DETAILED ACTION
Applicant's response, filed 8/4/2025, has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Response to Amendment
In view of applicant’s amendments to the claims, previous objections to claims 1 and 11 over minor informalities are withdrawn.
Claim Rejections - 35 USC § 112
Response to Amendment
In view of applicant’s amendments to the claims, previous rejections under 35 U.S.C. 112 have been withdrawn.
Claim Rejections - 35 USC § 101
Response to Amendment
In view of applicant’s amendments to the claims, previous rejections under 35 U.S.C. 101 have been reviewed and updated accordingly.
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-8, 10-18, and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas without significantly more. The claims recite a method and apparatus for analyzing calcimimetic activity using a pharmacokinetic or pharmacodynamic model to determine healthcare information and/or administer treatment to patients. The judicial exception is not integrated into a practical application because while claims 1-20 attempt to integrate the exception into a practical application, said application is either generically recited computer elements that do not add a meaningful limitation to the abstract idea, or it is insignificant extra solution activity and simply implementing the abstract idea on a computer. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the computer elements only store and retrieve information in memory as well as perform basic calculations that are known to be well-understood, routine and conventional computer functions as recognized by the decisions listed in MPEP § 2106.05(d).
Framework with which to Analyze Subject Matter Eligibility:
Step 1: Are the claims directed to a category of statutory subject matter (a process, machine,
manufacture, or composition of matter)? [see MPEP § 2106.03]
Claims are directed to a stator subject matter, specifically methods (claims 1-10), and an apparatus (claims 11-20).
Step 2A Prong One: Do the claims recite a judicially recognized exception, i.e., an abstract idea, a law of nature, or a natural phenomenon? [see MPEP § 2106.04(a)]
The claims herein recite abstract ideas, mental processes and mathematical concepts.
With respect to the Step 2A Prong One evaluation, the instant claims are found herein to recite abstract ideas that fall into the grouping of mental processes and mathematical concepts.
Claims 1 and 11: Determining calcimimetic information via the model, virtual administration, and determining a treatment recommendation are processes of comparing/contrasting and calculating that can be done via pen and paper or within the human mind and are therefore abstract ideas, specifically mental processes. Determining calcimimetic information via the model and virtual administration is a verbal articulation of a mathematical process and therefore an abstract idea, specifically a mathematical concept.
Claims 3 and 13: The virtual calcimimetic administration comprising at least one dose titration is merely further limiting the data itself which is an abstract idea, specifically a mental process.
Claims 4 and 14: The dose titration process comprising one or more of those specified from the group provided is merely further limiting the data itself which is an abstract idea, specifically a mental process.
Claims 5 and 15: Simulating pharmacokinetic functionality is a process of comparing/contrasting and calculating that can be done via pen and paper or within the human mind are therefore abstract ideas, specifically mental processes. The calcimimetic information comprising a concentration is merely further limiting the data itself which is an abstract idea, specifically a mental process.
Claims 6 and 16: The calcimimetic comprising etelcalcitide and the information comprising one of those specified in the group provided is merely further limiting the data itself which is an abstract idea, specifically a mental process.
Claims 7 and 17: The information being determined by the equation provided is a verbal articulation of a mathematical process and is therefore an abstract idea, specifically a mental process.
Claims 8 and 18: The model simulating pharmacodynamic functionality of the calcimimetic is a process of comparing/contrasting, and calculating that can be done via pen and paper or within the human mind are therefore abstract ideas, specifically mental processes. The information comprising one of those specified in the group provided is merely further limiting the data itself which is an abstract idea, specifically a mental process.
Claims 10 and 20: Determining at least one clinical trial based on the information is a process of comparing/contrasting, calculating, and selecting that can be done via pen and paper or within the human mind are therefore abstract ideas, specifically mental processes.
Step 2A Prong Two: If the claims recite a judicial exception under prong one, then is the judicial exception integrated into a practical application? [see MPEP § 2106.04(d) and MPEP § 2106.05(a)-(c) & (e)-(h)]
Because the claims do recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they integrate the abstract ideas into a practical application.
The following claims recite the following additional elements in the form of non-abstract elements:
Claims 1 and 11: Accessing a calcimimetic model is an insignificant extra solution activity, specifically necessary data gathering (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015) (presenting offers and gathering statistics amounted to mere data gathering), Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)) [See MPEP § 2106.05(g)]. An apparatus, processor, memory, and instructions are all generic and nonspecific elements of a computer that do not improve the functioning of any computer or technology described herein [See MPEP § 2106.04(d)(1) and MPEP § 2106.05(d)]. Providing an actual calcimimetic administration is an additional element as the step in claim 1 does not rise to being a particular treatment, as according to MPEP 2106.04(d)(2) Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition, and in subsequent subsection (b) The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). Furthermore, the integration of the administration in claim 11 is not an affirmative recitation, rather it is merely an intended use of the system.
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? [see MPEP § 2106.05]
Because the additional claim elements do not integrate the abstract idea into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept.
The claims do not recite additional elements that are sufficient to amount to
significantly more than the judicial exception because the claims recite additional
elements that are generic, conventional, nonspecific, or insignificant extra solution
activity. These additional elements include:
The additional elements of accessing a calcimimetic model (Conventional: Specification Paragraph [0148]), providing an actual calcimimetic administration (Conventional: Specification Paragraph [0063]), and providing a virtual calcimimetic administration (Conventional: Specification Paragraph [0068]) are insignificant extra solution activities, specifically necessary data gathering (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015) (presenting offers and gathering statistics amounted to mere data gathering), Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)) [See MPEP § 2106.05(g)].
The additional elements of and apparatus, processor, memory, and instructions are all generic and nonspecific elements of a computer that are well-understood, routine and conventional within the art and therefore do not improve the functioning of any computer or technology described therein (Receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), Performing repetitive calculations, Flook, 437 U.S. at 594, 198 USPQ2d at 199 (recomputing or readjusting alarm limit values), and Storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015)) [See MPEP § 2106.05(d)(II)]. Therefore, taken both individually and as a whole, the additional elements do not amount to significantly more than the judicial exception by providing an inventive concept.
Therefore, claims 1-20, when the limitations are considered individually and as a whole, are rejected
under 35 USC § 101 as being directed to non-statutory subject matter.
Response to Arguments
Applicant's arguments, see page 9 of Remarks, filed 2/4/2026, have been fully considered but they are not persuasive.
Applicant asserts on page 10 of the Remarks, filed 2/4/2026, that the final step includes providing an actual calcimimetic administration as treatment for a disorder in a patient and thus applies the judicial exception to a particular treatment. Examiner submits that due to lack of an actual disorder within the claim, a particular treatment argument cannot be made as according to MPEP 2106.04(d)(2) Examiners should keep in mind that in order to qualify as a "treatment" or "prophylaxis" limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition, and in subsequent subsection (b) The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). Furthermore, the integration in claim 11 is not an affirmative recitation, rather it is merely an intended use of the system. As such claims 2 and 12 recite particular diseases for claims 1 and 11, that if integrated, would provide an effective particular treatment argument if integrated into claims 1 and 11 respectively. As the claims currently stand however, only claims 2 and 12 recite a particular disease for the treatment and as such rejections under 35 U.S.C. 101 are withdrawn for those claims.
Claim Rejections - 35 USC § 103
Response to Amendment
In view of applicant’s amendments to the claims previous rejections under 35 U.S.C. 103 have been reviewed, updated, and provided below.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5, 10-13, 15, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Schappacher et al. (US 20200126632 A1; previously cited) in view of Hui et al. (American Control Conference. IEEE (2006) 1671-1676; previously cited) and Martin et al. (Drug Metabolism and Disposition (2016) 1435-1440; newly cited).
Claim 1 is directed to a method for determining calcimimetic information and indicating the efficacy of calcimimetic administration by use of a pharmacokinetic or pharmacodynamic model along with calcimimetic administration data.
Claim 11 is directed to an apparatus that performs the method of claim 1.
Schappacher et al. teaches in the abstract “The described technology may include processes to model parathyroid gland (PTG) functionality and/or calcimimetic administration to patients with a health abnormality that affects PTG function” and in paragraph [0007] “In accordance with various aspects of the described embodiments, a computer-implemented method of virtual parathyroid gland (PTG) functionality analysis may include, via a processor of a computing device…”, reading on a computer-implemented method of calcimimetic activity analysis of the parathyroid gland (PTG), the method comprising, via a processor of a computing device. Schappacher et al. teaches in paragraph [0020] “In various embodiments of the method, the calcimimetic model may be operative to determine a plurality of pharmacokinetic parameters simultaneously” and in paragraph [0059] “some embodiments may provide a PTG analysis process that may include various models to simulate the functionality of the PTG and/or calcimimetic activity based on, for example, CaSR expression and activity regulated by ionized calcium (Ca or Ca.sup.2+), phosphate (P), and vitamin D (D or 1,25D). Some embodiments may provide a multi-compartment calcimimetic model based on physiological considerations capturing all major pharmacokinetics parameters of a calcimimetic compound”, reading on accessing a calcimimetic model configured to simulate a functionality of a PTG of at least one patient, the calcimimetic model comprising at least one of a pharmacokinetic model or a pharmacodynamic model. Schappacher et al. teaches in paragraph [0060] “A further non-limiting example of a technological advantage may include providing a PTG analysis process operative to generate treatment recommendations and/or determine research outcomes using virtual simulations of PTG functionality and/or calcimimetic administration”, reading on providing a calcimimetic administration of a calcimimetic to the at least one patient via the calcimimetic model according to an administration process. Schappacher et al. teaches in paragraph [0019] “In accordance with various aspects of the described embodiments is a computer-implemented method of virtual PTG functionality analysis that may include, via a processor of a computing device, providing a calcimimetic model configured to simulate administration of a calcimimetic”, reading on determining calcimimetic information based on the calcimimetic administration via the calcimimetic model for the at least one patient, the calcimimetic information configured to indicate an efficacy of the calcimimetic administration, and wherein the pharmacodynamic model is configured to model etalcalcetide. Schappacher et al. teaches in paragraph [0020] “In exemplary embodiments of the method, the method may include determining at least one treatment recommendation based on the model output”, rendering obvious the actual treatment of a patient with a calcimimetic for a disorder, thereby reading on determining at least one treatment recommendation based on the calcimimetic information; and providing an actual calcimimetic administration corresponding to the at least one treatment recommendation to an actual patient to treat a disorder in the actual patient.
Hui et al. teaches in the abstract “Nonnegative and compartmental dynamical system models are widespread in biological, physiological, and ecological sciences and play a key role in understanding these processes. In the specific field of pharmacokinetics involving the study of drug concentrations (in various tissue groups) as a function of time and dose, nonnegative and compartmental models are vital in understanding system wide effects of pharmacological agents. These systems are stable with nonnegative system matrices. In this paper, we present a constrained optimization framework for nonnegative and compartmental system identification that guarantees asymptotic stability of the plant system dynamics as well as the nonnegativity of the system matrices”, reading on wherein the pharmacokinetic model includes an optimization process that uses constraint optimizations.
Martin et al. teaches in the abstract “A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy. To predict this contribution in humans, a pharmacokinetic (PK) modeling approach was developed… normalized metabolite AUCs were added to that of MRK-1 to yield a composite efficacious unbound AUC, expressed as “parent drug equivalents,” which was used as the target AUC for predictions of the human efficacious dose. In vitro and preclinical PK studies afforded predictions of the PK of MRK-1 and the two active metabolites in human as well as the relative pathway flux to each metabolite. These were used to construct a PK model (Berkeley Madonna, version 8.3.18; Berkeley Madonna Inc., University of California, Berkeley, CA) and to predict the human dose required to achieve the target parent equivalent exposure. These predictions were used to inform on the feasibility of the human dose in terms of size, frequency, formulation, and likely safety margins, as well as to aid in the design of preclinical safety studies”, in figure 1 is shown the biotransforms, and in Table 1 is described the model with volume of distribution for each of the active molecule, as well as the biotransforms, thereby reading on wherein the pharmacokinetic model is based at least in part on a volume of calcimimetic biotransforms.
It would have been obvious at the time of invention to modify the teachings of Schappacher et al. for the method of claim 1 with the teachings of Hui et al. for the constrained optimization model of pharmacokinetics as Hui et al. teaches on page 1676, column 1, paragraph 2 “The approach is based on subspace identification methods and guarantees asymptotic stability…”. One would have had a reasonable expectation of success given this would merely be substituting one pharmacokinetic model with another. Furthermore, it would have been obvious at the time of first filing to have modified the teachings of the prior to with the teachings of Martin et al. for the use of biotransforms within the pharmacokinetic model as the latter teaches on page 1439, column 2, paragraph 2 “the modeling approach described here facilitated a pragmatic prediction of the contribution of active metabolites to clinical efficacy for a discovery stage compound. The model afforded predictions of the clinically efficacious dose and was instrumental in the design of preclinical safety studies”. One would have had a reasonable expectation of success given that a link to the model code was provided on page 1438, column 2, paragraph 1, enabling open-source tinkering for individual use. Therefore, it would have been obvious at the time of invention to modify the teachings of each and to be successful.
Claim 2 is directed to the method of claim 1 but further specifies that the disorder is a bone disorder.
Claim 12 is directed to the apparatus of claim 11 but further specifies that the disorder is a bone disorder.
Schappacher et al. teaches in paragraph [0079] “Accordingly, PTG functionality models may operate to, inter alia, provide a complementary tool to study treatment strategies, like combinations of calcimimetics and vitamin D analogs. The only input variables are the key regulators of PTG cells in hemodialysis patients, i.e. calcium, 1,25D, and phosphate. Therefore, PTG functionality models can be combined with a bone model, allowing the analysis of a highly complex system involving a cascade of regulatory triggers and feedback loops”, in paragraph [0082] “The executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update recommends to maintain PTH within 14 pmol/L and 62 pmol/L. One strategy to reach this goal is to target the CaSR. Calcimimetics like cinacalcet or etecalcetide enhance the interaction between the ionized calcium concentration (Ca2+) and the CaSR by allosteric activation. The higher sensitivity of the CaSR to Ca2+ leads to an inverse relationship between plasma PTH and cinacalcet concentrations. PTH concentration declines after the administration of cinacalcet until it reaches a minimum approximately 2-3 hours after dosing”, in paragraph [0088] “Combined with a model for the parathyroid gland and bone metabolism, calcimimetic models according to some embodiments may provide a ready to use tool for clinical trial simulations to explore effects of relevant factors, such as patient adherence, off-label administration regiments, the effect of administration with food, and/or the like”, and in paragraph [0026] “Altered parathyroid gland biology in patients with chronic kidney disease (CKD) is a major contributor to chronic kidney disease-mineral bone disorder (CKD-MBD). This disorder is associated with an increased risk of bone disorders, vascular calcification, and cardiovascular events”, reading on wherein the disorder is a bone disorder in the actual patient.
Claim 3 is directed to the method of claim 1 but further specifies that the calcimimetic administration comprise dose titration.
Claim 13 is directed to the method of apparatus 11 but further specifies that the calcimimetic administration comprise dose titration.
Schappacher et al. teaches in paragraph [0103] “The analysis can help to evaluate dose titration schemes and administration schemes”, reading on the calcimimetic administration comprising at least one dose titration process for the calcimimetic.
Claim 5 is directed to the method of claim 1 but further specifies the pharmacokinetic model be configured to simulate pharmacokinetic functionality and the calcimimetic information comprise concentration.
Claim 15 is directed to the apparatus of claim 11 but further specifies that the pharmacokinetic model be configured to simulate pharmacokinetic functionality and the calcimimetic information comprise concentration.
Schappacher et al. teaches in paragraph [0094] “For example, a calcimimetic model according to some embodiments may include a pharmacokinetic model…” and in claim 11 “A computer-implemented method of virtual parathyroid gland (PTG) functionality analysis, the method comprising, via a processor of a computing device: providing a calcimimetic model configured to simulate administration of a calcimimetic compound to a patient with at least one health abnormality affecting PTG function, the calcimimetic model operative to: receive a calcimimetic dose, determine a concentration of the calcimimetic compound in at least one of a plurality of physiological compartments, each of the plurality of physiological compartments related to an adjacent physiological compartment via at least one constant rate function, and determine an output of a total calcimimetic concentration for at least one time period”, reading on the pharmacokinetic model configured to simulate pharmacokinetic functionality of the calcimimetic for the at least one patient, the calcimimetic information for the pharmacokinetic model comprising a calcimimetic concentration.
Claim 9 is directed to the method of claim 1 but further specifies that a treatment recommendation be determined from the calcimimetic information.
Claim 19 is directed to the apparatus of claim 11 but further specifies that a treatment recommendation be determined from the calcimimetic information.
Schappacher et al. teaches in claim 10 “comprising determining at least one treatment recommendation based on the model output”, reading on comprising determining at least one treatment recommendation based on the calcimimetic information.
Claim 10 is directed to the method of claim 1 but further specifies that a clinical trial be determined based upon the calcimimetic information.
Claim 20 is directed to the apparatus of claim 11 but further specifies that a clinical trial be determined based upon the calcimimetic information.
Schappacher et al. teaches in paragraph [0103], ”Such an approach may allow the analysis of the effect of different dosing regiments on the drug concentration in the body that could otherwise only be addresses by clinical studies” and in paragraph [0099] “To be of clinical use, the cinacalcet model should be readily adaptable to various conditions…”.
Schappacher et al. does not teach specifically determining a clinical trial based on the calcimimetic information.
It would have been obvious at the time of invention to modify the teachings of Schappacher et al. for the method of claim 1 to include clinical trial determinations as Schappacher et al. points out in paragraph [0060] “further non-limiting example of a technological advantage may include providing a PTG analysis process operative to generate treatment recommendations and/or determine research outcomes using virtual simulations of PTG functionality and/or calcimimetic administration without requiring clinical studies with actual patient participants” and in paragraph [0004] “clinical studies are expensive, time-consuming, and resource-intensive. Accordingly, virtual models of biological systems, such as the PTG, may be used in some situations to evaluate functionality and treatments without the need for real-world patients, regulations, and cost”. One would have had a reasonable expectation of success given that Schappacher et al. is teaching a method for determining information sans clinical studies, so one would only need to work backward to use the results to inform potential clinical studies. Therefore, it would have been obvious to one with ordinary skill in the art to incorporate the teachings of each and to be successful.
Claims 4 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Schappacher et al. (US 20200126632 A1; previously cited), Hui et al. (American Control Conference. IEEE (2006) 1671-1676; newly cited), and Martin et al. (Drug Metabolism and Disposition (2016) 1435-1440; newly cited) as applied to claims 1-3, 5, 10-13, 15, and 20 above, and further in view of Friedl et al. (Drug Design, Development and Therapy (2018) 1589-1598; newly cited).
Claim 4 is directed to the method of claim 3 and thus claim 1, but further specifies that the dose titration comprise one of those items specified in group provided.
Claim 14 is directed to the apparatus of claim 13 and thus claim 11 but further specifies that the dose titration comprise one of those items specified in group provided.
Schappacher et al. teaches in paragraph [0103] “The analysis can help to evaluate dose titration schemes and administration schemes” and in claim 11 “A computer-implemented method of virtual parathyroid gland (PTG) functionality analysis, the method comprising, via a processor of a computing device: providing a calcimimetic model configured to simulate administration of a calcimimetic compound to a patient with at least one health abnormality affecting PTG function, the calcimimetic model operative to: receive a calcimimetic dose, determine a concentration of the calcimimetic compound in at least one of a plurality of physiological compartments, each of the plurality of physiological compartments related to an adjacent physiological compartment via at least one constant rate function, and determine an output of a total calcimimetic concentration for at least one time period”.
Schappacher et al. does not teach the specific items in the group provided.
Friedl et al. teaches on page 1590, column 1, paragraph 3 “It is characterized by normal or slightly decreased serum-calcium levels…”.
It would have been obvious at the time of invention to modify the teachings of Schappacher et al. , Hui et al., and Martin et al. for the method of claim 1 wherein an evaluation of dose titration is provided in the output, with the teachings of Friedl et al. for the pathogenesis of PTH, to include adjustment of a dose, holding the dose below a specified concentration, reducing the dose or increasing the dose, as Friedl et al. provides the criteria for pathogenesis and therefore, monitoring of the disease. One would have had a reasonable expectation of success given that it is merely providing a criterion for monitoring the administration and that Friedl et al. is a review of PTH. Therefore, it would have been obvious to one with ordinary skill in the art to incorporate the teachings of each and to be successful.
Claims 6 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Schappacher et al. (US 20200126632 A1; previously cited), Hui et al. (American Control Conference. IEEE (2006) 1671-1676; newly cited) and Martin et al. (Drug Metabolism and Disposition (2016) 1435-1440; newly cited) as applied to claims 1-3, 5, 10-13, 15, and 20 above, and further in view of Wu et al. (Journal of pharmacokinetics and pharmacodynamics (2017) 43-53; previously cited).
Claim 6 is directed to the method of claim 5 and thereby claim 1, but further specifies that the calcimimetic and calcimimetic information comprise at least one of the three specified items.
Claim 16 is directed to the apparatus of claim 15 and thereby claim 11, but further specifies that the calcimimetic and calcimimetic information comprise at least one of the three specified items.
Schappacher et al. teaches in paragraph [0094] “In some embodiments, PTG functionality models may include all of the known adaptive mechanisms which regulate the CaSR. The predictions are based on positive and negative feedback systems acting on the CaSR. The effect of therapeutic interventions acting on the CaSR, such as the calcimimetic drugs cinacalcet or etelcalcetide may be incorporated by using an operational model of allosterism on the CaSR”.
Schappacher et al. does not teach the specific three items that the calcimimetic and calcimimetic information comprise.
Wu et al. teaches in the abstract “To characterize the time course of etelcalcetide in different matrices (plasma, dialysate, urine, and feces), a drug disposition model was developed. Nonlinear mixed-effect modeling was used to describe data from six adults with CKD on hemodialysis who received a single intravenous dose of etelcalcetide (10 mg; 710 nCi) after hemodialysis. A three-compartment model with the following attributes adequately described the observed concentration–time profiles of etelcalcetide in the different matrices: biotransformation in the central compartment; elimination in dialysate, urine, and feces; and a nonspecific elimination process”.
It would have been obvious at the time of invention to modify the teachings of Schappacher et al. , Hui et al., and Martin et al. for the method of claim 1, with the teachings of Wu et al. for the use of etelcalcetide in biotransforms and in peripheral compartments to quantitatively describe biotransformation, distribution, and elimination of etelcalcetide, as Wu et al. states “The model provided valuable insight into the disposition of this novel class of synthetic D-amino acid peptides”. One would have had a reasonable expectation of success given that Schappacher et al. uses a broad term covering the variants of etelcalcetide and does not specifically exclude them and Wu et al. specifically provides a pharmacodynamic model charting the course of etelcalcetide through the system. Therefore, it would have been obvious to one with ordinary skill in the art to incorporate the teachings of each and to be successful.
Claims 8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Schappacher et al. (US 20200126632 A1; previously cited), Hui et al. (American Control Conference. IEEE (2006) 1671-1676; previously cited), and Martin et al. (Drug Metabolism and Disposition (2016) 1435-1440; newly cited) as applied to claims 1-3, 5, 10-13, 15, and 20 above, and further in view of Chen et al. (CPT: pharmacometrics & systems pharmacology (2016) 484-494; previously cited).
Claim 8 is directed to the method of claim 1 but further specifies that the pharmacodynamic model simulate functionality and that the calcimimetic information comprise at least one of the specified items in the given list.
Claim 18 is directed to the apparatus of claim 11 but further specifies that the pharmacodynamic model simulate functionality and that the calcimimetic information comprise at least one of the specified items in the given list.
Schappacher et al. , Hui et al., and Martin et al. teach the methods of claims 1 and 11 as shown above.
Schappacher et al. , Hui et al., and Martin et al. do not teach a pharmacodynamic model.
Chen et al. teaches on page 485, column 1, paragraph 4 ” The objectives of this semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) analysis for etelcalcetide in subjects with SHPT were: (i) to develop a population PK/PD model relating etelcalcetide exposure to markers of efficacy (PTH) and safety (Ca)”, reading on the pharmacodynamic model configured to simulate pharmacodynamic functionality of the calcimimetic for the at least one patient, the calcimimetic information for the pharmacokinetic model comprising at least one of a parathyroid (PTH) concentration, a calcium concentration, or a phosphate concentration.
It would have been obvious at the time of invention to modify the teachings of Schappacher et al., Hui et al., and Martin et al. for the methods of claims 1 and 11, with the teachings of Chen et al. as Chen teaches the use of both pharmacokinetic and pharmacodynamic models for modeling etelcalcetide exposure, and also teaches the use of calcium concentrations. One would have had a reasonable expectation of success given they are interrogating the same medications with similar models in the same field. Therefore, it would have been obvious to one with ordinary skill in the art to incorporate the teachings of each and to be successful.
Response to Arguments
Applicant's arguments filed 2/4/2026 have been fully considered but they are not persuasive.
Applicant asserts on page 12 that the cited references do not teach the limitations of the currently amended claims, specifically citing the pharmacokinetic model being based on volume of calcimimetic biotransforms. Examiner submits that in view of the newly cited reference (Martin et al.), newly cited limitations are obvious.
Subject Matter Free From Prior Art
Claims 7 and 17 are free from the prior art because while the art teaches the use of stochastic differential equations for the use of pharmacokinetic models, the specificity of model, i.e. the exact model itself, is not taught within the prior art. Specifically, examiner submits Donnet al. (Advanced drug delivery reviews (2013) 929-939; newly cited) as review of the use of stochastic differential equations within the art with eample equations on page 930 column 2 – page 931 column 1. While there are similarities within the design of the equations this is merely due to the general structure of such types of equations because while both are calculating drug concentrations both total and compartmentally, claims 7 and 17 are also calculating the biotransforms and using information such as conjugation and deconjugation rates. Therefore, claims 7 and 17 are potentially free from the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 3-5, 8, 11, 13-15, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-18 of U.S. Patent No. 11450405 in view of Martin et al. (Drug Metabolism and Disposition (2016) 1435-1440; newly cited). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the instant application are directed to the calcimimetic etelcalcitide whereas those of 11450405 are directed to the calcimimetic cinacalcet, and Martin et al. describes the specific parameters at use in the instant application.
Application: 17/491,900
US Patent No. 11450405
Claim 1: A method comprising: accessing a calcimimetic model configured to simulate a functionality of a parathyroid gland (PTG) of at least one virtual patient, the calcimimetic model comprising at least one of a pharmacokinetic model or a pharmacodynamic model, wherein the pharmacokinetic model includes an optimization process that uses constraint optimizations and wherein the pharmacodynamic model is configured to model etelcalcetide, and wherein the pharmacokinetic model is based at least in part on a volume of calcimimetic biotransforms; providing a virtual calcimimetic administration of a calcimimetic to the at least one virtual patient via the calcimimetic model according to an administration process; determining calcimimetic information based on the virtual calcimimetic administration via the calcimimetic model for the at least one patient, the calcimimetic information configured to indicate an efficacy of the virtual calcimimetic administrations determining at least one treatment recommendation based on the calcimimetic information; and providing an actual calcimimetic administration corresponding to the at least one treatment recommendation to an actual patient to treat a disorder in the actual patient.
Claim 11: An apparatus, comprising: at least one processor; and a memory coupled to the at least one processor, the memory comprising instructions that, when executed by the at least one processor, cause the at least one processor to: access a calcimimetic model configured to simulate a functionality of a PTG of at least one patient, the calcimimetic model comprising at least one of a pharmacokinetic model or a pharmacodynamic model, wherein the pharmacokinetic model includes an optimization process that uses constraint optimizations and wherein the pharmacodynamic model is configured to model etalcalcetide[[,]];provide a calcimimetic administration of a calcimimetic to the at least one patient via the calcimimetic model according to an administration processl[,]]; and determine calcimimetic information based on the calcimimetic administration via the calcimimetic model for the at least one patient, the calcimimetic information configured to indicate an efficacy of the calcimimetic administration.
Claim 10: A computer-implemented method of virtual parathyroid gland (PTG) functionality analysis, the method comprising, via a processor of a computing device: providing a calcimimetic model configured to simulate administration of a calcimimetic compound to a patient with at least one health abnormality affecting PTG function, the calcimimetic model operative to: receive a calcimimetic dose, determine a concentration of the calcimimetic compound in at least one of a plurality of physiological compartments, each of the plurality of physiological compartments related to an adjacent physiological compartment via at least one constant rate function, and determine an output of a total calcimimetic concentration for at least one time period.
Martin et al. teaches in the abstract “A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy. To predict this contribution in humans, a pharmacokinetic (PK) modeling approach was developed… normalized metabolite AUCs were added to that of MRK-1 to yield a composite efficacious unbound AUC, expressed as “parent drug equivalents,” which was used as the target AUC for predictions of the human efficacious dose. In vitro and preclinical PK studies afforded predictions of the PK of MRK-1 and the two active metabolites in human as well as the relative pathway flux to each metabolite. These were used to construct a PK model (Berkeley Madonna, version 8.3.18; Berkeley Madonna Inc., University of California, Berkeley, CA) and to predict the human dose required to achieve the target parent equivalent exposure. These predictions were used to inform on the feasibility of the human dose in terms of size, frequency, formulation, and likely safety margins, as well as to aid in the design of preclinical safety studies”, in figure 1 is shown the biotransforms, and in Table 1 is described the model with volume of distribution for each of the active molecule, as well as the biotransforms.
Claim 3 and 13: The computer-implemented method of claim 1, the calcimimetic administration comprising at least one dose titration process for the calcimimetic.
Claim 10: A computer-implemented method of virtual parathyroid gland (PTG) functionality analysis, the method comprising, via a processor of a computing device: providing a calcimimetic model configured to simulate administration of a calcimimetic compound to a patient with at least one health abnormality affecting PTG function, the calcimimetic model operative to: receive a calcimimetic dose, determine a concentration of the calcimimetic compound in at least one of a plurality of physiological compartments, each of the plurality of physiological compartments related to an adjacent physiological compartment via at least one constant rate function, and determine an output of a total calcimimetic concentration for at least one time period.
Claim 12: The computer-implemented method of claim 10, the plurality of physiological compartments comprising an absorption compartment, a first pass metabolism compartment, a plasma free drug compartment, a plasma protein bound compartment, a fast tissue compartment, and a slow tissue compartment.
Claim 13: The computer-implemented method of claim 12, the absorption compartment arranged adjacent to the first pass metabolism compartment and related via a constant rate function.
Claim 14: The computer-implemented method of claim 10, the calcimimetic model operative to determine a plurality of pharmacokinetic parameters simultaneously, the plurality of pharmacokinetic parameters comprising C.sub.max, t.sub.max, Bio, CL/F, t.sub.1/2, t.sub.1/2.sup.D, and VD, where C.sub.max is a maximum plasma concentration, t.sub.max is a time to reach C.sub.max, Bio is a bioavailability, CL/F is an apparent oral clearance rate, t.sub.1/2 is a terminal half-life, t.sub.1/2.sup.D, is a distribution half-life, and VD is a volume of distribution.
Claim 4 and 14: The computer-implemented method of claim [[1]]3, the at least one dose titration process comprising one or more of adjusting a dose of the calcimimetic on a constant time span, holding calcimimetic administration responsive to a calcium concentration being below a hold threshold, reducing a dose of the calcimimetic responsive to a calcium concentration being below a reduce threshold, or raising a calcimimetic dose responsive to a PTH concentration being within a threshold range.
Claim 13: The computer-implemented method of claim 12, the absorption compartment arranged adjacent to the first pass metabolism compartment and related via a constant rate function.
Claim 5 and 15: The computer-implemented method of claim 1, the pharmacokinetic model configured to simulate pharmacokinetic functionality of the calcimimetic for the at least one patient, the calcimimetic information for the pharmacokinetic model comprising a calcimimetic concentration.
Claim 10: A computer-implemented method of virtual parathyroid gland (PTG) functionality analysis, the method comprising, via a processor of a computing device: providing a calcimimetic model configured to simulate administration of a calcimimetic compound to a patient with at least one health abnormality affecting PTG function, the calcimimetic model operative to: receive a calcimimetic dose, determine a concentration of the calcimimetic compound in at least one of a plurality of physiological compartments, each of the plurality of physiological compartments related to an adjacent physiological compartment via at least one constant rate function, and determine an output of a total calcimimetic concentration for at least one time period.
Claim 8 and 18: The computer-implemented method of claim 1, the pharmacodynamic model configured to simulate pharmacodynamic functionality of the calcimimetic for the at least one patient, the calcimimetic information for the pharmacokinetic model comprising at least one of a parathyroid (PTH) concentration, a calcium concentration, or a phosphate concentration.
Claim 14: The computer-implemented method of claim 10, the calcimimetic model operative to determine a plurality of pharmacokinetic parameters simultaneously, the plurality of pharmacokinetic parameters comprising C.sub.max, t.sub.max, Bio, CL/F, t.sub.1/2, t.sub.1/2.sup.D, and VD, where C.sub.max is a maximum plasma concentration, t.sub.max is a time to reach C.sub.max, Bio is a bioavailability, CL/F is an apparent oral clearance rate, t.sub.1/2 is a terminal half-life, t.sub.1/2.sup.D, is a distribution half-life, and VD is a volume of distribution.
Claim 15: The computer-implemented method of claim 10, the output provided as a calcium concentration input of a PTG functionality model.
Response to Arguments
Applicant's arguments filed 2/4/2026 have been fully considered but they are not persuasive.
Applicant asserts that the claims have been amended to be patently distinct over U.S. Patent No. 11450405. Examiner submits that in view of newly cited art Martin et al., the claims as amended are not patentably distinct from U.S. Patent No. 11450405 but rather are obvious.
Conclusion
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/K.N.A./Examiner, Art Unit 1687
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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