Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the genes C4, MMP9 and NAIP in the reply filed on 5/20/2025 is acknowledged.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 15/028732, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior application does not mention obtaining a biological sample of extracellular vesicles from a patient and determining an expression level of a cluster of at least three genes from the tables. Furthermore, with regard to the elected species, the previous disclosure does not mention this cluster of three genes. The effective filing date of the instant claims is 6/1/2021.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 29, 32-40, and 43-47 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 29 is indefinite because it recites three separate steps and does in include a conjunction joining them, so it is unclear if the claims are all three required or alternatives. In the interest of compact prosecution, the claim has been read as requiring all three steps.
Claim 29 is unclear because the steps set forth do not inherently detect upregulation and it is not clear how the “thereby” is accomplished by the mere contacting of the sample with affinity agents.
Claim 33 recites “said determining step” which lacks proper antecedent basis because claim 29 no longer recites a “determining step.” Furthermore, note: if claim 33 is amended to recite “said detecting upregulation” the claim will fail to further limit claim 29 which now requires the contacting set forth in claim 33.
Claim 34 is indefinite over the recitation “using an input quality method” because this term is not defined in the specification, nor is it a term of art such that it has a well-established definition. The metes and bounds of the term cannot be understood when the claim is read in light of the disclosure. The specification does refer to an “input quantity method” where “input sample quantity” refers to accurate measurement of the amount of the starting material used for extraction of RNA (p. 15, lines 11-23), but the specification does not define or explain “input quality method” as currently claimed.
Any claim not specifically addressed is indefinite in light of the issues identified in independent claim 29 because those additional claims depend from claim 29 and therefor incorporate the issues by dependency.
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 29, 32-40, and 43-47 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea and a natural phenomenon without significantly more.
The claim(s) recite(s) “detecting upregulation” relative to predetermined control levels, which could be accomplished by reviewing obtained data, and is an abstract idea judicial exception. Further the claims recite “upregulation relative to a predetermined control” which describes a comparison which is an additional abstract idea judicial exception. The claims recite the relationship between gene expression in EV and increased risk for development of acute ischemic stroke, which is a natural phenomenon.
The judicial exceptions are not integrated into a practical application because the majority of claims do not recite any steps that apply or use the judicial exceptions. The steps in addition to the judicial exceptions are presolution data gathering steps.
Claims 36 and 38-39 recite “administering an agent useful for the amelioration of stroke symptoms to said patient” but this does not integrate the judicial exception because (1) the treatment is general, not specific and (2) the treatment is applied to all patients tested no matter whether there is a finding of increased risk of stroke in the independent claim.
Claim 37 recites more specific agents, but it still applies the treatment to any patient tested, no matter the outcome, so it does not integrate the exceptions.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps of “obtaining a biological sample of EVs from a patient” and “detecting upregulation … by contacting said sample with agents having affinity for each of said markers in said cluster” is a mere data gathering step recited at an extremely high level of generality and would be necessary to apply the judicial exception.
The claims recite that the detecting upregulation step includes processes that comprise physical manipulation of the sample by isolating EVs using EV-MAP and contacting with affinity agents to detect gene expression levels. These steps do not amount to significantly more than the judicial exceptions because they are presolution data gathering steps recited at an extremely high level of generality and would be necessary to apply the judicial exception. Further, such methods were well established as of the filing date. See prior art references applied herein.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 29, 32-40, and 43-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for practicing the “obtaining” and “detecting upregulation” steps set forth in claim 29 with respect to the elected gene cluster: CA4, MMP9, and NAIP, and for identifying a patient having an increased risk for stroke by practicing steps (a) and (b) with respect to the elected gene cluster, wherein step (a) includes isolating EV using an anti-CD15 antibody, does not reasonably provide enablement for methods wherein upregulation of the cluster is indicative of increased risk for acute ischemic stroke by practicing the recited steps as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The claimed method encompasses obtaining EV from a patient by EV-MAP, including methods which isolate all EV in a sample using a variety of antibodies.
In a test of acute ischemic stroke (AIS) patients versus control patients, EV were isolated using both an affinity capture method (anti-CD8alpha mAB) and PEG precipitation. The Specification teaches that the mRNA profiling of the isolates for the tested five-gene panel differed (figure 10E) owing to “the fact that the PEG method cannot differentiate EVs by parental cell type origin.” Review of Figure 10E shows that the relative abundance of particular transcripts varies depending on the type of isolation procedure used.
With regard to the elected gene cluster, the specification teaches that the elected gene cluster is characteristic for ischemic stroke and was identified in CD15-granulocytes (Table 11, p. 82). The prior art also provides this teaching, see Adaminski et al. (2017; cited below). No prior art provides an additional guidance about how to predict AIS using the elected markers and any EV isolation technique other than affinity capture with anti-CD15 mAB.
It is highly unpredictable, however, in view of the teachings in the specification whether or not the presently claimed method would operate by employing methods for “obtaining” the EV using methods other than those that isolate EV using an antiCD-15 antibody. The experimentation required to determine the techniques for performing such a method would be extremely high, since there is no way to know if it is even possible to practice the method using EV isolation techniques other than isolation of the EV with CD15 on the surface.
Therefore, having considered all of this, it is concluded that it would require undue experimentation to practice the invention commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
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) 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, and 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adaminski 2017, Medical Research Archives, vol. 5, issue 11, November 2017 issue, 13 pages in view of Wijerathne et al. (Communications Biology(2020) 3:613, 11 pages).
Adaminiski et al. teach CD15+ granulocyte-based gene expression clusters for ischemic stroke detection, including a method which employs HT RT-qPCR for detecting CA4, MMP9, and NAIP in CD15+ cells, wherein the expression of these sells is significantly characteristic for acute ischemic stroke (section 2.4 and Table 3). Adaminski et al. teach a method in which this gene cluster was used to differentiate stroke patients from healthy controls (section 3.4).
The “wherein” clause is a statement of an inherent property of the relationship between gene expression and risk of stroke, and there is no further action implied or required by this statement. Further the statement in the preamble “for identifying patients having increased risk for acute ischemic stroke” is a statement of intended use, and the method taught by the reference could be used as intended. Claim 32 further defines the “wherein” clause and does not require any further action.
Regarding claim 33-35 and 40, the reference teaches determining expression levels by HT RT-PCR, including a step of counting the number of cells that were extracted (Section 2.2, 2.4, 2.5). This method inherently meets the limitations of the recited claims.
Adaminski et al. does not teach determining the expression levels of this cluster of three genes in a biological sample of extracellular vesicles from a patient.
Wijerathne teaches that affinity enrichment of extracellular vesicles from plasma reveals mRNA changes associated with acute ischemic stroke. Wijerathne demonstrates the method with 5 markers that had been previously shown to have differential expression in CD8+ blood cells, and teaches “[t]o improve the clinical sensitivity, larger gene panels can be usedalong with enrichment of both CD8(+) and CD15(+) EVs; CD15(+) neutrophils have been identified as a source of mRNA markers for AIS as well (p. 7, Col. 2).”
Regarding claims 36 and 37, Wijerthane teaches that if a patient tests positive for AIS, the patient would be transported to a stroke center for administration of rt-PA therapy (p. 9, second column). The reference teaches that the disclosed method could reflect the physiological perturbation imposed by AIS within three hours of stroke onset and thus provide indications of disease within time constraints imposed by effective rt-PA treatment (p. 7). The reference teaches that the assay required 3.7 hours of processing time (p. 7), and that the time the assay requires is optimizable and could be reduced by as much as 58 minutes by using photocleavable linkers (p. 8).
Regarding claims 41 and 42, the reference teaches isolating EVs from a biological sample by EV-MAP (p. 9).
It would have been prima facie obvious to one having ordinary skill in the art to have modified the method taught by Adaminski so as to have isolated EV from blood of a patient and measured the expression of CA4, MMP9, and NAIP in CD15+ EV. One would have been motivated to make such a modification by the teachings of Wijerathne regarding the benefits of a blood-based test for AIS such as to provide an assay that can operate as a point of care test for early response to AIS (p. 9, 1st column). Furthermore, upon identifying a patient having AIS profile, it would have been obvious to have delivered the rt-PA treatment as quickly as possible.
Claim(s) 29, 32-35, 36, 38-39, 40, 41, and 42-47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adaminski 2017, Medical Research Archives, vol. 5, issue 11, November 2017 issue, 13 pages in view of Reategui et al. (NATURE COMMUNICATIONS (2018) 9:175, 11 pages).
Adaminiski et al. teach CD15+ granulocyte-based gene expression clusters for ischemic stroke detection, including a method which employs HT RT-qPCR for detecting CA4, MMP9, and NAIP in CD15+ cells, wherein the expression of these cells is significantly characteristic for acute ischemic stroke (section 2.4 and Table 3). Adaminski et al. teach a method in which this gene cluster was used to differentiate stroke patients from healthy controls (section 3.4).
The “wherein” clause is a statement of an inherent property of the relationship between gene expression and risk of stroke, and there is no further action implied or required by this statement. Further the statement in the preamble “for identifying patients having increased risk for acute ischemic stroke” is a statement of intended use, and the method taught by the reference could be used as intended. Claim 32 further defines the “wherein” clause and does not require any further action.
Regarding claim 33-35 and 40, the reference teaches determining expression levels by HT RT-PCR, including a step of counting the number of cells that were extracted (Section 2.2, 2.4, 2.5). This method inherently meets the limitations of the recited claims.
Adaminski et al. does not teach determining the expression levels of this cluster of three genes in a biological sample of isolated extracellular vesicles from a patient. Adaminski does not teach administering an agent useful for the amelioration of stroke symptoms.
Reategui teaches isolating EV from specific cell types enhances tumor specific specificity for analysis of cargo, and is a rapid means to isolate the EV (p. 2). The reference teaches that EV allow biomarker monitoring in a much-needed non-invasive manner. Antibodies were used to enrich for target EV, including antibodies to surface markers highly expressed in target cells (p. 2, Col. 2). The EV were isolated using a microfluidic affinity purification system.
It would have been prima facie obvious to have modified the method taught by Adaminski so as to have isolated the CD15+ EV in blood samples and to have measured the expression of the diagnostic gene clusters. One would have been motivated to do so in order to provide an alternative diagnostic test that could be performed rapidly for the detection of diagnostic stroke markers in patients, since Reategui teaches that the microfluidic purification system allows for rapid isolation of EV from blood, and subsequently allows for release of cargo. Furthermore, treatments for patients experiencing stroke or stroke symptoms were widely known at the time of the invention. Following the identification of patients having stroke symptoms, it would have been obvious to have given them an agent to ameliorate those symptoms, whether or not the assay for determining EV gene expression had been completed. The claims do not require any particular order of steps. One would have been motivated to give a treatment to avoid as many effects of the stroke as possible, and to give the treatment as early as possible, within minutes, an hour or only a few hours. Further still, since the basic method claimed here was taught by the references, it would have been obvious to optimize the method to reduce the time the method required to be carried out, for the benefit of using less time. Absent an unexpected result, such optimization would have been obvious.
Claim(s) 36-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Adaminski 2017, Medical Research Archives, vol. 5, issue 11, November 2017 issue, 13 pages in view of Reategui et al. (NATURE COMMUNICATIONS (2018) 9:175, 11 pages) as applied to claims 29, 32-35, 36, 38-39, 40, 41, and 42-47 above, and further in view of Zoppo et al. (Stroke. 2009 August ; 40(8): 2945–2948. doi:10.1161/STROKEAHA.109.192535.).
The teachings of Adaminski in view of Reategui et al. are given previously in this office action and fully incorporated.
These do not teach treatment of the patient with rt-PA.
Zoppo et al. teach that patients with ischemic stroke are typically treated rtPA within 3 hours of symptom onset, and newly teach that patients who meet criteria can be treated in the time period of 3 to 4.5 hours (p. 3).
It would have been obvious to have treated any patient having an AIS with rt-PA within three hours of symptom onset for the benefit of improving neurological outcomes following stroke.
Response to Remarks
Any rejection not maintained or otherwise addressed was overcome by amendment to the claim 10/17/25.
Applicant traverses the rejection for an improper Markush group. Applicant argues that the different members of the group belong to the same “physical or chemical class or the same art-recognized class.” The argument is convincing because the prior art of Adamski et al. (2017) teaches all of these genes as stroke related transcripts identified in microarray gene expression studies. Consistent with MPEP 2117(II)(A), it is clear from the prior art that all of the recited markers have utility as being members of clusters that can distinguish patients having an increased risk for acute ischemic stroke.
Regarding the 101, applicant argues that the claims not recite or describe any recognized exception, and even if they do the embody practical applications of the exception because they use techniques to detect markers. However, the techniques used to detect the markers does not apply the exception; it does not use it in any way. The rejection is modified to address the amended claims and maintained.
Regarding the rejection under 112a, applicant argues that the technique is fully enabled, however, with regard to the elected combination, the claim is sufficiently broad so as to encompass EV-MAP isolation of any EV, where the specification clearly suggests that the cluster would only function for EV isolated using an anti-CD15 antibody. The rejection is maintained.
Applicant argues against the 103 rejections that rely on Wijeranthe because Wijeranthe is “improperly cited as prior art.” However, the reference is a grace period reference, and cites authors in addition to the inventors. In order to remove the reference, an executed declaration should have been timely filed. See MPEP 717.01.
Applicant argues against the 103 that rely on Reategui stating that EV-MAP refers to “Extracellular Vesicle Machine Learning Analysis Platform” which uses a machine learning approach to analyze data from EV and generate disease specific scores. Applicant further argues that EV-MAP combines microfluidic flow cytometry and clinical data to create predictive models for disease diagnosis.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., machine learning, flow cytometry, creating predictive models) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The broadest reasonable interpretation of “EV-MAP” is informed by p. 6 of the specification which states “EVs are isolated using EV microfluidic affinity purification (EV-MAP).” The technique taught by Reategui teaches affinity purification of extracellular vesicles using a microfluidic affinity purification system (p. 2, Col. 2) which is a technique that is withing the broadest reasonable interpretation of “EV-MAP” as set forth on p. 6 of the specification. The rejection is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at (571)-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/ Primary Examiner, Art Unit 1682