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 .
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on April 17, 2026 has been entered.
Claims 1, 3, 13, 15, 22, 23, 27, 38, 39, 53, 58 are now pending. Claims 1, 15, 22, 53 are amended. Claim 58 is new. Claims 13, 22, 23, and 58 remain/are withdrawn as being drawn to non-elected species. Claims 1, 3, 15, 27, 38, 39, 53 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 Rejections
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, 15, 27, 38, 39, and 53 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.
(i) Claim 1 recites the limitation "the genetic variants associated with FEV1-PS". There is insufficient antecedent basis for this limitation in the claim because there is no previous mention of genetic variants associated with FEV1-PS.
(ii) Claim 1 is unclear regarding how the genetic variants are “associated with” FEV1-PS. Associated how? The metes and bounds of the claim cannot be determined.
(iii) 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 (FEV1) polygenic score (FEV1-PS); and
administering or continuing to administer duplimab at a standard dosage amount when the subject’s FEV1-PS is greater than or equal to a threshold FEV1-PS; or
administering or continuing to administer duplimab at a dose that is greater than a standard dosage amount when the subject’s FEV1-PS is less than the threshold FEV1-PS,…”
Claim 1 never recites or requires that the subject is currently being treated or was previously treated with dupilumab at either a standard dosage amount or a greater than standard dosage amount, therefore it is unclear how the subject can be continuing treatment with such dosages. Clarification is required.
For the sake of compact prosecution, the claims will be examined as though there are two subject populations encompassed by the methods: (1) subjects continuously receiving dupilumab before and after FEV1-PS determination, and (2) subjects receiving dupilumab for the first time after FEV1-PS determination.
Dependent claims are rejected for encompassing the rejected limitations of claim 1.
Maintained Rejections
(amendments addressed)
Claim Rejections - 35 USC § 112
3. Claims 1, 3, 15, 27, 38, 39, and 53 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 now 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 duplimab at a standard dosage amount when the subject’s FEV1-PS is greater than or equal to a threshold FEV1-PS; or
administering or continuing to administer duplimab 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 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 FEV1-PS comprise at least ten of 2:18106357:T:C; ……and 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 there are genetic variants associated with FEV1-PS comprising at least ten of the genomic positions listed in claim 1. The claim is unclear regarding 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” is unclear. It is also noted that claim 1 as amended does not require utilizing the claimed “genetic variants associated with FEV1-PS” in determining the FEV1-PS score, nor indicate how the genetic variants would be used in the method.
The instant specification does not provide any limiting definition of what a FEV1-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 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 the scope of subjects receiving dupilumab at a greater than standard dosage amount or receiving a standard dosage amount.
B. The claim requires administering the dupilumab at a “standard dosage amount” or “greater than standard dosage amount”. The claim is unclear regarding 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 recites comparing the subject’s determined FEV1-PS value to a “FEV1-PS threshold” then defines the “FEV1-PS threshold” as the top quartile, top quintile, or top decile within a reference profile. Top quartile, top quintile, or top decile of what within what 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 the 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 unknown “FEV1-PS threshold” that are a top quartile, top quintile, or top decile within 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 claimed threshold, and the scope of subjects receiving dupilumab 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.
Dependent claims are rejected for encompassing the rejected limitations of claim 1.
Response to Arguments
4. Regarding section A above, Applicants argue:
Claim 1 recites 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's specification teaches that "Numerous methodologies can be used to calculate a FEV1-PS" (see, page 27, line 8 of the specification) including with respect to a strength of association and/or a probability distribution (see, page page 27, line 10 of the specification). Applicant' further teaches that the FEV1-PS can be "calculated using an LDPred or an SBayesR method, or any other available method" (see, page 27, lines 10-11 of the specification). Applicant then provides a summary teaching of the LDPred method, which is a known Bayesian approach to calculate a posterior mean effect for all variants based on a prior and subsequent shrinkage based on linkage disequilibrium, and that LDPred creates a PRS using genome-wide variation with weights derived from a set of GWAS summary statistics (citing, Vilhjálmsson et al., Am. J. Hum. Genet., 2015, 97, 576-92) (see, page 27, lines 13-18 of the specification). Applicant further teaches alternate approaches for calculating genetic variant scores may be used, including SBayesR (citing, Lloyd-Jones, LR, world wide web at "biorxiv.org/content/biorxiv/early/2019/ 01/17/522961.full.pdf", Pruning and Thresholding (P&T) (Purcell, Nature, 2009, 460, 748-752), and conditional and joint analysis (COJO) (Yang et al., Nat. Genet., 2012, 44, 369-375)) (see, page 27, lines 18-22). Applicant also provides a summary teaching that SBayesR is a Bayesian approach is similar to LDPred but allows for more flexibility in the posterior mean effects (see, page 27, lines 22-23 of the specification). Applicant then teaches that P&T requires that a minimum p-value threshold (p-value associated with the variant from the source data file) and r² threshold (measure of linkage disequilibrium (LD)) between variants be specified and that P&T identifies the variant with the smallest p-value in each region and then "clumps" under that variant all other variants in the region with an r² value that is larger than the specified r² (see, page 27, lines 23-28 of the specification). Applicant further explains that COJO is similar conceptually to P&T but incorporates additional variants in a given LD block into the score if they demonstrate independent contribution to disease risk after conditioning on the index variant (see, page 27, line 29 to page 28, line 2). Applicant then provides a detailed teaching of the calculation using the LDPred and P&T methods with specific values (see, page 28, lines 4-21 of the specification). Applicant even provides a working example and results of generating a therapeutic FEV1-PS (see, Example 1). Thus, Applicant provides ample teaching of calculating a subject's FEV1-PS and threshold FEV1-PS with respect to a strength of association and/or a probability distribution. Indeed, LDPred, SBayesR, P&T, and COJO are well known to the skilled artisan as evidenced in the cited references. It matters not which of any of these well known procedures are used to calculate a subject's FEV1-PS and threshold FEV1-PS. Persons of ordinary skill would have no difficulty in determining whether a particular threshold FEV1-PS or a particular subject's FEV1-PS meets the criteria recited in the claims.
5. The arguments have been considered but are not persuasive. Applicants have 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.
Applicants have not pointed to any claim limitations defining how the subject’s determined FEV1-PS and threshold FEV1-PS are/were calculated with respect to a strength of association and/or probability distribution. Applicants have not pointed to any limitations defining how the genetic variants associated with FEV1-PS listed in claim 1 are utilized in the method. Claim 1 currently does not recite or require using any of the claimed genetic variants associated with FEV1-PS in the determination of FEV1-PS. 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 dupilumab 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 FEV1-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” FEV1-PS. Therefore, the exemplary methods disclosed in the specification cannot be properly imported into the claimed method.
6. Regarding section B above, Applicants argue that claim 1 is amended and limited to administering dupilumab. Applicants argue:
Applicant submits that standard dosage amounts for dupilumab for a particular lung disease are well known to a person skilled in the art (see, for example, www.dupixent.com/atopicdermatitis/why-dupixent/dosing#recommended-dosing' (disclosing a 300 mg initial dose of dupilumab for an adult asthma subject having any weight) (last visited March 24, 2026). Persons of ordinary skill would have no difficulty in determining whether a particular standard dosage amount meets the criteria recited in the claims.
7. The arguments have been considered but are not persuasive. Applicants have not pointed to any definitions in the instant specification identifying what is encompassed by the claimed “standard dosage amount” or “greater than standard dosage amount” for dupilumab. Instead, Applicants point to 2026 website (5 years after the effective filing date) to argue that the definition of “standard dosage amount” or “greater than standard dosage amount” for dupilumab is known and can be readily determined. The claimed “standard doses” of any drug can be highly relative and dependent on a myriad of different variables, some including patient physiology, weight and age, 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 for dupilumab. 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 standard dosage of dupilumab can be determined are not persuasive. The instant claims and specification provide no information on what the scope of a standard dosage encompasses is or what a greater than standard dosage amount is for treating the subjects claimed with dupilumab.
8. Regarding section C above, Applicants argue:
Reference populations are used throughout the literature. Applicant teaches that a reference population comprises from at least about 100 subjects to at least about 100,000 subjects (see, page 26, lines 2-22 of the specification). Applicant further teaches that the reference population can be enriched for members of an ancestry group such as, for example, a European ancestry group, an African ancestry group, an admixed American ancestry group, an East Asian ancestry group, or a South Asian ancestry group (see, page 26, lines 23-27 of the specification). Nothing more or less is required in the "reference population". Persons of ordinary skill would have no difficulty in determining whether a particular population meets the criteria recited in the claims.
9. The arguments have been considered but are not persuasive. Applicants have not pointed to any definitions in the instant specification or claim limitations defining what the scope of a “reference population” encompasses. Reference population of what? Applicants argue that the specification suggests a reference population comprises at least about 100 subjects to at least 100,00 subjects and can be enriched for an ancestry group, however, MPEP 2111.01 states that it is improper to import claim limitations from the specification (see citation above).
Further, the claims recite that the “threshold FEV1-PS is the top quartile, top quintile, or top decile within a reference population…” How can the “threshold FEV1-PS” literally be a top quartile, top quintile, or top decile of a reference population? The claims as currently constituted are comparing a subject’s FEV1-PS score to a percentile reference population, however, the claims do NOT recite comparing the subject’s FEV1-PS score to the FEV1-PS score of a reference lung disease or control patient population percentile, which is what Applicants appear to be arguing. The claims as currently constituted are unclear with regard to what the threshold FEVI-PS is, therefore the scope of the subjects having an FEV1-PS above, equal to, or lower than the “FEV1-PS threshold” cannot be determined, and the scope of subjects receiving a standard dosage amount or greater than standard dosage amount cannot be determined. Given the above reasons, the metes and bounds of the claims cannot be determined.
New Rejection
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.
10. Claim interpretation: As stated above, due to the lack of clarity in claim language, the claims will be examined as though there are two subject populations encompassed by the methods: (1) subjects continuously receiving dupilumab before and after FEV1-PS determination and comparison to thresholds, and (2) subjects receiving dupilumab for the first time after FEV1-PS determination and comparison to threshold.
11. Claims 1, 3, 15, 27, 38, 39, 53 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature/ a natural phenomenon, natural phenomenon and abstract idea, without significantly more. The claim(s) recite(s):
(i) determining or having determined the subject’s forced expiratory volume in one second (FEVI) polygenic score (FEV1-PS); and
(ii) administering or continuing to administer duplimab at a standard dosage amount when the subject’s FEV1-PS is greater than or equal to a threshold FEV1-PS; or
administering or continuing to administer duplimab 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 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.
Thus, the claims are directed to the judicial exception of naturally occurring phenomenon represented by a mathematical FEV1-PS score in response to continuing dupilumab treatment and mental comparison to a reference population. This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite a step of “determining or having determined the subject’s FEV1 polygenic score” with no particular novel laboratory steps that would amount to significantly more than the judicial exception. The steps of determining a patient’s polygenic score or polygenic risk score associated with FEV1, are a mathematical representation of biological variables or abstract idea, and determining such scores are considered known, routine steps and are typically taken by those in the field to provide a numerical representation of patient genetic variation associated and FEV1, and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, Sordillo et al (J. Pers. Med. April 7, 2021, 11:319, 8 pages), Moll et al (The Lancet, July 2020, 8:696-708), Kim et al (medRxiv, March 29, 2021; 21254415); Shrine et al (Nature Genetics, 2019, 51:481-493); Sikdar et al (Thorax, May 7, 2021; 76:1219-1226); Milne et al (2020, American Thoracic Society International Conference Abstract; C13; abstract only); Huang et al (April 28, 2021, Research Square, DOI: 10.21203/rs.3.rs-423764/v1); and Kim (2020. Genome-wide Study of Emphysema Progression and Gene-by-smoking Interaction of Chronic Obstructive Pulmonary Disease; Doctoral dissertation, The Johns Hopkins University) demonstrate practicing routine determination of polygenic scores and associated FEV1 in patients having various lung diseases. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
Regarding the subset subjects continuously receiving dupilumab treatment through FEV1-PS testing, the step of “continuing to administer dupilumab” at an undefined standard dosage amount or greater than standard dosage amount of dupilumab after mentally comparing to a threshold fails to practically apply the judicial exception because the claim encompasses methods of continuously administering dupilumab to a patient population while measuring and comparing their naturally occurring FEV1-PS scores in response to the drug. Therefore, the claims read on continually observing the naturally occurring phenomenon/law of nature in response to dupilumab without making a practical application of that observation. No changes are made to the administration of dupilumab before and after FEV1-PS comparison to threshold FEV1-PS, therefore the subject’s observed FEV1-PS is not practically applied in any way.
Additionally, the continued administration of dupilumab at a standard dosage amount or greater than standard dosage amount after observing and comparing the FEV1-PS to the claimed threshold fails to amount to significantly more than the judicial exception. This is because the claims read on methods of continuous administration of the same drug while observing FEV1-PS scores with no changes in dosing.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
New Rejection
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
12. Claim 1 is rejected above under 35 USC 112(b) because the claim does not provide antecedent basis for “the genetic variants associated with FEV1-PS” and does not recite that 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 ten of the genetic variants listed in claim 1 in the process of “determining” the FEV1-PS, although the claim does not recite this limitation.
Additionally, as stated in the rejection under 35 USC 112(b) above, the standard dose of dupilumab and greater than standard dose of dupilumab are not defined anywhere in the specification or claims, and the scope of what dose that encompasses is unclear. For the sake of compact prosecution, the standard dose of dupilumab or greater than standard will be interpreted to encompass any dose of dupilumab.
13. Claim(s) 1, 3, 15, and 27 are 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); and Fieldes et al (ERJ Open Research, April 12, 2021, 7:00437-2020; p. 1-14).
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, and wherein the therapeutic agent is dupilumab.
Polygenic Risk Score comprises at least 10 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 10 genetic variants 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).
Administering doses of 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 extrapolated 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 Moll and Shrine. 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 and assess their FEV1-PRS; (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 Relevant Arguments
14. Applicant argues:
a. The Combination Of The Alleged Teachings Of The Cited References Do Not Disclose Determining The FEV1-PS Of A Subject Recited In Applicant's Claims.
Applicant's claims recite that the threshold FEV1-PS was calculated in a particular manner and that a subject's FEV1-PS is calculated in a particular manner. However, Applicant submits that the combination of the alleged teachings of the cited references do not disclose such manners. For example, Moll and Shrine report weighted scores (see, page 699 of Moll ("Using logistic regression, a combined model [was generated in which] PRSCombined=0 43847 X PRSFEV1 + 0.58833 X PRSFEV1/FVC, in which [FVC is forced vital capacity]."); see also, Shrine at pages 485-86 ("[A] genetic risk score (GRS) weighted by [FEV1]/FVC effect sizes comprising all 279 sentinel variants [was constructed].") (emphasis added)). Moreover, Miravitlles and Tashkin do not disclose any risk scores. Therefore, the combination of the alleged teachings of the cited references do not disclose determining the FEV1-PS of a subject recited in Applicant's claims (compare, PAR Pharm., Inc. V. TWI Pharms., Inc., 773 F.3d 1186, 1194 (Fed. Cir. 2014) (the Office has a "burden to prove that all claimed limitations are disclosed in the [cited] art")).
15. The arguments have been considered but are not persuasive. For the reasons stated in the rejection under 35 USC 112(b), how the claimed FEV1-PS score was or is determined is entirely unclear. Applicants are arguing limitations not recited in the claims. Applicants have argued specific calculations or formulas that are not recited in the claims. Applicants have not persuasively argued that the cited combined references fail to obviate the “FEV1-PS” score “determined” or “calculated” in the instant claims.
16. Applicants argue:
b. There Is No Evidence Of Record That Any Of The Genetic Scores Reported In Moll And Shrine Were Necessarily Determined Using At Least Ten Of The Particular Genetic Variants Recited In Applicant's Claims
As previously indicated, claim 1 has been amended to recite at least ten particular genetic variants. In this regard, the Office alleges that "the Biobank genetic variant data utilized by Shrine in the [reference's] GWAS comprises at least 10 of the instantly claimed genetic variants and the specific genetic variants were detected utilizing commercially available arrays" and that Shrine "demonstrate[s] utilizing this SNP dataset to correlate with FEV1 lung function values for COPD patients" (see, Office Action at page 20). In this regard, Applicant notes that page 699 of Moll reports that "GWAS summary statistics of approximately 7.4 million [SNPs] from the UK Biobank (n=321047) and SpiroMeta (n=79055) as weights for the development of [PRSs]" (emphasis added) (citing Shrine) (internal citation omitted). Moreover, Applicant notes that such page reports that "[a]fter filtering on variants present in test cohorts and applying a penalised regression framework, [the] final individual [PRS] for [FEV1] contained 1.7 million SNPs and the individual [PRS] for [FEV1]/FVC contained 1.2 million SNPs with non-zero effect sizes[ while] 455432 SNPs were present in both scores" (emphasis added). However, the number of genetic variants at issue in Moll and Shrine are a tiny fraction of the number of SNPs known as of Applicant's earliest claimed filing date (see, https://web.archive.org/web/20211107054736/https://medlineplus.gov/genetics/understandng/ge. nomicresearch/snp/ ("[S]cientists have found more than 100 million SNPs in populations around the world.") (emphasis added)). Viewing the evidence of record in a light least favorable to Applicant's position, Moll and Shrine report the identification of the genetic variants recited in the claims at issue rather than the calculation of a PRS using at least 10 of the genetic variants. Therefore, there is no evidence of record that any of the genetic scores reported in Moll and Shrine were necessarily determined using at least ten of the particular genetic variants recited in Applicant's claims.
17. The arguments have been considered but are not persuasive. Applicants are arguing limitations not recited in the claims. It is reiterated that claim 1 does not recite incorporating or using the at least ten “genetic variants associated with FEV1-PS” in the method at all, let alone determining or having determined the FEV1-PS score. There is no claim limitation reciting how the instantly claimed at least 10 genetic variants would be used in determining the FEV1-PS score. The cited combined references teach using a genetic variant dataset comprising at least 10 of the instantly claimed genetic variants in their process of determining FEV1-PS scores for the reasons of record, and the instant claims do not exclude the methods taught by the cited prior art.
18. Applicants argue:
c) There Would Have Been No Motivation To Modify Or Combine The Alleged Teachings Of The Cited References To Arrive At The Subject Matter Of Applicant's Claims
Applicant has generally found that as few as ten of the genetic variants recited in the claims at issue to be sufficient to determine whether a subject having a lung disease or at risk of developing a lung disease should be treated with a standard dosage amount of dupilumab or an amount greater than a standard dosage amount. Applicant submits that this finding is contrary to the reports of Moll. For example, page 696 of the reference discloses that "[GWASs] of COPD and lung function have identified numerous genetic variants associated with COPD risk" (citing Shrine and three other references). However, "[t]he effect size of each of these GWAS variants is generally small" (see, Moll at page 696 (emphasis added); see also, Moll at page 697 ("[V]ariants identified by [GWASs] are of individually small effect, and account for a modest fraction of genetic risk.") (emphasis added)). Moreover, Moll's PRSs are poorly predictive of lung disease (compare, Moll at page 701 ("The combined [PRS] was positively associated with both severe and frequent exacerbations after adjusting for age, sex, and pack-years.") with, Moll at page 701 ("[The reported] association did not persist after adjusting for [FEV1] and [FEV1]/FVC." (emphasis added) (internal citation omitted)). Indeed, page 704 of Moll acknowledges that "the [PRS at issue] is unlikely to add utility to the prediction of exacerbations when baseline lung function is already available and incorporated in the prediction model" (emphasis added). Applicant submits that Shrine does not cure the defects of Moll at least because the latter's reports are purportedly an improvement on those of the former (see, Moll at page 703 ("the meta-analysed AUC [area under the curve] for [Moll's PRS] was higher than the AUC for the 279-variant genetic risk score reported by Shrine ") (citation omitted)). And, as indicated above, Miravitles and Tashkin do not disclose any risk scores. Therefore, there would have been no motivation to modify or combine the alleged teachings of the cited references to arrive at the subject matter of Applicant's claims.
19. The arguments have been considered but are not found persuasive for the same reasoning above. Applicants continue to argue limitations that are not recited in the claims. Claim 1 does not recite incorporating or using the at least ten “genetic variants associated with FEV1-PS” in the method at all, let alone determining or having determined the FEV1-PS score. There is no claim limitation reciting how the instantly claimed at least 10 genetic variants would be used in determining the FEV1-PS score. The cited combined references teach using a genetic variant dataset comprising at least 10 of the instantly claimed genetic variants in their process of determining FEV1-PS scores for the reasons of record, and the instant claims do not exclude the methods taught by the cited prior art.
20. Applicants argue:
d. There Would Have Been No Reasonable Expectation of Success for Modifying Or Combining The Alleged Teachings Of The Cited References To Arrive At The Subject Matter Of Applicant's Claims
As described above, Moll's reports are limited. In particular, Applicant notes that page 705 of the reference acknowledges that "[d]espite the magnitude of effect sizes observed in this study, large [odds ratios] do not always translate into effective screening tests" (emphasis added). Indeed, "[f]uture research is needed to determine whether these scores can identify individuals most likely to benefit from preventive therapy " (see, Moll at page 697 (emphasis added); see also, Moll at page 704 ("[F]urther studies of specific interventions are needed before clinical application ") (emphasis added); see also Moll at page 704 ("[T]he significance of [particular] findings is unclear, and requires additional, systematic investigation across multiple cohorts.") (emphasis added)). Finally, page 705 of Moll acknowledges that "the role of polygenic risk scores for understanding COPD pathogenesis is an important area in need of exploration" (emphasis added). Applicant submits that the "reference[] provide[s] 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 " (see, M.P.E.P. §2143.02(II) (2024) (quoting OSI Pharm., LLC V. Apotex Inc., 939 F.3d 1375, 1385 (Fed. Cir. 2019)). Therefore, Applicant submits that there would have been no reasonable expectation of success for modifying or combining the alleged teachings of the cited references to arrive at the subject matter of the claims at issue.
21. The arguments have been considered but are not persuasive. Applicants are arguing the individual Moll reference. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
Contrary to arguments, the rejection of record spells out the motivation and reasonable expectation of success to combine references. As stated in the rejection:
Polygenic Risk Score comprises at least 10 of the genetic variants/SNPs recited in claim 1:
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 10 genetic variants 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).
22. Claim(s) 38 and 39 are 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); and Fieldes et al (ERJ Open Research, April 12, 2021, 7:00437-2020; p. 1-14); as applied to claims 1, 3, 15, and 27 above, and further in view of Huang et al (April 28, 2021, Research Square, DOI: 10.21203/rs.3.rs-423764/v1).
Moll, Shrine, and Fieldes (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 Relevant Arguments
23. Applicant argues that Huang does not cure the deficiencies argued above for Moll and Shrine.
24. The arguments have been considered but are not persuasive. Moll, Shrine, and Fieldes do not have the deficiencies argued above for the reasons stated above, therefore Huang does not have to remedy the deficiencies argued.
25. Claim(s) 53 is 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); and Fieldes et al (ERJ Open Research, April 12, 2021, 7:00437-2020; p. 1-14); as applied to claims 1, 3, 15, and 27 above, and further in view of Elliott et al (International J of Epidemiology, 2008, 37:234-244).
Moll, Shrine, and Fieldes (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 Relevant Arguments
26. Applicant argues that Elliott does not cure the deficiencies argued above for Moll and Shrine.
27. The arguments have been considered but are not persuasive. Moll, Shrine, and Fieldes do not have the deficiencies argued above for the reasons stated above, therefore Elliott does not have to remedy the deficiencies argued.
28. Conclusion: No claim is allowed.
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
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