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 .
1. The Amendment filed November 6, 2025 in response to the Office Action of July 8, 2025, is acknowledged and has been entered. Claims 1-20 are pending. Claims 1-20 are amended. Claims 8, 9, 18-20 remain withdrawn. Claims 1-7, 10-17 are currently being examined as drawn to the elected species of:
A. (i) first biomarker Ran protein
B. (i) second biomarker MMP2 protein; and
C. (ii) sample reference value for the biomarkers is the (ii) level of expression of the first and/or second biomarkers in a subject having invasive and/or metastatic tumor (claims 10 and 11).
New Rejection
(necessitated by amendments)
Claim Rejections - 35 USC § 112
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.
2. Claims 1-7, 10-17 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 is amended to recite the step of (v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential. Claim 1 does not identify what quantitative values of the first and second biomarkers as compared to their respective pre-determined threshold values indicate whether or not the primary tumor has invasive and/or metastatic potential. Claim 1 does not identify the basis used to provide treatment or not. Providing treatment based how on whether or not the primary tumor has invasive and/or metastatic potential? Is treatment provided when there is increased quantitative values of the first and second biomarkers as compared to their respective pre-determined threshold values, when there is decreased quantitative values of the first and second biomarkers as compared to their respective pre-determined threshold values, when there is a mix of increased and decreased values relative to thresholds? Therefore, one cannot determine when treatment is to be provided.
Although claims 12-15 identify specifically increased or decreased quantitative values of the first and second biomarker relative to the predetermined threshold to define the presence or absence of invasive and/or risk for metastatic potential, claim 1 does not identify what the basis of providing treatment is and when it should be provided. The metes and bounds of the claimed invention cannot be determined.
Maintained Rejections
(amendments are addressed)
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.
3. Claims 1-7 and 10-17 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more. The claim(s) recite(s): A method for treating a primary tumor in a subject comprising the steps of:
(i) determining a quantitative value in a sample taken from a subject of a first biomarker selected from the group consisting of Ran protein, Ran binding protein 1, an active fragment of a Ran protein, a nucleic acid sequence encoding Ran, a nucleic acid sequence encoding Ran binding protein 1, a nucleic acid sequence encoding an active fragment of Ran and a nucleic acid sequence encoding an active fragment of Ran binding protein 1;
(ii) comparing the quantitative value of the first biomarker in the sample with a selected pre-determined threshold value of the first biomarker;
(iii) determining a quantitative value in a sample from the same subject of a second biomarker selected from the group consisting of MMP2 protein, an active fragment of MMP2 protein, a nucleic acid sequence encoding MMP2 and a nucleic acid sequence encoding an active fragment of MMP2;
(iv) comparing the quantitative value of the second biomarker in the sample with a selected pre-determined threshold value of the second biomarker;
wherein the quantitative values of the first marker and the second biomarkers in the sample as compared to their respective selected pre-determined threshold values indicate whether or not the primary tumor sample has invasive and/or metastatic potential; and
(v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential.
Thus, the claims are directed to the judicial exception of detecting expression levels of Ran and MMP2 protein in a sample from a subject and correlating the levels to the invasive and/or metastatic potential of the tumor. This judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring levels of Ran and MMP2 proteins. The steps of detecting levels of Ran and MMP2 protein in tumor samples, as well as comparing to levels determined in metastatic tumors, are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)). For example, WO 2018/065771 teaches detection of both Ran and MMP2 proteins in various tumors and metastases utilizing commercially available antibodies. Deng et al (Cancer Biology & Therapy, 2014, 15:8, 1087-1093); Abe et al (International Journal of Cancer, 2008, 122:2391-2397); and Kurisetty et al (Oncogene, 2008; 27:7139-7149) teach detection of Ran protein expression levels in tumors and metastases using commercially available antibodies, and correlating increased Ran expression with increased risk of invasion and metastasis. Matsuyuma et al (Journal of Surgical Oncology, 2002; 80:105-110), Nagakawa et al (Pancreas, 2002; 24:169-178); Koshiba et al (Cancer, 1998; 82:642-650); Hao et al (Cancer, 2004; 100:1110-1122); and Garbisa et al (Cancer Research, 1992; 52:4548-4549) teach detection of MMP2 protein expression levels in tumors and metastases using commercially available antibodies, and correlating increased MMP2 expression with increased risk of invasion and metastasis. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
The step of “(v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential” recited in claim 1 is simply appending well-understood, routine, conventional activity of treating a tumor. The claimed step of “providing treatment” is specified at a high level of generality. It is a limitation that is well-understood, routine, conventional activity in the field of treating a tumor and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). The step of “providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential” recited in claim 1 is also a generic instruction to apply the judicial exception, or an insignificant extra-solution activity, and is not considered a practical application of the judicial exception. Applying or using the judicial exception to effect a particular treatment is considered a practical application, however, in the instant claims, “providing a treatment” is not considered administration of a particular treatment (see MPEP 2106.05(f)). Therefore, the judicial exception is not integrated into a practical application.
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Response to Arguments
4. Applicants argue that claim 1 is amended to recite the step of (v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential, and this step is a practical application in the method. Applicants argue the claimed method allows for a better understanding of the subject’s primary tumor and then providing the best treatment options, i.e., debilitating therapies such as surgery, chemotherapy, and radiation only when required, and non-invasive therapies when the debilitating therapies are not required). Applicants argue that this saves health care costs and provides the patient better quality of life if the invasive therapies are not needed.
Applicants argue that the practical application of claim 1 is similar to the decision in Classen Immunotherapies v. Biogen IDEC where the court found that although the analysis step was directed to a judicial exception, an additional step of immunization in accordance with a lower risk schedule provided a meaningful limitation and the claims were upheld as subject matter eligible.
5. The arguments have been considered but are not persuasive. Contrary to arguments, the step of (v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential does not provide a practical application of the judicial exception or provide a meaningful limitation.
As stated in the rejection, the step of “(v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential” recited in claim 1 is simply appending well-understood, routine, conventional activity of treating a tumor. The claimed step of “providing treatment” is specified at a high level of generality. It is a limitation that is well-understood, routine, conventional activity in the field of treating a tumor and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). The step of “providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential” recited in claim 1 is also a generic instruction to apply the judicial exception, or an insignificant extra-solution activity, and is not considered a practical application of the judicial exception. Applying or using the judicial exception to effect a particular treatment is considered a practical application, however, in the instant claims, “providing a treatment” is not considered administration of a particular treatment (see MPEP 2106.05(f)). Therefore, the judicial exception is not integrated into a practical application. Step (v) of claim 1 does not add a meaningful limitation because it does not integrate the judicial exception into a practical application (See MPEP 2106.05(e)).
The step of “(v) providing treatment based on whether or not the primary tumor has invasive and/or metastatic potential” recited in claim 1 also fails to meaningfully limit the judicial exception because it does not qualify as an additional element that is "significantly more" than the judicial exception. The fact patterns in Classen are not commensurate in scope with the instant claims, and the decision in Classen does not apply here. In Classen, the claimed method required a practical application of the judicial exception comprising the step of administering the particular treatment of infectious disease-causing organism-associated immunogens to a subject, and where administration provided the benefit of lower risk of development of chronic immune-mediated disorder(s) (i.e., (II) immunizing said subject according to a subject immunization schedule, according to which at least one of said infectious disease-causing organism-associated immunogens of said lower risk schedule is administered in accordance with said lower risk screened immunization schedule, which administration is associated with a lower risk of development of said chronic immune-mediated disorder(s) than when said immunogen was administered according to said higher risk screened immunization schedule).
MPEP 2106.05(e) states:
Classen Immunotherapies Inc. v. Biogen IDEC provides another example of claims that recited meaningful limitations. 659 F.3d 1057, 100 USPQ2d 1492 (Fed. Cir. 2011) (decision on remand from the Supreme Court, which had vacated the lower court’s prior holding of ineligibility in view of Bilski v. Kappos, 561 U.S. 593, 95 USPQ2d 1001 (2010)). In Classen, the claims recited methods that gathered and analyzed the effects of particular immunization schedules on the later development of chronic immune-mediated disorders in mammals in order to identify a lower risk immunization schedule, and then immunized mammalian subjects in accordance with the identified lower risk schedule (thereby lowering the risk that the immunized subject would later develop chronic immune-mediated diseases). 659 F.3d at 1060-61; 100 USPQ2d at 1495-96. Although the analysis step was an abstract mental process that collected and compared known information, the immunization step was meaningful because it integrated the results of the analysis into a specific and tangible method that resulted in the method "moving from abstract scientific principle to specific application." 659 F.3d at 1066-68; 100 USPQ2d at 1500-01. In contrast, in OIP Technologies, Inc. v. Amazon.com, Inc., the court determined that the additional steps to "test prices and collect data based on the customer reactions" did not meaningfully limit the abstract idea of offer-based price optimization, because the steps were well-understood, routine, conventional data-gathering activities. 788 F.3d 1359, 1363-64, 115 USPQ2d 1090, 1093 (Fed. Cir. 2015).
With respect to treatment or prophylaxis limitations, such as the immunization step in Classen, examiners should note that the other meaningful limitations consideration overlaps with the particular treatment or prophylaxis consideration that is evaluated in Step 2A Prong Two (see MPEP § 2106.04(d)(2)).
When evaluating whether additional elements meaningfully limit the judicial exception, it is particularly critical that examiners consider the additional elements both individually and as a combination. When an additional element is considered individually by an examiner, the additional element may be enough to qualify as "significantly more" if it meaningfully limits the judicial exception, and may also add a meaningful limitation by integrating the judicial exception into a practical application.
In the instant case, unlike in Classen, there is no practical application of the judicial exception because no particular treatment is being administered. Unlike in Classen, the instant claims do not recite that a particular treatment is administered to a specifically identified population that would benefit from the treatment, therefore the instant claims do not integrate the results of the analysis of Ran and MMP2 protein biomarker values into a specific and tangible method that results in the method "moving from abstract scientific principle to specific application” (See MPEP 2106.05(e)).
Applicants are arguing limitations not recited in the claims, with regard to administering surgery, chemotherapy, radiation and treating specifically identified populations that would benefit more from such therapies.
Maintained Rejection
(with additional reference added to address amendments)
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.
6. Claim(s) 1-3, 10-15, and 17 remain/are rejected under 35 U.S.C. 103 as being unpatentable over view of Deng et al (Cancer Biology & Therapy, 2014, 15:8, 1087-1093); in view of Nagakawa et al (Pancreas, 2002; 24:169-178); WO 2018/065771, El-Tanani, published April 12, 2018 (IDS); and McGuigan et al (World Journal of Gastroenterology, 2018, 24:4846-4861).
Deng teaches:
conducting an immunoassay for Ran protein expression on pancreatic tumor tissue samples from subjects, including from primary tumor, lymph node metastasis, non-distant metastasis, and distant metastasis using commercially available antibodies (Materials and Methods; Figure 1);
scoring the Ran expression levels quantitatively as 0, 1+, 2+, or 3+ (Materials and Methods “Immunohistochemistry”; Tables 1 and 2);
comparing the quantitative expression levels between the primary tumor, lymph node metastasis, non-distant metastasis, and distant metastasis (Tables 1 and 2);
determining the level of Ran protein expression is higher in metastasis compared to primary tumor, and determining upregulated Ran protein expression in tumors is significantly correlated with high metastatic potential (Results; Table 2; Discussion).
The levels of Ran protein expression determined in metastasis reasonably qualify as a “predetermined threshold value” and were used for comparison.
Deng also transfected cancer cells to express Ran, and determined that Ran expression increases cancer cells invasiveness and metastasis (p. 1088, col. 1-2; Figures 2 and 3; Discussion). Deng inhibited Ran expression in cancer cells and measured the effects on expression of other genes in response, including androgen receptor (AR), that was down regulated in response to Ran inhibition (Table 4). Deng teaches it is known AR can activate MMP2 to promote invasion and metastasis of tumors, and suggests Ran promotes invasion and metastasis of pancreatic cancer cells by enhancing AR (Discussion last paragraph on p. 1091).
Deng teaches pancreatic cancer will have progressed into advanced stage in 80-85% of the patients when first diagnosed, and local invasions and distant metastasis are the main causes of death (p. 1087, col. 1).
Deng does not teach their method further comprises conducting an immunoassay for MMP2, that the measured levels of both biomarkers can be above and/or below the threshold level associated with metastasis, providing a treatment based on whether or not the primary tumor has invasive and/or metastatic potential, and method further comprising monitoring the patient for metastasis following surgery.
Nagakawa teaches:
conducting an immunoassay for MMP2 protein expression on pancreatic tumor tissue samples from subjects without metastasis (H(-) group) and subject with metastasis (H(+) group), using commercially available antibodies (Materials and Methods);
scoring the MMP2 expression levels quantitatively as 0, 1+, 2+, or 3+, wherein 2+ and 3+ samples were labeled “positive” (+) (Materials and Methods “Evaluation of immunohistochemical staining”; Table 1);
comparing the quantitative expression levels between the H(+) tumors and H(-) tumors (Table 1);
determining the level of MMP2 protein expression is higher in the tumor of patients having metastasis (H(+)) compared to patients without metastasis (H(-)), and MMP2 expression was associated with venous invasiveness (p. 175, col. 2; Tables 5 and 6; p. 177, col. 2).
Nagakawa concludes increased expression of MMP2 in pancreatic tumors is associated with invasion and metastasis (Abstract).
Nagakawa teaches patients diagnosed with pancreatic cancer often have poor outcomes because of liver metastasis in early postoperative period and suggests improving treatment results by identifying risk factors for metastases (p. 169, col. 1).
El-Tanani teaches (p. 31, line 9): “Ran protein is known to have a role in carcinogenesis and metastasis.” El-Tanani teaches it is known Ran overexpression is observed in a number of cancers and is linked to poor prognosis. Ran overexpressing cancer cells exhibit rapid growth and high metastatic potential (p. 3, lines 19-24). It has been demonstrated that Ran gene silencing results in apoptosis of cancer cells (p. 3, lines 24-34; p. 5, lines 15 to p. 6, line 2). El-Tanani teaches based on the prior art successfully inhibiting Ran to treat cancer cells, El-Tanani suggests administering a small molecule directed at inhibiting Ran to treat cancers that have overexpression of Ran protein and that are associated with poor patient prognosis, such as Pimozide (p. 6-8; p. 14-15; claims 16-22). Ran tested treatment of cancer cells or xenograft tumors with small molecule Ran inhibitor Pimozide, and measured the effects of the inhibitor on Ran and MMP2 protein expression level utilizing commercially available antibodies, wherein Pimozide decreased levels of Ran protein (see Examples, Figure 6; p. 29-31), reduced the tumor burden in mouse xenografts, and decreased proliferation and metastasis incidence in the lung (see Examples; Figure 5; p. 29-31). El-Tanani measured RAN and MMP2 gene expression in cancer cells treated with difference concentrations of Pimozide, and determined Pimozide decreased levels of both RAN and MMP2 with increasing concertation (Figure 1D). With regard to Figure 1D, E-Tanani teaches (p. 27, lines 8-17):
“To establish the effects of pimozide treatment on Ran down stream target genes mRNA levels in cancer cells quantitative Real Time PCR (RT-PCR) experiments were performed. In more detail, MDA MB 231 breast cancer cells (Figure 1 D), were either untreated (control) or treated with 5 μΜ to 20 μΜ concentrations of pimozide. RNA was extracted from the cells after 48h and quantitative RT-PCR was then performed with a ABI PRISM 7500 instrument (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. The Taqman probe sets for RAN and its target genes and 18s RNA were used. Gene expression was normalized to 18s RNA. As can be seen a dose dependent decrease in Ran, C-MET and MMP2 mRNA in treated cells was observed indicating that pimozide decreases the transcriptional activity of RAN down stream targets.”
Thus, El-Tanani also recognizes MMP2 is a downstream target of RAN, and its expression levels correlated with RAN.
McGuigan teaches at the time of diagnosis most pancreatic adenocarcinomas have already spread beyond the pancreas and nodal metastases are not uncommon (p. 4851, col. 1). McGuigan teaches pancreatic cancer poses a significant diagnostic challenge and the majority of cases present late, with either locally advanced or metastatic disease (p. 4853, col. 1). McGuigan reviews known treatment of patients diagnosed with pancreatic cancer including for patients having metastasis and metastatic potential, comprising providing surgery and chemotherapy (p. 4855, col. 2 to p. 4856, col. 2; p. 4857, col. 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine the methods of Deng and Nagakawa. One would have been motivated to: (1) in order to perform the same function of assessing metastatic potential of pancreatic cancer with biomarker expression; (2) Deng and El-Tanani recognize that MMP2 is associated with Ran because it is a downstream target of Ran. One would have a reasonable expectation of success to given: (1) all of Deng, Nagakawa, and El-Tanani teach and successfully demonstrate utilizing commercially available antibodies to measure expression levels of Ran and MMP2 in tumor samples, including metastasis; and (2) Deng and Nagakawa successfully demonstrate that overexpression of Ran and MMP2 are indicative of invasive, metastatic pancreatic cancer.
MPEP 2144.06 states that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
In the instant case, it is prima facie obvious to combine the detection of two biomarkers, Ran and MMP2, for the same purpose of assessing risk of invasiveness/metastasis of pancreatic cancer, particularly since: (1) these two biomarkers serve the same function in the same cancer, (2) detection methods for the two proteins are established, and (3) the detection reagents are commercially available. Detection of both biomarkers, Ran and MMP2 protein, merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably identify risk of invasiveness/metastasis of pancreatic cancer through the combination of the two biomarkers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to detect various combinations of Ran and MMP2 as higher and/or lower (0, 1+, 2+, 3+) than the levels established as indicative of metastasis (claims 12-15). One would have been motivated to and have a reasonable expectation of success to given: (1) Deng and Nagakawa demonstrate successfully detecting variable expression levels of either Ran or MMP2 in pancreatic tumor samples that are the same, higher, or lower, compared to levels determined in metastatic patients, and given all of Deng, Nagakawa, and El-Tanani teach and successfully demonstrate utilizing commercially available antibodies to measure varying expression levels of Ran and MMP2 in tumor samples.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to provide treatment, surgery and chemotherapy, to the subject diagnosed with pancreatic cancer and based on whether or not the primary tumor is invasive or metastatic. One would have been motivated to and have a reasonable expectation of success to because: (1) Deng and Nagakawa recognize that pancreatic cancer is commonly already metastasized by first diagnosis and metastasized in early postoperative period, and Nagakawa suggests improving treatment results by identifying risk of metastasis; and (2) McGuigan teaches established treatments provided to patients diagnosed with pancreatic cancer and metastasis (high metastatic potential) include surgery and chemotherapy.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to monitor the patient for metastasis following surgery because: (1) McGuigan teaches surgery is established as the mainstay therapy of pancreatic cancer, and (2) Nagakawa teaches the early postoperative period often leads to liver metastasis and poor prognosis, identifying the need to monitor for metastasis after surgery.
Response to Arguments
7. Applicants argue that the combination of cited references do not teach every element of claim 1, nor do they provide a reasonable expectation of success to arrive at the claimed method.
Applicants argue that claim 1 is amended to recite treating a primary tumor. Applicants argue that “claim 1 as presented herein recites a method of treating a primary tumor that uses two biomarkers, Ran and MMP2, quantified in a primary tumor to assess the likelihood of tumor invasiveness/ metastasis well before it occurs and providing treatment based on this likelihood or potential.” Applicants argue that the claim “uses pre-determined quantitative threshold values of the biomarkers to predict long-term metastatic potential, sometimes years after remission of the primary tumor.” Applicants argue that the “cited references merely identify certain biomarkers that are correlated with tumors that are already metastatic or late-stage tumors. They do not teach or suggest using biomarker levels in primary tumors to predict future metastasis.”
8. The arguments have been considered but are not persuasive. Applicants are arguing limitations not recited in the claims. The claims do not recite determining quantitative values of Ran and MMP2 protein in a sample taken from a primary tumor. The claimed sample is “taken from a subject”. There is no claimed limitation to assay samples from the primary tumor directly. Contrary to arguments, there is no limitation requiring assessing the likelihood of tumor invasiveness/ metastasis well before it occurs. The claimed method does not exclude testing subjects who already have metastatic tumors or metastasis.
9. With regard to Deng, Applicants argue Deng teaches "the overexpression of Ran was significantly correlated with the status of metastasis." Applicants argue that this does not indicate that Ran levels in a primary tumor can be used as a predictive tool for future metastasis - it merely suggests that Ran is high in tissue that is already metastatic. Applicants argue: “instant claim 1 uses the primary tumor to predict the future outcome for the patient (i.e., invasiveness/ metastatic potential verses non-invasive/ metastatic) up to 10 to 20 years following the recovery from the primary tumor. See specification, FIG. 1 and Example 1. This allows for the further step of adapting the treatment plan according to the predicted future outcome.”
10. The arguments have been considered but are not persuasive. As stated above, Applicants are arguing limitations not recited in the claims. The claims do not require assaying primary tumor for Ran and MMP2 protein levels, and do not require testing subjects who do not have metastatic tumors or metastasis yet. Regardless, Deng does test primary tumor for Ran expression and determined that Ran was upregulated in pancreatic cancer tissues with high metastatic potential. Increasing Ran expression levels correlated with the increasing presence of distant metastasis (Table 1) and Ran expression increased in lymph node metastases (Table 2).
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Deng teaches Ran overexpression is also demonstrated as contributing to cancer cell invasion and metastastic phenotype in in renal cell and colon cancer. Deng concludes:
Discussion
One of the major hallmarks of pancreatic cancer is its systemic dissemination and extraordinary local tumor progression at early stage. Therefore, it was urgent to explore the mechanisms of pancreatic cancer metastasis. It was reported that, Ran promoted the metastasis of renal cell cancer and colon cancer. In colon carcinoma, Txl-2b could interacts with Ran via its RCC1 to regulating colon cancer cell metastasis. Ran also involved in OPN-mediated invasion and metastatic phenotype. However, the mechanism underlying Ran-mediated invasion and metastatic remains unclear.
In the present study, we found that the overexpression of Ran was significantly correlated with the status of metastasis of pancreatic cancer, and Ran was more highly expressed in lymph lode metastases than in primary tissues. These data suggested that Ran might serve as an oncogene in pancreatic cancer and played a positive role in cancer metastasis. We used wound-healing, transwell, and tail vein injection assays to observe the migration and invasion of pancreatic cancer cell lines with knockdown of Ran. In this study, we demonstrate that Ran could promote the invasion and metastasis of pancreatic cancer cells.
Deng further teaches (Discussion, p. 1091, col. 1):
As described above, we demonstrated that Ran enhanced pancreatic cancer cell invasion and metastasis and these effects were at least partly mediated by AR and CXCR4.
Thus, Deng makes clear that one of the major hallmarks of pancreatic cancer is its systemic dissemination and extraordinary local tumor progression at early stage, Ran expression is identified as a biomarker of metastasis, and increasing Ran expression enhances cancer cell invasion and metastasis and correlates to increasing metastatic potential and metastasis.
11. Applicants argue that Nagakawa does not remedy the deficiencies of Deng failing to teach detecting MMP2. Applicants argue that although Nagakawa investigated the expression of MMP2, MMP9, and VEGF in pancreatic cancer to determine vascularization and liver metastasis, Nagakawa did not conclude that increased expression of MMP2 alone is associated with invasion and metastasis. Applicants argue that Nagakawa teaches increased expression of both MMP2 and MMP9 were related to invasion in pancreatic cancers. Applicants argue that Nagakawa showed better correlation to metastasis with MMP9 than MMP2. Applicants argue that Nagakawa states that there was no significant difference in vascular density between MMP2-positive and MMP2-negative groups. And argues that Nagawaka further notes that "[b]ecause negative staining of both MMP- 2 and MMP-9 was found in four patients (22.2%) in H (+) group, we speculate that other factors besides MMP-2 and MMP-9 may also contribute to liver metastasis." See page 177, paragraph spanning column 1-2 (emphasis added). Applicants conclude that Nagawaka suggests that MMP2 would be a poor prognostic test for pancreatic cancer metastasis given its low sensitivity and selectivity. Applicants argue that one of ordinary skill in the art would not have had a reasonable expectation of success in arriving at the claimed invention, which uses MMP2 and Ran expression to predict a primary tumor's invasive and/or metastatic potential and providing treatment accordingly.
12. The arguments have been considered but are not persuasive. Nagawaka’s disclosure of additional biomarkers correlated to pancreatic cancer metastasis (i.e., MMP9) does not teach away from MMP2 disclosed as a biomarker increased in expression and correlated to invasiveness and metastasis. MPEP 2123 states:
Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." Id. at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Further, the instantly claimed method comprising the claimed steps does not exclude comprising additional steps of determining quantitative values of additional invasive/metastatic markers including MMP9.
Contrary to arguments, Nagawaka teaches MMP2 alone is a biomarker of pancreatic tumor invasiveness leading to metastasis. Nagawaka teaches invaded venous density in middle- and large-sized veins was greater in the MMP-2–positive group than in the MMP-2–negative group and that venous invasion by the tumor may be the most significant risk factor for liver metastasis (see copy and pasted sections below).
Nagawaka repeatedly teaches and demonstrates that MMP2 expression is correlated to increased invasion and metastasis and explains why MMP2 is involved in cancer cell invasion (bold emphasis added):
Abstract:
Results
Venous invasion was detected in 31 of 32 patients. Invaded venous densities of middle- and large-sized veins were significantly higher in patients with liver metastasis than in those with nonliver metastasis, and they were related to MMP-2 and MMP-9 overexpression. Invaded veins with fragmentation of the lumen through cancer cells were considered to be an intravasation of cancer (destroyed type vein), and their numbers were significantly related to liver metastasis, and MMP-2 and MMP-9 overexpression.
Conclusion
In conclusion, almost all the patients with pancreatic cancer showed venous invasion, indicating that invasion into large veins and destroyed type veins could be a risk factor for liver metastasis and that increased expression MMP-2 and MMP-9 were related to such invasion.
Page 173, col. 2:
Although there was no significant difference between groups, invaded venous density in middle- and large-sized veins was greater in the MMP-2–positive group than in the MMP-2–negative group (Table 4).
Discussion:
The first condition for generating hematogenous metastasis is vascular invasion of tumor cells at the primary focus; therefore, venous invasion by the tumor may be the most significant risk factor for liver metastasis
When tumor cells invade into the stroma and veins, it is essential to destroy basement membranes, and MMPs may be involved in this process (9). MMP-2 and MMP-9 show high activity in breaking down of type IV collagen, which is a major component of the vascular basement membrane. Therefore, MMP-2 and MMP-9 are believed to be important factors for vascular invasion of cancer (9,10). Because both proteinases are generated in tumors, fibroblasts, macrophages, and lymphocytes (27), immunohistochemical staining is useful to selectively detect MMP-2 and MMP-9 expression. In studying localization of these proteinases, Murray et al. (28) found that MMP-2 and MMP-9 were expressed in 100% of tumor cells of patients with gastric cancer and that the staining levels of the proteinases differed. In the current study, MMP-2 was stained in not only tumor cells, but also mainly in the surrounding fibroblasts. In a previous study, it was shown that an inactive precursor of MMP-2, produced by tumor stroma cells, is activated by a tumor cell-induced membrane-type MMP around the tumor, thus playing a role in cancer invasion (29). In the current study, MMP-2 was overexpressed in 13 (40.6%) of 32 patients with pancreatic cancer, and MMP-9 was overexpressed in 16 (50.0%) of 32 patients with pancreatic cancer.
The current study disclosed that significantly higher density levels of destroyed type veins were seen in patients with overexpression of MMP-2 and MMP-9, indicating the involvement of both proteinases in the metastatic process. We also found that MMP-2 and MMP-9 showed higher positive ratios in the H (+) group than those in the H (−) group. Expression of MMP-2 and MMP-9 in pancreatic cancer was strongly related to the vascular wall destruction by cancer and, of the destroyed vessels, the relatively large veins were related to liver metastasis. Because negative staining of both MMP-2 and MMP-9 was found in four patients (22.2%) in H (+) group, we speculate that other factors besides MMP-2 and MMP-9 may also contribute to liver metastasis.
Pancreatic cancer has a strong ability to invade into large veins. This suggests that liver metastasis from pancreatic cancer is more related to large venous invasion rather than to microvascular invasion and that MMP-2 and MMP-9 may be involved in this invasion process.
Thus, contrary to arguments, Nagawaka provides a clear association between increased MMP2 expression in pancreatic cancer and increasing invasive and metastatic phenotype, and provides motivation and reasonable expectation of success to detect MMP2 as a biomarker of pancreatic tumor invasiveness and metastatic potential.
13. Applicants argue that El-Tanani does not correct the deficiencies of Deng and Nagakawa. Applicants argue that El-Tanani does not teach use of Ran and MMP2 expression to predict future invasiveness/ metastatic potential of a primary tumor and providing treatment accordingly. Applicants argue that MMP2 expression was limited to studying the effects of pimozide treatment on Ran downstream targets including C-MET and MMP2. Applicants argue that El-Tahini teaches pimozide treatment inhibited Ran, C-MET, and MMP2 expression, but does not indicate that MMP2 expression can be used to predict future invasive/ metastatic potential of a primary tumor.
14. The arguments have been considered but are not persuasive. El-Tanani ties the two biomarkers Ran and MMP2 together, demonstrating MMP2 is a downstream target of Ran, and its expression levels correlated with Ran. El-Tanani demonstrates successfully detecting expression of both Ran and MMP2 in cancer cells. As stated in the rejection, El-Tanani teaches (p. 31, line 9): “Ran protein is known to have a role in carcinogenesis and metastasis” and teaches Ran overexpressing cancer cells exhibit rapid growth and high metastatic potential (p. 3, lines 19-24). El-Tanani demonstrates that in vivo tumor treatment with pimozide, a Ran inhibitor, successfully reduced tumor proliferation, reduced tumor metastasis, and decreased Ran expression levels. El-Tanani demonstrates that treating cancer cells with Ran inhibitor pimozide decreases expression levels of both Ran and MMP2. Therefore, El-Tanani demonstrates Ran and MMP2 expression are tied together and established that increasing Ran expression in cancer cells is correlated to rapid growth and high metastatic potential.
For the reasons stated above, Deng, Nagawaka, and El-Tanani provide motivation and reasonable expectation of success to measure levels of both Ran and MMP2 biomarkers in cancer, and correlate increasing expression levels to increasing invasiveness and metastatic phenotype.
15. All other 35 USC 112(b) rejections recited in the Office Action mailed July 8, 2025 are hereby withdrawn in view of claim amendments.
16. Conclusion: No claim is allowed.
Conclusion
17. 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.
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/Laura B Goddard/Primary Examiner, Art Unit 1642