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 .
Priority
This application 17/762,441 filed on 03/22/2022 is a 371 national phase of PCT/US2020/051961 filed on 09/22/2020, and claims the benefit of provisional U.S. Patent Application No. 62/944,523, filed on12/23/2019; and provisional U.S. Patent Application No. 62/904,552, filed on 09/23/2019.
The priority date of claim 1 and its dependent claims 2-13 is determined to be 09/23/2019, the filing date of provisional U.S. Patent Application No. 62/904,552.
Status of Claims
Applicant’s amendments to claims filed 10/24/2025 in response to the Non-Final Rejection mailed 07/25/2025 are acknowledged.
Claims 1 and 3 are amended.
Claims 14, 15, 36-39 and 71 have been canceled.
Claims 1-13 are pending and under examination.
Response to Remarks filed 10/24/2025
The amendments and arguments presented in the papers filed 10/24/2025 ("Remarks”) have been thoroughly considered. The issues raised in the Office action dated 07/25/2025 listed below have been reconsidered as indicated.
a) The objections to the specification regarding the use of trade names or marks are withdrawn in view of the amendments to the specification.
b) The objection to claim 1 over a missing preposition is withdrawn in view of the amendments to claim 1.
c) The 35 USC 112(b) indefiniteness rejections of claims 3 and 14 have been withdrawn in view of the amendments to claims 1 and 3, and the cancellation of claim 14.
d) The 35 U.S.C. 101 rejections of claims 14 and 15 are withdrawn in view of the cancellation of the claims.
New and modified grounds of rejection necessitated by amendment are detailed below and this action is made FINAL.
Claim Objections - New
Claim 1 is objected to because of the following informalities: The claim reci. This appears to be a typographical error intended to be “a U133A array”. Appropriate correction is required.
Claim Rejections - 35 USC § 101- Updated
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Step 1
The claimed invention is directed to the statutory category of a process (method).
Step 2A, Prong One
The claims are taken to be directed to abstract ideas (mental processes and mathematical concepts), judicial exceptions.
Claim 1 is directed to a method comprising “calculating a pLSC6 score for the subject using the weighted set.” This limitation is a mathematical concept (i.e. calculating, etc. See MPEP 2106.04(a)(2)(I)). As written, the calculating step encompasses mathematical concepts such as mathematical calculations.
Claims 2-13 depend from claim 1, and require the same step of “calculating a pLSC6 score for the subject using the weighted set.”
Claim 13 is directed to a method comprising the element a “score is calculated using the following algorithm”. This limitation is a mathematical concept (i.e. score is calculated using the following algorithm. See MPEP 2106.04(a)(2)(I)). As written, the calculating step encompasses mathematical concepts such as mathematical calculations.
Step 2A, Prong Two
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception.
While claim 1 recites “measuring a level of an RNA transcript of each of a set of genes--; normalizing the levels--; weighting each of the normalized levels; and (i) performing a hematopoietic stem cell transfer (HSCT) --; or (ii) administering a one or more chemotherapeutic agents -- ”, this is not an integration of the exception into a practical application.
Instead, the measuring, normalizing, and weighting elements are data gathering and analysis required to perform the method. (See MPEP 2106.04(a)(2)(III); claims to "collecting information, analyzing it, and displaying certain results of the collection and analysis," where the data analysis steps are recited at a high level of generality such that they could practically be performed in the human mind, Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016). Further, the elements of performing a hematopoietic stem cell transfer or administering a one or more chemotherapeutic agents are not to a particular patient, to a particular treatment specific to an identified genotype. It does not integrate a judicial exception under the “treatment or prophylaxis” consideration as discussed in MPEP 2106.04(d)(2). Further, claim 1 does not require a particular calculation of the claimed pLSC6 score. Thus, there is no nexus between the above judicial exceptions and the treating step.
Step 2B
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claims do not add a specific limitation other than what is well-understood, routine, and conventional in the field. Steps directed to measuring, normalizing, and weighting are techniques that are routine, conventional, and well-known in the art as demonstrated in the 103 rejection documented below. Steps directed to performing a hematopoietic stem cell transfer or administering chemotherapeutic agents are not a practical application to the exception. As such it does not integrate a judicial exception under the “treatment or prophylaxis”
Furthermore, the courts have recognized the following laboratory techniques as well-understood, routine, conventional activities in the life science arts when they are claimed in a merely generic manner or as insignificant extra-solution activity:
i. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
ii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
iii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
For these reasons, the claims are rejected under section 101 as being directed to non-statutory subject matter.
Response to Arguments against Claim Rejection - 35 U.S. C § 101
The response asserts that amendments to claim 1 overcome the rejection. Applicant cites MPEP § 2106, Step 2A Prong 2 of the Alice/Mayo test to argue that the therapeutic administration steps are "particular" and renders the claim directed to patent-eligible subject matter. The response specifically cites the addition of active steps of administering either (i) HSTC to a subject having a low-pLSC6 score, or one or more chemotherapeutic agents to a subject having a high-pLSC6 score. The response asserts the claim as amended integrates the alleged judicial exceptions into a practical application (p. 7-8).
Applicant's arguments have been fully considered but are not persuasive.
The instant claims recite a treating step at a high level of generality and do not require a specific treatment in response to a specific genotype or phenotype. As such, the claim is directed to the relationship and is not a practical application of the judicial exception. The claimed method of measuring, normalizing, and weighting RNA transcript levels is directed to generating a score, not identify a patient as a particular type, responsive or non-responsive.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-13 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (WO 2017/132749).
These are new/modified rejections necessitated by amendments.
Regarding claim 1, Wang teaches a method of identifying high-risk acute myeloid leukemia (AML) patients. The method comprising: determining the expression level of at least 3 genes in a sample from a subject with AML; comparing expression of the at least 3 genes in the test sample with reference expression levels of the at least 3 genes from control samples from a cohort of patients (p. 3, lines 14-22); normalizing to a reference set (p. 15, line 14); and calculating a LSC Score comprising the weighted sum of expression of each of the at least 3 genes (p 3, lines 23-24). Wang further teaches embodiments wherein the at least 3 genes is at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 genes (p. 11, lines 13-14). Wang further teaches the method comprises obtaining the gene expression levels of DNMT3B, GPR56, CD34, and SOCS2, SPINK2, and FAM30A (Table S8 beginning on p. 68).
Wang teaches the method comprises determining the expression level of at least 3 genes in a sample from a subject with AML (p. 3, lines 14-15), which satisfies a requirement of determining the levels of 6 genes as in the instant claim.
However, Wang does not explicitly teach a pLSC6 score with the 6 genes recited in the instant claim. Wang does teach determining the gene expression levels of DNMT3B, GPR56, CD34, SOCS2, SPINK2, and FAM30A (Table S8 beginning on p. 68) as recited in instant claim 1. Wang also teaches identifying 104 differentially expressed LSC-specific genes (p. 10, lines 18-20) and calculating both a LSC17 score and an LSC3 score calculated using microarray GE data (p. 6, lines 27-32). Wang teaches a LSC17 score that includes the claimed DNMT3B, GPR56, CD34, and SOCS2 (p. 22, lines 20-26). Wang states that both LSC17 and LSC3 scores provide rapid and accurate identification of high-risk patients for whom conventional chemotherapy is non-curative (p. 10, lines 29-30).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Wang to calculate different LSC scores by selecting different genes whose expression level had been measured to arrive at the instantly claimed invention. Wang states that 104 genes were differentially expressed and that two different LSC scores consisting of a different number of genes provided rapid and accurate identification of high-risk patients, demonstrating that more than one selection of genes and LSC scores work with the method of Wang. It would have been obvious to try combinations of genes with differential expression as found in Table S8. One would have been motivated to test different combinations of genes to calculate different LSC scores to determine an appropriate combination for a subject having leukemia. In addition to the LSC3 and LSC17 scores that Wang focuses on, Wang teaches the identification of an LSC13 sub-score (p. 43, lines 33-34 and Fig. 15), illustrating the fact that Wang teaches an ongoing process of gene identification and score calculations. Determining an appropriate combination would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Wang teaches measuring gene expression on RNASeq platforms and microarrays (p. 28, line 17) including the U133A array (p. 23, line 18). Wang teaches calculating LSC scores (p. 22, lines 20-26; p. 23, lines 1-2; and p. 23, lines 3-6) and using the median to discretize scores into high and low score groups (p. 22, lines 28-29). Wang further teaches stratifying patients based on high or low scores (p. 38, line15), classifying subjects into a high-risk group based on high LSC score (p. 3, lines 25-26) and selecting a therapy for a subject after classifying subject as high or low risk (p. 3, lines 27-31).
Wang teaches the low LSC17 scores are associate with better survival that high LSC scores for patients treated with allo-SCT (i.e. hematopoietic stem cell transfer) (Figs. 11A-F). Wang further teaches selecting intensified chemotherapy, for the high risk group (p. 3, lines 30-31)
However, Wang does not explicitly teach the claimed score thresholds for (i) performing a hematopoietic stem cell transfer (HSCT) when the subject has a low-pLSC6 score-- or (ii) administering a one or more chemotherapeutic agents when the subject has a high- pLSC6 score—".
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Wang to set a different high or low score threshold to determine appropriate treatment and arrive at the instantly claimed invention. The modification would have entailed determining the median threshold to determine high and low LSC scores for the subset of genes. One would have been motivated by the utility of a score to select appropriate therapy. Median thresholds are determined by the data and analysis, including differences in sample collection, normalization, among other variables. Determining an appropriate threshold for administering treatment would have been merely a matter of judicious selection and routine optimization. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Thus, the invention of claim 1 as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention, especially in the absence of evidence to the contrary.
Regarding claim 2, Wang teaches the method for acute myeloid leukemia (AML) (p. 1, Abstract).
Regarding claim 3, Wang teaches patients less than 60 years of age, encompassed by the claimed subject less than 19 years of age.
Regarding claim 4, Wang teaches a test sample that is a fluid or tissue sample (p. 12, line 1).
Regarding claim 5, Wang teaches the sample comprises WBCs from bone marrow (p. 12, lines 4-5).
Regarding claim 6, Wang teaches determining the expression of mRNA transcripts (p. 12, lines 6-8).
Regarding claim 7, Wang teaches the use of a microarray (hybridization-based assay) for detecting the level of RNA products (p. 15, lines24-25).
Regarding claim 8, Wang teaches the use of a microarray (p. 15, line 25).
Regarding claim 9, Wang teaches determining the gene expression level by Nanostring (nucleic acid sequencing assay) (p. 15, line 22).
Regarding claim 10, Wang teaches the use of Nanostring (digital gene expression) (p. 15, line 22).
Regarding claim 11, Wang teaches weighting using LASSO and COX regression models (p. 22, lines 14-19).
Regarding claim 12, Wang does not teach the recited regression coefficient values.
However, Wang teaches assigning each LSC signature gene a regression coefficient (p. 28, line 19).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Wang to determine regression coefficients for a different selection of genes with measured expression levels to arrive at the instantly claimed invention. One would have been motivated to do so to accurately predict the strength of prediction for the selected genes. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claim 13, Wang does not explicitly teach a formula of calculating the pLSC6 score using the recited algorithm.
However, Wang does teach calculating a LSC17 score with an algorithm comprising the addition of each gene multiplied by the estimated regression coefficient for the gene (p. 22, lines 20-25) and calculating a LSC3 score in the same manner (p. 23, lines 1-2). Wang also teaches the use of different regression coefficients for the same gene when calculating different LSC scores (p. 22, lines 20-26; p. 23, lines 1-2; p. 23, lines 306), demonstrating that these are not fixed values, but vary depending on the data analysis.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the algorithm of Wang to incorporate a different selection of genes with their estimated regression coefficients to arrive at the instantly claimed invention. It would have been obvious to try combinations of genes with differential expression as found in Table S8. One would have been motivated to test different combinations of genes to calculate different LSC scores to determine an appropriate combination for a subject having leukemia. Determining an appropriate combination would have been merely a matter of judicious selection and routine optimization. One would have been further motivated to do so for the advantage of using the proper combination of regression coefficients with the selected genes for the LSC score. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Response to Arguments against Claim Rejection - 35 U.S. C § 103
The response asserts that Wang does not disclose or suggest the pLSC6-low and pLSC6-high scoring thresholds recited in amended claim 1 or provide any guidance that would have allowed a skilled person to arrive at the specific genes used to produce the pLSC6 scoring thresholds recited in the amended claims. Applicant further argues that the obviousness finding is based on hindsight claims of obviousness (p. 8).
Applicant's arguments have been fully considered but are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
It is the Examiner’s position that a person of obvious skill in the art would recognize the obviousness rationales presented above.
The response asserts that a person of ordinary skill in the art could not have predicted, with any reasonable expectation of success, that any six gene expression levels would provide a meaningful LSC score, let alone the six particular gene expression levels used to calculate the pLSC6 score in the amended claims (p. 8-9).
Applicant's arguments have been fully considered but are not persuasive.
Wang teaches using data to determine multiple scores incorporating different genes and regression coefficients, including an LSC3 score, and LSC13 score, and an LSC17 score (p. 22, lines 20-26; p. 23, lines 1-2; p. 23, lines 3-6). These scores include genes claimed by the instant application, and the data in the Tables of Wang report gene expression measurements for all claimed genes as described in the rejection above. Wang teaches embodiments including 6 genes and the calculation of regression coefficients to determine LSC scores for the claimed genes. The reported genes vary from set to set and are not fixed.
The response asserts that even if a person of ordinary skill in the art could have arrived at the specific genes used to produce the pLSC6 scores recited in the amended claims (which Applicant does not concede), the claimed pLSC6 scoring methods represent a surprising and unexpected improvement over the pLSC17 scoring methods described by Wang. For example, as shown in FIG. 11C of the Application as originally filed, the pLSC6 scoring methods recited in the amended claims are a better predictor of event-free survival (EFS) for pediatric AML than the LSC17 score described in Wang.
Applicant's arguments have been fully considered but are not persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., FIG. 11C of the Application) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, WINSTON SHEN can be reached at (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682