DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's election with traverse of the species of (i) surface biomarkers formed of polypeptides and (ii) cell adhesion molecules (e.g., CEACAM5/6, EPCAM) in the reply filed on May 26, 2026 is acknowledged. The traversal is on the groups that the single inventive concept involves the discovery that combinations of diverse biomarkers, in combination, in their diversity, are significant. This argument has been fully considered. Regarding species (i) the traversal is moot because the claims as amended no longer recite surface biomarkers, intravesicular biomarkers, and intravesicular RNA biomarkers. Regarding species (ii) it is noted the polypeptides recited in the claims have a different chemical structure (different amino acid sequence) and have different biological activities. Therefore it is unclear how they have both a common property or activity AND a common structure. The requirement is still deemed proper and is therefore made FINAL.
Claims 1-5, 7-9, 12-16, 19-20, and 115 are currently pending.
Claim 4 has been examined to the extent that the claims read on the elected polypeptides (CEACAM5/6, EPCAM). The additionally recited polypeptides have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Nucleotide and/or Amino Acid Sequence Disclosures
3. Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because Specification (pages 177-181) contains disclosures of nucleotide sequences that fall within the definitions of 37 CFR 1.831(b).
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Claim Rejections - 35 USC § 101
4. 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 1-5, 7-9, 12-16, 19-20, and 115 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite abstract ideas. The claims recite the following limitation:
“wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold.
This limitation encompasses a mental process. For example one may classify a subject as having CRC by reading a laboratory report comprising the quantity of EV and the reference threshold thinking about whether the quantity of EV is above or below the threshold. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
The instant claims recite a law of nature. The claims recite the following limitation:
“wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold.
The claims recite a correlation between the quantity of EV and CRC. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition the judicial exceptions the claims recite the following steps:
capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles;
binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles;
binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles; and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe.
These steps do NOT integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition the judicial exceptions the claims recite the following steps:
capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles;
binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles;
binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles; and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe.
These steps do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The prior art demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017) teaches detection of EVs by ExoPLA. The method comprises the following steps: (A) Oligonucleotide-conjugated antibodies are immobilized by hybridization to oligonucleotides coupled to magnetic beads. (B) The immobilized antibodies are used to capture EVs from a sample. (C) Proximity probes with affinity for CD26(grey), CD10/CD14 (purple), CD13/Thy1 (blue), and Cathepsin B (green) are added to the beads with captured EVs. (D) Binding of pairs of proximity probes to their target antigens allows circularization and ligation of oligonucleotides (two common oligonucleotides—grey and red—and a set of three tag-specific oligonucleotides for CD10/CD14, CD13/Thy1, and Cathepsin B, colored as in panel C), creating circular DNA templates for rolling-circle amplification (RCA). (E) The EV-PLA complex is released from the beads by digestion of the uracil-containing oligonucleotides by treatment with uracil N-glycosylase (UNG). (F) RCA amplifies the circular DNA templates, and fluorophore-labeled oligonucleotides are hybridized to the RCA products (FIG 4.8.1). Lof teaches that the intense fluorescent signals produced in this assay allow detection and enumeration of individual EVs by flow cytometry (abstract).
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
5. 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 4, 9, 12-16, and 19-20 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 4 recites the limitation “the extracellular vesicle associated surface biomarker”. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation “wherein the sample has been subjected to size exclusion chromatography to isolated nanoparticles having a size range of interest that includes extracellular vesicles”. This recitation is confusing because the claims do not previously refer to a sample comprising nanoparticles. Clarification is required.
Claims 12-14 are rejected over the recitation of “the target capture moiety” in claims 12 and 14. There is insufficient antecedent basis for this limitation in the claim.
Claims 15, 16, 19, and 20 are rejected over the recitation of the phrase “a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide” in claim 15. This recitation is confusing because the claims do not previously require that the first oligonucleotide and the second oligonucleotide hybridize to one another. Clarification is required.
Claim Rejections - 35 USC § 102
6. 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, 2, 7-8, and 12-14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017).
Regarding Claim 1 Lof teaches detection of EVs by ExoPLA. The method is shown below:
PNG
media_image1.png
492
674
media_image1.png
Greyscale
(A) Oligonucleotide-conjugated antibodies are immobilized by hybridization to oligonucleotides coupled to magnetic beads. (B) The immobilized antibodies are used to capture EVs from a sample. (C) Proximity probes with affinity for CD26(grey), CD10/CD14 (purple), CD13/Thy1 (blue), and Cathepsin B (green) are added to the beads with captured EVs. (D) Binding of pairs of proximity probes to their target antigens allows circularization and ligation of oligonucleotides (two common oligonucleotides—grey and red—and a set of three tag-specific oligonucleotides for CD10/CD14, CD13/Thy1, and Cathepsin B, colored as in panel C), creating circular DNA templates for rolling-circle amplification (RCA). (E) The EV-PLA complex is released from the beads by digestion of the uracil-containing oligonucleotides by treatment with uracil N-glycosylase (UNG). (F) RCA amplifies the circular DNA templates, and fluorophore-labeled oligonucleotides are hybridized to the RCA products (FIG 4.8.1). Lof teaches that the intense fluorescent signals produced in this assay allow detection and enumeration of individual EVs by flow cytometry (abstract). Thus Lof teaches a method comprising the steps of:
capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles (see panel B);
binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles (see panel C and D);
binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles (see panel C and D); and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe (see abstract).
While Lof teaches all of the claimed method steps, Lof does not teach a correlation between the quantity of extracellular vesicles and colorectal cancer. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require such a correlation. Regarding the recitation “wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold”, Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Regarding Claim 2 Lof teaches that proximity probes with affinity for CD26(grey), CD10/CD14 (purple), CD13/Thy1 (blue), and Cathepsin B (green) are added to the beads with captured Evs (Fig 4.8.1). Thus Lof teaches a method wherein the second target biomarker (CD26) and the third target biomarker (CD10/CD14) are two different polypeptides on a surface of the extracellular vesicles.
Claim 7 recites wherein the reference threshold is determined by levels of target biomarker signature-expressing extracellular vesicles observed in comparable samples from a population of non-cancer subjects. Claim 8 recites therein the population of non-cancer subjects comprises one or more of the following subject populations: healthy subjects, subjects diagnosed with benign tumors, subject with colon-related diseases and subjects with non-colon-related diseases, disorders, and/or conditions. These recitations only further limit the “wherein” clause that is recited in claim 1. As discussed above, claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed.
Regarding Claims 12-14 Lof teaches that oligonucleotide-conjugated antibodies are im-mobilized by hybridization to oligonucleotides coupled to magnetic beads. Lof teaches that immobilized antibodies with affinity for CD63 are used to capture EVs from a sample. (Fig 4.8.1). Thus Lof teaches a method wherein the capture agent comprises a solid substrate (magnetic bead) comprising the target-capture moiety (antibody) conjugated thereto.
Claim Rejections - 35 USC § 103
7. 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.
8. Claims 3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017) in view of Lof (Scientific Reports 2016 6:34358).
The teachings of Lof (2017) are presented above.
Lof (2017) does not teach a method wherein co-occurrence of the first, second, and third target biomarkers on one extracellular vesicle of the extracellular vesicles defines a first target biomarker signature and wherein steps of the method are repeated for at least a second target biomarker signature, and wherein a classification cutoff references the reference threshold and at least a second reference threshold level corresponding to the at least a second target biomarker signature (clm 3). Lof does not teach a method wherein the first and/or second target biomarker signature comprises at least one extracellular vesicle-associated surface biomarker and at least two surface biomarkers (clm 5).
However Lof (2016) teaches that ExoPLA can distinguish different populations of EVs. Lof teaches that antibodies against CD63 were used to capture all EVs. Antibodies directed against CD114 were used to prepare PLA probes selective for EVs isolated from U937 cells. For selective detection of EVs from U937 cells we used PLA probes against CD114 together with probes against CD13, CD26 and cathepsin B. The CD114 selective probes could clearly identify and distinguish EVs from the U937 cell line both when mixed with prostasomes and with EVs from the MCF7 cell line (Fig. 4 and S3). Lof teaches that EVs from MCF7 were negative for CD114 and EVs from U937 were positive for CD114 (pages 4-5).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Lof (2017) by repeating the method to detect a second target biomarker signature comprising a an EV associated surface biomarker and at least two surface biomarkers as suggested by Lof (2016). One of skill in the art would have been motivated to detect a first target biomarker signature and a second target biomarker signature for the benefit of being able to distinguish different populations of EVs in a mixed sample.
9. Claims 4 and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017) in view of Ferlizza (Cancers 2021 Vol 13, 1101).
The teachings of Lof are presented above.
Lof does not teach a method wherein the extracellular vesicle-associated surface biomarker is or comprises a polypeptide encoded by human genes as follows: EPCAM, CEACAM6, CEACAM5, or combinations thereof (clm 4). The combined references do not teach a method wherein the target biomarkers are selected from polypeptides encoded by human genes as follows: EPCAM, CEACAMS, and CEACAM6 (clm 115).
Ferlizza teaches EPCAM as an examples of a molecule identified in EVs at increased levels in the bloodstream of CRC patients (page 12). Ferlizza cites the prior art of Cha which evaluated eight mRNA markers, including CEA (also known as CEACAM5) and EpCAM extracted from plasma EVs obtained from healthy and CRC patients (pages 12-13). Ferlizza cites the prior art of Rodia which used a novel bioinformatic approach to search for specific RNAs with high differential gene expression between CRC and normal blood. The authors reported that CEACAM6 was able to discriminate between the two groups (page 9).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Lof by targeting the EPCAM, CEACAMS, and CEACAM6 on the surface of the EVs. In the instant case Felizza teaches that each of the recited biomarkers are correlated with colorectal cancer. Thus one of skill in the art would have been motivated to use these biomarkers in the method of Lof for the benefit of being able to detect colorectal cancer.
10. Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017) in view of Boing (Journal of Extracellular vesicles 2014 3:23430).
The teachings of Lof are presented above.
Lof does not teach a method wherein the sample has been subjected to size exclusion chromatography to isolate nanoparticles having a size range of interest that includes extracellular vesicles.
However Boing teaches that isolation of extracellular vesicles from plasma is a challenge due to the presence of proteins and lipoproteins. Therefore they developed a single step protocol to isolate vesicles from human body fluids. Platelet-free supernatant, derived from platelet concentrates, was loaded on a sepharose CL-2B column to perform size-exclusion chromatography. SEC efficiently isolates extracellular vesicles with a diameter larger than 70 nm from platelet-free supernatant of platelet concentrates (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Lof by subjecting the sample to size exclusion chromatography as suggested by Boing. One of skill in the art would have been motivated to perform size exclusion chromatography on the sample for the benefit of being able to isolate extracellular vesicles with a diameter larger than 70 nm from plasma.
11. Claims 15-16 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Lof (Current Protocols in Cytometry 4.8.1-4.8.10 July 2017) in view of Routenberg (WO 2020/086751 Pub 4/30/2020).
The teachings of Lof are presented above.
Lof does not teach a method further comprising a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide (clm 15).
However Routenberg teaches a method of isolating and characterizing surface marker displaying agents, such as EVs (paras 0070, 0103). Routenberg teaches capturing EVs using antibodies to a solid surface and then analyzing the EVs using a combination of proximity probes (PPs) to different surface markers on the surface of the EV to assay for specific multi-marker EV populations (paras 0542-0544, 0589-0590, Figure 48C). Routenberg teaches the binding reagents (antibodies conjugated to oligonucleotides) comprise detection sequences that have a hybridization sequence that is complementary to at least a portion of the detection oligonucleotide sequence of at least one other binding reagent, hybridizing the detection sequences together, and detecting the hybridized sequences/specific combination through proximality ligation (paras 0358-0363, 0467, 0471, 0474, 0484).
Accordingly it would have been obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Lof by using a first probe and second probe comprising oligonucleotides that hybridize to one another as suggested by Routenberg. One would be motivated to do so given the assertion by Routenberg that this allows for more sensitive detection of biomarkers on the surface of EVs and provides greater combinatorial throughput for assessing populations of EVs (paras 0368, 0467, 0471, 0474, 0484, 0542-0544). One would have a reasonable expectation of success given that Routenberg performs this particular detection methodology on surface protein biomarkers of extracellular vesicles (paras 0467, 0471, 0474, 0484, 0542-0544, and 0589-0590).
Regarding Claim 16 Lof teaches a method wherein the capture assay is performed prior to the detection assay (see panels B and F).
Regarding Claims 19 and 20 Lof teaches a method wherein the detection assay comprises a proximity ligation assay (see title).
Double Patenting
12. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
13a. Claims 1-5, 7-9, 12-16, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 12-16, 19-20, and 115 of copending Application No. 18/580,412. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding Claim 1 both sets of claims are drawn to a method comprising: capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles; binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles; binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles; and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe (see clm 1 of the copending application). The instant claims further recite “wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold”, however claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. Regarding Claim 2 both sets of claims state that the second target biomarker and the third target biomarker are two different polypeptides on a surface of the extracellular vesicles (see clm 2 of the copending application). Regarding Claim 3 both sets of claims state that the co-occurrence of the first, second, and third target biomarkers on one extracellular vesicle of the extracellular vesicles defines a first target biomarker signature and wherein steps of the method are repeated for at least a second target biomarker signature, and wherein a classification cutoff references the reference threshold and at least a second reference threshold level corresponding to the at least a second target biomarker signature (see clm 3 of the copending application). Regarding Claim 4 both sets of claims state that the extracellular vesicle-associated surface biomarker is or comprises a polypeptide encoded by CEACAM6 or CEACAM5 (see clm 4 of the copending application). Regarding Claim 5 both sets of claims state that the first and/or second target biomarker signature comprises at least one extracellular vesicle-associated surface biomarker and at least two surface biomarkers (see clm 5 of the copending application). Regarding Claim 7 both sets of claims state that the reference threshold is determined by levels of target biomarker signature-expressing extracellular vesicles observed in comparable samples from a population of non-cancer subjects (see clm 7 of the copending application). Regarding Claim 8 both sets of claims state that the population of non-cancer subjects comprises one or more of the following subject populations: healthy subjects and subjects diagnosed with benign tumors (see clm 8 of the copending application). Regarding Claim 9 both sets of claims state that the sample has been subjected to size exclusion chromatography to isolate nanoparticles having a size range of interest that includes extracellular vesicles (see clm 9 of the copending application). Regarding Claim 12 both sets of claims state that the capture agent comprises a solid substrate comprising the target-capture moiety conjugated thereto (see clm 12 of the copending application). Regarding Claim 13 both sets of claims state that the solid substrate comprises a magnetic bead (see clm 13 of the copending claims). Regarding Claim 14 both sets of claims state that the target-capture moiety is or comprises an antibody agent (see clm 14 of the copending application). Regarding Claim 15 both sets of claims further comprise a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide (see clm 15 of the copending application). Regarding Claim 16 both sets of claims state that the capture assay is performed prior to the detection assay (see clm 16 of the copending application). Regarding Claim 19 both sets of claims state that the detection assay comprises immuno- PCR or a proximity ligation assay (see clm 19 of the copending application). Regarding Claim 20 both sets of claims state that the detection assay involves a proximity ligation assay (see clm 20 of the copending application).
13b. Claim 115 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-9, 12-16, 19-20, and 115 of copending Application No. 18/580,412 in view of Ferlizza (Cancers 2021 Vol 13, 1101). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the copending application are discussed above. The instant claims are different because they state that the target biomarkers are EPCAM, CEACAMS, and CEACAM6. However Ferlizza teaches EPCAM as an examples of a molecule identified in EVs at increased levels in the bloodstream of CRC patients (page 12). Ferlizza cites the prior art of Cha which evaluated eight mRNA markers, including CEA (also known as CEACAM5) and EpCAM extracted from plasma EVs obtained from healthy and CRC patients (pages 12-13). Ferlizza cites the prior art of Rodia which used a novel bioinformatic approach to search for specific RNAs with high differential gene expression between CRC and normal blood. The authors reported that CEACAM6 was able to discriminate between the two groups (page 9).
Accordingly, it would have been obvious to have modified the method of the copending application by targeting the EPCAM, CEACAMS, and CEACAM6 on the surface of the EVs. In the instant case Felizza teaches that each of the recited biomarkers are correlated with colorectal cancer. Thus one of skill in the art would have been motivated to use these biomarkers in the method of the copending application for the benefit of being able to detect colorectal cancer.
14a. Claims 1-3, 5, 7-9, 12-16, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-9, 12-16, 19-20, and 115-116 of copending Application No. 18/580,427. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding Claim 1 both sets of claims are drawn to a method comprising: capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles; binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles; binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles; and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe (see clm 1 of the copending application). The instant claims further recite “wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold”, however claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. Regarding Claim 2 both sets of claims state that the second target biomarker and the third target biomarker are two different polypeptides on a surface of the extracellular vesicles (see clm 2 of the copending application). Regarding Claim 3 both sets of claims state that the co-occurrence of the first, second, and third target biomarkers on one extracellular vesicle of the extracellular vesicles defines a first target biomarker signature and wherein steps of the method are repeated for at least a second target biomarker signature, and wherein a classification cutoff references the reference threshold and at least a second reference threshold level corresponding to the at least a second target biomarker signature (see clm 3 of the copending application). Regarding Claim 5 both sets of claims state that the first and/or second target biomarker signature comprises at least one extracellular vesicle-associated surface biomarker and at least two surface biomarkers (see clm 5 of the copending application). Regarding Claim 7 both sets of claims state that the reference threshold is determined by levels of target biomarker signature-expressing extracellular vesicles observed in comparable samples from a population of non-cancer subjects (see clm 7 of the copending application). Regarding Claim 8 both sets of claims state that the population of non-cancer subjects comprises one or more of the following subject populations: healthy subjects and subjects diagnosed with benign tumors (see clm 8 of the copending application). Regarding Claim 9 both sets of claims state that the sample has been subjected to size exclusion chromatography to isolate nanoparticles having a size range of interest that includes extracellular vesicles (see clm 9 of the copending application). Regarding Claim 12 both sets of claims state that the capture agent comprises a solid substrate comprising the target-capture moiety conjugated thereto (see clm 12 of the copending application). Regarding Claim 13 both sets of claims state that the solid substrate comprises a magnetic bead (see clm 13 of the copending claims). Regarding Claim 14 both sets of claims state that the target-capture moiety is or comprises an antibody agent (see clm 14 of the copending application). Regarding Claim 15 both sets of claims further comprise a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide (see clm 15 of the copending application). Regarding Claim 16 both sets of claims state that the capture assay is performed prior to the detection assay (see clm 16 of the copending application). Regarding Claim 19 both sets of claims state that the detection assay comprises immuno- PCR or a proximity ligation assay (see clm 19 of the copending application). Regarding Claim 20 both sets of claims state that the detection assay involves a proximity ligation assay (see clm 20 of the copending application).
14b. Claims 4 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 7-9, 12-16, 19-20, and 115-116 of copending Application No. 18/580,427 in view of Ferlizza (Cancers 2021 Vol 13, 1101). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the copending application are discussed above. The instant claims are different because they state that the target biomarkers are EPCAM, CEACAMS, and CEACAM6. However Ferlizza teaches EPCAM as an examples of a molecule identified in EVs at increased levels in the bloodstream of CRC patients (page 12). Ferlizza cites the prior art of Cha which evaluated eight mRNA markers, including CEA (also known as CEACAM5) and EpCAM extracted from plasma EVs obtained from healthy and CRC patients (pages 12-13). Ferlizza cites the prior art of Rodia which used a novel bioinformatic approach to search for specific RNAs with high differential gene expression between CRC and normal blood. The authors reported that CEACAM6 was able to discriminate between the two groups (page 9).
Accordingly, it would have been obvious to have modified the method of the copending application by targeting the EPCAM, CEACAMS, and CEACAM6 on the surface of the EVs. In the instant case Felizza teaches that each of the recited biomarkers are correlated with colorectal cancer. Thus one of skill in the art would have been motivated to use these biomarkers in the method of the copending application for the benefit of being able to detect colorectal cancer.
15a. Claims 1-3, 5, 7-9, 12-16, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12-16, 18-20, and 115-116 of copending Application No. 18/580,442. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding Claim 1 both sets of claims are drawn to a method comprising: capturing extracellular vesicles from a sample with a capture agent that binds a first target biomarker on the extracellular vesicles; binding a first probe comprising a first oligonucleotide to a second target biomarker of the captured extracellular vesicles; binding a second probe comprising a second oligonucleotide to a third target biomarker of the captured extracellular vesicles; and
determining a quantity of the extracellular vesicles that are captured and bound by the first probe and the second probe (see clm 1 of the copending application). The instant claims further recite “wherein the determined quantity classifies a subject as having or being susceptible to colorectal cancer when the determined quantity is elevated relative to a reference threshold”, however claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. Regarding Claim 2 both sets of claims state that the second target biomarker and the third target biomarker are two different polypeptides on a surface of the extracellular vesicles (see clm 2 of the copending application). Regarding Claim 3 both sets of claims state that the co-occurrence of the first, second, and third target biomarkers on one extracellular vesicle of the extracellular vesicles defines a first target biomarker signature and wherein steps of the method are repeated for at least a second target biomarker signature, and wherein a classification cutoff references the reference threshold and at least a second reference threshold level corresponding to the at least a second target biomarker signature (see clm 3 of the copending application). Regarding Claim 5 both sets of claims state that the first and/or second target biomarker signature comprises at least one extracellular vesicle-associated surface biomarker and at least two surface biomarkers (see clm 5 of the copending application). Regarding Claim 7 both sets of claims state that the reference threshold is determined by levels of target biomarker signature-expressing extracellular vesicles observed in comparable samples from a population of non-cancer subjects (see clm 7 of the copending application). Regarding Claim 8 both sets of claims state that the population of non-cancer subjects comprises one or more of the following subject populations: healthy subjects and subjects diagnosed with benign tumors (see clm 8 of the copending application). Regarding Claim 9 both sets of claims state that the sample has been subjected to size exclusion chromatography to isolate nanoparticles having a size range of interest that includes extracellular vesicles (see clm 9 of the copending application). Regarding Claim 12 both sets of claims state that the capture agent comprises a solid substrate comprising the target-capture moiety conjugated thereto (see clm 12 of the copending application). Regarding Claim 13 both sets of claims state that the solid substrate comprises a magnetic bead (see clm 13 of the copending claims). Regarding Claim 14 both sets of claims state that the target-capture moiety is or comprises an antibody agent (see clm 14 of the copending application). Regarding Claim 15 both sets of claims further comprise a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide (see clm 15 of the copending application). Regarding Claim 16 both sets of claims state that the capture assay is performed prior to the detection assay (see clm 16 of the copending application). Regarding Claim 19 both sets of claims state that the detection assay comprises immuno- PCR or a proximity ligation assay (see clm 19 of the copending application). Regarding Claim 20 both sets of claims state that the detection assay involves a proximity ligation assay (see clm 20 of the copending application).
15b. Claims 4 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12-16, 18-20, and 115-116 of copending Application No. 18/580,442 in view of Ferlizza (Cancers 2021 Vol 13, 1101). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the copending application are discussed above. The instant claims are different because they state that the target biomarkers are EPCAM, CEACAMS, and CEACAM6. However Ferlizza teaches EPCAM as an examples of a molecule identified in EVs at increased levels in the bloodstream of CRC patients (page 12). Ferlizza cites the prior art of Cha which evaluated eight mRNA markers, including CEA (also known as CEACAM5) and EpCAM extracted from plasma EVs obtained from healthy and CRC patients (pages 12-13). Ferlizza cites the prior art of Rodia which used a novel bioinformatic approach to search for specific RNAs with high differential gene expression between CRC and normal blood. The authors reported that CEACAM6 was able to discriminate between the two groups (page 9).
Accordingly, it would have been obvious to have modified the method of the copending application by targeting the EPCAM, CEACAMS, and CEACAM6 on the surface of the EVs. In the instant case Felizza teaches that each of the recited biomarkers are correlated with colorectal cancer. Thus one of skill in the art would have been motivated to use these biomarkers in the method of the copending application for the benefit of being able to detect colorectal cancer.
Improper Markush Grouping Rejection
16. Claim 4 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush group:
-wherein the extracellular vesicle-associated surface biomarker is or comprises a polypeptide encoded by human genes as follows: FERMT1, Page 4of8 EPCAM, EPHB2, CEACAM6, CEACAMS, CDH17, MARCKSL1, TOMM34, S100P, EPHB3, CDH1, MUC13, SLC12A2, RAB25, LAMC2, or combinations thereof.
This Markush group is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all polypeptides. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited polypeptides would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all polypeptides. While they are all made up of amino acids, the structure of comprising amino acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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, Wu-Cheng 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.
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.
/AMANDA HANEY/Primary Examiner, Art Unit 1682
Prosecution Insights