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 .
Response to Amendment
The amendment filed December 21st, 2025 is acknowledged. Regarding the Office Action mailed June 26th, 2025:
Maintained or modified rejections are set forth below. New grounds of rejection are set forth below, as necessitated by the addition of new claims. Responses to arguments, if necessary, follow their respective rejection sections.
Claim Status
Claims 1, 3, 5, and 11-13 have been amended. Claims 7-10 and 14-15 have been cancelled. Claims 16-18 have been added. Claims 1-6, 11-13, and 16-18 are pending and discussed in this Office Action.
Claim Objections
Claim 5 objected to because of the following informalities: the claim recites “wherein the cancer further comprising administering” which is grammatically incomplete and unclear. A word or phrase appears to be missing between “cancer” and “further”. Appropriate correction is required.
Applicant is advised that should claim 5 be found allowable, claim 12 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112b – Indefiniteness
Newly Applied as Necessitated by Claim Amendments
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.
Claims 1, 4, 11, 12, and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "disodium 2,2'-dithio-bis-ethane sulfonate" in step (d) and (e). There is insufficient antecedent basis for this limitation in the claim because the compound was introduced in step (b) as “a 2,2'-dithio- bis-ethane sulfonate” without specifying disodium. The claim therefore introduces “the disodium 2,2'-dithio-bis-ethane sulfonate” in step (d) and (e) without first establishing its antecedent basis.
Claim 4 recites the limitation "the 2,2'- dithio-bis-ethane sulfonate analog” in line 2. There is insufficient antecedent basis for this limitation in the claim. The term “analog” was removed from claim 1 during amendment, and claim 1 no longer recites a “2,2'-dithio- bis-ethane sulfonate analog” Therefore, the phrase “2,2'-dithio- bis-ethane sulfonate analog” in claim 4 lacks antecedent basis in the claim from which it depends.
Claim 11 recites the limitation " [t]he method of claim 9" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 11 depends from claim 9, a canceled claim, therefore it is unclear what method the limitation is referencing.
Claim 12 recites the limitation " [t]he method of claim 8" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 12 depends from claim 8, a canceled claim, therefore it is unclear what method the limitation is referencing.
Claim 17 recites the limitation " [t]he method of claim 14" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 17 depends from claim 14, a canceled claim, therefore it is unclear what method the limitation is referencing.
For the purpose of examination, the examiner interprets the claims as follows:
Claim 11 is interpreted as depending from claim 1, the nearest independent claim and is examined accordingly.
Claim 12 is interpreted as depending from claim 1, the nearest independent claim and is examined accordingly. It is noted that that, under this interpretation, claim 12 recites substantially the same subject matter as claim 5, which also depends from claim 1.
Claim 17 is interpreted as depending from claim 16, the nearest independent claim and is examined accordingly.
Claim Rejections - 35 USC § 101 – Modified – Necessitated by Amendment
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 1-6, 11-13, and 16-18 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. While the claim is directed to a process, and therefore meets step 1 of the subject matter eligibility test (see MPEP 2106.03), the claim recites the natural correlation between NRF2 expression levels in a tumor sample and sensitivity to disodium 2,2'-dithio-bis-ethane sulfonate. Such a correlation is a natural phenomenon because it is grounded in an endogenous biological relationship whose properties exist in natural independent of the claimed method.
Step 2A of the subject matter eligibility test requires a two-pronged analysis.
Prong One asks: does the claim recite an abstract idea, law of nature or natural phenomenon? As discussed in MPEP 2106.04(II)(A)(1), the meaning of "recites" is "set forth" or "describes". That is, a claim recites a judicial exception when the judicial exception is "set forth" or "described" in the claim. In the instant case, the claim describes a natural phenomenon: the natural correlation between NRF2 expression levels in a tumor sample following ex vivo contact with disodium 2,2'-dithio-bis-ethane sulfonate and the subject’s sensitivity to that compound. The specification also acknowledges this natural relationship, teaching that “nuclear expression of Nrf2 indicates sensitivity to 2,2'-dithio-bis- ethane sulfonate” [0086]. The claim further describes the mental process of comparing an expression level to a reference level and making an administration decision based on that comparison.
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP 2106.04(II)(A)(2), "Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC V. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) ("Adding one abstract
idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract"); Genetic Techs. V. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility "cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself."). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must "transform the nature of the claim" into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong Two or in Step 2B." The considerations to be used are set forth at MPEP 2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP 2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite contacting a sample of the cancer form the subject, contacting the sample of the cancer from the subject, contacting the sample ex vivo with the compound, performing a nucleic acid amplification assay, comparing the expression level to a reference, and administering the compound if the threshold is met. None of these steps improve upon existing methods of tumor sample collection, nucleic acid amplification, or expression analysis. The claim merely uses existing methods for these steps. Note that MPEP 2106.05(a) indicates that "[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample" is an example that the courts have indicated may not be sufficient to show an improvement to technology. That the above steps were known in the prior art will be shown below.
MPEP 2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. While nucleic acid amplification as recited in step c) of the claim would conventionally be performed using a PCR instrument, no particular machine is recited, and further considerations such as the particularity or generality of any recited machine, and whether such machine involvement is merely extra-solution activity. MPEP 2106.05(g) describes "extra-solution activity", noting that "[d]etermining the level of a biomarker in blood" is an example of "mere data gathering" which the courts have found to be insignificant extra-solution activity.
MPEP 2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. Contacting a cancer sample ex vivo with the compound does not transform the cancer sample into a different article. Performing a nucleic acid amplification assay to determine an NRF2 expression level does not transform NRF2 mRNA or the tumor sample into a different physical entity. The ex vivo contact step, while is a conventional sample preparation procedure that does not represent the kind of transformation that the courts have recognized as conferring patent eligibility.
MPEP 2106.05(e) has to do with “other meaningful limitations”. The additional limitations imposed upon the natural correlation between NRF2 expression levels and sensitivity to the compound, and the mental processes of comparing and administering, including: contacting a sample of the cancer from the subject; contacting the sample ex vivo with a 2,2'-dithio-bis-ethane sulfonate; performing a nucleic acid amplification assay; comparing the expression level to a reference level in non-cancer cells; and administering the compound to the subject if the expression level is greater than 1.0 times the reference level. These limitations are not considered “meaningful limitations”. MPEP 2106.05(e) states: "The phrase "meaningful limitations" has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole." However, as will be discussed below, these limitations do not arrive at an inventive concept. In addition, as has been discussed, they represent insignificant extra-solution activity, i.e. data gathering steps required to observe and apply the natural correlation.
MPEP 2106.05(f) raises the question as to whether the additional elements recited in the claim represent "mere instructions to apply an exception". Here, the judicial exception is the natural correlation between NRF2 expression levels and disodium 2,2'-dithio-bis-ethane sulfonate sensitivity. The additional elements recited in the claim (i.e. contacting a sample of the cancer from the subject; contacting it ex vivo with the compound; performing a nucleic acid amplification assay; comparing to a reference; and administering based on the result) amount to mere instructions to apply the natural correlation, since these steps collectively constitute the conventional laboratory workflow any practical use of the correlation would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that "[d]etermining the level of a biomarker in blood" is an example of "mere data gathering" which the courts have found to be insignificant extra-solution activity. Likewise, MPEP 2106.05(g) notes that "[p]erforming clinical tests on individuals to obtain input for an equation" also represents insignificant extra-solution activity. This aligns closely with the instant claims, where contacting a sample of the cancer from the subject; contacting it with the compound; and measuring NRF2 expression by nucleic acid amplification are all data gathering steps performed for the purpose of observing whether the natural correlation threshold is satisfied.
MPEP 2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitation of the method as applied to cancer treatment and the administration of a specific compound is considered a limitation to a particular field of use. However, as MPEP 2106.05(h) indicates, such limiting to a particular field of use does not confer patentability on otherwise ineligible subject matter.
Having considered the factors discussed in MPEP 2106.05 (a)-(c) and (e)-(h), it is clear that the additional elements recited in the claims, whether considered individually or as a combination, do not integrate the judicial exception into a practical application of that exception in such a way as to provide meaningful limits on the use of the judicial exception. The judicial exception is the natural correlation between NRF2 expression levels and sensitivity to disodium 2,2'-dithio-bis-ethane sulfonate, and the claim amount to using routine and conventional steps to observe and act on that correlation.
In addition, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception (as set forth in step 2B of the subject matter eligibility test; see MPEP 2106-III) because it was known in the prior art to contact a sample of the cancer cell from a subject, measure gene expression levels using nucleic acid amplification assays, and compare measured expression levels to reference levels derived from non-cancer tissue.
Klijn (US20190218618A1; previously cited) teaches a method of comprising contacting a tumor sample from a subject by biopsy [0035], measuring NRF2 pathway gene expression levels by nucleic acid amplification techniques including RT-PCR and RNA-seq [0196-0197], and comparing the measured expression level to a reference level from non-diseased tissue [0160].
Hausheer (US20170007561A1; previously cited) teaches that disodium 2,2′-dithio-bis-ethane sulfonate modulates the NRF2-Keap1 pathway, including that modification of Keap1 cysteine residues facilitate NRF1 nuclear translocation and upregulation of NRF2 target genes [808].
Therefore, the additional elements beyond the natural correlation between NRF2 expression levels and sensitivity to disodium 2,2'-dithio-bis-ethane sulfonate, and the mental process of comparing and administering based on a threshold do not represent an inventive concept, since contacting a cancer sample from a subject, measuring gene expression by nucleic acid amplification, and comparing to a non-cancer reference level were known in the art as demonstrated by Klijn and the relevant pharmacological indicator of NRF2 was known from Hausheer.
Claims 2-6, 11-18 depend directly or indirectly from claim 1 or claim 16 and are rejected under 35 USC § 101 for the same reasons set forth above with respect to claim 1.
Claim 16 is directed to a method of testing a tumor sample that recites the same natural correlation between NRF2 expression levels and sensitivity to disodium 2,2'-dithio-bis-ethane sulfonate as claim 1. The additional recitation of a treatment resistant patient population and specific hybridization device components does not alter the 101 analyses for the same reasons set forth above.
Response to Arguments – 35 USC § 101
Applicant’s argument filed December 21st, 2025 have been fully considered but they are not persuasive.
Applicant has traversed the reject of claim 1 under 35 USC § 101 as being directed to a judicial exception without significantly more. Applicant’s arguments have been considered but not persuasive to withdraw the rejection.
Applicant has argued that the ex vivo contact step distinguishes the claim from a mere observation of a natural correlation by requiring active manipulation of tumor tissue outside the body prior to the expression analysis. This argument is not persuasive. As addressed under MPEP 2106.05 (c) and (g) above, the ex vivo contact step is a conventional laboratory procedure recited at a high level of generality without any conventional technical feature. No particular concentration, duration, method of contact, or device is specified. The claim only recites generic steps required to gather the data needed to observe a natural correlation, those steps constitute insignificant extra-solution activity that does not transform the claim into a practical application.
Applicant has also argued that the administration step constitutes a practical application that integrates the natural correlation into a concrete clinical treatment decision. This argument is also not persuasive. As addressed under MPEP 2106.05(f) above, the administration step is entirely generic and imposes no particular treatment protocol, dosing regimen, routine of administration, combination therapy, or patient population limitation that would require or reflect a practical application of the correlation. The step merely directs the administration of the compound when the marker threshold is met.
Claim Rejections – 35 USC § 103 – Modified Necessitated by Amendment
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim 1-6, 11-13, and 16-18 is rejected under 35 U.S.C. 103 as being unpatentable over Klijn (US20190218618A1; previously cited) in view of Hausheer (US20170007561A1; previously cited).
Regarding instant claim 1, Klijn (US20190218618A1; previously cited) teaches contacting tumor samples from the subjects by biopsy [0035] and measuring NRF2 pathway gene expression levels by nucleic acid amplification techniques including RT-PCR and RNA-seq [0196-0197]. Klijn additionally teaches comparison of expression levels in tumor samples to reference levels derived from non-cancer cells or healthy tissue [0160], and application of fold-change thresholds to define elevated expression [0206].
It is noted that Klijn teaches a workflow in which a biopsy is contacted from a subject and expression is measured directly from the biopsy sample. A biopsy specimen is an ex vivo sample. However, Klijn does not teach or suggest contacting the ex vivo cancerous sample with the therapeutic compound prior to measuring expression. Klijn teaches: contact biopsy from subject; measure baseline gene expression from that biopsy; compare to reference; make treatment decision. This is biomarker measurement from a removed sample, not a drug sensitive assay in which the ex vivo sample is actively exposed to the therapeutic compound before measuring the molecular response. The applicant’s claimed ex vivo contact step is functionally a drug sensitivity assay. The cancerous sample is treated with the compound outside the body, and the NRF2 response to that treatment is then measured. Klijn provides no teaching of, or suggestion toward this workflow.
Hausheer (US20170007561A1; previously cited) teaches that Tavocept (2,2’-dithio-bis-ethane sulfonate) modulates the NRF2-Keapl pathway, including that modification of Keapl cysteine residues facilitates NRF2 dissociation from Keap1 and nuclear translocation, thereby upregulating NRF2 target genes [0808]. Hausheer thereby provides a method for the use of NRF2 expression as a molecular indicator of the compound activity. However, Hausheer teaches only in vivo intravenous administration of Tavocept of subjects receiving cancer treatment (Table 29; [0550]). Hausheer does not teach, describe, or suggest: contacting a tumor sample from a subject by biopsy; contacting that sample ex vivo with Tavocept; measuring NRF2 expression after that ex vivo contact; or using the result of such a measurement to select subjects for treatment.
It would have been obvious to one of ordinary skill in the art, before the filing date of the claimed invention, to combine the biopsy based cancer sample collection and NRF2 gene expression measurement method of Klijn with Hausheer’s teaching that disodium 2,2’-dithio-bis-ethane sulfonate activates the NRF2 pathway. The skilled artisan would have been motivated to test whether exposure of a tumor sample to Tavocept upregulates NRF2 expression, given Hausheer’s teachings of the compounds’ interaction with Nrf2-Keap1 and Rajiv’s teaching of NRF2 expression as measurable indicator of pathway activity. The skilled artisan would have been motivated to test whether contacting a tumor sample ex vivo with Tavocept upregulates NRF2 expression, given Hausheer’s teachings of the compound’s interaction with Nrf2-Keap1. The skilled artisan would have had a reasonable expectation of success based on the established use of the ex vivo drug sensitivity assays, nucleic acid amplification method taught by Klijn [0196-0197]. Example 1 of the instant application demonstrates that NRF2 pathway upregulation in response to disodium 2,2’-dithio-bis-ethane sulfonate is detectable by RNA-seq in a treated cell sample [0083]. Furthermore, [0036] presents ex vivo step as one element of laboratory procedure, which is consistent with the conclusion that the method was within the ordinary skill of the art.
Regarding instant claims 2 and 18, Klijn teaches the method of claim 1. Klijn further teaches that a plurality of biomarkers may be used in combination with NRF2 pathway gene expression measurement, including NQO1 (SEQ ID NO: 2) (Klijn, SEQ ID NO: 48). The use of a device comprising single-stranded nucleic acid molecules capable of specifically hybridizing with plurality of biomarker sequences is taught by Klijn’s disclosure of RT-PCR and RNA-seq method using sequence-specific nucleic acid components [0196-0197].
Regarding instant claim 3, Klijn teaches the method of claim 1. Klijn further teaches that reference expression levels are derived from non-diseased tissue or healthy reference samples [0160].
Regarding instant claim 4, Klijn in view of Hausheer teaches the method of claim 1. Hausheer teaches that the treatment that affects the expression of NRF2 is disodium 2,2'-dithio-bis-ethane sulfonate [0245; 0352; 0808].
Regarding instant claims 5 and 12, Klijn in view of Hausheer teaches the method of claim 1. Klijn further teaches that cancer chemotherapy treatments include platinum complex agents such as cisplatin [0171].
Hausheer further teaches taxanes, including paclitaxel and docetaxel as chemotherapy agent co-administered with disodium 2,2'-dithio-bis-ethane sulfonate in the treatment of cancer [0179; 0285; Table 29].
Regarding instant claim 6, Klijn teaches the method of claim 1. Klijn further teaches cancer treatment regimens that include radiation treatment [0171].
Regarding instant claim 11, Klijn in view of Hausheer teaches the method of claim 1 (as interpreted). Hausheer further teaches administration of disodium 2,2'-dithio-bis-ethane sulfonate at a dose ranging from approximately 14 g/m2 to approximately 22 g/m2, with a preferred dose of 18.4 g/m2 [0244].
Regarding instant claim 13, Klijn in view of Hausheer teaches the method of claim 12. Klijn further teaches that platinum complex chemotherapy agents include cisplatin [0171]. Oxaliplatin, carboplatin, and their derivatives and analogs are well-known platinum complex agents [0171].
Hausheer further teaches that Tavocept’s terminal sulfhydryl group as a substitution group for the active metabolites of platinum complexes including cisplatin and carboplatin [0242]. Hausheer further teaches oxaliplatin as a platinum containing anticancer compound used in cancer treatment [0813; 0864].
Regarding instant claim 16, Klijn teaches obtaining a tumor sample from a patient by biopsy [0035], measuring NRF2 pathway gene expression using nucleic acid amplification techniques including RT-PCR employing single-stranded nucleic acid molecules capable of specifically hybridizing with biomarker sequences [0196-0197], comparing expression levels to a non-cancer reference [0160], and applying a fold-change threshold to determine elevated expression [0206].
Hausheer teaches that disodium 2,2'-dithio-bis-ethane sulfonate modulates the NRF2-Keap1 pathway [0808] and teaches intravenous administration to subjects receiving cancer treatment [0550; Table 29].
Testing a patient who is resistant to one or more cancer therapies and has unknown responsiveness to disodium 2,2'-dithio-bis-ethane sulfonate is not a distinct method. Any diagnostic sensitivity assay directed to patients’ responsiveness is unknown.
Regarding instant claim 17, Klijn teaches the method of claim 16 (as interpreted). Klijn further teaches a 1.5-fold threshold as a measure of elevated expression [0206].
Response to Remarks – 35 USC § 103
It is noted that the prior Office Action rejected the claims under 35 USC §103 over Rajiv (US 2013/0005666) in view of Klijn (US 2019/0218618) and Hausheer (US PG PUB 2017/0007561). In light of the amendments to the claims, the rejection over Rajiv has been withdrawn.
Applicant has traversed the rejection of claims under 35 USC §103 as being unpatentable over Klijn et al. (US 2019/0218618; previously cited) in view of Hausheer (US PG PUB 2017/0007561; previously cited) Applicant’s arguments have been considered but are not persuasive to withdraw the rejection.
Applicant has argued that no reference in the cited combination teaches or suggests performing an ex vivo contact of patient-derived cancer sample with the claimed compound followed by nucleic acid amplification-based expression analysis of NRF2 relative to non-cancer reference cells as the basis of determining sensitivity and selectively administering disodium 2,2'-dithio-bis-ethane sulfonate. This argument has been considered but is not sufficient to withdraw the rejection. The combination of Klijn’s teaching of biopsy based cancer sample collection and NRF2 pathway gene expression measurement relative to non-cancer reference tissue [0035; 0160; 0196-0197] with Hausheer’s teaching that Tavocept activates the NRF2-Keap1 pathway through cysteine modification of Keap1 [0808] would have provided a skilled artisan with both the motivation and the reasonable expectation of success to test whether ex vivo contact of a tumor sample with Tavocept produces a measurable NRF2 expression response that could serve as an indicator of sensitivity. Also, example 1 of the instant specification discloses that NRF2 pathway upregulation is detectable by RNAseq following disodium 2,2'-dithio-bis-ethane sulfonate treatment of a cancer cell sample [0083]. The instant specification therefore validates the expected result reinforces the conclusion that a skilled artisan would have had a reasonable expectation of success in implementing the claimed workflow, and weighs against the applicant’s contention that the claimed combination was non-obvious.
Applicant has further argued that the motivation rational is insufficient because it does not explain why a skilled artisan would have been motivated to implement the specific ex vivo sample-contact step and comparator-driven decision rule, and that the rejection therefore rests on hindsight reconstruction. This argument is not persuasive. The motivation to combine does not rest on a general assertion of unmet need. Rather, the motivation arises directly from Hausheer’s teaching that Tavocept modulates the NRF2-Keap1 system through cysteine modification of Keap1, facilitating NRF2 dissociation and unclear translocation and upregulation of downstream phase 2 genes [0808]. This teaching would have directed a skilled artisan to investigate NRF2 pathway gene expression of Tavocept activity in a tumor sample. Klijn provides the method for that, measuring NRF2 pathway gene expression in biopsy-derived tumor samples relative to non-cancer reference tissue using nucleic acid amplification techniques [0035; 0160; 0196-0197; 0206]. The application of an ex vivo contact step prior to gene expression analysis is a logical extension of these combined teachings and does not require the skilled artisan to do anything beyond applying known techniques to a known method for expecting a predictable result. Furthermore, [0036] of the instant application presents ex vivo step as one element of laboratory procedure, which is consistent with the conclusion that the step constitutes routine laboratory method.
Applicant has also argued that the predictable results rationale fails because there is no reasonable expectation that NRF2 expression relative to non-cancer reference cells would indicate sensitivity to disodium 2,2’-dithio-bis-ethane sulfonate in the context of an ex vivo contact protocol. This argument is not persuasive. Hausheer teaches that Tavocept activates the NRF2-Keap1 pathway by facilitating dissociation of NRF2 from Keap1 through cysteine modification of Keap1 cysteine residues, leading to nuclear translocation of NRF2 and upregulation of NRF2 target genes [0808]. This method supports a reasonable expectation that ex vivo contact of a tumor sample with Tavocept would produce a measurable NRF2 expression response. The instant specification also confirms this expectation, as Example 1 at para [0083] demonstrates that NRF2 pathway upregulation is detectable by RNA-seq following disodium 2,2’-dithio-bis-ethane sulfonate treatment of a cancer cell sample.
Applicant has additionally argued that the limitations of claims 16 and 17 further distinguish the claims from the prior art. With respect to claim 16, Applicant argues that the claim is directed to a treatment-resistant patient population with unknown responsiveness to the compound, and that the specific hybridization device components and defined workflow further distinguish the claim. These arguments are not persuasive. The clinical context of treating patients with unknown or resistant responsiveness to a compound does not define a distinct method. Any diagnostic sensitivity assay is directed to patients whose responsiveness is unknown, and nothing in claim 16 requires a method that is different from the broader claimed method by virtue of the patient population. With respect to the device components, the recitation of a device comprising single-stranded nucleic acid molecules capable of specifically hybridizing with nucleotides of NRF2 (SEQ ID NO:1) and additional biomarker sequences does not impart patentable distinction. Klijn teaches the use of nucleic acid based techniques including RT-PCR, which employs single-stranded nucleic acid primers that hybridize specifically to target sequences, and RNA-seq for measuring NRF2 pathway gene expression in tumor samples [0196-0197]. Single-stranded nucleic acid molecules designed to specifically hybridize with target gene sequences are components of routine and conventional expression analysis techniques in the related art, and their recitation in the claim does not constitute a patentably distinct limitation.
With respect to claim 17, Applicant argues that the 1.5-fold expression threshold recited in claim 17 provides an additional structural limitation on the decision rule that further distinguishes the claim. This argument is not persuasive. Klijn teaches the use of fold-change thresholds as measures of elevated expression, including a 1.5-fold threshold [0206]. Klijn further teaches that fold-change measurement employs a comparator framework, measuring expression relative to a reference cell or control tissue. This aligns with the reference expression level limitation recited in the instant claims, further confirming that this aspect of the claims was within the ordinary skill of the art.
Conclusion
All claims are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nura Choudhury whose telephone number is (571)272-6148. The examiner can normally be reached M-F, 9-5 ET.
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/NURA M. CHOUDHURY/ Examiner, Art Unit 1683
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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