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 1-23 are pending and examined herein. No claims 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.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 14 July 2022. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner.
Sequences
Sequences were filed 24 March 2022.
Specification
The disclosure is objected to because of the following informalities: “modeling” is misspelled as “modellling” (pg. 2, line 18); the phrase “dashboards, charts, pictograms or graphs may are added” should likely read “dashboards, charts, pictograms or graphs may are added” (pg. 33, lines 6-7); “A” in “In addition A second 12 hour window…” is unnecessarily capitalized (pg. 37, line 30); and there is an mid-line break in pg. 39, line 16. Appropriate correction is required.
Objections
Claims 2 and 20 are objected to for not explaining the abbreviation PBPK as found in claim 1.
Claims 3-4 are objected to because where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation (MPEP 608.01(i)).
Claim 7 is objected to because the abbreviation for cfRNA is previously explained in parent claim 1.
Claim 12 is objected to because the article “the” should precede cfRNA.
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.
Claims 5 and 23 are 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 5, the claim recites ranges of at least 3, at least 5, at least 8, and at least 10. Use of a narrow numerical range that falls within a broader range in the same claim may render the claim indefinite when the boundaries of the claim are not discernible. Description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim. If stated in a single claim, examples and preferences lead to confusion over the intended scope of the claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph should be made. MPEPE 2173.05(c) pertains.
Regarding claim 23, the phrase "e.g" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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- 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 1-23), 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); performing an adjustment function (claims 1-2 and 20) and utilizing the data set to generate a PBPK model (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 pharmacokinetic, 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 2-5 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 about 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))?
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 treatment step in claim 20 may overcome the rejection at Step 2A Prong Two, second consideration, which is a particular treatment (MPEP 2106.04(d)(2)). However, claim 20 recites neither a particular condition nor a particular treatment, and thus does not overcome the rejection at this step Instead, this is interpreted as 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.
None of the other dependent claims recite any additional non-abstract elements; they are all directed to further aspects of the information being analyzed, the manner in which that analysis is performed, or the mathematical operations performed on the information. [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; newly cited) 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; newly cited) 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.
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 6-23
Claims 1-2 and 6-23 are rejected under 35 U.S.C. 103 as being unpatentable over Ramanathan (WO 0200935 A1; newly cited) in view of Jing (University of Washington doctoral dissertation, 170 pgs., 2017; newly cited) and Lo (US 20090162842 A1; newly cited).
Claim 1 recites isolating total cell free RNA (cfRNATOTAL) from a liquid biopsy obtained from each individual subject comprised within the population.
Ramanathan teaches RNA isolated from blood cells (pg. 8, lines 15-16).
Claim 1 recites quantifying an amount of a first cell free RNA (cfRNA) present in the liquid biopsy, wherein the first cfRNA originates from a specified organ/tissue within the bodies of the subjects, and wherein the first cfRNA encodes a protein from the organ/tissue that is involved in pharmacokinetic activity relevant to the xenobiotic molecule selected from one or more of the group consisting of: absorption; distribution; localization; biotransformation; and excretion of the xenobiotic molecule.
Ramanathan teaches an example in which RNA in blood is used to estimate CYP levels in the liver (pg. 20, lines 16-17) for the purposes of estimating drug metabolizing enzymes in the liver (abstract). CYPs are disclosed as linked to xenobiotic (e.g., drug) metabolism and clearance (specification: pg. 15, lines 1-2), which is interpreted as tantamount to at least absorption, distribution, or excretion.
Claim 1 recites performing an adjustment function on the amount of the first cfRNA so as to correct for inherent levels of RNA shedding within each of the plurality of individual subjects.
Ramanathan does not teach adjustment for RNA shedding.
Claim 1 recites identifying the abundance of the protein within the specified organ/tissue for each subject by comparison of the corrected amount of the first cfRNA with abundance data for the corresponding amount of protein in the specified organ/tissue.
Ramanathan teaches the concept of RNA abundance, and by extension protein abundance (pg. 10, lines 33-34) but not following a shedding correction.
Claim 1 recites determining a pharmacokinetic activity relevant to the xenobiotic molecule for each individual subject based upon the abundance of the protein within the specified organ/tissue of the subject.
Ramanathan teaches drug clearance (abstract) but not specific xenobiotics.
Claim 1 recites combining the pharmacokinetic activities of each individual subject to create a data set of pharmacokinetic activities for the population of individuals.
Ramanathan does not teach application to a population of subjects.
Claim 1 recites utilizing the data set to generate the PBPK model.
Ramanathan teaches drug clearance having physiological factors in pharmacokinetics (pg. 1, lines 21-24), and using a model based on these data for individualized drug dosage.
Jing teaches application of PBPKs to xenobiotics (abstract) including analysis of a population of individuals with a shared condition (pg. 36, Section 2.3.1). Jing teaches application to all-trans retinoic acid and domoic acid (pg. 22, Section 1.6), which are interpreted as xenobiotics to which the models are directed.
Lo teaches normalizing transcript levels compared to a common transcript (pg. 12, col. 2, paragraph [114]), where the recited RNA shedding correction reads on normalization. Lo also teaches determining abundance of transcripts as “transcripts with increased expression” (pg. 3, col. 1, paragraph [27]). A specific tissue is taught in the form of placenta (Fig. 7).
Claim 2 recites the steps of claim 1, which are taught by the combination of Ramanathan, Jing, and Lo, except it is applied to an individual rather than a population with the above “combining” step omitted.
Lo teaches obtaining a blood sample from an individual (abstract).
Claim 6 recites the organ/tissue is selected from one or more of the group consisting of: the liver; the kidney; the gastrointestinal tract; the brain/CNS; and the pancreas.
Ramanathan also teaches drug metabolism and clearance by the kidney and gastrointestinal tract (pg. 2, lines 6-7).
Claim 7 recites quantifying an amount of a second cell free RNA (cfRNA) present in the liquid biopsy, wherein the second cfRNA originates from an organ/tissue within the body of the subject which has the capacity to undertake metabolic xenobiotic clearance, and wherein the second cfRNA encodes a protein from the organ/tissue that is involved in metabolic xenobiotic clearance.
Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance. Ramanathan also teaches drug metabolism and clearance by the kidney and gastrointestinal tract (pg. 2, lines 6-7).
Claim 8 recites quantifying an amount of a plurality of cell free RNAs (cfRNAs) present in the liquid biopsy, wherein the each of the plurality of cfRNAs originates from an organ/tissue within the body of the subject which has the capacity to undertake metabolic xenobiotic clearance, and wherein the plurality cfRNAs encode proteins from the organ/tissue that are involved in metabolic xenobiotic clearance.
Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance.
Claim 9 recites the organ/tissue-derived cfRNA encodes a xenobiotic handling protein selected from the group consisting of: a xenobiotic clearance protein; a xenobiotic metabolizing enzyme; and a xenobiotic transporting protein.
Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Claim 10 recites the cfRNA encodes a cytochrome P450 monooxygenase (CYP) protein.
Ramanathan teaches detecting CYPs from blood mRNA (pg. 1, first paragraph).
Claim 11 recites the CYP is selected from one of the group consisting of: CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7.
Ramanathan teaches CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 (Table 1), CYP2D6 (pg. 20, line 5), CYP2E1 (pg. 20, line 5), CYP3A4(pg. 20, line 5), CYP3A5 (pg. 20, line 5).
Claim 12 recites cfRNA encodes a transferase selected from one of the group consisting
of: a methyltransferase; a sulfotransferase; an N-acetyltransferase; a glucuronosyltransferase
including, but not limited to, one or more of the group consisting of UGT1A1, UGT1A3, UGT1A4,
UGT1 A6, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17; a glutathione-S-transferase; and a
choline acetyl transferase.
Ramanathan teaches enzymes including methyltransferases (Table 2), sulfotransferase (Table 2), an N-acetyltransferase (pg. 21, line 27), glucuronosyltransferase including UGT2B4 and UGT2B15 (Table 2), and glutathione-S-transferase (Table 2).
Claim 13 recites the cfRNA encodes a transporting protein selected from an ATP-binding cassette (ABC) transporter or a solute carrier (SLC) transporter.
Ramanathan teaches levels of monocarboxylic acid transporter (SLC16A1) and amiloride sensitive NA+/H+ antiporter (SLC9A1) (Table 3), which are solute carrier transporters.
Claim 14 recites the liquid biopsy comprises a sample of a bodily fluid selected from one of the group consisting of: blood; urine; saliva; semen; tears; lymphatic fluid; stool; bile; cerebrospinal fluid; and a mucus secretion.
Ramanathan teaches a method that is “blood-based” (pg. 1, first paragraph).
Claim 15 recites the liquid biopsy comprises whole blood, or a component thereof selected from serum or plasma.
Ramanathan teaches blood collected from an individual by any standard means (pg. 8, lines 11-12).
Claim 16 recites the xenobiotic is a pharmaceutical compound or a drug.
Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Claim 17 recites the xenobiotic is a toxin or an environmental contaminant.
Ramanathan teaches a toxin as far as drug toxicity (pg. 1, line 27).
Claims 18 and 21 recite the individual subject is a human.
Ramanathan teaches application to humans (pg. 3, line 23).
Claims 19 and 22 recite the individual subject is a non-human animal.
Jing teaches “animal studies” (pg. 27, last paragraph).
Claim 20 recites a method similar to claim 2 as taught by Ramanathan, Jing, and Lo, except it is directed to a pharmaceutical compound rather than a xenobiotic molecule, and culminates in treating the individual according to a dosage regimen for the pharmaceutical compound that is optimized to the individual based upon their personalized virtual PBPK model.
Jing teaches treatment of a condition following modeling using a PBPK (pg. 80, section 3.4.3).
Claim 23 recites the individual subject is suffering from a disease selected from any one of the group selected from: cancer; inflammatory disease; auto-immune disorders; allergy; metabolic diseases, including metabolic deficiency; degenerative diseases, including neurodegenerative diseases (e.g. Alzheimer's, Parkinson's, ALS, multiple sclerosis, Huntington's); psychiatric disorders; and infection, including chronic or acute infection from bacterial, viral, fungal or parasitic pathogens.
Jing teaches application of PBPK to cancer populations (pg. 32, Section 1.7).
Combining Ramanathan, Jing, and Lo
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 modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Jing with that of Ramanathan because Jing teaches application of a physiologically-based pharmacokinetic model to a xenobiotic specifically as well as treatment of the condition based on the outcome of the model. One would have been motivated to perform such a combination because treatment following creation of the PBPK model is a natural outcome having determined the model for how the body will react to the xenobiotic. Further combination of Lo, which teaches methods involving cell-free RNA normalization, would be desirable because expression levels should be seen as relative to common transcripts from a tissue (pg. 12, paragraph [114]). Normalizing data is a commonly performed statistical procedure and would be expected to succeed. It would have been obvious to combine Ramanathan, Jing, and Lo, because each reference discloses methods for analyzing RNA data. The cited prior art is directed to determination of pharmacokinetic models and/or treatment of cell-free RNA. Thus, the invention is prima facie obvious.
Claim 3
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ramanathan, Jing, and Lo as applied to claims 1-2 and 6-23 above and further in view of Koh (WO 2015 069900 A1; newly cited)
Claim 3 recites the adjustment function comprises identifying the amount of the first cfRNA present by correcting against a RNA organ Shedding Correction Factor (SCF) that is determined for the individual subject by performing an analysis of the cfRNATOTAL in order to quantify an amount of
mRNA present within the cfRNATOTAL that corresponds to each of two or more marker genes, wherein
a marker gene is defined as a gene that is expressed principally and consistently in the organ/tissue;
and determining SCF as the mean concentration of mRNA of the each of two or more marker genes
present within the cfRNATOTAL.
Lo teaches a method for normalizing transcripts against a single reference in the form of human placental lactogen (hPL) (pg. 12, paragraph [114]).
Koh teaches normalization against two housekeeping genes (pg. 116, last paragraph).
Combining Ramanathan, Jing, Lo, and Koh
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 modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Ramanathan, Jing, and Lo with that of Koh because Koh teaches methods for characterizing RNA in a blood sample (abstract), which are normalized against housekeeping genes to rescale their expression (pg. 13, last paragraph). Lo teaches normalization against a single housekeeping gene with a predictable expression level and Koh teaches two, where having more reference genes for comparison in the normalization is interpreted as providing greater confidence in the normalization procedure. Koh is directed to using cell-free RNA to ultimately treat a condition, and thus is in the same field of endeavor as previously cited art. Therefore the invention is prima facie obvious.
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.
Claims 1-4, 6, 10-15, 19-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-11, and 13-15 of copending Application No. 17/656,299 in view of Jing.
Claims 7-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/656,299 in view of Jing as applied to claims 1-4, 6, 10-15, 20, and 22-23 above and further in view of Lo and Ramanathan.
Claims 9, 16-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/656,299 in view of Jing as applied to claims 1-4, 6, 10-15, 20, and 22-23 above and further in view of Ramanathan.
This is a provisional nonstatutory double patenting rejection.
Regarding instant claim 1, reference claim 1 discloses the limitations except for application to a population and generating a pharmacokinetic model.
Jing teaches application of PBPKs to xenobiotics (abstract) including analysis of a population of individuals with a shared condition (pg. 36, Section 2.3.1). Jing teaches application to all-trans retinoic acid and domoic acid (pg. 22, Section 1.6), which are interpreted as xenobiotics to which the models are directed.
Regarding instant claim 2, reference claim 1 discloses the limitations except generating a pharmacokinetic model.
Jing teaches application of PBPKs to xenobiotics (abstract) including analysis of a population of individuals with a shared condition (pg. 36, Section 2.3.1). Jing teaches application to all-trans retinoic acid and domoic acid (pg. 22, Section 1.6), which are interpreted as xenobiotics to which the models are directed.
Regarding instant claim 3, the limitations are taught be reference claim 8.
Regarding instant claim 4, the limitations are taught be reference claim 9.
Regarding instant claim 6, the limitation of liver tissue is taught by reference claim 2.
Regarding instant claim 7, Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance. Ramanathan also teaches drug metabolism and clearance by the kidney and gastrointestinal tract (pg. 2, lines 6-7).
Regarding instant claim 8, Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance.
Regarding instant claim 9, Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Regarding instant claim 10, reference claim 10 teaches CYP.
Regarding instant claim 11, reference claim 11 teaches the CYP loci.
Regarding instant claim 12, reference claims 13-14 teach the required markers.
Regarding instant claim 13, reference claim 15 teaches the required proteins.
Regarding instant claim 14, reference claim 6 teaches the required biopsy liquids.
Regarding instant claim 15, reference claim 7 teaches the required biopsy liquids.
Regarding instant claim 16, Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Regarding instant claim 17, Ramanathan teaches a toxin as far as drug toxicity (pg. 1, line 27).
Regarding instant claims 18 and 21, Ramanathan teaches application to humans (pg. 3, line 23).
Regarding instant claims 19-22, Jing teaches “animal studies” (pg. 27, last paragraph).
Regarding instant claim 20, reference claim 1 teaches the required limitations except generating a pharmacokinetic model and treating the subject.
Jing teaches application of PBPKs to xenobiotics (abstract) including analysis of a population of individuals with a shared condition (pg. 36, Section 2.3.1). Jing teaches application to all-trans retinoic acid and domoic acid (pg. 22, Section 1.6), which are interpreted as xenobiotics to which the models are directed. Jing also teaches treatment following generation of the PBPK (e.g., pg. 19, Section 1.4).
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 modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Jing with that of the reference application because Jing teaches application of a physiologically-based pharmacokinetic model to a xenobiotic specifically as well as treatment of the condition based on the outcome of the model. One would have been motivated to perform such a combination because treatment following creation of the PBPK model is a natural outcome having determined the model for how the body will react to the xenobiotic. Further combination of Lo, which teaches methods involving cell-free RNA normalization, would be desirable because expression levels should be seen as relative to common transcripts from a tissue (pg. 12, paragraph [114]). One would have been motivated to combine the reference claims with the teachings of Ramanathan because Ramanthan teaches pharmacokinetic models for clearing drugs as related to drug dosage (pg. 2, second paragraph). It would have been obvious to combine the reference application and Jing, Loh, and Ramanathan because each reference discloses methods for analyzing RNA data. The cited prior art is directed to determination of pharmacokinetic models and/or treatment of cell-free RNA. Thus, the invention is prima facie obvious.
Claims 1-6, 9-18, and 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4-9, and 12-13 of copending Application No. 17/032,498 in view of Ramanathan.
Claims 7-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/656,299 in view of Ramanathan as applied to claims 1-6, 9-18, and 20-22 above and further in view of Loh.
Claims 19 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 17/656,299 in view of Ramanathan as applied to claims 1-6, 9-18, and 20-22 above and further in view of Jing.
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1-2, reference claim 1 discloses the limitations of instant claims 1-2 except for generating a model.
Ramanathan teaches drug clearance having physiological factors in pharmacokinetics (pg. 1, lines 21-24), and using a model based on these data for individualized drug dosage.
Regarding instant claim 3, reference claim 1 teaches a shedding correction factor.
Regarding instant claim 4, reference claim 12 teaches the calculation of the correction shedding factor.
Regarding instant claim 5, reference claim 13 teaches at least 3 markers.
Regarding instant claim 6, reference claim 2 teaches the required tissues/organs.
Regarding instant claim 7, Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance. Ramanathan also teaches drug metabolism and clearance by the kidney and gastrointestinal tract (pg. 2, lines 6-7).
Regarding instant claim 8, Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance.
Regarding instant claim 9, reference claim 4 teaches a xenobiotic metabolizing enzyme and a xenobiotic transporting protein
Regarding instant claim 10, reference claim 5 teaches a cytochrome P450 monooxygenase (CYP) protein.
Regarding instant claim 11, reference claim 6 teaches the required limitations.
Regarding instant claim 12, reference claim 7 teaches the required limitations.
Regarding instant claim 13, reference claims 8 and 9 teach the required limitations.
Regarding instant claims 14 and 21, reference claim 1 teaches the subject is a human.
Regarding instant claims 15 and 22, reference claim 1 teaches the subject is an animal.
Regarding instant claim 16, Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Regarding instant claim 17, Ramanathan teaches a toxin as far as drug toxicity (pg. 1, line 27).
Regarding instant claims 18 and 21, Ramanathan teaches application to humans (pg. 3, line 23).
Regarding instant claims 19 and 22, Jing teaches “animal studies” (pg. 27, last paragraph).
Regarding instant claim 20, reference claim 1 discloses the limitations except for treating according to a dosage regimen based on the personalized PBPK. Ramanathan teaches drug clearance having physiological factors in pharmacokinetics (pg. 1, lines 21-24), and using a model based on these data for individualized drug dosage.
Regarding instant claim 23, Jing teaches application of PBPK to cancer populations (pg. 32, Section 1.7).
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 modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the reference claims with the teachings of Ramanathan because Ramanthan teaches pharmacokinetic models for clearing drugs as related to drug dosage (pg. 2, second paragraph). One would have been motivated to combine the work of Jing with that of the reference application because Jing teaches application of a physiologically-based pharmacokinetic model to a xenobiotic specifically as well as treatment of the condition based on the outcome of the model. One would have been motivated to perform such a combination because treatment following creation of the PBPK model is a natural outcome having determined the model for how the body will react to the xenobiotic. Further combination of Lo, which teaches methods involving cell-free RNA normalization, would be desirable because expression levels should be seen as relative to common transcripts from a tissue (pg. 12, paragraph [114]). It would have been obvious to combine the reference claims with Ramanathan, Loh, and Jing because they are in the shared field of endeavor of determination of pharmacokinetic models and/or treatment of cell-free RNA. Thus, the invention is prima facie obvious.
Claims 1-2, 7, 10, 12-14, 16, 19-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 7, and 31 of copending Application No. 18/431,820 in view of Jing and Lo.
Claim 3 is are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 10, 12-14, 16, 19-20, and 22-23 above in view of the copending application in view of Jing and Lo and further in view of Koh.
Claims 6, 8-9, 11, 15, 17-18, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 7, 10, 12-14, 16, 19-20, and 22-23 above in view of the copending application in view of Jing and Lo and further in view of Ramanathan.
This is a provisional nonstatutory double patenting rejection.
Regarding instant claims 1-2, reference claim 1 discloses the limitations of instant claims 1-2 and 20 except application to xenobiotics, performing an adjustment function, and identifying the abundance of a protein.
Jing teaches application of PBPKs to xenobiotics (abstract) including analysis of a population of individuals with a shared condition (pg. 36, Section 2.3.1). Jing teaches application to all-trans retinoic acid and domoic acid (pg. 22, Section 1.6), which are interpreted as xenobiotics to which the models are directed.
Lo teaches normalizing transcript levels compared to a common transcript (pg. 12, col. 2, paragraph [114]), where the recited RNA shedding correction reads on normalization. Lo also teaches determining abundance of transcripts as “transcripts with increased expression” (pg. 3, col. 1, paragraph [27]). A specific tissue is taught in the form of placenta (Fig. 7).
Regarding instant claim 3, Lo teaches a method for normalizing transcripts against a single reference in the form of human placental lactogen (hPL) (pg. 12, paragraph [114]) and Koh teaches normalization against two housekeeping genes (pg. 116, last paragraph).
Regarding claim 6, Ramanathan also teaches drug metabolism and clearance by the kidney and gastrointestinal tract (pg. 2, lines 6-7).
Regarding instant claim 7, reference claim 7 teaches diseases affecting the liver, kidney, gastrointestinal tract, and brain.
Regarding claim 8, Lo teaches analysis of circulating RNA (abstract) and Ramanathan teaches application of monitoring liver enzymes in the blood (abstract), where the liver is an organ with the capacity of undertaking xenobiotic clearance.
Regarding claim 9, Ramanathan teaches clearance of drugs (abstract), where a xenobiotic reads on a drug, based on RNA in the blood.
Regarding instant claim 10, reference claim 31 teaches CYPs.
Regarding claim 11, Ramanathan teaches CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19 (Table 1), CYP2D6 (pg. 20, line 5), CYP2E1 (pg. 20, line 5), CYP3A4(pg. 20, line 5), CYP3A5 (pg. 20, line 5).
Regarding instant claim 12, reference claim 31 teaches transferases.
Regarding instant claim 13, reference claim 31 teaches membrane transport proteins.
Regarding instant claim 14, reference claim 4 teaches the required limitations.
Regarding claim 15, Ramanathan teaches blood collected from an individual by any standard means (pg. 8, lines 11-12).
Regarding instant claim 16, reference claim 3 recites the xenobiotic comprises a pharmaceutical agent.
Regarding claim 17, Ramanathan teaches a toxin as far as drug toxicity (pg. 1, line 27).
Regarding claims 18 and 21, Ramanathan teaches application to humans (pg. 3, line 23).
Regarding claims 19 and 22, Jing teaches “animal studies” (pg. 27, last paragraph).
Regarding instant claim 23, reference claim 7 recites diseases of the individual subject.
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 modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Jing with that of the reference application because Jing teaches application of a physiologically-based pharmacokinetic model to a xenobiotic specifically as well as treatment of the condition based on the outcome of the model. One would have been motivated to perform such a combination because treatment following creation of the PBPK model is a natural outcome having determined the model for how the body will react to the xenobiotic. Further combination of Lo, which teaches methods involving cell-free RNA normalization, would be desirable because expression levels should be seen as relative to common transcripts from a tissue (pg. 12, paragraph [114]). Normalizing data is a commonly performed statistical procedure and would be expected to succeed. One would have been motivated to combine the reference claims with the teachings of Ramanathan because Ramanthan teaches pharmacokinetic models for clearing drugs as related to drug dosage (pg. 2, second paragraph). Koh teaches two reference genes, where having more reference genes for comparison in the normalization is interpreted as providing greater confidence in the normalization procedure. Koh is directed to using cell-free RNA to ultimately treat a condition, and thus is in the same field of endeavor as previously cited art. It would have been obvious to combine the reference application with the cited prior art because each reference discloses methods for analyzing RNA data. The cited prior art is directed to determination of pharmacokinetic models and/or treatment of cell-free RNA. Thus, the invention is prima facie obvious.
Claims Free of the Prior Art
Subject to resolution of the above 112 and double patenting rejections, claims 4-5 are clear of the prior art. Close art, for example Lo and Koh cited above, while addressing normalizing cell-free RNA data, does not teach the shedding correction equation as required in the limitation of claim 4, and it is not clear that any combination of art would have rendered the claims obvious.
Conclusion
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/R.J.K./Examiner, Art Unit 1685
/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685