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 .
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.
Priority
The present application was filed as a continuation of National Stage (371) entry PCT Application No. PCT/EP2022/071014, filed 07/27/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 21188404.4, filed on 07/29/2021 in the European Patent Office.
Information Disclosure Statement
The information disclosure statement (IDS) filed 07/02/2025 is considered, initialed and is attached hereto.
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.
Claim 7 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
See as discussed in more detail below under 35 U.S.C. 112(b), it is not clear if the claimed antibodies (which appear to be monoclonal antibodies) are novel biological material or material that is commercially available/from another source. As such, it appears that the claimed invention could employ novel biological materials, specifically monoclonal antibodies described as MAB43941 and NBPI-76769. Since the monoclonal antibodies are essential to practice the claimed invention, it must be readily available or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If the monoclonal antibody is not so obtainable or available, the requirements of 35 U.S.C. 112(a) may be satisfied by a deposit of the hybridoma cell lines.
The specification fails to indicate that the hybridoma cell lines were either deposited with a depository in accordance with the terms of the Budapest Treaty or indicate public availability. If a deposit of the monoclonal antibody (or hybridoma cell line) has indeed been made under the terms of the Budapest Treaty, then an affidavit of declaration by Applicants, or a statement by an attorney of record over his or her signature and registration number, or someone empowered to make such a statement, stating that the instant invention will be irrevocably and without restriction released to the public upon issuance of a patent, would satisfy the deposit requirement made herein. In instances where the claimed invention consists of sexually unstable material, a deposit of the parental material is required if the parental material is considered sexually stable. If the deposit has not been made under the terms of the Budapest Treaty, then in order to certify that the deposit meets the criteria set forth in 37 CFR 1.801-1.809 and MPEP 2402-2411.05,
Applicant may provide assurance of compliance by affidavit or declaration, or by someone empowered to make the same, or by a statement by an attorney of record over his or her signature and registration number showing that:
a. during the pendency of the application, access to the invention will be afforded to the Commissioner upon request;
b. all restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
c. the deposit will be maintained in a public depository for a period of 30 years, or after 5 years after the last request for the enforceable life of the patent, whichever is longer;
d. a test of the viability of the biological material at the time of deposit (see 37 CFR 1.807); and the deposit will be replaced if it should ever become available.
If the deposit(s) was/were made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the cell line that produces the claimed antibody described in the specification as filed is the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in Applicant's possession at the time the application was filed.
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 6 and 7 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 6 recites the limitation "the biotin streptavidin system" in line 1. There is insufficient antecedent basis for this limitation in the claim. There is no earlier reference to “a biotin streptavidin system” recited in the claims such that would make clear what is being referenced by the language at claim 6. It is not readily clear what is or is not meant by “the biotin streptavidin system” beyond merely requiring involvement of biotin and streptavidin. The scope of what is encompassed not readily clear, as there are many ways biotin and streptavidin could be involved in the claimed method, as such the recited language is indefinite.
Claim 7 recites “wherein the ASGPR1 recognizing antibody is MAB434941 and the PD-L1 antibody is NBPI-76769”, the claim refers to antibodies using an unspecified nomenclature (e.g., it is unclear if the reference is a laboratory name). As a result, the claim language is indefinite because an antibody, referred to by its laboratory name for example, isn’t clearly specified. For example, different laboratories could use the same abbreviations for different antibodies. There is nothing in the originally filed specification which clearly identifies what is meant by these antibodies such that one can readily identify the antibody being claimed and compare it to the closest prior art, it is not clear if these are commercially available antibodies or, for example, novel biological material.
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.
Claim(s) 1-5, 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Stemmer et al., US PG Pub No. 2019/0391163A1 in view of Zhang et al., Circulating tumor cells in hepatocellular carcinoma: single-cell based analysis, preclinical models, and clinical applications, Theranostics, 10(26), (2020), p. 12060-12071, Julich-Haertel et al., Cancer-associated circulating large extracellular vesicles in cholangiocarcinoma and hepatocellular carcinoma, Journal of Hepatology, 67, (2017), p.282-292 and Chen et al., CN111537726A (English Machine Translation obtained via PE2E Search tool).
Stemmer teach methods using exosomes (i.e., extracellular vesicles, see for example Stemmer para [0006], exosomes belong to EVs that carry functional proteins) as biomarkers for diseases, identifying tissue/organ specific exosomes (abstract), exosomes from biological samples (see para [0018]). Stemmer et al. teach using antibody binding in order to achieve isolation or extraction of a tissue specific exosomes by use of binding to a tissue specific exosomal surface marker, namely by using an organ-specific antibody for capture/isolation (see para [0063]). See further, for example at paras [0108], [0166], Stemmer immobilizing capture antibody for exosome isolation on a solid support, and see further para [0108], describes further producing a signal, for example by labeled binding partner (referring to formats including, for example, sandwich assay format), to determine the presence or amount of a surface exosome analyte/marker.
Although Stemmer is detecting organ specific exosomes (i.e., extracellular vesicle), their method comprising providing a biological sample, contacting the sample with an organ specific antibody and detecting expression of surface antigen/marker on the exosome, Stemmer differs from the claimed invention in that Stemmer fails to teach organ-specific antibody that binds ASGPR1 protein, and fails to teach the capture exosomes contacted with antibody recognizing PD-L1 protein, thereby detecting exosomes (extracellular vesicles) expressing both ASGPR1 and PD-L1.
Zhang et al. report the use of circulating tumor cells (CTCs) in order to assess the progression of hepatocellular carcinoma (HCC) (see abstract), HCC recognized as the seventh most common cancer and the second leading cause of cancer-related deaths worldwide (page 12060, col. 2, para 2), Zhang teaching approaches for diagnosing and monitoring HCC are important (page 12061, col. 1, para 1). Zhang is also teaching that immune checkpoint inhibitors are a new era of immunotherapy, with exceptional long-term remissions in some patients with diverse tumor entities, Zhang teaching however, that only a few patients respond, that many others experience severe side effects (see page 12067, col. 2, para 2). Zhang teach the importance of monitoring expression of targets, such as PD-L1, of these therapies. Zhang et al. acknowledge that the art recognizes evaluation of PD-L1+ CTCs discriminated between HCC patients with early state and advanced/metastatic disease, the art suggesting PD-L1+ CTCs as potentially predictive of immunotherapy response.
Regarding capture of HCC CTCs, Zhang teach ASGPR (i.e., ASGPR1 as referenced in the present claims) as an art recognized biomarker for the immunocapture of HCC CTCs (page 12061, col. 2, second full paragraph, see also Figure 1, capture achieved using solid support capture assays such as magnetic bead capture or microfluidic chip.
Julich-Haertel et al. teach microparticles are small vesicles that bleb from the membrane of every cell (reading on the claimed extracellular vesicles), including cancer cells, and are released into bloodstream circulation (see page 282, end of col. 2), that these microparticles can be isolated and screened by their surface components, in order to detect and discriminate between patients baring liver cancer and chronic liver cirrhosis. Julich-Haertel et al. teach ASGPR1 is a biomarker recognized in the prior art as allowing the distinction of liver malignancies, such as HCC or CCA and cirrhosis from tumor-free individuals, and from patients carrying non-liver cancers. The reference teaches ASGPR1 as a biomarker of HCC and CCA (see abstract, see also page 284, col. 1, regarding ASGPR1, not detectable on human pancreas ductal adenocarcinoma cell lines, data suggesting this marker as liver tumour specific antigen). Julich-Haertel teach isolating cell derived microparticles (EVs) from human serum, using FACs staining (see page 283, col. 2, last paragraph).
Chen et al. teach a two antibody detection method for capturing extracellular vesicles on a solid support, and further using an anti-PD-L1 antibody to detect PD-L1 protein on the outer vesicle (see abstract). See Chen (page 2, para 4) teaching it is known that tumor cells secrete PD-L1+ extracellular vesicles into blood and can be used to predict the patient reactivity to treatment (consistent with Zhang, as referenced in detail previously above).
It would have been prima facie obvious to one having ordinary skill in the art to have modified the organ specific capture/detection method of Stemmer et al., to provide antibody to ASGPR1 as capture antibody to detect organ specific cancer that is HCC, one motivated to do so because the prior art recognized the importance of diagnosing/monitoring HCC, HCC recognized in the prior art as the seventh most common cancer and the second leading cause of cancer-related deaths worldwide (Zhang), further the prior art recognized that HCC CTC, and more importantly exosomes derived from HCC CTCs (see each of Zhang et al. and Julich Haertel et al.., cited above), express on their surface ASGPR1 (this is a tumor specific surface marker known to those of skill in the art for HCC).
One having ordinary skill in the art would have a reasonable expectation of success modifying to target HCC derived exosomes to indicate HCC because ASGPR1 was known to be a target organ specific marker for HCC (Zhang and Julich-Haertel) and because the prior art support this marker detectable/expressed on exosome (exosomes recognized as suitable diagnostic biomarkers related to this diagnosis, see for example Julich-Haertel).
It would have been further prima facie obvious to one having ordinary skill in the art to have modified Stemmer and the cited art in order to use, as a detectable second antibody, antibody that targets PD-L1 as in Chen et al. (rather than a tetraspanin, as in Stemmer) because the prior art teach screening for PD-L1+ exosomes is important for indicating candidates who may benefit from PD-L1 immunotherapy (see each of Zhang, and also Chen), one motivated to screen isolated/captured HCC exosomes which are positive for PD-L1 because such an immune checkpoint inhibitor is part of an art recognized new era of immunotherapy, recognized as having exceptional long-term remissions, one motivated to determine those who are candidates from those who are not because Zhang teach that only a few patients respond to such therapy, with many others experiencing severe side effects. As a result, it would be beneficial to screen those exosomes specific to HCC to determine those who would be expected to respond to PD-L1 therapy from those who would not and could suffer side effects, as it would be beneficial to know who would be candidate considering the promising remissions observed using these immune checkpoint inhibitors.
One having ordinary skill in the art would have a reasonable expectation of success considering PD-L1 is known present on tumor cell secreted vesicles (Chen), the art recognizing that secreted vesicles/exosomes are recognized as derived directly from circulating tumor cells, and are known to express analytes consistent with those as present on those original tumor cells (Julich-Haertel), and further would expect success considering it was a known strategy to detected PD-L1+ exosomes using antibody binding/capture assays consistent with two antibody binding as in Stemmer (see specifically Chen, also a two antibody assay, using one antibody for capture of the vesicles, and a second for detection of the target).
The combination of the prior art results in a method which achieves detection of exosomes (extracellular vesicles) expressing both ASGPR1 and PD-L1.
Regarding claim 2 and the combination of the cited art teaching a method detecting exosomes expressing both ASGPR1 and PD-L1, see further, Julich-Haertel teach extracellular vesicles are known to be present in all body fluids, such as urine, blood serum/plasma and bile (page 283, col. 1., para 1, making their isolation, quantification, characterization promising and attractive as a potential clinical tool). This is consistent with, for example, Stemmer et al., who also generally teach tissue-specific exosomes maybe isolated from sample including blood, plasma, serum, lymph, saliva, bile, feces, breastmilk, urine, CSF or an organ/tissue biopsy (see paras [0018], [0028], [0065]), and also Chen (see page 3, preferable from blood, saliva, urine, CSF, etc.).
As a result, it would have been further prima facie obvious to one having ordinary skill in the art to have tried any of urine, CSF or saliva, as taught by the prior art, namely as an obvious matter to try different samples in which exosomes/vesicles are known to be present and detectable (particularly for detection of organ specific/PD-L1+ exosomes, see the art referenced above), namely by selecting from a finite list of suitable available alternatives known to those skilled in the art for containing exosomes/vesicles. The prior specifically teaching these as suitable samples, the art teaching such sample availability making their isolation, quantification, characterization promising and attractive as a potential clinical tool (referring to Julich-Haertel). One having ordinary skill in the art would have a reasonable expectation of success in trying these samples as claimed (namely urine, saliva, CSF), given that the prior art specifically suggests each of these as a potential source of exosomes for diagnostic use/clinical diagnosis.
Regarding claim 3, see as cited above, the prior art is teaching exosomes.
Regarding claim 4, see for example, Julich-Haertel teach enrichment prior to assay (see Figure 2, workflow, enrichment by sequential centrifugation to achieve an ultrapure fraction). Stemmer et al. also teach ultracentrifugation of crude extracts first (see e.g., para [0077], importantly para [0100]). See for example, para [0193], centrifugation to remove excess reagent and potential impurities, see also para [0208], removing debris, broken cells, followed by enrichment of exosome fractions. Based on the prior art of record, it would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have enriched the extracellular vesicles (exosomes) in the sample in order to obtain only the exosomes (omit impurities/debris, etc. as suggested by the prior art). One having ordinary skill in the art would have a reasonable expectation of success, since this is an art recognized technique (based on the cited art presently) for preparing exosomes for isolation/detection.
Regarding claim 5, and the capture and detection of the antibody, Chen as cited above is teaching the use of the two antibodies for binding/detection of exosomes by way of ELISA (as cited above, see further page 3 describing ELISA, see also page 4, ELISA described as a way to efficiently quantitatively determine PD-L1 level in EVs. It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Stemmer and the cited art, to have executed the assay as an ELISA assay as an obvious matter of applying a known technique for a known method, one further motivated because such an ELISA is expressed as an efficient quantitative solution to determining PD-L1 level expressed on extracellular vesicles (Chen). One having ordinary skill in the art would have a reasonable expectation of success using a known technique (ELISA) for its art recognized, known purpose (determining present/amount of PD-L1 on extracellular vesicles).
Regarding claim 8, the combination of the cited art indicated above teach organ specific detection of HCC (liver derived extracellular vesicles, as HCC is hepatocellular carcinoma, liver specific).
Regarding claim 9, the combination of the cited art is suggesting ASGPR1 and PD-L1+ positive exosomes in humans (see for example, Zhang and Julich-Haertel, referring to human cancer).
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Stemmer et al. in view of Zhang et al., Julich-Haertel et al. and Chen et al., as applied to claim 5 above, and further in view of Koivunen et al., Principles of Immunochemical Techniques Used in Clinical Laboratories, Lab Medicine, 37(8), (2006), p. 490-497.
Regarding claim 6, the combination of the cited art teach a method substantially as claimed, however fails to teach the ELISA using a biotin-streptavidin system.
Koivunen et al. teach using avidin-biotin system in a variety of clinical assays requiring increased sensitivity and shorter incubation times, Kouivunen refer to this modification using biotinylated capture antibodies bound on the solid support through avidin, teaching this as a modification that provides amplification for detection of low concentration analytes (see page 493, col. 2, para 3).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified Stemmer and the cited prior art to have implemented the biotin-streptavidin system, as in Koivunen (namely biotinylated antibody bound to solid support via streptavidin), as an obvious matter of using a known technique for a known method, one additionally motivated because using this type of system increase sensitivity and amplifies detection for low concentration analytes (see Koivunen). One having ordinary skill in the art would have had a reasonable expectation of success using a known technique for its art recognized purpose of providing capture antibody bound to a solid support.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
Prosecution Insights