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 .
Election/Restrictions
Applicant’s election with traverse of Species 1 applicant elects the first member of the proximity pair is a donor molecule and the second member of
the proximity pair is an acceptor molecule; Species 2, applicant elects (a) the first member of the proximity pair is a donor molecule and the second member of
the proximity pair is an acceptor molecule (b) first binding agent is conjugated to the first member of the donor-acceptor pair via biotin-streptavidin; Species 3, applicant elects CD9 ; Species 4 applicant elects PD-L1 ; Species 5 applicant elects anti-PD-L1 ; Species 6 applicant elects non-small cell lung cancer, in the reply filed on April 30, 2026 is acknowledged.
The restriction requirement of Species 5 has been reconsidered as there is no longer a burden to examine the invention of species 5. The restriction requirement of Species 5 is hereby withdrawn.
In view of the above noted withdrawal of the restriction requirement of Species 5, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Regarding the remaining arguments, the Applicant’s traversal is on the ground(s) of:
Argument(s): Applicant argues that there was no establishment of lack of unity regarding the invention and that no art is cited regarding species election and lack of unity of invention.
Applicant’s arguments have been fully considered but are not persuasive.
Applicant argues that the Office failed to establish lack of unity under PCT Rules 13.1 and 13.2 because the Office did not identify a single general inventive concept, identify a special technical feature, or cite prior art demonstrating that the claimed species lack unity.
Applicant’s arguments are not persuasive because the present requirement is an election of species requirement issued during examination of a national stage application under 35 U.S.C. § 371. Such a requirement is based on the presence of patentably distinct species recited in the claims. Neither PCT Rule 13.1 nor PCT Rule 13.2 requires the Examiner to identify a single general inventive concept, identify special technical features, or establish an a posteriori lack of unity through prior art before requiring election of a species.
The election requirement identified distinct species recited in the claims, including distinct donor/acceptor configurations, conjugation arrangements, and binding systems. As stated in the Election Requirement, these alternatives possess different chemical, structural, and/or functional characteristics and are not obvious variants of one another based on the current record. Applicant has not presented persuasive technical evidence demonstrating that these identified species are patentably indistinct or that examination of one species would necessarily encompass examination of the remaining species.
Applicant’s assertions that the identified species merely represent routine substitutions or specific embodiments within a common inventive framework are unsupported and are insufficient to rebut the Examiner’s determination.
Accordingly, Applicant has not shown that the election requirement was improper, and the requirement for election of species is maintained. Therefore, the arguments as presented are not found persuasive because the requirement(s) for species election, as stated, are still deemed proper and is therefore made FINAL.
Claim Status
Claims 1-20 are examined, as encompassing the elected invention. No claims are withdrawn.
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.
Claim 8 is 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 8, the claim recites “AlphaLISA®” assay, the trademark name refers to the name of a good itself but it is not clear if a specific instrument, series of specific reagents, and/or method(s) are required for the measurements for the assay in accordance with the proposed claim limitation, which causes confusion regarding the scope of the claim, and renders the claim indefinite (see MPEP 2173.05 (u)). Appropriate correction is required.
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (abstract idea) without significantly more. The claim(s) recite(s) a method of detecting and/or determining agent(s) that bind to a target protein present on the surface of extracellular vesicles (EVs). The judicial exception is not integrated into a practical application because the mental steps of detecting, determining, integrating, and/or automation are abstract concepts which are performed in the human mind, including an observation, evaluation, judgement, selection, and/or opinion, corresponds to the method steps of a process. In instant case, the assessment step(s) is not defined as anything more than collecting and assessing measurements, provided by automated instrumentation followed by interpretations, to make judgements regarding the administration and responsiveness of antibody inhibitors (described as immunotherapy and/or check-point inhibitors) to subjects with cancer. All these methods may be done mathematically and/or mentally.
With regards to Step 1, Claims 12-19, are considered to be in a statutory category of process.
With regards to Step 2A, prong 1, Claims 12-19 are directed towards to the abstract idea of determining responsiveness of a subject to immunotherapy.
With regards to Step 2A, prong 2, claim 12-19, the additional elements selecting a first binding agent/first target protein expressed on the surface of the EV and/or the second agent/second target protein targets, that are EV surface markers. These are data generating steps, that merely facilitate obtaining the information used in the comparison and do not apply the result for any purpose. Accordingly, the claim does not recite additional elements that alone or together amount to significantly more than the judicial exception itself and does not integrate the exception into a practical application.
With regards to Step 2B: in claims 12-19 , the additional elements beyond the abstract idea, of detecting the level of target(s) is recited in a generic manner and are routine conventional in the prior art as evidenced by Yoshioka et al., (2014). As such, the claim(s) do not recite additional elements that alone or together amount to significantly more than the judicial exception itself.
For the forgoing reasons, claims 12-19 are not deemed to encompass patent eligible matter under 35 USC § 101.
Claim Rejections - 35 USC § 102
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.
Claims 1-4,6-8, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yoshioka, Y et al., Ultra-Sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nature Communications. 2014. (5:3591); pp.1-8 and evidenced by Beaudet, L. et al., AlphaLISA immunoassays: the no-wash alternative to ELISAs for research and drug discovery (PerkinElmer® Advertising Feature). Nature Methods. 2008; pp. an8-an9.
Regarding Claims 1-4,6-8, and 11, Yoshioka et al., disclose a first binding agent that binds a first target protein and a second binding agent that bind a second target protein where both are expressed on the surface of EVs. Additionally, the first binding agent is conjugated to a member of a proximity pair and the second to a second proximity pair (page 2, Figure 1). The ExoScreen method includes an acceptor molecule and a donor molecule and/or vice versa (claims 2 and 3) -- where a streptavidin coated bead is conjugated to streptavidin, captures an analyte-specific biotinylated antibody and is used in conjunction with beads conjugated to a second antibody (page 2, Figure 1) (claim 6). The method of (claim 7) where the biotinylated first binding agent binds to the first target protein and a streptavidin donor molecule and seconding binding agent that binds to the second target protein (evidenced by Beaudet et al., page an9, Figure 3), where the sample can be from plasma or serum (evidenced by Beaudet et al., page an9, paragraph 1). The ExoScreen (claim 8) is a method developed using the AlphaLISA® platform (as evidenced by Beaudet et al., page an8) and detects for EV marker CD9 from control and cancer patients (page 5, Figure 4) (claim 4), from EVs isolated from serum samples (not plasma) (claim 11) (page 7, ‘Patient serum samples’).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 5,9, 10, 12-17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Yoshioka, Y et al., Ultra-Sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nature Communications. 2014. (5:3591); pp.1-8 and evidenced by Beaudet, L. et al., AlphaLISA immunoassays: the no-wash alternative to ELISAs for research and drug discovery (PerkinElmer® Advertising Feature). Nature Methods. 2008; pp. an8-an9, as applied to claims 1-4,6-8, and 11 above, and further in view of Zhang, C. et al., Anti-PD-1 Therapy Response Predicted by the Combination of Exosomal PD-L1 and CD28. Frontiers in Oncology. May 27, 2020; (10: 760); pp. 1-16
The teachings of Yoshioka, et al., are previously discussed.
Further, Yoshioka, et al., teaches using EVs to measure cancer antigens to detect disease and make diagnosis and therapy decisions.
Yoshioka et al., does not teach instant claims 5, 9, 10, and 12-17
However, regarding claims 5 9,and 10 Zhang et al., does teach detecting and quantitating a first target protein that is PD-L1 and CD9 expression from EVs isolated from patients using multiple methods (page 3, sections titled: ‘Western Blot Analysis’, ‘Flow Cytometry’, and ‘ELISA’) for NSCLC.
Regarding claims 12- 17 Zhang et al., does teach the responsiveness of patients to anti-PD-1 treatment as compared to controls at a baseline expression level of PD-L1 and/or PD-1 and relative to responders and/or non-responders, where detection levels were measured from EVs and soluble PD-L1, along with fold-change in expression, pre- and post-treatment (Figure 3, page 7).
It would have been obvious to one of ordinary skill in the art at the effective date of filing, to have elected as a first target protein, PD-L1, as a predictive/ diagnostic antigenic target that is highly expressed in some NSCLC and is therefore an efficacious target for immunotherapy treatment to minimize immune evasion by tumors, in responsive cohorts.
Secondly, detection of PD-L1 in a ExoScreen Assay as taught by Yoshioka et al., teaches the same assay methods and selection process of target(s) for analysis, from EVs.
Thirdly, a skilled artisan would have measured the expression levels of PD-L1 from subjects pre- and post- anti-PD-1 treatment relative to controls; where controls are at a specified threshold level for PD-L1, in patients that are defined as responders and/or non-responders so as to assess therapeutic outcome and continue treatment with a PD-1 inhibitor, for its therapeutic efficacy. Accordingly, an artisan would have used measurements from plasma and/or serum for the identified antigens to determine therapeutic decision-making regarding anti- PD-1 treatment for NSCLC, using companion diagnostics/therapeutic assays that provide expression levels of target antigens, using immunoassay platforms.
The motivation, to combine the teachings of Yoshioka et al., with Zhang et al., are simply to use a singular immunoassay platform that detects both PD-L1 and EV antigen(s) , including CD9, as expressed on EVs, using the platform components of an AlphaLISA®, as described by Yoshioka et al., for the ExoScreen, for cancer diagnostic/therapeutic decision-making. Secondly, Zhang et al., teaches detecting the same cancer antigen(s) for therapeutic purposes and from EVs (CD9 and/or PD-L1/PD-1) for NSCLC, along with comparing non-respondent and respondent patients to their respective controls. One would have expected success with the combined art of Yoshioka et al., and Zhang et al., as both accomplish the same diagnostic methods and/or therapeutic decisions as the instant application. Therefore, it would be prima facie obvious as the combined prior art prescribes the same methods and outcome as the instant application.
Claim(s) 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Yoshioka, Y et al., Ultra-Sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nature Communications. 2014. (5:3591); pp.1-8 and evidenced by Beaudet, L. et al., AlphaLISA immunoassays: the no-wash alternative to ELISAs for research and drug discovery (PerkinElmer® Advertising Feature). Nature Methods. 2008; pp. an8-an9, as applied to claims 1-4,6-8, and 11 above, and further in view of Zhang, C. et al., Anti-PD-1 Therapy Response Predicted by the Combination of Exosomal PD-L1 and CD28. Frontiers in Oncology. May 27, 2020; (10: 760); pp. 1-16 and Poulsen, T.B.G. et al., Protein array-based companion diagnostics in precision medicine. Expert Review of Molecular Diagnostics. December 14, 2020; (20:12); pp. 1183-1198.
The teachings of Yoshioka, et al., and Zhang et al., are previously discussed.
Additionally, Zhang et al., teaches anti-PD-1 treatment in NSCLC based on PD-L1 expression levels compared between control and treatment cohorts, from patient populations, and further detects PD-L1 expression pre- and post- treatment using immunoassay platforms, where PD-L1 is a first target and an EV- specific antigen is a second target antigen.
Yoshioka et al., and/or Zhang et al., do not specifically teach an antibody inhibitor (claims 18 and 19) as a treatment.
However, regarding claims 18 and 19 Poulsen et al., teaches detecting EV expression of PD-L1 levels for NSCLC and treating with the antibody inhibitor, pembrolizumab or nivolumab (page 1189, section titled ‘3.1 Role of companion diagnostics in oncology treatment’; paragraph 1).
It would have been obvious to an artisan at the effective date of filing to combine the teachings of Yoshioka et al., with Zhang et al., and Poulsen et al: Poulsen et al., specifies that anti-PD-1 treatment for NSCLC patients are the antibody inhibitors, among the commonly prescribed and FDA approved monoclonal antibodies, pembrolizumab or nivolumab—wherein these diagnostic and therapeutic decision-making are based on the expression of cancer antigens from EVs, in which assays include targeted immunoassays
Secondly, .Yoshioka, et al. Zhang et al., and Poulsen et al., teach detecting cancer antigens from EVs as a diagnostic method for cancer and resulting therapeutic decision-making, based on immunoassays specific to EV antigens.
Thirdly, Zhang et al., specifies detecting PD-L1 from NSCLC patient cohorts that are (1) controls and/or treatment groups and that are (2) therapy respondents and non-respondents, as discussed previously. Additionally, Zhang et al., teaches anti-PD-1 treatment relative to diagnostic outcome determined from immunoassays.
Therefore, it would have been obvious to a skilled artisan, to combine the teachings of Yoshioka et al., and Zhang et al., to assess NSCLC EV antigens using the EXOScreen assay, to assess PD-L1 and CD9 expression, for downstream diagnostic/therapeutic decision-making. Further, it would have obvious to a skilled artisan to then combine the teachings of Yoshioka et al, Zhang et al., and Poulsen et al., to provide respondent patients with an antibody inhibitor target as claimed in the instant application.
One would have been motivated to combine the teachings of Yoshioka et al., Zhang et al., and Poulsen et al., to simply provide a specified anti-PD-1/PD-L1 antibody as a therapeutic for NSCLC based on the diagnostic methods described previously. Since antibody check-point inhibitors, including pembrolizumab or nivolumab, are treatments for patients who are deemed as respondent cohorts, based on antigen expression, on EVs-- one would have expected success as they are targeted therapeutics used in NSCLC. Therefore, it is prima facie obvious to combine the teachings of Yoshioka et al., with Zhang et al., and Poulsen et al., to identify the same cancer antigen(s) expressed on EVs using an immunoassay platform to then make therapy decision(s) in NSCLC patients, that would result in an anti-PD-1 therapy that is an antibody, and further is pembrolizumab or nivolumab.
Conclusion
No claims are deemed patentable.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ENUSHA KARUNASENA whose telephone number is (571)272-3972. The examiner can normally be reached Monday-Friday 7:30am-5pm.
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/ENUSHA KARUNASENA/Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
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