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 .
Claim Status
Currently, claims 1-3, 5-16 are pending in the instant application. Claim 4 has been canceled and claims 9-16 are withdrawn. This action is written in response to applicant' s correspondence submitted 09/26/2025. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant' s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is FINAL.
Claims 1-3, 5-8 are under examination. The claims are under examination with respect to CYTIP and TNFSF8.
Withdrawn Objections/Rejections
The objection to claim 1 is withdrawn in view of the amendment to the claims.
The rejection of claims 2 and 5-6 under 35 USC 112(b) is withdrawn in view of the amendment to the claims.
The rejection of claims 1-8 under 35 USC 102(a)(1) as anticipated by Duruisseaux is withdrawn in view of the amendment to the claims.
The rejection of claims 1-3 and 8 under 35 USC 102(a)(1) as anticipated by Zhang is withdrawn in view of the amendment to the claims.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5-6 and 8 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.
With regard to claims 5 and 6, the claims depend from claim 1. Claim 1 requires determining responder or non-responder when measured DNA methylation level is less, greater than or equal to a predetermined level. Claim 5 and 6 depend from claim 1 and require evaluating response when DNA methylation level is less than 50% or less than 60%. The claims require level calculated as the proportion of methylated cytosines among total cytosines within the pDMR. Claim 1 does not require methylation percentage, it is unclear how 50% or 60% is related to the DNA methylation level that is less, greater than or equal to a predetermined level. Claim 5 and claim 6 does not further limit the DNA methylation level because the DNA methylation level and evaluating response is not dependent on percentages but dependent on DNA methylation levels. Claims 5 and 6 does not further limit claim 1 determines a responder and non-responder by DNA methylation levels and claim 5 and 6 determines therapeutic response by methylation percentage, however claim 1 already determined therapeutic response. Claim 5 and claim 6 does not further limit the determined response and does not further limit claim 1.
With regard to claim 8, claim 8 depends from claim 1. Claim 1 requires anti-PD1 therapy. Claim 8 requires wherein the anti-PD1 therapy includes at least one therapy selected from the group consisting of anti-CTLA-4 therapy, anti-PD-1 therapy, anti-CD28 therapy, anti-KIR therapy, anti-TCR therapy, anti-LAG-3 therapy, anti-TIM-3therapy, anti-TIGIT therapy, anti-A2aR therapy, anti-ICOS therapy, anti-0X40 therapy, anti-4-1BB therapy, and anti-GITR therapy. This does not further limit the anti-PD1 therapy because none of the recited therapies are anti-PD1 therapies. Additionally the claim 8 requires one of the anti-PD1 therapies to be anti-PD1 therapy. This embodiment does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112-New Matter
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 5-6 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. This is a new matter rejection.
Newly amended claim 5 requires when the DNA methylation level of pDMRs for the CYTIP gene in the biological sample, calculated as the proportion of methylated cytosines among total cytosines within the pDMRs is less than 50%. Newly amended claim 6 requires when the DNA methylation level of pDMRs for the TNFSF8 gene in the biological sample, calculated as the proportion of methylated cytosines among total cytosines within the pDMRs, is less than 60%. This amendment to the claims is not supported in the specification and raises the issue of new matter.
The specification does not teach methylation levels with respect percentages. The specification does not teach methylation percentages. The disclosure does not disclose calculating a proportion of methylated cytosines among total cytosines within a pDMR in general nor does it teach calculating with respect to CYTIP and TNFSF8 gene. The response addresses para 24 and para 83 of the published application provides support for the amendment (see pg. 7 of the remarks mailed 9/26/2025). Paragraph 24 addresses pDMR and what is encompassed by the pDMR. Paragraph 24 does not discuss calculating a proportion of methylated cytosines among total cytosines within a pDMR to determined a %. Paragraph 83 addresses Fig 4D and Fig 4E. These figures address the chromosomal location, primers, probes, methylation level and gene expression levels. There is no percentages determined for methylation level or gene expression levels. There is no calculation of total methylated cytosines among total cytosines within pDMR of either CTY1P and TNF2F8. While bisulfite pyrosequencing was used to measure methylation, this was not calculated as a percentage for methylation level.
The specification teaches in paragraph 27 and 28, “In this connection, the DNA methylation level of pDMRs for the CYTIP gene predetermined in the evaluation of a therapeutic response can be 50%. However, it is not limited thereto.” There is no teaching as to how the DNA methylation level of pDMR is determined. Para 61 refers to figure 2A, the DNA methylation level of pDMRs for the CYTIP gene. Figure 2A depicts methylation level (%) but there is no description in the specification of how this methylation level is determined and what it encompasses. There is no support for calculation of total methylated cytosines among total cytosines to arrive at methylation level (%) in figure 2A. Because the disclosure does not provide support for methylation level % and how this was calculated, the recitation of calculated total methylation cytosine to total cytosine is new matter.
Maintained Rejections
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 1-3, 5-8 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.
Claim 1 is indefinite over the recitation of “promotor associated differentially methylated regions”. It is unclear if the claim is requiring measuring methylation in the promoter region of a gene or if the claim is requiring measuring methylation in a region that is associated with a promoter. It is unclear what is encompassed by “promotor associated” if this requires the promoter or some other unstated region that is in some way associated with the promoter region of a gene. Because it unclear what is encompassed by a promoter associated differentially methylated region one of skill in the art cannot determine the metes and bounds of the claimed subject matter.
Claim 5 recites “DNA methylation level…less than 50%” and claim 6 recites “DNA methylation level…less than 60%”. The percentage recited in the claim renders the claim indefinite. The claim recites the DNA methylation level of pDMNR calculated as the proportion of methylated cytosines among total cytosines with the pDMRN is less than 50% (claim 5) and less than 60% (claim 6). However claim 5 and 6 depend from claim 1 and claim 1 requires the methylation levels are less or greater than a predetermined level. It is unclear if less than 50% and less than 60% is less or greater than a predetermined level. It is not clear if the subject would be a responder or a non-responder based on less than 50% or less than 60% methylation. It is unclear how this claim further limits claim 1 and the metes and bounds of claim 5 and 6 are indefinite. Additionally because the pDMR is indefinite, the calculation as the proportion of methylated cytosines among total cytosines within the pDMR is indefinite. It is unclear what the region is that used to calculate the total cytosines and what the region comprises for methylated cytosines. Because the region is indefinite the calculation of the total cytosines within the pDMR is indefinite.
Claim 8 is indefinite for the recitation of “wherein the anti-PD1-therapy includes at least one therapy selected from the group consisting of..”. It is unclear if the claim is requiring a combination therapy of anti-PD1 therapy and one of the therapies listed in claim 8 or if claim 8 is requiring that the anti-PD1 therapy is one of the therapies listed in claim 8. If it is the later the claim is indefinite because none of the recited therapies, except anti-PD1 therapy comprises an anti-PD1 therapy. Each of the therapies listed in claim 8 are different therapies that are not a type of anti-PD1 therapy. It is unclear how claim 8 is intended to limit the anti-PD1 therapy and what the metes and bounds of the claims encompass.
Claims 2-8 depend from claim 1 and are indefinite for the reasons applied to claim 1.
Response to Arguments
The response traverses the rejection on pages 7-8. The response asserts the claims have been amended and are definite. The response asserts that claim 5-6 have support for the amendment in para 24 and 83 of the published application. These response has been considered but not found persuasive.
With regard to claim 1, the specification defines the promoter associated differentially methylated regions refer to regions in which the presence or absence of DNA methylation of a promoter for a gene differs between a responder and a non-responder (see pg. 6, lines 22-25). The specification continues that pDMRs are not limited and can include DNA regions having different methylation states among tissues, cells, and subjects and can be a functional region capable of regulating gene transcription (see pg. 7, lines 1-4). The claim is therefore not limited a promoter region and include other regions of the gene. The metes and bounds of the claims are indefinite as it is unclear what region of the gene CYTIP and TNFSF8 is being measured and what region is methylated that is indicative of being a responder or non-responder to anti-PD1 therapy. Because it is unclear what is encompassed by a promoter associated differentially methylated region of CYTIP and TNFSF8, the claim is indefinite and the rejection is maintained.
With regard to claim 5 and 6, the claim requires DNA methylation is less than 50% for CYTIP or less than 60% for TNFSF8 gene for a positive response to anti-PD1 therapy, however claim 1 requires that when methylation is less than a predetermined level for CYTIP and TNFSF8 than the subject is a responder. There is no indication that less than 50% or less than 60% is less than a predetermined level. The specification does not define the predetermined level or the methylation level in terms of percentages. The response points to para 24 and 83 of the published application however para 24 provides examples of the promoter associated differentially methylated regions without any indication of a percent methylation or how a methylation level or percentage is determined. Para 83 addresses figure 4D and 4E. Figure 4 D is a table with chromosome positions and DEG, p values for CYT1P and TNFSF8 while figure 4E is a table for primers for CYT1P and TNFSF8. The response asserts that these paragraph describe the region of the gene promoter and that bisulfite pyrosequencing was used to measure methylation of the selected genes. While these paragraphs indicate a promoter associated differentially methylation gene region and provide an overview of fig 4D and fig 4E, these paragraphs do not provide calculating a percentage of methylation. It is unclear how the percentage of methylation corresponds to a responder or nonresponse and there is no indication in the specification how this is related. The metes and bounds of the claim is indefinite because is it unclear how a 50% or 60% methylation is correlated to responder, predetermined level and what is encompassed by this value. Additionally because the region is indefinite the recitation of calculated as the proportion of methylated cytosines among total cytosines within the pDMR is indefinite because it is unclear what is encompassed by the region in order to determined the total cytosines in the region. For these reasons and reasons of record the rejections are 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 1-3, 5-8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recites an abstract idea and are directed to a law of nature. This judicial exception is not integrated into a practical application and the claims not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow. The following three inquiries are used to determine whether a claim is drawn to patent-eligible subject matter: This rejection was previously presented and has been rewritten to address the amendment to the claims.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? Yes, all of the claims are directed to a process.
Step 2A. Is the claim directed to a law of nature, a natural phenomenon or an abstract idea (judicially recognized exception) and does the claim recite additional elements that integrate the judicial exception into a practical application?
Yes, the claims are directed to law of nature/natural phenomenon. The claims recite the correlation between therapeutic response to anti-PD1 therapy and methylation levels. The recited relationship is a natural phenomenon that exists apart from any human action.
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
With regard to claim 1, the claim recite the abstract idea of a mental process, the step of “evaluating” the therapeutic response to anticancer immunotherapy on the basis of measured DNA methylation of promoter associated differentially methylated regions. The claim further recites “providing information” about a therapeutic response in the preamble of the claim. The claim recites “determining” a responder or non-responder Claim 5-7 recite “evaluating” the therapeutic response. Neither the specification or the claims set forth limiting definition for evaluating, providing information, and determining and the claims do not set forth how determining, evaluating and providing information is accomplished. The broadest reasonable interpretation of the evaluating, providing information, and determining step is a step that can be accomplished mentally by evaluating data and critical thinking process wherein one mentally reads information in a database or report regarding methylation levels then draws a mental conclusion of therapeutic response. Such “determining”, “evaluating” and “providing” thereby encompasses process that may be performed mentally and this is an abstract idea. The broadest reasonably interpretation of these steps is that the steps may be accomplish mentally and thus are an abstract step/process. Providing information for the subject may be accomplished verbally. Such verbal communication is also abstract having no particular concrete or tangible form.
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, claims 1-3, 5-8 do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exceptions. While the claims recite measuring DNA methylation of pDMRs in a biological sample isolated from the subject the claims encompass recitation of a generic methylation. The dependent claims further limit the independent claim however none of the limitations add additional elements that result in a practical application. The steps of the claims and the dependent claims do no more than limit the mental processes that are used to evaluate methylation data.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
A claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. When evaluating this consideration one must the following:
(i) the particularity or generality of the treatment or prophylaxis limitation;
(ii) whether the limitations have more than a nominal or insignificant relationship to the exception; and
(iii) whether the limitations are merely extra solution activity or field of use.
Here, none of the claims recite a step of administering a treatment. While claim 2 recites the biological sample is isolated before the anticancer immunotherapy is performed, the claim does not require administering an anticancer immunotherapy. Even if the claim did recite administering an anticancer immunotherapy, this recitation is not particular i.e., specifically identified so that it does not encompass all applications of the judicial exception. In other words the claims broadly encompass any and all treatments for any cancer and any anticancer immunotherapy. Additionally the treatment limitations do not appear to have a significant relationship to the exception. The claims do not set forth how the methylation relates to the treatment.
In addition to the judicial exceptions the claims recite that the methylation of pDMR includes measuring the presence or absence of DNA methylation (claim 3), these additional steps/elements are not considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception. Claims 5 and 6 require evaluating the subject as positive for therapeutic response when DNA methylation is less than 50% or less than 60%. Claim 7 requires evaluating response when DNA methylation level is less than a predetermined level. Claim 8 limits the anticancer immunotherapy. These additional steps/elements are not considered to integrate the judicial exception into a practical application because they merely limit the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite that measuring methylation levels isolated from a subject (claim 1), a subject suspected of having NSCLC (claim 2), methylation levels of CYTIP and TNFSF8 (claims 4-8) and antiPD1 therapy (claim 8). These additional steps/elements do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The steps are recited at a high level of generality. Determining the methylation level of genes in a sample merely instructs a scientist to use any technique capable of measuring expression levels. The claims does not require the use of any particular non-conventional reagents (primers, probes, etc.). When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. Zhang (Oncotarget, 2017, vol 8, pp 101535-101544) and Duruisseaux (Lancet Respir Med 2018, 23:30, pp 1-11) demonstrate it was well known in the art to determine methylation levels in biological samples including samples from NSCLC subjects.
Response to Arguments
The response traverses the rejection on pages 8-9 of the remarks mailed 09/26/2025. The response asserts that the claims apply a novel natural phenomenon and add significantly more to the judicial exception. The response asserts the claims provide a new way to evaluate therapeutic response to an anti-PD1 therapy before it is provided to a subject and avoiding use of an anti-PD1 therapy for when it is unlikely to produce a positive therapeutic response. The response asserts the claimed methods are directed to patent eligible subject matter. This response has been thoroughly reviewed but not found persuasive.
As address in MPEP 2106.4, the Supreme Court’s decisions make it clear that judicial exceptions need not be old or long-prevalent, and that even newly discovered or novel judicial exceptions are still exceptions. As such even though applicant assert that the claims provide a new way to evaluate a therapeutic response to an anti-PD1 therapy and the claims apply a novel natural phenomenon, this is still an exception and is not patent eligible regardless of the novelty. With regard to applicants assertion that the claims provide a new way to evaluate a therapeutic response to an anti-PD1 therapy, the claims recite mental processes, the mental processes provide a new way to evaluate a therapeutic response. There are no active process steps that evaluate a new way to evaluate a therapeutic response. The claims encompass measuring methylation levels, which is routine and conventional in the art as evidence by Zhang and Duruisseaux. Additionally the specifically recited genes are encompassed by the methylation EPIC array, which was commercially available, demonstrating it was routine and conventional to evaluate and measure methylation with respect to the elected genes using commercially available products. There are no additionally recited steps that are not routine or conventional in the art that would integrate the recited judicial exceptions. The recitation of evaluating and determining response to therapy is a mental process, a judicial exception and does no integrate the judicial exception because it encompasses a judicial exception. For these reasons and reasons of record this rejection is maintained.
Conclusion
No claims are allowable.
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 SARAE L BAUSCH whose telephone number is (571)272-2912. The examiner can normally be reached M-F 9a-4p.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699
