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 .
DETAILED ACTION
Claims 2-5, 12, 20, 23-24, 29, 32-34, and 37 are pending in the instant application.
Claim status
The Applicant previously elected the species of B), the detection of nuclear proteins and/or genomic DNA in the reply filed on 18 November 2024.
Instant claims 32-34 remain withdrawn.
Claims 2-5, 12, 20, 23-24, 29, and 37 are under examination.
Claim Objections and Rejections Withdrawn
The objection to claim 20 is withdrawn in view of claim amendment.
The rejections to claims 2-5, 12, 20, 23-24, 29, and 37 under 35 USC §112(a) are withdrawn in view of claim amendment.
The rejections to claims 2-5, 12, 23-24, and 37 under 35 USC §101 are withdrawn in view of claim amendment.
The rejections to claims 2-5, 12, 20, 23-24, 29, and 37 under 35 USC §103 are withdrawn in view of claim amendment.
New Objections and Rejections Necessitated by Amendment
Objections to the Claims
Claim 20 is objected to because of the following informalities:
Regarding instant claim 20, the claim uses different articles of “a PARP inhibitor” in line 2 and “an PARP inhibitor“ in line 3. Appropriate correction is required.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 37 comprises administering a PARP inhibitor to the selected patient, but the parent claim 23 includes treating a selected patient with the PARP inhibitor. Thus, claim 37 does not further narrow the scope of the parent claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections – 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 20 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding instant claim 20, the method comprises selecting a subject for treatment…and administering a PARP inhibitor to the subject and further administering a PARP inhibitor; and treating the selected patient with the PARP inhibitor. The metes and bounds of the claim are unclear because it is unclear what the metes and bound of further treating the selected patient with a PARP inhibitor are after a patient has been selected then administered a PARP inhibitor already.
Claim Rejections – 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-5, 12, 20, 23-24, 29, and 37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding instant claims 2-5, 12, 20, 23-24, 29, and 37, a method of selecting a cancer patient for treatment with a PARP inhibitor is claimed, wherein exosomes are isolated from body fluid of a patient and assaying for the presence of PARP protein and genomic DNA is claimed, but there are 17 separate PARP proteins. The instant disclosure doesn’t have written description of a method for selecting patients and treating patients with PARP inhibitors that have exosomes comprising all PARP protein isoforms and genomic DNA.
Regarding instant claims 2, 12, 20, 23-24, and 37, a method of selecting a cancer patient for treatment is claimed, wherein isolating exosomes and assaying for PARP protein and genomic DNA is claimed, but the assay does not involve comparing the sample to a non-cancer reference sample, wherein the patient exosome sample has higher levels of PARP protein and genomic DNA than the reference sample and PARP inhibitor treatment is administered to the patients. A reference comparison is present in instant claims 3-4, thus instant claims 2, 12, 20, 23-24, and 37 are specifically not requiring a comparison.
Scope of the claimed genus
Regarding instant claims 2-5, 12, 20, 23-24, 29, and 37, a method of selecting a cancer patient for treatment with a PARP inhibitor is claimed, wherein exosomes are isolated from body fluid of a patient and assaying for the presence of PARP protein and genomic DNA is claimed. The claim would encompass all PARP protein isoforms and genomic DNA.
Regarding instant claims 2, 12, 20, 23-24, and 37, methods for selecting a cancer patient for treatment is claimed, wherein exosomes are isolated from body fluid of a patient and assaying for the presence of PARP protein and genomic DNA is claimed, but the assay does not involve comparing the sample to a non-cancer reference sample, wherein the patient exosome sample has higher levels of PARP protein and genomic DNA than the reference sample and PARP inhibitor treatment is administered to the patients. A reference comparison is present in instant claims 3-4, thus instant claims 2, 12, 20, 23-24, and 37 are specifically not requiring a comparison.
State of the Relevant Art
The PARP family of proteins has 16 members with 3 separate groups: 1) PARP-1 to PARP-4, PARP-6, PARP-8, and PARP-16; 2) PARP-5a-c; 3) PARP-7 and PARP-9 to 15 (Ame J-C et al. (BioEssays 2004 26:882–893 reference of record) (Fig. 1 and page 886, right column, second paragraph). PARP-4 has been previously identified in urine exosomes from healthy human samples (Gonzales PA et al. (Journal of the American Society of Nephrology 2009 20(2):p 363-379 reference of record) page 373, right column, second paragraph and Supplemental Table page 53, fifth result from the bottom of the page). Thus, exosomes comprising PARP protein are present in healthy human body fluid.
The prior art has detected chromosomal and mitochondrial DNA in exosomes derived from healthy donor human plasma and culture supernatant of human primary vascular smooth muscle cells, HEK293 cells (human embryonic kidney cells) and K562 cells (human immortalized myelogenous leukemia cells) (Kalluri R et al. (Cold Spring Harb Symp Quant Biol 2016. 81: 275-280) page 277, second paragraph).
Therefore, methods for selecting a patient for PARP inhibitor treatment comprising isolating exosomes and assaying for the presence of any PARP protein and genomic DNA in the exosomes without a comparison to control, wherein PARP protein and genomic DNA is known to be present in healthy subjects would contradict the prior art because healthy humans have PARP protein and genomic DNA in their exosomes in body fluid samples.
Summary of Species disclosed in the original specification
The specification discloses PARP proteins exist in ovarian cancer cell exosomes and 80.4% of the exosomes co-localized with gDNA (Fig 14). The instant disclosure does not identify the PARP protein isoform in the exosomes. Further, “PARP protein” is not defined as a specific isoform in the instant specification. Fig. 2B taught that the number of exosomes in fallopian tube cultures is less than the number of exosomes in cancer cultures. Fig. 2C taught that the number of DNA+ exosomes in fallopian tube cultures is less than the number of DNA+ exosomes in cancer cultures.
Fig. 2D taught that the number of DNA+ exosomes in DMSO vehicle control treated cancer cell cultures is less than the number of DNA+ exosomes in olaparib or topotecan treated cancer cells. Fig. 3I taught that the number of DNA+ exosomes in serum from non-tumor bearing mice was less than the number of DNA+ exosomes in serum from OVCAR-5 tumor bearing mice. Fig. 3J taught that the number of DNA+ exosomes in serum from vehicle treated OVCAR-8 tumor bearing mice was less than the number of DNA+ exosomes in topotecan treated OVCAR-5 tumor bearing mice. Fig. 9C taught that the number of exosomes from vehicle treated OVCAR-8 cancer cells was less than the number of exosomes from olaparib treated OVCAR-8 cancer cells. Fig. 11 taught characterization of exosomes in human plasma and ascites-derived exosomes.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant disclosure does not identify the number of PARP protein isoforms present as PARP protein in Figure 14.
The instant disclosure does not teach if PARP protein is present in exosomes in cultures from non-cancerous cells.
Summary
Regarding instant claims 2-5, 12, 20, 23-24, 29, and 37, the instant disclosure doesn’t have written description of a method for selecting patients and treating patients with PARP inhibitors that have exosomes comprising genomic DNA and all PARP protein isoforms because there are 17 separate PARP isoforms and the prior art taught PARP protein and genomic DNA is present in exosomes from the body fluid of healthy patients.
Regarding instant claims 2, 12, 20, 23-24, and 37, the instant disclosure doesn’t have written description of a method of selecting a cancer patient for treatment, wherein exosomes are isolated and PARP protein and genomic DNA are assayed, wherein the assay does not involve comparing the sample to a non-cancer reference sample or the patient exosome sample has higher levels of PARP protein than the reference sample, wherein PARP inhibitor treatment is administered to the patients. A reference comparison is present in instant claims 3-4, thus instant claims 2, 12, 20, 23-24, and 37 are specifically not requiring a comparison. The prior art taught PARP protein and genomic DNA is present in exosomes from the body fluid of healthy patients.
Response to Arguments
Applicant argues that the instant specification provides clear support for the claimed subject matter. As disclosed, 80.4% of exosomes isolated from ovarian cancer samples contain PARP proteins that are co-localized with genomic DNA (see, e.g., FIG. 14, reproduced below).
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This co-localization is not dependent on any particular PARP isoform; rather, it is the presence of PARP proteins together with genomic DNA within the exosomes that is critical. Importantly, the specification teaches that co-localization of PARP proteins with genomic DNA is specific to cancer patients, thereby distinguishing cancer-derived exosomes from those obtained from non-cancerous subjects.
Thus, the specification directly supports the asserted distinction from healthy subjects. As such, reconsideration and withdrawal of the rejections is respectfully requested.
In response, Applicant's arguments filed 1/27/2026 have been fully considered but they are not persuasive. Regarding 80.4% of exosomes isolated from ovarian cancer samples contain PARP proteins that are co-localized with genomic DNA and this co-localization is not dependent on any particular PARP isoform; rather, it is the presence of PARP proteins together with genomic DNA within the exosomes that is critical –
The Applicant does not provide evidence of a specific PARP gene or multiple PARP genes with genomic DNA are elevated in exosomes from ovarian cancer cells. The Applicant does not have written description of every PARP gene with genomic DNA in exosomes from ovarian cancer cells. As detailed above, there are 16 separate PARP genes. Thus, the PARP protein gene is required to be recited in the claim.
Regarding the specification teaches that co-localization of PARP proteins with genomic DNA is specific to cancer patients, thereby distinguishing cancer-derived exosomes from those obtained from non-cancerous subjects –
The prior art taught: 1) PARP protein has been previously identified in urine exosomes from healthy human samples (Gonzales PA et al. (Journal of the American Society of Nephrology 2009 20(2):p 363-379 reference of record) page 373, right column, second paragraph and Supplemental Table page 53, fifth result from the bottom of the page); and 2) chromosomal genomic DNA in exosomes derived from healthy donor human plasma (Kalluri R et al. (Cold Spring Harb Symp Quant Biol 2016. 81: 275-280) page 277, second paragraph). Therefore, methods for selecting a patient for PARP inhibitor treatment comprising isolating exosomes and assaying for the presence of any PARP protein and genomic DNA in the exosomes without a comparison to control, wherein PARP protein and genomic DNA is known to be present in healthy subjects would not allow for selection of a patient sensitive to a PARP inhibitor because healthy humans have PARP protein and genomic DNA in their exosomes in body fluid samples.
Thus, the instant claims do not have written description of the presence of PARP protein and genomic DNA in an exosome fraction from a cancer patient allowing a determination of PARP inhibitor treatment to be made. Thus, the assay requires comparing the sample to a non-cancer reference sample wherein the patient exosome sample has genomic DNA and higher levels of PARP protein than the reference sample, wherein PARP inhibitor treatment is administered to the patients.
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 2-5, 12, 23-24, and 37 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The rationale for this determination is explained below:
Claims 2-5, 12, 23-24, and 37 are directed to a natural phenomenon and an abstract idea because the claims recite natural phenomenon and an abstract idea (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: “the presence of PARP protein and genomic DNA” in an assay which allows: selection of a patient for treatment with a PARP inhibitor only if PARP protein and genomic DNA are present in the method (claims 2-5, 12, and 23-24, and 37). The “abstract idea” is: comparing the level of PARP protein in exosomes from a cancer patient to a reference number or sample from a healthy subject (instant claims 3-4) or determining if the number of PARP protein containing exosomes increases over time (instant claim 5). It is noted claim 37 recite a potential treatment step; however, the methods include an embodiment which would only observe the phenomenon without a treatment step following assaying for the presence of PARP protein in exosomes if there is no PARP protein in the exosomes. Therefore, claim 37 would be classified as “mere data gathering” and do not integrate the judicial exception(s) into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of measuring PARP protein in exosomes (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. 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);
Recited active steps of the claims impose no meaningful limit on the scope of the claims and are recited at a high level of generality such that substantially all methods of measuring PARP protein in exosomes would conventionally and routinely perform such steps. Further, the specification discloses protein identification via mass spectrometry (specification, page 44-45, paragraph 127). Mass spectrometry has previously been used to identify PARP proteins in the exosomes of healthy human urine samples (Gonzales PA et al. (Journal of the American Society of Nephrology 2009 20(2):p 363-379 reference of record) page 373, right column, second paragraph and Supplemental Table page 53, fifth result from the bottom of the page). Further, identification of PARP-1 protein in exosomes from liquid culture medium of cancer and non-transformed cells via mass spectrometry is also known to the art (Chan Y-K et al. Proteomic analysis of exosomes from nasopharyngeal carcinoma cell identifies intercellular transfer of angiogenic proteins. (Int J Cancer. 2015 137(8):1830-41 reference of record) Supp Table 1 A). The prior art has also detected chromosomal and mitochondrial DNA in exosomes derived from healthy donor human plasma and culture supernatant of human primary vascular smooth muscle cells, HEK293 cells (human embryonic kidney cells) and K562 cells (human immortalized myelogenous leukemia cells) (Kalluri R et al. (Cold Spring Harb Symp Quant Biol 2016. 81: 275-280) page 277, second paragraph). Thus, identification of PARP protein and genomic DNA in exosomes via mass spectrometry has previously been taught in the art. Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods measuring PARP protein in exosomes encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting expression) are routinely performed in the art to obtain data regarding expression and treat subjects. In regards to “selecting a cancer patient for treatment with a PARP inhibitor" and “monitoring response to PARP inhibitor in a cancer patient”, it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Response to Arguments
Applicant argues claim 23 has been amended to recite treating the selected patient with the PARP inhibitor. Therefore, the claims recite an additional and specific element that integrates the judicial exception into a practical application, the treatment of a patient with a P ARP inhibitor. As such, the claims do not relate merely to a law of nature or abstract idea.
In response, Applicant's arguments filed 1/27/2026 have been fully considered but they are not persuasive. The claims includes an embodiment wherein if the PARP protein and genomic is not present then the patient would not be treated with a PARP inhibitor. An example of claim language that requires patient selection and treatment is:
A method of selecting a cancer patient for treatment with a PARP inhibitor, the method comprising:
(a) obtaining a body fluid sample from the cancer patient;
(b) isolating an exosomes fraction of the body fluid sample;
(c) assaying for the presence of PARP protein in the exosomes fraction and genomic
DNA in the exosomes fraction, wherein PARP protein and genomic DNA are present in the exosomes fraction, and the cancer patient is selected for treatment with the PARP
inhibitor; and
(d) treating the selected patient with the PARP inhibitor.
Note the amended claim language is only an example that would negate 101 issues and not other rejections within this Office Action. Further, claim 20 which includes the same subject matter would require cancelation.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 2-5, 12, 20, 23-24, 29, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2010/056337 (Kuslich C et al. IDS reference), Makvandi et al. (Cancer Research, 2016 76:15 4516-4524; IDS reference), Sinha A et al. (Biochemical and Biophysical Research Communications 2014 445(4) 694-701 reference of record), Pavlyukov MS et al. (Cancer Cell 2018 34(1) 119-134 reference of record), and San Lucas FA et al. (Annals of Oncology 2016 27: 635–641).
Regarding instant claims 20, 23-24 and 37, Kuslich taught the general method of: a) obtaining a biological sample; b) isolating exosomes; and c) assaying the exosomes (Fig. 61). Kuslich taught a method of selecting a cancer patient for treatment (“Selecting a subject for treatment who is particularly likely to benefit from the treatment, or to provide an early and objective indication of treatment efficacy in an individual subject”, Specification ¶0287), the method comprising treating a selected patient with a method comprising:
obtaining a body fluid sample from a patient (peptides from exosomes can be analyzed by systems described ... {to} generate sensitive molecular fingerprints of proteins present in a body fluid as well as in exosome, Specification ¶0709; the biological sample obtained from the subject may be any bodily fluid, Specification ¶0105;
isolating an exosomes fraction of the body fluid sample (protein expression of exosomes can also be identified, such as following the isolation of cell-of-origin specific exosomes”, Specification ¶0709; and
assaying for the presence of protein in the exosomes fraction (for molecular features, for example, by determining an amount, presence or absence of one or more biomarkers, ¶0846; methods for analyzing biomarkers of tissues or cells can be used to analyze the biomarkers associated with or contained in exosomes, Specification ¶0681; peptide or protein biomarkers can be analyzed by ... flow cytometry”, Specification ¶0706)”.
Regarding instant claim 20, 23, 29, and 37, Kuslich taught the therapy is a genotoxic or anti-cancer therapy (“Therapy related diagnostics are also useful in clinical diagnosis and management of a variety of diseases and disorders, which include, but are not limited to ... the prediction of drug toxicity”, Specification, ¶0288 and an exosome bio-signature can be used to assess the efficacy of a therapy of chemotherapy or any other therapeutic approach for inhibiting cancer in a subject, Specification, ¶0303).
Regarding instant claim 20, 23, 29, and 37, Kuslich taught, “an exosome bio-signature can also be used in therapy related diagnostics to provide tests useful to choose the correct treatment regimen, as well as monitor a subject's response”, Specification ¶0287; “Therapy related diagnostics are also useful in clinical diagnosis and management of a variety of diseases, including but not limited to ... the prediction of drug resistance or response”, Specification ¶0288; “an exosomal bio-signature can be used to monitor drug efficacy, determine response or resistance to a given drug”, Specification ¶0309
Regarding instant claim 24, Kuslich further taught wherein the patient has ovarian cancer (“Cancer detected or assessed by products or processes described herein includes, but is not limited to ovarian cancer”, Specification ¶00951.)”
Regarding instant claim 12, Kuslich taught the method of claim 23, wherein the body fluid sample is a body fluid, including but not limited to serum, urine, cerebrospinal fluid, saliva, tears, lymph, (Specification, ¶0105.)
Regarding instant claim 2, Kuslich taught the method of claim 23, further comprising quantifying the number of nuclear proteins and/or genomic DNA-containing exosomes in the patient (“Homogeneous population of exosomes, such as those with a particular biomarker profile or signature ... can be isolated from a heterogeneous population of exosomes and quantitated”, Specification ¶0113).
Regarding instant claim 3, Kuslich taught the method of claim 2, wherein the number of nuclear proteins and/or genomic DNA-containing exosomes in the patient is higher than a reference number (“If the amount of exosomes with one or more cancer specific biomarkers is higher than a reference value, the subject is diagnosed with a cancer”, Specification ¶0292).
Regarding instant claim 4, Kuslich taught the method of claim 3, wherein the reference number is the number of nuclear proteins and/or genomic DNA-containing exosomes in a sample obtained from a healthy subject (“One or more exosome bio-signatures can be grouped so that information obtained about the set of bio-signatures in a particular group provides a reasonable basis for making a clinically relevant decision, such as but not limited to a diagnosis, prognosis, or management of treatment, such as treatment selection”, Specification ¶0311; “If the amount of exosomes with one or more cancer specific biomarkers is higher than a reference value, the subject is diagnosed with a cancer”, Specification ¶0292, such reference values may be set according to data pooled from groups of sample corresponding to a particular cohort, including but not limited to ... normal versus diseased subjects”, Specification ¶0259).
Regarding instant claim 5, Kuslich taught the method comprising monitoring response to a therapy in a cancer patient, wherein if the number of nuclear proteins and/or genomic DNA-containing exosomes increases over time, then the patient is said to have had a positive response to the therapy (“An exosome bio-signature can also be used in therapy related diagnostics to provide tests useful to choose the correct treatment regimen, as well as monitor a subject's response”, Specification ¶0287; “Therapy related diagnostics are also useful in clinical diagnosis and management of a variety of diseases, including but not limited to ... the prediction of drug resistance or response”, Specification ¶0288; “an exosomal bio-signature can be used to monitor drug efficacy, determine response or resistance to a given drug”, Specification ¶0309).
Regarding instant claim 29, Kuslich taught the method of claim 5, wherein a different anti-cancer therapy is administered if the patient is not found to have a positive response to the therapy (“a bio-signature can determine whether a particular disease or condition is resistant to a drug, and therefore, a physician need not waste valuable time with hit- and-miss treatment. Instead, to obtain early validation of a drug choice or treatment regimen, a bio- signature is determined for an exosome obtained from a subject, which then determines whether the particular subject's disease has the biomarker associated with drug resistance. Therefore, such a determination enables doctors to devote critical time as well as the patient's financial resources to effective treatments. Specification, ¶0288.)
Kuslich fails to explicitly disclose selecting a cancer patient for treatment with a PARP inhibitor, and further, fails to explicitly disclose wherein the exosome protein is a PARP protein, but this is obvious in view of Makvandi, Sinha, Pavlyukov, and San Lucas.
Regarding instant claim 23, Makvandi is in the field of preselecting patients who could benefit from PARP inhibitor (PARPi) therapy (p. 4516, Col. 2, ¶2) and taught a genotoxic therapy is a PARP inhibitor (“Regardless of the differences in potency, all clinical PARPi’s require PARP-1 expression for cytotoxic effects”, p. 4221, Col. 2, ¶2).
Regarding instant claim 23, Makvandi taught the PARP inhibitor olaparib is FDA approved for the treatment of advanced ovarian cancer with BRCA mutations (p. 4516, Col. 1, ¶1).
Regarding instant claims 20, 23, and 37, Makvandi’s disclosures relate to the field of preselecting patients who could benefit from PARP inhibitor (PARPi therapy) (p. 4516, Col. 2, ¶2) and taught selecting a cancer patient for treatment with a PARP inhibitor (“PARP-1 can now serve as an additional biomarker in precision medicine for the clinical management of cancer”, p. 4522, Col. 1-2; preselecting patients who could benefit from PARPi therapy, p. 4516, Col. 2, ¶2). Furthermore, Makvandi taught the importance of PARP protein (“PARP inhibitor sensitivity (of cancer cells) was directly related to the level of PARP-1 protein expression”, p.4521, Col. 2. ¶3, and “PARP-1 expression may be the singular most important determinant of patient response… and… it is therefore imperative to develop a quantitative and reliable means to measure PARP-1 expression in vivo”, p. 4516, Col. 2, Para. 2; quantifying PARP-1 in vivo, p. 4518, Col. 1, ¶3). Furthermore, Makvandi taught ovarian cancer cell lines with higher levels of PARP1 are more sensitive to PARP inhibitors, wherein SKOV3 has lower levels of PARP1 and SNU-251 has higher levels of PARP1, Fig. 4.
Regarding instant claims 20, 23, and 37, Sinha taught isolation of cancer cell secreted exosomes in ovarian cancer cells and assaying for protein within the exosomes (Fig 1A), wherein the assay identified PARP1 in ovarian cancer cell exosomes (Supplemental Table, Row 138).
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Regarding instant claims 5, 23, and 29, Pavlyukov taught aggressive cancers contain intermingled apoptotic cells adjacent to proliferating tumor cells (abstract). Pavlyukov taught that induction of apoptosis in cancer cells released exosomes that were measured by mass spectrometry (page 122-123 bridging paragraph), wherein the apoptotic cancer cell exosomes contained PARP1, while untreated control cancer cells did not secrete PARP1 (Supplemental Table S1, row 51, label #94).
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San Lucas taught liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling (abstract). San Lucas taught assaying exosomes of cancer patients identified actionable mutations in genomic DNA from the exosomes, including alterations in BRCA2 (abstract). San Lucas taught assaying exosomes identified a genomic DNA somatic mutation of BRCA2, wherein the BRCA2 V3091I mutation is known to confer a homologous recombination defect in cancer cells and further evidence suggest that this BRCA2 mutation is indeed pathogenic:1) the high mutant allele frequency in exosomal genomic DNA, underscoring its ‘driver’ status; 2) the ‘unstable’ genome phenotype on genome-wide copy number assessment; and 3) the exceptional response to a platinum-containing adjuvant regimen that this patient has had to date (page 637, right column, second to last paragraph). San Lucas taught several clinical trials are ongoing that incorporate platinum-based regimens of poly ADP ribose polymerase inhibitors in PDAC patients with such DNA damage repair defects (page 640, left column, second paragraph).
Regarding instant claims 2-4, 12, 20, 23-24, and 37, it would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the method of Kuslich of selecting a cancer patient for treatment who is likely to benefit from the treatment, or to provide an early and objective indication of treatment efficacy in an individual subject, the method comprising treating a selected patient with a method comprising:
obtaining a body fluid sample, wherein the body fluid is serum, urine, cerebrospinal fluid, saliva, tears, lymph from an ovarian cancer patient;
(b) isolating an exosomes fraction of the body fluid sample; and
(c) assaying for the presence of protein in the exosomes fraction,
– by 1) assaying and quantifying exosomes with PARP1 protein, then treating with a PARP inhibitor wherein the body fluid sample has higher levels of PARP1 protein in exosomes compared to a reference control from a healthy subject; 2) assaying exosomes for genomic DNA of targets that are known to be sensitive to PARP inhibitor treatment; and 3) including a patient with ovarian cancer.
This is obvious because Kuslich taught: i) quantifying exosomes and assessing the efficacy of a therapy of chemotherapy or any other therapeutic approach for inhibiting cancer in a subject, wherein the number of nuclear proteins and/or genomic DNA-containing exosomes in the patient is higher than a reference number; ii) the reference number is the number of nuclear proteins and/or genomic DNA-containing exosomes in a sample obtained from a healthy subject and: 1a) Makvandi taught selecting a cancer patient for treatment with a PARP inhibitor by quantifying PARP-1, that PARP-1 can serve as a biomarker in precision medicine for the clinical management of cancer, and PARP inhibitor sensitivity of cancer cells was directly related to the level of PARP-1 protein expression; 1b) Sinha taught PARP1 protein is known to be in ovarian cancer exosomes; 2a) San Lucas taught liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling; 2b) San Lucas taught assaying exosomes of cancer patients identified actionable mutations in genomic DNA from the exosomes, including alterations in BRCA2, wherein the BRCA2 V3091I mutation is known to confer a homologous recombination defect in cancer cells; 2c) Makvandi taught the PARP inhibitor olaparib is FDA approved for the treatment of advanced ovarian cancer with BRCA mutations;
3a) Kuslich taught including patients with ovarian cancer; 3b) Makvandi taught ovarian cancer cell lines with higher levels of PARP1 are more sensitive to PARP inhibitors; 3c) Sinha taught ovarian cancer cell secreted exosomes contain PARP1 protein.
There is a reasonable expectation of success because: 1a) Makvandi taught: PARP inhibitor sensitivity of cancer cells was directly related to the level of PARP-1 protein expression; selecting a cancer patient for treatment with a PARP inhibitor by quantifying PARP-1, wherein PARP-1 can serve as an additional biomarker in precision medicine for the clinical management of cancer; and PARP-1 expression may be the singular most important determinant of patient response; 1b) Sinha taught PARP1 protein is known to be in ovarian cancer exosomes; 2a) San Lucas taught liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling; 2b) San Lucas taught assaying exosomes of cancer patients identified actionable mutations in genomic DNA from the exosomes, including alterations in BRCA2, wherein the BRCA2 V3091I mutation is known to confer a homologous recombination defect in cancer cells; 2c) Makvandi taught the PARP inhibitor olaparib is FDA approved for the treatment of advanced ovarian cancer with BRCA mutations; and 3) Makvandi taught ovarian cancer cell lines with higher levels of PARP1 are more sensitive to PARP inhibitors and Sinha taught ovarian cancer cell secreted exosomes contain PARP1 protein. Thus, isolating and quantifying: i) PARP1 protein – which is a known biomarker wherein cancer cells with higher levels of PARP1 are known to be more sensitive to PARP inhibitors when compared to controls with less PARP1 protein and genomic DNA harboring mutations of genes that are known to be sensitive to PARP inhibitors; ii) in exosomes – which is a location known that is known to contain genomic DNA and PARP1 protein secreted from ovarian cancer cells; iii) in a body fluid – wherein exosomes are known to be located in body fluids, would have a reasonable expectation of success for selecting patients wherein patients with higher levels of exosomes with PARP1 protein compared to a reference control from a healthy subject are treated with a PARP1 inhibitor.
The motivation would have been to conduct said method of selecting a cancer patient for treatment with a PARP inhibitor with application of quantitative methods for measuring the expression of PARP-1, which is especially important in the prospective selection of appropriate patients for PARPi therapy.
This would produce a method of selecting an ovarian cancer patient (instant claim 24) for treatment who is likely to benefit from the treatment, or to provide an early and objective indication of treatment efficacy in an individual subject, the method comprising treating a selected patient with a method comprising:
obtaining a body fluid sample, wherein the body fluid is serum, urine, cerebrospinal fluid, saliva, tears, lymph (instant claim 12) from an ovarian cancer patient;
(b) isolating an exosomes fraction of the body fluid sample; and
(c) assaying and quantifying exosomes with PARP1 protein (instant claim 2) and genomic DNA with mutant targets sensitive to PARPi,
(d) comparing exosomes with PARP1 protein to a reference control from a healthy subject (instant claims 3-4) wherein the ovarian cancer patient has higher levels of exosomes with PARP1 protein and is administered a PARP1 inhibitor (instant claim 20, 23, and 37).
Regarding instant claims 5 and 29, it would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the method of Kuslich, Makvandi, and Sinha above – and: 1) further monitoring response to a therapy in a cancer patient, wherein if the number of exosomes containing PARP1 increases over time, then the patient is said to have had a positive response to the therapy, wherein a positive response continues with PARP inhibitor treatment and a non-positive response changes the treatment to a different anti-cancer therapy.
This is obvious because: 1a) Kuslich taught an exosomal bio-signature can be used to monitor drug efficacy, determine response or resistance to a given drug and choose the correct treatment regimen, as well as monitor a subject's response; 1b) Kuslich taught therapy related diagnostics are also useful in clinical diagnosis and management of a variety of diseases, for the prediction of drug resistance or response; and 1c) Pavlyukov taught cancer cells undergoing apoptosis are known to contain a higher number of exosomes that contain PARP1 compared to exosomes from cancer cells that did not undergo apoptosis. Thus, an effective cancer therapy would induce apoptosis and release higher numbers of exosomes with PARP1 protein compared to reference controls. If PARP inhibitor treatment was ineffective then another anti-cancer agent would be used.
There is a reasonable expectation of success because: 1) apoptotic cancer cells are known to have higher levels of exosomes that contain PARP1 protein. Thus, isolating and quantifying: i) PARP1 protein – which is a known biomarker wherein cancer cells with higher levels of PARP1 are known to be more sensitive to PARP inhibitors when compared to controls with less PARP1 protein; ii) in exosomes – which is a location known that is known to contain PARP1 protein secreted from ovarian cancer cells; iii) in a body fluid – wherein exosomes are known to be located in body fluids, would have a reasonable expectation of success for monitoring treatment for PARP inhibitor treatment, wherein effective cancer treatments that induce apoptosis would release a higher number of exosomes that contain PARP1 protein over time. If PARP1 inhibitors were ineffective then then another anti-cancer agent would provide a more reasonable expectation of success for treatment.
The motivation would have been to conduct said method of monitoring treatment of an ovarian cancer patient for treatment with a PARP inhibitor to ensure the treatment is effective and change to a different treatment if the PARP inhibitor was ineffective.
This would produce a method of monitoring ovarian cancer patient treatment who is likely to benefit from the treatment, the method comprising treating a selected patient with a method comprising:
obtaining a body fluid sample, wherein the body fluid is serum, urine, cerebrospinal fluid, saliva, tears, lymph from an ovarian cancer patient;
(b) isolating an exosomes fraction of the body fluid sample; and
(c) assaying and quantifying exosomes with PARP1 protein and genomic DNA with mutant targets sensitive to PARPi,
(d) comparing exosomes with PARP1 protein to a reference control from before treatment with the PARP inhibitor to monitor treatment effects, wherein when the ovarian cancer patient has higher levels of exosomes with PARP1 protein, the response is a positive response and the patient is continuously administered a PARP1 inhibitor, while when the ovarian cancer patient has no increase in levels of exosomes with PARP1 protein the patient is administered a different anti-cancer therapy. This method meets the claim limitation of instant claims 5 and 29.
Response to Arguments
Applicant has amended independent claim 23.
The updated rejection is above.
Conclusion
Claims 2-5, 12, 20, 23-24, 29, and 37 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643