DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments and Arguments
2. Claims 1, 2, 4, 6-17, 19, 21-33, 35, 37, 60, 62-64, 67, 69-73, 75, 77-91 and 93-100 are pending.
Claim 29, drawn to non-elected inventions and non-elected species withdrawn from examination.
Claims 65 and 92 have been cancelled.
Claims 1, 2, 6, 19, 37, 60, 62, 63, 69-71, 77, 88, 89, 93 and 99 have been amended.
Claims 1, 2, 4, 6-17, 19, 21-28, 30-33, 35, 37, 60, 62-64, 67, 69-73, 75, 77-91 and 93-100 are examined on the merits with species,
(detected biomarker): c. thrombospondin 2 (THBS2) and CA19-9; and (detected molecule): protein.
New and Maintained Grounds of Rejection
Claim Rejections - 35 USC § 112
3. 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.
4. The rejection of claims 1, 2, 4, 6-17, 19, 21-28, 30-33, 35, 37, 60, 62-64, 67, 69-73, 75 and 77-87 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 is maintained and made. Claim 65 has been cancelled.
a. Independent claims 1, 2, 19, 60, 62, 63, 70 and 71 continue to read on methods of diagnosing pancreatic cancer, predisposition for developing pancreatic cancer, improving the efficacy of anti-cancer treatment for pancreatic cancer and treating pancreatic cancer based on detecting a combination of values of both, THBS2 protein and CA19-9 protein concentrations within a subject’s biological sample, as compared with a concentration cutoff value for either THBS2 or CA19-9 is indicative of the method endpoint, i.e. positive diagnosis, improved success of the treatment.
Applicant asserts with the amendment to the said claims reading on comparison of both proteins, THBS2 and CA19-9 to their recited cutoff values, this instant rejection has been overcome, see Remarks submitted December 15, 2025, paragraph (para.) bridging pages 12 and 13.
Applicant’s assertion has been carefully considered, but fails to persuade.
Applicant has now amended independent claim 60 to have the same issue as the other independent claims with the inclusion of “or”. More specifically, the preamble and/or the first step of each independent claim reads on determining the concentration or detecting both proteins, THBS2 and CA19-9. However, further steps set forth utilizing the concentration or detection of just one of the two proteins. Consequently, the issue continues to exist, wherein, it is not clear if the measure, comparison and/or difference in concentration and detection is between just one protein biomarker or two protein markers is required to meet the method endpoint(s).
In the absence of clarity, one of ordinary skill in the art cannot arrive at a definitive diagnosis of pancreatic cancer, determining the predisposition for developing pancreatic cancer, nor efficacy of anti-cancer treatment and additional method endpoints. Accordingly, the metes and bounds continue not to be able to be determined.
Claim Rejections - 35 USC § 101
5. 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.
6. The claimed invention (claims 1, 2, 4, 6-17, 19, 21-28, 30-33, 35, 37, 60, 62-64, 67, 69-73, 75, 77-91 and 93-100) is directed to a judicial exception and/or natural phenomenon without significantly more. Claims 65 and 92 have been cancelled.
Applicant argues the Office takes a 180 degree turn with the reintroduction of this rejection, see Remarks submitted December 15, 2025, page 13. Applicant further argues the rejection does not explain the change in position and continues to assert how their present invention does not exemplify a natural principle, nor directed to a natural principle, see pages 13-18 of the Remarks.
Applicant’s arguments and points of view have been carefully, considered but fail to persuade.
The 101 was reintroduced and made because of the indefiniteness of the claim language as emphasized in the pending 112(b), wherein the methods do not set forth definitive and clear methods steps that will yield the method endpoint(s). Moreover, the judicial exception is not integrated into a practical application when the anti-cancer treatment is generic, different and broader than the law of nature. These treatment steps are not a practical application of the law of nature. And while these limitations do indicate that a treatment is to be administered, they do not clearly provide any information as to what the general, altered and/or modified anti-cancer treatment is. In fact, this limitation is recited at such a high level of generality that it does not even require a clinician to take into account the outcome of the measure of either protein when deciding the unnamed anti-cancer treatment to administer, making the limitation’s inclusion in these claims at best nominal. Hence, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Accordingly, the rejection is maintained and made.
Claim(s) 1, 19, 62, 63, 70, 71 and 88 recite(s) methods of diagnosing pancreatic cancer, a predisposition for developing pancreatic cancer or treating pancreatic cancer comprising determining the concentration of both, THBS2 protein and CA19-9 protein in an individual’s biological sample, wherein an increase in the combination of values of the concentration of said combination as compared with a concentration cutoff value for THBS2 protein or CA19-9 protein is indicative or suggests the said individual has pancreatic cancer or a predisposition for developing a pancreatic cancer and administering an generic anti-cancer treatment to the individual.
Claim(s) 2 recite(s) a method for improving the efficacy of an anti-cancer treatment for pancreatic cancer comprising determining the concentration of both, THBS2 protein and CA19-9 protein in an individual’s biological sample, wherein when the combination of values of the concentration of both, THBS2 protein and CA19-9 protein is unchanged or lower as compared with a concentration cutoff value for THBS2 protein or CA19-9 protein, the treatment is deemed efficacious and when the treatment is not efficacious an additional or modified anti-cancer treatment is administered to the individual.
Slightly in the same vein, claim(s) 60 recite(s) a method of managing a subject suspected of having pancreatic cancer comprising detecting both, THBS2 protein measurement and CA19-9 protein measurement in one or more biological samples, comparing the detected THBS2 measurement to at least one of a THBS2 measurement from a healthy subject and THBS2 and THBS2 cutoff and comparing the detected CA19-9 measurement to a CA19-9 cutoff values, wherein an increase in the THBS2 or increase in CA19-9 measurements as compared to the respective protein cutoff value is indicative that the subject has pancreatic cancer and should be further confirmed by additional assays (i.e. imaging, biopsy), screening/ surveillance and followed by anti-cancer treatment.
This judicial exception is not integrated into a practical application because gathering information and observing levels of the said markers in a biological sample from a subject required to use the correlation do not add a meaningful limitation to the method as they are insignificant extra-solution activity. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because it does not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The analysis as set forth in the 2019 Guidance is as follows:
Step 1: Yes, claims are drawn to a method which is one of the four statutory categories, a process.
Step 2A, prong 1: Yes, the claims recite/describe/set forth a judicial exception. The claims describe the relationship between the difference of the combination of values of the concentration of both biomarker(s), THBS2 protein and CA19-9 protein in an individual’s biological sample and the concentration cutoff value for THBS2 protein or CA19-9 protein and whether or not said individual is predisposed to developing a pancreatic and/or has pancreatic cancer or indicative of efficacious anti-cancer treatment based upon difference(s).
Step 2A, prong 2: No, the judicial exception is not integrated into a practical application. The claims do not rely on or use the exception here. Once the presence of the biomarker(s) are detected by conventional means of detecting the said proteins, there are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. And in particular, while both biomarker proteins are set forth in the preamble and/or initial steps of the method(s), the diagnosis and predisposition seem to rely only on the difference observed between one biomarker protein and not both.
In the claims, once the presence of the biomarker(s) are detected by conventional means of detecting both proteins, treatment is listed as an active step, however it is a generic and/or modified anti-cancer treatment and as stated previously, the claims base the treatment on the difference observed measurement of between one of the two biomarker proteins. There are no additional elements or combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Step 2B: There is no inventive concept present in the clams. The steps of analyzing the presence or amount of candidate pancreatic biomarker(s) in a biological sample is established by well understood, routine conventional methods, and in addition they are pre-solution activity, i.e. data gathering necessary to perform the correlation. The following claims and steps inform one of ordinary skilled in the art the comparison and the presence/amount/ concentration of biomarker(s) identifies an individual as suffering from pancreatic cancer. The claims do not recite additional elements that amount to significantly more than the judicial exception. Accordingly, these claims are not be eligible under step 2A or step 2B.
Claims 1, 2, 4, 6-17, 19, 21-28, 30-33, 35, 37, 60, 62-64, 67, 69-73, 75, 77-91 and 93-100, are drawn to a non-statutory method having a "natural principle" as a limiting element or step without reciting additional elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself. In the instant case, the "natural principle" is: detecting particular biomarker(s) in a biological sample from a human subject, which is indicative pancreatic cancer or predisposition of pancreatic cancer or an anti-cancer treatment will be efficacious or not, as well as if further assays should be conducted to confirm the pancreatic cancer diagnosis with screening/surveillance and administration of an anti-cancer treatment. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because assaying for candidate cancer biomarkers does not add significantly more and is not an inventive concept. Because methods for making such determinations were well known in the art, these steps simply tell researchers to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field. Such activities are normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such law. Detection of complexes comprising candidate cancer biomarkers and binding agents has been observed by applicant but not engineered by applicant. The claims do not add significantly more to the natural phenomenon because the claims do not require a novel reagent, apparatus of incorporate a novel treatment based on the correlation.
A claim that focuses on use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, and added something significant to, the natural principle itself. See Mayo, 101 USPQ2d at 1966. Recited elements such as “determining”, “detecting” and “comparing” based on the natural principle impose no meaningful limit on the performance of the claimed invention. As set forth the claims do not impose meaningful limits on the performance of the claimed invention. Patents cannot be obtained on subject matter identified by the courts as being exempted from eligibility (i.e., laws of nature, natural phenomenon, and abstract ideas). Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the recited natural principle. The claims do not "practically apply" the natural principle; rather, the claims "simply inform" the natural principle to one performing routine active method steps and do not amount to significantly more than the natural principle itself. Thus, the technology used by the instant claims is well-known in the art and does not contribute significantly more to the judicial exception. See the 2019 Revised Patent Subject Matter Eligibility Guidance and Federal Register https://www.federalregister.gov/documents/2019/10/18/2019-22782/october-2019-patent-eligibility-guidance-update; and FDsys.gov.
Claim Rejections - 35 USC § 103
7. 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 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.
8. 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.
9. The rejection over claim(s) 1, 2, 4, 6-17, 19, 21-28, 30-33, 35, 37, 60, 62-64, 67, 69-73, 75, 77-81, 83-85 and 88-91 under 35 U.S.C. 103 as being unpatentable over Williams et al., US 2012/0040861 A1 (published February 16, 2012/ IDS reference #6 on sheet 2 submitted January 4, 2022), and further in view of Zaret et al., US 2016/022355 (published August 4, 2016) and Brand et al. (Clin. Cancer Res. 17(4): 805-816, 2010) is maintained and made. Claims 65 and 92 have been cancelled.
Applicant argues there is “[h]indsight [b]ias”, “[u]expected [r]esults”, “[e]xpectation of [s]uccess” and “[b]iomarker [p]anel [v]alidation”, see pages 18-24 of the Remarks submitted December 15, 2025. In particular, Applicant asserts “Williams’ disclosure merely expressed a hope that testing of other biomarkers with or without CA 19-9 may improve sensitivity, specificity, and/or AUC for detecting pancreatic cancer (or other pancreatic cancer-related uses) as compared to CA 19-9 alone. Notably, the combination of references [does] not disclose or suggest measuring the
concentrations of both CA 19-9 and THBS-2 without the hindsight benefit of Applicant's disclosure or a reasonable expectation of success, nor provide any experimental results documenting or confirming early-stage pancreatic ductal adenocarcinoma (PDAC) detection.”, see lines 1-7 on page 19 of the Remarks.
Applicant argues “[t]he combination of references…of the present rejections underscore the unexpected and surprising results at least because Williams’ results would have led a person in the art away from combining CA19-9 with THBS-2 at least for the reasons described in in paragraphs 11-12 of the Zaret Declaration.”, see page 21, sentences before the first full paragraph (para.).
Applicant states, “the [Examiner’s] assertion that there is "no delineation between CA 19-9, THBS2, Lewis antigen negative and Lewis antigen positive" is not factually supported and the Declaration clearly provides a nexus between the invention as claimed and the evidence in the declaration… It should be noted, that the claims clearly require determining the concentration of both a THBS2 protein and CA19-9 protein in a biological samples. Regardless of whether a single value may be diagnostic for early stage pancreatic cancer detection, the claims require evaluation of the two-marker panel for the reasons described herein and the prior art provides insufficient grounds for doing so.”, see sentences before segment 3 on page 23 of the Remarks.
Applicant states “[t]he July 15, 2025 Non-Final Office Action repeated the foregoing argument verbatim and failed to provide a sufficiently
reasoned basis espousing a predictable expectation of success for combining the teachings of Williams, Zaret, Brand, and/or Yu in accordance with the claimed subject matter, much less an expectation of success for diagnosing and treating early stage PDAC in view of the underlying facts.
As stated in the Zaret Declaration, besides Williams, neither of the other references (Zaret and/or Brand) provide a technical basis for those of ordinary skill in the art to combine CA19-9 with THBS2, let alone with any reasonable expectation of success for diagnosing early stage pancreatic cancer to the exclusion of other medical conditions. This is consistent with the lack of data in any published reports comprising any biomarker panel or even a multi-specific panel comprising CA19-9 with THBS2. In this case, the July 15, 2025 Office Action failed to provide rebuttal arguments to the contrary.”, see segment 3 spanning pages 23 and 24.
Applicant concludes arguments noting “[t]here is no dispute that the cited references fail to provide any evidence in support of the CA 19-9/THBS2 biomarker panel being validated for diagnosing pancreatic cancer or a predisposition for developing pancreatic cancer (e.g., claims 80-87), let alone validated for diagnosing early stage pancreatic cancer (claim 87, 88, 93, 99, 100) and/or validated in accordance with the c-statistic and/or specificity/sensitivity features recited in claims 7-10, 82-85, 94, and 96-98. The Office Action merely identifies teachings suggesting that such determinations can be made without providing any expectation of success for achieving the claimed features associated with the use and validation of this biomarker panel.
As noted in the Zaret Declaration, validation of the biomarker panel is an important feature of the present invention:
An important feature of our invention further concerns validation of our biomarker panel, which is covered by claims 80-87. It is my understanding that these claims, including claims 86 and 87 that recite validation of early stage pancreatic cancer diagnosis based on a clinical study comprising subjects with resectable PDAC and control subjects who are PDAC negative, were not rejected in the final office action. Clinical use of our two-marker panel was performed in phase 2a and 2b validation studies as further described in paragraph 9 above. None of the cited references could have provided any expectation of success for the results achieved, let alone provide a basis for combining these two markers to obtain such results.
Accordingly, the Office has failed to present a prima facie case of obviousness over the above-identified claims, since the Office has failed to present any arguments rebutting Applicant's biomarker panel validation arguments, particularly as they relate to claims 7-10 and 81-87.”, see page 24 of the Remarks.
Applicants’ arguments and points of view have been carefully considered, but fail to persuade.
Foremost, Applicant has not provided any scientific evidence that would dissuade one of ordinary skill in the art that modification of the prior art references would differ from what is claimed and from combining the prior art references to arrive at the claimed invention.
Applicants are reminded that the instant rejection is based on the combination of references and not a sole reference for the teachings of the claimed invention.
Addressing Applicants concerns regarding hindsight, rather than using hindsight, the Examiner points to specific disclosures in the prior art that describe the limitations of Applicants’ claimed invention. The Examiner’s obviousness conclusion is based on sufficiently articulated reasoning that overcomes any concerns about hindsight bias. See KSR, 550 U.S. at 418. Moreover, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant has not provided judicious argument as to why the combination of references could not be relied upon to arrive at the claimed subject matter with a reasonable expectation of success.
In conclusion, the combination of references teaches the claimed invention as noted herein and the rejection of record. The combination of these teachings do not differ from Applicants’ claimed invention, nor what is exemplified in Applicants’ teachings herein. Hence, the same results would render the same effects as espoused by Applicants. Applicants have not presented any scientific evidence that would dissuade the Office from the combination of references. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Williams teaches methods of assaying one or more protein biomarkers including CA 19-9 and THBS for the diagnosis of human pancreatic cancer by several techniques including enzyme-linked immunosorbent assay (ELISA), see page 2, section 0027; page 3, section 0040; page 7, section 0089; page 11, section 0140; biomarker #58 within Table 1 on page 38; and sections 0190-0195 on page 18. These disclosed biomarkers are used to diagnose early stage pancreatic cancer, as well as resectable disease, see page 2, section 0024; page 12, section 0146; and page 13, section 0152. Individuals that present as asymptomatic are also screened for the pancreatic cancer biomarkers, see page 3, sections 0033 and 0037; page 8, section 0121; section 0366 spanning pages 31 and 32; and claim 25 on page 72. These methods also extend to managing a patient undergoing pancreatic cancer treatment, as well as improving the efficacy of pancreatic cancer treatment, see page 13, sections 0150 and 0151.
The expression level or value of the chosen protein biomarker within a biological sample from an individual to be tested is compared with respective levels in normal tissue or biological sample from the same individual or another healthy individual., see sections 0133-0144, spanning pages 10-11. Both polyclonal and monoclonal antibodies, specific for a biomarker were used as immunodetection reagents, see page 2, section 0027; and page 18, section 0190. Absent evidence to the contrary, the disclosed THBS2 protein is the same as Applicants’ THBS2 protein comprising the amino acid sequence of SEQ ID NO: 1.
“"Biological sample", "sample", and "test sample" are used interchangeably herein to refer to any material, biological fluid, tissue, or cell obtained or otherwise derived from an individual. This includes blood…”, serum, urine, cystic fluid, pancreatic fluid, lymph fluid, pleural fluid, serum, plasma, a stool sample, see page 10, section 0129.
Algorithms, computer programs or instructions for manually performing quantifications by a human can be executed to compare “…the amount of each biomarker quantified in the test sample to one or more predetermined cutoffs and assigning a score for each biomarker quantified based on said comparison, combining the assigned scores for each biomarker quantified to obtain a total score, comparing the total score with a predetermined score, and using said comparison to determine whether an individual has pancreatic cancer”, see page 27, section 0276.
While the taught biomarkers are used for diagnosing pancreatic cancer after the measurement, comparison and differential expression is detected between test patient and healthy individual and cutoff value is determined and additional tests can be implemented to confirm the diagnosis, see section 13 on page 151. The biomarkers can also be detected before treatment, see page 14, section 0153. Radiologic screening, endoscopic ultrasound can be performed, as well as further treatment with radiation therapy or cancer vaccine is administered, see page 13, sections 0151 and 0152; page 14, sections 0153-0158.
“Pancreatic cancer treatment may include, for example, administration of a therapeutic agent to the individual, performance of surgery (e.g., surgical resection of at least a portion of a pancreatic tumor or removal of pancreatic and surrounding tissue), administration of radiation therapy, or any other type of pancreatic cancer treatment used in the art, and any combination of these treatments.”, see page 14, section 0153.
Williams does not teach the methods wherein the concentration cutoff value for CA19-9 protein is between about 40 to about 1000 U/ml and more specifically 55 U/ml. Nor, does Williams teach the concentration cutoff value for THBS2 protein is between about 40 to about 50 ng/ml and more specifically 42 ng/ml. Williams does not explicitly teach the specificity of the combination of cutoff values is at least 90% and the sensitivity of the combination of values is least 80%.
However, Zaret teaches the concentration cutoff for THBS2 averages between 24.8493 ng/ml and 97.6785 ng/ml, see Figure 26. This range overlaps with Applicants’ concentration cutoff values. It is within the Examiner’s purview that given the method steps of claims 1 and 2 taught herein, the specificity and sensitivity of the combination of values is inherently arrived upon.
Additionally, Brand teaches the concentration cut-off concentration for CA 19-9 range is 2.61U/ml up to 56.04 U/ml, see page 811, Table 3. Williams teaches sensitivity and specificity values can be established based on the combination of biomarker values, see page 9, section 0124. These quantitative results can be obtained with detection of concentration of both, THBS2 protein and CA19-9 protein by ELISA, see section 0135 on page 10; and Determination of Biomarker Values Using Immunoassays on page 18.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Williams, Zaret and Brand to arrive at assaying the particular combination of THSB2 and CA19-9 because the teachings within all the documents address the evaluation of a biomarker panel with at least two potential biomarkers to identify classifiers and construct classifiers to arrive at an optimal set of biomarkers, see all references in their entirety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Williams, Zaret and Brand to arrive at the designated concentration cutoff values for THBS2, CA19-9, as well as the specificity and sensitivity of the combination of values is at least 90% and at least 80%, respectively. Williams teaches implementing specific antibodies for detecting corresponding target proteins within an immunoassay, which will allow enhanced specificity and sensitivity of the assay methods, see Determination of Biomarker Values Using Immunoassays on page 18. Williams also teaches how to arrive at cutoffs, see page 27, section 0276.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Williams, Zaret and Brand with the implementation of specific monoclonal antibodies detecting to target proteins, such as THBS2 and CA19-9 within an immunoassay method specificity and sensitivity is improved and multimarker panels comprising different biomarkers “…discriminating PDAC from benign disease may offer a high level of clinical utility in combination with conventional imaging modalities to provide a diagnostic role…’”, see Williams in its entirety and in particular Determination of Biomarker Values Using Immunoassays on page 18 and specifically section 0190; Zaret in its entirety; Brand in its entirety and in particular page 814, 2nd column.
10. The rejection of claim(s) 1, 2, 4, 6-17, 19, 21-28, 31-33, 35, 60, 62-64, 67, 69-73, 75, 77-91 and 93-100 under 35 U.S.C. 103 as being unpatentable over Williams et al., US 2012/0040861 A1 (published February 16, 2012/ IDS reference #6 on sheet 2 submitted January 4, 2022), and further in view of Zaret et al., US 2016/022355 (published August 4, 2016), Brand et al. (Clin. Cancer Res. 17(4): 805-816, 2010) and Yu et al., (PLoS 11(1): e0146473, 14 pages, published January 11, 2016) is maintained. Claims 65 and 92 have been cancelled.
Applicant argues there is “[h]indsight [b]ias”, “[u]expected [r]esults”, “[e]xpectation of [s]uccess” and “[b]iomarker [p]anel [v]alidation”, see pages 18-24 of the Remarks submitted December 15, 2025. In particular, Applicant asserts “Williams’ disclosure merely expressed a hope that testing of other biomarkers with or without CA 19-9 may improve sensitivity, specificity, and/or AUC for detecting pancreatic cancer (or other pancreatic cancer-related uses) as compared to CA 19-9 alone. Notably, the combination of references [does] not disclose or suggest measuring the
concentrations of both CA 19-9 and THBS-2 without the hindsight benefit of Applicant's disclosure or a reasonable expectation of success, nor provide any experimental results documenting or confirming early-stage pancreatic ductal adenocarcinoma (PDAC) detection.”, see lines 1-7 on page 19 of the Remarks.
Applicant argues “[t]he combination of references…of the present rejections underscore the unexpected and surprising results at least because Williams’ results would have led a person in the art away from combining CA19-9 with THBS-2 at least for the reasons described in in paragraphs 11-12 of the Zaret Declaration.”, see page 21, sentences before the first full paragraph (para.).
Applicant states, “the [Examiner’s] assertion that there is "no delineation between CA 19-9, THBS2, Lewis antigen negative and Lewis antigen positive" is not factually supported and the Declaration clearly provides a nexus between the invention as claimed and the evidence in the declaration… It should be noted, that the claims clearly require determining the concentration of both a THBS2 protein and CA19-9 protein in a biological samples. Regardless of whether a single value may be diagnostic for early stage pancreatic cancer detection, the claims require evaluation of the two-marker panel for the reasons described herein and the prior art provides insufficient grounds for doing so.”, see sentences before segment 3 on page 23 of the Remarks.
Applicant states “[t]he July 15, 2025 Non-Final Office Action repeated the foregoing argument verbatim and failed to provide a sufficiently
reasoned basis espousing a predictable expectation of success for combining the teachings of Williams, Zaret, Brand, and/or Yu in accordance with the claimed subject matter, much less an expectation of success for diagnosing and treating early stage PDAC in view of the underlying facts.
As stated in the Zaret Declaration, besides Williams, neither of the other references (Zaret and/or Brand) provide a technical basis for those of ordinary skill in the art to combine CA19-9 with THBS2, let alone with any reasonable expectation of success for diagnosing early stage pancreatic cancer to the exclusion of other medical conditions. This is consistent with the lack of data in any published reports comprising any biomarker panel or even a multi-specific panel comprising CA19-9 with THBS2. In this case, the July 15, 2025 Office Action failed to provide rebuttal arguments to the contrary.”, see segment 3 spanning pages 23 and 24.
Applicant concludes arguments noting “[t]here is no dispute that the cited references fail to provide any evidence in support of the CA 19-9/THBS2 biomarker panel being validated for diagnosing pancreatic cancer or a predisposition for developing pancreatic cancer (e.g., claims 80-87), let alone validated for diagnosing early stage pancreatic cancer (claim 87, 88, 93, 99, 100) and/or validated in accordance with the c-statistic and/or specificity/sensitivity features recited in claims 7-10, 82-85, 94, and 96-98. The Office Action merely identifies teachings suggesting that such determinations can be made without providing any expectation of success for achieving the claimed features associated with the use and validation of this biomarker panel.
As noted in the Zaret Declaration, validation of the biomarker panel is an important feature of the present invention:
An important feature of our invention further concerns validation of our biomarker panel, which is covered by claims 80-87. It is my understanding that these claims, including claims 86 and 87 that recite validation of early stage pancreatic cancer diagnosis based on a clinical study comprising subjects with resectable PDAC and control subjects who are PDAC negative, were not rejected in the final office action. Clinical use of our two-marker panel was performed in phase 2a and 2b validation studies as further described in paragraph 9 above. None of the cited references could have provided any expectation of success for the results achieved, let alone provide a basis for combining these two markers to obtain such results.
Accordingly, the Office has failed to present a prima facie case of obviousness over the above-identified claims, since the Office has failed to present any arguments rebutting Applicant's biomarker panel validation arguments, particularly as they relate to claims 7-10 and 81-87.”, see page 24 of the Remarks.
Applicants’ arguments and points of view have been carefully considered, but fail to persuade.
Foremost, Applicant has not provided any scientific evidence that would dissuade one of ordinary skill in the art that modification of the prior art references would differ from what is claimed and from combining the prior art references to arrive at the claimed invention.
Applicants are reminded that the instant rejection is based on the combination of references and not a sole reference for the teachings of the claimed invention.
Addressing Applicants concerns regarding hindsight, rather than using hindsight, the Examiner points to specific disclosures in the prior art that describe the limitations of Applicants’ claimed invention. The Examiner’s obviousness conclusion is based on sufficiently articulated reasoning that overcomes any concerns about hindsight bias. See KSR, 550 U.S. at 418. Moreover, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant has not provided judicious argument as to why the combination of references could not be relied upon to arrive at the claimed subject matter with a reasonable expectation of success.
In conclusion, the combination of references teaches the claimed invention as noted herein and the rejection of record. The combination of these teachings do not differ from Applicants’ claimed invention, nor what is exemplified in Applicants’ teachings herein. Hence, the same results would render the same effects as espoused by Applicants. Applicants have not presented any scientific evidence that would dissuade the Office from the combination of references. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Williams teaches methods of assaying one or more protein biomarkers including CA 19-9 and THBS for the diagnosis of human pancreatic cancer by several techniques including enzyme-linked immunosorbent assay (ELISA), see page 2, section 0027; page 3, section 0040; page 7, section 0089; page 11, section 0140; biomarker #58 within Table 1 on page 38; and sections 0190-0195 on page 18. These disclosed biomarkers are used to diagnose early stage pancreatic cancer, as well as resectable disease, see page 2, section 0024; page 12, section 0146; and page 13, section 0152. Individuals that present as asymptomatic are also screened for the pancreatic cancer biomarkers, see page 3, sections 0033 and 0037; page 8, section 0121; section 0366 spanning pages 31 and 32; and claim 25 on page 72. These methods also extend to managing a patient undergoing pancreatic cancer treatment, as well as improving the efficacy of pancreatic cancer treatment, see page 13, sections 0150 and 0151.
The expression level or value of the chosen protein biomarker within a biological sample from an individual to be tested is compared with respective levels in normal tissue or biological sample from the same individual or another healthy individual., see sections 0133-0144, spanning pages 10-11. Both polyclonal and monoclonal antibodies, specific for a biomarker were used as immunodetection reagents, see page 2, section 0027; and page 18, section 0190. Absent evidence to the contrary, the disclosed THBS2 protein is the same as Applicants’ THBS2 protein comprising the amino acid sequence of SEQ ID NO: 1.
“"Biological sample", "sample", and "test sample" are used interchangeably herein to refer to any material, biological fluid, tissue, or cell obtained or otherwise derived from an individual. This includes blood…”, serum, urine, cystic fluid, pancreatic fluid, lymph fluid, pleural fluid, serum, plasma, a stool sample, see page 10, section 0129.
Algorithms, computer programs or instructions for manually performing quantifications by a human can be executed to compare “…the amount of each biomarker quantified in the test sample to one or more predetermined cutoffs and assigning a score for each biomarker quantified based on said comparison, combining the assigned scores for each biomarker quantified to obtain a total score, comparing the total score with a predetermined score, and using said comparison to determine whether an individual has pancreatic cancer”, see page 27, section 0276.
While the taught biomarkers are used for diagnosing pancreatic cancer after the measurement, comparison and differential expression is detected between test patient and healthy individual and cutoff value is determined and additional tests can be implemented to confirm the diagnosis, see section 13 on page 151. Radiologic screening, endoscopic ultrasound can be performed, as well as further treatment with radiation therapy or cancer vaccine is administered, see page 13, sections 0151 and 0152; page 14, sections 0153- 0158.
“Pancreatic cancer treatment may include, for example, administration of a therapeutic agent to the individual, performance of surgery (e.g., surgical resection of at least a portion of a pancreatic tumor or removal of pancreatic and surrounding tissue), administration of radiation therapy, or any other type of pancreatic cancer treatment used in the art, and any combination of these treatments.”, see page 14, section 0153.
Williams does not teach the methods wherein the concentration cutoff value for CA19-9 protein is between about 40 to about 1000 U/ml and more specifically 55 U/ml. Nor, does Williams teach the concentration cutoff value for THBS2 protein is between about 40 to about 50 ng/ml and more specifically 42 ng/ml. Williams does not explicitly teach the specificity of the combination of cutoff values is at least 90% and the sensitivity of the combination of values is least 80%.
Williams also does not teach the biomarker panel comprising and consisting of THBS2 and CA19-9 are validated and exhibit an increases c-statistic compared to either biomarker alone with an increased specificity and sensitivity compared to either biomarker alone.
However, Zaret teaches the concentration cutoff for THBS2 averages between 24.8493 ng/ml and 97.6785 ng/ml, see Figure 26. This range overlaps with Applicants’ concentration cutoff values. It is within the Examiner’s purview that given the method steps of claims 1 and 2 taught herein, the specificity and sensitivity of the combination of values would be intrinsically arrived upon.
Additionally, Brand teaches the concentration cut-off concentration for CA19-9 range is 2.61U/ml up to 56.04 U/ml, see page 811, Table 3. Williams teaches sensitivity and specificity values can be established based on the combination of biomarker values, see page 9, section 0124. These quantitative results can be obtained with detection of concentration of both, THBS2 protein and CA19-9 protein by ELISA, see section 0135 on page 10; and Determination of Biomarker Values Using Immunoassays on page 18.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Williams, Zaret and Brand to arrive at assaying the particular combination of THSB2 and CA19-9 because the teachings within all the documents address the evaluation of a biomarker panel with at least two potential biomarkers to identify classifiers and construct classifiers to arrive at an optimal set of biomarkers, see all references in their entirety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Williams, Zaret and Brand to arrive at the designated concentration cutoff values for THBS2, CA19-9, as well as the specificity and sensitivity of the combination of values is at least 90% and at least 80%, respectively. Williams teaches implementing specific antibodies for detecting corresponding target proteins within an immunoassay, which will allow enhanced specificity and sensitivity of the assay methods, see Determination of Biomarker Values Using Immunoassays on page 18. Williams also teaches how to arrive at cutoffs, see page 27, section 0276.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Williams, Zaret and Brand with the implementation of specific monoclonal antibodies detecting to target proteins, such as THBS2 and CA19-9 within an immunoassay method specificity and sensitivity is improved and multimarker panels comprising different biomarkers “…discriminating PDAC from benign disease may offer a high level of clinical utility in combination with conventional imaging modalities to provide a diagnostic role…’”, see Williams in its entirety and in particular Determination of Biomarker Values Using Immunoassays on page 18 and specifically section 0190; Zaret in its entirety; Brand in its entirety and in particular page 814, 2nd column.
Moreover, Yu teaches the value of a marker or a model that is able to evaluate the performance of statistical “…models with respect to discrimination and calibration.”, see page 4, Model validation, 1st paragraph (para.). “Discrimination is a model’s ability to distinguish between non-events and events. This can be quantified by calculating the c-statistic for the survival model developed by Nam…. The c-statistic is a concordance measure analogous to the receiver operating characteristic (ROC) curve area for the logistic model…. The value indicates the probability that a model produces higher risks for those who develop pancreatic cancer within 8 years of follow-up compared to those who do not develop pancreatic cancer…”., see 2nd para. under the Model Validation title.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Williams, Zaret and Brand with Yu to utilize a risk prediction model for pancreatic cancer with biomarkers, THBS2, CA19-9, as well analyze the specificity and sensitivity of the biomarker panel comprising said biomarkers. Williams also teaches “[t]he biomarker or set of biomarkers identified are generally clinically validated or shown to be a reliable indicator for the original intended use for which it was selected.”, see page 2, section 0025.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Yu to screen asymptomatic pancreatic cancer in high risk individuals to calculate the c-statistic to classify individuals in order to surveil and predict those that may have having or not having pancreatic cancer utilizing pancreatic cancer marker CA19-9 alone or in combination with anther pancreatic cancer biomarker. “[S]creening for asymptomatic pancreatic cancer will likely require filtering the population into at least two sequential groups in order to enrich the population and allow cost-effective screening…”., see page 2, 1st paragraph.
Conclusion
11. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
12. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can normally be reached 8AM-8PM, Monday through Friday.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
10 April 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
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