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 .
Claims Status
Claim(s) 1-19 are pending. The Amendment, filed on 26Jun2025, is acknowledged in which claim(s) 4-7, and 15-19 are canceled by Applicant, and claim(s) 20-25 are newly added by Applicant.
Claim(s) 1-3, 8-14, and 20-25 are presented for examination on the merits.
Response to Amendment
Applicant’s claim amendments overcame the following rejections:
All previous rejections of claim(s) 4-7 and 15-19 are moot in view of claim cancellation.
Rejection of claim(s) 1, 11, under 35 U.S.C. § 112(b) are withdrawn in view of claim amendments.
Rejection of claim(s) 1-3, and 8-13 under 35 U.S.C. § 102.
Rejections of claim(s) 14, under 35 U.S.C. § 103.
The previously set forth 35 U.S.C. § 102 rejections of claim(s) 1-3 and 8-13 and 35 U.S.C. § 103 rejections of claim(s) 14 have been withdrawn in view of the recent claim amendment filed on 26Jun2025, which added new limitations to the claims, that were not considered in the previous rejections, necessitating new and/or modified rejections (see below).
Additionally, the amendment filed on 26Jun205 added new claims 20-25, necessitating new rejections (see below).
All other previously presented objections and/or rejections are maintained for reasons given in the "Response to Arguments" below. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Rejections/Objections Maintained/New Rejections Necessitated by Claim Amendments
Drawings
The drawings are objected to because figures 2-6 are not of sufficient resolution to clearly read and/or understand. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Response to Arguments
Applicant indicated under response to Drawings objections that “Claims 11 and 15 are objected to because of informalities…”. [e.g., pg.1, Drawings]
The drawings were objected to because “…figures 2-6 are not of sufficient resolution to clearly read and/or understand…”, see prior office action [e.g., pg. 2]. Applicant arguments have been fully considered but are not considered relevant to the objections at hand and therefore the drawing objections are maintained.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 10, 13, and 21 is/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.
Regarding claim 10, the phrase "including observing that…" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purposes of compact prosecution, the limitations following the phrase “including observing that…” are not considered part of the instant claimed invention. This rejection can be overcome by amending claim 10 to (1) remove the phrase “including observing that” and all of the limitations following said phrase.
The phrase “other relevant pancreatic conditions” in claim 10 is a relative phrase which renders the claim indefinite. The term “other relevant pancreatic conditions” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. This language results in ambiguity as to whether this is the embodiment under examination or is an example. For the purpose of compact prosecution, the Examiner will consider this term to be any human pancreatic disease for which extracellular vesicles serve as biomarkers. This rejection may be overcome by amending claim 10 to (1) remove the phrase “other relevant pancreatic conditions”, or (2) replace “other relevant pancreatic conditions” with a specific pancreatic condition or list of specific pancreatic conditions.
Regarding claim 13, the phrase “enriched compounds (biomarkers)” renders the claim indefinite because the word(s) in parenthesis should define the preceding limitation; for example “extracellular vesicle (EV)” is appropriate. However, the recitation of “enriched compounds (biomarkers)” in the instant claim renders unclear if the limitation requires (1) an enriched compound, (2) biomarkers, or (3) enriched biomarkers. This rejection may be overcome by amending claim 13 to (1) remove “enriched compounds”, or (2) remove “(biomarkers)”.
Regarding claim 21, the phrase "including observing that…" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purposes of compact prosecution, the limitations following the phrase “including observing that…” are not considered part of the instant claimed invention. This rejection can be overcome by amending claim 21 to (1) remove the phrase “including observing that” and all of the limitations following said phrase.
Response to Arguments
Applicant argues “Claims 1 and 10-11 are rejected under 35 U.S.C. 112(b) as being indefinite. Applicant respectfully submits that the claims are amended to clarify and/or remove the indefinite and relative recitations. Reconsideration and withdrawal of these rejections is therefore respectfully requested.” [e.g., pg. 1, rejections under 35 USC 112]
Applicant amendments overcame all previous 112b rejections except the rejection for “other relevant conditions” which was amended to “other relevant pancreatic conditions”. The addition of the word ‘pancreatic’ to the phrase did not render the claim definite. Briefly, there is no indication in the specification or the claim language as to which other pancreatic conditions would be ‘relevant’.
Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive. For the above reasons, the rejection has been maintained in modified form.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3 and 8-9 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 1-3 and 8-9 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a composition of matter (product) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards the natural phenomenon (product of nature) of a “biomarker consists of extracellular vesicle (EV) proteins enriched from blood using a method for Extracellular Vesicles total recovery and purification (EVtrap), resulting in greater than 95% recovery yield, greater than 99% purity and with less than 5% coefficient of variation of the biomarker; and wherein the biomarker is capable of differentiating blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change”. In the broadest reasonable interpretation of the claim, the compound as claimed comprises EV proteins which occur naturally within a human body.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim 1 recites that the EV proteins claimed “…are capable of differentiating blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change.”, these do not integrate the judicial exception into a practical application, but rather are generally linking the use of the judicial exception to a particular technological environment or field of use (see MPEP § 2106.05(h)).
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. The applicant disclosure summarizes the state of the art (e.g., specification, paragraph 0011), that EVs are involved in cellular communication, oncogenic signals, inflammatory signals, are more abundant than circulating tumor cells, and are uniquely stable (e.g., versus soluble proteins), underscoring the utility of EV proteins as potential serological biomarkers and attractive strategies for diagnosing cancers (e.g., liquid biopsies). The EV proteins are natural phenomena in humans, and given the Applicant’s disclosure, the invention as claimed does not recite additional specific limitations other than what is well-understood, routine, conventional activity in the field (see MPEP § 2106.05(d)). Additionally, enriching EVs that are naturally present in the human population does not make them markedly different from cells that exist naturally. Further, the instant claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements fail to modify the structural or function characteristics of the naturally occurring EV proteins.
Claims 2-3 and 8-9, which depend from claim 1, act to further limit the biomarker type (e.g., exosome(s), protein(s), pre-determined panel), detection (e.g., capture, enrichment, isolation), and/or matrix (e.g., human biofluid, plasma, serum). The limitations do not amount to significantly more than the judicial exception.
As the instant claims 1-3 and 8-9 recite judicial exceptions and claim a population of subjects for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
Claims 10-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 10-14 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a process (method) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards the abstract idea “early-stage detection of pancreatic cancer from one or more blood samples…”. In the broadest reasonable interpretation of the claim using an enriched biomarker level in any of the ways recited above comprise the mental step of identifying that the biomarker level is detectable and/or a mental comparison between the biomarker level and a reference level.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim 10 recites “early-stage detection of pancreatic cancer from one or more blood samples comprising the steps of: providing the one or more blood samples, wherein the one or more blood samples are from humans with at least one of the following; pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis of different etiologies, intraductal papillary mucinous neoplasm (IPMN), or other relevant pancreatic conditions…” and discloses purposes (see Step 2A, Prong One) for doing so, these do not integrate the judicial exception into a practical application. Specifically, the Applicant’s recitation of ‘other relevant pancreatic conditions’ portion combined with Applicant’s disclosure regarding the utility (e.g., diagnosis) of EV biomarkers in multiple cancer indications [e.g., specification, paragraph 0011] demonstrates that the recitation of detecting biomarkers (as presently claimed) in a given patient population is not a practical application, but rather are generally linking the use of the judicial exception to a particular technological environment or field of use (see MPEP § 2106.05(h)).
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. Additionally, enriching EVs that are naturally present in the human population does not make them markedly different from cells that exist naturally. Additionally, while the act of determining the enriched biomarker level in the sample from a patient could require performance of an assay, this is considered to be necessary data gathering steps for the judicial exception and, therefore, do not amount to significantly more than the judicial exception that is claimed.
Claims 11-14, which depend from claim 10, act to further limit the enriched biomarker selection (e.g., pre-determined panel), sample processing (e.g., filtering, protein profiling), and/or analysis (e.g., predictive capacity, novel biomarker identification, biostatistical analysis, fold change). The limitations do not amount to significantly more than the judicial exception.
As the instant claims 10-14 recite judicial exceptions and claim a population of subjects for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
Claims 20-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature (natural phenomenon) without significantly more.
Claims 20-25 are evaluated using the “Subject Matter Eligibility Test for Products and Processes” flow chart as shown in MPEP § 2106 (III).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Yes. The claim is drawn to a process (method) which is one of the four statutory categories.
Step 2A, Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes. The claims are directed towards the abstract idea “early-stage detection of pancreatic cancer…”. In the broadest reasonable interpretation of the claim using an enriched biomarker level in any of the ways recited above comprise the mental step of identifying that the biomarker level is detectable and/or a mental comparison between the biomarker level and a reference level.
Step 2A, Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No. While claim 10 recites “…comprising the steps of: isolating extracellular vesicles (EVs) from blood samples from humans with pancreatic cancer and healthy controls; capturing at least one extracellular vesicle (EV) compound, wherein the compound consists of EV proteins enriched from the blood using a method for Extracellular Vesicles total recovery and purification (EVtrap), resulting in a greater than 95% recovery yield, greater than 99% purity and with less than 5% coefficient of variation of the at least one EV compound; analyzing the at least one EV compound by liquid chromatography-mass spectrometry, wherein the analysis step generates an EV protein profile (EV proteomics) for each blood sample; and detecting differences between the EV proteomics of humans having pancreatic cancer and of the EV proteomics of humans having non-cancer conditions or healthy controls.” and discloses purposes (see Step 2A, Prong One) for doing so, these do not integrate the judicial exception into a practical application. Specifically, the Applicant’s recitation of ‘detecting differences between…humans having pancreatic cancer and… humans having non-cancer conditions or healthy controls’ portion combined with Applicant’s disclosure regarding the utility (e.g., diagnosis) of EV biomarkers in multiple cancer indications [e.g., specification, paragraph 0011] demonstrates that the recitation of detecting biomarkers (as presently claimed) in a given patient population is not a practical application, but rather are generally linking the use of the judicial exception to a particular technological environment or field of use (see MPEP § 2106.05(h)).
Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?
No. The judicial exception is recited without additional limitations amounting to significantly more than the exception. As discussed above, enriching EVs that are naturally present in the human population does not make them markedly different from cells that exist naturally. Additionally, while the act of determining the enriched biomarker level in the sample from a patient could require performance of an assay, this is considered to be necessary data gathering steps for the judicial exception and, therefore, do not amount to significantly more than the judicial exception that is claimed.
Claims 20-25, which depend from claim 20, act to further limit the enriched biomarker selection (e.g., pre-determined panel), sample processing (e.g., filtering, protein profiling), and/or analysis (e.g., predictive capacity, novel biomarker identification, biostatistical analysis, fold change). The limitations do not amount to significantly more than the judicial exception.
As the instant claims 20-25 recite judicial exceptions and claim a population of subjects for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are recited, the claims were found not to be drawn to eligible subject matter under 35 USC § 101.
Response to Arguments
Applicant asserts that the amended claims are not “directed to” a judicial exception. As amended, independent claim 1 recites a biological composition, isolated from an enriched specific population of nanoparticles (EVs), and characterized as a specific biomarker for a disease. Although nature-based product limitations are recited in the claim (e.g., biological samples and biomarker), analysis of the claim as a whole indicates that the claim is focused on a biomarker useful in detecting whether a person has a disease, and is not focused on the products per se. Claim 1 and Claim 11, as a whole, each integrates the abstract idea (i.e.: EV proteins isolated from enriched EVs not naturally occurring) into a practical application by applying, relying on, or using the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Accordingly, the claims recite a biomarker that is more than a mere instruction to “apply” a law of nature using well-understood, routine or conventional techniques in the field. Prior to the Applicant’s invention, and at the time the application was filed, isolating vesicles from biological samples was not routinely or conventionally used to detect the specific vesicle biomarkers recited in amended Claim 1 and Claim 11. Furthermore, these proteins are not apparent or detectable without the enrichment required in the currently amended claims. [e.g., pgs. 1-2, rejections under 35 USC 101]
Claims 1-3 and 8-9 are drawn to the enriched compound of EV protein biomarkers. Claims 10-14 and 20-25 are drawn to methods of detecting cancer comprising detecting the EV protein biomarkers in a sample. No specific biomarkers are recited by name in the Applicant indicated claims 1 and 11, rather the claims refer broadly to EV compounds or ‘the panel of detected compounds’. Additionally, the concentration (e.g., enrichment) of EVs does not overcome the rejection under 101 without a change in the properties of the naturally occurring EVs. Applicant does not provide a way that changes to the EV concentration changes the properties of the EVs of the instant claims. Therefore, the Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive. For the above reasons, the rejection has been maintained in modified form.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-3, 8-14, and 20-25 is/are rejected under 35 U.S.C. 103 as being unpatentable Yang et al. (Sci. Transl. Med. 9, eaal3226 (2017), 24May2017; hereinafter “Yang”), in view of Weiguo and Ilyuk. (US 20190301985 A1, 2019; hereinafter “Weiguo”).
Regarding claims 1, 10-13, 20-23 and 25, Yang teaches a compound comprising a biomarker for pancreatic cancer form a group consisting of extracellular vesicle (EV) proteins wherein the EV protein is capable of differentiating a human with pancreatic ductal adenocarcinoma (PDAC) from a healthy human and a human with other non-cancer conditions (e.g., pancreatitis) [e.g., pg. 6, figs 4A-D]. Yang teaches the EVs including the biomarker(s) are enriched from a human’s biofluid [e.g., pg. 8, materials and methods]. Yang further teaches a method of diagnosis and detection of disease (e.g., PDAC) comprising isolating, detecting, and analyzing EV protein biomarkers [e.g., pg. 1, introduction; pg. 7-9, materials and methods]. Yang further teaches the biomarkers reflected the small tumor mass and/or favorable treatment response (e.g., predictive of drug response to a selected therapy) [pg. 5, col 2, para 1]. One of ordinary skill in the art would understand that biomarkers predictive of response to drug would necessarily be used to inform therapy selection (e.g., a therapy with a predicted favorable response would be selected). Further, one of ordinary skill in the art would understand the enriched biomarkers of the instant claim would necessarily be “capable of differentiation blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change” because this is an observed characteristic of the naturally occurring biomarker composition.
Regarding claim 2, Yang teaches a biomarker with a putative compound identification and name (e.g., MUC1) [e.g., pg. 4, col 1, para 2].
Regarding claim 3, Yang teaches the biomarker protein(s) are from EVs [e.g., pg. 1, abstract].
Regarding claim 8, 14, 24, Yang teaches the biomarker is selected from a pre-determined biomarker panel [e.g., pg. 8, selection of markers].
Regarding claim 9, Yang teaches the EVs include exosomes [e.g., pg. 1, introduction].
Yang does not expressly teach the (1) EV proteins are enriched using EVtrap, resulting in greater than 95% recovery yield, greater than 99% purity, and with less than 5% coefficient of variation of the biomarker, (2) selectively and reversibly binding EVs to enrich the EVs using EVtrap, (3) assessing the predictive capacity of the panel of EVtrap isolated/enriched EV proteins, (4) identification of EVtrap isolated/enriched novel biomarkers, (5) analyzing EVtrap isolated EVs by liquid chromatography-mass spectrometry (LCMS) to generate EV proteomics, (6) detecting differences in EVtrap EV proteomics results of humans having pancreatic cancer and humans having non-cancer conditions or healthy controls, (7) performing biostatistical analysis between cancer and non-cancer control EV proteomics of EVtrap isolates, (8) the EVtrap isolated/enriched biomarker has a putative identification, (9) the EVtrap enriched biomarker is in the EV, (10) the EVtrap isolated/enriched EV is an exosome, or (11) the biomarker from the EVtrap isolated/enriched sample is selected from a pre-determined biomarkers panel.
Weiguo teaches capturing and purifying EV biomarkers using the EVtrap method in human blood samples from subjects with cancer [e.g., title, abstract]. Weiguo further teaches the EVtrap selectively captures (e.g., binds) EVs and then the EVs can be eluted (e.g., were reversibly bound) [e.g., 0051]. Weiguo teaches the EV trap was compared to other known methods and the EVtrap produced the highest exosome yield recovery and lower levels of contamination [e.g., para 0056, figs 3A-B]. The EV biomarkers isolated by EVtrap method necessarily meet the greater than 95% recovery yield, greater than 99% purity, and less than 5% coefficient of variation of the instant claims because these are necessarily direct results of the EVtrap method. Weiguo teaches a step of enrichment of EV cargo (e.g., proteins) from the protein in human biofluids [e.g., pg. 24, paragraph 0060]. Weiguo further teaches the disclosed methods have been demonstrated in plasma (e.g., blood component) [e.g., pg. 21, paragraph 0007]. Weiguo further teaches the utility of EVtrap isolated/enriched EV proteins for the purposes of disease (e.g., cancer) detection, profiling, diagnosis, and monitoring [e.g., pg. 21, background and summary]. Weiguo further teaches EV based disease biomarkers can be identified well before the onset of symptoms or physiological detection of a tumor, making them promising candidates for early-stage cancer and other disease detection [e.g., para 0004]. One of ordinary skill in the art would understand that cancers are stratified by stage, and further that early-stage detection of cancer to be generally associated with a better prognosis. Weiguo teaches the utility of EV methods in biomarker research, discovery and diagnostics including where the presence, absence, increased, or decreased levels of certain EVs or their cargo molecules (e.g., proteins) can serve as an identification of disease state (e.g., a predictive capacity) [e.g., pg. 23, paragraph 0042]. Weiguo teaches the method’s great potential of EV cargo analysis for biomarker research and discovery (e.g., novel biomarker identification) [e.g., pg. 21, paragraph 0004]. Weiguo teaches analyzing the isolated EVs by LCMS proteome analysis (e.g., EV proteomics) [e.g., paras 0043, 0059]. Weiguo teaches performing biostatistical analysis (e.g., fold-change, total number of unique analytes, unique protein identification) of detected biomarkers [e.g., pg. 24, paragraph 0060].
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the method for isolating/enriching EV protein biomarkers taught by Yang, with the EVtrap isolation/enrichment method taught by Weiguo, in the context of designing and developing methods for isolating and/or enriching an EV protein composition for use as cancer biomarkers. A PHOSITA would have been motivated to substitute the EVtrap methods for EV protein biomarker isolation/enrichment as taught by Weiguo in place of the EV protein biomarker isolation/enrichment methods of Yang, because both Yang and Weiguo teach the use of EV protein biomarkers in cancer and methods for isolating/enriching said biomarkers, and Weiguo further teaches the EVtrap method for isolating/ enriching EV proteins results in superior yields with lower contamination than existing methods. There would have been a reasonable expectation of success for a PHOSITA to substitute the EVtrap methods for EV protein biomarker composition isolation and/or enrichment as taught by Weiguo in place of the EV protein biomarker isolation and/or enrichment methods of Yang, Weiguo teaches the EVtrap method for isolating and enriching EV proteins results in superior yields with lower contamination than existing methods. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified methods of EVtrap EV protein biomarker composition isolation/enrichment as taught by Yang and Weiguo (see above) to include the (1) EV proteins are enriched using EVtrap, resulting in greater than 95% recovery yield, greater than 99% purity, and with less than 5% coefficient of variation of the biomarker, (2) selectively and reversibly binding EVs to enrich the EVs using EVtrap, (3) assessing the predictive capacity of the panel of EVtrap isolated/enriched EV proteins, (4) identification of EVtrap isolated/enriched novel biomarkers, (5) analyzing EVtrap isolated EVs by liquid chromatography-mass spectrometry (LCMS) to generate EV proteomics, (6) detecting differences in said EV proteomics of humans having pancreatic cancer and humans having non-cancer conditions or healthy controls, (7) performing biostatistical analysis between cancer and non-cancer control EV proteomics of EVtrap isolated, (8) the EVtrap isolated/enriched biomarker has a putative identification, (9) the EVtrap enriched biomarker is on, in or about and EV, (10) the EVtrap isolated/enriched EV is an exosome, and (11) the biomarker from the EVtrap isolated/enriched sample is selected from a pre-determined biomarkers panel as taught by Weiguo, because both Yang and Weiguo teach the use of EV protein biomarkers in cancer and methods for isolating/enriching said biomarkers, and Weiguo teaches EVtrap is superior to previous methods of EV isolation/enrichment (see above) as well as additional EVtrap method parameters. There is an expectation of success for a PHOPSITA to substitute the modified EVtrap method parameters as taught by Weiguo in place of the modified methods of EVtrap EV protein biomarker composition isolation/enrichment as taught by Yang and Weiguo because Yang and Weiguo both teach the isolation/enrichment of EV protein compositions, characteristics, and usefulness as cancer biomarkers, and Weiguo teaches additional parameters for the superior EV isolation/enrichment method, EVtrap . This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant incorporates the claim amendments and arguments used in response to the Office Action’s 102 rejection above. Applicant respectfully submits that none of the cited references discloses nor suggests the recitations of amended Claim 10 or new Claim 20. For at least these reasons, the combination of Weiguo and Yang results in a different method and therefore does not obviate independent Claim 10 and 20 [e.g., pgs. 3-4, rejections under 35 USC 103]
Claim 14 depends from claim 10, therefore any arguments regarding claim 20 from Applicant are not addressed herein. Further, all of the limitations of claim 10 are rendered obvious by a modified 35 USC 103 rejection in view of Yang and Weiguo (see rejection above for details). As the Applicant failed to directly and distinctly point out any specific limitation(s) of claim 10 or claim 14 that are believed to not be disclosed or rendered obvious, specific arguments are unable to be addressed herein. Therefore, the Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive. For the above reasons, the 35 USC 103 rejection of claim 14 has been maintained in modified form.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claim(s) 1-3, 8-14, and 20-25 is/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-18 of copending Application No. 19/250,181 (reference application; hereinafter “A181”). Although the claims at issue are not identical, they are not patentably distinct from each other. It is noted that the new grounds for NSDP rejection is/are necessitated by Applicant filing a new copending Patent Application on 26Jun2025.
Regarding instant claim 1, A181 claim 1 teaches a method of producing an enhanced biomarker compound comprising selecting a biomarker selecting a biomarker for pancreatic cancers, wherein the biomarker consists of EV proteins, enriching a human’s biofluid for the selected biomarker using EVtrap, resulting in greater than 95% recovery yield, greater than 99% purity, and with less than 5% coefficient of variation of the biomarker, wherein the biomarker is capable of differentiating blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change. While A181 teaches a method for producing, it necessarily teaches the produced product (e.g., the enriched biomarker compound).
Regarding instant claim 2, A181 claim 2 teaches the biomarker has a putative compound identification, match form, name, or pathway.
Regarding instant claim 3, A181 claim 3 teaches the biomarker is located on, in or about an EV.
Regarding instant claim 8, A181 claim 5 teaches the biomarker is selected from a predetermined biomarkers panel.
Regarding instant claim 9, A181 claim 6 teaches the EV is selected from the group consisting of an exosome, a microvesicle, and an endosome.
Regarding instant claim 10, A181 claim 7 teaches a method of early-stage detection of pancreatic cancer from one or more blood samples comprising the steps of: providing one or more blood samples, wherein the one or more blood samples are from humans with at least one of the following; pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis of different etiologies, intraductal papillary mucinous neoplasm (IPMN), or other relevant pancreatic conditions; selectively and reversibly binding native EBs from the one or more blood samples to capture and enrich the EVs of the one or more blood samples using EVtrap; detecting at least one compound in at least one or more blood samples, wherein the at least one compound consists of EV proteins enriched from the at least one blood sample, resulting in greater than 95% recovery yield, greater than 99% purity and with less than 5% coefficient of variation of the at least one EV compound; generating a panel of detected compounds for the purposes of pancreatic cancer diagnosis, prognosis, detection, monitoring, patient stratification, drug response analysis, and therapy selection; and analyzing difference in the panel of detected compounds between cancer and non-cancer blood samples including observing that the panel of detected compounds of humans having pancreatic cancer has a clear separation from the panel of detected compounds of humans having non-cancer conditions or healthy controls.
Regarding instant claim 11, A181 claim 8 teaches the panel of detected compounds (of claim 7) is capable of differentiating blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change.
Regarding instant claim 12, A181 claim 9 teaches the method of claim 7 further comprising the step of: assessing the predictive capacity of the panel of detected compounds.
Regarding instant claim 13, A181 teaches the method of claim 7, further comprising the step of: identification of novel enriched compounds (biomarkers).
Regarding instant claim 14, A181 claim 11 teaches the method of claim 7, wherein the at least one compound is selected from a pre-determined biomarkers panel.
Regarding instant claim 20, A181 claim 12 teaches a method for early-stage detection of pancreatic cancer, comprising the steps of: isolating EVs from blood samples from humans with pancreatic cancer and healthy controls; capturing at least one EV compound; analyzing the at least one EV compound by LCMS, wherein the analysis step generates an EV protein profile (EV proteomics) for each blood sample; and detecting differences between the EV proteomics of humans having pancreatic cancer and of the EV proteomics of humans having non-cancer conditions or healthy controls. A181 claim 18 teaches the method of claim 12, wherein the compound consists of EV proteins enriched from the blood using a method for EVtrap, resulting in greater than 95% recovery yield, greater than 99% purity and with less than 5% coefficient of variation of the at least one EV compound.
Regarding instant claim 21, A181 claim 13 teaches the method of claim 12 further comprising: performing biostatistical analysis in the EV protein profile (EV proteomics) between pancreatic cancer and non-cancer controls including observing that the EV proteomics of humans having pancreatic cancer has clear separation from the EV proteomics of humans having non-cancer conditions or healthy controls
Regarding instant claim 22, A181 claim 14 teaches the method of claim 12 further comprising: assessing a disease predictive capacity of the EV protein profile (EV proteomics).
Regarding instant claim 23, A181 claim 15 teaches the method of claim 12 further comprising: identification of novel biomarkers form the EV protein profile (EV proteomics).
Regarding instant claim 24, A181 claim 16 teaches the method of claim 12, wherein at least one EV compound is selected from a pre-determined biomarkers panel.
Regarding instant claim 25, A181 claim 17 teaches the method of claim 12, wherein at least one EV compound is capable of differentiating blood from a human with pancreatic cancer from blood from a healthy human and blood from a human with non-cancer conditions with at least a 4-fold change.
A181 does not expressly teach EVtrap is the method of isolation in claim 12 for dependent methods of A181 claims 13-17.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the broad methods of EV isolation of EVs taught by A181 claim 12, with the specific EVtrap methods of isolation of EVs taught by A181 claim 18, in the context of designing and developing a method for EV isolation. A PHOSITA would have been motivated to substitute the specific EVtrap EV isolation methods of claim 18 in place of the general teaching of an EV isolation method of claim 12 as taught by A181, because A181 teaches EV isolation and continually (in multiple claims) recites the specific use of the EVtrap method for isolation of EV compounds. There would have been a reasonable expectation of success for a PHOSITA to substitute the specific EVtrap isolation method of claim 18 in place of the general EV isolation method of claim 12 taught by A181 because A181 teaches EV isolation and continually (in multiple claims) recites the specific use of the EVtrap method for isolation of EV compounds. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Further, it would have been obvious to a PHOSITA to modify the modified methods of EVtrap isolation of EV compounds (for A181 claims 12 and 18, see above) to include the method limitations of A181 claims 13-17. There is an expectation of success for a PHOPSITA to substitute the additional method limitations of A181 claims 13-17, because A181 doesn’t teach any other specific EV isolation methods other than EVtrap in the claims, and therefore one of ordinary sill in the art would reasonably expect the use of the only specific EV isolation method to function with any dependent methods within the overall claim set as they pertain to isolated EV compounds. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is currently allowed.
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.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643