DETAILED ACTION
Applicant’s response, filed 23 Oct. 2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Status of Claims
Claims 1-29, 36-103, and 117 are cancelled.
Claims 30-35, 104-116, and 118 are pending.
Claims 30-35, 104-116, and 118 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application, U.S. Provisional App. Nos. 62/878,095 filed 24 July 2019 and 62/949,025 filed 17 Dec. 2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 24 July 2019.
Drawings
The objection to the drawings received 21 Jan. 2022 in the Office action mailed 25 July 2025 has been withdrawn in view of replacement drawing sheets and amendments to the specification filed 23 Oct. 2025.
The drawings received on 21 Jan. 2022 and replacement drawing sheets filed 23 Oct. 2025 are accepted.
Specification
The objections to the specification and abstract in the Office action mailed 25 July 2025 have been withdrawn in view of amendments to the specification and abstract filed 23 Oct. 2025.
Claim Objections
The objection to claims 105 and 107-108 in the Office action mailed 25 July 2025 has been withdrawn in view of claim amendments received 23 Oct. 2025.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claim 118 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This rejection is newly recited and necessitated by claim amendment.
Claim 118 recites “A system…comprising one or more processors and a memory coupled to the processors comprising instructions executable by the processors, the processors being operable when executing the instructions to:…administer an effective amount of the checkpoint blockade therapy to the subject”.
Applicant’s specification does not disclose any automated equipment comprising a processor that is configured to administer a checkpoint inhibitor as claimed. The only mention of administering the checkpoint inhibitor is at para. [0225], [0235], and [0245], which each disclose a method of treating a subject comprising administering the checkpoint inhibitor to the individual based on the determination of the tumor as being non-neurally related. However, there is no disclosure to automated systems (e.g. automated IV pump) for performing the administration as part of a system.
For the reasons discussed above, the specification does not provide a sufficient disclosure of the limitation above recited in claim 118 to demonstrate to one of ordinary skill in the art that the inventor possessed the invention at the time the application was filed. THIS IS A NEW MATTER REJECTION. For more information regarding the written description requirement, see MPEP §2161.01- §2163.07(b).
Claim Rejections - 35 USC § 112(b)
The previous rejection of 107-118 in the Office action mailed 25 July 2025 has been withdrawn in view of claim amendments and cancellations received 23 Oct. 2025.
Claim Rejections - 35 USC § 101
The rejection of claims 30-35 and 104-118 under 35 U.S.C. 101 in the Office action mailed 25 July 2025 has been withdrawn in view of claim amendments and cancellations received 23 Oct. 2025.
Independent claims 30 and 118 recite “administering an effective amount of the checkpoint blockade therapy to the subject” after “identifying a therapy approach that includes initial use of a checkpoint blockade therapy based on the determination of the tumor as non-neuronal and non-neuroendocrine”. Applicant’s specification at para. [0003] discloses that checkpoint blockade therapies are not effective at treating all tumors, and at para. [0047], [0052], and [0092] that checkpoint inhibitor therapies are effective as first-line therapies when a tumor has gene expression that does not correspond to a neuronal signature, while neural related tumors, including brain tumors and neuroendocrine tumors are not likely to respond to immune checkpoint blockade therapy. Accordingly, the claims integrate the recited judicial exception of analyzing gene expression data of a specific gene signature to determine a subject has a non-neuronal and non-neuroendocrine tumor into the practical application of effecting a particular treatment. See MPEP 2106.04(d)(2).
However, it is noted that Applicant’s specification does not have support for a system that has processors operable to administer an effective amount of the checkpoint blockade therapy, as discussed above under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
The rejection of Claims 30-35 and 104-118 under 35 U.S.C. 103 as being unpatentable over Graeber (2019) in view of Spetzler (2018) in the Office action mailed 25 July 2025 has been withdrawn in view of claim amendments and cancellations received 23 Oct. 2025.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 30-35, 104-116, and 118 are rejected under 35 U.S.C. 103 as being unpatentable over Graeber (2019) in view of Spetzler (2018) and Taube (2018). This rejection is newly recited and necessitated by claim amendment.
Cited references:
Graeber et al., US 2022/0244263 A1, effectively filed 28 May 2019 (previously cited);
Spetzler et al., US 2018/0045727 A1 (previously cited); and
Taube et al., Implications of the tumor immune microenvironment for staging and therapeutics, 2018, Modern Pathology, 31, pg. 214-234 (newly cited).
Regarding claims 30 and 118¸ Graeber discloses a method for identifying a neuroendocrine tumor in a patient (Abstract) by identifying neuroendocrine features in tumors ([0055]) comprising the following steps:
Graeber discloses accessing expression levels comprising an expression level (i.e. metric) for each of a plurality of biomarker genes, measured from a biological sample of the patient ([0011]-[0013]), wherein the set of genes include SV2A, NCAM1, ITGB6, SH2D3A, and TACSTD2 ([0163], e.g. genes in SCN gene signature; [0008]; [0017], e.g. biomarkers in Table 1 measured; claim 8).
Graeber determining the gene expression levels’ are different than a to a small cell neuroendocrine (SCN) signature (i.e. a neuronal genetic signature) using a trained machine learning model ([0020], e.g. level of measured markers determined to statistically different compared to control expression levels of biomarkers in a SCN cancer; [0023]-[0024]; [0055]; [0053]-[0054] and [0263-[0265], e.g. prediction of samples with SCN using logistic regression model). Graeber discloses the model distinguishes between cancer types, including lung cancer (LUAD), small cell lung cancer (SCLC), ovary, breast, bladder, and pancreas cancer, that are positive or negative to SCN (i.e. determining that the tumor is non-neuronal and non-endocrine) ([0016]; [0265]; FIG. 15E-F).
Graeber discloses selecting a cancer treatment including an immunotherapy of checkpoint inhibitors ([0063]-[0064]). Graeber discloses the patient has not been previously treated (i.e. the therapy is an initial use) ([0098]).
Regarding claims 30 and 118¸Graeber does not disclose the following limitations:
First, Graeber does not disclose the above method steps are carried out by a computer including a processor coupled to memory or a computer-readable non-transitory storage media (i.e. memory) with instructions for performing the method.
However, the courts have found that broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.). Broadly claiming an automated means to replace a manual function to accomplish the same result does not distinguish over the prior art. See Leapfrog Enters., Inc. v. Fisher-Price, Inc., 485 F.3d 1157, 1161, 82 USPQ2d 1687, 1691 (Fed. Cir. 2007) ("Accommodating a prior art mechanical device that accomplishes [a desired] goal to modern electronics would have been reasonably obvious to one of ordinary skill in designing children’s learning devices. Applying modern electronics to older mechanical devices has been commonplace in recent years."); In re Venner, 262 F.2d 91, 95, 120 USPQ 193, 194 (CCPA 1958). See MPEP 2114 IV. and also MPEP 2144.04.
Second, Graeber does not explicitly disclose the identification of the therapy approach is based on the determination of the tumor as non-neuronal and non-neuroendocrine, and then administering an effective amount of the checkpoint blockade therapy to the subject.
However, Graeber does disclose that, in addition to distinct cancer types like SRBCTs, blood cancers, or small cell and non-small cell histologies seen in biopsies, the SCN phenotype exists along an expression signature-defined spectrum which influences therapeutic vulnerabilities in individual cancers, and thus screening for and targeting the SCN phenotype has clinical benefit ([0204]-[0205]), generally disclosing that SCN status informs treatment decisions.
Furthermore, Taube overviews the implications of the immune microenvironment in cancer therapeutics, including checkpoint inhibitors such as anti-PD-/PD-L1, and discloses characterizing the tumor immune microenvironment enables the identification of therapeutic strategies to guide first-line treatment algorithms (Abstract). Taube discloses various cancers in which checkpoint inhibitors are a first line of treatment either alone or in combination therapies (pg. 218, col. 2, para. 2; Figure 3). Taube discloses prognostic indicators of a response to checkpoint inhibitors involving immunoscores which quantify immune infiltration within the central region and invasive margin of a broad range of tumors, wherein patients with higher immunoscores (e.g. immune infiltration) are recommended for checkpoint inhibitor therapy (pg. 218, col. 1, para. 2-3; FIG. 4). Taube then explains that many solid tumor types, such as neuroendocrine tumors (e.g. such as SCN in Graeber) are not classically recognized as immune infiltrated, and thus if an immune checkpoint blockade were to be effective, it could be used in a combination treatment after treatment of some other inhibitor that first incites an immune response prior to treatment with the checkpoint inhibitor (pg. 227, col. 2, para. 2), rather than using a checkpoint inhibitor as an initial first-line of treatment. This demonstrates that neuroendocrine tumors, such as SCN, generally have low immune infiltration, or immunoscores and do not respond well to immune checkpoint inhibitors as an initial treatment. Last, Taube discloses the administration of checkpoint inhibitors to cancer patients results in responses to treatment between 2 and 12 weeks and show durable responses (pg. 215, col. 2, para. 2 to pg. 216, col. 1, para. 1)
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Graeber to have further identified the therapy approach based on the determination of the tumor as non-neuronal and non-neuroendocrine (e.g. not having a low immunoscore), and then administering an effective amount of the checkpoint blockade therapy to the subject, as shown by Taube, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Graeber and Taube to provide durable treatment responses to cancer patients who do not have tumors with low immune infiltration, as shown by Taube (pg. 215, col. 2, para. 2 to pg. 216, col. 1, para. 1). This modification would have had a reasonable expectation of success given Graeber discloses determining various cancer types do not have the SCN signature, including bladder cancer, head and neck squamous cell cancer, and lung cancer, ([0016]), which Taube discloses can be treated with checkpoint inhibitors (Table 4), and thus the method of Taube is applicable to Graeber.
Further regarding performing the administration automatically via a processor in claim 118, broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art. See MPEP 2144.04 III.
Last, Graeber does not disclose outputting an indication that the subject is amenable to the therapy approach.
However, Spetzler discloses methods and systems, including a computer system with a processor coupled to memory (claim 83) and non-transitory computer readable medium ([0310]) for molecular profiling of cancer via a clinical decision support system for personalized medicine (Abstract). Spetzler discloses the method involves generating a report that identifies a molecular profile for the patient that includes a list describing the expected benefit of the plurality of treatment options based on the assessed characteristics (i.e. outputting an indication the subject is amenable to a therapy approach) ([0006]; [0350]; [0360] FIG. 6). Spetzler additionally discloses clinical responses to immune checkpoint inhibitor therapy ranges by tumor type, and provides an example in which expression data is used to identify a subset of cancer cases as candidates for immune checkpoint inhibitor therapy ([0531]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to have modified the method of Graeber to have further utilized the gene expression data to output an indication that the subject is amenable to the therapy approach, as shown by Spetzler, discussed above. One of ordinary skill in the art would have been motivated to combine the methods of Graeber and Spetzler in order to provide more informed and effective treatment options, resulting in improved patient care and enhanced treatment outcomes, as shown by Spetzler ([0006]). This modification would have had a reasonable expectation of success because both Graeber and Spetzler analyze gene expression data of a patient to identify cancer and cancer treatments, and thus the method of Spetzler is applicable to Graeber.
Regarding the dependent claims:
Regarding claim 31, Graeber discloses the cancer treatment may be used alone ([0063]), which demonstrates the therapy approach does not include the use of chemotherapy.
Regarding claim 32¸ Graeber discloses determining the gene expression levels’ are different than a to a small cell neuroendocrine (SCN) signature ([0020]; [0023]-[0024]; [0055]) by classifying the expression data of the patient using a classifier trained on a training set of SCN positive cases and a second subset of small cell lung cancer (SCLC) samples to assign the patient to the SCN class or non-SCN class, wherein the SCN and non-SCN classes are differentiated by expression levels of one or more genes ( [0263], e.g. gene expression profiles used)
Regarding claim 33, Graeber further discloses determining the SCN signature by training a logistic regression classifier using training data ([0263]-[0265]), wherein the training data includes the following:
Graeber discloses the training data includes gene expression values of for each gene in the SCN signature ([0263]).
Graeber discloses the training data includes a set of samples as part of a SCN class (i.e. a first subset with a first label being indicative of a tumor having a neuronal property) and a set of samples as part of a non-SCN class (i.e. a second subset with a second label being indicative of a tumor not having the neuronal property) ([0265]).
Regarding claims 34-35, Graeber discloses the set of genes includes SV2A, NCAM1, ITGB6, SH2D3A, and TACSTD2 ([0163], e.g. genes in SCN gene signature; [0008]; [0017], e.g. biomarkers in Table 1 measured; claim 8).
Regarding claim 104, Graeber discloses the neuronal genetic signature comprises genes that are used to determine of a sample has a tumor with a SCN or neuroendocrine features (i.e. the first class of tumors ) or non-neuronal (the second class of tumors) [0055]. It is noted that the limitation regarding how the set of genes was previously identified is a product by process limitation, and step of identifying the set of genes as informative of assignment is not required by the claims. See MPEP 2113.
Regarding claim 105, Graeber discloses the signature distinguishes between a SCN, or small cell neuroendocrine tumor (i.e. developed from cells of the neuroendocrine system) and a non-neuronal tumor (i.e. the first class is a neuroendocrine tumor) ([0055]).
Regarding claim 106¸ Graeber further discloses that the expression data for each of the samples that are part of the non-SCN class included expression data from SCLC samples (i.e. non-neuronal and neuroendocrine derived from a respective type of tissue) and expression data for each samples part of the SCN class include pan-cancer SCN SCLC cases confirmed by pathology (i.e. a neuroendocrine tumor derived from the same respective type of tissue) ([0265]).
Regarding claim 107, Graeber discloses training the model includes identifying the set of genes [0053]-[0054], comprising the following.
Graeber discloses using a gene expression profile for each of a first tumor class with a label indicative of the tumor having a neuronal property (i.e. having the neuronal genetic signature) and a second non-SCN class (i.e. tumors not having the neuronal genetic signature) ([0263]; [0265]), wherein the gene expression profile includes, for each gene, an expression level (i.e. an expression-metric statistic) indicating a level (i.e. a degree) to which the gene is expressed for the given class ([0020]).
Graeber discloses each gene in the determined set of genes has a signature weight greater than a predefined threshold ([0013]-[0015]), wherein the signature weight reflects a difference between the expression levels of the respective gene between the two classes (i.e. between the first and second expression-metric statistic ([0184], e.g. weights determined by PCA between SCN cases and non-SCN tumors).
Regarding claims 108 Graeber discloses measuring the set of genes including SV2A, NCAM1, ITGB6, SH2D3A, TACSTD2, C19orf33, SFN, RND2, PHLDA3, OTX2, and TBC1D2 ([0163], e.g. genes in SCN gene signature; [0008]; [0017], e.g. biomarkers in Table 1 measured; claim 8), and that the genes are measured in a tumor sample ([0025]; claims 1 and 15)
Graeber further discloses using the measured expression levels are used to determine whether the subject has the SCN cancer ([0020]) and ultimately determine whether the patient would benefit from an immune checkpoint inhibitor ([0027]; [0065]), as shown by Graeber in view of Taube and Spetzler as applied to claim 30 above.
Regarding claims 109-116, Graeber discloses the set of genes measured includes SV2A, NCAM1, ITGB6, SH2D3A, TACSTD2, C19orf33, SFN, RND2, PHLDA3, OTX2, and TBC1D2 (i.e. ten or more genes in Tables 2, 3, and 4) ([0163], e.g. genes in SCN gene signature; [0008]; [0017], e.g. biomarkers in Table 1 measured; claim 8).
Therefore, the invention is prima facie obvious.
Response to Arguments
Applicant's arguments filed 23 Oct. 2025 regarding 35 U.S.C. 103 have been fully considered but they are not persuasive.
Applicant remarks Graeber and Spetzler fail to disclose or suggest “wherein the set of genes comprises at least one gene selected from the group consisting of SV2A, NCAM1…, and KIAA1257” and “identifying a therapy approach that includes initial use…based on the determination of the tumor as non-neuronal and non-neuroendocrine”, because Graeber only generally describes administration of immune checkpoint inhibitors, which is not “based on the determination”, and furthermore, Graeber lists many hundreds of genes in Table 1 which may be used for classification, and states that preferred biomarkers are those having an absolute value of the signature weight greater than 0.025 (Applicant’s remarks at pg. 20, para. 2-3). Applicant then remarks none of the recited genes have an absolute value of the signature greater than 0.025, and thus Graeber fails to disclose the set of genes as claimed (Applicant’s remarks at pg. 20, para. 3).
This argument is not persuasive. First, regarding the step of identifying the therapy based on the determination, Graeber is not relied upon for this limitation, which is instead disclosed by the newly cited reference Taube, discussed above.
Regarding the claimed set of genes, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005). See MPEP 2123 I.
It is acknowledged that Graeber discloses a preferred embodiment in which all genes used for classification have an absolute value of the signature weight greater than 0.025, as noted by Applicant. Graeber also discloses that in some embodiments at least 18,000 biomarkers are measured ([0017]), and generally discloses one or more biomarkers from Tables 1-3 may be measured, which includes embodiments in which all biomarkers are measured. Therefore, Graeber does disclose the claimed set of genes, wherein at least one gene is selected from the recited group including SV2A, NCAM1, etc., regardless of whether Graeber discloses other embodiments in which only certain genes with a threshold absolute value of the signature weight are used. Last, it is further noted, that because the claims use the transitional phrase “comprising”, the claimed set of genes is not closed to unrecited elements (i.e. additional genes outside the group consisting of SV2A, NCAM1, etc. See MPEP 2111.02.
Applicant remarks Spetzler fails to cure the deficiencies of Graeber and is silent regarding determining a tumor as non-neuronal and non-neuroendocrine based on “a gene-expression data element” as claimed, or “identifying a therapy approach…based on the determination…” as recited in claim 30, and thus claims 30 and 118 are allowable (Applicant’s remarks at pg. 20, para. 3 to pg. 21, para. 2).
This argument is not persuasive for the same reasons discussed above regarding Graeber and because Spetzler is not relied upon for these limitations.
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.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAITLYN L MINCHELLA whose telephone number is (571)272-6485. The examiner can normally be reached 7:00 - 4:00 M-Th.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685