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 ACTIONPriority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 15-18, 20, 27-28, 31, and 33-34 have an effective filing date of 23OCT2020.
Status of Claims
Claims 15-18, 20, 27-28, 31, and 33-34 are currently pending and presented for examination on the merits.
Claims 15 and 31 are amended.
Claims 1-14, 19, 21-26, 29-30, and 32 are canceled.
Rejections Withdrawn
The rejections filed under 35 U.S.C. 101 are withdrawn in view of Applicant’s amendments to claims.
The rejections filed under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendments.
Rejection Maintained
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 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 15-18, 20, 27, 31, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Iliopoulos et al (US 20100222230 A1), and further in view of Raimondo et al (Differential protein profiling of renal cell carcinoma urinary exosomes, Mol. BioSyst., 2013, 9, 1220, pgs. 1220-1233).
Applicant defines, “extracellular vesicles” as “heterogenous vesicles formed by budding of the plasma membrane of eukaryotic cells, to the exterior of the cell. Microvesicles are secreted in larger amounts by cancer cells than normal cells. These membrane vesicles are heterogeneous in size with diameters ranging from about 10 nm to about 5000 nm, but also in biogenesis pathway or cellular source. All membrane vesicles shed by cells < 0.8 m in diameter are referred to herein collectively as "microvesicles". Examples of extracellular vesicles include, but are not limited to, microvesicles, microvesicle-like particles, prostasomes, exosomes, dexosomes, texosomes, ectosomes, oncosomes, microparticles, apoptotic bodies, retrovirus-like particles, and human endogenous retrovirus (HERV) particles” [pg. 5 of Specification].
In regards to claims 15 and 31, Iliopoulos et al teaches a method of diagnosing and prognosing renal cell carcinoma [Abstract]. Iliopoulos et al further teaches the methods are useful for clear cell Renal cell carcinoma (ccRCC) [0019]. Iliopoulos et al further teaches treating with an appropriate therapy if cancer is detected [0033]. Iliopoulos et al further teaches useful biomarkers for RCC is CA9 [0021]. Iliopoulos et al further teaches comparing the level of the biomarker to a reference level indicating the subject is at increased risk of developing RCC [0026]. Iliopoulos et al further teaches CA9 levels decreasing after nephrectomy [Fig 6.]. Iliopoulos et al further teaches increases in ccRCC tumors and comparing to normal kidney tissue level [Fig. 11A-14B].
Iliopoulos et al does not specifically teach measuring the level of extracellular vesicles expressing CA9+ EVs. However, this deficiency is made up in the teachings of Raimondo et al.
Raimondo et al teaches a method of establishing a protein profile of exosomes isolated from sample from ccRCC patients [Abstract]. Raimondo et al further teaches only samples from ccRCC were included [Right column, 3rd Paragraph, pg. 1221]. Raimondo et al further teaches comparing the results to control subjects [Abstract]. Raimondo et al further teaches measuring CA9 in RCC and control samples [Fig. 9A]. Raimondo et al further teaches CA9 is significantly more abundant in RCC patient urinary exosomes [Left column, 1st Paragraph, pg. 1231]. Raimondo et al further teaches RCC is associated with a high potential of metastasis and is resistant to both chemotherapy and radiotherapy, and nephrectomy remains the most effective treatment [Right column, 1st Paragraph, pg. 1220].
One of ordinary skill, before the effective filing date, would have been motivated to combine Iliopoulos’s method for diagnosing, prognosing, and treating ccRCC in a subject by measuring the biomarker CA9, comparing the level to a reference level to indicating the subject is at increased risk of developing ccRCC, with Raimondo’s method of measuring CA9 expression levels on exosomes and comparing to control samples and that CA9 is significantly more abundant in RCC patient exosomes. The idea of combining them flows logically from their having been individually taught in the prior art (MPEP 2144.06). Combining prior art elements according to known methods to yield predictable results is an exemplary rationale for a prima facie case of obviousness. MPEP2143. It would have been prima facie obvious to combine Iliopoulos and Raimondo’s methods for a method of predicting the risk of recurrence in a subject undergoing treatment for, or having undergone treatment for, ccRCC comprising measuring CA9+ EVs in a sample for a subject, comparing the level of CA9+ EVs with a reference level, and assigning the subject to s high-risk or low-risk group for ccRCC recurrence or treating depending on CA9 level compared to reference, because both Iliopoulos and Raimondo teach detecting CA9 in ccRCC samples to diagnose and prognose patients. Furthermore, Raimondo teaches detecting CA9 on exosomes was shown to be advantageous, since reduction of the complexity of the urine proteosome together with enrichment in renal proteins towards plasmatic ones is achieved.
In regards to claim 16, Raimondo et al teaches the vesicles comprised a diameter of between 30-50 nm [Right column, 2nd Paragraph, pg. 1223].
Applicant states, “Microvesicles are secreted in larger amounts by cancer cells than normal cells. These membrane vesicles are heterogeneous in size with diameters ranging from about 10 nm to about 5000 nm” pg. 5 of Specification.
In regards to claim 17, Iliopoulos et al teaches the absolute value of mRNA signal detected in RCC tumors [0351].
In regards to claim 18, Raimondo et al teaches exosomes were prepared by differential centrifugation [Right column, 4th Paragraph, pg. 1221].
With regard to centrifuging at 260 g for about 15 minutes, then centrifuging the supernatant at about 1500 g for 20 minutes is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each centrifugation needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of centrifugation amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In regards to claim 20, Iliopoulos et al teaches comparing results of CA9 and comparing to a reference value [0026]. Furthermore, Raimondo et al teaches the levels of CA9 are significantly increased in RCC urinary exosomes, a powerful RCC marker, and shown to correlate with tumor size [Right column, 2nd Paragraph, pg. 1231]. One of ordinary skill would have found it obvious to set a reference level for a sample and is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize.
In regards to claim 27, Iliopoulos et al teaches the sample is blood [0030].
In regards to claim 33, Iliopoulos et al teaches comparing results of CA9 and comparing to a reference value [0026]. Furthermore, Raimondo et al teaches the levels of CA9 are significantly increased in RCC urinary exosomes, a powerful RCC marker, and shown to correlate with tumor size [Right column, 2nd Paragraph, pg. 1231]. One of ordinary skill would have found it obvious to set express the CA9+ EV as a percentage of CA9+ EVs out of the total extracellular vesicles in the sample.
In regards to claim 34, Iliopoulos et al teaches the sample is blood [0030].
Claims 15-18, 20, 27-28, 31, and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Iliopoulos et al (US 20100222230 A1), Raimondo et al (Differential protein profiling of renal cell carcinoma urinary exosomes, Mol. BioSyst., 2013, 9, 1220, pgs. 1220-1233) as applied to claims 15-18, 20, 27, 31, and 33-34 above, and further in view of Morales-Kastresana et al (Labeling Extracellular Vesicles for Nanoscale Flow Cytometry, Scientific reports, 7, 1878, 2017, pgs. 1-10).
The teachings of Iliopoulos et al and Raimondo et al are discussed above.
Iliopoulos et al does not specifically teach measuring the EV by flow cytometry. However, this deficiency is made up in the teaches of Morales-Kastresana et al.
In regards to claim 28, Morales-Kastresana et al teaches extracellular vesicles are released cell and carry biomarkers of disease [Abstract]. Morales-Kastresana et al further teaches using flow cytometry to evaluate the samples [Abstract].
One of ordinary skill, before the effective filing date, would have been motivated to combine Iliopoulos’s method for diagnosing and prognosing ccRCC in a subject by measuring the biomarker CA9, comparing the level to a reference level to indicating the subject is at increased risk of developing ccRCC, with Raimondo’s method of measuring CA9 expression levels on exosomes and comparing to control samples and that CA9 is significantly more abundant in RCC patient exosomes, with Morales-Kastresana’s measuring extracellular vesicles by flow cytometry. It would have been prima facie obvious to combine Iliopoulos and Raimondo’s methods for a method of predicting the risk of recurrence in a subject undergoing treatment for, or having undergone treatment for, ccRCC comprising measuring CA9+ EVs in a sample for a subject, comparing the level of CA9+ EVs with a reference level, and assigning the subject to s high-risk or low-risk group for ccRCC recurrence, because both Iliopoulos and Raimondo teach detecting CA9 in ccRCC samples to diagnose and prognose patients. Furthermore, Raimondo teaches detecting CA9 on exosomes was shown to be advantageous, since reduction of the complexity of the urine proteosome together with enrichment in renal proteins towards plasmatic ones is achieved. Furthermore, to detect CA9 by flow cytometry as taught by Morales-Kastresana.
Applicant’s Arguments:
These rejections are respectfully traversed
… neither Iliopoulos nor Raimondo disclose or suggests a method for predicting the risk of recurrence in a subject undergoing treatment for, or having undergone treatment for, clear cell renal cell carcinoma (ccRCC), based on the measure of level of CA9+ extracellular vesicles.
… since neither document discloses nor suggests any reference level of approximately at least 200 CA9+ EVs/ μL of sample.
Examiner’s Response:
Applicant states, “…neither document discloses nor suggests any reference level of approximately at least 200 CA9+ EVs/ μL of sample”
Iliopoulos et al teaches a method of diagnosing and prognosing renal cell carcinoma [Abstract]. Iliopoulos et al further teaches the methods are useful for clear cell Renal cell carcinoma (ccRCC) [0019]. Iliopoulos et al further teaches treating with an appropriate therapy if cancer is detected [0033]. Iliopoulos et al further teaches useful biomarkers for RCC is CA9 [0021]. Iliopoulos et al further teaches comparing the level of the biomarker to a reference level indicating the subject is at increased risk of developing RCC [0026]. Iliopoulos et al further teaches CA9 levels decreasing after nephrectomy [Fig 6.]. Iliopoulos et al further teaches increases in ccRCC tumors and comparing to normal kidney tissue level [Fig. 11A-14B].
Raimondo et al teaches a method of establishing a protein profile of exosomes isolated from sample from ccRCC patients [Abstract]. Raimondo et al further teaches only samples from ccRCC were included [Right column, 3rd Paragraph, pg. 1221]. Raimondo et al further teaches comparing the results to control subjects [Abstract]. Raimondo et al further teaches measuring CA9 in RCC and control samples [Fig. 9A]. Raimondo et al further teaches CA9 is significantly more abundant in RCC patient urinary exosomes [Left column, 1st Paragraph, pg. 1231].
With regard to a reference level of approximately at least 200 CA9+ EVs/ μL of sample or 1.85% of CA9+ MVs of total microvesicles, the amount of CA9+ EVs and MVs are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of ingredient amounts would have been obvious at the time of applicant's invention.
The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."(Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DENNIS JOHN SULLIVAN whose telephone number is (571)272-0509. The examiner can normally be reached Mon - Fri: 7:30AM - 4:30PM.
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/DENNIS J SULLIVAN/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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