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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/17/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
Acknowledgment is made of applicant’s claim for priority. Application claims benefit of U.S. Provisional Application No. 63/166,803 filed on 3/30/2021. As such, the effective filing date of claims 1-21 is 3/26/2021.
Claim Status
Claims 1-21 are pending.
Claims 1-21 are rejected.
Claim Objections
Claim 10 objected to because of the following informalities: “herein a pathogenic mutation or strength altering variation in a gene, is used to predict the disease, drug response, or a severity of a disease, level of drug response, or drug dosage” should be changed to “herein a pathogenic mutation or strength altering variation in a gene, is used to predict the disease, drug response, a severity of a disease, level of drug response, or drug dosage”, removing the first use of the word “or”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2, 4-7, 12, 14-15, 17 and 20 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.
Claims 2, and 4-5 recite “the plurality of variants”, however, claim 1 recites two “a plurality of variants”. It is unclear which of these two recitations the limitation in claim 2 is referencing or if these are intended to be the same plurality of variants.
Regarding claim 2, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 4-5, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 9, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claims 13-14, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 19, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The term “similar” in claims 4-6 and 15 is a relative term which renders the claim indefinite. The term “similar” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The use of the term renders the “pathogenic variation in the same gene”, “strength altering variation”, “pathogenic or strength altering mutations”, and “genes of a biochemical or biological type” indefinite.
In claims 7 and 12 it is unclear if the limitations in parentheses are limitations on the claim or merely examples of what is encompassed in the term pathogenic and strength altering variations.
The phrase “PGx” in claim 14 is defined in paragraph [0107] as “Pharmacogenomics module”, however the relation to what makes a “PGx gene” is not clearly defined and is therefore indefinite.
The terms “high” and “low” in claim 15 are relative terms which render the claim indefinite. The terms “high” and “low” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The use of the term renders the “dosage” indefinite.
Claim 17 states “identifying pharmacogene biomarkers or therapeutic gene biomarkers but then requires the predicting based on both biomarkers. It is therefore unclear if there is a need to identify one in the metes and bounds of the claim or to identify both.
Regarding claim 20, the phrase "or”, in conjunction with the latter use of both items joined said phrase renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are necessitated or not. See MPEP § 2173.05(d). Additionally, the use of the word “or” suggests a need for only one, while the direction in the second part of the claim necessitates the need for both. The specification provides no clarification in this regard.
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 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and natural phenomenon (the natural relationship between the genotype of an individual and drug efficacy/metabolism/etc.) without significantly more. The claims recite methods for performing a comprehensive use of genetic data in pharmaceutical and therapeutic applications. The judicial exception is not integrated into a practical application because while claims 1-21 attempt to integrated the exception into a practical application, said application is either generically recited computer elements that do not add a meaningful limitation to the abstract idea or it is insignificant extra solution activity and merely implementing the abstract idea on a computer. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the computer elements only store and retrieve information in memory as well as perform basic calculations that are known to be well-understood, routine and conventional computer functions as recognized by the decisions listed in MPEP § 2106.05(d).
Framework with which to Analyze Subject Matter Eligibility:
Step 1: Are the claims directed to a category of stator subject matter (a process, machine, manufacture, or composition of matter)? [see MPEP § 2106.03]
Claims are directed to statutory subject matter, specifically methods (Claims 1-21).
Step 2A Prong One: Do the claims recite a judicially recognized exception, i.e., an abstract idea, a law of nature, or a natural phenomenon? [see MPEP § 2106.04(a)]
The claims herein recite abstract ideas, specifically mental processes and mathematical concepts.
With respect to the Step 2A Prong One evaluation, the instant claims are found herein to recite abstract ideas that fall into the grouping of mental processes and mathematical concepts.
Claim 1: Identifying a plurality of variants, determining a pathogenic mutation, and predicting that the therapeutic gene is indicative of an effective drug, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 2: Determining a pathogenic effect of a variant is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 3: Determining that a pathogenic mutation in a gene indicates effectiveness is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 4: Determining similar pathogenic variation in the same gene is indicative of the particular disease is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 5: Determining that a similar strength altering variation is indicative of the particular disease is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 6: Determining that a fraction of mutations in a gene are pathogenic, determining that a remainder of mutations in the same gene are indicative of improved therapeutics, and predicting that other genes will be therapeutically effective, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 7: Determining that a fraction of causal mutations are pathogenic, and the remainder are strength altering indicative of the disease, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 8: Determining a strength of the pathogenic mutation is a process of calculating data which is an abstract idea, specifically a mental process.
Claim 9: Determining the dosage of the therapeutically effective drug is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 10: Using a combination of information of strength altering or pathogenic mutation to determine a therapeutic status, determining an efficacy of a therapeutic drug response gene, and determining a recommendation for a drug or disease response, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 11: Identifying a plurality of variants, determining a pathogenic mutation, and predicting that the therapeutic gene is indicative of an effective drug, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 12: Determining that a pathogenic or strength altering mutation causes the gene to be defective, determining a pharmacogenetic status of the gene, and predicting that the mutation indicates a side effect, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 13: Determining the drug metabolizing status of a mutation is a process of comparing/contrasting information, and calculating and classifying data which is an abstract idea, specifically a mental process.
Claim 14: Determining the drug metabolizing status of one or more PGx genes, determining the drug metabolizing status of a PGx gene are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 15: Determining that a fraction of the plurality of mutations are pathogenic, determining that a remainder of the plurality of mutations are strength altering variations, and predicting that other genes of a similar type indicate similar effects for the same drug, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 16: Determining a dose of the drug, and calculating the dose of the drug, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 17: Identifying pharmacogene biomarkers, and predicting a drug and dosage recommendation, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 19: Predicting one or more therapeutic drugs, predicting at least one pharmacogene biomarker, and selecting the drug recommendation, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 20: Calculating an efficacy score, and determining a drug recommendation, are processes of comparing/contrasting information, and calculating and classifying data which are abstract ideas, specifically mental processes.
Claim 21: Determining if a mutation in a gene is actionable to indicate a therapeutic drug is a process of comparing/contrasting information, and classifying data which is an abstract idea, specifically a mental process.
Step 2A Prong Two: If the claims recite a judicial exception under prong one, then is the judicial exception integrated into a practical application? [see MPEP § 2106.04(d) and MPEP § 2106.05(a)-(c) & (e)-(h)]
Because the claims do recite judicial exceptions, direction under Step 2A Prong Two provides that the claims must be examined further to determine whether they integrate the abstract ideas into a practical application.
The following claims recite the following additional elements in the form of non-abstract elements:
Claim 1: A computer is a generic and nonspecific element of a computer that does not improve the functioning of any computer or technology described herein [See MPEP § 2106.04(d)(1) and MPEP § 2106.05(d)]. Receiving a nucleotide string is an insignificant extra solution activity specifically, mere data gathering (See Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)) [See MPEP § 2106.05(g)].
Claim 11: A computer is a generic and nonspecific element of a computer that does not improve the functioning of any computer or technology described herein [See MPEP § 2106.04(d)(1) and MPEP § 2106.05(d)]. Receiving a nucleotide string is an insignificant extra solution activity specifically, mere data gathering (See Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)) [See MPEP § 2106.05(g)].
Claim 17: A computer is a generic and nonspecific element of a computer that does not improve the functioning of any computer or technology described herein [See MPEP § 2106.04(d)(1) and MPEP § 2106.05(d)]. Receiving a nucleotide string is an insignificant extra solution activity specifically, mere data gathering (See Performing clinical tests on individuals to obtain input for an equation, In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989) and Determining the level of a biomarker in blood, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968. See also PerkinElmer, Inc. v. Intema Ltd., 496 Fed. App'x 65, 73, 105 USPQ2d 1960, 1966 (Fed. Cir. 2012) (assessing or measuring data derived from an ultrasound scan, to be used in a diagnosis)) [See MPEP § 2106.05(g)]. Graphically displaying the drug recommendation for the disease is an insignificant extra solution activity, specifically necessary data outputting (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015)) [See MPEP § 2106.05(g)].
Claim 18: Depicting a pathogenic or strength altering mechanism is an insignificant extra solution activity, specifically necessary data outputting (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015)) [See MPEP § 2106.05(g)].
Claim 20: Providing a summary recommendation of the particular drug for a disease is an insignificant extra solution activity, specifically necessary data outputting (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015)) [See MPEP § 2106.05(g)].
Claim 21: Graphically representing the disease, mutation, gene, or therapeutic drug is an insignificant extra solution activity, specifically necessary data outputting (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015)) [See MPEP § 2106.05(g)].
Step 2B: If the claims do not integrate the judicial exception, do the claims provide an inventive concept? [see MPEP § 2106.05]
Because the additional claim elements do not integrate the abstract idea into a practical application, the claims are further examined under Step 2B, which evaluates whether the additional elements, individually and in combination, amount to significantly more than the judicial exception itself by providing an inventive concept.
The claims do not recite additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that are generic, conventional or nonspecific. These additional elements include:
The additional elements of a computer is a generic and nonspecific element of a computer that is well-understood, routine and conventional within the art and therefore does not improve the functioning of any computer or technology described therein (Receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), Performing repetitive calculations, Flook, 437 U.S. at 594, 198 USPQ2d at 199 (recomputing or readjusting alarm limit values), and Storing and retrieving information in memory, Versata Dev. Group, Inc. v. SAP Am., Inc., 793 F.3d 1306, 1334, 115 USPQ2d 1681, 1701 (Fed. Cir. 2015)) [See MPEP § 2106.05(d)(II)]. Therefore, taken both individually and as a whole, the additional elements do not amount to significantly more than the judicial exception by providing an inventive concept.
The additional elements of receiving a nucleotide string are insignificant extra solution activities specifically, mere data gathering (Receiving or transmitting data over a network, e.g., using the Internet to gather data, Symantec, 838 F.3d at 1321, 120 USPQ2d at 1362 (utilizing an intermediary computer to forward information), TLI Communications LLC v. AV Auto. LLC, 823 F.3d 607, 610, 118 USPQ2d 1744, 1745 (Fed. Cir. 2016) (using a telephone for image transmission), OIP Techs., Inc., v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015) (sending messages over a network), buySAFE, Inc. v. Google, Inc., 765 F.3d 1350, 1355, 112 USPQ2d 1093, 1096 (Fed. Cir. 2014)) [See MPEP § 2106.05(g)]. Therefore, taken both individually and as a whole, the additional elements do not amount to significantly more than the judicial exception by providing an inventive concept.
The additional elements of providing a summary recommendation of the particular drug for a disease, graphically displaying the drug recommendation for the disease (Daly et al. Tables 1 and 2), depicting a pathogenic or strength altering mechanism (Daly et al. Tables 1 and 2), and graphically representing the disease, mutation, gene, or therapeutic drug (Daly et al. Tables 1 and 2), are insignificant extra solution activity, specifically necessary data outputting (See Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015)) [See MPEP § 2106.05(g)]. Therefore, taken both individually and as a whole, the additional elements do not amount to significantly more than the judicial exception by providing an inventive concept.
Therefore, claims 1-21, when the limitations are considered individually and as a whole, are rejected under 35 USC § 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-12, 15-17 and 21 are rejected under 35 U.S.C. 102(a)(I) as being anticipated by Daly et al. (Nature Reviews Genetics (2010) 241-246).
Claim 1 is directed to a method of receiving a nucleotide string, identifying a plurality of variants, determining a pathogenic mutation, and predicting a therapeutic gene and pathogenic mutation is indicative of a therapeutically effective drug.
Claim 11 is directed to a method of receiving a nucleotide string, identifying a plurality of variants, determining a pathogenic mutation, and predicting a therapeutic gene and pathogenic mutation is indicative of a therapeutically effective drug.
Claim 17 is directed to a method of receiving a nucleotide string, identifying a plurality of biomarkers, predicting a drug and dosage, and graphically displaying the drug recommendations.
Daly et al. teaches on page 241, column 1, paragraph 3 “since 2007, genome-wide association (GWA) studies have increasingly been applied to pharmacogenomics”, and in paragraph 2 of column 2 of the same page “approximately 70% of published GWA studies in pharmacogenomics are concerned with drug response, and the remaining studies are concerned with adverse drug reactions. In studies on drug response, genome-wide significant associations have been detected for interferon-α and clopidogrel response, and for anticoagulant dose requirement. For adverse drug reactions, significant associations have been reported for statin-induced myopathy and flucloxacillin-induced liver injury”, which reads on receiving a nucleotide string comprising a plurality of nucleotides from at least a portion of one or more individual patients genome, wherein the portion of the genome includes at least one genetic element of: a 5'-UTR, a promoter, an enhancer, a silencer, an exon, an intron, a coding sequence, a splice acceptor, a splice donor, a branch point site, a 3'-UTR, a Kozak sequence, a poly-A addition site or signal, or a cryptic version thereof, from a known protein coding gene or a regulatory, splicing, or functional element of a non-protein coding RNA gene, and within genes not yet identified in a Dark Matter genome; identifying a plurality of variants in said nucleotide string by comparing a sequence of said nucleotide string with at least one reference genome; determining a pathogenic mutation from a plurality of variants in a therapeutic indicator gene; and predicting that the therapeutic gene with the pathogenic mutation is indicative of a therapeutically effective drug. This is because a GWAS is merely a genome wide association study, in which nucleotides are compared to a reference genome, variants are extracted, and compared to diseases to see if there is a correlation between the two. Applying said method to pharmacogenetics would inherently perform the method of claims 1 and 11 as pharmacogenetics is the field of medicine that investigates how a person's genetic makeup may affect how their body processes certain medications. Additionally, Daly et al. teaches on page 241, column 3, paragraph 1 “The US Food and Drug Administration (FDA) now recommends testing for TPMT variants in patients being treated with azathioprine and suggests a lower dose of irinotecan for patients known to be homozygous for the UGT1A1*28 allele… Dose adjustments for individual antidepressant drugs on the basis of the CYP2D6 genotype have been proposed”, and on page 244, column 1, paragraph 1 “Three independent GWA studies show that polymorphisms adjacent to interleukin-28B (IL28B, also known as interferon-λ3) predict the likelihood of a positive response to interferon-α”, reading on predicting a drug and dosage recommendation based on a combination of efficacy and side effects based on the therapeutic gene biomarkers and the pharmacogene biomarkers, as a biomarker and a variant are the same thing. Daly et al. teaches in both Table 1 and Table 2 drug recommendations, significance, correlation and significant associated genes reading on graphically displaying the drug recommendations for the disease, illustrating the biomarkers on the gene structure or sequence view, and correlating with the genetic, biological and biochemical effects of the mutations of the gene with the mechanism of drug action.
Claim 2 is directed to the method of claim 1 but further specifies determining a pathogenic or strength altering effect of a variant causing an aberration.
Daly et al. teaches on page 241, column 1, paragraph 2 “The genes investigated include those encoding enzymes involved in drug metabolism, such as the cytochrome P450 oxidases, and genes coding for drug targets, typically receptors or enzymes”, reading on determining a pathogenic or strength altering effect of a variant of the plurality of variants causing an aberration such as abolition, increase, or decrease in rate, kinetics, or quantity of transcription, splicing, or translation, or the biochemical activity of the protein, as an indicator of therapeutic efficacy of a drug.
Claim 3 is directed to the method of claim 1 but further specifies determining that any pathogenic mutation in a therapeutic indicator gene indicates that a drug is effective for a disease.
Daly et al. teaches on page 241, column 2, paragraph 4 “Candidate gene studies have provided valuable data in the areas of pharmacogenetics and pharmacogenomics. This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the drug”, reading on determining that any pathogenic mutation in a therapeutic indicator gene indicates that a drug is effective for a disease. Candidate gene studies are merely studies that are done on genes that have a biological relation to the trait in question (in pharmacogenetics this would be a medication or disease/medication combination) reducing the number of potential tests required in an association, thereby reading on a “therapeutic indicator gene”.
Claim 7 is directed to the method of claim 1 but further specifies determining a fraction of causal mutations are pathogenic, and determining the remainder are strength altering.
Daly et al. teaches on page 241, column 3, paragraph 1 “Susceptibility to hypersensitivity reactions induced by the anti-HIV drug abacavir was also shown to relate to a single gene in several candidate studies. The gene involved is not a metabolic gene but the class I human leukocyte antigen gene HLA‑B; most hypersensitivity cases carry the HLA‑B*5701 allele, so genotyping for HLA‑B*5701 before commencing abacavir treatment is recommended by the FDA14 and other drug regulators worldwide. There is also limited evidence from candidate-gene studies showing that individuals with polymorphisms that result in the absence of activity of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) may show more adverse events”, reading on determining that a fraction of causal mutations in genes that indicate a particular disease are pathogenic (deleterious, making the protein defective), and determining that a remainder of the causal mutations are strength altering variations (overexpress or under express a gene, over splice or under splice in a splicing reaction, or making a protein overactive or underactive) indicative of the particular disease.
Claim 8 is directed to the method of claim 1 but further specifies determining a strength of the pathogenic mutation.
Daly et al. teaches on page 241, column 1, paragraph 3 “since 2007, genome-wide association (GWA) studies have increasingly been applied to pharmacogenomics”, and it is inherent to associations that a beta value is calculated (also known as an effect size) for each variant associated with the trait, thereby reading on determining a strength of the pathogenic mutation, or the extent of deleteriousness, in a therapeutic indicator gene to determine an efficacy or a dosage of the therapeutically effective drug, based on a molecular effect of the pathogenic mutation leading to an alteration in a coding, regulatory or splicing process, in at least one genetic element, in the one or more individual patients genome.
Claim 9 is directed to the method of claim 1 but further specifies determining the dosage of the therapeutically effective drug.
Daly et al. teaches on page 241, column 2, paragraph 2 approximately 70% of published GWA studies in pharmacogenomics are concerned with drug response, and the remaining studies are concerned with adverse drug reactions. In studies on drug response, genome-wide significant associations have been detected for interferon-α and clopidogrel response, and for anticoagulant dose requirement”, reading on determining the dosage of the therapeutically effective drug, based on overexpression or under expression of therapeutic drug response genes by strength altering mutations in regulatory elements such as a promoter, poly-A site, or splicing elements, as an increased, normal, or decreased dose compared with a standard dose, based on if the therapeutically effective drug has an enhancing or inhibiting biochemical or biological effect or based on the zygosity of the pathogenic mutation.
Claim 10 is directed to the method of claim 1 but further specifies using a combination of information to determine a therapeutic status, efficacy or dose of an effective drug, determining an efficacy of the drug, and determining a recommendation for a drug.
Daly et al. teaches on page 241, column 2, paragraph 4 “Candidate gene studies have provided valuable data in the areas of pharmacogenetics and pharmacogenomics. This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the drug”, and in paragraph 2 of column 2 of the same page “approximately 70% of published GWA studies in pharmacogenomics are concerned with drug response, and the remaining studies are concerned with adverse drug reactions. In studies on drug response, genome-wide significant associations have been detected for interferon-α and clopidogrel response, and for anticoagulant dose requirement”, reading on using a combination of information of strength altering or pathogenic mutation and a zygosity of the therapeutic indicator gene to determine a therapeutic status, efficacy or dose of the therapeutically effective drug for a disease; determining an efficacy of a therapeutic drug response gene, based on strengthening or weakening of a therapeutic drug response gene by strength altering mutations in at least one genetic element, including coding, regulatory or splicing elements, or cryptic versions, as a poor, intermediate or high efficacy response; and, determining a recommendation for a drug or disease response, wherein a pathogenic mutation or strength altering variation in a gene, is used to predict the disease, drug response, or a severity of a disease, level of drug response, or drug dosage, in one or more patients.
Claim 12 is directed to the method of claim 11 but further specifies determining that a pathogenic or strength altering mutation causes a protein to be defective, determining a pharmacogenomic status of the drug metabolizing gene, and predicting based upon that status a potentiality for a side effect.
Daly et al. teaches on page 241, column 3, paragraph 1 “This is especially the case for adverse drug reactions attributable to alleles of a single gene, often one that encodes an enzyme contributing to metabolism of the drug. For example, thiopurine drugs (such as azathioprine), which are used as immunosuppressants and in cancer treatment, can cause bone-marrow suppression associated with inactivating polymorphisms in thiopurine S-methyltransferase… Susceptibility to hypersensitivity reactions induced by the anti-HIV drug abacavir was also shown to relate to a single gene in several candidate studies”, and in paragraph 2 of column 2 of the same page “approximately 70% of published GWA studies in pharmacogenomics are concerned with drug response, and the remaining studies are concerned with adverse drug reactions. In studies on drug response, genome-wide significant associations have been detected for interferon-α and clopidogrel response, and for anticoagulant dose requirement. For adverse drug reactions, significant associations have been reported for statin-induced myopathy and flucloxacillin-induced liver injury”, which reads on determining that a pathogenic or strength altering mutation of the drug metabolizing gene causes a protein encoded by the drug metabolizing gene to be defective, change activity level, or change metabolism level, wherein the pathogenic or strength altering mutation occurs in the coding, regulatory, or splicing elements or the cryptic versions thereof; determining a pharmacogenomic status of the drug metabolizing gene based on the effects of the pathogenic or strength altering mutations; and predicting, based on the pharmacogenomic status, that the pathogenic or strength altering mutation in the drug metabolizing gene indicates a side effect for a drug associated with the drug metabolizing gene.
Claim 15 is directed to the method of claim 11 but further specifies determining that some mutations are indicative of side effects while others indicate levels of side effects, and then using said data to predict the effect of similar drugs.
Daly et al. teaches on page 245, column 2, paragraph 2 “A study of adverse reaction to the drug ximelagatran reported an association between raised alanine aminotransferase levels (a marker for liver injury) and the class II HLA allele DRB1*0701. This association is similar to that detected for flucloxacillin-induced liver injury, in which the frequency of this class II HLA allele is also increased”, reading on determining that a fraction of the plurality of mutations in the drug metabolizing gene that indicates harmful side effects of the drug are pathogenic; determining that a remainder of the plurality of mutations are strength altering variations indicative of various levels of side effects for the drug; and predicting, based on the fraction and the remainder, that other genes of a biochemically or biologically similar type to the drug metabolizing gene, with similar pathogenic or strength altering mutations, indicates similar side effects for the same drug.
Claim 16 is directed to the method of claim 11 but further specifies determining a does of the drug based on a drug metabolizing status of one or more genes, and calculating the does of the drug.
Daly et al. teaches on page 242, column 3, paragraph 2 “Before any GWA study was initiated, there was good evidence that up to 50% of variability in dose requirement for the coumarin anticoagulants warfarin and acenocoumarol could be explained by patient-specific factors, both genetic and non-genetic (for example, age and body mass index). One third (~35%) of this variation related to two genes: CYP2C9, which encodes the main metabolizing enzyme for both drugs, and vitamin K epoxide reductase complex 1 (VKORC1), which encodes the drug target”, and in column 2, paragraph 1 of the same page “For example, some patients do not respond at all to certain drug treatments, and for other drugs the precise dose required to achieve a response may vary. Until now, GWA studies on drug response have been mainly concerned with drugs for which the dose needs to individualized”, reading on determining a dose of the drug based on a drug metabolizing status of a combination of one or more drug metabolizing genes that metabolizes the drug and variant zygosity or gene zygosity; and calculating the dose of the drug based on a number of pathogenic mutated or strength altering mutated genes, enzymatic efficacy of the pathogenic or strength altering mutated genes, and zygosity, such that a number of mutated alleles and the enzymatic efficacy of genes metabolizing the drug is inversely proportional to the dose of the drug based on whether the drug is active, prodrug or post-drug, and such that the dose varies between low and high dosage.
Claim 21 is directed to the method of claim 17 but further specifies determining if a mutation in a gene is actionable, and graphically representing the disease, mutation, gene or therapeutic.
Daly et al. teaches on page 241, column 2, paragraph 2 “approximately 70% of published GWA studies in pharmacogenomics are concerned with drug response, and the remaining studies are concerned with adverse drug reactions. In studies on drug response, genome-wide significant associations have been detected for interferon-α and clopidogrel response, and for anticoagulant dose requirement”, and in column 3, paragraph 1 of the same page “Dose adjustments for individual antidepressant drugs on the basis of the CYP2D6 genotype have been proposed”, reading on determining if a mutation in a gene is actionable to indicate a therapeutic drug or to avoid drugs with harmful side effects for a disease, based on a reference data set with known details of the disease, mutation, gene, or therapeutic drug; and graphically representing the disease, mutation, gene, or therapeutic drug or the drug recommendations, or biological or biochemical effect, on the gene structure or sequence views, tables and various graphical blocks with color codes and graphical notations.
Claims 4 and 5 are also directed to the method of claim 1 but are contingent claims; MPEP § 2111.04(II) “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met”, and as such are therefore not included under BRI.
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.
Claims 6 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Daly et al. (Nature Reviews Genetics (2010) 241-246).
Claim 6 is directed to the method of claim 1 but further specifies determining that a fraction of mutations are pathogenic, determining that a remainder are indicative of improved therapeutics, and predicting that the drug will be effective.
Daly et al. teaches the method of claims 1, 11 and 17 as previously described. Daly et al. further teaches on page 241, column 1, paragraph 1 “Until the 1990s, pharmacogenetic studies were concerned with the effects of single genes on drug disposition and drug response… The genes investigated include those encoding enzymes involved in drug metabolism”, and in paragraph 2, column 2 of the same page “In studies on drug response, genome-wide significant associations have been detected for interferon-α3–5 and clopidogrel6 response, and for anticoagulant dose requirement”
Daly et al. does not explicitly teach the “and” case of pathogenic and improved therapeutic mutations within the same gene. However, it would be prima facie obvious given that mutations are random that some would inevitably be beneficial and others pathogenic within the same gene.
Claim 19 is directed to the method of claim 17 but further specifies predicting one or more therapeutic drugs based on the biomarkers, predicting at least one pharmacogene biomarker, and selecting the drug recommendation based on the combinations of drug response phenotypes.
Daly et al. teaches the method of claims 1, 11 and 17 as previously described.
Daly et al. does not explicitly teach the prediction of a pharmacogene biomarker, however the mere performance of an association of genetic variants with a specific side effect, renders obvious the prediction of said biomarkers based upon side effects, as an association is merely setting up a mathematical relationship between two things, therefore given there exists a relationship and the performance of an association, a prediction of the biomarker is merely performing the association in reverse.
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Daly et al. (Nature Reviews Genetics (2010) 241-246) as applied to claims 1, 11, and 17 above, and further in view of Crist et al. (CNS Drugs (2018) 305-320).
Daly et al. teaches the method of claims 1, 11 and 17 as previously described.
Daly et al. does not teach the determining of a metabolizer status as low, intermediate, or high.
Crist et al. teaches on page 308, column 1, paragraph 2 “The potential metabolism statuses produced by the various alleles for each enzyme are generally termed ‘poor’, ‘intermediate’, ‘extensive’, and ‘ultrarapid’. ‘Slow metabolizer’ may also be used for alleles that are not null but result in severely reduced enzymatic function”, which in view of the method taught by Daly et al., reads on determining the drug metabolizing status of a mutation, biomarker, or the drug metabolizing gene based on the mutation or zygosity, wherein deleterious mutation in one allele is an intermediate metabolizer, and in two alleles is a non-metabolizer; determining the drug metabolizing status of the mutation, biomarker, or drug metabolizing gene, based on zygosity of strength altering mutations in the regulatory element such as a promoter, a splicing element or a coding sequence, wherein a combination of strengths in at least one allele indicates a low, intermediate, or high metabolizer or a non-metabolizer status; and determining the drug metabolizer status of the drug metabolizing gene in a range spanning a poor metabolizer to a rapid metabolizer from the pathogenic or strength altering mutations in a genetic element in a combination of different pharmacogenes that metabolize the drug.
It would have been obvious at the time of first filling to modify the teachings of Daly et al. for the method of claims 1, 11 and 17, with the teachings of Crist et al. for ranking metabolizing status as Crist et al. is merely a newer paper within the same field as Daly et al. which is a review on pharmacogenetic methods using variant data, effectively it would be prima facie obvious to not only obtain biomarkers that are associated and predict metabolism of drugs as taught by Daly et al. but then to rank those biomarkers in terms of their effects as Crist et al. teaches. One would have had a reasonable expectation of success given that the two papers are within the same field exploring the same type of effects in the same superfamily of genes. Therefore, it would have been obvious at the time of first filing to modify the teachings of each and to be successful.
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 17/698,905 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not exactly the same many of them overlap in scope such that one or multiple claims will encompass one or multiple claims from the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17/698,868 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because while the claims are not exactly the same many of them overlap in scope such that