DETAILED ACTION
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 .
Status of the Claims
Claims 1-2 and 5-23 are pending and examined herein.
Claims 3-4 are canceled.
Priority
As detailed on the 29 March 2022 filing receipt, the application claims priority as early as 25 September 2019. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Sequences
Sequences were filed 24 March 2022.
Withdrawn Objections
The objections to the specification are withdrawn in view of correction of typographical errors.
The objections to claims 2 and 20 are withdrawn in view of amendment explaining the abbreviation PBPK in the independent claims.
The objections to claims 3-4 are withdrawn in view of cancelation of the claims.
The objection to claim 7 is withdrawn in view of amendment regarding explanation of the abbreviation.
The objection to claim 12 is withdrawn in view of amendment adding the article “the” preceding cfRNA.
The rejection of claim 5 under 35 USC 112(b) is withdrawn in view of amendment to require N is at least three.
The rejection under 35 USC 103 is withdrawn in view of incorporation of the shedding correction factor formula into the independent claims. Close art, for example Lo (US 20090162842 A1; previously cited on the 15 December 2025 PTO-892 form) and Koh (WO 2015 069900 A1; previously cited on the 15 December 2025 PTO-892 form), while addressing normalizing cell-free RNA data, does not teach the shedding correction equation as required in the limitation.
Similarly, the non-statutory double patenting rejections are withdrawn in view of the amended independent claims which teach the combination of the corrected shedding factor equation, quantifying and weighing each gene for use in the formula, and application to individual and populations.
The following objections and/or rejections are either maintained or newly applied, and constitute the complete set of objections and/or rejections applied to the instant claims.
Claim Objection
Claim 20 is objected to for a minor informality: “regimen” is misspelled as “regiment.” Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 23, the parenthetical, even without the “e.g.” language, renders the claim indefinite because it remains unclear whether Alzheimer’s, Parkinson’s, ALS, multiple sclerosis, and Huntington’s are meant to be examples of neurodegenerative diseases that the subject may have or the only neurodegenerative diseases that may be considered. This rejection may be overcome by removing the parenthetical and instead recite “neurodegenerative diseases Alzheimer’s, Parkinson’s, ALS, multiple sclerosis, and Huntington’s;” or a similar amendment be entered.
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 1-2 and 5-23 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), 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)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of establishing a physiologically based pharmacokinetic model.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
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)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to methods (claims 1-2 and 5-23), which falls within one of the categories of statutory subject matter. [Step 1: Yes]
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))?
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)).
Mathematical concepts recited in the independent claims include: quantifying cell-free RNA (claims 1-2 and 20); executing an adjustment function including quantifying marker amounts, assigning weights, determining a correction factor, and correcting cfRNA amounts based on the correction factor (claims 1-2 and 20); and utilizing the data set to generate a PBPK model, which is recited to be “a multi-compartment model that simulates distribution, metabolism, or excretion of the xenobiotic molecule in a body” (claims 1-2 and 20). A mathematical relationship may be expressed in words and there is no particular word or set of words that indicates a claim recites a mathematical calculation (MPEP 2106.04(a)(2)). Adjusting numerical values is interpreted as a mathematical concept, the using data to generate the physiologically based pharmacokinetics, which is disclosed as “a series of differential equations with physiological parameters to represent a system” (specification: pg. 2, lines 16-17) is also interpreted as math.
Mental processes, defined as concepts practically performed in the human mind such as steps of observing, evaluating, or judging information, recited in the claims include: identifying abundance differences based on a comparison (claims 1-2 and 20), determining pharmacokinetic activity relevant to the xenobiotic molecule (claims 1-2 and 20), and combining the pharmacokinetic activities (claims 1-2 and 20). Identifying differences in values is interpreted as data evaluation and thus a mental process, but comparing values may also be a mathematical concept. Determining pharmacokinetic activity is interpreted as determining a result based on the data and thus is interpreted as a mental process. Combining the pharmacokinetic activities to create a dataset is interpreted as considering information together than thus also a mental process.
Claims 2 and 5 recite additional information about the adjustment function, which is a mathematical concept.
Claim 6 recites selecting an organ or tissue, where a selection is a mental process.
Claims 7-8 recite additional information about the quantification and thus directed to the mathematical steps.
Claims 9-13 recite additional information about the protein derived from the cfRNA sample. Claims 9 and 13 recite the selected protein’s function and claims 10-12 recite the protein itself, which are considered to be aspects of which protein is selected and selecting is a mental process.
Claims 16-17 recite information about the xenobiotic as a drug or toxin. This is interpreted as information related to the screening and selection of metabolizing proteins and thus part of the mental process.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: 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))?
Because the claims recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they integrate the judicial exceptions into a practical application (MPEP 2106.04(d)). A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception. This is performed by analyzing the additional elements of the claim to determine if the judicial exceptions are integrated into a practical application (MPEP 2106.04(d)(I); MPEP 2106.05(a-h)). If the claim contains no additional elements beyond the judicial exceptions, the claim is said to fail to integrate the judicial exceptions into a practical application (MPEP 2106.04(d)(III)).
Elements in addition to the abstract ideas recited are: isolating cell-free RNA from a liquid biopsy from individuals (claims 1 and 20) or a population (claim 2); the origin of the biopsy (claims 14-15, 18-19, and 21-22); treatment of the condition (claim 20); and the disease of the subject (claim 23).
Most of these claim elements are related to the biopsy and contents of the biopsy from the subject. The biopsy contains the cell-free RNA which is the basis of the correction and abundance modeling culminating in the physiologically-based pharmacokinetic model, and thus is interpreted as data gathering. Data gathering for use in the claimed processes is thus tangentially related and considered to be insignificant extra-solution activity (MPEP 2106.05(g)),which does not integrate the abstract idea into a practical application.
The last step of claim 20 recites administering a pharmaceutical compound in accordance with a dosage regimen optimized to an individual based on their personalized PBPK model. Claim 20 recites neither a particular condition being treated nor a particular pharmaceutical. Therefore, the claim does not recite a particular treatment or prophylaxis (MPEP 2106.04(d)(2)) and instead recites mere instructions to apply the exception where the claim recites only the idea of a solution or outcome without reciting details of how the solution is accomplished (MPEP 2106.05(f)), which does not integrate the abstract idea into a practical application. [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Elements in addition to the abstract ideas recited are: isolating cell-free RNA from a liquid biopsy from individuals (claims 1 and 20) or a population (claim 2); the origin of the biopsy (claims 14-15, 18-19, and 21-22); treatment of the condition (claim 20); and the disease of the subject (claim 23).
Zaporozhchenko (Expert Review of Molecular Diagnostics 18(2): 133-145, 2018; previously cited on the 15 December 2026 PTO-892 form) teaches cell-free RNA biomarkers from blood for use in diagnosing and ultimately treating cancer (abstract).
Dong (Frontiers in Veterinary Science 4(186): 7 pgs., 2017; previously cited on the 15 December 2026 PTO-892 form) teaches using circulating RNAs as biomarkers in a veterinary and thus non-human context (abstract).
Therefore, the aforementioned claim elements are interpreted as conventional in combination [Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Response to the 15 May 2026 Applicant Remarks
Applicant remarks state the claims recite “a specific computational technique for improving the accuracy and reliability of PBPK model generation from liquid biopsy data” and “the claimed subject matter improves the functioning of the PBPK modeling system itself - and by extension, the underlying computing system - by generating corrected and normalized biological inputs that permit more accurate simulation” (end of pg. 13). That is, the alleged improvement stems from the combination of liquid biopsy data and the model. However, the isolation of cfDNA for biomedical modeling is known within the state of the art at the date of filing and thus mere data gathering, which does not integrate the abstract idea into a practical application.
Applicant remarks recite the claims improve operation of a computer-based model (pg. 14, first paragraph). This argument is interpreted as improvement to a computer model comprising abstract ideas. A claim can be said to integrate a judicial exception into a practical application when it applies, relies on, or uses the judicial exception in a manner that imposes a meaningful limit on the judicial exception (MPEP 2106.04(d)). The biopsy and computer are for data gathering and instruction to apply in a computational environment (MPEP 2106.05(g) and MPEP 2106.05(f)). The model being improved is abstract and thus the abstract model is not integrated into a practical application. Applicant remarks state the claims are implemented using specific laboratory and computational operations (pg. 14, second paragraph) and determine pharmacokinetic activity and treatment-related dosing (pg. 14, third paragraph). Applicant remarks state administering a treatment according to a dosage regimen based on the PBPK model is directed analogous to Example 29 (pg. 14, fourth paragraph).
The claims do not appear to recite specific laboratory operations which are not known with the state of the art and computational operations on their own, as judicial exceptions, cannot provide an improvement. The treatment and dosage limitation of claim 20 is not particular to a condition or treatment itself and thus is not considered an improvement but mere instructions to apply the abstract ideas (MPEP 2106.04(d)(2)). Example 29 recites treatment of a particular condition, which is julitis, with a particular treatment, anti-JUL-1, topical vitamin D, or anti-TNF antibodies. Therefore, the particularity of instant claims and example 29 are not analogous.
Regarding Step 2B, applicant remarks state the claims recite an ordered combination of elements which amount to significantly more than any alleged exception, including cfRNA analysis, weighted normalization, shedding factor determination, correction, generation of models, and treatment optimization, which is not well-understood, routine, or conventional (pg. 15, first paragraph). At Step 2B, the elements in addition to the abstract ideas are further examined to determine if, alone or in combination, they are unconventional and thus provide significantly more than the abstract ideas. Of the listed elements, cfRNA analysis, normalization, shedding factor determination, subsequent correction, model generation, and treatment optimization are all abstract ideas. Elements in addition to the abstract ideas, such as collection of cfRNA and treatment of a condition, are conventional in combination and thus do not provide significantly more.
Therefore, the rejection under 35 USC 101 is maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/R.J.K./Examiner, Art Unit 1685
/OLIVIA M. WISE/Supervisory Patent Examiner, Art Unit 1685
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