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 .
Election/Restrictions
Applicant’s election of Group I (claims 3-5 and 8-17), drawn to methods involving determining SDC1 in a blood sample or fraction thereof from a subject and diagnosing, treating, and/or monitoring pancreatic cancer, in the reply filed on 08/06/2026 is acknowledged. Since Applicant did not expressly state that the election was made with traverse, the election is treated as an election without traverse. Claims 6-7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Status of the Claims
Claims 3-17 are pending. Claims 6-7 are withdrawn. Claims 3-5 and 8-17 are examined herein in view of the restriction.
Priority
The present application, filed 12/28/2023, is a 371 of PCT/IL2022/050700, filed 06/29/2022, which claims benefit of U.S. Provisional Patent Application 63/216,071, filed 06/29/2021. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 06/29/2021.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 04/29/2025 are acknowledged and have been considered.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The enablement requirement is such that the specification of the described invention in such terms that one skilled in the art can make and use the invention to ensure that the invention is communicated to the interested public in a meaningful way. (MPEP 2164)
The standard for determining whether the specification meets the enablement requirement is determined in view of the Wands factors (MPEP 2164.01(a)), to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation needed to make or use the invention based on the content of the disclosure, (2) the amount of direction provided by the inventor, (3) the existence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the level of one of ordinary skill, (7) the level of predictability in the art, and (8) the breadth of the claims. While all of these factors are considered a sufficient amount for a prima facie case are discussed below.
The breadth of the claims
Claim 4 recites a method of monitoring treatment of pancreatic cancer in a subject in need thereof, comprising treating the subject with anti pancreatic cancer therapy and determining a level of at least syndecan 1 (SDC1) in a blood sample or a fraction thereof of the subject prior to and following (a), wherein when a decrease in SDC1 is determined an efficacious treatment is indicated. The claimed function therefore is not accomplished merely by measuring SDC1. Claim 4 requires that the observed direction of the longitudinal change carry a particular clinical meaning: when a decrease in SDC1 is determined an efficacious treatment is indicated. Claim 4 does not recite a particular anti-pancreatic-cancer therapy, therapeutic mechanism, dose, treatment duration, time between therapy and the post-treatment blood measurement, magnitude of decrease required, reference interval, response criterion, tumor-response assessment, or method for distinguishing an SDC1 change caused by therapeutic response from an SDC1 change caused directly by treatment or other biological processes.
The specification confirms the breadth of anti pancreatic cancer therapy. It describes treatment as including modalities such as surgery (palliative or potentially curative), ablation or embolization treatments, radiation therapу, chemotherapy, targeted therapy (e.g., EGFRi, PARPI), immunotherapy (e.g., anti PD1 or any other checkpoint inhibitors and the like) (p. 15). Thus, the claimed relationship must be usable in the context of materially different therapeutic interventions rather than one experimentally defined treatment protocol. This breadth is important because the claim requires the skilled artisan to interpret a post-treatment SDC1 decrease as evidence of efficacy, notwithstanding that treatment itself may affect SDC1 biology, as demonstrated by the prior art below.
The nature of the invention
The invention concerns a longitudinal cancer-treatment biomarker having a functional clinical interpretation. The invention therefore requires considerably more than the technical ability to measure serum SDC1. A skilled artisan must be able to determine SDC1 before and after treatment and use the direction of that change to determine whether the pancreatic-cancer treatment was efficacious.
The amount of direction provided by the inventor / The existence of working examples
Applicant provides a textual description of the desired claim 4 method, but the experimental disclosure does not demonstrate it. This distinction is particularly clear from Applicant’s Examples. Example 1 concerns design and patient population and states that the study included subjects with newly diagnosed and histologically proven pancreatic ductal adenocarcinoma (PDAC) (p. 20). Example 1 further involves measuring serum SDC1 concentrations using human syndecan-1 enzyme-linked immunosorbent assay (ELISA) (p. 21). Those disclosures demonstrate that the skilled artisan can measure serum SDC1. They do not demonstrate that the skilled artisan can use a post-treatment decrease to determine treatment efficacy as required by claim 4.
Applicant’s subsequent Examples remain diagnostic or prognostic rather than longitudinal treatment-response experiments. Example 3 addresses serum syndecan-1 level diagnostic accuracy for PDAC (p. 23). Example 4 addresses diagnostic utility of serum syndecan-1 for PDAC staging – secondary outcome (p. 23). Example 5 addresses serum syndecan-1 for association analysis and prediction of survival (p. 24). Most significantly, Example 5 uses baseline SDC1 for prognosis. The corresponding Figure 4 is a Kaplan-Meyer survival analysis stratified according to serum syndecan-1 (ng/ml) at thresholds of <35 and ≥35; it is not a comparison of SDC1 before versus after therapy and does not establish treatment efficacy from an SDC1 decrease (Fig. 4).
The remaining drawings confirm the same evidentiary gap. Figures 1A and 1B compare control subjects with PDAC patients; Figures 2A and 2B provide ROC curves; Figure 3A compares controls and disease stages; and Figure 3B compares control, non-metastatic PDAC, and metastatic PDAC. None of Figures 1A–4 depicts a pancreatic-cancer patient’s SDC1 level before and following an anti-pancreatic-cancer therapy, much less correlates a treatment-associated decrease with independently determined treatment efficacy. Thus, the specification teaches the skilled artisan how to measure serum SDC1 and demonstrates diagnostic/prognostic associations in PDAC, but it does not experimentally teach the skilled artisan how to use a treatment-induced decrease in SDC1 to determine efficacy, which is the functional relationship that defines claim 4. This factor weighs strongly against enablement.
The state of the prior art / the level of predictability in the art
The state of the art reinforces, rather than resolves, the uncertainty left by Applicant’s disclosure. Anttonen et al. (Effect of Treatment of Larynx and Hypopharynx Carcinomas on Serum Syndecan-1 Concentrations. Journal of Cancer Research and Clinical Oncology. Vol. 132, No. 7, July 2006) is particularly informative because it actually investigated SDC1 longitudinally during cancer treatment. Anttonen studied patients having locoregional squamous cell larynx or hypopharynx carcinoma (n=44) who were treated with surgery and/or radiation therapy, and states that serum syndecan-1 (S-syndecan-1) and S-bFGF levels were measured with ELISA prior to, during, and following primary treatment of patients (Abstract, p. 451). Anttonen therefore demonstrates that longitudinal serum SDC1 measurement itself was technically feasible. It does not, however, establish that Applicant’s claimed relationship was predictable in pancreatic cancer. To the contrary, Anttonen begins from uncertainty regarding treatment effects. The authors state little is known about the effect of cancer therapy on serum syndecan-1 (S-syndecan-1) levels and the origin of soluble syndecan-1 in cancer patients is not established, and characterize the expected decrease following successful eradication of cancer as hypothetically occurring provided that at least a part of soluble syndecan-1 is shed from the tumour cells. (p. 452).
Anttonen’s actual results also demonstrate treatment- and time-dependent behavior. Although serum syndecan-1 levels decreased following locoregional treatment of cancer at three months, the investigators observed a transient rise in the serum syndecan-1 levels during the second week of radiotherapy among the patients treated with definitive radiation therapy as their primary treatment. The median pretreatment serum syndecan-1 level was 74 ng/ml prior to radiotherapy, 86.5 ng/ml during the second week of radiotherapy (P=0.0096), and 60 ng/ml 3 months following the last date of radiotherapy (P=0.0073 as compared with the baseline) (Results, p. 454; Fig. 2). Thus, even in the cancer population studied by Anttonen, the direction of the SDC1 change depended on when it was measured relative to treatment. This is directly relevant because claim 4 merely requires measurement following treatment without specifying a post-treatment interval. Moreover, Anttonen expressly cautions against assuming that the observed decrease automatically yields a clinically reliable monitoring marker. The authors report that the median S-syndecan-1 level of 58 ng/ml measured 3 months following completion of the primary therapy is only 29% less than the median pretreatment S-syndecan-1 value of 75 ng/ml, and state that the relatively small absolute difference suggests that S-syndecan-1 might not be reliable enough as a serum marker for monitoring of head and neck carcinoma patients for clinical purposes (Discussion, p. 456).
Anttonen also identifies biological confounding. The authors state that the rate of syndecan-1 ectodomain cleavage cannot be assessed by immunohistochemistry, that a high rate of syndecan-1 cleavage might result in low syndecan-1 expression levels in tumour tissue samples accompanied by high serum syndecan-1 levels, and that radiation-related effects might have influenced the syndecan-1 values measured during the radiation course (Discussion, p. 456). Finally, Anttonen explains that the association between tumor tissue syndecan-1 expression and outcome appears to vary greatly depending on the histological type of tumour (Discussion, p. 456).Accordingly, Anttonen provides evidence that (1) longitudinal SDC1 measurement was known, but (2) the biological interpretation of those measurements was cancer-, treatment-, and time-dependent. Anttonen therefore does not supply the pancreatic-cancer treatment-response teaching missing from Applicant’s disclosure.
Ramani et al. (Chemotherapy Stimulates Syndecan-1 Shedding: A Potentially Negative Effect of Treatment That May Promote Tumor Relapse. Matrix Biology. Vol. 35, April 2014) provides still more directly relevant evidence regarding the unpredictability of SDC1 following anti-cancer treatment. Ramani explains that commonly used anti-myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors and that enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death (Abstract, p. 215). Critically, this phenomenon was not confined to myeloma. Ramani expressly reports that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that treatment-induced SDC1 shedding can occur in pancreatic cancer (Abstract, p. 215). The experimental data specifically include Panc-1 pancreatic-cancer cells. Ramani reports that Panc-1, a pancreatic cancer cell line was treated with bortezomib (Bort) and doxorubicin (Dox) and that both these drugs significantly elevated the level of shed syndecan-1 in Panc-1 cells (Results §2.1, p. 216; Fig. 1E).
Ramani further determined that drug concentrations affecting tumor-cell viability elevated the level of SDC1 shedding and concluded that the process of tumor cell killing by chemotherapy leads to a burst of syndecan-1 shedding (Results §2.2, p. 216; Fig. 2A). This evidence is particularly probative of claim 4 because Applicant’s claim requires an artisan to interpret a decrease in SDC1 as indicating efficacious treatment, whereas Ramani demonstrates a mechanistically plausible circumstance in pancreatic-cancer cells in which treatment-associated tumor-cell killing is accompanied by an increase in shed SDC1. Ramani is not relied upon to establish that every successful treatment in every human pancreatic-cancer patient increases serum SDC1. Rather, Ramani establishes that the direction of treatment-associated SDC1 change is not biologically self-evident or uniformly predictable. Treatment can itself induce synthesis and shedding of SDC1, including in pancreatic-cancer cells.
The combination of Anttonen and Ramani is therefore particularly significant. Anttonen demonstrates that SDC1 can decrease months after treatment yet transiently increase during treatment, and expressly questions whether the magnitude of the decrease is reliable enough for clinical monitoring. Ramani independently demonstrates treatment-induced SDC1 shedding in pancreatic-cancer cells. Accordingly, the state of the prior art does not fill Applicant’s missing teaching. It instead provides objective evidence that treatment-associated SDC1 behavior is sufficiently complex and treatment-dependent that the claimed efficacy inference could not simply be presumed. This factor weighs strongly against enablement.
The level of ordinary skill in the art
The level of ordinary skill in the relevant art would have been relatively high (MD and/or PhD). A skilled artisan would reasonably have possessed substantial knowledge of oncology, cancer biomarkers, molecular biology, clinical pathology, immunoassay methodology, and/or pancreatic cancer. Such an artisan could readily perform the underlying laboratory operations. Applicant itself demonstrates use of ELISA to measure serum SDC1. The deficiency therefore is not technical inability to obtain an SDC1 measurement.
Rather, the missing information is the biological and clinical significance that claim 4 requires the artisan to assign to the difference between two measurements. High skill does not tell the artisan whether a post-treatment decrease signifies efficacy for the particular pancreatic cancer and treatment, what magnitude of decrease is meaningful, when the post-treatment measurement should be taken, or how treatment-induced SDC1 shedding should be distinguished from tumor-response-associated changes. Indeed, Anttonen and Ramani demonstrate that those matters cannot be resolved simply from proficiency in performing the assay. Accordingly, the high level of ordinary skill does not overcome the deficiency.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The experimentation necessary to establish and practice the claimed method would be substantial. Applicant has not supplied a pancreatic-cancer treatment-response dataset from which the skilled artisan can derive the claimed relationship. Therefore, the artisan would first have to generate the clinical evidence that the specification omits. At a minimum, the artisan would need to enroll appropriately characterized pancreatic-cancer subjects; establish pretreatment circulating SDC1 levels; administer the relevant anti-pancreatic-cancer therapy; determine appropriate post-treatment sampling intervals; repeatedly measure SDC1; independently determine therapeutic response using accepted clinical endpoints; correlate longitudinal SDC1 changes with those independently established responses; distinguish treatment-induced SDC1 release or shedding from changes caused by reduction in tumor burden; determine what magnitude of decrease is clinically meaningful rather than analytical or biological variation; and validate that relationship in an adequate patient population.
Because claim 4 does not specify the treatment modality or sampling interval, those determinations could not simply be assumed to transfer from one therapeutic setting to another. Anttonen’s results illustrate precisely why: SDC1 increased during radiotherapy but was lower 3 months after discontinuation of the primary therapy. The skilled artisan would therefore have to determine not merely how to measure SDC1, but when a decrease occurs, whether it is attributable to efficacy, and under what treatment and temporal conditions the decrease has the clinical meaning required by claim 4.
Ramani further demonstrates why this investigation is not routine confirmation of an established relationship. Because tumor-cell killing can itself produce increased SDC1 shedding in pancreatic-cancer cells, the artisan would need to experimentally distinguish competing biological effects rather than merely optimize a known assay. Such experimentation constitutes the generation and validation of the very treatment-response relationship required to make the claimed method operative, rather than routine optimization of a relationship already taught by Applicant. Considering the disclosure together with the state of the art, the quantity and nature of the experimentation required are undue.
Considering the Wands factors as a whole, claim 4 is not enabled. Applicant expressly describes the desired method, but the specification does not provide experimental evidence demonstrating the claimed treatment-monitoring relationship in pancreatic cancer. Applicant’s working examples instead concern baseline serum SDC1 in PDAC for diagnosis, staging, metastatic status, and survival. The drawings likewise contain no paired pre-treatment/post-treatment pancreatic-cancer experiment and no experimental determination that a decrease in SDC1 following treatment indicates efficacy. The state of the art does not supply the missing teaching. Anttonen demonstrates that longitudinal serum SDC1 can be measured, but also demonstrates a transient rise during radiotherapy and expressly concludes that the observed difference might not be reliable enough as a serum marker for monitoring in the cancer population studied. Ramani further demonstrates that chemotherapy can stimulate SDC1 shedding in pancreatic-cancer cells and that tumor-cell killing can produce a burst of SDC1 shedding.
Accordingly, the deficiency is not an inability to perform the SDC1 assay. Rather, the specification fails to provide sufficient teaching, supported by working evidence or predictable knowledge in the art, that would permit the skilled artisan to use a decrease in SDC1 following anti-pancreatic-cancer therapy as the claimed indicator of treatment efficacy without first undertaking substantial empirical investigation to establish the relationship itself. Therefore, given the nature of the claimed treatment-response relationship, the absence of a working pancreatic-cancer treatment-monitoring example, the limited guidance regarding treatment and sampling conditions, the treatment- and time-dependent behavior of SDC1 demonstrated by Anttonen, the treatment-induced SDC1 shedding demonstrated by Ramani in pancreatic-cancer cells, and the substantial clinical experimentation necessary to establish when a decrease in SDC1 reliably signifies treatment efficacy, claim 4 is rejected under 35 U.S.C. 112(a) for lack of enablement.
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.
Claim 5 is 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.
Regarding claim 5, the limitation “said MMP7” lacks proper antecedent basis. Claim 5 first recites “determining a level of MMP7,” but subsequently recites “wherein said level of SDC1 and said MMP7 are above a predetermined threshold.” It is unclear whether said MMP7 refers to the previously recited level of MMP7, or to MMP7 itself. Accordingly, the metes and bounds of the claim are unclear. For purposes of compact prosecution, said MMP7 will be interpreted as referring to said level of MMP97. Appropriate correction is required.
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 3–5, 8-12, and 14–17 are rejected under 35 U.S.C. 101 because the claimed inventions are directed to judicial exceptions, specifically naturally occurring biological relationships and, where applicable, mental processes, without significantly more. Claims 3, 5, 8–12, and 14-17 recite the naturally occurring relationship between an elevated level of syndecan 1 (SDC1) in a subject’s blood and the presence of pancreatic cancer, and use that biological relationship to diagnose pancreatic cancer. Claim 4 recites the naturally occurring relationship between a decrease in SDC1 following anti-pancreatic cancer therapy and an indication of treatment efficacy. The additional limitations recite obtaining or evaluating biological information, conventional laboratory measurement, broadly recited pancreatic-cancer treatment or treatment selection, patient/disease characteristics, and corroborative diagnostic information.
This rejection is made in accordance with Patent Subject Matter Eligibility as set forth in MPEP §2106. Analysis of subject-matter eligibility under 35 U.S.C. §101 requires consideration under these steps as followed:
Step 1 – Statutory Category (Refer to MPEP §2106.03): Claims 3–5, 8-12, and 14–17 are drawn to methods, which fall within the process statutory category under 35 U.S.C. §101.
Step 2A, Prong One – Recitation of a Judicial Exception (Refer to MPEP §2106.04): Regarding claim 3, the claim recites diagnosing pancreatic cancer by determining a level of SDC1 in a blood sample or fraction thereof and providing that, when the SDC1 level is above a predetermined threshold, the subject is diagnosed with pancreatic cancer. The claim therefore recites a law of nature, namely the naturally occurring biological relationship between an elevated level of SDC1 and the presence of pancreatic cancer. The SDC1 level is a biological characteristic of the subject, and the diagnostic significance attributed to a level above the predetermined threshold is based upon the natural relationship between the biomarker and the subject’s disease state. The claim does not create that biological relationship; rather, the claim detects and evaluates it.
Claim 3 additionally recites a mental process in diagnosing pancreatic cancer based upon whether the determined SDC1 level exceeds a predetermined threshold. Once the SDC1 level and predetermined threshold are available, evaluating whether the measured level is above the threshold and concluding from that comparison that pancreatic cancer is present constitute evaluation and judgment of information capable of being performed in the human mind. Accordingly, claim 3 recites both a law of nature and an abstract idea within the mental-process grouping.
Claim 4 recites treating the subject with anti-pancreatic cancer therapy, determining SDC1 in a blood sample or fraction thereof before and after treatment, and providing that when a decrease in SDC1 is determined, efficacious treatment is indicated. Claim 4 therefore recites a law of nature, namely the naturally occurring biological relationship between a decrease in SDC1 following treatment and the biological response associated with treatment efficacy. The conclusion that treatment is efficacious is drawn from observation of that naturally occurring change in the patient’s biomarker level. Claim 4 additionally recites mental evaluation because, once the pre-treatment and post-treatment SDC1 values are available, determining whether the level decreased and assigning treatment efficacy based upon that decrease constitute evaluation and judgment of biological information.
Claim 5 incorporates the judicial exceptions of claim 3 and further requires determining a level of MMP7 and diagnosing the subject when the recited biomarker levels are above predetermined thresholds. The additional biomarker measurement supplies further naturally occurring biological information used in the same diagnostic determination. Evaluating multiple naturally occurring biomarker levels against predetermined thresholds does not remove the underlying SDC1/pancreatic-cancer relationship or the recited evaluation of biological information.
Claim 8 limits the pancreatic cancer of claim 3 to pancreatic ductal adenocarcinoma (PDAC), but retains the same naturally occurring relationship between elevated SDC1 and the presence of the recited pancreatic malignancy and the same threshold-based diagnostic evaluation. Claim 9 specifies that the determined SDC1 level is a protein level. This limitation further identifies the biological information being measured but leaves unchanged the natural relationship between elevated SDC1 and pancreatic cancer and the diagnostic evaluation based upon that relationship. Claim 10 specifies that the protein level is determined by ELISA. ELISA is the physical laboratory technique by which the SDC1 information subsequently evaluated under the recited biological relationship is acquired. The limitation does not remove the naturally occurring SDC1/pancreatic-cancer relationship or the diagnostic evaluation from the claim. Claim 11 specifies that the pancreatic cancer is KRAS+. This limitation further characterizes the pancreatic cancer population to which the claimed natural relationship is applied but retains the naturally occurring SDC1/disease relationship and threshold-based diagnostic evaluation.
Claim 12 specifies that the pancreatic cancer is resectable. This limitation further characterizes the disease state of the diagnosed subject but retains the same naturally occurring biomarker/disease relationship and diagnostic evaluation. Claim 14 specifies that the location of the cancer is in the head of the pancreas. The anatomical limitation further characterizes the pancreatic cancer but does not alter the naturally occurring relationship between circulating SDC1 and the subject’s disease or the threshold-based diagnostic evaluation. Claim 15 adds corroboration of the pancreatic cancer or treatment thereof with imaging or molecular markers. The corroborative information provides additional biological or clinical information for evaluating the same diagnosis or treatment but does not remove the underlying naturally occurring SDC1 relationship or the evaluation of that information.
Claim 16 specifies that the molecular markers comprise HPA, MMP, and CA 19-9. These limitations add further naturally occurring biological information as inputs to the corroborative assessment but retain the same SDC1/pancreatic-cancer relationship and evaluation of biological information. Claim 17 limits the subject by excluding autoimmune disease, systemic active infectious disease, and/or extra-pancreatic malignancy. This limitation defines the patient population in which the SDC1 relationship is evaluated but does not alter the underlying naturally occurring relationship or the threshold-based diagnostic determination. Accordingly, claims 3–5, 8-12, and 14–17 recite judicial exceptions in the form of laws of nature and, where applicable, mental processes.
Step 2A, Prong Two – Integration into a Practical Application (Refer to MPEP §2106.04 (d)): Regarding claim 3, the additional physical activity includes obtaining biological information by determining an SDC1 level in a blood sample or fraction thereof and, after the diagnostic determination, broadly treating the diagnosed subject with an anti-pancreatic cancer therapy or merely selecting such a treatment. Determining the SDC1 level supplies the biological information necessary to observe and apply the natural relationship. The claim does not recite an improvement to a blood assay, SDC1-detection technology, sample-processing technique, or other technological process. Rather, the measured SDC1 level supplies the information upon which the natural correlation and threshold-based diagnostic evaluation operate.
The recitation of an anti-pancreatic cancer therapy also does not meaningfully integrate the exception into a practical application as claimed. The limitation does not require a particular drug, dose, regimen, surgical procedure, radiation protocol, or other particular therapeutic intervention selected as a consequence of a particular SDC1 result. Instead, the claim encompasses treating the diagnosed subject with the broad class of anti-pancreatic cancer therapy or, alternatively, merely selecting a treatment. Thus, the natural relationship is used to reach a pancreatic-cancer diagnosis and is then followed by a broadly stated instruction to treat or select treatment, rather than being applied through a particular treatment limitation that meaningfully confines the natural relationship.
Claim 4 likewise does not integrate the judicial exception into a practical application. The broadly recited anti-pancreatic cancer therapy is administered before the claimed biomarker comparison is made. The subsequent determination of SDC1 before and after therapy is used to observe whether SDC1 decreases and thereby infer whether the already-administered treatment was efficacious. The claim does not require changing, discontinuing, increasing, decreasing, or otherwise modifying treatment responsive to the SDC1 result. Thus, the treatment step does not apply the subsequently determined SDC1 relationship to effect a particular therapeutic intervention; rather, the biomarker measurements are used to evaluate treatment efficacy through the recited natural relationship.
Claim 5’s additional MMP7 determination supplies another biological measurement for the diagnostic evaluation. It does not require a technological improvement or a particular treatment responsive to the resulting biomarker information. Claims 8, 11, 12, 14, and 17 further define the cancer or patient as PDAC, KRAS+, resectable, located in the head of the pancreas, or lacking specified other diseases. These limitations narrow the population or disease context in which the natural relationship is applied, but they do not change how the SDC1 level is determined or require a particular therapeutic action dictated by the SDC1 result.
Claims 9 and 10 specify measurement of SDC1 protein and use of ELISA. These limitations concern acquisition of the biological information required for application of the natural relationship. Claim 10 does not recite an improved ELISA architecture, reagent, detection mechanism, or assay operation. ELISA therefore functions as the mechanism for obtaining the SDC1 value that is subsequently evaluated under the judicial exception rather than as a technological improvement attributable to the claimed method.
Claims 15 and 16 add corroboration using imaging or molecular markers, including HPA, MMP, and CA 19-9. These limitations provide further clinical or biological information for the diagnostic or treatment assessment. They do not require a particular treatment responsive to the corroborative result, improve the operation of the imaging or molecular-marker technology, or otherwise transform the natural relationship into a different technological process.
When claims 3–5, 8-12, and 14–17 are considered as a whole, the additional limitations therefore obtain or refine biological information, define the patient or disease population, corroborate the resulting assessment, or append broadly recited treatment or treatment-selection activity. They do not meaningfully apply the recited natural relationships through a particular technological improvement or sufficiently particular therapeutic intervention. Accordingly, the judicial exceptions are not integrated into a practical application.
Step 2B, Inventive Concept (Refer to MPEP §2106.05): The additional elements are considered individually and as an ordered combination to determine whether they amount to significantly more than the judicial exceptions. One consideration is whether the additional elements constitute well-understood, routine, conventional activities previously engaged in within the relevant field. The references discussed below are relied upon for this limited Step 2B purpose to demonstrate the conventional nature of the additional laboratory, treatment, imaging, staging, and biomarker-assessment activities, and not to establish the judicial exceptions themselves.
Regarding claims 3, 9, and 10, determining SDC1 protein in a blood-derived sample, including by ELISA, does not supply an inventive concept. Anttonen et al. reports that peripheral venous blood samples were collected in sterile test tubes, centrifuged at 3,000 G for 10 min and serum syndecan-1 concentrations were determined using human syndecan-1 enzyme-linked immunosorbent assay (ELISA) (p. 452). Anttonen further reports that the assay uses a biotinylated monoclonal B-B4 antibody raised against human syndecan-1 (p. 452). Thus, obtaining serum from blood and determining SDC1 protein by ELISA were previously practiced laboratory activities and do not provide an inventive concept separate from the claimed biological relationship.
Claim 4’s pre- and post-treatment SDC1 measurements likewise do not supply significantly more. Anttonen expressly states that S-syndecan-1 and S-bFGF levels were measured with ELISA prior to, during, and following primary treatment of patients (p. 451), and that the serum syndecan-1 levels were determined from samples taken prior to cancer treatment (baseline samples), during the second week of radiotherapy, 3 months after completion of the primary treatment, at the time of disease locoregional recurrence, and 6 months following treatment of recurred cancer (p. 453). Thus, longitudinal measurement of serum SDC1 before and after cancer treatment by ELISA was previously practiced laboratory activity surrounding the claimed biological inference.
The broadly recited anti-pancreatic cancer treatment activity likewise does not supply an inventive concept. Tempero et al. (Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network, Vol. 15, No. 8, August 2017) teaches that systemic therapy is used in all stages of pancreatic cancer, including neoadjuvant (resectable or borderline resectable), adjuvant, locally advanced unresectable, and metastatic disease and that close follow-up of patients undergoing chemotherapy is indicated (p. 1042). Tempero further identifies established treatment options including FOLFIRINOX ± subsequent chemoradiation and Gemcitabine + albumin-bound paclitaxel ± subsequent chemoradiation (p. 1042). Khorana et al. (Potentially Curable Pancreatic Adenocarcinoma: ASCO Clinical Practice Guideline Update. Journal of Clinical Oncology. Vol. 37, No. 23, August 2019) similarly states that all patients with resected pancreatic adenocarcinoma who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy in the absence of medical or surgical contraindications and identifies 5-fluorouracil, oxaliplatin, and irinotecan (mFOLFIRINOX), gemcitabine and capecitabine, and gemcitabine alone or fluorouracil plus folinic acid alone as treatment options (p. 2082). Accordingly, the generic recitation of anti-pancreatic cancer therapy does not itself provide an inventive concept.
Claims 8 and 12’s limitations to PDAC and resectable pancreatic cancer do not alter this conclusion. Khorana teaches that primary surgical resection of the primary tumor and regional lymph nodes is recommended for patients with potentially curable pancreatic cancer satisfying specified clinical criteria (Table 1, p. 2084), while Tempero expressly addresses systemic therapy for resectable or borderline resectable pancreatic cancer (p. 1042). These limitations therefore further define the clinical setting in which the judicial exception is applied rather than adding an unconventional technological activity.
Claims 14–16 likewise do not supply significantly more through anatomical location, imaging, or molecular-marker corroboration. Tempero teaches that patients with clinical suspicion of pancreatic cancer should therefore undergo initial evaluation by CT performed according to a dedicated pancreas protocol and identifies Multidetector CT angiography as the preferred imaging tool for dedicated pancreatic imaging (p. 1045). Tempero also incorporates preoperative CA 19-9 into pancreatic-cancer assessment (p. 1030). Khorana similarly identifies high-definition cross-sectional imaging and a CA 19-9 level (in absence of jaundice) suggestive of potentially curable disease as clinical criteria for potentially curable pancreatic cancer (Table 1, p. 2084). Thus, imaging and CA 19-9 assessment constitute established clinical activities and do not provide an inventive concept.
Claim 5’s additional MMP7 measurement and claim 16’s HPA, MMP, and CA 19-9 limitations merely add biomarker information to the diagnostic or corroborative assessment. Likewise, claims 11, 14, and 17’s limitations concerning KRAS+ pancreatic cancer, cancer located in the head of the pancreas, and exclusion of subjects having specified additional diseases further define the disease or patient population. These limitations do not recite an improved assay, unconventional treatment procedure, or other technological improvement and therefore do not provide significantly more.
When the additional limitations of claims 3–5, 8-12, and 14–17 are considered as an ordered combination, the claims still amount to obtaining blood-derived biomarker information, determining SDC1—including by ELISA—evaluating that information under the recited natural relationship, optionally adding biomarker or imaging information or defining the patient/disease population, and broadly treating or selecting treatment for pancreatic cancer. Anttonen demonstrates previously practiced serum SDC1 measurement by ELISA, including before and after cancer treatment, while Tempero and Khorana demonstrate established pancreatic-cancer treatment, imaging, resectability assessment, and biomarker evaluation. The claimed combination does not recite an unconventional assay architecture, improved detection or imaging technology, or a sufficiently particular therapeutic intervention dictated by the SDC1 result. Accordingly, considered individually and as an ordered combination, the additional elements do not provide an inventive concept sufficient to transform the claimed judicial exceptions into patent-eligible subject matter.
Ultimately, claims 3–5, 8-12, and 14–17 are therefore rejected under 35 U.S.C. 101 because the claimed inventions are directed to laws of nature and, where applicable, abstract ideas, without additional elements that integrate the judicial exceptions into a practical application or amount to significantly more than the exceptions themselves.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 3, 8–13, and 15–17 are rejected under 35 U.S.C. 103 as being unpatentable over Kumaki et al. (US 2020/0408769 A1) in view of Ankeny et al. (Circulating Tumour Cells as a Biomarker for Diagnosis and Staging in Pancreatic Cancer. British Journal of Cancer. Vol. 114, No. 12, June 2016) and Chaganty et al. (US 20200392241 A1 – IDS dated 02/04/2024)
Regarding claim 3, for (a) diagnosing pancreatic cancer in the subject by determining a level of at least syndecan 1 (SDC1) in a blood sample or a fraction thereof of the subject, Kumaki teaches that samples include whole blood collected from a patient, components derived from whole blood, such as serum, plasma, cord blood, or blood component fluid, and fractions containing a tumor cell ([0030], p. 2). Kumaki further teaches that the tumor cell is detected based on the expression level of any of the polypeptides (i) to (iii) or the gene encoding the polypeptide derived from the tumor cell, and that detection may be performed quantitatively based on the number of tumor cells or detected intensity ([0033], p. 2). Kumaki identifies the polypeptide consisting of the amino acid SEQ ID NO:3 a protein called SDC1 (Syndecan 1) ([0038], pp. 2-3), and teaches that SDC1 protein (SEQ ID NO: 3) is expressed in pancreatic cancer cells ([0154], p. 12, Table 11).
More specifically, Kumaki investigates whether SDC1 can be used for specific detection of breast cancer cells and pancreatic cancer cells contained in a blood sample ([0155], p. 12). Importantly, Kumaki’s experimental pancreatic-cancer blood sample is a spiked blood sample rather than blood obtained from a pancreatic-cancer patient. Specifically, Kumaki teaches that blood was collected from a healthy individual, erythrocytes were removed from the blood, and the sample was spiked with human pancreatic cancer (ASPC-1), and the resulting sample was subjected to SDC1-based detection ([0155]–[0160], pp. 12–13, Fig. 13). Kumaki concludes from this experiment that SDC1 (SEQ ID NO: 3) can be used as a tumor marker for detection of breast cancer cells and pancreatic cancer cells contained in a blood sample in distinction from leukocytes contained in the sample ([0160], pp. 12–13, Fig. 13).
Regarding wherein when said level of SDC1 is above a predetermined threshold, Kumaki teaches that a cell may be judged as a tumor cell when the detection signal is not weaker than a certain threshold and alternatively when the signal is not weaker than a certain value relative to a signal from a contaminant cell contained in the sample or when the signal is not less than 2SD, 3SD, or 4SD from the average of the signal from such contaminant cells ([0033], p. 2). Kumaki further determines SDC1 expression according to fluorescence-signal intensity and teaches that the higher the intensity of the signal, the higher the expression (signal intensity (expression level) ([0154], p. 12, Table 11).
Kumaki additionally provides an express reason to pursue clinical use of its tumor-cell detection method because Kumaki explains that the tumor cell that circulates in blood is also called CTC (Circulating Tumor Cell) and that the number of CTCs contained in blood collected from a patient is counted or protein expression in the CTCs is investigated to provide information related to prediction of prognosis or cancer recurrence in the patient ([0002], p. 1). Thus, Kumaki expressly places its tumor-cell detection technology in the context of obtaining clinically useful information from CTCs in patient blood, while experimentally establishing that SDC1 can discriminate pancreatic cancer cells from leukocytes in a blood matrix.
However, Kumaki does not expressly teach diagnosing the subject with pancreatic cancer when the determined SDC1 level is above the predetermined threshold. Kumaki also does not expressly teach treating the subject diagnosed with pancreatic cancer with, or selecting for that subject, an anti-pancreatic-cancer therapy following such diagnosis.
Ankeny teaches the clinical patient-level diagnostic use missing from Kumaki. Ankeny teaches that venous blood (VB) was collected prospectively from 100 consecutive, pre-treatment patients with PDAC, that the blood samples were evaluated for the presence and number of CTCs,, and that CTC enumeration data was then evaluated as a diagnostic and staging biomarker in the setting of PDAC (p. 1367). Ankeny reports CTCs in 54 of 72 patients with confirmed PDAC, with 75.0% sensitivity, 96.4% specificity, and AUROC 0.867, and concludes that CTCs appear to function well as a biomarker for diagnosis and staging in PDAC (p. 1367). Ankeny further expressly states that its purpose was to evaluate CTCs as a biomarker for diagnosis and staging of PDAC at the time of disease presentation (p. 1368). Ankeny also provides particularly relevant support for translating Kumaki’s spiked-blood experiment to patient blood. Before applying its CTC assay to patient samples, Ankeny itself performed blood-matrix optimization wherein PDAC cells were spiked in healthy donor blood to create artificial blood samples and thereafter successfully applied the CTC assay to venous blood obtained from actual PDAC patients (p. 1368). Thus, Ankeny provides a direct example of progressing from a healthy-donor spiked-blood pancreatic-cancer-cell model, like that used by Kumaki, to clinical detection of pancreatic CTCs in patient blood.
Chaganty teaches the cancer is a pancreatic cancer, that CD138 (also known as Syndecan 1) is expressed in pancreatic cancer, and that anti-CD138 antibody molecules may be used alone or in combination with a second therapeutic agent, procedure, or modality to treat a pancreatic cancer ([0599], pp. 68-69). Chaganty expressly identifies that the anti-CD138 antibody molecule is used in combination with a surgery, ablation, embolization, a radiation therapy, or a chemotherapy (cemcitabine, 5-flurouracil (5-FU), irinotecan, oxaliplatin, albumin-bound paclitaxel, capecitabine, cisplatin, paclitaxel, docetaxel, or irinotecan liposome ([0599], pp. 68-69). Chaganty additionally teaches that its CD138 detection or diagnostic methods may be used in combination with methods for treating or preventing the disclosed disorder ([0669], p. 73).
Therefore, 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 modify Kumaki’s method of determining SDC1 expression and applying an SDC1 detection threshold to pancreatic cancer cells in a blood matrix by applying that SDC1-based pancreatic CTC detection to blood obtained from a subject and using an SDC1-threshold-positive pancreatic CTC result as diagnostic information for pancreatic cancer in that subject, as taught by Ankeny, and thereafter treating the diagnosed subject with, or selecting, a pancreatic-cancer therapy as taught by Chaganty. A skilled artisan would have been motivated to make the first modification because Kumaki expressly identifies CTC analysis in patient blood as clinically informative and experimentally demonstrates that SDC1 distinguishes pancreatic cancer cells from leukocytes in healthy-donor blood artificially containing pancreatic cancer cells, while Ankeny expressly teaches that pancreatic CTCs detected in actual patient venous blood function as a diagnostic biomarker for PDAC. Ankeny additionally provides a direct technical bridge for the modification because Ankeny itself first used PDAC cells spiked in healthy donor blood to create artificial blood samples to optimize its CTC detection approach and thereafter successfully applied the approach to actual patient venous blood for PDAC diagnosis. Thus, a skilled artisan would have had both a reason and a reasonable expectation of success in progressing Kumaki’s SDC1 pancreatic-cancer-cell detection from its spiked-blood model to patient blood for the clinical diagnostic purpose expressly taught by Ankeny. A skilled artisan would further have been motivated to act on the resulting pancreatic-cancer diagnosis using Chaganty’s pancreatic-cancer therapies because Ankeny identifies improved diagnosis and accuracy of staging at the time of disease presentation as useful to better inform first-line therapy, and Chaganty expressly supplies known treatment modalities for pancreatic cancer. The proposed modification therefore follows the express clinical direction and experimental progression, and there would have been a reasonable expectation that the modification would predictably provide diagnostically useful pancreatic CTC information and permit selection or administration of established pancreatic-cancer treatment.
Regarding claim 8, Ankeny expressly teaches pancreatic ductal adenocarcinoma (PDAC) and evaluates blood CTCs as a diagnostic biomarker specifically in PDAC patients (p. 1367). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to apply the Kumaki-Ankeny-Chaganty method specifically to PDAC because Ankeny expressly identifies PDAC as the pancreatic cancer for which blood CTC detection provides diagnostic information. A skilled artisan would reasonably have expected success because Ankeny actually demonstrated diagnostic CTC detection in confirmed PDAC patients rather than merely proposing such use.
Regarding claim 9, Kumaki expressly teaches that SDC1 protein (SEQ ID NO: 3) is expressed in pancreatic cancer cells and determines SDC1 expression using an anti-SDC1 antibody ([0152]–[0160], p. 12, Table 11).
Regarding claim 10, Chaganty teaches CD138/SDC1 detection and expressly teaches that conventional detection assays include an enzyme-linked immunosorbent assays (ELISA) and further teaches determining the amount of CD138 in the sample by immunoassay ([0668], p. 73). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify Kumaki’s SDC1 protein determination by employing Chaganty’s ELISA detection technique because Chaganty expressly identifies ELISA as a conventional assay for detecting the same protein, CD138/SDC1, and determining its amount in a biological sample. A skilled artisan would reasonably have expected success because Chaganty expressly teaches ELISA for the same analyte being detected by Kumaki, such that the modification applies an established SDC1/CD138 detection technique for its known analytical purpose.
Regarding claim 11, Ankeny teaches that KRAS mutations occur in >95% of PDAC and that 98% of the KRAS mutations found in PDAC are located in codon 12 (p. 1368). Ankeny further experimentally identified codon-12 activating KRAS point mutations in captured PDAC CTCs and used KRAS analysis to establish pancreatic tumor origin (p. 1371). Ankeny found 100% concordance for KRAS mutation subtype between primary tumour and CTCs in all five patients tested (p. 1367). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to practice the method in a subject having KRAS-positive pancreatic cancer because Ankeny expressly identifies KRAS mutation as a highly prevalent molecular feature of PDAC and uses KRAS mutation to validate the pancreatic origin of detected CTCs. A skilled artisan would reasonably have expected success because Ankeny experimentally demonstrated concordance between KRAS mutation subtype in pancreatic CTCs and primary tumor tissue
Regarding claim 12, Ankeny teaches patients initially believed to be resectable based on imaging are found to have metastases at surgical exploration and explains the clinical importance of determining resectability and staging before treatment (p. 1368). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to apply the Kumaki-Ankeny-Chaganty diagnostic method to subjects presenting with resectable pancreatic cancer because Ankeny expressly identifies patients believed to have resectable disease as part of the clinical setting in which improved pancreatic-cancer biomarkers are needed to improve staging and inform treatment. A skilled artisan would reasonably have expected success because Ankeny evaluated CTCs at disease presentation across PDAC stages and demonstrated diagnostic discrimination using patient venous blood.
Regarding claim 13, Chaganty expressly teaches treating pancreatic cancer with therapeutic procedures and specifically identifies surgery as a treatment modality for pancreatic cancer ([0599], p. 69). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to select surgery as the anti-pancreatic-cancer therapy following diagnosis because Chaganty expressly teaches surgery as a pancreatic-cancer treatment modality, while Ankeny teaches that improved diagnosis and staging at disease presentation are useful for informing first-line therapy. A skilled artisan would reasonably have expected success in selecting surgery for an appropriately staged pancreatic-cancer patient because surgery was an established therapeutic option for such disease and the modification concerns selection of an established treatment based upon the clinical diagnosis rather than alteration of the underlying SDC1 detection method.
Regarding claim 15, Ankeny teaches inclusion of patients having suspicious pancreatic lesions based on cross-sectional imaging or recent diagnosis of PDAC by biopsy and teaches that all PDAC diagnoses were confirmed via biopsy or surgical pathology (p. 1368). Ankeny additionally teaches molecular analysis using KRAS mutations in captured CTCs and comparison with primary tumor tissue (pp. 1367, 1371). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to corroborate the blood-based pancreatic-cancer assessment using imaging and/or molecular markers because Ankeny expressly employs cross-sectional imaging and KRAS molecular analysis in conjunction with pancreatic CTC assessment to establish disease status and tumor origin. A skilled artisan would have been motivated to use these complementary modalities to increase confidence that the detected CTCs represent pancreatic malignancy, with a reasonable expectation of success because Ankeny actually employed these complementary approaches in PDAC patients.
Regarding claim 16, Ankeny expressly teaches that CA19-9 values were recorded when available in the PDAC patient cohort ( p. 1368). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to use CA19-9 as the molecular marker for corroborating the pancreatic-cancer assessment because Ankeny expressly measures CA19-9 in the same PDAC patient population evaluated using its CTC assay. A skilled artisan would have been motivated to use CA19-9 as complementary molecular information for pancreatic-cancer assessment and would reasonably have expected success because CA19-9 was already being clinically measured in the PDAC patients evaluated by Ankeny.
Regarding claim 17, Ankeny further teaches selecting a PDAC patient population that does not suffer from an extra-pancreatic malignancy. Specifically, Ankeny teaches that exclusion criteria included previous PDAC-directed treatment of any kind (surgical or non-surgical), active inflammatory bowel disease, synchronous malignancies, or other malignancy in the past 5 years (p. 1368). Ankeny further reports that patients were excluded from the study for concurrent second malignancy (p. 1369). Thus, Ankeny teaches selecting pancreatic cancer subjects who do not suffer from an extra-pancreatic malignancy. Therefore, 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 apply Ankeny’s patient-selection criterion to the method of Kumaki as modified by Ankeny and Chaganty because Ankeny expressly applies the exclusion of subjects having synchronous or other malignancies to the PDAC patient population used for pancreatic-cancer diagnosis. One of ordinary skill in the art would have had a reasonable expectation of success because Ankeny actually employed this exclusion criterion in its PDAC diagnostic study, thereby providing a known patient-selection protocol for evaluating pancreatic cancer in the claimed subject population.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Kumaki et al., Ankeny et al., and Chaganty et al., as applied to claim 3 above, and further in view of Park et al. (Serum CA19-9, Cathepsin D, and Matrix Metalloproteinase-7 as a Diagnostic Panel for Pancreatic Ductal Adenocarcinoma. Proteomics. Vol. 12, Nos. 23-24, December 2012)
With respect to the teachings of Kumaki, Ankeny, and Chaganty, refer to the discussion above, which equally applies here. However, the combination does not expressly teach or specify additionally determining an MMP7 blood level and requiring the MMP7 level to exceed a predetermined threshold.
Park teaches the relevant additional blood biomarker. Park measured serum levels of MMPs including MMP-7 in 248 PDAC patients and 216 controls and found that the concentrations of cathepsin D and MMP-7 were significantly higher in PDAC subjects than control subjects (p. 3590). Park further teaches that the threshold of each marker was defined to maximize sensitivity and specificity (p. 3592) and reports an MMP-7 cutoff of 2080 pg/mL (Table 2, p. 3594). Figure 1 expressly identifies cut-off levels for MMP-7 (2080 pg/mL) and states that “positive” indicates values that were higher than cut-off levels (Park, Fig. 1, p. 3594).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to further modify the Kumaki-Ankeny-Chaganty method by additionally determining serum MMP-7 and comparing the MMP-7 level with a predetermined diagnostic threshold as taught by Park. A skilled artisan would have been motivated to make the modification to strengthen blood-based pancreatic-cancer discrimination because Park expressly teaches that alternative and/or additional markers are therefore needed and experimentally identifies MMP-7 as an additional serum marker for PDAC. Park further demonstrates that combining biomarkers improves diagnostic performance, providing a reason to supplement rather than replace the existing pancreatic-cancer biomarker determination. A skilled artisan would have reasonably expected success because Park experimentally established MMP-7 thresholds in PDAC patient serum and applied the resulting marker cutoffs to an independent validation cohort.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Kumaki et al., Ankeny et al., and Chaganty et al., as applied to claim 3 above, and further in view of Ducreux et al. (Cancer of the Pancreas: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Annals of Oncology. Vol. 26, No. suppl 5, September 2015)
With respect to the teachings of Kumaki, Ankeny, and Chaganty, refer to the discussion above, which equally applies here. However, the combination does not expressly teach or specify that the pancreatic cancer is to be located in the pancreatic head.
Ducreux teaches that approximately 60%–70% of pancreatic cancer arises in the head of the pancreas and distinguishes tumors of the head from tumors of the body and tail (p. v57). Ducreux further teaches that the location and the size of the tumour determine the type of surgery, and patients with tumours in the head of the pancreas are treated with pancreatoduodenectomy (Whipple procedure) (p. v60).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to further apply the Kumaki-Ankeny-Chaganty method to a subject whose pancreatic cancer is located in the head of the pancreas because Ducreux establishes that the pancreatic head is the predominant anatomical location of pancreatic cancer and expressly links tumor location to clinical management. A skilled artisan therefore would have had reason to apply the blood-based diagnostic method to this recognized and prevalent pancreatic-cancer subgroup. A skilled artisan would reasonably have expected success because restricting the patient population to pancreatic-head cancer does not alter the SDC1/CTC blood-detection mechanism, and Ducreux establishes pancreatic-head tumors as an ordinary clinical presentation with established diagnostic and treatment pathways.
Conclusion
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 28, 2026
