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
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 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.
Response to Restriction/Election
Applicant’s election of without traverse of Group I, claims 1-4, 7, 9, 10, 12, 14, 16, 17, 19, 20, 22, 24, 25, 30, 33-35 and 37-40, in response to restriction requirement is acknowledged. Applicant’s election of “combination of all polypeptide in Table 18” for polypeptides and “lung cancer” as type of cancer, is also acknowledged. Applicant stated that claims 1, 5, 6, 8, 10-13, 15-19 and 29-31 read on the elected species. However, a careful review of the election of species shows that claims 9, 14, and 17, do not read on the elected species of combination of all polypeptides in Table 18.
Examiner search prior arts with the scope of the elected species of Table 18 polypeptides for “target molecules” and lung cancer as a type of “cancer”, and found arts anticipates the claims with the scope of the elected species. Therefore, claim 9, 14, 17 and 42-43 and non-elected subject matter of claims 1-4, 7, 10, 12, 16, 19, 30, 33, 37 and 38 (i.e. all other non-elected species of polypeptides as target molecules and other types of cancers except lung cancer) are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention. See MPEP 803.02. Applicants preserve their right to file a divisional on the non-elected subject matter. See 37 CFR 1.142(b) and MPEP § 821.03. Applicants preserve their right to file a divisional on the non-elected subject matter.
Status of the claims
Claims 1-4, 7, 10, 12, 16, 19-20, 22, 24-25, 30, 33-35 and 37-40 are examined on merits in this office action to the extant it encompasses the elected species.
Improper Markush Grouping
Claims 1-4, 7, 10, 12, 16, 19-20, 22, 24-25, 30, 33-35 and 37-40 are rejected under the judicially approved "improper Markush grouping" doctrine. (See Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, page 7166). This rejection is appropriate when the claim contains an improper grouping of alternatively useable species. See In re Harnisch, 631 F.2d 716, 719-20 (CCPA 1980). A Markush claim contains an "improper Markush grouping" if: (1) the species do not share a common use; or (2) the species of the Markush group do not share a "single structural similarity" wherein the structural similarity is essential to a common use. See MPEP § 803.02.
Here the claims disclose detection of different alternative combination (two or more) of species selected from different tables (Tables 1-6, 8, 11-19), wherein each combination (different combinations of two or more) polypeptide is considered a separate species.
The recited alternative species do not share a single structural similarity, as each method relies on detection of a different polypeptide sequence by detecting cell free cfRNA or cfDNA sequence for the polypeptide. Each cfRNA and each polypeptide has a different chemical structure in that it consists of a different polynucleotide and polypeptide sequence. Each polypeptide sequence has a different biological activity and each cfRNA has different biological activity in that it has a different specificity of hybridization. Thus, the polypeptides and the cell free polynucleotides that are been detected do not share a single structural similarity or biological activity. The only structural similarity present is that all of the polypeptides have peptide sequences and all polynucleotides are nucleic acids. The fact that the polypeptide listed in the tables have polypeptide sequence and the fact that the cfRNA or cfDNA polynucleotides comprise nucleotides per se, does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleic acid alone is not essential to the common activity of being correlated with different types of cancers. Accordingly, they do not share a single structural similarity essential to this activity.
Note that when the Markush grouping is for alternatives of chemical compounds, the alternatives are regarded as being of a similar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity; AND
(B)(1) a common structure is present, that is, a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In the present situation, there is no evidence of record to establish that it is clear from their very nature that the different particular polypeptide combinations have some particular sequence that is relevant to identification.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Claim Rejections - 35 USC § 112
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.
The expressions “target molecules are selected from Table 11” (recited in claim 1); “polypeptides of one or more of Tables 8 or 12-19” (recited in claim 2); “at least 5, 10, 15 or 20 polypeptides of Tables 8, 11-14 or 17-19” (recited in claim 3); “target molecules comprises a plurality of polypeptides from (i) Table 11; (ii) each of Tables 2, 5, 12, (iii) each of Tables 3, 4, 6 and 13, (iv) Table 8, or (vi) tables 18 and 19” (recited in claim 4); “(a) polypeptides of one or more of Tables 11-14, and (b) one or more polypeptides of Tables 1-6” (recited in claim 10); “target molecules detected above a threshold are selected from polypeptides of Table 18” (recited in claim 12); and “plurality of target molecules comprises polypeptides of Table 16A or Table 16B” recited in claim 16), renders the claims indefinite because reciting multiple tables in various claims makes the claim scope confusing and the claim scope cannot be understood without consulting the tables and even after consulting the table. As for example, many of the elected Table 18 polypeptides are not present in the polypeptides of Table 11 from which it depends and claims 2-4 and 10 claims multiple tables having overlapping peptides in different tables, whose scope could not be determined. The claims do not itself define the invention but rely on external material and modern claim practice requires that the claim must stand alone to define the invention and incorporation into claims by express reference to the specification is not permitted (Ex parte Fressola, 27 USPQ 2d 1608). MPEP 2173.05(s). The omission of failing to describe the claimed invention renders the claim incomplete. MPEP 2173.05(s) explains that whenever possible claims must be complete in themselves and must not require to a table in the specification.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 7, 10, 12, 16, 19-20, 22, 24-25, 30, 33-35 and 37-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 drawn to a method of detecting cancer tumor in a subject comprising plurality of target molecules in a biological fluid of the subject, wherein the plurality of target molecules are selected from polypeptide listed in Table 11, and detecting cancer wherein detecting the cancer comprises detecting one or more of the target molecules above a threshold level. Claims 2-4, 10 and 16, which are dependent from claim 1, are directed to plurality of target molecules from different tables.
Claim 1 encompasses detecting all types of cancer by detection of two (i.e. plurality) or more of the target molecules selected from an inordinately an enormous number of polypeptides listed in the various Tables over a threshold level and correlating the two of more of the detected target molecules over a threshold level to a particular type of cancer. Cancer types include various cancers, as for example, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head/neck cancer, hepatobiliary cancer, hematological cancer, liver cancer, lung cancer, a lymphoma, a melanoma, multiple myeloma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, urethral cancer and uterine cancer, a carcinoma, a sarcoma, a myeloma, a leukemia, a lymphoma, a blastoma, a germ cell tumor, adenocarcinoma, squamous cell carcinoma, small cell lung cancer, non-small-cell lung cancer, nasopharyngeal, colorectal, anal, liver, urinary bladder, testicular, cervical, ovarian, gastric, esophageal, head-and-neck, pancreatic, prostate, renal, thyroid, melanoma, and breast carcinoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma (mesothelioma), fibrosarcoma, angiosarcoma, liposarcoma, glioma, and astrocytoma, myelogenous, granulocytic, lymphatic, lymphocytic, and lymphoblastic leukemia, Hodgkin's lymphoma and Non- Hodgkin's lymphoma.
The specification does not provide descriptive support and critical guidance of detecting two of the polypeptide biomarkers over a threshold level from an inordinate a large number of biomarkers listed on the various Tables and correlating the increased expression or over a threshold to a particular type of cancer among the various cancers as described above. Throughout the specification detection of target molecule is strictly limited to detection of plurality of target cell free RNA (cfRNA) or cell free DNA (cfDNA) wherein the plurality of targets are one or more genes for biomarkers of Tables 11, 8, 12-19. Throughout the specification, descriptive support of detecting polypeptide biomarker has not clearly been described and there is not a single example of detecting plurality of polypeptide biomarker and relating the detected polypeptide biomarker over a threshold expressed amount to a type of cancer. The specification provides figures that provide techniques for identifying polypeptide expression from cfDAN or cfRNA (p. 14 and figures 2 and 4-6). Specification discloses combination of a few of the genes expressed over threshold (over normal subject) for lung cancer and breast cancer (see Figs. 16A-16D) and detection overexpression of certain combination of a few of the genes in lung cancer and breast cancer cannot be considered representative of relating various types of cancer from overexpression of two of more genes from the enormous number of various genes listed in the claimed tables.
Although expression can be determined, the specification has not provided guidance as to how this expression data functionally predicts different cancer types. Many of the cancers may have the same proteins overexpressed and the specification does not clearly identified criticality of expression of two polypeptides listed from the Tables and correlate to a specific type of cancer. The specification provides that certain expression profile data relative to other date can indicate lung cancer and breast cancer, but however, two critical overexpressed polypeptides that clearly identifies a specific type of cancer and distinguish it from the other types of cancers have not been clearly described. However, the specification has not provided which gene expressions have the critical data for identification of each type. This is compounded by the use of “the subject” in the claims. As the claims are drawn to any subject, the claims are drawn to any species. The specification has not provided guidance that expression in one species is functionally equivalent to any other species.
The art does not provide the critical structural elements for the asserted functionality. In particular Enard et al. (Science 2002 Vol 296 p. 340) teaches that even between closely related species gene expression patterns differ (abstract). Enard et al. teaches that mRNA expression levels are different between humans, chimpanzees, orangutans and rhesus marcques (p. 340 1st column last sentence-2nd column 1st paragraph). Enard et al. teaches that there are a large number of quantitative differences in gene expression in closely related mammals (p. 342 2nd column last paragraph). Therefore the art teaches that even between very closely related mammals there is a divergence of gene expression. As such Enard et al. teaches that merely being RNA expression in one species would not be sufficient to provide support for the identification of the various types of cancer in various species.
The art of Cobb et al (Crit Care Med 2002 Vol. 30 p. 2711) teaches the unpredictability in analysis of gene expression in spleen and liver sample from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). As such the art teaches that expression levels of the same nucleic acids in different tissue samples differ. Therefore the art indicates that an association of expression level to types in one sample would not be functionally correlative to an association to any other sample type.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note regarding genus/species situations that “Satisfactory disclosure of a ``representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.” (See: Federal Register: December 21, 1999 (Volume 64, Number 244), revised guidelines for written description.) In the instant case, the specification fails to teach the necessary common attributes or features of the genus of encompassed scores in view of the species disclosed. As such, one of skill in the art would not recognize that applicant was in possession of the genus of determination of all types of cancer in all types subject using any combination of peptides derived from expression data from cell free RNA and cell free DNA.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See page 1116).
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude, "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood , 107 F.3d at 1572, 41 USPQ2d at 1966.
An adequate written description of a DNA, such as the cDNA of the recombinant plasmids and microorganisms of the '525 patent, "requires a precise definition, such as by structure, formula, chemical name, or physical properties," not a mere wish or plan for obtaining the claimed chemical invention. Fiers v. Revel , 984 F.2d 1164, 1171, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993). Accordingly, "an adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." Id. at 1170, 25 USPQ2d at 1606.
The claims do not meet the written description provision of 35 USC 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115.)
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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.
Claims 2-4, 7, 12 and 16 are 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 1 is recites “plurality of target molecules are selected from polypeptides of Table 11”. However, many of the target polypeptides claimed in the various tables of claims 2-4, 10, and 16 and the target polypeptides disclosed in claims 7 and 12 are not present in the polypeptides of Table 11. As for example, many of the Table 8, 19, 16A and 16B polypeptides are not present in Table 11. Many of the polypeptides (as for example, WFDC2, CXCL17, MMP12, CEACAM5) of claims 7 and 12 are not present in Table 11. 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 § 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 1-4, 7, 10, 12, 16, 19-20, 22, 24-25, 30, 33-35, and 37-40 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and to laws of nature/nature/natural phenomena without significantly more.
Step 1: The instantly claimed invention is directed a method of detection of cancer in a subject. Therefore, the instantly claimed invention falls into one of the four statutory categories. (Step 1: YES)
ELIGIBILITY STEP 2A; WHETHER A CALIM IS DIRECTED TO A JUDICIAL EXCEPTION. First it is determined in Prong One whether a claim recites a judicial exception, and if so, then it is determined in Prong Two if the recited judicial exception is integrated into a practical application of that exception.
Step 2A Prong 1
In claim 1, the following limitations fall under the natural phenomena and abstract ideas:
Claim 1 is directed to detecting cancer in a subject by measuring a plurality of target molecules in a biological fluid and correlating the measured detection based on the measured level of the target molecules. The claim thereby recites the laws of nature/natural phenomena because the natural relationship of the biomarker and disease (i.e., naturally occurring correlation between cancer and the level of the biomarker target molecules).
Additionally, the limitations of detecting the subject as having cancer when a difference of measured biomarkers over a threshold level (i.e. as compared to a control level) are abstract ideas of mental processes. In this case, the step of detecting and comparing the biomarker levels involve thinking about the levels, which can be practically performed in the practitioner’s mind. The broadest reasonable interpretation of such limitations can be practically performed in the mind assisted with pen and paper. Therefore, these limitations recite a mental process.
The dependent claims 2-4, 7, 10, 12, 16, 19, 20, 22, 24, 25, 30, and 33-35, further recite limitations of detecting various biomarker and relating to cancer based on comparing with a control threshold value and falls under abstract ideas and natural phenomena.
Therefore, the limitations of the claims fall under the natural phenomena and abstract ideas (Step 2A, Prong 1: YES).
Step 2A: Prong 2:
The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception. Besides the abstract ideas and natural phenomena, claims 19, 24, 25, 33 and 34 recite the additional elements of measuring comprises sequencing cell-free polynucleotides to produce sequence reads. Such limitations in the claims are thus insignificant extra-solution activity, which is required to measure the levels of the target molecules. Therefore, the judicial exceptions are not integrated into a practical application.
In addition, claims 39 further limits treating the subject detected with cancer with a selected treatment and claim 40 recites general treatment of radiation therapy or administering an anti-cancer drug. Although this limitation indicates treatment, it does not provide any information as to how the patient is to be treated or what kind of treatment it is but instead covers a generic treatment for cancer. In fact, this limitation is recited at such a high level of generality because the treatment is not part of a class or classes of specific treatment for a specific cancer. Therefore the treatment step of claims 32 and 36 do not apply or use the judicial exception in a meaningful way. (Step 2A, Prong 2: NO).
Step 2B: In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05. The claims do not include any additional steps appended to the judicial exception that are sufficient to amount to significantly more than the judicial exception.
Thus, the claims as a whole do not amount to significantly more than the exception itself. (Step 2B: NO)
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to an abstract idea without significantly more. For additional guidance, applicant is directed generally to applicant is directed generally to the MPEP § 2106.
Claim Rejections - 35 USC § 103
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 7, 10, 12, 16, 19, 20, 22, 24-25, 30, 33-35, and 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Borgia et al. (US 10365281B2) in view of Pan et al. (US 2020/0199671 A1).
In regards to claims 1 and 7, Borgia teaches biomarkers for rapid detection of non-small cell lung cancer (Title). Borgia teaches methods comprising obtaining biological sample from a subject and assaying the level of biomarker in a biomarker panel in the biological sample wherein the panel includes at least on biomarker selected from Table I and Table II (Abstract). Borgia teaches that the biomarker panel may include a plurality of biomarkers. In some embodiments, the biomarker panel may include ten or fewer biomarkers. In yet other embodiments, the biomarker panel may include 1, 2, 3, 4, 5, 6 or 7 biomarkers. In some embodiments, the biomarker panel may be optimized from a candidate pool of biomarkers (Detailed description). Borgia teaches that measurement of a biomarker generally relates to a quantitative measurement of an expression product, which is typically a protein or polypeptide. In some embodiments, the measurement of a biomarker may relate to a quantitative or qualitative measurement of nucleic acids, such as DNA or RNA. The measurement of the biomarker of the subject detects expression levels of one or more biomarkers in subjects having lung cancer, and in some embodiments, compares the expression level of each biomarker measured to a cutoff value (i.e. threshold value) listed in Table I or in Table II. Borgia teaches expression of the biomarkers may be measured using any method known to one skilled in the art. Methods for measuring protein expression include, but are not limited to Western blot, immunoprecipitation, immunohistochemistry, Enzyme-linked immunosorbent assay (ELISA), Radio Immuno Assay (RIA), radioreceptor assay, proteomics methods, mass-spectrometry based detection (SRM or MRM) or quantitative immunostaining methods. Methods for measuring nucleic acid expression or levels may be any techniques known to one skilled in the art. Expression levels from the one or more biomarkers are measured in the subject and compared to the levels of the one or more biomarkers obtained from a cohort of subjects described below (col. 4 “Biomarker measurement).
Borgia does not disclose the biomarkers for detection of lung cancer as claimed in instant claims.
Pan teaches method of detection of cancer in a subject, the method comprising measuring one or more (i.e. plurality) target molecules in a biological fluid from the subject selected from the group consisting of ROS1, NKX2-1, GGTLC1, SLC34A2, SFTPA2, BPIFA1, SFTA3, GABRG1, AGR2, GNAT3, MUC5B, SMIM22, CXCL17, and WFDC2 and detecting lung cancer when one or more of the target molecules is detected above a threshold {claim 29(b)(i), claim 42 and 61; Fig. 16(A-D)}. Note that Applicant elected target molecules of Table 18 and Table 18 includes target molecules SMIM22, CXCL17, and WFDC2 disclosed by Pan, whose detection above a threshold indicates lung cancer as described above by Pan. Pan does not mention detection of plurality of the target molecules but however, teaches detection of one or more of the target molecules and more is considered plurality of target molecules and Pan specifically discloses detection of ARG2, SMIM22, CXCL17, and WFDC2 (Figs. 16A-D) which falls within the plurality of target molecules as claimed. Pan also, specifically discloses detection of lung adenocarcinoma above a threshold of SFTPA2 and CXCL17, which reads on plurality (e.g. 2 or 3) of target molecules as claimed in claims 1 and 7.
Therefore, from the description in mind of Borgia and Pan, it would be obvious to one of ordinary skilled in the art to easily envisage including the biomarker of Pan as described above with the expectation of expanding the arsenal of biomarker panel for detection of various types of lung cancer and for detection with improved certainty with a reasonable expectation of success because providing expression level of more than one biomarker for detection would provide correlation and detection certainty with a reasonable expectation of success. One of ordinary skilled in the art from the description in mind of Pan and Borgia, would obviously consider detection of the biomarker polypeptides by detecting genes for the polypeptides by detecting cell free RNA and cell free DNA as described by Pan.
In regards to claims 2 and 4, each of the claims include Table 18 polypeptides and the polypeptides SMIM22, CXCL17, and WFDC2 are disclosed on Table 18.
In regards to claim 3, Pan, as described above, teaches detecting none or more polypeptides which includes ROS1, NKX2-1, GGTLC1, SLC34A2, SFTPA2, BPIFA1, SFTA3, GABRG1, AGR2, GNAT3, MUC5B, SMIM22, CXCL17, and WFDC2. Pan discloses at least 5 polypeptides of Table 18, as for example, at least WFDC2, CXCL17, TFF1, AGR2 and SFTPA2 (see Figs. 16A-16D) from Table 18 of claim 3.
In regards to claim 7, as described above, Pan specifically discloses detection of ARG2, CXCL17, and WFDC2 among others, (Figs. 16A-D) which reads on the limitation of measuring plurality of target molecules claims in claim 7.
In regards to claim 10, Pan teaches detection of lung cancer by detection of target molecules above threshold of ROS1, NKX2-1, SLC34A2, SFTPA2, BPIFA1, SFTA3, GABRG1, AGR2, GNAT3, S100A7, TFF1, VTCN1, CSN1S1, MUC5B, SMIM22, CXCL17, and WFDC2 (Figs. 16A-16D) and the above disclosed target molecules are included in Table 1 target molecules.
In regards to claim 12, as described above, Pan teaches detection of lung cancer by detection of target molecules above threshold of ROS1, NKX2-1, SLC34A2, SFTPA2, BPIFA1, SFTA3, GABRG1, AGR2, GNAT3, S100A7, TFF1, VTCN1, CSN1S1, MUC5B, SMIM22, CXCL17, and WFDC2 (Figs. 16A-16D) and the above disclosed target molecules includes WFDC2 and CXCL17 of the optional target molecules and SFTPA2, TFF1, ARG2, WFDC2 and CXCL17 of Table 18.
In regards to claim 16, as described above, Pan teaches detection of lung cancer by detection of target molecules above threshold of ROS1, NKX2-1, SLC34A2, SFTPA2, BPIFA1, SFTA3, GABRG1, AGR2, GNAT3, S100A7, TFF1, VTCN1, CSN1S1, MUC5B, SMIM22, CXCL17, and WFDC2 (Figs. 16A-16D), and the above disclosed target molecules reads on the plurality of target molecules disclosed in Tables 16A and 16B.
In regards to claims 19-20, 22, 24, 25 and 30, the limitations of the measuring methods are fully disclosed throughout the claims 1-2, 46-47, 51, 54.
In regards to claims 33 and 34, claim 17 recites “wherein detecting one or more non-excluded sequence reads above a threshold comprises: (a) determining an expression level of a plurality of target cfRNA molecules; (b) determining an indicator score for each target cfRNA molecule by comparing the expression level of each of the target cfRNA molecules to an RNA tissue score matrix; (c) aggregating the indicator scores for each target cfRNA molecule; and, (d) detecting presence of the condition in the subject when the indicator score exceeds a threshold value” and claim 18 recites “wherein detecting one or more non-excluded sequence reads above a threshold comprises inputting the sequence reads into a machine learning or deep learning model”.
In regards to claim 37, detection of lung cancer has been described above by detection target molecules above a threshold level and further, Pan teaches detection of various cancers including a carcinoma, a sarcoma, a myeloma, a leukemia, a lymphoma, a blastoma, a germ cell tumor, or any combination thereof; (ii) a carcinoma selected from the group consisting of adenocarcinoma, squamous cell carcinoma, small cell lung cancer, non-small-cell lung cancer, nasopharyngeal, colorectal, anal, liver, urinary bladder, testicular, cervical, ovarian, gastric, esophageal, head-and-neck, pancreatic, prostate, renal, thyroid, melanoma, and breast carcinoma; (iii) hormone receptor negative breast carcinoma or triple negative breast carcinoma; (iv) a sarcoma selected from the group consisting of: osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma (mesothelioma), fibrosarcoma, angiosarcoma, liposarcoma, glioma, and astrocytoma; (v) a leukemia selected from the group consisting of myelogenous, granulocytic, lymphatic, lymphocytic, and lymphoblastic leukemia; or (vi) a lymphoma selected from the group consisting of: Hodgkin's lymphoma and Non-Hodgkin's lymphoma (claim 61).
In regards to claim 38, Pam teaches detecting the cancer comprises determining a cancer stage, determining cancer progression, determining a cancer type, determining cancer tissue of origin, or a combination thereof (claim 62).
In regards to claim 39, Pam teaches selecting a treatment based on the cancer detected, and optionally treating the subject with the selected treatment (claim 63).
In regards to claim 40, Pam teaches that treatment comprises surgical resection, radiation therapy, or administering an anti-cancer agent (claim 64).
Conclusion
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678