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 .
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.
Status of claims
Claims 1-6 are pending.
Claims 1, 4 and 5 are independent claims.
Claims 1-6 are examined on the merits.
Priority
As detailed on the 04/26/2023 filing receipt, this application is a CON of PCT/CN2020/104900 filed on 07/27/2020.
Information Disclosure Statement
No Information Disclosure Statement has been provided.
Drawings
The drawings filed 04/21/2023 are accepted.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 20, line 5. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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.
Claims 1-4 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.
Claim 1 recites the limitation "…the number of patients falling in the four different combinations of treatments comprising (1) the number of patients having been treated both by the first drug and second drug, (2) the number of patients having been treated by the first drug but not the second drug, (3) the number of patients having been treated by the second drug but not the first drug, and (4) the number of patients having not been treated by either the first drug or the second drug…". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of “number of patients” in the claim.
Claim 4 recites the limitation "… (1) the number of patients having the biomarker and having been treated with the drug, (2) the number of patients having the biomarker but having not been treated by the drug, (3) the number of patients not having the biomarker and having been treated with the drug, and (4) the number of patients not having the biomarker and not having been treated by the drug…". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of “number of patients” in the claim.
Dependent claims are rejected for depending on rejected claims.
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 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Analysis of claims in Step 1.
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Independent claim 1 is directed to a 101 process, here a "computer-implemented method of determining effects of drug combinations on treatment outcomes," with process steps such as "generating…, determining…"
Independent claim 4 is directed to a 101 process, here a "computer-implemented method of determining drug effect on treatment outcomes" with process steps such as "generating…, determining…"
Independent claim 5 is directed to a 101 process, here a "computer-implemented method of determining drug effect on treatment outcomes" with process steps such as "generating…, determining…"
[Step 1: claims 1-6: YES]
In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Mental processes recited include:
Claims 1 and 4 recite: "determining the nature of the combination of the first drug and the second drug as being one of additive, synergistic, and antagonistic with respect to treating the disease." Determining is an act of evaluating, analyzing and judging data that could be practically performed in the human mind and/or with pen and paper.
Claim 5 recites: "determining the nature of all possible binary combinations of the first, second and third drug as being one of additive, synergistic, and antagonistic with respect to treating the disease." Determining is an act of evaluating, analyzing and judging data that could be practically performed in the human mind and/or with pen and paper.
Claim 6 recites: "selecting a combination of two drugs based on the determined nature of all possible binary combinations of drugs." Selecting is an act of evaluating, analyzing and judging data that could be practically performed in the human mind and/or with pen and paper.
Mathematical concepts recited include:
Claim 1 recites: "using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first drug and the second drug."
Claim 4 recites: "using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the drug and the biomarker."
Claim 5 recites: "using a Cox Proportional Hazards model, calculating independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first and the second drug, the combination of the first and the second drug, and the combination of the first and the second drug.
Claims 1 and 4-6 recite mental processes as indicated above. Claim 1 recites determining the nature of the combination of the first drug and the second drug as being one of additive, synergistic, and antagonistic with respect to treating the disease; claim 4 recites determining the nature of the combination of the drug and the biomarker as being one of additive, synergistic, and antagonistic with respect to treating the disease; claim 5 recites determining the nature of all possible binary combinations of the first, second and third drug as being one of additive, synergistic, and antagonistic with respect to treating the disease and claim 6 recites selecting a combination of two drugs based on the determined nature of all possible binary combinations of drugs. Determining and selecting are acts of evaluating, analyzing, observing and judging data as indicated above. Acts of evaluating and analyzing data could be practically performed in the human mind and/or with pen and paper because they merely require making observations, evaluations, judgments, and opinions (See MPEP 2106.04(a)(2) subsection III). Although, claims 1, 4 and 5 recite a computer implemented method, there are no additional limitations to indicate that anything other than a generic computer is required. However, merely requiring that the steps are carried out with a generic computer does not negate the mental nature of these steps and equates rather to merely using a computer as a tool to perform the mental process. Therefore, under the broadest reasonable interpretation, the indicated claims above can be practically carried out in the human mind or with pen and paper as claimed, which falls under the "Mental processes" grouping of abstract ideas.
Claims 1, 4 and 5 recite mathematical concepts and formulas as indicated above. Using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values are mathematical concepts and/or formulas that falls under the “mathematical concepts” grouping of abstract ideas.
As such, claims 1-6 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The above indicated judicial exceptions are not integrated into a practical application because the claims do not recite an additional elements that apply, rely on or use the judicial exception in such a manner to amount to integration into a practical application. For example, there are no limitations that reflect an improvement to technology or applies or uses the recited judicial exception in some other meaningful way. Rather, the instant claims recite additional elements that equate to mere instructions to implement an abstract idea or insignificant extra solution activity. Specifically, the instant claims recite the following additional elements:
Claims 1, 4 and 5 recite "generating a plurality of genomic and clinical variables from the combination of (1) comprehensive genomic data, (2) EHR data, and (3) clinical treatment data, for each of a plurality of patients…"
Claim 2 recites "clinically testing the combination of the first drug and the second drug in treating the disease on a group of subjects if the combination of the first drug and the second drug has been determined to be synergistic."
The elements of claims 1 and 4-5 as indicated above equate to insignificant extra solutional activities of data gathering. Data gathering serves as input to the recited judicial exception in the claims. Claims 1 and 4-5 recite a computer-implemented method that invoke the computer components merely as tools to execute the abstract idea. The use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more. (see MPEP 2106.05(f)). Additionally, the listed additional elements are mere instructions to apply an exception because they recite no more than an idea of a solution or outcome and does not recite a technological solution to a technological problem. (See MPEP 2106.05(f)(1)). The limitation of claim 2 of “…clinically testing the combination of the first drug and the second drug in treating the disease on a group of subjects if the combination of the first drug and the second drug has been determined to be synergistic” applies the exception in a generic way and does not integrate the recited exception into a practical application (see MPEP 2106.04(d)(2)). As such, as currently recited, the claims do not appear to recite an improvement to technology or apply or use the recited judicial exception in some other meaningful way. Therefore, claims 1-6 are directed to an abstract idea (Step 2A, Prong 2: NO).
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). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite additional elements that equate to well-understood, routine and conventional activities, insignificant extra-solution activity or mere instructions to implement the abstract idea on a generic computer. The instant claims recite the following additional elements:
Claims 1, 4 and 5 recite "generating a plurality of genomic and clinical variables from the combination of (1) comprehensive genomic data, (2) EHR data, and (3) clinical treatment data, for each of a plurality of patients…"
Claim 2 recites "clinically testing the combination of the first drug and the second drug in treating the disease on a group of subjects if the combination of the first drug and the second drug has been determined to be synergistic."
The additional elements indicated above do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception. The limitations equate to mere data gathering activities, which are insignificant extra solutional activities. The courts have recognized that techniques for determining the level of a biomarker in blood by any means; analyzing DNA to provide sequence information or detect allelic variants; amplifying and sequencing nucleic acid sequences and detecting DNA or enzymes in a sample as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. (See MPEP 2106.05(d)). As explained by the Supreme Court, the addition of insignificant extra-solution activity does not amount to an inventive concept, particularly when the activity is well-understood or conventional. (see MPEP 2106.05(g)). The limitations that equate to mere data gathering and outputting via generic computer components, such as receiving data at a computer or outputting data, amount to insignificant extra-solution activity as set forth by the courts in Mayo, 566 U.S. at 79, 101 USPQ2d at 1968 and OIP Techs., Inc, v, Amazon.com, Inc., 788 F.3d 1359, 1363, 115 USPQ2d 1090, 1092-93 (Fed. Cir. 2015). Also, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application or provide significantly more as identified by the courts in Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). Therefore, the claims do not amount to significantly more than the judicial exception itself (Step 2B: No). As such, claims 1-6 are not patent eligible.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Masclee ("Risk of upper gastrointestinal bleeding from different drug combinations." Gastroenterology 147.4 (2014): 784-792.; cited on the attached “Notice of References Cited” form 892), in view of Phillips ("Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE‐inhibitor, or calcium‐channel blocker in ALLHAT." The Journal of Clinical Hypertension 15.11 (2013): 825-832.; cited on the attached“Notice of References Cited” form 892.).
Regarding independent claim 1, Masclee teaches the claim limitation of generating a plurality of genomic and clinical variables from the combination of (1) comprehensive genomic data, (2) EHR data, and (3) clinical treatment data, for each of a plurality of patients with “Data were obtained from a network of 7 electronic health record (EHR) databases from 3 countries. The EU-ADR Project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) has successfully established a platform that integrates data from various repositories of European EHRs for evaluation of drug safety.” (page 785, col. 1, para. 5)
Masclee teaches the claim limitation of wherein the plurality of patients comprise at least a first subset who have been treated with at least one first drug for a disease, and a second subset who have been treated with at least one second, different drug for the same disease, the first subset not entirely overlapping the second subset; based on the plurality of genomic and clinical variables and a two by two contingency table representing the number of patients falling in the four different combinations of treatments comprising (1) the number of patients having been treated both by the first drug and second drug, (2) the number of patients having been treated by the first drug but not the second drug, (3) the number of patients having been treated by the second drug but not the first drug, and (4) the number of patients having not been treated by either the first drug or the second drug with Table 2 titled Relative Risk of Diagnosed UGIB During Exposure to Specific Drug Groups (With Corresponding 95% Cls) in Monotherapy and in Combination With Other Drugs (page 787). Masclee also teaches in Figure 1 (page 788) a Heat map of nsNSAIDs, Coxibs and low-dose aspirin drugs in combination with other drugs.
Masclee teaches the claim limitation of determining the nature of the combination of the first drug and the second drug as being one of additive, synergistic, and antagonistic with respect to treating the disease with “To estimate the magnitude of drug interaction (excess risk), the following measures were calculated: the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S).32 Interaction on an additive scale meant that the observed effect of the drug combination was larger than the sum of the effects of the drugs separately but less than multiplicative. If the IRR of the combination was more than the sum of the 2 drugs separately, interaction (at least on an additive scale) was present. Corresponding 95% CIs were also calculated for the RERI using the Hosmer–Lemeshow delta method.33 The estimated measure of the RERI, AP, or S itself does not provide any information on risk and cannot be interpreted in isolation. However, based on the relative risk, it can be concluded that an excess risk is present when the RERI is larger than 0 and the CIs around it do not cross 0.” (page 786, col. 2, para. 2).
Masclee teaches determining the relative excess risk due to interaction (RERI) and the proportion attributable to interaction (AP). Masclee does not explicitly teach using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first drug and the second drug in claim 1. However, this limitation is taught by Phillips.
Phillips teaches the claim limitation of using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first drug and the second drug with “Cox proportional hazards models were used to obtain HRs and 95% CIs for the time to the first hospitalized GI bleed, adjusting for both baseline and time-dependent covariates.” (page 826, col. 2, para. 5); Table II (page 828) titled Cox Regressions for Hospitalized GI Bleeding depicts calculate risk factors, hazard-ratios, and p-values for interactions; and “The Figure 1 shows the cumulative hospitalized GI bleeding rates by randomized treatment group, and Cox regression analysis (Table 2) revealed no significant difference between the chlorthalidone and amlodipine treatment groups (HR, 1.09; 95% CI, 0.92–1.28). However, when compared with amlodipine‐ or chlorthalidone‐, the lisinopril‐treated participants had a significantly higher risk of hospitalized GI bleeding (HR, 1.27; 95% CI, 1.06–1.51 and HR, 1.16; 95% CI, 1.00–1.36, respectively). There were no significant differences in treatment effect (ie, interactions) when analyzed by race, sex, ethnicity, aspirin use, or smoking at baseline. When limiting the sample to participants taking monotherapy, the findings were similar for the amlodipine vs chlorthalidone (HR, 1.05; 95% CI, 0.80–1.39) comparison. The HRs for the monotherapy cohort were higher, however, for the lisinopril vs amlodipine comparisons (HR, 1.52; 95% CI, 1.12–2.07) and for the lisinopril vs chlorthalidone comparisons (HR, 1.44, 95% CI, 1.12–1.87) (data not shown). Table 3 provides the cumulative incidence of participants, by treatment arm, with a hospitalized GI bleed by the end of years 1, 3, and 5. Of the 3 treatment arms, participants assigned to the amlodipine group experienced the lowest bleeding incidence over the entire trial, although it was statistically indistinguishable from the chlorthalidone group.” (page 827, col. 2, para. 2).
It would have been prima facia obvious to one having ordinary skill to combine the teachings of Masclee and Phillips to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Masclee to include using cox proportional hazards model as taught by Phillips to determine the hazard ratios of drug interactions. Furthermore, there would have been a reasonable expectation of success because both Masclee and Phillips teach methods that relate to determining the risk of gastrointestinal bleeding due to the usage of drug combinations.
Regarding claim 3, Masclee teaches the claim limitation of wherein the genomic and clinical variables comprise one of: gene expression, loss of heterozygosity (LOH), copy number alteration (CNA), somatic and germline mutations, Microsatellite instability (MSI), tumor mutational burden (TMB), Chromosomal Variation, Mutational signatures, human Leukocyte Antigen Typing (HLA), and human pathogen. Maclee teaches gene expression with “In elderly subjects, prostaglandin levels decreased due to decreased conversion of arachidonic acid to prostaglandin, resulting in an increased risk of UGIB. This partially accounts for the recommendation to use gastroprotective measures in elderly patients. We hypothesize that COX enzyme selectivity with aging might explain the difference in drug interaction between nsNSAIDs and COX-2 inhibitors. In animal studies, older rats expressed different COX enzyme mRNA levels than younger rats and an impaired response of prostaglandin synthesis to irritants with older age was shown. In humans, higher basal acid output in the stomach among elderly patients results in lower mucosa) prostaglandin concentrations in the stomach and duodenum.” (page 790, col. 1, para. 1).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Masclee ("Risk of upper gastrointestinal bleeding from different drug combinations." Gastroenterology 147.4 (2014): 784-792.; cited on the attached “Notice of References Cited” form 892), in view of Phillips ("Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE‐inhibitor, or calcium‐channel blocker in ALLHAT." The Journal of Clinical Hypertension 15.11 (2013): 825-832.; cited on the attached “Notice of References Cited” form 892.) as applied to claims 1 and 3 above; and in further view of He (“Combination therapeutics in complex diseases.” Journal of cellular and molecular medicine vol. 20,12 (2016): 2231-2240. doi:10.1111/jcmm.1293.; cited on the attached “Notice of References Cited” form 892.)
Masclee and Phillips are applied to claims 1 and 3 as discussed above.
Masclee does not explicitly teach clinically testing the combination of the first drug and the second drug in treating the disease on a group of subjects if the combination of the first drug and the second drug has been determined to be synergistic of claim 2. However, this limitation is taught by He.
Regarding claim 2, He teaches the claim limitation of clinically testing the combination of the first drug and the second drug in treating the disease on a group of subjects if the combination of the first drug and the second drug has been determined to be synergistic with “A common strategy to investigate combination therapeutics prior to the initiation of clinical trials is through the use of cell lines and animal models. These models provide important insights into the mechanisms of action and interactions between drugs, which are important in the preparation for clinical trials [63]. For example, DiCosimo et al. estimated the efficacy of combined ridaforolimus and dalotuzumab for the treatment of breast cancer in human cell lines and mouse models, and the results of those studies led to the initiation of a phase I clinical trial [64]. In fact, preclinical studies make up the majority of studies investigating (Fig. 1) and play an essential role in the development of combination therapeutics [65]. In general, preclinical studies of combination therapeutics rapidly assess the synergy of combined drugs and explore physical interactions among them. They also evaluate anti-disease activity, mechanisms of action and additional factors, such as the effects of the drugs on their targets and their pharmacokinetics.” (page 2234, col. 2, para. 4).
It would have been prima facia obvious to one having ordinary skill to combine the teachings of Masclee and He to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Masclee to include testing the combination of drugs as taught by He to evaluate anti-disease activity, mechanisms of action and additional factors, such as the effects of the drugs on their targets and their pharmacokinetics. Furthermore, there would have been a reasonable expectation of success because both Masclee and He teach methods that relate to studying drug combinations.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Vivot (Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker Testing. Sci Rep 7, 6882 (2017).; cited on the attached “Notice of References Cited” form 892), in view of Low (Synergistic drug combinations from electronic health records and gene expression, Journal of the American Medical Informatics Association, Volume 24, Issue 3, May 2017, Pages 565–576; cited on the attached“Notice of References Cited” form 892.).
Regarding independent claim 4, Vivot teaches the claim limitation of generating a plurality of genomic and clinical variables from the combination of (1) comprehensive genomic data, (2) EHR data, and (3) clinical treatment data, for each of a plurality of patients; wherein some, but not all, of the plurality of patients share a common biomarker, and wherein some, but not all, of the plurality of patients have been treated with a same drug for a disease with “From the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling19, we identified the drug–biomarker pairs with required genetic testing in the drug label that were indicated for oncology as previously described. We used the most recent label (as of June 10, 2015) to search for all indications of a drug. We did not include indications for which the biomarker was not relevant and non-oncology indications. We also excluded indications for which the proportion of biomarker-positive patients was very high (Supplementary Table S1) acknowledging that, in these cases, conducting studies with a sufficient number of biomarker-negative patients to demonstrate a treatment-by-biomarker interaction would be unfeasible. Example diseases included chronic myeloid leukemia (CML), which is almost always the result of a genetic translocation (Philadelphia chromosome). For each drug indication, we extracted the list of clinical studies on which the FDA bases its approval decision from the FDA medical review. When this review was not available, we used the content of the approval letter and the drug label. We included studies relevant to the indication only and excluded studies reviewed for only safety data as well as pharmacology and ongoing studies. (page 6882, Methods, Source of data section).
Vivot teaches the claim limitation of based on the plurality of genomic and clinical variables and a two by two contingency table representing the following combinations: (1) the number of patients having the biomarker and having been treated with the drug, (2) the number of patients having the biomarker but having not been treated by the drug, (3) the number of patients not having the biomarker and having been treated with the drug, and (4) the number of patients not having the biomarker and not having been treated by the drug with Figure 3 (page 7). Figure 3’s caption states Characteristics of evidence supporting the clinical utility of pharmacogenomic biomarkers and treatment effect for 9 approvals of oncology drugs with at least one non-enriched clinical trial. Treatment effects are represented for biomarker-positive patients and biomarker-negative patients. N represents the total number of patients enrolled in the trial, N_bm the number of patients with a known biomarker status and n the number of patients in each biomarker-based subgroup. For randomized controlled trials, P is the p-value of the treatment-by-biomarker interaction. For single-arm trial, P is the p-value of the test comparing outcomes in biomarker-positive and biomarker-negative patients. Regarding fulvestrant/ESR1,when the superiority objectives were not met, the two pivotal trials were retrospectively assessed for non-inferiority with a 10% margin for overall response rate. Regarding Lapatinib/ERBB2, this approval is for the following indication: “in combination with letrozole for the treatment of postmenopausal women with HR + Metastatic breast cancer expressing HER2 receptor for whom hormonal therapy is indicated”. Regarding Crizotinib/ALK, a cohort of ALK-negative patients was added to study B (A8081001), which had enrolled 119 ALK-positive patients (105 evaluable by an independent committee review).
Vivot teaches the claim limitation of using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the drug and the biomarker; and determining the nature of the combination of the drug and the biomarker as being one of additive, synergistic, and antagonistic with respect to treating the disease with “When not reported in the original paper, we extracted data needed to compute the treatment-by-biomarker interaction test and we computed the p-value for the interaction by a Z-test to com pare two log hazard ratios (HRs) for survival endpoints or two odds ratios for binary endpoints24; 95% confidence intervals were estimated. For single-arm trials, we computed a p-value for differences in outcome for biomarker-negative and -positive patients by using Fisher’s exact test for binary endpoints. Because interaction tests are generally underpowered, we used a significance level of p < 0.10. All analyses involved use of R v3.1 (R Core Team, Vienna, Austria).” (page 3, para. 3).
Vivot does not explicitly teach EHR data and determining the nature of the combination of the drug and the biomarker as being one of additive, synergistic, and antagonistic with respect to treating the disease in claim 4. However, this limitation is taught by Low.
Low teaches EHR data with “Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.” (Abstract, Objective)
Low teaches determining the nature of the combination of the drug and the biomarker as being one of additive, synergistic, and antagonistic with respect to treating the disease with “This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.” (Abstract, Conclusions)
It would have been prima facia obvious to one having ordinary skill to combine the teachings of Vivot and Low to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Vivot to include EHR data as taught by Low to obtain real-world treatment and outcome patterns. A person of ordinary skill in the art would have been motivated to modify the method of Vivot to include determining the nature of the combination of the drug and the biomarker as taught by Low for the benefit of optimizing treatment efficacy. Furthermore, there would have been a reasonable expectation of success because both Vivot and Low teach methods that relate to studying drug combinations.
Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Masclee ("Risk of upper gastrointestinal bleeding from different drug combinations." Gastroenterology 147.4 (2014): 784-792.; cited on the attached “Notice of References Cited” form 892), in view of Phillips ("Risk of hospitalized gastrointestinal bleeding in persons randomized to diuretic, ACE‐inhibitor, or calcium‐channel blocker in ALLHAT." The Journal of Clinical Hypertension 15.11 (2013): 825-832.; cited on the attached“Notice of References Cited” form 892.).
Regarding independent claim 5, Masclee teaches the claim limitation of generating a plurality of genomic and clinical variables from the combination of (1) comprehensive genomic data, (2) EHR data, and (3) clinical treatment data, for each of a plurality of patients with “Data were obtained from a network of 7 electronic health record (EHR) databases from 3 countries. The EU-ADR Project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) has successfully established a platform that integrates data from various repositories of European EHRs for evaluation of drug safety.” (page 785, col. 1, para. 5)
Masclee teaches the claim limitation of wherein the plurality of patients comprise at least a first subset who have been treated with at least one first drug for a disease, a second subset who have been treated with at least one second, different drug for the same disease, and a third subset who have been treated with at least one third drug which is different from the first drug and different from the second drug for the same disease, each of the first, second, and third subsets not entirely overlapping with any of other subsets; based on the plurality of genomic and clinical variables and contingency tables including information of patients having been treated by one or more of the first, second and third drugs with Table 2 titled Relative Risk of Diagnosed UGIB During Exposure to Specific Drug Groups (With Corresponding 95% Cls) in Monotherapy and in Combination With Other Drugs (page 787). Masclee also teaches in Figure 1 (page 788) a Heat map of drugs in combination with other drugs.
Masclee teaches the claim limitation of determining the nature of the combination of the first drug and the second drug as being one of additive, synergistic, and antagonistic with respect to treating the disease with “To estimate the magnitude of drug interaction (excess risk), the following measures were calculated: the relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP), and the synergy index (S).32 Interaction on an additive scale meant that the observed effect of the drug combination was larger than the sum of the effects of the drugs separately but less than multiplicative. If the IRR of the combination was more than the sum of the 2 drugs separately, interaction (at least on an additive scale) was present. Corresponding 95% CIs were also calculated for the RERI using the Hosmer–Lemeshow delta method.33 The estimated measure of the RERI, AP, or S itself does not provide any information on risk and cannot be interpreted in isolation. However, based on the relative risk, it can be concluded that an excess risk is present when the RERI is larger than 0 and the CIs around it do not cross 0.” (page 786, col. 2, para. 2).
Masclee teaches determining the relative excess risk due to interaction (RERI) and the proportion attributable to interaction (AP). Masclee does not explicitly teach using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first drug and the second drug in claim 5. However, this limitation is taught by Phillips.
Phillips teaches the claim limitation of using a Cox Proportional Hazards model to calculate independent risk factors, cumulative hazard-ratios, and p-values for the combination of the first drug and the second drug with “Cox proportional hazards models were used to obtain HRs and 95% CIs for the time to the first hospitalized GI bleed, adjusting for both baseline and time-dependent covariates.” (page 826, col. 2, para. 5); Table II (page 828) titled Cox Regressions for Hospitalized GI Bleeding depicts calculate risk factors, hazard-ratios, and p-values for interactions; and “The Figure 1 shows the cumulative hospitalized GI bleeding rates by randomized treatment group, and Cox regression analysis (Table 2) revealed no significant difference between the chlorthalidone and amlodipine treatment groups (HR, 1.09; 95% CI, 0.92–1.28). However, when compared with amlodipine‐ or chlorthalidone‐, the lisinopril‐treated participants had a significantly higher risk of hospitalized GI bleeding (HR, 1.27; 95% CI, 1.06–1.51 and HR, 1.16; 95% CI, 1.00–1.36, respectively). There were no significant differences in treatment effect (ie, interactions) when analyzed by race, sex, ethnicity, aspirin use, or smoking at baseline. When limiting the sample to participants taking monotherapy, the findings were similar for the amlodipine vs chlorthalidone (HR, 1.05; 95% CI, 0.80–1.39) comparison. The HRs for the monotherapy cohort were higher, however, for the lisinopril vs amlodipine comparisons (HR, 1.52; 95% CI, 1.12–2.07) and for the lisinopril vs chlorthalidone comparisons (HR, 1.44, 95% CI, 1.12–1.87) (data not shown). Table 3 provides the cumulative incidence of participants, by treatment arm, with a hospitalized GI bleed by the end of years 1, 3, and 5. Of the 3 treatment arms, participants assigned to the amlodipine group experienced the lowest bleeding incidence over the entire trial, although it was statistically indistinguishable from the chlorthalidone group.” (page 827, col. 2, para. 2).
It would have been prima facia obvious to one having ordinary skill to combine the teachings of Masclee and Phillips to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Masclee to include using cox proportional hazards model as taught by Phillips to determine the hazard ratios of drug interactions. Furthermore, there would have been a reasonable expectation of success because both Masclee and Phillips teach methods that relate to determining the risk of gastrointestinal bleeding due to the usage of drug combinations.
Regarding claim 6, Masclee teaches selecting a combination of two drugs based on the determined nature of all possible binary combinations of drugs with Figure 1 (page 788). Figure 1 is a Heat map of nsNSAIDs, Coxibs and low-dose aspirin drugs in combination with other drugs and the intensity of the interactions.
Conclusion
No claims are allowed.
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/K.K./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686
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