DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
This action is in response to papers filed 8/28/2025.
Applicant's election with traverse Group 2 and NAALAD2 and PRKCB in the reply filed on 2/03/2025 is acknowledged.
Claims 24-43 are pending. Claims 1-23 have been cancelled.
Claims 24-27, 33-34, 37-43 have been withdrawn as being drawn to a nonelected invention.
The following rejections for claims 28-32 and 35-36 are maintained or newly applied as necessitated by amendment. Response to arguments follows.
This action is FINAL.
Withdrawn Objections and Rejections
The objection to the rejection made in the previous office action is withdrawn based upon amendments to the specification.
The objection to the claims made in the previous office action is withdrawn based upon amendments to the claims.
The 35 USC 112b rejection made in the previous office action is withdrawn based upon amendments to the claims. However, it is noted that based upon amendments to the claims a newly applied 35 USC 112b provided below.
The 35 USC 35 USC 103 rejection made in the previous office action is withdrawn based upon amendments to the claims.
Maintained 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 28-32 and 35-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for determining DNA methylation level, does not reasonably provide enablement for assisting in treatment selection or patient’s monitoring. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The breadth of the claims and nature of the invention
The claims are drawn to assisting in treatment selection or patients monitoring in an individual diagnosed with PCa or CRPC comprising providing a sample obtained from said individual and determining DNA methylation level of NAALAD2 and PRKCB, nucleotide sequences complementary, sequences at least 90% or a fragment of at least 16 nucleotides.
However, the specification has not provided any guidance for any treatment or any monitoring based upon any level of methylation, whereas, the art, as discussed below, teaches that expression level in tissue types from various species are not directly correlative.
Nature of the Invention
The invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
Guidance in the Specification and Working Examples
The specification teaches detection of methylation levels in PRKCB and NAALAD2 (p. 24). However, merely detecting methylation levels does not provide support for the correlation to assisting in treatment selection or patients monitoring.
The claims are drawn to assisting in any treatment, however, the specification does not provide support for any treatment. Rather, the specification asserts resistance to abiraterone acetate (AA) (p. 29). The specification appears to asserts that methylation status in urine collected from CRPC patients with AA treatment had a higher methylation value (p. 54), however, the specification does not provide guidance for NAALAD2. The specification asserts that increased levels of methylation of PRKCB are associated to abiraterone acetate, however, this does not provide guidance to any other treatment or any level of methylation and in combination with NAALAD2.
The claims are drawn to monitoring. The specification asserts that monitoring data can include time to PSA progression, overall progression, radiologic progression or death, treatment resistance (p. 25-26). The specification asserts that there is a correlation of PRKCB and NAALAD2 methylation levels as associated with recurrence free survival analysis (p. 46). However, the specification does not provide guidance for the breadth of the claims to any methylation level in any sample from any species and PSA progression, overall progression, radiologic progression or death, treatment resistance
As such the experiments provided by the instant specification provide a scope of enablement; however, they do not provide guidance the breadth of the correlations. Whereas the art, provided below, teaches that each of these factors have different expression of genes.
The unpredictability of the art, the state of the prior art
In the instant case it is unpredictable as to whether the results obtained in human individuals could be extrapolated to non-human individuals. Knowledge that particular gene is hypermethylated in one organism (i.e. humans) does not allow one to conclude that loci will also be hypermethylated in other organisms and will be associated with an abnormal condition. In particular Feng (PNAS 2010 Vol 107 No 19 pages 8689-8694) teaches that although DNA methylation likely has a conserved role in gene silencing, the levels and patterns of DNA methylation appear to vary drastically among different organisms (abstract). As such it is unpredictable as to whether methylation levels in one species would be predictive of monitoring or assisting in treatment selection in any other species.
Quantity of Experimentation and Conclusion
The quantity of experimentation in this area is extremely large as it requires the analysis methylation expression level of these two genes in any sample from any species and correlations to a myriad of different disease responses.
As neither the art nor the specification provides guidance as to the breadth of these associations, the claims require trial and error experimentation, with the outcome of each analysis being unpredictable. The skilled artisan would have to test each sample type in each species for correlation to each of the encompassed correlations. This correlation would take many intervening steps without providing any guarantee of success.
The specification does not provide clear guidance for the breadth of the claims, and the art teaches that these types of associations are unpredictable.
Thus given the broad claims in an art whose nature is unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, and the negative teachings in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the methods of the claims as broadly written.
Response to Arguments
The reply traverses the rejection. A summary of the arguetmsn is provided below with response to arguetmsn following. The claims have been amended to human patients and therefore does not require correlation to tissue types in various species (p. 9). The reply asserts that the claims require detecting DNA methylation level and/or status before a treatment and/or during the treatment using at least two primers or probes set forth in SEQ ID No. 44-64 (p. 9). The reply asserts that the specification provides this guidance in the figures and paragraphs 93, 96, 102, 105 (p. 9). The reply asserts that there are 32 figures and statistical analysis for correlation of methylation levels of PRKCB and NAALAD2 (p. 10). The specification asserts that the speciation provides abiraterone acetate, docetaxel, and ADT therapy (p. 10). The reply asserts that the amendments are to a scope of monitoring response to treatment based upon methylation level or status (p. 11).
These arguetmsn have been reviewed but have not been found persuasive.
First it is noted that the amendments are not limited to a scope of monitoring treatment. Rather, although the preamble sets for a method for assisting in treatment selection or monitoring response to treatment, the wherein clause states that the methylation level and/or status is indicative of presence or state of PCa or CRPC. The reply groups the figures together, however, these figures are not all associated with correlations of treatments and methylation levels or status. The specification asserts resistance to abiraterone acetate (AA) (p. 29). The specification appears to asserts that methylation status in urine collected from CRPC patients with AA treatment had a higher methylation value (p. 54), however, the specification does not provide guidance for NAALAD2. The specification asserts that increased levels of methylation of PRKCB are associated to abiraterone acetate, however, this does not provide guidance to any other treatment or any level of methylation and in combination with NAALAD2. Furthermore the specification does not provide guidance to any methylation level or status but rather in CRPC patients with AA treatment in a specific tissue samples had a higher methylation value. This does not provide guidance to any other potential treatments and methaytlion levels or status in any sample from a human with PCa or CRPC. Further with regard to monitoring response to a treatment, however, the specification has not provide guidance to the determination of any methylation level or status to any monitoring of response to treatment, as discussed above.
New Rejection 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 28-32 and 35-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 28-32 and 35-36 are indefinite over the wherein clause in claim 28. In particular the wherein clause states “wherein DNA methylation level and/or status is indicative of presence or stage of PCA or CRPC”. This wherein clause is unclear as the human patient that the sample is from has been diagnosed with PCa or CRPC. As such it is not clear how the methylation level is associated with presence as all samples have the presence. Further, the preamble is drawn to treatment selection or monitoring response to a treatment, however, the wherein appears to be correlated to presence or stage of the cancer.
Further the wherein clauses are unclear as the claims are drawn to providing a sample and determining DNA methylation levels in particular biomarkers, however, the wherein clause indicate that the methylation is detected before or during treatment using at least two primers or probes. It is not clear if the step of determining is intending to be limited to the wherein clause or if the claims intends to encompass any “determining” steps. Therefore the claims are unclear.
Maintained 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 28-31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural phenomenon without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Note that the unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012).
The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014).
Applicant’s attention is directed to the USPTO January 7, 2019 Revised Patent Subject Matter Eligibility Guidance (i.e., “PEG”) available at URL:
<https://www.govinfo.gov/content/pkg/FR-2019-01-07/pdf/2018-28282.pdf>.
Regarding Step 1 of the PEG, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature / natural phenomenon. The claims recite relationship between analyzing methylation level and “assisting in treatment selection or patient’s monitoring”. As in Mayo Collaborative Services v. Prometheus, the recited relationship to the disease is a natural phenomenon that exists apart from any human action.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The steps of providing a sample and determining DNA methylation, is not considered an integration as rather, it is using any routine and conventional methods of methylation analysis. Further, the dependent steps merely limit the types of conventional assay techniques and methylation detected but do not limit the steps themselves to integrate the method and the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited steps are routine in the prior art. The claims are using a known method of analysis of methylation. Further Mueller et al. (US Patent Application Publication 2019/0256921 August 22, 2019) teaches a method of obtaining a sample from a patient with prostate cancer and determining DNA methylation of PRKCB (para paragraphs 118, 183-190). Skog et al. (US Patent Application Publication 2014/0045915 Feb 13, 2014) teaches a method of obtaining a sample from a patient with prostate cancer and determining DNA methylation of NAALAD2 (para 119-129 and table 8).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Response to Arguments
The reply traverses the rejection. A summary of the arguetmsn is provided below with response to arguetmsn following. The reply asserts that the claims have been included to include claim 32 into the limitations of Claim 28. It is noted that the limitations of claim 32 required that the method of claim 28 utilized the specific primer or probes of SEQ ID NO. 44-64. However, as amended the primers or probes are only utilized when the methylation levels and/or status is detected before a treatment and/or during the treatment. However, the claim positive active steps do not require any step of detecting. Rather, the claims only require determining DNA methylation level and/or status. Therefore the claims encompass limitations of determining DNA methylation level and/or status regardless of treatment.
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 KATHERINE D SALMON whose telephone number is (571)272-3316. The examiner can normally be reached 9-530.
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/KATHERINE D SALMON/ Primary Examiner, Art Unit 1682