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.
Election/Restrictions
Applicant’s election without traverse of Group I claims 1-7 and 13-16 in the reply filed on 7/30/2025 is acknowledged.
Claims 8-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/30/2025.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/JP2020/037516, filed 10/02/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. JP2019-193707, filed on 10/24/2019 in Japan.
Information Disclosure Statement
The information disclosure statement filed on 4/20/2022, the information disclosure statement filed on 11/3/2023, the information disclosure statement filed on 4/8/2025, and the information disclosure statement filed on 8/22/2025 are being considered by the examiner.
Note that CN 110142068 A (Cite No. 15 of IDS 4/8/2025) is currently being cited on the PTO-892 given that Applicant failed to include an English translation of CN 110142068 A. A machine translation of CN 110142068 A accompanies the PTO-892 citation.
Note that WO 2015068772 A1 (Cite No. AO of IDS filed 4/20/2022) is currently being cited on the PTO-892 given that Applicant failed to include an English translation of WO 2015068772 A1. A machine translation of WO 2015068772 A1 accompanies the PTO-892 citation.
Claim Objections
Claims 2are objected to because of the following informalities:
In claim 2 line 2, Applicant uses the abbreviation CSV; and in claim 3 line 5 Applicant uses the abbreviation EpCAM and PD-L1, it is recommended that abbreviations be accompanied by their full meaning at least at first instance that the abbreviation is used in order to improve clarity and avoid confusion.
Appropriate correction is required.
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 1-7 and 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 and its dependent claims require a specific binding substance for cell-surface vimentin. Claims 2-4 require an anti-CSV antibody. Claims 3-4 require an anti-EpCAM antibody or an anti-PD-L1 antibody.
The specification does not describe which amino acid residues, nucleic acid residues, or other molecular components are present in the genus of agents encompassed by claims 1-7 and 13-16. The specification fails to disclose the structures common to all members of the genus and fails to provide sufficient specific examples of agents to be used. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described. Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement.
Regarding the claimed scope that includes antibodies, the Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1. Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies and variants, fragments or derivates of the antibodies of the claims.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
In this case, the specification does not describe sufficient examples of a specific binding substance for cell-surface vimentin. The only species of substances that specifically bind cell-surface vimentin disclosed are “Nkp46 protein” (paragraph 27) and anti-CSV antibody from Abnova Corporation (page 13 lines 13-15, page 29 lines 4-7, page 30 lines 9-10, page 31 lines 9-10, page 38 lines 2-3 and 7-8 and page 39 lines 16-17). In the same way, the specification only discloses one species of anti-CSV antibody, i.e. anti-CSV antibody from Abnova Corporation (“catalogue No.: H00007431-M08” page 29 lines 4-7). Furthermore, the only species of anti-EpCAM antibody disclosed is that from JSR Corporation (page 30 line 7 and page 38 line 3). Finally, the only species of anti-PD-L1 antibody disclosed is that from MBL International Corporation (page 31 lines 12-13 and page 39 line 14). Note that the catalogue number of the anti-EpCAM antibody from JSR or the anti-PD-L1 antibody from MBL is not disclosed.
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the full genus of specific binding substances or antibodies encompassed by the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of encompassed antibodies.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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 1-7 and 13-16 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 1 recites “[a] method for separation and detection of exosome, the method comprising: a complex formation comprising bringing a biological sample into contact with a capture molecule, the capture molecule including a specific binding substance for an antigen expressed on a cancer cell surface, to form a complex of an exosome and the capture molecule; and a detection comprising bringing the complex into contact with a detector molecule, the detector molecule including a specific binding substance for an antigen expressed on a cancer cell surface and a labeling substance, to detect the complex by using the detector molecule, wherein the antigen expressed on a cancer cell surface for at least one of the capture molecule and the detector molecule is cell-surface vimentin”.
However, it is not clear how the capture molecule, which includes a specific binding substance for an antigen expressed on a cancer cell surface, forms a complex with an exosome given that there is no clear connection between the exosome and the antigen expressed on a cancer cell surface. Similarly, it is not clear how the detector molecule, which includes a specific binding substance for an antigen expressed on a cancer cell surface, enables the detection of said complex given that there is no connection between the exosome and the antigen expressed on a cancer cell surface.
Claim 13 recites “…a signal derived from exosomes detected by the method of claim 1…”. However, as stated above, it is not clear how the exosomes are detected given that the capture molecule and detector molecule include a specific binding substance for an antigen expressed on a cancer cell surface, and this substance does not appear to be drawn to exosomes. Indeed the substances recited in claim 1 appear to be for capturing and detecting cancer cells, not exosomes.
Claims 2-7 and 14-16 are included because they depend from rejected claim 1 but do not clarify the scope of patent protection sought.
Claim 16 recites the limitation "the kit" in line 2. There is insufficient antecedent basis for this limitation in the claim. It is not clear what “the kit” refers to because a kit is not recited in claims 1 or 13.
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 13-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to at least one judicial exception without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Prong One asks does the claim recite an abstract idea, law of nature, or natural phenomenon? In Prong One examiners evaluate whether the claim recites a judicial exception, i.e. whether a law of nature, natural phenomenon, or abstract idea is set forth or described in the claim. While the terms "set forth" and "described" are thus both equated with "recite", their different language is intended to indicate that there are two ways in which an exception can be recited in a claim. For instance, the claims in Diehr, 450 U.S. at 178 n. 2, 179 n.5, 191-92, 209 USPQ at 4-5 (1981), clearly stated a mathematical equation in the repetitively calculating step, and the claims in Mayo, 566 U.S. 66, 75-77, 101 USPQ2d 1961, 1967-68 (2012), clearly stated laws of nature in the wherein clause, such that the claims "set forth" an identifiable judicial exception. Alternatively, the claims in Alice Corp., 573 U.S. at 218, 110 USPQ2d at 1982, described the concept of intermediated settlement without ever explicitly using the words "intermediated" or "settlement." See MPEP 2106.04 (II)(A)(1).
The claims recite “[a] method for diagnosing cancer, the method comprising: using a biological sample collected from an examinee to compare a signal derived from exosomes detected by the method of claim 1 with an exosome-derived signal that serves as a background in a biological sample collected from a control subject; and determining that the examinee has developed cancer when the signal derived from exosomes in the sample of the examinee is stronger than the signal derived from exosomes in the sample of the control subject”.
The natural relationship to which the claims are directed (i.e., the relation between exosomes and cancer) is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of exosome in a biological sample and the presence of cancer.
The correlation between the amount of exosomes and disease is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility.
Additionally, the claims also recite “to compare …”. The “comparing” step of claim 13 also expresses a natural law as above (the naturally occurring relationship between exosome levels and cancer vs. control subjects).
Furthermore, the claimed method of detecting renal injury by comparing exosome levels to a background value from a control subject may also be categorized as abstract ideas, namely mental processes/ concepts performed in the human mind (such as a doctor simply thinking about the measured level of exosome signal in relation to a background value and making an evaluation, judgment, or opinion). The claims, under their broadest reasonable interpretation, cover performance of identifying risk solely within the human mind, or by a human using pen and paper. Comparing information regarding a sample to a control or target data (in this case, comparing a signal level to a background value) represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo.
Claims 14-15 merely limits the cancer to be early-stage or lung cancer. Therefore claims 14-15 are also drawn to the judicial exception(s).
Step 2A, Prong 2
The above-discussed steps of “diagnosing cancer” and “using a biological sample collected from an examinee to compare a signal derived from exosomes..” are insufficient to integrate the judicial exception(s) into a practical application because steps corresponding to mental activity, which could be performed in a practitioner’s head, are insufficient to constitute a practical application. In this case, diagnosing cancer and comparing signal values, represent judicial exceptions and not a practical application thereof.
The claims also recite “a complex formation comprising bringing a biological sample into contact with a capture molecule, the capture molecule including a specific binding substance for an antigen expressed on a cancer cell surface, to form a complex of an exosome and the capture molecule; and a detection comprising bringing the complex into contact with a detector molecule, the detector molecule including a specific binding substance for an antigen expressed on a cancer cell surface and a labeling substance, to detect the complex by using the detector molecule, wherein the antigen expressed on a cancer cell surface for at least one of the capture molecule and the detector molecule is cell-surface vimentin” (claim 1).
Such steps of providing a sample and measuring cell-surface vimentin therein using a specific binding substance are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed. Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps of detecting cell-surface vimentin/an antigen expressed on a cancer cell surface are recited at a high level of generality and are not tied, for example, to any particular substance, machine or apparatus.
Claim 16 is unclear. However, in the interest of compact prosecution, claim 16 is interpreted to be drawn to the method of claim 13. Claim 16 merely limits the method to be used for companion diagnostics. Therefore, claim 16 recites insignificant extra-solution activity and fails to integrate the judicial exception(s) into a practical application, i.e. it does not use, rely on, or apply the judicial exception(s) such to amount to a practical application thereof.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims, including the steps of providing a biological sample and detecting exosome-derived signals therein, do not add significantly more to the judicial exception(s). The step of detecting exosomes is recited at a high level of generality and is not limited, for example, to any specific testing technique.
Although the detection of exosomes is performed using specific binding substance that specifically binds to vimentin and specific binding substance for an antigen expressed on a cancer cell surface, no particular or specific substance is set forth.
In this case, it was well-understood, routine and conventional to use binding substances specific for cell surface vimentin/ an antigen expressed on a cancer cell surface to form a complex and get a detection. See for example Cui et al. (CN 110142068 A)-Cite No. 15 of IDS 4/8/2025, (also currently being cited on PTO-892) (“Cui”). Cui teaches “a kit for detecting epithelial-mesenchymal mixed circulating tumor cells, and a method for enriching and detecting epithelial-mesenchymal mixed and PD-L1 positive circulating tumor cells” (Abstract). Cui further teaches “biotin-labeled anti-CSV (cell surface vimentin) antibody…fluorescein-labeled PD-L1 secondary antibody” (paragraph 23). Cui further teaches “Example 2 (Detection of Typing of Circulating Tumor Cells in Lung Cancer and Detection of PD-L1 Expression)” (paragraph 93). Cui further teaches step “1.3…biotin-labeled anti-CSV (cell surface vimentin) antibody…added to the microfluidic carrier” (paragraph 99) and step “5.3. …Alexa Fluor 647-labeled PD-L1 secondary antibody…add it to the microfluidic chip” (paragraph 121). Cui further teaches step “5.4. The microfluidic carrier was slowly rinsed three times with 300 μL PBS buffer to complete the PD-L1 phenotype detection of different subtypes of CTCs, and the PD-L1 staining results were observed using an inverted fluorescence microscope” (paragraph 122).
Furthermore, methods for detecting exosomes are well-understood, routine and conventional. For example, Spetzler et al. (WO 2012024543 A1) (“Spetzler”) teaches that “[v]esicles such as exosomes can be assessed to provide a phenotypic characterization by comparing vesicle characteristics to a reference. In some embodiments, surface antigens on a vesicle are assessed…For example, wherein vesicles found in a patient sample, e.g., a bodily fluid such as blood, serum or plasma, are assessed for surface antigens indicative of colorectal origin and the presence of cancer…For example, overexpression in a sample of cancer-related surface antigens” (paragraph 194-195). Spetzler further teaches “detecting a biomarker comprises… performing a sandwich assay. A vesicle in the population can be captured with a capture agent. The capture agent can be a capture antibody, such as a primary antibody.…The captured or bound vesicle can be detected with a detection agent, such as a detection antibody. For example, the detection antibody can be for an antigen of the vesicle…the capture agent can be an antibody …EpCam…the detection agent can be an agent that binds or detects…EpCam” (paragraph 837). Spetzler further teaches that “[t]he biosignature for theranosing a cancer can comprise one or more of…Vimentin” (paragraph 1045).
Also Weber et al. J. Vis. Exp. (143), e58731, doi:10.3791/58731 (2019) (“Weber”) teaches “rapid isolation of EVs and characterization with … specific surface markers such as… vimentin” (Abstract). Weber further teaches “EVs were isolated from whole blood and characterized by nanoparticle tracking analysis with fluorescing reagents… with Alexa Fluor 488 labeled…vimentin” (page 4 paragraph 1).
Skolnick et al. (US 20140113310 A9)- Cite No. 1 of IDS 11/3/2023 (“Skolnick”) also teaches “[m]ethods and compositions involving molecular markers for the detection and characterization of cancer in a patient are provided” (Abstract). Skolnick further teaches “determining the status of exosomes and/or an exosome-associated marker in a sample obtained from a patient, wherein an abnormal exosome (and/or exosome-associated marker) status in the sample indicates the presence of cancer (paragraph 5). Skolnick further teaches that “"[e]xosome- associated" marker means a biomolecule…on the surface of an exosome…Since exosomes are formed from membranes of the cell, they also carry molecules (e.g. , cell- surface molecules such as CD63 or EpCAM) on their surface” (paragraph 28). Skolnick further teaches “that capturing these items with a capture reagent and then detecting them with a detection reagent can separate cancer patients from controls” (paragraph 19). Skolnick further teaches that “when elevated exosome levels are found in a patient's sample…Vimentin…may be tested” (paragraph 46). Similarly WO 2010065968 A1-(Cite No. 15 of IDS 11/3/2024), teaches detecting exosome using capture and detector agents as in Skolnick (same patent family as in Skolnick).
Fujii et al. (WO 2015068772 A1)-Cite No. AO of IDS filed 4/20/2022) (also currently being cited on PTO-892) (“Fujii”) also teaches “a complex forming step of bringing a biological sample containing a vesicle having a lipid bilayer membrane into contact with a solid-phase carrier to which a ligand recognizing a surface antigen present on the surface of the vesicle is bound, and forming a complex of the vesicle and the solid-phase carrier…wherein the vesicle is an exosome…wherein the surface antigen is an antigen protein present on an exosome surface, and the ligand is an antibody that recognizes an antigen protein present on an exosome surface… The method further includes a protein detection step of detecting a protein present in at least one of the inside and the surface of the vesicle” (claims 1, 7-8 and 12).
Bosio et al. (US 20160334402 A1) (“Bosio”) teaches “methods for analyzing markers on the surface of vesicles” (Title). Bosio further teaches “contacting said sample with a set of at least two capture agents, marker of said vesicles; … b) contacting the captured at least two subpopulations of vesicles with at least two different detection agents, … and c) determining the levels” (Abstract).
In view of the above evidence, the claimed steps of detecting exosomes using binding substances specific for cell surface vimentin or cancer cell surface antigens do not add any feature that is more than well-understood, purely conventional, or routine in the field of diagnostics and biochemical assay methodologies.
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using a substance specific to that protein. See also MPEP 2106.05(g).
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
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.
Claims 1-7 and 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Spetzler et al. (WO 2012024543 A1) ("Spetzler") in view of Weber et al. J. Vis. Exp. (143), e58731, doi:10.3791/58731 (2019) (“Weber”).
Regarding claims 1-2, 4 and 13, Spetzler suggests a method for separation and detection of exosomes (“Disclosed herein are products and processes for characterizing a phenotype of an individual by analyzing a vesicle” paragraph 163, “ the invention relates to the analysis of vesicles to provide a biosignature” para. 165, “The term "phenotype" as used herein can mean any trait or characteristic that is attributed to a vesicle biosignature” para. 166, “Vesicles such as exosomes can be assessed to provide a phenotypic characterization by comparing vesicle characteristics to a reference. In some embodiments, surface antigens on a vesicle are assessed. A vesicle or vesicle population carrying a specific marker can be referred to as a positive (biomarker+) vesicle or vesicle population.” para. 194, “A number of technologies known to those of skill in the art can be used for isolation and detection of vesicles to carry out the methods of the invention” para. 1435), and a method of diagnosing cancer (“[f]or example, overexpression in a sample of cancer-related surface antigens … as compared to a reference, can indicate the presence of cancer in the sample” para. 195) the method comprising: a complex formation comprising bringing a biological sample into contact with a capture molecule (“Biosignatures can be detected using capture agents and detection agents” para. 835, “detecting a biomarker comprises… performing a sandwich assay. A vesicle in the population can be captured with a capture agent” para. 837), the capture molecule including a specific binding substance for an antigen expressed on a cancer cell surface, to form a complex of an exosome and the capture molecule, wherein the specific binding substance for the antigen expressed on a cancer cell surface in the capture molecule is an anti-EpCAM antibody (“the vesicle can be captured using an antibody to the cancer specific antigen” para. 835, “the capture agent can be an antibody …EpCam” para. 837); and a detection comprising bringing the complex into contact with a detector molecule, the detector molecule including a specific binding substance for an antigen expressed on a cancer cell surface and a labeling substance (“[v]esicle levels may be determined using binding agents as described above. For example, a binding agent to vesicles can be labeled and the label detected and used to determine the amount of vesicles in a sample” para. 330, “The captured or bound vesicle can be detected with a detection agent, such as a detection antibody. For example, the detection antibody can be for an antigen of the vesicle” para. 837), to detect the complex by using the detector molecule, wherein the antigen expressed on a cancer cell surface for at least one of the capture molecule and the detector molecule is cell-surface vimentin (“ A biosignature can be determined to provide a theranosis for a subject” para. 1044, “The biosignature for theranosing a cancer can comprise…vimentin” para. 1045). Spetzler further suggests using a biological sample collected from an examinee to compare a signal derived from exosomes detected by the method of claim 1 with an exosome-derived signal that serves as a background in a biological sample collected from a control subject; and determining that the examinee has developed cancer when the signal derived from exosomes in the sample of the examinee is stronger than the signal derived from exosomes in the sample of the control subject (“The circulating biomarkers can be evaluated by comparing the level of circulating biomarkers with a reference level or value. … the reference value can be…from a representative population of samples ( e.g., samples from normal subjects not exhibiting a symptom of disease)” para. 319, para. 195)
Spetzler fails to explicitly teach cell surface vimentin and an anti-CSV antibody and using an anti-CSV antibody as the specific binding substance for the detector molecule.
Weber teaches that “Extracellular vesicles (EVs), including exosomes, are specialized membranous nano-sized vesicles found in bodily fluids that are constitutively released from many cell types and play a pivotal role in regulating cell-cell communication and a diverse range of biological processes…The protocol that is presented…provides the complete workflow for rapid isolation of EVs and characterization with…specific surface markers such as…vimentin” (Abstract). Weber further teaches that “EVs are released in their environment from many different cell types, e.g., endothelial cells, immune cells, and tumor cells, and can be detected in body fluids such as serum semen, urine, breast milk, saliva, or cerebrospinal fluid. Increasing numbers of studies highlight the diverse contribution of EVs as potential biomarkers for early diagnosis of several diseases and/or prediction of disease progression” (page 1 paragraph 1). Weber further suggests using a labeled anti-CSV antibody as the specific binding substance for a detector molecule to characterize exosomes (“rapid isolation of EVs from human whole blood and fast characterization of specific markers by fluorescence-based nanoparticles-tracking analysis” page 2 para. 1, “Stain samples with specific antibodies… Add 2.5-5 μL of the specific antibody (Table 1) to the reaction tube” page 2 para. 5, see Table 1 page 7 showing antibody to vimentin, “Representative results after staining with Alexa Fluor 488 labeled…vimentin” Figure 4 page 6). Note that although Weber fails to use the language “anti-CSV antibody”, the teaching of specific surface markers to vimentin together with the use of an antibody to vimentin, suggests that the antibody to vimentin is targeting cell surface vimentin. Furthermore, note that although Weber fails to use the language “detector molecule” the teaching of using anti-CSV antibody labeled with Alexa Fluor 488 to characterize exosomes based on the fluorescence detected inherently provides a detector molecule.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Spetzler to rely on the antigen expressed on the cancer cell surface for the detector molecule being cell-surface vimentin and wherein the specific binding substance for the cell-surface vimentin being an anti-CSV antibody taught by Weber because Weber suggests that this enables a rapid isolation and characterization of exosomes as well as potential early diagnosis of several diseases and/or prediction of disease progression. A person having ordinary skill in the art would have had a reasonable expectation of success because both Spetzler and Weber teach isolation and characterization of exosomes using cancer cell surface antigens. Furthermore, both Spetzler and Weber teach analyzing vimentin in exosomes in the field of immunodiagnostics.
Regarding claim 3, Spetzler in view of Weber teach the method of claim 1 as discussed above.
Spetzler in view of Weber suggest wherein the specific binding substance for the antigen expressed on a cancer cell surface in the capture molecule is an anti-CSV antibody (“In some embodiments, a same biomarker is recognized by both a capture agent and a detection agent” para. 836 of Spetzler, “One of skill will appreciate that targets of capture agents and detection agents can be used interchangeably” para. 839 of Spetzler), and the specific binding substance for the antigen expressed on a cancer cell surface in the detector molecule is an anti-CSV antibody (page 2 paragraph 5, Table 1 and Figure 4 of Weber). Note that although Spetzler in view of Weber fail to use the language “wherein the specific binding substance for the antigen expressed on a cancer cell surface in the capture molecule is an anti-CSV antibody”, the suggestion of Spetzler of using the same target antigen for both the capture and detector molecules together with the teaching of Weber of using cell surface vimentin and anti-CSV antibody as the detector molecule, suggests using anti-CSV antibody and cell surface vimentin as the specific binding substance for the antigen expressed on a cancer cell surface in the capture molecule. A person having ordinary skill in the art would have had a reasonable expectation of success given that Spetzler teaches that vimentin may be analyzed in exosomes (para. 1045) and both Spetzler and Weber teach isolation and characterization of exosomes using cancer cell surface antigens.
Regarding claim 5, Spetzler in view of Weber address the method of claim 1 as discussed above.
Spetzler in view of Weber further suggest wherein the capture molecule is immobilized on a magnetic particle (“A binding agent bound to a magnetic bead can also be used to isolate a vesicle” paragraph 265 of Spetzler).
Regarding claims 6-7, Spetzler in view of Weber address the method of claim 1 as discussed above.
Spetzler in view of Weber further suggest further comprising, after the complex formation (“Example 50: Microsphere Vesicle Analysis from Concentrated Plasma” para. 1456 of Spetzler, “Capture antibodies are conjugated to desired microspheres selected from …MagPlex microsphere beads (Luminex Corporation, Austin, TX)” para. 1461 of Spetzler, “k. Add bead mixture to all samples… v. Incubate in 37°C (35°C to 39°C) Jitterbug at 550 rpm for 2 hours” page 331 of Spetzler) and before the detection : a washing comprising adding a washing liquid to remove foreign substances other than the complex (“w. Using a plOOO electronic multichannel pipette and 1000 µl NON-FILTERED tips, wash each well with 200 µl of PBS-BN, aspirate, press vacuum release button, then remove plate from manifold and thoroughly blot bottom of plate on a clean paper towel. x. Repeat previous step for a total of 2 washes with 200 ul PBS-BN per wash” page 333 of Spetzler). Note that although Spetzler fails to use the language “complex formation” the teaching of bringing into contact the sample and the beads conjugated with the capture antibodies, together with the incubation step would inherently provide a complex formation. Spetzler in view of Weber further suggest wherein the detection comprises bringing the complex into contact with the detector molecule (“z. Using a p 1000 electronic single channel pipette, add 50 ul of the diluted detection antibody (from above) to each well” page 333 of Spetzler), subsequently adding a washing liquid to remove foreign substances other than the complex to which the detector molecule is bound (“ff. Using a p 1000 electronic multichannel pipette and 1000 ul non-filtered tips, wash each well with 100 ul of PBS-BN, aspirate, press vacuum release button, then remove plate from manifold and thoroughly blot bottom of plate on a clean paper towel. gg. Repeat previous step for a total of 2 washes with 100 ul PBS-BN per wash” page 334 of Spetzler), and then detecting the complex by using the detector molecule (“jj. …Analyze plate on Luminex 200 machine” page 334 of Spetzler). Also note that although Spetzler fails to use the language “to remove foreign substance other than the complex”, the teaching of the washing steps comprising aspiration, and blotting steps would inherently remove foreign substances other than the complex.
Regarding claim 14, Spetzler in view of Weber address the methods of claims 1 and 13 as discussed above.
Spetzler in view of Weber further suggest wherein the cancer is an early-stage cancer (“The biosignature can also be utilized to determine if a subject is afflicted with cancer or is at risk for developing cancer. A subject at risk of developing cancer can include those who… have pre-symptomatic early stage disease” paragraph 384 of Spetzler).
Regarding claim 15, Spetzler in view of Weber address the methods of claims 1 and 13 as discussed above.
Spetzler in view of Weber further suggest wherein the cancer is lung cancer (“Vesicle biosignatures can be used in the theranosis of a cancer, such as identifying whether a subject suffering from cancer is a likely responder or non-responder to a particular cancer treatment. The subject methods can be used to theranose cancers including those listed herein, e.g., in the "Phenotype" section above. These include without limitation lung cancer, non-small cell lung cancer small cell lung cancer (including small cell carcinoma (oat cell cancer)…” para. 1042, and 1044-1045 of Spetzler). Spetzler further teaches that “[c]irculating microvesicles can provide a simple and reliable tool to obtain important information about malignant and cancer progression processes occurring in a patient without the need for a biopsy or standard pathology evaluation such as immunohistochemistry” (paragraph 1526).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have picked lung cancer from the list of cancer types taught by Spetzler because Spetzler teaches a finite list of possible cancer types to be paired with the method to diagnose cancer. Given that Spetzler suggests that there is a need for noninvasive methods to diagnose cancer, a person having ordinary skill in the art would have been motivated to try picking lung cancer as a cancer type to be paired with the method of diagnosing cancer involving exosomes (i.e. because the method of analyzing exosome taught by Spetzler is a noninvasive method, does not involve the use of a biopsy). A person having ordinary skill in the art would have had a reasonable expectation of success given that Spetzler teaches both analyzing vimentin and lung cancer in the context of theranosis (see para. 1042, and 1044-1045).
Regarding claim 16, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the claim is interpreted to be drawn to the method of claim 13, i.e. “the kit” is interpreted as a typographical error and meant to read as “the method”. Spetzler in view of Weber address the methods of claims 1 and 13 as discussed above.
Spetzler in view of Weber further suggest wherein the kit is used for companion diagnostics (“One example involves comparing biomarker expression profiles for various biomarkers ( or biosignature portfolios) to ascribe diagnoses” para. 1222 of Spetzler). Note that the specification fails to define “companion diagnostics”, therefore, using the broadest reasonable interpretation in light of the specification “wherein the kit is used for companion diagnostics”, is interpreted to mean wherein the method is used for diagnosing cancer as well as other diseases.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678