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 .
1. The Amendment filed December 5, 2025 in response to the Office Action of September 9, 2025, is acknowledged and has been entered. Claims 1-3, 9, 11, 13, 15-19, 22, 23, 27, 38, 39, 53, 56, 57 are now pending. Claims 1, 2, 3 are amended. Claims 2, 11, 13, 17-19, 22, 23 remain withdrawn. Claims 1, 3, 9, 15, 16, 27, 38, 39, 53, 56, 57 are currently being examined as drawn to the elected species of:
European ancestry group;
at least 150 genetic variants;
asthma lung disease;
blood biological sample; and
treatment with interleukin-4 receptor alpha antagonist/and/or interlueking-13 receptor antagonist that is dupilumab.
New Rejection
(necessitated by amendments)
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.
2. Claims 1, 3, 9, 15, 16, 27, 38, 39, 53, 56, 57 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 genetic variants associated with pre-bronchodilator FEVI". There is insufficient antecedent basis for this limitation in the claim. Dependent claims are rejected for encompassing this rejected limitation.
Maintained Rejection
(amendments addressed)
Claim Rejections - 35 USC § 112
3. Claims 1, 3, 9, 15, 16, 27, 38, 39, 53, 56, 57 remain 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:
A method of treating a subject having a lung disease or at risk of developing a lung disease with a therapeutic agent that treats or inhibits a lung disease, the method comprising:
determining or having determined the subject’s forced expiratory volume in one second (FEVI) polygenic score (FEV1-PS); and
administering or continuing to administer the therapeutic agent that treats or inhibits a lung disease at a standard dosage amount when the subject’s FEV1-PS is greater than or equal to a threshold FEV1-PS; or
administering the therapeutic agent that treats or inhibits a lung disease at a dose that is greater than a standard dosage amount when the subject’s FEV1-PS is less than the threshold FEV1-PS,
wherein the subject’s FEV1-PS and the threshold FEV1-PS are calculated with respect to a strength of association and/or probability distribution;
wherein the therapeutic agent that treats or inhibits lung disease comprises an interleukin-4 receptor alpha antagonist and/or an interleukin-13 receptor antagonist, an interleukin-33 antagonist, and/or a bronchodilator;
wherein the threshold FEV1-PS is the top quartile within a reference population, the top quintile within a reference population, or the top decile within a reference population;
and wherein the genetic variants associated with pre-bronchodilator FEV1 comprise 2:18106357:T:C; ……or 22:30201679:A:G according to GRCh38/hg38 assembly coordinates.
A. The claim requires determining or having determined the subject’s FEV1-PS that, wherein the subject’s FEV1-PS and the threshold FEV1-PS are calculated with respect to a strength of association and/or probability distribution; and wherein the genetic variants genetic variants associated with pre-bronchodilator FEV1 comprise one of the genomic positions listed in claim 1. The claim is unclear with regard to how the FEVI-PS is/was “determined” or calculated, using what values, what mathematical determination, what strength of association to what variables, and what probability distribution. The determined FEV1-PS value is unclear and the scope of patients having an FEV1-PS value greater than, equal to, or less than a threshold FEV1-PS value/percentage is unclear. It is also noted that claim 1 as amended does not require utilizing the claimed “genetic variants associated with pre-bronchodilator FEV1” in determining the FEV1-PS score, nor indicate how the variants would be used in the method.
The instant specification does not provide any limiting definition of what a FEVI-PS value is and how it is calculated. The specification discloses: ([69]) “Numerous methodologies can be used to calculate a FEV1-PS. In some embodiments, the genetic variant performance is calculated with respect to a strength of association and/or a probability distribution. In some embodiments, the FEV1-PS is calculated using an LDPred or an SBayesR method, or any other available method. In some embodiments, genetic variant scores are calculated using PRS calculation methodologies, such as the LDPred method (or variations and/or versions thereof). LDPred is a Bayesian approach to calculate a posterior mean effect for all variants based on a prior (effect size in the prior genome-wide association study) and subsequent shrinkage based on linkage disequilibrium. LDPred creates a PRS using genome-wide variation with weights derived from a set of GWAS summary statistics.” The instant specification does not provide any definitive, limiting calculation for determining a “FEV1-PS”, but rather, discloses that “numerous methodologies can be used to calculate a FEV1-PS”. Given the unknown calculation of and value for a “FEV1-PS” and unknown “association” of genetic variants with pre-bronchodilator FEV1, one cannot clearly determine what the FEV1-PS is, how it was determined, and what the scope of claimed subjects are having an FEV1-PS value that is great than, equal to, or below a threshold, and the scope of subjects receiving a therapeutic agent at a greater than standard dosage amount or receiving a standard dosage amount.
B. The claim requires administering the therapeutic agent at a “standard dosage amount” or “greater than standard dosage amount”. The claim is unclear with regard to what the standard dosage amount is. Those of ordinary skill in the art recognize there is great variability in what is considered a “standard dosage amount” because it depends on: patient physiology and age, what the therapeutic agent is, what formulation it is in, how it is delivered, the frequency of delivery/dosing, what disease it treats, which patient population, what result is needed to be achieved, and which drug agency standards. Given the “standard dosage amount” is unknown, one could not determine the scope of dosage amount that is standard or greater than standard in order to treat the subject having a lung disease or at risk of a lung disease.
C. The claim requires administering a therapeutic agent at standard dosage amount when the subject’s FEV1-PS is “greater than or equal to a threshold FEV1-PS” and administering a therapeutic agent at a greater than standard dosage amount when the subject’s FEV1-PS is “less than the threshold FEV1-PS”. The claim recites the threshold FEV1-PS is the top quartile within a reference population, the top quintile within a reference population, or the top decile within a reference population. The claim is still unclear with regard to: (1) what the FEV1-PS value is and how it is calculated or determined, (2) what a reference population is, and (3) what the threshold FEV1-PS is in such a reference population.
The instant specification does not provide any limiting definition of what constitutes a “reference population” and suggests it can be a population enriched for members of an ancestry group ([65-68]). Therefore, it is unclear if the reference population is healthy or has a lung disease, is untreated with therapeutic agent, is being treated with therapeutic agent, or is enriched for an ancestry group or not. Given the unknown reference population and the effect of its members on a FEV1-PS value and the unknown values representing top quartile, top quintile, or top decile values for a threshold derived form a “reference population”, one cannot determine the scope of claimed subjects having an FEV1-PS value that is greater than, equal to, or below the threshold, and the scope of subjects receiving a therapeutic agent at a greater than standard dosage amount or receiving a standard dosage amount are unclear.
Given the above reasons, the metes and bounds of the claims cannot be determined.
Response to Arguments
4. With regard to sections A and C above, Applicant argues that claim 1 is amened to be even more clear and definite by reciting that: i) the subject's FEV1-PS and threshold FEV1-PS are calculated with respect to a strength of association and/or a probability distribution; and ii) the genetic variants associated with pre-bronchodilator FEV1 comprise particular genetic variants. Applicant argues that persons of ordinary skill would have had no difficulty in calculating an FEV1-PS for a particular subject or identifying particular genetic variants associated with pre-bronchodilator FEV1.
Regarding what the FEV1-PS value is and how it is calculated or determined, Applicant points to page 4, lines 23-24 of the specification and argue that Applicant teaches that "FEV1-PS is an aggregate of a plurality of genetic variants associated with the pulmonary metric FEV1." In addition, regarding how FEV1-PS is calculated or determined, Applicant points to page 4, line 24 to page 5, line 1 of the specification and argue that Applicant teaches an exemplary method of calculating FEV1-PS in a representative hypothetical GWAS in Table 2. Applicant argues that additional instructions regarding the calculation or determination of FEV1-PS is provided at page 27, line 6 to page 28, line 3. Applicant argues they have amended claim 1 to recite that the subject's FEV1-PS and the threshold FEV1-PS are calculated with respect to a strength of association and/or a probability distribution. Applicant argues such exemplary instructions are provided in the specification and need not be recited in the claims for the claims to be clear.
Regarding what a reference population is and what the threshold FEV1-PS is in such a reference population, Applicant points to page 22, line 20 to page 23, line 14 and argue that, in some embodiments, the disclosure provides methods of assigning a risk group to a subject. Applicant argues the methods comprise identifying whether genetic variants are present in a biological sample from the subject, calculating a FEV1-PS for the subject based on the identified genetic variants, and assigning the subject to a risk group based on the FEV1-PS. The FEV1-PS for a population (i.e., a reference population) may be divided into quintiles, e.g., top quintile, top-intermediate quintile, intermediate quintile, intermediate-bottom quartile, and bottom quintile, wherein the top quintile of FEV1-PSs correspond to the highest genetic risk group and the bottom quintile of FEV1-PSs corresponds to the lowest genetic risk group. The number of identified genetic variants can be at least about 150 to at least about 10,000,000 genetic variants. In some embodiments, the threshold FEV1-PS is the top quartile, top quintile, or top decile within the reference population. Applicant argues that persons of ordinary skill would have had no difficulty in calculating an FEV1- PS or a threshold FEV1-PS for at least the reasons described above.
5. The arguments have been carefully considered but are not persuasive. With regard to sections A and C in the rejection, Applicant has not pointed to any claim limitations defining how the FEV1-PS is determined and what the reference population is. As stated in the rejection, the specification does not provide any limiting definition of how a FEV1-PS score is determined or calculated, but rather, discloses that numerous methodologies can be used to calculate a FEV1-PS. Applicant has not pointed to any limitations defining how the subject’s determined FEV1-PS and threshold FEV1-PS are calculated with respect to a strength of association and/or probability distribution. Applicant has not pointed to any limitations defining how the genetic variants associated with pre-bronchodilator FEV1 listed in claim 1 are utilized in the method. Given the unknown calculation of, and value for, a “FEV1-PS”, one cannot clearly determine what the FEV1-PS is, how it was determined, and what the scope of claimed subjects are having an FEV1-PS value that is great than, equal to, or below a threshold, and cannot clearly determine the scope of subjects receiving a therapeutic agent at a greater than standard dosage amount or receiving a standard dosage amount.
Although Applicant points to the specification and argues exemplary methods of determining FEVI-PS disclosed in the specification, MPEP 2111.01 states that it is improper to import claim limitations from the specification:
"Though understanding the claim language may be aided by explanations contained in the written description, it is important not to import into a claim limitations that are not part of the claim. For example, a particular embodiment appearing in the written description may not be read into a claim when the claim language is broader than the embodiment." Superguide Corp. v. DirecTV Enterprises, Inc., 358 F.3d 870, 875, 69 USPQ2d 1865, 1868 (Fed. Cir. 2004). See also Liebel-Flarsheim Co. v. Medrad Inc., 358 F.3d 898, 906, 69 USPQ2d 1801, 1807 (Fed. Cir. 2004) (discussing recent cases wherein the court expressly rejected the contention that if a patent describes only a single embodiment, the claims of the patent must be construed as being limited to that embodiment); E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1369, 67 USPQ2d 1947, 1950 (Fed. Cir. 2003) ("Interpretation of descriptive statements in a patent’s written description is a difficult task, as an inherent tension exists as to whether a statement is a clear lexicographic definition or a description of a preferred embodiment. The problem is to interpret claims ‘in view of the specification’ without unnecessarily importing limitations from the specification into the claims."); Altiris Inc. v. Symantec Corp., 318 F.3d 1363, 1371, 65 USPQ2d 1865, 1869-70 (Fed. Cir. 2003) (Although the specification discussed only a single embodiment, the court held that it was improper to read a specific order of steps into method claims where, as a matter of logic or grammar, the language of the method claims did not impose a specific order on the performance of the method steps, and the specification did not directly or implicitly require a particular order).”
In the instant case, the specification discloses on p. 22 “an exemplary method” of determining FEV1-PS and does not limit the instantly claimed method to any specific calculations, specific aggregates of genetic variants, or define their “association with” pre-bronchodilator FEV1. Therefore, the exemplary methods disclosed in the specification cannot be properly imported into the broadly claimed method.
6. With regard to section B in the rejection, Applicant argues that a person skilled in the art, such as a physician, would have understood that a particular therapeutic agent that treats or inhibits a lung disease has a standard dosage amount that is routinely administered to a subject. Applicant argues that the particular therapeutic agents that treat or inhibit a lung disease recited in Applicant's claims are known in the art and many have been extensively used for such treatment. Applicant argues that because a person skilled in the art would be able to determine what is a standard dosage amount and an amount that is greater than a standard dosage amount for any such therapeutic agents, the claims are definite.
7. The arguments have been carefully considered but are not persuasive. With regard to section B in the rejection, as stated in the rejection, standard dosages are unclear, as are amounts greater than them. This is because “standard doses” of a drug are highly relative and dependent on a myriad of different variables, some including patient physiology and age, what the therapeutic agent is, what formulation it is in, how it is delivered, the frequency of delivery/dosing, what disease it treats, which patient population, what result is needed to be achieved, and which drug agency standards. There are no limitations recited in the claims to provide any scope of what a “standard dosage amount” actually is. Given the “standard dosage amount” is unknown, one could not determine the scope of dosage amount that is standard or greater than standard in order to treat the subject having a lung disease or at risk of a lung disease. Applicant’s arguments that the particular therapeutic agents that treat or inhibit a lung disease recited in Applicant's claims are known in the art and many have been extensively used for such treatment are not persuasive. Knowledge of the treating effects of some known drugs provides no information on what the scope of a standard dosage amount is or what a greater than standard dosage amount is for treating the subjects claimed with an IL-4 receptor alpha antagonist and/or IL-13 receptor antagonist, an IL-33 antagonist, or bronchodilator.
Maintained Rejections
(amendments addressed)
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.
Claim Interpretation
8. Claim 1 is rejected above under 35 USC 112(b) because the claim does not provide antecedent basis for “the genetic variants associated with pre-bronchodilator FEV1” and does not indicate how any of the genetic variants listed are used in the claimed method. For the sake of compact prosecution, the rejections below presume the method of claim 1 requires utilizing at least one of the genetic variants listed in claim 1 in calculating the FEV1-PS, although the claim does not currently recite this limitation.
9. Claim(s) 1, 3, 27, 56, and 57 remain rejected under 35 U.S.C. 103 as being unpatentable over Moll et al (Lancet Respiratory Medicine, 2020, 8:969-708), in view of Shrine et al (Nature Genetics, 2019, 51:481-493); Miravitlles et al (Arch Bronconeumol. 2012, 48:247-257); and Tashkin et al (Respiratory Research 2013, 14:49).
Moll teaches a method comprising:
(i) determining a patient’s polygenic risk score (PRS) comprising an aggregate of a plurality of genetic variants associated with pre-bronchodilator FEV1 or FEV1/FVC ratio, wherein the patient has or is at risk of COPD lung disease (p. 697, col. 1-2; p. 698, col. 1-2; Figure 1; Table 1);
(ii) determining and providing a reference or threshold PRS and determining an increased risk of COPD per standard deviation (SD) of the PRS (p. 700, col. 1-2; Figure 2)
wherein 7.4 million SNPs from genome-wide association studies (GWAS) were weighted for development of the PRS, therefore the PRS was calculated with respect to the strength of association of genetic variants and FEV1 to disease (p. 699, col. 2);
wherein the PRS included 1.7 million or 1.2 million highest performing SNPs (p. 699, col. 2);
wherein the reference PRS score was based on a European ancestry population with thousands of participants (p. 698, col. 1-2; Figures 2 and 3; p. 703, col. 1);
wherein the patient PRS is compared to the top quartile, quintile, or decile of the reference population (Figure 3; p. 700, col. 2 to p. 701, col. 1);
Moll teaches that their PRS can identify patients at markedly increased risk of COPD (Figure 4; p. 702, col. 2; p. 703, col. 2). PRS was significantly associated with CT imaging phenotypes such as patterns of reduced lung growth that predisposes individuals to COPD, and higher PRS correlated with higher levels of emphysema (p. 702, col. 1-2; Table 3; p. 704, col. 2 to p. 705, col. 1). Moll teaches that children with persistent asthma and reduced growth of lung function have increased risk for COPD in early adulthood (p. 702, col. 2). Moll teaches:
(p. 704, col. 1):
“The only routine genetic screening recommended in COPD is for α1 antitrypsin deficiency, which is present in about 1% of individuals with COPD.54, 55 Our score identifies 10% of the population at around three-times greater odds for COPD compared with the middle tertile of the population, and around 15–20% of individuals who will develop COPD. Thus, at a young age, we could potentially identify individuals at risk for COPD and implement strategies to optimise lung health.”
(p. 705, col. 1):
“The polygenic risk score was associated with patterns of reduced lung growth in children with asthma, and with incident COPD among participants aged 23–30 years at the conclusion of 16–18 years of observation. Impaired or reduced lung growth during development may predispose individuals to COPD. These data are consistent with genetic association studies of COPD that find associated variants enriched (ie, statistically more likely to occur) in regions of the genome that are important for gene regulation in the fetal lung.10, 11 These findings are also consistent with the study by Lange and colleagues,64 which found that a substantial proportion of individuals with COPD have low lung function in early adulthood. When patterns of normal or reduced lung growth were used to stratify participants in the CAMP study, 18% of individuals with reduced patterns of lung growth developed COPD compared with 3% of individuals with a normal pattern of lung growth.18 Thus, the polygenic risk score is capturing combinations of genetic variants responsible for impaired lung growth and susceptibility to COPD.”
(p. 706, col. 1):
“The past decade has seen important progress in genomic medicine. Leveraging recent large GWASs, we developed a polygenic risk score that has substantial predictive power and complements clinical risk factors for COPD across nine different cohorts. The polygenic risk score is related to a range of imaging phenotypes, including emphysema patterns, as well as reduced lung growth. These findings could have important implications for understanding the mechanisms underlying COPD and provide future opportunities for prevention and early intervention, as genomics become more widely adopted in health care.”
Thus, Moll teaches and suggests that the PRS score associated with FEV1 can identify patients having or at increased risk of developing COPD and other CT imaging lung conditions, and can be used to identify patients in need of prevention or early intervention treatment.
With regard to determining PRS, Moll teaches in their Summary (bold emphasis added):
“Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve.”
Moll teaches in their Methods section, p. 697:
“GWASs for FEV1 and FEV1/FVC were done for participants in the UK Biobank and SpiroMeta.7 We used the GenKOLS case-control study from Bergen, Norway20–22 to tune hyperparameters. We calculated polygenic risk scores in both case-control and population-based studies across a range of ethnicities. Case-control studies included COPDGene (non-Hispanic white and African American participants),23 ECLIPSE,24 NETT25 and Normative Aging Study (NAS),26 SPIROMICS,27,28 and the Lung Health Study (LHS).29,30 Population-based studies included MESA (African American, non-Hispanic white, Hispanic, and Chinese participants),31,32 Cardiovascular Health Study (CHS; African American and European ancestry participants),33 the Rotterdam Study (all three cohorts),34 and a study by Kangwon University.35”
Moll teaches:
“Results
A schematic of the study design is shown in figure 1. We used GWAS summary statistics of approximately 7·4 million single nucleotide polymorphisms (SNPs) from the UK Biobank (n=321047) and SpiroMeta (n=79055) as weights for the development of polygenic risk scores (appendix pp 20–21).7 After filtering on variants present in test cohorts and applying a penalised regression framework, our final individual polygenic risk score for FEV1 contained 1·7 million SNPs and the individual polygenic risk score for FEV1/FVC contained 1·2 million SNPs with non-zero effect sizes; 455 432 SNPs were present in both scores (appendix pp 19–20). The selected shrinkage was 0·9, with a selected λ of 0·0013 for the FEV1 polygenic risk score and 0·0016 for the FEV1/FVC polygenic risk score. Using logistic regression, we generated a combined model: PRSCombined=0·43847 × PRSFEV1 + 0·58833 × PRSFEV1/FVC, in which PRS is polygenic risk score. In GenKOLS, individual polygenic risk scores for FEV1 and FEV1/FVC explained 32% and 31% of their corresponding phenotypic variance, respectively.”
Therefore, Moll teaches the GWAS (genome-wide association study) associated with FEV1 and FEV1/FVC was based on SNP (single nucleotide polymorphism) data obtained from the UK Biobank, and Moll cites the source for that data in reference #7, Shrine et al (cited below).
Moll further teaches p. 698, col. 1 (bold emphasis added):
“Derivation of polygenic risk scores
To develop individual polygenic risk scores for FEV1 and FEV1/FVC, we generated weights based on effect sizes from GWASs of FEV1 and FEV1/FVC in the UK Biobank and SpiroMeta.7 To reduce the chance of genetic variant drop-out between studies, we included variants that were either genotyped or well imputed (R2>0·5) in four cohorts: COPDGene, GenKOLS, ECLIPSE, and NETT/NAS. We then applied a penalised regression framework, accounting for linkage disequilibrium (lassosum v0.4.4),38 in which linkage disequilibrium was calculated using European ancestry individuals in the UK Biobank.39”
Moll teaches their GWAS data was obtained from and based on the UK Biobank disclosed by Shrine to calculate the PRS, however, Moll does not teach the specific SNPs or genetic variants in the UK Biobank data include at least 1 of the instantly claimed genetic variants recited in claim 1.
Moll does not teach administering a therapeutic agent that treats lung disease at standard dose when the patient has a greater than or equal to a threshold PRS, or administering the therapeutic agent at a greater than standard dosage amount when the patient’s PRS is less than the threshold PRS.
Polygenic Risk Score comprises at least 1 of the genetic variants/SNPs recited in claim 1:
Moll teaches the GWAS associated with FEV1 and FEV1/FVC was based on SNP data obtained from the UK Biobank, and Moll cites the source for that data in reference #7, Shrine.
Shrine teaches on p. 482, col. 1: “Genetic variants associated with lung function and COPD susceptibility can provide etiological insights, assisting with risk prediction as well as drug target identification and validation.”
Shrine teaches, p. 482, col. 1:
“Through new detailed quality control and analyses of spirometric measures of lung function in the UK Biobank and expansion of the SpiroMeta Consortium, we undertook a large genome-wide association study (GWAS) of lung function. Our study entailed a near seven-fold increase in sample size over previous studies of similar ancestry to address the following aims: (1) to generate a high yield of genetic markers associated with lung function; (2) to confirm and fine-map previously reported lung function signals; (3) to investigate the putative causal genes and biological pathways through which lung function–associated variants act, and their wider pleiotropic effects on other traits; and (4) to generate a weighted genetic risk score for lung function and test its association with COPD susceptibility in individuals of European and other ancestries.”
Results:
“Genome-wide association analyses of forced expired volume in 1 second (FEV1), forced vital capacity (FVC) and FEV1/FVC were undertaken in 321,047 individuals in UK Biobank (Supplementary Table 1) and in 79,055 individuals from the SpiroMeta Consortium (Supplementary Tables 2 and 3)”.
“A total of 19,819,130 autosomal variants imputed in both UK Biobank and SpiroMeta were analyzed. Peak expiratory flow (PEF) was also analyzed genome-wide in UK Biobank and up to 24,218 samples from SpiroMeta.”
“To maximize statistical power for discovery of new signals while maintaining stringent significance thresholds to minimize reporting of false positives, we adopted a study design incorporating both two-stage and one-stage approaches (Fig. 1). In the two-stage analysis, new distinct signals, defined using conditional analyses, were associated with one or more traits at P<5x10-9 in UK Biobank and showed association (P<10-3) with a consistent direction of effect in SpiroMeta (tier 1 signals, Supplementary Fig. 2 and Supplementary Table 4). In the one-stage analysis, we meta-analyzed UK Biobank and SpiroMeta (up to 400,102 individuals), and identified 40 additional new distinct signals associated with one or more lung function traits reaching P<5×10-9 (Supplementary Fig. 2 and Supplementary Table 4) that were also associated with P<10-3 separately in UK Biobank and in SpiroMeta, with consistent direction of effect (tier 2 signals). An additional 323 autosomal signals were significantly associated with one or more lung function traits in the meta-analysis of UK Biobank and SpiroMeta (P<5x10-9) and reached P<10-3 for association in only one of UK Biobank or SpiroMeta (tier 3 signals, Supplementary Table 5).
See Figure 1.
Methods:
“UK Biobank. The UK Biobank resource is described elsewhere (see URLs). Individuals were selected for inclusion in this study if they (1) had complete data for age, sex, height and smoking status; (2) had spirometry meeting quality control requirements (based on analyses of acceptability, reproducibility and blow curve metrics; Supplementary Note); (3) had genome-wide imputed data and (4) were of European ancestry based on genetic data (Supplementary Note and Supplementary Fig. 1). Genotyping was undertaken using the Affymetrix Axiom UK BiLEVE and UK Biobank arrays13. Genotypes were imputed to the Haplotype Reference Consortium panel56 (Supplementary Note), and retained if minor allele count was ≥3 and imputation quality (info) was >0.5. In total, 321,047 individuals were included in our analyses (Supplementary Table 1). Residuals from linear regression of each trait (FEV1, FVC, FEV1/FVC and PEF) against age, age2 , sex, height, smoking status (ever or never) and genotyping array were ranked and inverse-normal transformed, giving normally distributed Z-scores. These Z-scores were used for genome-wide association testing under an additive genetic model using BOLT-LMM v2.3 (ref. 20). Principal components were not included as BOLT-LMM uses a linear mixed model to account for relatedness and fine-scale population structure.”
Thus, Shrine teaches identifying SNPs in a European population (UK Biobank) utilizing commercially available Affymetrix Axiom UK BiLEVE and UK Biobank arrays, and calculating associations of the SNPs with FEV1, FVC, FEV1/FVC and PEF lung function in COPD.
As evidenced by the Biobank website, https://biobank.ctsu.ox.ac.uk/ukb/refer.cgi?id=149601, the Affymetrix Axiom UK Biobank array annotation file teaches that the array detects SNPs or genetic variants including at least 10 genetic variants listed in instant claim 1 (see Table below).
As evidenced by the Biobank website, https://biobank.ctsu.ox.ac.uk/ukb/refer.cgi?id=149600, the Affymetrix Axiom UK BiLEVE array annotation file teaches that the array detects SNPs or genetic variants including at least 10 genetic variants listed in instant claim 1 (see Table below). The Excel files from Biobank are too large to include in the office action. Please see the links provided, they are publicly available.
The Table below lists the instantly claimed genetic variants in claim 1, their corresponding and more commonly used rsID number (as identified by the NCBI website, https://www.ncbi.nlm.nih.gov/, SNP database), and Excel sheet item # for the variant/SNP in each array at their respective Biobank website Excel annotation files.
Table:
Claimed variant
GRCh38 coordinate
rsID #
UK BiLEVE array
Excel item #
Axiom UK Biobank array Excel item #
4:169087957 :G:A
rs2706720
72938
77090
6:108946847 :C:T
rs2798641
661639
670178
17:7463300 :T:C
rs34914463
710553
719786
20:35437976 :G:A
rs143384
38361
42031
10:12235993:C:T
rs7068966
243314
251901
10:76555466:G:A
rs11001819
11069
14281
2:18544473:G:A
rs11890443
641682
649888
4:105897896:G:A
rs34712979
82613
86961
5:148476959:G:A
rs7733410
239568
248098
4:144737912:T:C
rs11727676
18285
21610
Thus, the Biobank genetic variant data utilized by Shrine in the GWAS comprises at least 10 of the instantly claimed genetic variants or SNPs, and the specific genetic variants were detected utilizing commercially available arrays. Shrine demonstrated utilizing this SNP dataset to correlate with FEV1 lung function values for COPD patients.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the Affymetrix Axiom UK BiLEVE array and/or Affymetrix Axiom UK Biobank arrays of Shrine to obtain GWAS or SNP data from a test subject and UK Biobank reference population of Moll, and include at least 1 genetic variant listed in instant claim 1, for determining FEV1-PRS. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Moll teaches they constructed a polygenic risk score (PRS) using a genome-wide association study (GWAS) of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank data, citing Shrine as the source; (2) Shrine demonstrated their GWAS/genetic variant data was obtained by Affymetrix Axiom UK BiLEVE array and/or Affymetrix Axiom UK Biobank arrays that detect at least 10 of the instantly claimed genetic variants (listed in the Table above); (3) Shrine demonstrated utilizing the genetic variant/SNP dataset obtained from the arrays to generate a weighted genetic risk score for lung function and to test its association with COPD susceptibility in individuals of European ancestry; and (4) the arrays are commercially available and demonstrated as successfully used to detect thousands of SNPs or genetic variants in subjects as associated with COPD and FEV1 lung function. Given the arrays for detecting the genetic variants claimed are commercially available and successfully used for obtaining the genetic variant data correlated to lung disease and FEV1 function, one of skill in the art would have a reasonable expectation of success to utilize the commercially available arrays or their resulting data in the method of Moll, and utilize at least 10 of the claimed genetic variants detected by these arrays in methods correlating genetic variant data to lung disease and FEV1 function, and generating a polygenic risk score (PRS).
Standard or greater than standard doses of therapeutic comprising bronchodilator such as long-acting beta agonists (LABA):
Miravitlles teaches standard therapeutic treatments for patients diagnosed with COPD, including inhaled corticosteroids (IC), long-acting bronchodilators (LABD) (beta-agonists (LABA), moterol, indacaterol), long-acting muscarinic antagonists (LAMA) (tiotropium bromide), short-acting bronchodilators (muscarinic antagonists, ipratropium bromide, beta2 agonists, salbutamol, terbutaline), theophylline, phosphodiesterase IV inhibitors, mucolytic agents, and antibiotics (p. 251, Box “Treatment of Stable COPD”; p. 251, col. 2 to p. 255, col. 1). Miravitlles teaches that treatment dosage and intensity should be adjusted (increased, decreased, high or low doses) depending on severity of COPD and phenotype (p. 251, col. 1; p. 254, col. 2 to p. 255, col. 1; Table 3).
Tashkin teaches numerous treatment regimens and dosing of various bronchodilators, including LABAs, and therapies for COPD, including combination therapies and doses that are relatively greater than or lower than others, wherein various dosing regimens are successful in improving FEV1 lung functions values (Tables 2-4). Tashkin also teaches there are fix-dose combinations of bronchodilators that offer improved convenience and compliance over using separate inhalers, and have demonstrated improved bronchodilation over monotherapies, demonstrating improvement in FEV1 lung function (p. 4, col. 1-2; Table 4; p. 7, col. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer any of the known therapeutic agents/bronchodilators to treat COPD and at standard or greater than standard doses when the patient’s PRS is greater than or equal to a threshold PRS or when the patient’s PRS is less than a threshold PRS. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Moll teaches PRS values associated with FEV1 that are diagnostic of subjects having COPD and having various CT Imaging traits associated with reduced airway function; (2) Moll, Miravitlles, and Tashkin recognize that patients diagnosed with CODP having these PRS values and poor FEV1 lung function values are in need of therapeutic treatment; (3) Miravitlles and Tashkin summarize known and established therapeutic agents/bronchodilators for treating patients diagnosed with COPD, teach variations in therapeutic amounts and intensity are necessary as symptoms/phenotypes of COPD change; and teach several known clinical treatments of COPD comprising bronchodilators at various relatively higher and lower doses, and at fixed dose combinations that are successful in improving FEV1 lung function in COPD patients. Given both Moll, Miravitlles, and Tashkin recognize COPD patients are in need of therapeutic agent/bronchodilator treatment, including those with variable PRS values and FEV1 values indicative of COPD and lung pathologies, and given various higher, lower, or fixed doses and changing intensities/frequencies of bronchodilators for treating COPD are known and established, one of skill in the art could have predictably and successfully treated COPD patients and improved FEV1 lung function in the method of Moll by administering standard or higher doses of known CODP therapeutic agents/bronchodilators to any of the COPD patients with a reasonable expectation of success.
Response to Arguments
10. Applicant argues that: a) the combination of cited references do not teach determining the FEV1-PS of a subject recited in Applicant’s claims. Applicant argues that that the cited references do not teach the methodology claimed for calculating the FEV1-PS. Applicant argues Moll and Shrine teach weighted scores, where Moll teaches PRSCombined=0·43847 × PRSFEV1 + 0·58833 × PRSFEV1/FVC, in which PRS is polygenic risk score and Shrine teaches a genetic risk score (GRS) weighted by FEV1/FVC effect sizes comprising all 279 sentinel variants. Applicant argues that Miravitlles, and Tashkin do not teach any risk scores. Applicant argues that the combination of cited references do not teach determining FEV1-PS of a subject as required by the claims.
11. The arguments have been considered but are not persuasive. Applicants are arguing limitations not recited in the claims. There is no mathematical calculation including the genetic variants recited for determining the claimed FEV1-PS that excludes the polygenic risk score (PRS) taught by Moll. There is no limitation recited in the claims that excludes how the genetic variant was used in the process of calculating the PRS. Applicants have not persuasively argued how the PRS score calculated by Moll fails to meet the claim limitations of determining the subject’s forced expiratory volume in one second (FEV1) polygenic score (PS) (FEV1-PS) and threshold scores for comparison, including calculating PRS with respect to a strength of association or a probability distribution.
12. Applicants argue that: b) there is no evidence of record that any of the genetic scores in Moll and Shrine necessarily used the particular variants claimed. Applicants argue that Moll reports the final PRS for FEV1 contained 1.7 million SNPs and the individual PRS for FEV1/FCV contained 1.2 million SNPs with 455,432 SNPs present in both scores. Applicants argue that Moll does not teach which SNP was comprised in the 1.7 million, 1.2 million, or shared 455,432 SNPs. Applicants argue there is no evidence that Moll used the instantly claimed genetic variants in calculating their PRS.
13. The arguments have been considered but are not persuasive. As stated above, the claims do not recite any limitations indicating how or when the genetic variant is used during the process of calculating the FEV1-PS. Contrary to arguments, the rejection of record provides evidence that Moll utilized data comprising detection of at least 1 to 10 of the claimed genetic variants in their process of calculating the PRS.
14. Applicant argues that: c) there would have been no motivation to modify or combine the cited references to arrive at the claimed invention. Applicant argues that they generally found that as few as 10 of the genetic variants recited in the claims at issue are sufficient to determine whether a subject having lung disease or at risk of lung disease should be treated with a standard dose of the claimed therapeutic agent or an amount greater than standard dose. Applicant argue their finding is contrary to the reports of Moll, where Moll identified numerous genetic variants associated with COPD risk (citing Shrine) and teach the effect size of each of these GWAS variants is generally small. Applicant argues that Moll teaches variants identified by GWAS are of individually small effect and account for a modest fraction of genetic risk. Applicants argues that Moll’s PRSs are poorly predictive of lung disease. Applicants argue that Shine, Miravitlles, and Tashkin do not remedy this deficiency.
15. The arguments have been considered but are not persuasive. Applicants are arguing limitations not recited in the claims. The claims as amended no longer recite or require as few as 10 genetic variants to determine the FEV1-PS, and now recite as few as 1. As stated above, the claims do not recite any limitations indicating how or when the genetic variant is used during the process of calculating the FEV1-PS. Contrary to arguments, there is no claimed limitation requiring a specific FEV1-PS mathematical calculation requiring one of the specifically claimed genetic variants, or that the genetic variant is required to have a large effect versus a small effect. Contrary to arguments, the rejection of record provides evidence that Moll utilized data comprising detection of at least 1 to 10 of the claimed genetic variants in their process of calculating the PRS.
16. Applicant argues that: d) there is no reasonable expectation of success for modifying or combining the cited references to arrive at the claimed invention. Applicant argues that Moll’s reports are limited. Applicants argue that Moll teaches further testing and experimentation is required to determine the role of polygenic risk scores for understanding COPD pathogenesis. Applicants argue that Moll provides “no more than hope – and hope that a potentially promising [PRS] will treat a particular [lung disease] is not enough to create a reasonable expectation of success, citing MPEP 2143.02(II).
17. The arguments have been considered but are not persuasive. MPEP 2143.02(II) states:
II. AT LEAST SOME DEGREE OF PREDICTABILITY IS REQUIRED; APPLICANTS MAY PRESENT EVIDENCE SHOWING THERE WAS NO REASONABLE EXPECTATION OF SUCCESS
Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (Claims directed to a method for the commercial scale production of polyesters in the presence of a solvent at superatmospheric pressure were rejected as obvious over a reference which taught the claimed method at atmospheric pressure in view of a reference which taught the claimed process except for the presence of a solvent. The court reversed, finding there was no reasonable expectation that a process combining the prior art steps could be successfully scaled up in view of unchallenged evidence showing that the prior art processes individually could not be commercially scaled up successfully.). See also OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("These references provide no more than hope—and hope that a potentially promising drug will treat a particular cancer is not enough to create a reasonable expectation of success in a highly unpredictable art such as this. Indeed, given a 99.5% failure rate and no efficacy data or any other reliable indicator of success, the only reasonable expectation at the time of the invention was failure, not success."); Amgen, Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1207-08, 18 USPQ2d 1016, 1022-23 (Fed. Cir. 1991), cert. denied, 502 U.S. 856 (1991) (In the context of a biotechnology case, testimony supported the conclusion that the references did not show that there was a reasonable expectation of success.); In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.).
In the instant case, contrary to arguments, Moll and the combined references do provide a degree of predictability to calculate a FEV1-PS, determine a threshold correlated to COPD risk, and treat the COPD as claimed. Moll explicitly states the success of their method in the abstract:
Findings
The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·82 [95% CI 1·74–1·89] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.
Interpretation
A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.
Therefore, contrary to arguments, Moll teaches their PRS calculation was successfully associated with risk of COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.
Contrary to arguments, the secondary references provide a reasonable expectation of success to treat the patients identified by Moll and Shrine with the claimed standard or greater than standard dose of treatment. As stated in the rejection:
Given Moll, Miravitlles, and Tashkin recognize COPD patients are in need of therapeutic agent/bronchodilator treatment, including those with variable PRS values and FEV1 values indicative of COPD and lung pathologies, and given various higher, lower, or fixed doses and changing intensities/frequencies of bronchodilators for treating COPD are known and established, one of skill in the art could have predictably and successfully treated COPD patients and improved FEV1 lung function in the method of Moll by administering standard or higher doses of known CODP therapeutic agents/bronchodilators to any of the COPD patients with a reasonable expectation of success.
Applicants have not provided persuasive evidence showing there was no reasonable expectation of success to treat the lung disease patients identified by Moll with standard or greater than standard doses of well-established therapeutics taught by the secondary references.
18. Claim(s) 9, 15, 16 remain rejected under 35 U.S.C. 103 as being unpatentable over Moll et al (Lancet Respiratory Medicine, 2020, 8:969-708), Shrine et al (Nature Genetics, 2019, 51:481-493); Miravitlles et al (Arch Bronconeumol. 2012, 48:247-257), and Tashkin et al (Respiratory Research 2013, 14:49); as applied to claims 1, 3, 27, 56, and 57 above, and further in view of Fieldes et al (ERJ Open Research, April 12, 2021, 7:00437-2020; p. 1-14).
Moll, Shrine, Miravitlles, and Tashkin (the combined references) teach a method of treating a patient diagnosed as having COPD, the method comprising:
(i) determining the patient’s polygenic risk score (PRS) associated with pre-bronchodilator FEV1 (PRS-FEV1) and comprising at least 10 of the instantly claimed genetic variants in determination;
(ii) diagnosing the patient as having COPD based on a threshold PRS-FEV1 value;
(iii) treating the subject diagnosed with COPD by administering known and established therapeutic agents/bronchodilators that treat COPD, including treatment by administering standard doses or increasing doses or intensities of the treatment based on need, severity, and phenotype, as set forth above.
The combined references do not teach the therapeutic agent is dupilumab.
Fieldes teaches a significant proportion of COPD patients with severe COPD and eosinophilic inflammation experience uncontrolled symptoms despite optimal pharmaceutical treatment (Conclusion, p. 9). Fieldes teaches the IL-4/IL-13 pathway plays a role in the development of COPD (Figure 1) and teaches that the success of dupilumab (binding IL-4Rα) in treating asthma must be extralated to the treatment of COPD, and a clinical trial treating COPD [patients with dupilumab is underway (p. 7):
“Dupilumab is a human mAb targeting IL-4Rα leading to inhibition of IL-13 and IL-4 signalling [129]. A randomised, placebo-controlled, phase IIb clinical trial showed a significant increase in FEV1 parameter and a reduction in the rate of severe exacerbations in patients with uncontrolled asthma under dupilumab treatment. Improvements were consistent in two different treatment groups; dupilumab 200 or 300 mg every 2 weeks regardless of baseline eosinophil count [130]. These encouraging data must be transposed to COPD patients. The BOREAS (A Pivotal Study to Assess the Efficacy, Safety and Tolerability of Dupilumab in Patients With Moderate-to-severe COPD With Type 2 Inflammation) study is underway (NCT03930732) and will give some insights for patients with COPD.”
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer dupilumab to the COPD patients in the method of the combined references. One would have been motivated and have a reasonable expectation of success because: (1) all of the cited references recognize the need to treat patients diagnosed with COPD; (2) Fieldes teaches a significant proportion of COPD patients with severe COPD and eosinophilic inflammation experience uncontrolled symptoms despite optimal pharmaceutical treatment with known therapeutics and suggest alternative treatments that target IL4Ra/IL13R such as dupilumab; and (3) Fieldes teaches COPD patients are already being treated with dupilumab and at a known dose of 200 or 300 mg every 2 week.
Response to Arguments
19. Applicant argues that Fields does not cure the deficiencies argued above for Moll, Shrine, Miravitles, and Tashkin.
20. The arguments have been considered but are not persuasive. Moll, Shrine, Miravitles, and Tashkin do not have the deficiencies argued above for the reasons stated above, therefore Fields does not have to remedy the deficiencies argued.
21. Claim(s) 38 and 39 remain rejected under 35 U.S.C. 103 as being unpatentable over Moll et al (Lancet Respiratory Medicine, 2020, 8:969-708), Shrine et al (Nature Genetics, 2019, 51:481-493); Miravitlles et al (Arch Bronconeumol. 2012, 48:247-257), and Tashkin et al (Respiratory Research 2013, 14:49); as applied to claims 1, 3, 27, 55-57 above, and further in view of Huang et al (April 28, 2021, Research Square, DOI: 10.21203/rs.3.rs-423764/v1).
Moll, Shrine, Miravitlles, and Tashkin (the combined references) teach a method of treating a patient diagnosed as having COPD, as set forth above.
The combined references do not teach the PRS-FEV1 is calculated using LDPred and pruning and thresholding method.
Huang teaches successfully calculating PRS-FEV1 for patients using LDPred (“DL-PRS”) to assess risk of COPD. Huang teach regarding the relevance of COPD, their methods of calculating DL-PRS had a consistent and closer relationship regarding individual deciles and lung functions such as FEV1/FVC and predicted FEV1%. Huang concludes: “Not only does DL-PRS show favorable predictive performance with current benchmark PRS methods, but it also extends the ranges of PRS deciles in predicting different stages of COPD. Moreover, our DL-PRS results were replicated in an independent cohort” (abstract). Huang teaches their method of calculating PRS also utilized pruning and thresholding (P+T) (Methods: “PRS benchmark methods” p. 4).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to calculate the DL-PRS score of Huang in the method of the combined references using LDPred and P+T. One would have been motivated to and have a reasonable expectation of success to because the combined references teach the need and success for calculating PRS in COPD and lung pathology diagnostics, and Huan teaches their method of calculating DL-PRS with P+T is superior and successful for COPD diagnostics.
Response to Arguments
22. Applicant argues that Huang does not cure the deficiencies argued above for Moll, Shrine, Miravitles, and Tashkin.
23. The arguments have been considered but are not persuasive. Moll, Shrine, Miravitles, and Tashkin do not have the deficiencies argued above for the reasons stated above, therefore Huang does not have to remedy the deficiencies argued.
24. Claim(s) 53 remains rejected under 35 U.S.C. 103 as being unpatentable over Moll et al (Lancet Respiratory Medicine, 2020, 8:969-708), Shrine et al (Nature Genetics, 2019, 51:481-493); Miravitlles et al (Arch Bronconeumol. 2012, 48:247-257), and Tashkin et al (Respiratory Research 2013, 14:49); as applied to claims 1, 3, 27, 56, and 57 above, and further in view of Elliott et al (International J of Epidemiology, 2008, 37:234-244).
Moll, Shrine, Miravitlles, and Tashkin (the combined references) teach a method of treating a patient diagnosed as having COPD, as set forth above.
Moll teaches they obtained genetic data for PRS calculations from the UK Biobank collection (Methods, p. 697, col. 2), and Shrine teaches obtaining their genetic variant data from the UK Biobank for correlation to lung function and COPD, as set forth above.
The combined references do not teach the genetic data/PRS was determined from biological samples that are blood or urine.
Elliott teaches the UK Biobank collected blood and urine samples from subjects to obtain genetic data (Methods; Box 2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to determine PRS from blood or urine samples collected form subjects. One would have been motivated to and have a reasonable expectation of success to because Moll teaches the US Biobank was a source of their genetic information for calculating PRS, and Elliott teaches the UK Biobank collected blood and urine samples to provide that genetic data.
Response to Arguments
25. Applicant argues that Elliott does not cure the deficiencies argued above for Moll, Shrine, Miravitles, and Tashkin.
26. The arguments have been considered but are not persuasive. Moll, Shrine, Miravitles, and Tashkin do not have the deficiencies argued above for the reasons stated above, therefore Elliott does not have to remedy the deficiencies argued.
27. Conclusion: No claim is allowed.
Conclusion
28. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
29. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642