DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/20/2025 has been entered.
Claim Status and Formal Matters
The instant action is in response to papers filed 2/20/2025.
Claims 35, 37, 39, 41 and 45-52 are pending.
Claims 47-52 have been added by amendment.
Claims 35-36 and 41 have been amended.
Applicant’s election without traverse of, group II, ERG and PCA3, ERG1, ERG2, ERG3 and ERG4, KLK3 and prostatectomy in the reply filed on 5/2/2024 is acknowledged.
Claims 27, 37, 44 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/2/2024.
Claims 35, 39, 41 and 45-52 are being examined.
Priority
The instant application was filed 11/22/2021 and is a continuation of 16744783 , filed 01/16/2020,which is a continuation of 14508603 , filed 10/07/2014, which is a continuation of 14240727 01/01/0001, which is a national stage entry of PCT/US2012/051918 with an international filing date: 08/22/2012and claims priority from provisional application 61621693 , filed 04/09/2012 and claims Priority from Provisional Application 61561092 , filed 11/17/2011and claims priority from provisional application 61526238 , filed 08/22/2011.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 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.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 35, 39, 41 and 45-47 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 35 has been amended to recite, “administering at least one prostate cancer therapy to the subject identified as having prostate cancer, wherein the at least one prostate cancer therapy is selected from the group consisting of prostatectomy, localized radiation therapy, chemotherapy, adjuvant therapy, cryotherapy, ablation therapy and an anti-cancer agent..” Thus the claim encompass treatment with at least one prostate cancer therapy from those recited in the claim.. The response asserts, “ Support can be found in the abstract, paragraph [0006], [0007], [0015], [0016], [0038], [0042], [0160], [0161], claim 35, and claim 36 of the application as filed.. “ Review and searching did not reveal antecedent basis for, “administering at least one prostate cancer therapy to the subject identified as having prostate cancer, wherein the at least one prostate cancer therapy is selected from the group consisting of prostatectomy, localized radiation therapy, chemotherapy, adjuvant therapy, cryotherapy, ablation therapy and an anti-cancer agent.” While the specification recites prostatectomy, it does not specifically envision performing prostatectomy based on the expression level or ERG or PCA isoforms of the claims. Further the specification recites radiation therapy three times, but the specification does not specifically envision performing prostatectomy based on the expression level or ERG or PCA isoforms of the claims. The specification recites chemotherapy once, however the claim does not specifically envision performing prostatectomy based on the expression level or ERG or PCA isoforms of the claims. Further the limited teachings found in the specification with respect to adjuvant therapy, cryotherapy, ablation therapy and an anti-cancer agent, also does not appear to support the claim as amended>
Response to Arguments
The response traverses the rejection by asserting , “. Support can be found in the abstract, paragraph [0006], [0007], [0015], [0016], [0038], [0042], [0160], [0161], claim 35, and claim 36 of the application as filed.” This argument has been thoroughly reviewed but is not considered persuasive as the cited paragraphs do not provide support for the amendment.
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.
Claims 35, 39, 41 and 45-47are 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 35 has been amended to recite, “(c) determining a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 to identify the subject as having prostate cancer, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene.” The metes and bounds are unclear if “(c) determining a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 “ by itself allows for identification or if a specific expression pattern, increase, decrease, etc of the recited isoforms allows for identification as the specification appears to suggest.
Response to Arguments
This is a new grounds of rejection necessitated by amendment.
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 35, 39, 41 and 45-52 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step without significantly more when relative expression ratio is at or below of the relative expression level of the recited genes or isoforms. The claim(s) recite(s) the abstract idea or mental step of comparing and identifying. The claims recite, “35, 39, 41 and 45-52 “ which is a mental step. This judicial exception is not integrated into a practical application because the claim only requires treatment for those identified as having normalized expression of ERG and PCA3 . Fhe claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no specific reagents are required. Further the claims do not require administering if the determining normalized expression does not identify the subject as having prostate cancer..
Claim analysis
The instant claim 35 is directed towardsA method for treating prostate cancer in a human subject, the method comprising the steps of:(a) extracting one or more nucleic acids from a microvesicle fraction of a urine sample from the human subject;(b) detecting an RNA expression level of one or more isoforms of ETS-related gene (ERG), one or more isoforms of prostate cancer antigen 3 (PCA3), and a reference gene in the extracted nucleic acids, wherein the one or more isoforms of ERG is ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, or ERG9;(c) determining a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 to identify the subject as having prostate cancer, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene;(d) administering at least one prostate cancer therapy to the subject identified as having prostate cancer, wherein the at least one prostate cancer therapy is selected from the group consisting of prostatectomy, localized radiation therapy, chemotherapy, adjuvant therapy, cryotherapy, ablation therapy and an anti-cancer agent... The determining a normalized relative expression level is a mental step or abstract idea. Further the identifying is a mental step is a mental step or abstract idea and natural correlation.
Claim 48 recites, “A method comprising:(a) extracting one or more nucleic acids from a microvesicle fraction of a urine sample from a human subject having or suspected of having prostate cancer, wherein the urine sample is obtained without performing a digital rectal exam or a prostate massage on the subject;(b) detecting an RNA expression level of one or more isoforms of ETS-related gene (ERG), one or more isoforms of prostate cancer antigen 3 (PCA3), and a reference gene in the extracted nucleic acids, wherein the one or more isoforms of ERG is selected from the group consisting of ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, and ERG9; and(c) measuring a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene.” The step of “c) measuring a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene” requires a mental step.
The extracting, detecting is considered to be an active step requiring the analysis of a sample.
Dependent claims set forth further limitations to about the reference level, the type of cancer, the type of marker, method of isolation,.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea and natural correlation or natural phenomenon .
With regards to claim 35, the claim recites, “determining a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 to identify the subject as having prostate cancer, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene;;.” This is an abstract idea or mental step and includes a natural correlation of the RNA being detected being used to identify the subject with prostate cancer..
Further claim 48 recites, “((c) measuring a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene..” This is an abstract idea and natural correlation.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no, as the is only required when the subject is identified as having prostate cancer by the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3. (claim 35)
Claim 48 does not require an active step, which depends from or otherwise integrates the judicial exception.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, the active steps are generic are rely on the prior art.
With regards to claims 35 and 48 requires steps of extracting nucleic acids urine and extracting nucleic acids and detecting RNA expression. The specification teaches:
[0087] Methods for procuring a microvesicle fraction from a urine sample are described in this application as well as in scientific publications and patent applications (Chen et al., 2010; Miranda et al., 2010; Skog et al., 2008). See also WO 2009/100029, WO 2011009104, WO 2011031892, and WO 2011031877. These publications are incorporated herein by reference for their disclosures pertaining to microvesicle isolation or fraction procurement methods and techniques.
[0088] For example, methods of microvesicle procurement by differential centrifugation are described in a paper by Raposo et al. (Raposo et al., 1996), a paper by Skog et al. (Skog et al., 2008) and a paper by Nilsson et. al. (Nilsson et al., 2009). Methods of anion exchange and/or gel permeation chromatography are described in U.S. Pat. Nos. 6,899,863 and 6,812,023. Methods of sucrose density gradients or organelle electrophoresis are described in U.S. Pat. No. 7,198,923. A method of magnetic activated cell sorting (MACS) is described in a paper by Taylor and Gercel-Taylor (Taylor and Gercel-Taylor, 2008). A method of nanomembrane ultrafiltration concentration is described in a paper by Cheruvanky et al. (Cheruvanky et al., 2007). Further, microvesicles can be identified and isolated from a subject's bodily fluid by a microchip technology that uses a microfluidic platform to separate tumor-derived microvesicles (Chen et al., 2010). Each of the foregoing references is incorporated by reference herein for its teaching of these methods.
[0089] In one embodiment of the methods described herein, the microvesicles isolated from urine are enriched for those originating from prostate or tumor cells. Because the microvesicles often carry surface molecules such as antigens from their donor cells, surface molecules may be used to identify, isolate and/or enrich for microvesicles from a specific donor cell type (Al-Nedawi et al., 2008; Taylor and Gercel-Taylor, 2008). In this way, microvesicles originating from distinct cell populations can be analyzed for their nucleic acid content. For example, tumor (malignant and non-malignant) microvesicles carry tumor-associated surface antigens and may be detected, isolated and/or enriched via these specific tumor-associated surface antigens. In one example, the surface antigen is epithelial-cell-adhesion-molecule (EpCAM), which is specific to microvesicles from carcinomas of lung, colorectal, breast, prostate, head and neck, and hepatic origin, but not of hematological cell origin (Balzar et al., 1999; Went et al., 2004).
[0090] Additionally, tumor specific microvesicles may be characterized by the lack of surface markers, such as CD80 and CD86. In these cases, microvesicles with the markers, such as CD80 and CD86, may be excluded for further analysis of tumor specific markers. The exclusion may be achieved by various methods, for example, affinity exclusion.
[0091] The procurement of microvesicle fractions from prostate can be accomplished, for example, by using antibodies, aptamers, aptamer analogs or molecularly imprinted polymers specific for a desired surface antigen. In one embodiment, the surface antigen is specific for a cancer type. In another embodiment, the surface antigen is specific for a cell type which is not necessarily cancerous.
[0092] One example of a method of microvesicle separation based on cell surface antigen is provided in U.S. Pat. No. 7,198,923. As described in, e.g., U.S. Pat. Nos. 5,840,867 and 5,582,981, WO/2003/050290 and a publication by Johnson et al. (Johnson et al., 2008), aptamers and their analogs specifically bind surface molecules and can be used as a separation tool for retrieving cell type-specific microvesicles. Molecularly imprinted polymers also specifically recognize surface molecules as described in, e.g., U.S. Pat. Nos. 6,525,154, 7,332,553 and 7,384,589 and a publication by Bossi et al. (Bossi et al., 2007) and are a tool for retrieving and isolating cell type-specific microvesicles. Each of the foregoing references is incorporated herein for its teaching of these methods.
[0093] In the methods described herein, a urine sample may be pre-processed by one or more filtration or centrifugation steps to remove cell debris and other non-microvesicle matter. For example, the urine sample may be filtered through a 0.8 um filter. Optionally, the filtrate acquired from the 0.8 um filter may be further filtered through a 0.22 um filter. To isolate the urine microvesicles, the pre-processed samples are then concentrated using a filtration concentration step. This step comprises utilizing a filter that has a molecular cutoff to retain and concentrate the microvesicles that are greater than 10 nm in diameter. For example, the sample is then concentrated to a volume of less than 1 ml, preferably 100-200 ul. For example, the molecular weight cutoff is at least 100 kDa. Preferably, the molecular weight cutoff is 100 kDa.
[0095] Methods for nucleic acid extraction are generally based on procedures well-known in the art. Persons of skill will select a particular extraction procedure as appropriate for the particular biological sample. Examples of extraction procedures are provided in patent publications WO/2009/100029, US 20100196426, US 20110003704, US 20110053157, WO 2011009104, and WO 2011031892. These publications are incorporated herein by reference for their disclosure pertaining to microvesicle nucleic acid extraction methods and techniques.
[0107] For another example, the analysis of RNA may carried out using the Digital Gene Expression (DGE) analysis method (Lipson et al., 2009). For yet another example of RNA analysis, the RNA may be digested and converted into single stranded cDNA which may then be subject to sequencing analysis on a DNA sequencing machine, e.g., the HeliScope.TM. Single Molecule Sequencer from Helicos BioSciences as described in a publication by Ting et al. (Ting et al., 2011).
[0108] In other instances, the RNA may be reverse-transcribed into complementary DNA (cDNA) before further amplification. Such reverse transcription may be performed alone or in combination with an amplification step. One example of a method combining reverse transcription and amplification steps is reverse transcription polymerase chain reaction (RT-PCR), which may be further modified to be quantitative, e.g., quantitative RT-PCR as described in U.S. Pat. No. 5,639,606, which is incorporated herein by reference for this teaching. Another example of the method comprises two separate steps: a first step of reverse transcription to convert RNA into cDNA and a second step of quantifying the amount of cDNA using quantitative PCR.
[0109] Nucleic acid amplification methods include, without limitation, polymerase chain reaction (PCR) (U.S. Pat. No. 5,219,727) and its variants such as in situ polymerase chain reaction (U.S. Pat. No. 5,538,871), quantitative polymerase chain reaction (U.S. Pat. No. 5,219,727), nested polymerase chain reaction (U.S. Pat. No. 5,556,773), self-sustained sequence replication and its variants (Guatelli et al., 1990), transcriptional amplification system and its variants (Kwoh et al., 1989), Qb Replicase and its variants (Miele et al., 1983), cold-PCR (Li et al., 2008), BEAMing (Li et al., 2006) or any other nucleic acid amplification methods, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. Especially useful are those detection schemes designed for the detection of nucleic acid molecules if such molecules are present in very low numbers. The foregoing references are incorporated herein for their teachings of these methods. In another embodiment, the step of nucleic acid amplification is not performed. Instead, the extracted nucleic acids are analyzed directly, e.g., through next-generation sequencing..
[0116] Gene expression levels may be determined by the serial analysis of gene expression (SAGE) technique (Velculescu et al., 1995), quantitative PCR, quantitative reverse transcription PCR, microarray analysis, and next generation DNA sequencing, as known in the art.
[0117] In general, the methods for analyzing genetic aberrations are reported in numerous publications, not limited to those cited herein, and are available to skilled practitioners. The appropriate method of analysis will depend upon the specific goals of the analysis, the condition/history of the patient, and the specific cancer(s), diseases or other medical conditions to be detected, monitored or treated.
Further Shen (Genes & Development (2010) volume 24, pages 1967-2000) teaches, “ These new recommendations were proposed because the widespread use of PSA testing has led to a vast increase in the diagnosis of patients with clinically localized low Gleason grade carcinomas that may not require treatment, since their tumors are relatively indolent. In particular, patients with a Gleason pattern of 3 or less almost never relapse after local therapy, and very likely can be managed conservatively with ‘‘watchful waiting’’; nonetheless, a small fraction of these tumors will progress rapidly and require immediate treatment (Albertsen et al. 2005; Eggener et al. 2007; Lu-Yao et al. 2009.” (page 1968, 1st column top). Thus treatment encompasses watchful waiting.
The art of Skog et al (US 2010/0196426, published Aug 8, 2010) and Shen (Genes & Development (2010) volume 24, pages 1967-2000) demonstrate the active steps of the claim are routine and conventional.
Response to Arguments
The response traverses the rejection in view of the amendment of the claim to recite, “determining a normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 to identify the subject as having prostate cancer, wherein the normalized RNA expression level of the one or more isoforms of ERG and the one or more isoforms of PCA3 is a ratio between the RNA expression level of the one or more isoforms of ERG or the one or more isoforms of PCA3 to the RNA expression level of the reference gene;(d) administering at least one prostate cancer therapy to the subject identified as having prostate cancer, wherein the at least one prostate cancer therapy is selected from the group consisting of prostatectomy, localized radiation therapy, chemotherapy, adjuvant therapy, cryotherapy, ablation therapy and an anti-cancer agent.” This argument has been thoroughly reviewed but is not considered persuasive as this is either conditional depended on the expression levels or alternatively requires all subjects in which expression is determined to be diagnosed with prostate cancer. If the claim is interpreted as identifying is conditional, then in the absence of the expression pattern, expression level, etc. which identifies there is no treating and thus no integration. Alternatively if everyone is treated then the treatment is not dependent on the judicial exception and thus does not integrate the judicial exception.
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 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claim 35, 39, 41 and 45-52 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Skog et al (US 2010/0196426, published Aug 8, 2010), Shen (Genes & Development (2010) volume 24, pages 1967-2000), Srivastava (WO2009126122).
While the claims have been amended to recite, “one or more isoforms” of PCA3 or ERG this broadly encompasses the detection of anything that can be identified as PCA3 or ERG as detection of a gene with the recited names would be considered an isoform.
With regards to claim 35, Skog teaches a method for diagnosis for a medical condition of the prostate gland in a subject, comprising the steps of: (a) obtaining a microvesicle fraction from a urine sample from a subject (para [0217] - "In this experiment, a fresh morning urine sample of 220 ml was collected from a 28-year old healthy male subject and processed via differential centrifugation to isolate urinary exosomes. Specifically, urine was first spun at 300xg spin for 10 minutes to remove any cells from the sample. The supernatant was collected and then underwent a 20-minute 16,500xg spin to bring down any cell debris or protein aggregates. The supernatant was then passed through a 0.22 um membrane filter to remove debris with diameters larger than 0.22 um. Finally, the sample underwent ultra-centrifugation at 100,000 x g for 1 hour to pellet the exosomes. The pellet was gently washed in phosphate buffered saline (PBS) and RNA was extracted using a Qiagen RNeasy kit pursuant to the manufacturer's instructions. The isolated RNA was converted to cDNA using the Omniscript RT kit (Qiagen) followed by PCR amplification"); (b) extracting one or more nucleic acids from the microvesicle fraction (para [0217]); and (c) analyzing the extracted nucleic acids to detect the presence or absence of a biomarker associated with a medical condition of the prostate gland, wherein the biomarker is TMPRSS2-ERG and PCA3 (para [0228] - "In addition, the nucleic acids analyzed by nested-RT- PCR as detailed in Example 7 were TMPRSS2-ERG and PCA3, two of the newly identified biomarkers of prostate cancer"; para [0229] - "As shown in FIG. 15a, in both patient 1 and 2, but not in patient 3 and 4, the expected amplicon of TMPRSS2- ERG could be detected and digested into two fragments of expected sizes. As shown in FIG. 15b, in all four patients, the expected amplicon of PCA3 could be detected and digested into two fragments of expected sizes.
Skog teaches normalization of expression levels of RNA from microsomes using GAPDH (0101, 0202)
Skog thus teaches detection of ERG, PCA3 and GAPDH in microvesicles isolated from urine of subject with and without prostate cancer and determining relative normalized expression levels in the subjects with prostate cancer and subjects without prostate cancer.
Skog teaches, “These data, although not conclusive due to the small sample size, demonstrate the applicability of the new method in detecting biomarkers of prostate cancer. Further, the exosome method is not limited to diagnosis but can be employed for prognosis and/or monitoring other medical conditions related to prostate cancer.(0229).
Skog does not specifically teach treating with a therapy, prostatectomy, and castration resistant prostate cancer.
However, Shen teaches, “Patients are also diagnosed by the status of their primary tumors, from organ-confined to fully invasive (T1–4), with or without lymph node involvement (N0 or 1), and the presence and degree of distant metastases (M0 and 1a–c) (Ohori et al. 1994). If prostate cancer is diagnosed, conventional treatment regimens include surgical excision of the prostate (radical prostatectomy), or irradiation through external beam therapy or implantation of radioactive ‘‘seeds’’” (page 1967, 2nd column, 2nd full paragraph).
Shen on page 1968 1st column teaches castration resistant prostate cancer.
Therefore it would have been prima facie obvious to one of ordinary skill in the art at the time invention was made to treat subjects with prostate cancer or castration resistant prostate cancer and normalized expression of PCA3 and/or ERG in urine microvesicles above the level of normalized expression of PCA3 and/or ERG in urine microvesicles from subjects without prostate cancer with radiation therapy or localized radiation. The artisan would be motivated to treat subjects with prostate cancer or castration resistant prostate cancer to treat the cancer to prolong the life of the subject. The artisan would have a reasonable expectation of success as the artisan is merely using known methods to characterize known markers of prostate cancer and treating prostate cancer.
While Skog and Shen teach the detection of ERG, they do not specifically teach ERG1, ERG2, ERG3, ERG4.
However, Srivastava teaches, “[060] The term "ERG" refers to the ERG gene, as well as to the various ERG cDNAs and mRNAs described in the disclosure. Unless a specific isoform or subset of isoforms is indicated, the term ERG includes ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, ERG9, EPC1, EPC2, and the truncated ERG transcripts that result from activation of the prostate cancer-specific promoter described herein.”
Therefore it would have been prima facie obvious to one of ordinary skill at the time the invention was made to detect ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, ERG9, EPC1, EPC2, and the truncated ERG transcriptsaccording to the teachings of Shen and Skog. The artisan would be motivated as Srivastava teaches the ERG isoforms activate prostate cancer specific promoters. The artisan would have a reasonable expectation of success as the artisan is merely detecting known nucleic acids.
With regards to claim 39, 50 Shen on page 1968 1st column teaches castration resistant prostate cancer.
With regards to claim 41, 51Skog teaches normalizing with GAPDH (0101, 0202).
With regards to claim 45-46, 51-52(a) obtaining a microvesicle fraction from a urine sample from a subject (para [0217] - "In this experiment, a fresh morning urine sample of 220 ml was collected from a 28-year old healthy male subject and processed via differential centrifugation to isolate urinary exosomes. Specifically, urine was first spun at 300xg spin for 10 minutes to remove any cells from the sample. The supernatant was collected and then underwent a 20-minute 16,500xg spin to bring down any cell debris or protein aggregates. The supernatant was then passed through a 0.22 um membrane filter to remove debris with diameters larger than 0.22 um. Finally, the sample underwent ultra-centrifugation at 100,000 x g for 1 hour to pellet the exosomes. The pellet was gently washed in phosphate buffered saline (PBS) and RNA was extracted using a Qiagen RNeasy kit pursuant to the manufacturer's instructions. The isolated RNA was converted to cDNA using the Omniscript RT kit (Qiagen) followed by PCR amplification"); (b) extracting one or more nucleic acids from the microvesicle fraction (para [0217]); and (c) analyzing the extracted nucleic acids to detect the presence or absence of a biomarker associated with a medical condition of the prostate gland, wherein the biomarker is TMPRSS2-ERG and PCA3 (para [0228] - "In addition, the nucleic acids analyzed by nested-RT- PCR as detailed in Example 7 were TMPRSS2-ERG and PCA3, two of the newly identified biomarkers of prostate cancer"; para [0229] - "As shown in FIG. 15a, in both patient 1 and 2, but not in patient 3 and 4, the expected amplicon of TMPRSS2- ERG could be detected and digested into two fragments of expected sizes. As shown in FIG. 15b, in all four patients, the expected amplicon of PCA3 could be detected and digested into two fragments of expected sizes.
With regards to claim 47, Skog teaches, “lthough these biomarkers may give increased specificity due to overexpression in prostate cancer cells (e.g., PCA3 expression is increased 60- to 100-fold in prostate cancer cells), a digital rectal examination is required to milk prostate cells into the urine just before specimen collection (Nakanishi et al., 2008). Such rectal examinations have inherent disadvantages such as the bias on collecting those cancer cells that are easily milked into urine and the involvement of medical doctors which is costly and time consuming.[0228] Here, a new method of detecting the genetic profiles of these biomarkers is proposed to overcome the limitation mentioned above. The method comprises the steps of isolating exosomes from a bodily fluid and analyzing the nucleic acid from said exosomes. The procedures of the method are similar to those detailed in Example 9. “
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to obtain a urine sample without digitcal rectal exam or prostate massage as suggested by Skog in 0228. The artisan would be motivated as Skog suggests overcoming the disadvantages of rectal exams and milking of the prostate. The artisan would have a reasonable expectation of success as the artisan is merely following the guidance of the art.
Response to Arguments
The response traverses the rejection asserting none of the cited prior art expressly teaches the detection of one or more ERG isoforms in urine. This argument has been thoroughly reviewed but is not considered persuasive as the instant rejection is an obviousness rejection, not anticipatory. The rejection identies the
Claim 35 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Skog et al (US 2010/0196426, published Aug 8, 2010) and Shen (Genes & Development (2010) volume 24, pages 1967-2000) as applied to claim 35-36, 39, 41, 45-46 above, and further in view of Srivastava (WO2009126122) .
This rejection is to the election of ERG1, ERG2, ERG3, ERG4.
While Skog and Shen teach the detection of ERG, they do not specifically teach ERG1, ERG2, ERG3, ERG4.
However, Srivastava teaches, “[060] The term "ERG" refers to the ERG gene, as well as to the various ERG cDNAs and mRNAs described in the disclosure. Unless a specific isoform or subset of isoforms is indicated, the term ERG includes ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, ERG9, EPC1, EPC2, and the truncated ERG transcripts that result from activation of the prostate cancer-specific promoter described herein.”
Therefore it would have been prima facie obvious to one of ordinary skill at the time the invention was made to detect ERG1, ERG2, ERG3, ERG4, ERG5, ERG6, ERG7, ERG8, ERG9, EPC1, EPC2, and the truncated ERG transcripts that result from activation of the prostate cancer-specific promoter described herein. The artisan would be motivated as Srivastava teaches the ERG isoforms activate prostate cancer specific promoters. The artisan would have a reasonable expectation of success as the artisan is merely detecting known nucleic acids.
Response to Arguments
The response traverses the rejection for the reasons set forth with the independent claim. This argument is not persuasive for the reasons of record.
Claim 41 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Skog et al (US 2010/0196426, published Aug 8, 2010) and Shen (Genes & Development (2010) volume 24, pages 1967-2000) as applied to claims 35-36, 39, 41, 45-46 above, and further in view of Hessels (US2010/0021884).
This rejection is to the election of KLK3.
The specification teaches, “[0010] The detection of prostate cancer markers such as PSA (also called KLK3).”
While Skog and Shen teach the detection of normalizing to GAPDH, they do not specifically teach use of PSA or KLK as a reference..
However, Hessels teaches, “[0214] In a further embodiment, cells contained in voided urine samples obtained after an attentive digital rectal examination are harvested and lysed in a lysis buffer. Nucleic acids are extracted (e.g., from the lysate by solid phase extraction on silica beads for example). Detection of the presence of RNA encoded by the PCA3 gene in the nucleic acid extract is done by an in vitro specific RNA amplification coupled to real-time detection of amplified products by fluorescent specific probes. In this method, simultaneously to the amplification of the PCA3 prostate cancer specific RNA undergoes the amplification of the second prostate-specific marker (such as the PSA RNA) as a control for the presence in the urine sample of prostate cells..”
Therefore it would have been prima facie obvious to one of ordinary skill at the time the invention was made to use PSA/KLK3. The artisan would be motivated as Hessels teaches PSA/KLK3 is a control for prostate cells in urine. The artisan would have a reasonable expectation of success as the artisan is merely detecting known nucleic acids.
Response to Arguments
The response traverses the rejection for the reasons set forth with the independent claim. This argument is not persuasive for the reasons of record.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 35, 39, 41, 45-52are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-36, 38-43 of U.S. Patent No. 10,301,681.
The instant claims are drawn to A method for treating cancer in a subject, the method comprising the steps of:(a) microvesicle fraction from the urine sample; (b) extracting one or more nucleic acids from a urine sample from the subject;b)detecting ]an expression level of one or more isoforms of ERG the extracted nucleic acids; ]c)determining a normalizedthe one or more isoforms of ERG and PCA3, wherein the normalized expression level of the ne or more isoforms of ERG and PCA3 is a ratio between the expression level ofthe one or more isoforms of ERG or PCA3 to the expression level of the reference gened)identifying that the subject has prostate cancer based on the normalized expression level of the one or more isoforms of ERG and PCA3; and(el administering at least one therapy to the subject identified as having prostate cancer.
The claims of 681 are drawn to a method of treating a subject with a high risk for a high Gleason score prostate cancer, wherein the high Gleason score prostate cancer has a Gleason score of greater than 6, the method comprising the steps of: a. extracting one or more mRNAs from a urine sample from the subject; b. detecting the level of mRNA expression of PCA3, ERG and SPDEF; c. normalizing the level of mRNA expression of PCA3 and ERG to SPDEF; d. computing an EXO106 score using the formula: .times..function..times..times..times..times..times..function..times..tim- es..times..times..times..times. ##EQU00003## wherein ERG copies is the level of mRNA expression of ERG, PCA3 copies is the level of mRNA expression of PCA3 and SPDEF copies is the level of SPDEF mRNA expression; e. comparing the EXO106 Score to a predetermined cutoff value; and f. treating the subject at a high risk for a high Gleason score prostate cancer when the EXO106 score is greater than the predetermined cutoff value. Claim 5 depends from claim 1 and draws the invention to wherein extracting one or more mRNAs in step (a) comprises: a. isolating a microvesicle fraction from the urine sample; and b. extracting one or more mRNAs from the microvesicle.
Thus it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made the claims of 681 encompasses the instant claims by the breadth of claims. The artisan would be motivated to treat a subject with high risk of prostate cancer to prolong life.
Response to Arguments
The response traverses the rejection arguing the claims of 681 require a formula which is not required of the instant claims. This argument has been thoroughly reviewed but is not considered persuasive as the claims of 6781 render the instant claims obvious as they appear to be a species of the claims.
Summary
No claims are allowed.
Conclusion
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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