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 .
Election/Restrictions
The restriction requirement between inventions groups, as set forth in the Office action mailed on 11/26/2025, is hereby withdrawn. All pending claims are hereby rejoined and fully examined for patentability. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Application Status
Claims 1-20 are pending and examined on the merits herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 42 and 44. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-19 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The rationale for this determination is explained below:
Claims 1-2, 12, and 13 are directed to a natural phenomenon and an abstract idea because the claims recite natural phenomenon and an abstract idea (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: 1) the level of expression of cCol I, DDR1 and/ or NRF2 in a tumor sample (claims 1-2 and 12-13). The “abstract idea” is: comparing the changed level of cCol I, DDR1 and/or NRF2 expression experience a favorable outcome or longer survival with aggressive anti-tumor therapy or an inhibitor of DDR1 or mitochondrial biogenesis (claim 1 and 19).
It is noted claim 1 recites a treatment step; however, the treatment is administered regardless of the results of the expression level and the measurement is only an indicator of a predicted response to the treatment – and thus the treatment defines the population that is being measured for expression and does not include an active method step of administration. Therefore, the treatment step of claim 1 does not integrate the judicial exception(s) into a practical application. Further, this step is directed to the data gathering step, e.g., the steps necessary to observe the phenomenon, which the Court has recognized as not a practical integration. Therefore, the application step of claim 1 does not integrate the judicial exception(s) into a practical application (“Step 2A”).
It is noted claim 19 recites a treatment step; however, the aggressive treatment by multi-modal therapy is standard of care and therefore routine and conventional in the art for these types of cancer regardless of the expression level of cCol I, DDR1, and/or NRF2 as taught by Park (JAMA. 2021 Sep 7;326(9):851-862; PTO-892). Therefore, the treatment step of claim 19 does not integrate the judicial exception(s) into a practical application. Therefore, the application step of claim 19 does not integrate the judicial exception(s) into a practical application (“Step 2A”).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of measuring protein expression in the tumor sample and treatment with standard of care treatment for PDAC (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
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Recited active steps of the claims 1 and 12 impose no meaningful limit on the scope of the claims, implicate a relevant pre-existing audience, and are recited at a high level of generality such that substantially all methods of measuring protein expression in the tumor would conventionally and routinely be performed by one of ordinary skill in the art. Claims 6, 7, 17, and 18 further limit the measurement of expression to immunohistochemical detection which is conventional and routine in the art.
Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods of measuring protein expression in the tumor encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting protein expression) are routinely performed in the art to obtain data regarding expression and treat subjects. In regards to “determining", it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Claims 2-11 and 13-19 are also rejected because they are dependents of claims 1 and 12 that narrow the scope of claimed invention to still be directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more.
Claim Rejections - 35 USC § 112(b)
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 1-20 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 is drawn to a method of treating a subject suffering from cancer with a higher level of cCol I in a tumor as compared to a subject without cancer or a cancer with a lower level of cCol I and/ or a more favorable outcome.
This renders the claim indefinite as it is unclear how a sample of tumor could be derived from a patient not suffering from a cancer; further it is not clearly defined what the lower level of cCol I is in comparison to or the more favorable outcome.
The instant specification discloses that the method further comprises isolating a tumor sample by tumor resection, liquid biopsy or needle biopsy (para 0082), but does not clarify where the control sample is derived from.
The instant specification discloses that the lower cCol I level in cancer patients in comparison to a patient not suffering from a cancer are more likely to experience longer survival (para 0073).
This indicates that the lower cCol I level is relative to a patient without cancer, but as the sample is derived from a tumor it is unclear how this comparison would be established; or how a patient with lower cCol I could have a more favorable outcome versus a patient not suffering from a cancer.
Claim 2 is drawn to a tumor with higher DDR1 level and or NRF2 as compared to a subject not suffering from cancer or having a cancer with a lower level of DDR1 or NRF2 and/ or a more favorable outcome.
This renders the claim indefinite as it is unclear how a sample of tumor could be derived from a patient not suffering from a cancer; further it is not clearly defined what the lower level of DDR1/NRF2 is in comparison to or the more favorable outcome.
The instant specification discloses that the method further comprises isolating a tumor sample by tumor resection, liquid biopsy or needle biopsy (para 0082), but does not clarify where the control sample is derived from.
The instant specification discloses that the lower DDR1/NRF2 level in cancer patients in comparison to a patient not suffering from a cancer are more likely to experience longer survival (para 0074).
This indicates that the lower DDR1/NRF2 level is relative to a patient without cancer, but as the sample is derived from a tumor it is unclear how this comparison would be established; or how a patient with lower DDR1/NRF2 could have a more favorable outcome versus a patient not suffering from a cancer.
Claims 3-11 depend from claim 1 or 2 without correcting the issue(s) identified above and are therefore included in this rejection.
Claim 12 is drawn to a method of determining is a subject suffering from a desmoplastic cancer, a fibrolytic cancer or PDAC I smore of less likely to experience a change in survival based on the level of cCol I in a tumor as compared to a subject without cancer.
This renders the claim indefinite as it is unclear how a sample of tumor could be derived from a patient not suffering from a cancer.
The instant specification discloses that the method further comprises isolating a tumor sample by tumor resection, liquid biopsy or needle biopsy (para 0082), but does not clarify where the control sample is derived from.
The instant specification discloses that the lower cCol I level in cancer patients in comparison to a patient not suffering from a cancer are more likely to experience longer survival (para 0073).
This indicates that the lower cCol I level is relative to a patient without cancer, but as the sample is derived from a tumor it is unclear how this comparison would be established; or how a patient with lower cCol I could have a more favorable outcome versus a patient not suffering from a cancer.
Claim 13 is drawn to detecting the level of DDR1 and/ or NRF2 in the tumor sample as compared to a subject not suffering from cancer; wherein a lower level of DDR1 or NRF2 are more likely to have longer survival.
This renders the claim indefinite as it is unclear how a sample of tumor could be derived from a patient not suffering from a cancer.
The instant specification discloses that the method further comprises isolating a tumor sample by tumor resection, liquid biopsy or needle biopsy (para 0082), but does not clarify where the control sample is derived from.
The instant specification discloses that the lower DDR1/NRF2 level in cancer patients in comparison to a patient not suffering from a cancer are more likely to experience longer survival (para 0074).
This indicates that the lower DDR1/NRF2 level is relative to a patient without cancer, but as the sample is derived from a tumor it is unclear how this comparison would be established; or how a patient with lower DDR1/NRF2 could have a more favorable outcome versus a patient not suffering from a cancer.
Claims 14-20 depend from claim 12 or 13 without correcting the issue(s) identified above and are therefore included in this rejection.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 6-9, 11-15, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Willumsen (Sci Rep. 2019 Dec 24;9(1):19761; PTO-892), Aguilera (Molecular Cancer Therapeutics, 2017, 16(11): 2473-85; IDS entered 02/08/2024) and Vijver (Front. Immunol, 2021, 12:733561; PTO-892).
Regarding claims 1, 3-4, 6, 8-9, 11-12, 17, and 19-20, Willumsen teaches that pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment being associated with a dense and active stroma and tumor fibrosis (desmoplasia) which is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation (abstract). Willumsen further teaches measurement of matrix metalloprotease (MMP)-degraded type I collagen (C1M) by ELISA in pre-treatment serum of stage III/ IV PDAC treated with 5-fluorouracil based therapy and evaluation of correlation with overall survival (OS) (abstract) and confirmed that collagen turnover measured in serum by C1M, C3M and C4M is elevated in PDAC compared to healthy controls (discussion, para 2). Willumsen further teaches that higher levels of C1M were found in the PDAC patients versus the normal reference range (Fig 1) and that these levels were associated with significantly shorter OS and further that this marker could have a prognostic/ predictive potential for future treatment trials (abstract). Willumsen further teaches that one arm of the trial received octreotide (somatostatin, a somatotrophin-release inhibiting factor analogue) and continuous infusion of 5-fluorouracil (5-FU) and another arm received placebo and 5-FU (patients and study design). The instant specification discloses that aggressive treatments include multimodal therapies (para 0069).
Willumsen does not teach measurement in a tumor sample, or measurement of DDR1 or NRF2.
Regarding claims 1-3, 7-9, 11, 13-15, and 18 Aguilera teaches that the ECM is a principal component of PDAC is rich in fibrillar collagens that facilitate tumor cell survival and chemoresistance and that discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that specifically binds fibrillar collagens and has been implicated in promoting cell proliferation, migration, adhesion, ECM remodeling, and response to growth factors (abstract). Aguilera further teaches that pharmacologic inhibition of DDR1 with an ATP-competitive orally available small-molecule kinase inhibitor (7rh) abrogated collagen-induced DDR1 signaling in pancreatic tumor cells and showed striking efficacy in combination with chemotherapy in orthotopic xenografts and autochthonous pancreatic tumors by reducing primary tumor burden and improving chemoresponse (abstract). Aguilera further teaches measurement of level of phosphor-DDR1 by immunohistochemistry in primary tumor samples as well as patient matched xenografts (Fig 1). Aguilera further demonstrates measurement of DDR1 and collagen signaling in a mouse model of PDAC tumors before and after treatment, that showed that combination treatment with a DDR1 inhibitor and chemotherapy provided improved overall survival as well as reduced phosphor-DDR1 levels and collagen signaling (Fig 6).
Vijver teaches that the ECM undergoes a dramatic transformation during tumor development due to tissue remodeling and that changes in collagen expression, density and stiffness correlate with worse prognosis of cancer patients ( discussion, para 1). Vijver further teaches that ECM signatures, increased collagen expression, and increased expression of collagen-crosslinking enzymes associate with poor prognosis of cancer patients (discussion, para 2) and further that collagen remodeling by matrix metalloproteinases (MMPs) generates specific collagen fragments, that can be detected in the circulation of cancer patients and correlate with poor disease outcome (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to measure DDR1 in tumor samples and selectively inhibit DDR1 in combination with standard treatment as taught by Aguilera in the measurement of cleaved collagen I in serum combined with aggressive treatment of PDAC as taught by Willumsen because of the correlation of between increased collagen expression and signaling concomitant with increased cleaved collagen in the circulation and poor prognosis in cancer patients as taught by Vijver. The ordinary artisan would have been motivated to do so because Willumsen teaches that PDAC patients have poor prognosis and poor response to treatment and both Willumsen and Aguilera teach that PDAC has extensive ECM involvement through collagen and that DDR1 is downstream of collagen signaling. Willumsen teaches measurement of c Col I (or C1M) in the serum of patients with and without PDAC and Aguilera teaches elevated levels of DDR1 in numerous cancers and specifically detection of phosphor-DDR1 in PDAC tumor samples. As Vijver teaches that cancer increases both expression of collagen which in turn increases downstream signaling, as well as circulation of cleaved collagen fragments which both correlate with poor prognosis, Willumsen teaches that patients with an increased measurement of cCol I had improved OS with aggressive treatment, and Aguilera teaches that inhibition of DDR1 enhanced standard of care chemotherapy response and overall survival in a PDAC mouse model. The ordinary artisan would have a reasonable expectation of success to measure cCol I and/ or DDR1 in a sample from a PDAC patient and if elevated relative to a control to treat with a DDR1 inhibitor in combination with a standard of care chemotherapeutic or another aggressive treatment modality to improve overall survival of the patient(s).
Claims 5, 10, and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Willumsen (Sci Rep. 2019 Dec 24;9(1):19761; PTO-892), Aguilera (Molecular Cancer Therapeutics, 2017, 16(11): 2473-85; IDS entered 02/08/2024), and Vijver (Front. Immunol, 2021, 12:733561; PTO-892) as applied to claims 1-4, 6-9, 11-15, and 17-20 above, and further in view of Sakaguchi (Pancreatology. 2019 Jul;19(5):672-680; PTO-892).
The teachings of Willumsen, Aguilera, and Vijver regarding claims 1-4, 6-9, 11-15, and 17-20 are detailed above.
Willumsen, Aguilera and Vijver do not teach that the cancer has metastasized to the liver or that the method further comprises resection or radiation therapy.
Sakaguchi teaches that in a comprehensive literature review on metastatic PDAC patients who underwent resection for synchronous liver metastasis after chemotherapy had favorable overall survival (abstract). Sakaguchi further teaches that the incidence of PDAC is equal to its mortality, virtually 100% of diagnosed patients will die from the disease irrespectively from the therapeutic approach and the majority of patients have synchronous metastatic disease on an initial presentation (background). Sakaguchi further teaches that aggressive chemotherapy can convert unresectable disease to resectable disease (page 673, col 1, para 1). Sakaguchi further teaches that favorable prognoses can be expected for highly selected patients under certain circumstances: (i) conversion surgery, which can be defined as additional surgical resection after favorable response to anti-cancer treatments in patients with initially unresectable PDAC and (ii) resection with only a few metastases (so-called oligometastases, which can be defined as distant metastases to a single or limited number of organs and a number of metastases consistent with a high potential for a complete operative resection (page 673, col 1, para 1). Table 1 summarizes the studies used for resection of liver metastasis. Sakaguchi further teaches that there are substantial survival benefits of conversion surgery for patients with synchronous mPDAC of the liver and peritoneum who responded favorably to initial chemotherapy for a certain period of time (conclusion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add resection to the method of treatment when the PDAC metastasizes to the liver as taught by Sakaguchi to the method of treatment comprising measuring cCol I/ DDR1 in tumor samples and selectively inhibiting DDR1 or other aggressive anti-cancer therapy in PDAC patients as taught by Willumsen, Aguilera, and Vijver. The ordinary artisan would have been motivated to do so because Sakaguchi teaches that there are substantial survival benefits of conversion surgery for patients with synchronous mPDAC of the liver who responded favorably to initial chemotherapy for a certain period of time. Therefore the ordinary artisan has a reasonable expectation of success to add resection to the treatment for patients with synchronous liver metastasis of PDAC with the measurement of c Col I/ DDR1 and aggressive anti-tumor therapy.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643