DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of Claims
Applicant' s amendment filed 01/29/2026 is acknowledged. Claims 1, 5, and 18 have been amended. Claims 2-4, 9-10, 12, 15, and 19 have been cancelled. Claims 1, 5-8, 11, 13-14, and 16-18 are pending in the instant application and claims 1, 5-8, 11, 13, and 17-18 the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The objections to claims 1, 5, 9, and 19 are withdrawn in view of the amendments to or cancellation of the respective claims.
The 112(a)/1st written description rejection of claims 1, 3, 5-11, and 17-19 is withdrawn in view of the amendment to claim 1 or cancellation of the respective claim.
The 112(b)/2nd rejections to claim(s) 1, 3, 5-11, 13, and 17-19 is/are withdrawn in view of the amendments to the respective claims or those from which they dependent or the cancellation of the respective claim.
The 101 rejection of claims 1, 5-8, 11, 13, and 17-18 is maintained and modified in view of the amendments.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 19 as being unpatentable over Clark is withdrawn in view of the cancellation of the claims.
The double patenting rejections over claims of US patents 10,577,661 B2; 10,851,427 B2; 11,505,832 B2; and 12,180,551 B2 have been modified in view of the amendments to the claims.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112 Fourth
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claim 8, the claim recites “wherein the step of mathematically combining comprises a step of applying an algorithm to values representative of an expression level of a given gene, wherein said algorithm is a linear combination of said values representative of an expression level of a given gene, or ...”.
The amended claim 1 recites “wherein said a mathematically combining comprises:”
generating a plurality of predictive member scores using the determined RNA expression levels, wherein each predictive member score is calculated as a linear combination of the expression levels of at least two different genes from the set of genes”.
Claim 8 requires no additional elements beyond those are already required in the amendments to claim 1. The predictive member scores are calculated as a linear combination of [i.e., an algorithm is applied to] the expression levels of at least two different genes [i.e., values representative of a given gene].
For this reason, claim 8 fails to further limit the claim upon which it depend and, therefore, does not comply with the requirements of 112(d).
Claim Rejections - 35 USC § 101
Claims 1, 5-8, 13, and 17-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim(s) recite(s) an abstract idea. This judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The following three inquiries are used to determine whether a claim is drawn to patent-
eligible subject matter:
Step 1. Is the claim to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed to a process/method.
Step 2A, prong 1. Does the claim recite a law of nature, a natural phenomenon, or an abstract idea (recognized judicial exceptions)?
The amended claims recite determining the expression level of a selection of genes and mathematically combining the expression level values to yield a combined score, wherein the amendment adds specific steps to the mathematical calculation, including those that may be performed within the human mind (or with paper). The claims are thus directed to the abstract idea of a mathematical calculation. See MPEP 2106.04(a)(2)(I)(C).
It is noted that the act of determining also encompasses the abstract idea of a mental process (observations, evaluations, or judgements of visual input, data, or information to render a judgement or opinion) as it may be interpreted to encompass looking up values in a table, for example.
Step 2A, prong 2. Is the judicial exception(s) are integrated into a practical application?
Regarding claim 1, the claim does not integrate the judicial exception into a practical application because it fail to recite more than limitations that encompass abstract ideas. As no practical (e.g., physical) steps are required, the claim is not integrated into a practical application.
Further, for the sake of argument, under a narrower interpretation of the determining to involve laboratory steps, such would be a considered insignificant extra-solution activity, i.e., necessary data gathering and selection of a particular type of data. See MPEP 2106.04(d) and 2106.05(g).
It is also noted that a generic step of “outputting” without further limitations imposed or requiring particular components used to output the data does not tie the mathematical calculation to a practical application. Under the broadest reasonable interpretation, the equation itself may output the result. And even under a narrower interpretation requiring a generic computer, abstract ideas capable of being performed by humans without a computer do not integrate the claims into a practical application. See MPEP 2106.04(a)(2)(III) and (III)(C).
Regarding claims 6 and 17, these claims provide further limitations on the chemotherapy or tumor sample and thus are directed to the data type. They therefore fall the same as claim 1.
Regarding claim 5, the courts have identified that limitations that add insignificant extra-solution activity to the judicial exception do not integrate a judicial exception into a practical application. Performing such tests to obtain input for an equation amounts to mere data gathering.
Regarding claim 7, the claim encompasses a further computation and thus fails to recite more than an abstract idea.
Regarding claims 8, 11, 13, and 18, the claims recite further calculations in the step of mathematically combining or indications that may be determined from the step and therefore these claims likewise fall as with claim 1.
Step 2B. Does the claim amount to significantly more?
Regarding claims 1, 5-9, 13, and 17-18, the claims do not include addition elements that are sufficient to amount to significantly more than the judicial exceptions because the active steps require only abstract ideas or insignificant extra-solution activity. It is further noted that PCR, hybridization, and sequencing each have been recognized as well-understood, and conventional activity. See MPEP 2106.05(d)(II).
MPEP 2106.05(I) recites that the inventive concept cannot be furnished by the abstract idea itself. This section also recites that the courts have made clear that that lack of novelty or obviousness is of no relevance in determining whether the subject matter of a claim falls within the 101 categories.
Accordingly, when considered as a whole, the claims fail to add significantly more than the judicial exception of abstract idea(s).
Double Patenting
The following claims are rejected on the ground of nonstatutory double patenting as being unpatentable over the indicated claims of the following U.S. Patents in view of Park (Park PJ, et al. Linking gene expression data with patient survival times using partial least squares. Bioinformatics. 2002;18 Suppl 1:S120-7) and Bonnefoi (Bonnefoi H, et al. Predictive signatures for chemotherapy sensitivity in breast cancer: are they ready for use in the clinic? Eur J Cancer. 2009 Jul;45(10):1733-43. Epub 2009 May 26.)
Patent:
Instant claims rejected:
Rejected over claims:
Fails to recite:
Other notes:
10,577,661 B2
1, 5-8, 13, and 17-18
1-19
• Combined score has plurality of member scores determined using RNA expression levels; • Chemo comprises taxanes or anthracycline; • Explicit neoadjuvant use; • Sensitivity value
• Determining comprises applying an algorithm that is a linear combination of values representative of levels of gene expr.
10,851,427 B2
1, 5-8, 13, and 17-18
1-41
• Combined score has plurality of member scores determined using RNA expression levels; • Chemo comprises taxanes/anthracycline; • Explicit neoadjuvant use; • Sensitivity value
• Determining comprises applying an algorithm that is a linear combination of values representative of levels of gene expr.
11,505,832 B2
1, 5-8, 13, and 17-18
1-20
• Combined score has plurality of member scores determined using RNA expression levels; • Sensitivity value
• The instant combined score may comprise other values; see, e.g., instant claim 11
12,180,551 B2
1, 5-8, 13, and 17-18
1-20
• Combined score has plurality of member scores determined using RNA expression levels; • Sensitivity value
• The instant combined score may comprise other values; see, e.g., instant claim 11
All sets of claims are directed to determining the expression levels of a set of genes in a tumor sample comprising the claimed set of genes and mathematically combining the expression level values to yield a combined score.
The instant specification recites that an algorithm using UBE2C, BIRC5, DHCR7, STTC2, AZGP1, RBBP8, IL6ST, and MGP in a population has the inherent capacity to achieve a sensitivity of at least about 96% with a chosen threshold in relevant breast cancer populations (pg. 21, lines, 22-31). As the sensitivity is, in part, determined by the threshold chosen, it is further noted that the sensitivity is based on routine optimization (e.g., adjusted based on user preference of true negatives/true positives, weights in an algorithm, etc.; see Bonnefoi pg. 1736, 2.2.1.1. Techniques for construction of multigene classifiers, Conventional supervised analysis, which discusses optimization processes, and Bonnefoi pg. 1734, col 1, lines 4-7, which discusses the impact of “cut-off” [threshold] choice).
Bonnefoi rectifies the lack of explicit teaching that the combined score predicts a response to and/or benefit from chemotherapy by teaching supervised analyses that identify a list of discriminant genes and meta gene analyses to predict pCR [pathological complete response] status for chemosensitivity (pg. 1736, 2.2.1.1. Techniques for construction of multigene classifiers).
As all patents above teach determining whether the patient will benefit from at least a cytotoxic chemotherapy, Bonnefoi rectifies the lack of explicit teaching by teaching the species of anthracycline and taxanes (pg. 1733, col 2, para 1, spanning pg. 1734; pg. 1737, col 1, para 1). Bonnefoi teaches patient cohorts relevant to the species of chemotherapies (pg. 1734, Retrospective trials).
Bonnefoi further teaches that the chemotherapy comprises anthracycline-containing chemotherapy and neoadjuvant use by teaching a signature developed based on patients treated with chemotherapy comprising neoadjuvant doxorubicin [an anthracycline], and further combined with a taxanes or a non-taxane regimen, wherein the classifier was able to significantly predict pCR in patients treated with the appropriate arm, wherein the two arms had 96% and a 93% sensitivities, respectively (pg. 1737, col 1, para 1). Bonnefoi teaches using pCR after neoadjuvant chemotherapy as a surrogate for chemosensitivity (pg. pg. 1734, col 2, para 4).
Bonnefoi teaches that the development of such personalized medicine will reduce the risk significantly to warrant the toxicity of a particular treatment (pg. 1741, 5. Conclusion).
Park teaches that the classification problem in which gene expression data serve as predictors and patient survival times are used as the response variable has complications that arise from censoring (Abstract, para 1), but that these can be addressed by it method (Abstract para 2) and allow for a predictive model that can aid in diagnosis and treatment (pg. S120, col 2, para 1). Park teaches that its method solves the
Park teaches that it applies partial least squares regression to find new variables [i.e., predictive member scores] by constructing appropriate linear combinations of original covariates [i.e., gene expression levels], wherein the random response variable y is predicted from p covariates x1, x2, ... xp and each xi represents a gene [if gene expression data is used as the only covariates] [i.e., each member score constitutes an independent predictor of response] (pg. S121, Partial least squares, para 1-2; see also pg. S121, col 1, para 2-3, spanning col 2: e.g., “partial least squares attempts to find orthogonal linear combinations that explain variability in the predictor space while being highly correlated with the response variable”).
Park teaches fitting the latent variable to a regular linear regression model as predictors [i.e., combining the plurality of predictive member scores to yield said combined member score and outputting said combined score] (pg. S212; Partial least squares, para 2).
See also section “A proposed algorithm” and Fig. 3.
Therefore, it would have been obvious to one of ordinary skill in the before the effective filing date of the claimed invention to utilize the PLS regression model of Park for predicting the response to the species of cytotoxic chemotherapy of Bonnefoi and/or disclosed in the patents, motivated by the desire to be able to meaningfully address censoring of data, as taught by Park, and to help justify any toxicity of particular treatments, as taught by Bonnefoi, and/or because of the high sensitivity achievable with anthracycline, as taught by Bonnefoi. See also MPEP 2144.08, wherein relevant species of cancer are taught by the instant patents and Bonnefoi, resulting in a high level of predictability. There would have been a strong expectation of success as all are directed toward techniques to classify outcomes of cancer patients and present the application of known techniques to known methods.
It is further noted that any additional limitations of the patent claims are encompassed by the open claim language “comprising” found in the instant claims.
Response to Arguments
Applicant's arguments filed 01/29/2026 have been fully considered but they are not persuasive.
Regarding the 101 rejection, on pg. 7-8 of the Remarks, the applicant argues that the claims are not directed to the abstract idea itself, reciting rather a specific practical application that amounts to “significantly more” than the judicial exception. The applicant alleges that the amended claim 1 recites a particularly unique computational method and is no longer directed to a generic “mathematically combining” step, but instead a specific, multi-level computational architecture. Applicant argues there is a tangible step of “outputting” the score, supported by paragraph [0096] which discloses a “diagnostic system capable of outputting values”. The applicant argues that the multi-step process is not a mere recitation of an abstract idea but a specific, man-made method and an improvement in the technical field of computer-aided diagnosis.
Contrary to the arguments, the claims require no more than abstract ideas or insignificant extra-solution activity, which as analyzed under Step 2B is also well-known and conventional. See 101 for the amended claims above. The amended steps directed to the particular mathematic calculation (e.g., an ensemble of Cox or similar regressions, such as the method of Park cited in the double patenting rejection) is not directed to a “computational architecture” but rather a calculation itself. The “outputting” encompasses merely deriving the combined score via the mathematical calculation. No limitations are placed on how the data is output, and even if it were directed to a generic computer environment, such would not be sufficient to integrate the claim. See MPEP 2106.04(a)(2)(III) and (III)(C) and July 2024 Subject Matter Eligibility Examples Example 47 Claim 2 (https://www.uspto.gov/sites/default/files/documents/2024-AI-SMEUpdateExamples47-49.pdf). Further, it is noted that, as addressed in the 101, 101 analysis does not depend on the novelty or uniqueness of the subject matter and that the abstract idea itself cannot provide the element that is “significantly more”. See MPEP 2106.05(I).
Applicant appears to be attempting to argue integration of the claim under “Clear Improvement to a Technology or to Computer Functionality” (MPEP 2106.06(b)). However, as stated in the Remarks, the improvement is to computer-aided diagnosis, rather than an improvement to some aspect of the practical (i.e., physical) technology or the computer functionality itself. Further, the claim limitations do no more than generally link the use of the mathematical calculation judicial exception to a particular field of use of pharmacogenomic risk assessment. See MPEP 2106.05(h). As such, these elements are not sufficient to amount to either a practical application or significantly more for these reasons and those discussed above.
Applicant’s arguments regarding a secondary judicial exception of a natural phenomenon goes beyond the scope of the rejection as set forth. The rejection is based on abstract ideas, which apply to the claimed embodiments as a whole under the broadest reasonable interpretation.
Applicant’s arguments with respect to the double patenting rejections have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
It is noted that ‘661 and ‘427 do teach a “two-level” computational method as they apply an algorithm linearly combining values representative of expression levels of given genes in the step of determining before combining the expression level values. However, it is not explicitly teach generating the predictive member scores in the method claimed. This modification would have been obvious over Park as discussed and cite above.
Conclusion
No claims are allowed.
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 Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636