DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of “surface biomarkers formed of polypeptides” and “the ErbB/HER receptor tyrosine kinases, namely EGFR, ERBB2, ERBB3, and ERBB4” in the reply filed on 6/22/2026 is acknowledged. Applicant’s traversal is moot in light of amendments to the claims which eliminate the alternative embodiments presented in the original claims.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1-3, 5, 7-9, 12-16, 19-20, and 115-116 are pending and being examined on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement (e.g., paragraphs [0106, 0132] and page 286 (NOT an exhaustive list)). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
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 there are sequences included in the specification that are in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 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.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (paragraph [0173] and pg 286). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms “Texas Red” (paragraph [0366]), and “Abraxane” (paragraph [0393]), which are trade names or marks used in commerce, have been noted in this application. These terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 8 is objected to because of the following informalities:
Claim 8 reads “healthy subjects, subjects diagnosed with benign tumors, subject with breast-related diseases” and should read “healthy subjects, subjects diagnosed with benign tumors, subjects with breast-related diseases”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112b - Indefiniteness
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 1-3, 5, 7-9, 12-16, 19-20, and 115-116 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 the limitation "the subject" in line 13 (excluding lines that have been entirely marked through). There is insufficient antecedent basis for this limitation in the claim. For purposes of examination, it is being interpreted that the subject is who the sample was taken from, however further clarification is required.
Claim 1 comprises comparing a quantity of EVs captured and bound by the first and second probes to reference information including a first reference threshold level, and if the determined quantity is elevated relative to a classification cutoff referencing the first reference threshold level classifying the subject as having or being susceptible to breast cancer. First, it is unclear if the classification cutoff is different than the first reference threshold level or is essentially the same thing (i.e., defined by the reference threshold level). “classification cutoff referencing the first reference threshold level” does not clearly indicate whether these are two separate numbers or the same number. For the purposes of examination, the reference threshold level and the classification cutoff are being interpreted as the same value. Second, claim 1 required comparison to “reference information” but does not specify what a reference would be. Given that the specification indicates that a reference may be a population of healthy individuals or a subject prior to treatment (presumably with cancer), the comparison to a reference here would yield different results with regard to classification of the subject as having or being susceptible to breast cancer depending on what reference population is employed with regard to the threshold level and the classification cutoff. For the purposes of examination, it is being interpreted that the reference information is from comparable samples in a healthy population, enabling classification of the subject as having or being susceptible to breast cancer. However, further clarification is required.
Claims 2-3, 5, 7-9, 12-16, 19-20, and 115-116 depend from claim 1, inherit these deficiencies, and are rejected on the same basis.
Claim 3 recites the limitation "the steps of (b) and (c)" in line 3. There is insufficient antecedent basis for this limitation in the claim. Claim 1 has been amended to remove reference to lettered steps. For purposes of examination, step (b) is being interpreted as the capturing of the extracellular vesicles by a first target biomarker and step (c) is being interpreted as the binding of the first and second probes to a second and third target biomarker, respectively. However, further clarification is required. Additionally, claim 3 is indefinite given the recitation of a second reference threshold level for the reasons as stated in the rejection of claim 1 above. The failure to define a reference population makes it unclear how the classification could be performed. Furthermore, it is unclear how the classification of a subject as having or being susceptible to breast cancer is carried out with two different comparisons (the first target biomarker signature to a first reference threshold level and the second target biomarker signature to a second reference threshold level). Are the threshold levels both compared to the same classification cutoff? Are the classification cutoffs different given that the classification cutoff in claim 1 is in reference to the first reference threshold level? Do both target biomarker signatures need to indicate classification? Clarification is required.
Claim 5 recites the limitation "the first and/or second target biomarker signature". There is insufficient antecedent basis for this limitation in the claim. Claim 1, from which claim 5 depends, does not define what a target biomarker signature is or a first or second version of said signature.
Claim 7 recites the limitation "the reference threshold level" in line 2-3. There is insufficient antecedent basis for this limitation in the claim. The only threshold level defined in claim 1 is “a first reference threshold level”. Given that there are multiple reference threshold levels in other dependent claims, it is important to specify.
Claim 8 depends from claim 7, inherits this deficiency, and is rejected on the same basis.
Claim 9 recites the limitation "the bodily fluid-derived sample" in line 1. There is insufficient antecedent basis for this limitation in the claim. For purposes of examination, this is being interpreted as the sample as defined in claim 1 (“a sample”). Clarification is required.
Claim 12 recites the limitation "the target-capture moiety" in line 2. There is insufficient antecedent basis for this limitation in the claim. No target-capture moiety is defined in claim 1. For purposes of examination, this is being interpreted as the capture agent that binds a first target biomarker on the extracellular vesicle. Clarification is required.
Claims 13 and 14 depend from claim 12, inherit this deficiency, and are rejected on the same basis.
Claim 14 recites the limitation "the target-capture moiety" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 is directed to the method of claim 1 “further comprising a detection assay to detect hybridization of the first oligonucleotide to the second oligonucleotide”. It is unclear when this detection may occur. Is this prior to the binding of the probes to the second and third target biomarkers? After the binding of the probes to the second and third target biomarkers? For purposes of examination, it is being interpreted that this hybridization is detected after binding of the probes (comprising the oligonucleotides) to the biomarkers on the surface of the EVs. However, clarification is required. Additionally, no structural limitations are defined with regard to the oligonucleotides of the probes that would indicate that they are even able to hybridize together.
Claims 19-20 depend from claim 15, inherit these deficiencies, and are rejected on the same basis.
Claim 16 recites the limitation "the detection assay" in line 3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-3, 5, 7-9, 12-16, 19-20, and 115-116 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas (e.g.: mental processes) and a natural phenomenon without significantly more.
The claim(s) recite(s) methods of comparing determined quantities of extracellular vesicles to reference quantities and classifying breast cancer or susceptibility of breast cancer (as recited in claim 1) with a step of capturing extracellular vesicles and binding said extracellular vesicles with probes. The claims are thus directed to the assessment of collected data (determination of quantity and comparison to a reference level), which is an abstract idea that is a mental process (e.g.: MPEP 2106.04(a (2)(III)(A)); it is the observation and evaluation of information to reach a judgment or conclusion, as set forth in claim 1. Where the evaluation of data to reach a conclusion is based in the asserted correlation between biomarker levels (proteome) and the presence of a particular pathology (phenotype), such an association is accepted part of how a biological organism functions (i.e.: proteome:phenotype relationships), and as such this element of the claims is a natural phenomenon (e.g.: MPEP 2106.04(b)(I)).
This judicial exception is not integrated into a practical application because there are no practical steps related to the determination of breast cancer or susceptibility to breast cancer in a subject. There are no additional steps of the claims that are directed to applying or using the judicial exception(s) noted above (e.g.: MPEP 2106.04(d)(I)). The claims end with an asserted association between quantity of exosomes capture and bound by first and second probes and the presence of a pathology, which is an abstract idea (as noted above).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only broadly recite steps of capturing extracellular vesicles and binding said extracellular vesicles with probes. However, such steps were well understood, routine and convention in the prior art (e.g.: MPEP 2106.05(d)). For example: Moura (Moura et al., Talanta 2020) teaches performing immuno-magnetic capture of extracellular vesicles wherein exosome-specific antibodies (capture agents) are immobilized on a solid surface (a magnetic particle) to capture exosomes from a sample, which are then labeled with a breast cancer-specific antibody (probe; Abstract and 2.8. Magneto-actuated immunoassay for the detection of serum-derived from breast cancer patient). Additionally, Klass (Klass et al., US 2010/0184046 A1) teaches determining the bio-signature of an exosome (extracellular vesicle) in a sample from a subject by capturing the exosomes using a capture agent and then determining a biosignature of the capture exosomes using binding agents specific to one or more biomarkers on the surface of the exosome through binding of probes (paragraphs [0006-0008, 0010-0011, 0121-0122, 0278, 0334]).
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 1-3, 5, 7-9, 12-14, 16, and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Klass (Klass et al., US 2010/0184046 A1).
Klass teaches a method of determining the biosignature of an exosome in a biological sample from a subject to characterize a phenotype of the subject based on said biosignature (such as diagnosis of a disease; paragraphs [0006-0007]). Exosomes are a type of extracellular vesicle (paragraph [0111]). Klass teaches that said disease is breast cancer (paragraphs [0010, 0096, 0176, 0323]). Klass teaches capturing EVs (exosomes) from a sample with a capture agent that binds a first target biomarker (paragraph [0080, 0121, 0123, 0126, 0129]). Klass teaches binding a first probe to a second target biomarker and a second probe to a third target biomarker of the captured EVs (“detecting a plurality of biomarkers can provide greater sensitivity or specificity as compared to detecting less than a plurality of biomarkers” (paragraph [0010, 0323]); “exosome capture can be more easily accomplished using a more common, less cancer-specific protein, and cancer-specific proteins used in the detection phase” (paragraph [0080])). Klass teaches that the probes comprise oligonucleotides that detect target biomarkers (paragraph [0334]). Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]).
Claim 2: Klass teaches that a target biomarker is a polypeptide/protein (paragraph [0320]) Klass does not explicitly teach that the first and second target biomarkers are two different polypeptides on a surface of the EV, but it would be obvious to target two different biomarkers on the surface of the EV given the teaching by Klass that the exosome bio-signature may include a number of the same type of biomarkers (e.g., two different mRNAs; paragraph [0324]). One would be motivated to do so given the teaching by class that using a pluralty of biomarkers rather than a single biomarker provides greater sensitivity and specificity (paragraph [0010, 0315]). One would have a reasonable expectation of successfully targeting two different surface biomarkers following capture of EVs given the exemplification of Klass of capturing EVs with one biomarkers (such as EpCam or PCSA) and then detecting two separate biomarkers on the captured EVs (such as CD9 and CD63; paragraph [0684]).
Claim 3: Klass teaches that the first biomarker signature is the combination of the first second and third target biomarkers on the extracellular vesicles (paragraph [0278]). Klass does not explicitly teach repeating the steps of capturing and binding probes to the EVs (see 112b of claim 3 above, steps b and c are being interpreted as the capture and probe binding steps of claim 1). However, Klass does teach that multiple exosome bio-signatures can be grouped together (reads on at least a second biomarker signature). It would have been prima facie obvious to repeat steps b and c of the teachings of Klass to obtain a second target biomarker signature. One would be motivated to do so given the teaching by Klass that combining multiple biomarker signatures “provides a reasonable basis for making a clinically relevant decision, such as but not limited to a diagnosis” (paragraph [0312]). Klass, as indicated above, teaches determining a reference threshold value based on particular biosignatures in a reference population (paragraph [0291]).
Claim 5: Klass teaches that the first target biomarker signatures comprises at least one extracellular vesicle-associated surface biomarker and at least two surface biomarkers (paragraph [0080, 0684]).
Claims 7 and 8: Klass teaches that the first reference threshold level is determined by the same target biomarker signature-expressing EVs observed in comparable samples from a population of non-cancer subjects, more particularly healthy subjects (“samples from normal subjects not exhibiting a symptom of disease”; paragraph [0260, 0292]).
Claim 9: Klass teaches that the sample can be subjected to size exclusion chromatography to isolate the desired extracellular vesicles from the sample (paragraph [0116-0117]).
Claims 12-14: Klass teaches that the capture agent comprises a solid substrate (such as a magnetic bead) comprising a target-capture moiety (such as an antibody) conjugated thereto (paragraphs [0131-0133]).
Claim 16: Klass teaches detecting the targeted biomarkers after capturing EVs (paragraph [0078, 0167, 0683]).
Claim 115: Klass teaches that the second and third target biomarkers can be HER2 and ERBB4 for breast cancer biosignatures (paragraph [0175-0176]).
Claims 15 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Klass (Klass et al., US 2010/0184046 A1) as applied to claims 1-3, 5, 7-9, 12-14, 16, and 115 above, and further in view of Routenberg (Routenberg et al., WO 2020/086751 A1).
The teachings of Klass regarding claim 1, from which claims 15 and 19-20 depend, are detailed above.
Klass teaches detecting multiple biomarkers on captured exosomes (paragraph [0010-0011]). Klass does not teach that the detecting is achieved by detecting hybridization of the first oligonucleotide to the second oligonucleotide of the probes that are bound to target biomarkers on the surface of capture EVs or that the detection assay comprises a proximity ligation assay. However, use of hybridization between oligonucleotide comprising probes to detect a profile of surface markers on captured EVs via proximity ligation assays is known in the art, as taught by Routenberg.
Routenberg teaches a method of isolating and characterizing surface marker displaying agents, such as EVs (paragraphs [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 (paragraphs [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 (paragraphs [0358-0363, 0467, 0471, 0474, 0484]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Klass to include detection of particular combinations of biomarkers using PLA between proximity probes, as taught 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 (paragraphs [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 (paragraphs [0467, 0471, 0474, 0484, 0542-0544, and 0589-0590]).
Claim 116 is rejected under 35 U.S.C. 103 as being unpatentable over Klass (Klass et al., US 2010/0184046 A1) as applied to claims 1-3, 5, 7-9, 12-14, 16, and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019).
The teachings of Klass regarding claims 1 and 115, from which claim 116 depends, are detailed above.
Klass does not teach detecting both ERBB2 and ERBB3 as biomarkers for breast cancer on EVs. However, the correlation between these two proteins associated with EVs and known subtypes of breast cancer is known in the art, as taught by Rontogianni.
Rontogianni teaches detecting proteomic profiles of EVs in breast cancer cells. Rontogianni teaches that HER2-positive breast cancer patient serum EVs “contain active kinases in the ErbB signaling pathway (p-value = 1.13E−08), as exemplified by hyperphosphorylations of ERBB2, ERBB3, and PAK4” (Results - EV phosphoproteome).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of Klass to specifically examine ERBB2 and ERBB3, as taught by Rontogianni. One would be motivated to do so given the teaching by Rontogianni that “proteome profiles of EVs secreted by different breast cancer cell lines are highly indicative of their respective molecular subtypes, even more so than the proteome changes within the cancer cells” (Abstract). Therefore, one of skill in the art would be motivated to examine these specific proteins to determine a specific molecular subtype of human breast cancer, such as HER2-positive, especially given the teaching by Rontogianni that specific subtypes of breast cancer “present distinct challenges in diagnosis and therapeutic needs” (Introduction, paragraph 3). One would have a reasonable expectation of successfully identifying these proteins given the Rontogianni teaches their increased presence in extracellular vesicles of breast cancer samples.
Double Patenting
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.
Copending Application No. 18/580,444
Claims 1-3, 5, 7-9, 12-16, 19-20 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 of copending Application No. 18/580,444 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above..
Regarding claim 1: The claims of ‘444 teach capturing EVs from a sample with a capture agent that binds a first target biomarker on the EV, binding a first probe comprising a first oligonucleotide to a second target biomarker of the EV, binding a second probe comprising a second oligonucleotide to a third target biomarker of the EV, detrmining a quantity of the EVs that are capture and bound by the first and seconde probes and classifying the subject as having or being susceptible to colorectal cancer when the determined quantity of EVs is elevated relative to a reference threshold level.
The claims of ‘444 teach the exact same methodology of instant claim 1 applied to colorectal cancer instead of breast cancer. However, the application of this same methodology to breast cancer is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘444 to apply this methodology to breast cancer, as taught by Klass. Using this methodology to diagnosis breast cancer, as opposed to colorectal cancer, is an obvious variation of the methodology of ‘444. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches that this methodology can be applied to both breast cancer and colorectal cancer (paragraph [0023, 0096, 0371]).
Claim 116 is 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 of copending Application No. 18/580,444 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/580,422
Claims 1-3, 5, 7-9, 12-16, 19-20 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-9, 12-14 and 17 of copending Application No. 18/580,422 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above..
Regarding claim 1: The claims of ‘422 teach detecting EVs by proximity ligation assay by capturing EVs from a sample with a capture agent that binds a surface biomarker on the EV expressing a first target biomarker signature comprising that at least one EV-associated surface biomarker and at least one further biomarker such as a surface biomarker selected from polypeptides, comparing a level of the signature-expressing EVs to a first reference threshold level, and classifying the subject as having or being susceptible to liver cancer when the determined level of EVs is elevated relative to a first reference threshold level. The claims of ‘422 go on to teach that the biomarker signature comprises at least on EV biomarker and at least two other biomarkers (such as surface biomarkers, claim 5).
The claims of ‘422 teach a very similar methodology as that of instant claim 1 applied to liver cancer instead of breast cancer. The claims of ‘422 also do not teach the binding of two probes that comprise oligonucleotides. However, the application of this same methodology to breast cancer using probes comprises of oligonucleotides is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]). Klass teaches that the probes comprise oligonucleotides that detect target biomarkers (paragraph [0334]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘422 to apply this methodology to breast cancer, as taught by Klass. Using this methodology to diagnosis breast cancer, as opposed to liver cancer, is an obvious variation of the methodology of ‘422. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches that this methodology can be applied to both breast cancer and liver cancer (paragraph [0191-0192]).
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-9, 12-14 and 17 of copending Application No. 18/580,422 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Copending Application No. 18/580,442
Claims 1-3, 5, 7-9, 12-16, 19-20 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. 18/580,442 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above..
Regarding claim 1: The claims of ‘442 teach capturing EVs from a sample with a capture agent that binds a first target biomarker on the EV, binding a first probe comprising a first oligonucleotide to a second target biomarker of the EV, binding a second probe comprising a second oligonucleotide to a third target biomarker of the EV, determining a quantity of the EVs that are capture and bound by the first and second probes and classifying the subject as having or being susceptible to pancreatic cancer when the determined quantity of EVs is elevated relative to a reference threshold.
The claims of ‘442 teach the exact same methodology of instant claim 1 applied to pancreatic cancer instead of breast cancer. However, the application of this same methodology to breast cancer is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘442 to apply this methodology to breast cancer, as taught by Klass. Using this methodology to diagnosis breast cancer, as opposed to pancreatic cancer, is an obvious variation of the methodology of ‘442. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches that this methodology can be applied to both breast cancer and pancreatic cancer (paragraph [0035, 0425-0430]).
Claim 116 is 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. 18/580,442 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/580,412
Claims 1-3, 5, 7-9, 12-16, 19-20 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-14, 16, and 20 of copending Application No. 18/580,412 in view of Klass (Klass et al., US 2010/0184046 A1.
Regarding claim 1: The claims of ‘412 teach detecting EVs expressing a first target biomarker signature comprising at least one EV-associated surface biomarker and at least one further biomarker such as a surface biomarker selected from polypeptides, comparing a level of the signature-expressing EVs to a first reference threshold level, and classifying the subject as having or being susceptible to pancreatic cancer when the determined level of EVs is elevated relative to a first reference threshold level. The claims of ‘412 go on to teach that the biomarker signature comprises at least on EV biomarker and at least two other biomarkers (such as surface biomarkers, claim 5). The claims of ‘412 also teach that the method comprises a capture step of the EVs (claims 10-14).
The claims of ‘412 teach a very similar methodology as that of instant claim 1 applied to pancreatic cancer instead of breast cancer. The claims of ‘412 also do not teach the binding of two probes that comprise oligonucleotides. However, the application of this same methodology to breast cancer using probes comprises of oligonucleotides is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]). Klass teaches that the probes comprise oligonucleotides that detect target biomarkers (paragraph [0334]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘412 to apply this methodology to breast cancer, as taught by Klass. Using this methodology to diagnosis breast cancer, as opposed to pancreatic cancer, is an obvious variation of the methodology of ‘412. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches that this methodology can be applied to both breast cancer and pancreatic cancer (paragraph [0035, 0425-0430]).
Regarding claim 115: Klass teaches that the breast cancer specific surface biomarkers are HER2 (ERBB2) and ERBB4 for breast cancer biosignatures (paragraph [0175-0176]).
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-14, 16, and 20 of copending Application No. 18/580,412 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Copending Application No. 18/580,445
Claims 1-3, 5, 7-9, 12-14, 16, and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 16-20 of copending Application No. 18/580,445 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above..
Regarding claim 1: The claims of ‘445 teach detecting EVs expressing a first target biomarker signature comprising at least two surface biomarkers selected from polypeptides, comparing a level of the co-localization level of the biomarkers to a reference threshold level, and classifying the subject as having or being susceptible to cancer when the determined level of co-localization is elevated relative to a reference threshold level for the biomarker combination. The claims of ‘445 go on to teach that the biomarker signature also comprises at least one EV biomarker in a capture step (such as surface biomarkers, claim 19-20). The claims of ‘445 teach that the cancer is breast cancer (claims 10-11).
The claims of ‘445 do not teach the binding of two probes that comprise oligonucleotides. However, the application of this same methodology to detect biomarkers associated with breast cancer using probes comprises of oligonucleotides is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]). Klass teaches that the probes comprise oligonucleotides that detect target biomarkers (paragraph [0334]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘445 to employ probes comprising oligonucleotides to determine biomarker co-localization, as taught by Klass. The claims of ‘445 do not teach how the biomarkers are detected. Using oligonucleotide comprising probes is an obvious variation of the methodology of ‘445. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches successful use of this methodology to diagnose cancer (paragraph [0035, 0425-0430]).
Claims 15 and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 16-20 of copending Application No. 18/580,445 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-14, 16, and 115 above, and further in view of Routenberg (Routenberg et al., WO 2020/086751 A1) according to citations and rationales provided above.
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 16-20 of copending Application No. 18/580,445 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-14, 16, and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Copending Application No. 17/435,697
Claims 1-3, 5, 7-9, 12-16, 19-20 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 120, 125-127, and 139 of copending Application No. 17/435,697 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above.
Regarding claim 1: The claims of ‘697 teach capturing EVs from a sample with a binder agent that binds a first target biomarker on the EV, binding a second binder comprising a first oligonucleotide to a second target biomarker of the EV, binding a third binder comprising a second oligonucleotide to a third target biomarker of the EV, and detecting the ligation product of the first and second oligonucleotide indicating EVs with co-occurrence of the three targeted biomarkers. The claims of ‘697 teach that the biomarkers are a signature for a disease such as cancer.
The claims of ‘697 do not teach determining a quantity of the EVs that are captured and bound by the first and second probes and classifying the subject as having or being susceptible to breast cancer when the determined quantity of EVs is elevated relative to a reference threshold. However, determination of the quantity of EVs by co-occurrence of target biomarkers, comparison to a reference threshold level, and classification of the subject as having breast cancer when the level is elevated relative to the reference threshold level is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to a reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘697 to apply this methodology to breast cancer and to use comparisons to a reference threshold level, as taught by Klass. One would be motivated to do so given the teaching by class that use of a reference threshold level allows for diagnosis of a disease, such as cancer (paragraph [0263]). One would have a reasonable expectation of success given that Klass teaches that the methodology of identifying biosignatures on EVs can be applied, through comparison to reference values, diagnose breast cancer (paragraph [0260-0268, 0270, 0278, 0292-0293]).
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 120, 125-127, and 139 of copending Application No. 17/435,697 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
This is a provisional nonstatutory double patenting rejection.
Copending Application No. 18/015,051
Claims 1-3, 5, 7-9, 12-16, 19-20 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 76, 79, 82, and 86-87 of copending Application No. 18/015,051 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above.
Regarding claim 1: The claims of ‘051 teach detecting EVs expressing a biomarker signature comprising an EV-associated surface biomarker and a further biomarker such as a protein, detecting the biomarkers via a proximity ligation assay using a set of detection probes comprising oligonucleotides, comparing a level of the signature-expressing EVs to a reference level, and identifying the sample as having lung cancer when the determined level of EVs (ligated product) is elevated relative to the reference level. The claims of ‘015 go on to teach that the biomarker signature comprises the EV biomarker and at least two other biomarkers (such as surface biomarkers, claims 86-87).
The claims of ‘051 teach a very similar methodology as that of instant claim 1 applied to lung cancer instead of breast cancer. However, the application of this same methodology to breast cancer is known in the art, as taught by Klass.
Klass teaches determining a quantitative value (level) of exosomes based on a particular combination of biomarkers and comparing this level to a reference threshold level and classifying the subject as having a disease (such as breast cancer) when the determined quantity is elevated relative to the first reference threshold level (or relative to the cutoff, see 112b of claim 1 above; paragraphs [0260-0268, 0270, 0278, 0292-0293]).
It would have been prima facie obvious to one having ordinary skill in the art, before the effective filing date of the instant application, to have modified the method of ‘051 to apply this methodology to breast cancer, as taught by Klass. Using this methodology to diagnosis breast cancer, as opposed to lung cancer, is an obvious variation of the methodology of ‘051. It is the use of a known technique to arrive at a diagnosis of a type of cancer using cancer-specific biomarkers. One would have a reasonable expectation of success given that Klass teaches that this methodology can be applied to both breast cancer and lung cancer (paragraph [0179-0180]).
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 76, 79, 82, and 86-87 of copending Application No. 18/015,051 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Copending Application No. 19/726,290
Claims 1-2, 5, 7-9, 12-16, and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 81, 86-95, 99, 103 and 105 of copending Application No. 19/726,290 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because they encompass the same claim limitations. The claims at issue involve capturing EVs and detecting target biomarkers through the use of detection probes comprising oligonucleotides, determining sample information (levels) of EVs that are captured and detected, and comparing these to a reference threshold and diagnosing a disease such as breast cancer when the levels are elevated relative to the reference threshold level.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3 and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 81, 86-95, 99, 103 and 105 of copending Application No. 19/726,290 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above.
Regarding claim 3: The claims of ‘290 do not teach repeating the capturing, detecting, and determining steps for a second target biomarker signature. However, computing multiple biomarker signatures for the diagnosis of cancer is known in the art, as taught by Klass.
Klass teaches that the first biomarker signature is the combination of the first second and third target biomarkers on the extracellular vesicles (paragraph [0278]). Klass does not explicitly teach repeating the steps of capturing and binding probes to the EVs (see 112b of claim 3 above, steps b and c are being interpreted as the capture and probe binding steps of claim 1). However, Klass does teach that multiple exosome bio-signatures can be grouped together (reads on at least a second biomarker signature).
It would have been prima facie obvious to repeat the detecting of a biomarker signature as taught by ‘290 to obtain a second target biomarker signature, as taught by Klass. One would be motivated to do so given the teaching by Klass that combining multiple biomarker signatures “provides a reasonable basis for making a clinically relevant decision, such as but not limited to a diagnosis” (paragraph [0312]). Klass, as indicated above, teaches determining a reference threshold value based on particular biosignatures in a reference population (paragraph [0291]).
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 81, 86-95, 99, 103 and 105 of copending Application No. 19/726,290 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, 19-20 and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Copending Application No. 19/656,471
Claims 1-3, 5, 7-9, 12-16, and 115 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, and 17-19 of copending Application No. 19/656,471 in view of Klass (Klass et al., US 2010/0184046 A1) according to citations and rationales provided above.
Claims 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, and 17-19 of copending Application No. 19/656,471 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, and 115 above, and further in view of Routenberg (Routenberg et al., WO 2020/086751 A1) according to citations and rationales provided above.
Claim 116 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, and 17-19 of copending Application No. 19/656,471 in view of Klass (Klass et al., US 2010/0184046 A1 as applied to claims 1-3, 5, 7-9, 12-16, and 115 above, and further in view of Rontogianni (Rontogianni et al., Communications Biology 2019) according to citations and rationales provided above.
Conclusion
No claims are allowed.
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/KAILEY ELIZABETH CASH/Examiner, Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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