DETAILED ACTION
Preliminary Amendment filed on 03/21/2024 is acknowledged. Claims 3-5, 8, 12, 16-17 and 28-46 are cancelled. Claims 1-2, 6-7, 9-11, 13-15 and 18-27 are pending in the application and are considered on merits.
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 .
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.
Claim 1, 2, 6, 7, 9-11, 13-15, and 18-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions without reciting additional elements that are sufficient to amount to significantly more than the judicial exceptions.
Step 1: Statutory category
Independent claim 1 recites a series of acts including determining an amount of a metabolic biomarker, performing a comparison, selecting a treatment, and administering the treatment. Accordingly, claim 1 is nominally directed to a process, which is one of the statutory categories identified in 35 U.S.C. 101. The analysis therefore proceeds to Step 2A.
Step 2A, Prong One: Judicial exceptions
Claim 1 recites determining an amount of 5-oxoproline in a biological sample and comparing that amount to a reference, “wherein presence of a change in amount of the at least one metabolic biomarker is associated with presence of the pancreatic disease or disorder or increased risk of developing the pancreatic disease or disorder.” The recited association between the naturally occurring amount of 5-oxoproline in a subject and the presence of, or increased risk for, pancreatic disease describes a consequence of natural biological processes occurring in the subject. The recited association is therefore a law of nature.
Claim 1 also recites comparing the determined amount with a reference, determining from that comparison whether the subject has or is at increased risk for pancreatic disease, and selecting a treatment based on the comparison. Comparing information, evaluating the significance of the comparison, and making a treatment judgment based on the evaluation are observations, evaluations, judgments, or opinions that can be practically performed in the human mind. These limitations therefore additionally recite a mental process within the abstract-idea grouping. MPEP §§ 2106.04(a)(2) and 2106.04(b). The MPEP specifically recognizes that comparing collected information with a reference or threshold is a mental evaluation and that a naturally occurring relationship between a biological characteristic and a disease manifestation is a law of nature. (USPTO)
Accordingly, claim 1 recites judicial exceptions under Step 2A, Prong One.
Step 2A, Prong Two: No integration into a practical application
The additional elements beyond the identified judicial exceptions include determining or having determined the amount of 5-oxoproline in a biological sample and administering an effective amount of a treatment when the comparison indicates that the subject has, or is at increased risk for, pancreatic disease.
The step of determining the biomarker amount is recited only at a high level of generality and does not require any particular assay, instrument, sample-processing procedure, or measurement technique. The determining step merely obtains the biological data that are subsequently used in the recited natural correlation and mental evaluation. It therefore constitutes insignificant extra-solution activity in the form of data gathering. See MPEP § 2106.05(g).
Although claim 1 affirmatively requires “administering an effective amount of the treatment,” the claim does not identify what drug is administered, what procedure is performed, what dose or regimen is used, or which treatment is selected in response to a particular 5-oxoproline amount. Rather, the claim broadly covers the administration of whatever treatment a medical professional selects after considering the biomarker comparison. The administering limitation therefore does not effect a particular treatment tied to the recited natural correlation. It instead amounts to a generic instruction to apply the result of the natural correlation and mental evaluation.
The administering limitation is analogous to “administering an appropriate treatment” in USPTO Subject Matter Eligibility Example 49, which did not integrate the judicial exception into a practical application because the claim did not specify how the patient was treated or what treatment was administered. In contrast, the dependent claim in Example 49 became eligible when it specifically required Compound X eye drops for the identified patient population. MPEP § 2106.04(d)(2) similarly distinguishes a particular treatment, such as administering a specified medication in a defined manner, from generically administering a suitable medication.
The claim also does not improve a biomarker-measurement technique, sample-processing technology, treatment technology, or another technical field. At most, it applies the discovered natural relationship to the medical field of diagnosing and treating pancreatic disease. Merely limiting or generally linking use of a judicial exception to a particular medical environment does not integrate the exception into a practical application. See MPEP §§ 2106.05(f) and 2106.05(h).
Considered individually and as an ordered combination, the additional elements merely instruct a practitioner to obtain biomarker information, evaluate the information using the recited natural correlation, and generically treat the subject based on the evaluation. The additional elements therefore do not integrate the judicial exceptions into a practical application. Claim 1 is consequently directed to the judicial exceptions.
Step 2B: No significantly more
The additional elements, individually and in combination, do not amount to significantly more than the judicial exceptions.
Determining the amount of a metabolite in a biological sample at the claimed level of generality is well-understood, routine, and conventional laboratory activity. In Mayo Collaborative Services v. Prometheus Laboratories, Inc., the Court determined that measuring metabolite levels using any known process was routine and conventional activity that did not provide an inventive concept when appended to a natural correlation. MPEP § 2106.05(d). (USPTO)
The present specification also expressly states that “[m]ethods of identifying and quantifying biomarkers are well known in the art” and identifies ELISA, electrophoresis, mass spectrometry, spectrophotometry, chromatography, and other conventional analytical methods without requiring any particular method in claim 1 (Spec. par [0060]).
The comparison and treatment-selection limitations are themselves part of the identified judicial exceptions. The generic administration of an unspecified treatment merely instructs the practitioner to apply the result of the natural correlation and does not supply a particular application or unconventional treatment arrangement. The claim does not require that a particular measured amount result in administration of a particular drug, procedure, dosage, or treatment protocol.
Thus, considered separately and as an ordered combination, the additional elements merely append routine data gathering and a generic instruction to treat to the recited natural correlation and mental evaluation. They do not provide an inventive concept. Claim 1 therefore does not amount to significantly more than the judicial exceptions and is ineligible under 35 U.S.C. 101.
Dependent claims
Claim 2 further recites sending the sample to a testing laboratory that performs the determining and comparison. Sending a sample to another entity merely specifies who performs the data-gathering and evaluation steps. It does not change the measurement technology, alter the natural correlation, or require a particular treatment. This limitation is an administrative arrangement and insignificant extra-solution activity that does not integrate the judicial exceptions into a practical application or provide significantly more.
Claims 6 and 7 further specify that lower amounts of 5-oxoproline are associated with increased risk of pancreatic disease and that the amount is at least twofold lower than the reference. These limitations more narrowly define the naturally occurring relationship and the threshold used in the mental comparison. A more specific statement of the natural correlation remains a law of nature, and the twofold threshold does not add a technological application or inventive concept.
Claim 9 further recites determining amounts of additional biomarkers and comparing those amounts with a reference. These limitations add further collection and evaluation of naturally occurring biological information. The specification acknowledges that methods for identifying and quantifying biomarkers are well known (Spec. par [0060]). Accordingly, the additional measurements are routine data gathering, and the additional comparisons are mental evaluations that do not integrate the judicial exceptions or provide significantly more.
Claim 10 further recites acquiring the biological sample from the subject. Acquiring a sample is preliminary data gathering performed to obtain the material on which the biomarker determination is conducted. It is insignificant extra-solution activity and does not provide a particular technological or therapeutic application of the natural correlation.
Claims 11 and 13 specify that the sample comprises pancreatic tissue, pancreatic juice or fluid, pancreatic cyst tissue, or pancreatic cyst fluid. These limitations merely limit the source or environment from which the biological information is obtained. Restricting the judicial exceptions to particular types of biological samples does not integrate the exceptions into a practical application and does not add an inventive concept.
Claim 14 further recites analyzing cyst characteristics, cytology, or a combination thereof. The additional analysis supplies further diagnostic information for consideration together with the biomarker amount. It constitutes additional data gathering and evaluation rather than an improvement to cytology, imaging, or another diagnostic technology. The specification itself identifies cyst characteristics, CEA testing, and cytology as existing diagnostic approaches (Spec. par [0022]).
Claim 15 further recites differentiating cysts as malignant or benign and/or mucinous or non-mucinous. Differentiating or classifying the cysts based on the collected biological information is a diagnostic judgment and therefore an additional mental process. The limitation states the result of the evaluation but does not require a particular assay improvement, physical transformation, or treatment resulting from a specified classification.
Claims 18 and 19 further recite the naturally occurring association between decreased 5-oxoproline and a mucinous cyst, including a level that is at least twofold lower than a non-mucinous reference. These limitations further define a natural biological correlation and a comparison threshold. They therefore recite an additional law of nature and mental evaluation rather than an additional element integrating the exceptions into a practical application.
Claims 20 and 21 limit the pancreatic disease or disorder to cancer and early-stage cancer. These limitations merely restrict the field in which the natural correlation and mental evaluation are used. A field-of-use limitation does not meaningfully limit the judicial exceptions or provide significantly more.
Claim 22 further identifies broad categories of possible treatments, including surgery, radiation therapy, administration of an anti-cancer agent, immunotherapy, ablation, embolization, and palliative care. Claim 22, however, does not require administering a specifically identified anti-cancer agent, performing a specified surgical or ablative procedure, applying a defined radiation regimen, or selecting a particular one of the listed treatments in response to a defined 5-oxoproline result. Instead, the claim permits administration of any one or more of numerous materially different treatment categories whenever the comparison generally indicates disease or increased risk. The limitation therefore does not meaningfully tie the natural correlation to a particular treatment for a particular identified patient population and remains a generic instruction to select and apply an appropriate pancreatic-disease treatment. The limitation does not integrate the judicial exceptions into a practical application or provide an inventive concept.
Accordingly, claims 1, 2, 6, 7, 9-11, 13-15, and 18-22 are ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 6, 9-10 and 20-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Reszka et al. (WO 2013/079594) (Reszka).
Regarding claim 1, Reszka teaches a method for treating or selecting a treatment for a subject at risk of or having a pancreatic disease or disorder (abstract), comprising:
determining or having determined an amount of at least one metabolic biomarker in a biological sample from the subject (page 3, line 5-10);
performing a comparison or having performed a comparison of the amount of the at least one metabolic biomarker in the biological sample to a reference for a subject not having the pancreatic disease or disorder (page 3, line 9-10, claim 2), wherein presence of a change in amount of the at least one metabolic biomarker is associated with presence of the pancreatic disease or disorder or increased risk of developing the pancreatic disease or disorder (page 13, line 20-22);
selecting a treatment based on the comparison (page 16, lines 27-34); and
administering an effective amount of the treatment when the comparison indicates the subject has or is at increased risk for the pancreatic disease or disorder (page 16, lines 39-41),
wherein the at least one metabolic biomarker comprises 5-oxoproline (Table 6, 8, 15, 17, 24).
Regarding claim 6, Reszka teaches wherein lower amounts of 5-oxoproline are associated with an increased risk of the pancreatic disease or disorder (Table 6, 8, 15, 17, 24).
Regarding claim 9, Reszka teaches the method further comprising determining the amount of valine and comparing the amount to a reference for a subject not having the pancreatic disease or disorder (Table 6).
Regarding claim 10, Reszka teaches the method further comprising acquiring the biological sample from the subject (page 7, line 25-26).
Regarding claim 20, Reszka teaches wherein the pancreatic disease or disorder comprises cancer (page 3, line 18-19).
Regarding claim 21, Reszka expressly teaches that there was a need for increasing the sensitivity of biomarker-based tools for “early diagnosis” of pancreatic cancer because timely surgical resection of “early stage tumors” was the only effective treatment. Reszka further states:
“new approaches are urgently needed to increase the diagnostic sensitivity towards the detection of very small, early stage PDAC and its precursor lesions (PanINs and IPMNs).” (page 1, line 29-31).
Immediately thereafter, Reszka states that the technical problem is solved by the disclosed embodiments and provides its method of determining pancreatic-cancer metabolic-biomarker amounts and comparing the amounts with a reference to diagnose pancreatic cancer (page 1-3). Thus, Reszka expressly applies its biomarker-determination and comparison method to detecting very small, early-stage pancreatic ductal adenocarcinoma.
Regarding claim 22, Reszka teaches wherein the treatment comprises one or more of: surgery, radiation therapy, administration of an anti-cancer agent, immunotherapy, ablation, embolization, and palliative care (page 16, lines 36-37).
Claim(s) 23-27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Morgell et al. (Journal of Proteome Research, 2021) (Morgell).
Regarding claim 23, Morgell teaches a method comprising:
determining an amount of at least one metabolic biomarker in a pancreatic tissue or pancreatic juices or fluids sample from a subject (page 2727, par 5), wherein the at least one metabolic biomarker is 5-oxoproline (page 2731, par 1).
Regarding claim 24, Morgell teaches the method further comprising determining the amount of any or all of: carcinoembryonic antigen (CEA), glucose, carbohydrate antigen 19-9 (CA 19-9), 4-hydroxyL-proline, N-acetyl-DL-serine, 3-methoxytyrosine, cystathionine, trans-4-hydroxyproline, 5-aminolevulinic acid, corticosterone, isocitric acid, cortisol, myristic acid, lauric acid, phytanic acid, hypoxanthine, theophylline, citric acid, caffeine, ascorbic acid, uric acid, 3-hydroxybenzaldehyde, hippuric acid, succinic acids, 1-methylxanthine, 4-acetaminophen sulfate, inosine, acetate, valine, creatine, methionine, omithine, glutamate, isoleucine, and 1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (16:0 Lyso PC) (page 2731, par 1).
Regarding claim 25, Morgell teaches wherein the determining amount of the at least one metabolic biomarker comprises mass spectrometry, liquid chromatography, gas chromatography, capillary electrophoresis, nuclear magnetic resonance, spectrophotometry, or any combination thereof (page 2728, par 1).
Regarding claim 26, Morgell teaches the method further comprising obtaining the sample from the subject (page 2727, par 5).
Regarding claim 27, Morgell teaches wherein the pancreatic tissue or pancreatic juices or fluids sample comprises pancreatic cyst tissue or fluid (page 2727, par 5).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Reszka et al. (WO 2013/079594) (Reszka).
Regarding claim 2, Reszka further teaches that the biomarker-determination and comparison method is preferably performed ex vivo and may be assisted by automation (page 3, lines 14-15). Reszka teaches determining the biomarkers using specialized analytical techniques, including liquid chromatography, gas chromatography, LC-MS, GC-MS, CE-MS, HPLC-MS, and NMR. Reszka further teaches that sample processing may be automated by robotics and that “data processing and comparison is, preferably, assisted by suitable computer programs and databases.” (page 9).
Reszka does not expressly teach “wherein the having determined and/or having performed a comparison comprises sending the sample to a testing laboratory that conducts the determining and performing a comparison.”
However, one of ordinary skill in the art would have recognized that Reszka’s ex vivo analysis of a biological sample using specialized chromatography, mass-spectrometry, automated sample-processing, and computer-assisted comparison equipment would conventionally be conducted at a testing laboratory having the instruments and trained personnel needed to perform those operations. Accordingly, it would have been obvious to send the collected sample to such a testing laboratory, where the laboratory would determine the biomarker amount and compare the determined amount with Reszka’s reference.
The modification would merely locate Reszka’s disclosed ex vivo determining and comparison steps at a conventional facility equipped to perform those steps and would not change the sample, analytical method, reference, or diagnostic result. One of ordinary skill in the art would have been motivated to use a testing laboratory to provide access to the specialized analytical equipment, automated processing, computerized databases, trained personnel, and quality-control procedures used for Reszka’s biomarker analysis. The resulting arrangement would predictably permit the laboratory to perform both the biomarker determination and the reference comparison.
Claim 7, 11, 13-15 and 18-19 is rejected under 35 U.S.C. 103 as being unpatentable over Reszka et al. (WO 2013/079594) (Reszka) in view of Morgell et al. (Journal of Proteome Research, 2021) (Morgell).
Regarding claim 7, Reszka does not expressly teach “wherein 5-oxoproline is at least 2-fold lower in a subject with an increased risk of the pancreatic disease or disorder compared to the reference.”
Morgell teaches subjects having intraductal papillary mucinous neoplasms with low-grade dysplasia, i.e., IPMN-LGD, which are precancerous pancreatic cysts having the potential to progress through high-grade dysplasia to pancreatic cancer (page 2725, par 2). Morgell contrasts these potentially malignant IPMNs with essentially benign serous cystic neoplasms, i.e., SCNs (page 2725, par 2). Thus, an IPMN-LGD subject is a subject having an increased risk of pancreatic cancer relative to an SCN reference subject.
Morgell’s publicly available Supplementary Table 1, worksheet “Rel quant – CYST,” reports the following median relative 5-oxoproline amounts:
IPMN-LGD: 969,633.05; and
SCN: 5,759,874.
Accordingly, the median 5-oxoproline amount in the increased-risk IPMN-LGD group is approximately 5.94-fold lower than the median amount in the essentially benign SCN reference group, thereby teaching the claimed at-least-twofold decrease. The supplementary dataset was publicly posted with the Morgell article on March 15, 2021.
It would have been obvious to one of ordinary skill in the art before the effective filing date to use Morgell’s disclosed magnitude of the 5-oxoproline decrease when applying Reszka’s quantitative 5-oxoproline pancreatic-disease assessment to subjects having precancerous pancreatic cysts. Reszka already teaches determining relative 5-oxoproline amounts and interpreting a decrease relative to a non-cancer reference as indicative of pancreatic disease (Table 6), while Morgell provides pancreatic-cyst-fluid data showing that an increased-risk IPMN-LGD subject has a 5-oxoproline amount more than twofold lower than an SCN reference.
One of ordinary skill in the art would have been motivated to improve the 5-oxoproline-based pancreatic-disease risk-assessment method by using the pronounced decrease observed in IPMN-LGD cyst fluid to distinguish subjects having precancerous pancreatic cysts from subjects having essentially benign SCNs, as suggested by Morgell’s quantitative comparison.
Regarding claim 11 and 13, Reszka teaches the method of claim 1 as set forth above, including determining the amount of 5-oxoproline in a biological sample, comparing the amount with a reference from subjects not having pancreatic cancer, diagnosing pancreatic cancer from a change in the biomarker amount, and selecting and applying pancreatic-cancer therapy.
Reszka teaches that the biological sample may be a tissue sample obtained by biopsy or a biological or physiological fluid (page 7, line 20-21). However, Reszka does not expressly teach that the biological sample comprises pancreatic tissue or pancreatic juices or fluids, as required by claim 11, or that the biological sample is pancreatic cyst tissue or pancreatic cyst fluid, as required by claim 13.
Morgell teaches obtaining and analyzing pancreatic cyst fluid from subjects having pancreatic cystic neoplasms (page 2725, par 2). Morgell explains that patients undergoing pancreatic surgery for suspected pancreatic cystic neoplasms were included and that the study analyzed cyst fluid from serous cystic neoplasms, low- and high-grade intraductal papillary mucinous neoplasms, and pancreatic ductal adenocarcinoma (page 2727, par 4).
Morgell specifically teaches collecting pancreatic fluid and pancreatic cyst fluid:
“Fluid from the main pancreatic duct was collected using a syringe without needle. When the cystic lesion was readily identified in the intact specimen, the fluid was aspirated using a syringe with needle.” (page 2727, par 5).
Morgell further teaches that 55 pancreatic cyst-fluid samples were analyzed and that the cyst fluid was subjected to metabolite extraction and mass-spectrometric analysis (page 2727, par 7). Thus, Morgell teaches both a pancreatic fluid, satisfying claim 11, and pancreatic cyst fluid, satisfying claim 13.
Morgell also teaches determining 5-oxoproline in pancreatic cyst fluid. Morgell reports that quantitative biomarker analysis of cyst fluid from subjects having serous cystic neoplasms and pancreatic ductal adenocarcinoma identified gamma-glutamyl-cycle metabolites including 5-oxoproline as pancreatic-cyst-fluid biomarkers (page 2731, par 1).
Reszka and Morgell are analogous art because both concern metabolomic analysis for diagnosing pancreatic cancer, including determining and comparing metabolic-biomarker amounts in biological samples obtained from subjects.
Reszka expressly permits the biological sample to be a tissue sample or biological fluid but primarily exemplifies blood, plasma, and serum. Morgell teaches that pancreatic cyst fluid is a suitable biological fluid for determining metabolic biomarkers, including 5-oxoproline, in subjects having pancreatic cystic neoplasms and pancreatic ductal adenocarcinoma.
It would have been obvious to one of ordinary skill in the art before the effective filing date to use Morgell’s pancreatic cyst fluid as the biological fluid in Reszka’s 5-oxoproline pancreatic-cancer diagnostic and treatment method. The modification would merely select a known pancreatic biological fluid containing the same metabolic biomarker for use in Reszka’s disclosed determination and comparison process.
Regarding claim 14, Morgell teaches the method further comprises analyzing cyst characteristics, cytology, or a combination thereof (page 2727, par 5 & 7).
Morgell teaches that fresh pancreatic resection specimens were examined by a specialist pancreatic pathologist and that:
“Macroscopic assessment to identify the cystic lesion and main pancreatic duct was done by a specialist pancreatic pathologist.” (page 2727, par 5).
Morgell further teaches:
“Resection specimens were fixed in 4% formaldehyde and processed for routine histopathological diagnosis. The cystic lesions were classified by light microscopy examination of hematoxylin-eosin-stained slides by a specialized pancreatic pathologist as IPMN or SCN. The grade of dysplasia in IPMN was assessed using a 2-grade (high/low) scale.” (page 2727, par 7).
Thus, Morgell analyzes cyst characteristics including the macroscopic appearance of the cystic lesion, the histopathological characteristics of the cyst tissue, the cyst type, and the grade of dysplasia. Because claim 14 recites the alternatives “cyst characteristics, cytology, or a combination thereof,” Morgell’s analysis of cyst characteristics is sufficient to satisfy the limitation; Morgell need not additionally perform cytology.
It would have been obvious to one of ordinary skill in the art, when using Morgell’s pancreatic cyst fluid in Reszka’s biomarker method, to also analyze the characteristics of the cyst from which the fluid was obtained. Morgell uses the macroscopic and histopathological analyses to establish the cyst diagnosis and grade against which the cyst-fluid metabolite measurements are evaluated. The combined method would therefore predictably permit the 5-oxoproline result to be correlated with the pathological characteristics of the pancreatic cyst.
Regarding claim 15, Morgell teaches the method further comprises differentiating any or all of the pancreatic cysts as malignant or benign, mucinous or non-mucinous, or a combination thereof (page 2725, par 2; page 2727, par 7; page 2731, par 1).
Morgell teaches that pancreatic cystic neoplasms include:
“intraductal papillary mucinous neoplasms (IPMNs), which have a potential to transform from low-grade dysplasia (LGD) through high-grade dysplasia (HGD) to cancer.” (page 2725, par 2).
Morgell further teaches:
“Discriminating these potentially malignant cysts from essentially benign cysts of the pancreas, such as serous cystic neoplasms (SCNs) is a delicate matter.” (page 2725, par 2).
Morgell performs that differentiation by histopathologically classifying the cystic lesions as IPMN or SCN, grading the IPMNs as LGD or HGD, and separately classifying specimens having invasive pancreatic ductal adenocarcinoma as PDAC:
“The cystic lesions were classified by light microscopy examination of hematoxylin-eosin-stained slides by a specialized pancreatic pathologist as IPMN or SCN.” (page 2727, par 7).
“Specimens with concomitant invasive pancreatic ductal adenocarcinoma were classified as ‘PDAC’ and considered as a separate class for further analyses.” (page 2727, par 7).
Morgell further expressly uses its quantitative metabolite measurements to distinguish:
“precancerous and cancerous (HGD or PDAC) vs noncancerous IPMNs and serous cystic neoplasms (LGD or SCNs) in pancreatic cyst fluid” (page 2731, par 1).
Thus, Morgell differentiates pancreatic cysts as cancerous or noncancerous, corresponding to the claimed malignant or benign categories. Morgell also differentiates mucinous IPMNs from serous cystic neoplasms, thereby distinguishing mucinous cysts from non-mucinous cysts.
It would have been obvious to one of ordinary skill in the art to use Morgell’s cyst classification together with Reszka’s pancreatic-cancer biomarker method because the classification permits the measured metabolic-biomarker amounts to be correlated with clinically relevant pancreatic-cyst categories. One of ordinary skill would have been motivated to improve the diagnostic utility of the combined pancreatic-cyst-fluid biomarker method by differentiating potentially malignant or cancerous cysts from benign or noncancerous cysts, as suggested by Morgell’s express objective of distinguishing cysts that may progress to pancreatic cancer from essentially benign cysts.
Regarding claim 18, Morgell teaches wherein decreased amounts of 5-oxoproline are associated with a mucinous cyst when compared to a reference non-mucinous cyst sample,” Morgell analyzes cyst fluid from intraductal papillary mucinous neoplasms (IPMNs) and serous cystic neoplasms (SCNs). IPMNs are mucinous pancreatic cysts, whereas SCNs are non-mucinous pancreatic cysts. Morgell classifies the cyst-fluid samples as SCN, IPMN with low-grade dysplasia, IPMN with high-grade dysplasia, or pancreatic ductal adenocarcinoma and performs quantitative metabolomic analysis of the samples.
Morgell expressly identifies 5-oxoproline among the top pancreatic cyst-fluid biomarkers distinguishing SCN from PDAC. (page 2731, par 1). Morgell’s publicly available Supplementary Table 1, in the worksheet titled “Rel quant – CYST,” further reports the following median 5-oxoproline measurements:
IPMN LGD: 969,633.05;
IPMN HGD: 2,997,738; and
SCN: 5,759,874.
Accordingly, the measured 5-oxoproline amount is lower in the mucinous IPMN cyst-fluid groups than in the non-mucinous SCN cyst-fluid group. Morgell therefore teaches that decreased amounts of 5-oxoproline are associated with a mucinous cyst when compared with a non-mucinous cyst reference. The supplementary dataset was publicly posted with Morgell on March 15, 2021.
It would have been obvious to one of ordinary skill in the art to use Morgell’s disclosed direction of change in 5-oxoproline when applying Reszka’s 5-oxoproline pancreatic-disease assessment to pancreatic cyst fluid. Morgell expressly demonstrates that comparing the 5-oxoproline amount in mucinous IPMN cyst fluid with the amount in non-mucinous SCN cyst fluid provides a metabolic distinction between the cyst types.
Regarding claim 19, Morgell teaches wherein 5-oxoproline is at least 2-fold lower in the mucinous cyst compared to the reference non-mucinous cyst sample.
Morgell’s Supplementary Table 1 reports a median 5-oxoproline measurement of 969,633.05 for the mucinous IPMN-LGD cyst-fluid group and 5,759,874 for the non-mucinous SCN cyst-fluid group. The IPMN-LGD amount is approximately 0.168 times the SCN amount, or approximately 5.94-fold lower than the non-mucinous SCN reference amount.
Thus, Morgell expressly provides quantitative data showing that the amount of 5-oxoproline in a mucinous pancreatic cyst is at least twofold lower than the amount in a non-mucinous pancreatic cyst sample.
It would have been obvious to use Morgell’s disclosed magnitude of decrease in Reszka’s quantitative 5-oxoproline comparison because Reszka already teaches quantitatively determining the amount of 5-oxoproline and using a decrease relative to a non-cancer reference to assess pancreatic disease. Morgell supplies the cyst-type-specific quantitative relationship and demonstrates that the difference is sufficiently large to distinguish mucinous IPMN cyst fluid from non-mucinous SCN cyst fluid.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797
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