DETAILED ACTION
Notice of 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 .
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 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.
Status of the Claims
Claims 1-9 are pending.
Claims 1, 7 and 9 are objected to.
Claims 1-9 are rejected.
Priority
This application US 18/224,308 (07/20/2023) is a CON of US Application 17/374,315 (07/13/2021) which is a CON of US Application 17/070,599 (10/14/2020) which is a CON of US Application 16/092,396 (10/09/2018) which is a 371 of PCT/US2017/027309 0(4/13/2017) which claims benefit of US Application 62/323,015 (04/15/2016) and US Application 17/070,599 (10/14/2020) is a ClP of 14/311,113 (06/20/2014) which claims benefit of US Application 61/881,214 (09/23/2013) and claims benefit of US Application 61/840,969 (06/28/2013) and US Application 61/837,421 (06/20/2013), as reflected in the filing receipt mailed on 08/03/2023.
Having reviewed the disclosures of the priority applications, the examiner has been unable to find sufficient support for the limitation wherein the minimum threshold level is less than 20%" (claim 5) in 14/311,113 or any of the prior provisional applications. Accordingly, each of claims 1-4 and 6-9 are afforded the effective filing date of 06/20/2013 and claim 5 is afforded the effective filing date of 04/15/2016.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/20/2023, 02/02/2024 and 06/05/2024 were considered.
Drawings
The drawings are objected to as failing to comply with 37 CPR 1.84(p)(5) because they include: illegible labels in Figs. 32-35.
Corrected drawing sheets in compliance with 37 CPR 1.121 (d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as "amended." If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either "Replacement Sheet" or "New Sheet" pursuant to 3 7 CPR 1.121 (d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim objections
Claims 1-2, 7 and 9 are objected to because of the following informalities. Appropriate correction is required.
Claims 1 and 9 are objected to under 37 CFR 1.75 as being improper. Colons should begin lists in which list elements are separated by newlines, e.g. claim 1 "a specified dosing interval including (i) … and (ii)…" (5th claim element – 3rd determining step) should include a colon after “including” and list each sub step in a newline after the colon as set forth in 37 CPR 1.75. Claim 9 repeats the issue described.
In claim 2, the recited “the estimated pharmacokinetic profile of the patient upon previous treatments of the patient” should read “the estimated pharmacokinetic profile of the patient upon previous treatments of the patient” for proper grammar.
Claim 7 recites “wherein the estimated pharmacokinetic is based upon” should read “wherein the estimated pharmacokinetic profile is based upon” for proper claim agreement.
In claim 9, the active verbs in each step should not be recited in the present participle form, instead the steps should be in the present tense (i.e. calculate).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION —The specification shall 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.
Claim 5 is rejected under 35 U.S.C. 112(b)as being indefinite for failing to particularly point out and distinctly claim the subject matter the invention. Dependent claims are rejected similarly, unless otherwise noted below. The following issues cause the respective claims to be rejected under 112(b) as indefinite:
Claim 5 is indefinite because the recited “wherein the minimum threshold level is less than 20%” does not particularly point out what "20%" as a minimum threshold level means in this context; it could be interpreted as 20% of a maximum level, 20% of a median or normal level, 20% total volume or weight, or relative to some other quantity. For compact prosecution, the recited is being interpreted as a threshold relative to the plasma protein level.
Claim Rejections - 35 USC § 101
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 1-9 are rejected under 35 USC § 101 because the claimed inventions are directed to one or more Judicial Exceptions (JEs) without significantly more. Regarding JEs, "Claims directed to nothing more than abstract ideas..., natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 §I). Abstract ideas include mathematical concepts and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)).
101 background
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below. MPEP 2106 and the following USPTO website provide further explanation and case law citations: uspto.gov/patent/laws-and-regulations/examination-policy/examination-guidance-and-training-materials.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Analysis of instant claims
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The instant claims are directed to a method (claims 1-7) and a system (claims 8-9); each of which falls within one of the categories of statutory subject matter. [Step 1: claims 1-9: Yes]
Claim 8 recites “machine-accessible device having instructions stored thereon that are configured” in which “device” is being interpreted as limiting the claim to a machine (i.e. non-transitory embodiment).
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Background
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Analysis of instant claims
With respect to the instant claims, under Step 2A, Prong One evaluation, the claims are found to recite abstract ideas that fall into the grouping of mathematical concepts (in particular mathematical relationships and formulas) and mental processes (in particular procedures for observing, analyzing and organizing information) are as follows.
Mathematical concepts (in particular mathematical relationships and formulas) include:
• "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β" (independent claims 1 and 9);
• "determining, …, an estimated pharmacokinetic profile of a patient using a Bayesian model of pharmacokinetic profiles of sampled patients, the estimated pharmacokinetic profile being calculated such that: a first weighting factor is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is less than or equal to 1, and a second weighting factor, less than the first weighting factor, is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is greater than 1, such that patient-specific clearance data is weighted more heavily than population data" (independent claims 1 and 9) and
• "adjusting, …, the estimated pharmacokinetic profile of the patient upon previous treatments of the patient" (claim 2).
The claims identified above read on math. The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation and determined each element performed by mathematical operation. The step directed to “calculating an empirical estimate” to “estimate an estimated pharmacokinetic profile” requires mathematical techniques as the only supported embodiments because it describes a mathematical technique (MPEP 2106.04(a)(2) pertains). Further support for the mathematical techniques used in the claims is provided in the specification at pg. 1 para. 1, which discloses an algorithm implemented in the processing unit which generates a network map based on the plurality of datasets in the database and which allows for identifying nodes within network map based on predefined parameters; and at pg. 9 para. 3 which discloses the execution of logical operations. Thus, the recited terms correspond to verbal equivalents of mathematical concepts because they constitute actions executed by a group of mathematical steps in a form of a mathematical algorithm; thus, mathematical concepts (MPEP 2106.04(a)(2)). A mathematical concept need not be expressed in mathematical symbols, because "words used in a claim operating on data to solve a problem can serve the same purpose as a formula." In re Grams, 888 F.2d 835, 837 and n.1, 12 USPQ2d 1824, 1826 and n.1 (Fed. Cir. 1989). MPEP 2106.04(a)(2) pertains.
Mental processes, defined as concepts or steps practically performed in the human mind such as steps of observations, evaluations, judgments, analysis, opinions or organizing information include:
• “determining, …, the clotting factor dosing regimen for a specified dosing interval including (i) a dosage of a clotting factor therapeutic and (ii) an estimated clotting factor clearance for the patient over a time period based at least upon the estimated pharmacokinetic profile" (independent claims 1 and 9).
The abstract ideas recited in the claims are evaluated under the Broadest Reasonable Interpretation (BRI) and determined to each cover performance either in the mind (i.e. concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) or because the method only requires a user to manually determine action based on an added number. Under the BRI, the recited limitations are mental processes because a human mind is also sufficiently capable of determining a dosing regimen including an estimated parameter based on data acquired.
Dependent claims 3-7 recite further steps that limit the judicial exceptions in independent claim 1 and, as such, also are directed to those abstract ideas. For example, claim 3 recites further details about the dosing interval; claims 4-5 recites further details about the clotting dosing factor dosing regimen; claim 6 recites further details about the Bayesian model and claim 7 recites further details about the estimated pharmacokinetic.
[Step 2A Prong One: claims 1-9: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Background
MPEP 2106.04(d).I lists the following example considerations for evaluating whether a judicial exception is integrated into a practical application:
An improvement in the functioning of a computer or an improvement to other technology or another technical field, as discussed in MPEP §§ 2106.04(d)(1) and 2106.05(a);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, as discussed in MPEP § 2106.04(d)(2);
Implementing a judicial exception with, or using a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, as discussed in MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP § 2106.05(c); and
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception, as discussed in MPEP § 2106.05(e).
Analysis of instant claims
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2).
Instant claims 1 and 8-9 recite additional elements that are not abstract ideas:
• "processor/processors" (independent claims 1 and 9);
• "displaying the clotting factor dosing regimen on a client device" (independent claims 1 and 9);
• "machine-accessible device having instructions stored thereon" (claim 8) and
• "drug dosing tool” with processors coupled to memory” (claim 9).
Considerations under Step 2A, Prong Two
The limitations recited in claims 1-9 are interpreted as requiring the use of a computer. Hence, the claims explicitly recite steps executed by computers and therefore can be described as computer functions or instructions to implement on a generic computer.
Further steps directed to additional non-abstract elements of a computing device/computer do not describe any specific computational steps by which the "computer parts" perform or carry out the judicial exceptions, nor do they provide any details of how specific structures of the computer are used to implement these functions. The claims state nothing more than a generic computer which performs the functions that constitute judicial exceptions.
The judicial exceptions in the claims are considered to perform the claimed abstract idea with a computer, which is not sufficient to integrate an abstract idea into a practical application (see MPEP 2106.05(f)); since steps that can be performed mentally and merely performing the mental process in a computer environment do not negate the fact that something that can be carried out in the human mind. See MPEP 2106.04(a)(2).III.C.
Claims directed to "displaying the clotting factor dosing regimen on a client device" are interpreted as data outputting (i.e. the output from mathematical calculations in the judicial exception) and as such insignificant extra-solution activity.
Hence, these are mere instructions to apply the abstract idea using a computer and insignificant extra-solution activity and therefore the claims do not integrate that abstract idea into a practical application (see MPEP 2106.04(d) § I; 2106.05(f); and 2106.05(g)).
In Step 2A, Prong One above, claim steps and/or elements were identified as part of one or more judicial exceptions (JEs).
In this Step 2A, Prong Two immediately above claim steps and/or elements were identified as part of one or more additional elements. Additional elements are further discussed in Step 2B below.
Here in Step 2A, Prong Two, no additional step or element clearly demonstrates integration of the JE(s) into a practical application.
[Step 2A Prong Two: claims 1-9: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
According to analysis so far, the additional elements described above do not provide significantly more than the judicial exception. A determination of whether additional elements provide significantly more also rests on whether the additional elements or a combination of elements represent other than what is well-understood, routine, and conventional. Conventionality is a question of fact and may be evidenced as: a citation to an express statement in the specification or to a statement made by an applicant during examination that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
Claims 1-9 recite a computer or computer functions, interpreted as instructions to apply the abstract idea using a computer, where the computer does not impose meaningful limitations on the judicial exceptions; which can be performed without the use of a computer (MPEP 2106.04(d) § I; and MPEP 2106.05(f)).
Further, the courts have found that outputting data is a well-understood, routine, and conventional functions of a computer when claimed in a generic manner or as insignificant extra-solution activity (see Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014) (computer receives and sends information over a network), Versa ta Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015), and OIP Techs., 788 F.3d at 1363, 115 USPQ2d at 1092-93, as discussed in MPEP 2106.05(d)(Il)(i)).
When the claims are considered as a whole, they do not integrate the abstract idea into a practical application; they do not confine the use of the abstract idea to a particular technology; they do not solve a problem rooted in or arising from the use of a particular technology; they do not improve a technology by allowing the technology to perform a function that it previously was not capable of performing; and they do not provide any limitations beyond generally linking the use of the abstract idea to a broad technological environment. See MPEP 2106.05(a) and 2106.05(h).
The instant claims constitute insignificant extra solution activity, and when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(g)). Hence, these elements, when considered individually, are insufficient to constitute inventive concepts that would render the claims significantly more than an abstract idea (see MPEP 2106.05(d)).
[Step 2B: claims 1-9: No]
Conclusion: Instant claims are directed to non-statutory subject matter
For the reasons above, the claims in this instant application, when the limitations are considered individually and as a whole, are directed to an abstract idea and lack an inventive concept not clearly anything significantly more.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
A. Claims 1-3 and 6-9 are rejected under 35 U.S.C. 103(a) as being unpatentable over Björkman12 ("Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight." Blood, The Journal of the American Society of Hematology 119.2:612-618 (2012)) in view of Dansirikul ("A Bayesian approach for population pharmacokinetic modelling of sirolimus." British journal of clinical pharmacology 62.4: 420-434 (2006)) in view of Björkman11 ("Evaluation of the TCIWorks Bayesian computer program for estimation of individual pharmacokinetics of FVIII." Haemophilia 17.1: e239 (2011)), as cited on the attached Form PTO-892.
Claim 1 recites a method comprising steps. Claim 9 recites a drug dosing tool comprising one or more processors coupled to memory, the one or more processors configured to perform the actions comprising said steps.
The prior art to Björkman12 discloses a method and a system related a model built for clotting factor VIII pharmacokinetics from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A (pg. 612 Abstract); which was built using the SAS Version 9.13 software (i.e. use of a processor) (pg. 613 col. 1 para. 2). Dansirikul teaches a Bayesian analysis from therapeutic drug monitoring - to aid dose individualization (pg. 421 col. 2 para. 1) using PKBUGS (v 1.1), an interface of the software program WinBUGS 1.3 (MRC Biostatistics Unit, Cambridge, UK) and Markov chain Monte Carlo (MCMC) techniques to make inferences about posterior distributions of the parameters of interest with MCMC as an iterative simulation-based approach (i.e. use of a processor) (pg. 422 col. 1 para. 4). Additionally, Björkman11 teaches a Bayesian computer program TCIWorks for estimation of the PK of clotting factor VIII (FVIII) in individual patients (pg. e239 col. 1 para. 1) and calculation of practical dose to be given on alternate days (pg. e240 col. 1 para. 3) for PK-based dose tailoring of FVIII (pg. e240 col. 2 para. 2) (i.e. drug dosing tool).
The steps performed by the method of claim 1, a drug dosing tool of claim 9 comprise:
calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression;
calculating a population estimated clotting factor elimination rate constant β;
determining a ratio of λz /β
• Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract); wherein parameters were obtained for all patients and all study occasions as empirical Bayes estimates - by Bayesian estimation using the population model parameters in conjunction with the clotting factor VIII (FVIII) level data from each person - and individual clearance rate values (i.e. elimination rate constant) or the mean of the 2 values in case of repeated infusion - [of FVIII concentrate] - from the 100 patients (i.e. calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic) were used to investigate the statistical distribution of CL in the 10- to 65-year age group (i.e. calculating a population estimated clotting factor elimination rate constant β) (pg. 613 col. 2 para. 3); wherein elimination rate was originally estimated by linear regression (pg. 616 Fig. 5 C); wherein clearance estimate for the final model based on data from all patients was reported at 193 mL/h with a 30% interindividual variability (pg. 615 Table 3) (i.e. the reported 30% interindividual variability reads on the recited ratio of λz /β since, conceptually, a patient with 30% positive variability – for example - would have an estimated clearance of 250.9 mL/h then the recited ratio would be calculated as 250.9/193 which would be 1.3 – arriving at the taught 30% variability).
determining, via a processor, an estimated pharmacokinetic profile of a patient using a Bayesian model of pharmacokinetic profiles of sampled patients, the estimated pharmacokinetic profile being calculated such that:
a first weighting factor is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is less than or equal to 1, and
a second weighting factor, less than the first weighting factor, is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is greater than 1, such that patient-specific clearance data is weighted more heavily than population data
• Björkman12 teaches “determining, via a processor, an estimated PK profile of a patient using a Bayesian model of pharmacokinetic profiles of sampled patients” as parameters estimates obtained for all patients and all study occasions as empirical Bayes estimates (pg. 613 col. 2 para. 3); wherein the model was built using the SAS Version 9.13 software (pg. 613 col. 1 para. 2).
• Björkman12 does not teach “the estimated pharmacokinetic profile being calculated such that: a first weighting factor is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is less than or equal to 1, and a second weighting factor, less than the first weighting factor, is applied to the Bayesian model of pharmacokinetic profiles of sampled patients if the ratio of λz /β is greater than 1, such that patient-specific clearance data is weighted more heavily than population data.” However, Dansirikul teaches a Bayesian population modelling approach with informative priors for the analysis of poorly informative data for sirolimus - from therapeutic drug monitoring - to aid dose individualization (pg. 421 col. 2 para. 1); wherein implementation of a fully conditional Bayesian approach for the analysis allows the posterior distribution of parameters to be estimated, conditional on informative priors (pg. 428 col. 2 para. 2); wherein a total of 14 sets of pharmacokinetic parameter data were available for computation of the priors and a reciprocal variance weighting approach was used to calculate the weighted means of structural pharmacokinetic parameters and their between subject variance (pg. 422 col. 1 para. 3); wherein, in the computation of priors, wk as the weight applied to the kth PK parameter values (pg. 433 col. 1 para. 3); wherein prior parameters included CL (clearance rate), V (volume of distribution rate), and ka (absorption constant rate), for the two-compartment model (pg. 425 Table 2); wherein an empirical additional weighting factor of 0.5 was applied to information gathered from different populations - multiplying the number of subjects by 0.5 - and the sensitivity of said additional weighting factor was tested using weighting factors of 0.25 and 0.75 in place of 0.5 (pg. 434 col. 1 para. 2).
• Here, the model taught by Dansirikul teaches the use of multiple weighting factors applied to multiple parameters where clearance rate is one of said parameters studied by the proposed Bayesian pharmacokinetic model. An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. For the ratio of λz /β parameter, it would be obvious for one of ordinary skill to assign different weight factors to different ranges of estimated parameter (i.e. >1 or <=1) to improve the quality of the data being generated for the PK model and to stabilize the modelling process in a population analysis were data would otherwise have been missed without the use of Bayesian analysis with informative priors (i.e. estimated pharmacokinetic profiles of sampled patients) (pg. 431 col. 1 para. 4 Dansirikul). 2144.05 II states - The Supreme Court has clarified that an "obvious to try" line of reasoning may properly support an obviousness rejection. In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because "obvious to try" is not a valid rationale for an obviousness finding.
determining, via the processor, the clotting factor dosing regimen for a specified dosing interval including
(i) a dosage of a clotting factor therapeutic and
(ii) an estimated clotting factor clearance for the patient over a time period based at least upon the estimated pharmacokinetic profile; and
displaying the clotting factor dosing regimen on a client device
• Björkman12 does not teach the recitation above. However, Björkman11 teaches a Bayesian computer program TCIWorks for estimation of the PK of clotting factor VIII (FVIII) in individual patients (pg. e239 col. 1 para. 1) and calculation of practical dose to be given on alternate days (i.e. dosing interval – 48 hrs) during prophylaxis for 21 patients (pg. e240 col. 1 para. 3) for PK-based dose tailoring of FVIII (pg. e240 col. 2 para. 2); wherein calculations of optimal dose for a 1.0 U dL-1 were validated (i.e. (i) a dosage of a clotting factor therapeutic) (pg. e239 col. 1 para. 2); wherein Bayesian estimates of clearance (CL) and half-life (t½) with parameters from the model-fit of the full data were obtained (i.e. (ii) an estimated clotting factor clearance for the patient over a time period based at least upon the estimated pharmacokinetic profile) (pg. e240 col. 1 para. 3). Here, the display of the described dosing regimen by Björkman11 is an inherent function of a computer program that has been used to calculate such regimen because the software in use inherently outputs the result of any calculation made in the computer screen which reads on “displaying the clotting factor dosing regimen on a client device.”
Claim 2 recites:
further comprising adjusting, via the processor, the estimated pharmacokinetic profile of the patient upon previous treatments of the patient
• Björkman12 teaches that measured FVIII levels from the patient can be used to adjust the PK model parameters (p. 613, col. 2). Since some of the FVIII measurements are made after the patient has been treated with FVIII, subsequent adjustment of the PK model parameters constitutes "adjusting … the estimated PK profile of the patient [based] upon previous treatments of the patient".
Claim 3 recites:
wherein the specified dosing interval is 48 hours or 72 hours.
• Björkman12 does not teach the recitation above. However, Björkman11 teaches a Bayesian computer program TCIWorks for estimation of the PK of FVIII in individual patients (pg. e239 col. 1 para. 1) and calculation of practical dose to be given on alternate days (i.e. dosing interval – 48 hrs) during prophylaxis for 21 patients (pg. e240 col. 1 para. 3) for PK-based dose tailoring of FVIII (pg. e240 col. 2 para. 2).
Claim 6 recites:
wherein the Bayesian model includes a two-compartment model having a first compartment corresponding to a time to metabolize the clotting factor and a second compartment corresponding to a dose for achieving a certain amount of the clotting factor within the patient
• Björkman12 teaches a two-compartment PK model; the second compartment corresponds to the clearance rate (i.e. time to metabolize the clotting) and the first corresponds to the amount of clotting factor VIII in plasma (i.e. dose for achieving a certain amount of the clotting factor within the patient) (pg. 613 col. 1 para. 3).
Claim 7 recites:
wherein the estimated pharmacokinetic is based upon at least one of a body weight or an age of the patient
• Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract) investigating the relationships of pharmacokinetics to age and body weight (pg. 612 Title).
Claim 8 recites:
A machine-accessible device having instructions stored thereon that are configured, when executed, to cause a machine to at least carry out the method of claim
• Björkman12 teaches a model built for clotting factor VIII pharmacokinetics from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A (pg. 612 Abstract); wherein was built using the SAS Version 9.13 software (i.e. use of a processor) (pg. 613 col. 1 para. 2). Similarly, Dansirikul teaches a Bayesian analysis from therapeutic drug monitoring - to aid dose individualization (pg. 421 col. 2 para. 1) using PKBUGS (v 1.1), an interface of the software program WinBUGS 1.3 (MRC Biostatistics Unit, Cambridge, UK) and Markov chain Monte Carlo (MCMC) techniques to make inferences about posterior distributions of the parameters of interest with MCMC as an iterative simulation-based approach (i.e. use of a processor) (pg. 422 col. 1 para. 4). Additionally, Björkman11 teaches a Bayesian computer program TCIWorks for estimation of the PK of clotting factor VIII (FVIII) in individual patients (pg. e239 col. 1 para. 1) and calculation of practical dose to be given on alternate days (pg. e240 col. 1 para. 3) for PK-based dose tailoring of FVIII (pg. e240 col. 2 para. 2) (i.e. drug dosing tool).
Rationale for combining (MPEP §2142-2143)
Regarding claims 1-3 and 6-9, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Björkman12 in view of Dansirikul and Björkman11 because all references disclose methods for creating a patient-specific optimal prophylactic therapy. The motivation would have been to:
• stabilize the modelling process in a population analysis were data would otherwise have been missed without the use of Bayesian analysis with informative priors (pg. 431 col. 1 para. 4 Dansirikul) and
• to incorporate sparse blood sampling and Bayesian estimation of individual FVIII PK in a simulated clinical setting, during prophylactic treatment (pg. e239 col. 1 para. 1 Björkman11).
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the creation of patient-specific optimal prophylactic therapy of Björkman12 to the methods by Dansirikul and Björkman11 because such a substitution is no more than the simple substitution of one known element for another. One of ordinary skill in the art would be able to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for creating a patient-specific optimal prophylactic therapy.
B. Claim 4 is rejected under 35 U.S.C. 103(a) as being unpatentable over Björkman, Dansirikul and Björkman11 as applied to claim 1 above further in view of Collins ("Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia." Haemophilia 17.1: 2-10 (2011)) in view of Condurso (US Application No. 2006/0047538A1)), as cited on the attached Form PTO-892.
Claim 4 recites:
wherein the clotting factor dosing regimen is determined such that a level of clotting factor in the patient over time does not fall below a minimum threshold level
• Neither Björkman12 or Dansirikul or Björkman11 teach the recitation above. However, Collins teaches that an important parameter for planning a FVIII dosage regimen is the amount of time that the FVIII concentration is below a minimum target level (pg. 7 col. 2 para. 2). Similarly, Condurso teaches that an objective of the PK modeling system is to provide the drug in a manner that maintains the concentration of the drug within a desired range [0136, 0138, 0140]; in this context, "maintaining" a concentration within a range implies that the concentration should be in the range for as long as possible, which reads on a concentration “in the patient over time does not fall below a minimum threshold level.”
Rationale for combining (MPEP §2142-2143)
Regarding claim 4, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Björkman12, Dansirikul and Björkman11 in view of Collins and Condurso because all references disclose methods for creating a patient-specific optimal prophylactic therapy. The motivation would have been to:
• minimize the trough time of FVIII activity maintaining FVIII/IX above a certain level to achieve the desired phenotypic changes (pg. 3 col. 2 para. 4 Collins); and
• maintain the concentration of the drug within a desired range [0136, 0138, 0140] Condurso).
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the creation of patient-specific optimal prophylactic therapy of Björkman12, Dansirikul and Björkman11 to the methods by Collins and Condurso because such a substitution is no more than the simple substitution of one known element for another. One of ordinary skill in the art would be able to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for creating a patient-specific optimal prophylactic therapy.
C. Claim 5 is rejected under 35 U.S.C. 103(a) as being unpatentable over Björkman, Dansirikul and Björkman11 as applied to claim 1 above further in view of Loew-Baselli (US Patent Application 20140379629A1), as cited on the attached Form PTO-892.
Claim 5 recites:
wherein the minimum threshold level is less than 20%.
• Neither Björkman12 or Dansirikul or Björkman11 teach the recitation above. However, Loew-Baselli teaches method of claim 1, wherein the minimum threshold level is less than 20% ([0016] "the minimum threshold level is less than 20 percent").
Rationale for combining (MPEP §2142-2143)
Regarding claim 5, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Björkman12, Dansirikul and Björkman11 in view of Loew-Baselli because all references disclose methods for creating a patient-specific optimal prophylactic therapy. The motivation would have been to:
• design a system to avoid any chance of a patient falling below a predetermined threshold ([0016] Loew-Baselli).
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the creation of patient-specific optimal prophylactic therapy of Björkman12, Dansirikul and Björkman11 to the methods by Loew-Baselli because such a substitution is no more than the simple substitution of one known element for another. One of ordinary skill in the art would be able to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for creating a patient-specific optimal prophylactic therapy.
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.
A. Claims 1-9 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 3-4, 6-7 and 9 of US Patent No. 11,081,211 B2 in view of Björkman12 ("Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight." Blood, The Journal of the American Society of Hematology 119.2: 612-618 (2012))
• Reference claims 1 and 9 teach instant claim 1 except for the limitations "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β", which the prior art teaches.
• Regarding the recited "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β” in instant claim 1, Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract); wherein parameters were obtained for all patients and all study occasions as empirical Bayes estimates - by Bayesian estimation using the population model parameters in conjunction with the clotting factor VIII (FVIII) level data from each person - and individual clearance rate values (i.e. elimination rate constant) or the mean of the 2 values in case of repeated infusion - [of FVIII concentrate] - from the 100 patients (i.e. calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic) were used to investigate the statistical distribution of CL in the 10- to 65-year age group (i.e. calculating a population estimated clotting factor elimination rate constant β) (pg. 613 col. 2 para. 3); wherein elimination rate was originally estimated by linear regression (pg. 616 Fig. 5 C); wherein clearance estimate for the final model based on data from all patients was reported at 193 mL/h with a 30% interindividual variability (pg. 615 Table 3) (i.e. the reported 30% interindividual variability reads on the recited ratio of λz /β since, conceptually, a patient with 30% positive variability – for example - would have an estimated clearance of 250.9 mL/h then the recited ratio would be calculated as 250.9/193 which would be 1.3 – arriving at the taught 30% variability).
• Patent No. 11,081,211 B2 does not teach instant claim 2. However, Björkman12 teaches that measured FVIII levels from the patient can be used to adjust the PK model parameters (p. 613, col. 2). Since some of the FVIII measurements are made after the patient has been treated with FVIII, subsequent adjustment of the PK model parameters constitutes "adjusting … the estimated PK profile of the patient [based] upon previous treatments of the patient".
• Reference claim 1 teaches instant claim 2.
• Reference claim 3 teaches instant claim 3.
• Reference claim 4 teaches instant claims 4-5.
• Reference claim 6 teaches instant claims 6.
• Reference claim 1 teaches instant claims 7.
• Reference claim 7 teaches instant claims 8.
• Reference claims 1 and 9 teach instant claim 9 except for the limitations "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β", which the prior art teaches.
• Regarding the recited "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β” in instant claim 9, Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract); wherein parameters were obtained for all patients and all study occasions as empirical Bayes estimates - by Bayesian estimation using the population model parameters in conjunction with the clotting factor VIII (FVIII) level data from each person - and individual clearance rate values (i.e. elimination rate constant) or the mean of the 2 values in case of repeated infusion - [of FVIII concentrate] - from the 100 patients (i.e. calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic) were used to investigate the statistical distribution of CL in the 10- to 65-year age group (i.e. calculating a population estimated clotting factor elimination rate constant β) (pg. 613 col. 2 para. 3); wherein elimination rate was originally estimated by linear regression (pg. 616 Fig. 5 C); wherein clearance estimate for the final model based on data from all patients was reported at 193 mL/h with a 30% interindividual variability (pg. 615 Table 3) (i.e. the reported 30% interindividual variability reads on the recited ratio of λz /β since, conceptually, a patient with 30% positive variability – for example - would have an estimated clearance of 250.9 mL/h then the recited ratio would be calculated as 250.9/193 which would be 1.3 – arriving at the taught 30% variability).
Rationale for combining (MPEP §2142-2143)
Regarding claims 1-9, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Patent No. 11,081,211 B2 in view of Björkman12 because all references disclose machine learning methods for creating a patient-specific optimal prophylactic therapy. The motivation would have been to:
• incorporate a feasible PK analysis into easily used therapeutic drug monitoring computer programs allowing allow hemophilia centers to assess individual FVIII PK in children and adults using only 2 or 3 post infusion samples (pg. 617 col. 2 para. 2 Björkman12).
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the creation of patient-specific optimal prophylactic therapy of Patent No. 11,081,211 B2 to the methods by Björkman12 because such a substitution is no more than the simple substitution of one known element for another. One of ordinary skill in the art would be able to be motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for creating a patient-specific optimal prophylactic therapy.
B. Claims 1-9 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-5, 7, 9 and 15 of US Patent No. 11,670,409 B2 in view of Björkman12 ("Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight." Blood, The Journal of the American Society of Hematology 119.2: 612-618 (2012))
• Reference claims 1 and 15 teaches instant claim 1.
• Reference claim 2 teaches instant claim 2.
• Reference claim 3 teaches instant claim 3.
• Reference claim 4 teaches instant claims 4.
• Reference claim 5 teaches instant claims 5.
• Reference claim 7 teaches instant claims 6.
• Reference claim 1 teaches instant claims 7.
• Reference claim 9 teaches instant claims 8.
• Reference claims 1 and 15 teach instant claim 9
C. Claims 1-4 and 6-9 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1, 3-5 and 8-9 of US Patent No. 11,749,394 B2 in view of Björkman12 ("Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight." Blood, The Journal of the American Society of Hematology 119.2: 612-618 (2012))
• Reference claims 1 and 9 teach instant claim 1 except for the limitations "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β", which the prior art teaches.
• Regarding the recited "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β” in instant claim 1, Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract); wherein parameters were obtained for all patients and all study occasions as empirical Bayes estimates - by Bayesian estimation using the population model parameters in conjunction with the clotting factor VIII (FVIII) level data from each person - and individual clearance rate values (i.e. elimination rate constant) or the mean of the 2 values in case of repeated infusion - [of FVIII concentrate] - from the 100 patients (i.e. calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic) were used to investigate the statistical distribution of CL in the 10- to 65-year age group (i.e. calculating a population estimated clotting factor elimination rate constant β) (pg. 613 col. 2 para. 3); wherein elimination rate was originally estimated by linear regression (pg. 616 Fig. 5 C); wherein clearance estimate for the final model based on data from all patients was reported at 193 mL/h with a 30% interindividual variability (pg. 615 Table 3) (i.e. the reported 30% interindividual variability reads on the recited ratio of λz /β since, conceptually, a patient with 30% positive variability – for example - would have an estimated clearance of 250.9 mL/h then the recited ratio would be calculated as 250.9/193 which would be 1.3 – arriving at the taught 30% variability).
• Patent No. 11,749,394 B2 does not teach instant claim 2. However, Björkman12 teaches that measured FVIII levels from the patient can be used to adjust the PK model parameters (p. 613, col. 2). Since some of the FVIII measurements are made after the patient has been treated with FVIII, subsequent adjustment of the PK model parameters constitutes "adjusting … the estimated PK profile of the patient [based] upon previous treatments of the patient".
• Reference claim 3 teaches instant claim 3.
• Reference claim 5 teaches instant claim 4.
• Reference claim 4 teaches instant claim 6.
• Reference claim 8 teaches instant claims 7-8.
• Reference claims 8 and 9 teach instant claim 9 except for the limitations "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β", which the prior art teaches.
• Regarding the recited "calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic, and wherein the empirical estimate λz of the patient's clotting factor elimination rate constant is calculated by obtaining an absolute value of a slope of a log-linear regression; calculating a population estimated clotting factor elimination rate constant β; determining a ratio of λz /β” in instant claim 9, Björkman12 teaches the comparison of the pharmacokinetics (PK) model of a coagulation factor between groups of patients (pg. 612 Abstract); wherein parameters were obtained for all patients and all study occasions as empirical Bayes estimates - by Bayesian estimation using the population model parameters in conjunction with the clotting factor VIII (FVIII) level data from each person - and individual clearance rate values (i.e. elimination rate constant) or the mean of the 2 values in case of repeated infusion - [of FVIII concentrate] - from the 100 patients (i.e. calculating an empirical estimate λz of a patient's clotting factor elimination rate constant based on two blood samples having been collected from the patient after an infusion of a clotting factor therapeutic) were used to investigate the statistical distribution of CL in the 10- to 65-year age group (i.e. calculating a population estimated clotting factor elimination rate constant β) (pg. 613 col. 2 para. 3); wherein elimination rate was originally estimated by linear regression (pg. 616 Fig. 5 C); wherein clearance estimate for the final model based on data from all patients was reported at 193 mL/h with a 30% interindividual variability (pg. 615 Table 3) (i.e. the reported 30% interindividual variability reads on the recited ratio of λz /β since, conceptually, a patient with 30% positive variability – for example - would have an estimated clearance of 250.9 mL/h then the recited ratio would be calculated as 250.9/193 which would be 1.3 – arriving at the taught 30% variability).
Rationale for combining (MPEP §2142-2143)
Regarding claims 1-4 and 6-9, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine, in the course of routine experimentation and with a reasonable expectation of success, the methods of Patent No. 11,749,394 B2 in view of Björkman12 because all references disclose machine learning methods for creating a patient-specific optimal prophylactic therapy. The motivation would have been to:
• incorporate a feasible PK analysis into easily used therapeutic drug monitoring computer programs allowing allow hemophilia centers to assess individual FVIII PK in children and adults using only 2 or 3 post infusion samples (pg. 617 col. 2 para. 2 Björkman12).
Therefore, it would have been obvious to one of ordinary skill in the art to substitute the creation of patient-specific optimal prophylactic therapy of Patent No. 11,749,394 B2 to the methods by Björkman12 because such a substitution is no more than the simple substitution of one known element for another. One of ordinary skill in the art would be able to be motivated to combine the teachings in these references with a reasonable expectation of success since the described teachings pertain to methods for creating a patient-specific optimal prophylactic therapy.
Conclusion
No claims are allowed.
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/F.F.L./Examiner, Art Unit 1685
/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685
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