Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claim Status
Currently, claims 8, 15-16, 20, 23, 25-37 are pending in the instant application. Claims 1-7, 9-14, 17-19, 21-22, and 24 have been canceled and claims 28-36 are withdrawn. This action is written in response to applicant’s correspondence submitted 07/09/2025 and 11/26/2025. 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 Any rejections not reiterated in this action have been withdrawn as necessitated by applicant’s amendments to the claims.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.
Withdrawn Rejections
The rejection of claims 1, 3-4, 6, 8-11, 13, 15-17, 19, 23, 25 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment to the claims.
The rejection of claim 25 under 34 USC 112(d) is withdrawn in view of the amendment to the claims.
The rejection of claims 1, 3-4, 6, 8-11, 13, 15-17, 19, 23, 25 under 35 U.S.C. 102(a)(1) as being anticipated by Teschendorff et al. is withdrawn in view of the amendment to the claims.
Election/Restrictions
Applicant's election with traverse of the 200 DMPs listed in table 1 in the reply filed on 11/26/2025 is acknowledged. The traversal is on the ground(s) that the Markush groups is proper and the members of the group share a single structural similarity and common use. The response points to Ex parte Narva in which a grouping of nucleic acid sequences share a common structure and function. The response asserts that the nucleic acid all belong to the same recognized chemical class that are within a genome and share a common function of contributing as part of a molecule signature for an individual that has lung cancer, has a preinvasive lesion that will progression to lung cancer or a precancerous cell population that will progress to lung cancer. The response asserts that the Ex parte Narva and Ex parte Buyyarapu highlight the latitude in the nature of structural similarity that may be deemed sufficient. The response further asserts that even when grouping may be considered proper if the alternative share a common use that flows from the substantial structural feature. This is not found persuasive because each of the positions recited in tables 1-10 reference a different locus that has a different biological activity and each has a different specific of hybridization and may have methylation associated with a specific role or biological function in a cell or tissue. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity. The fact that each CG site is located at a distinct location within the genome and within different genes is relevant because this is how the CG position is identified, described and located. The CG locations recited within the claim do not have a common structure or function other than that which is shared with all CGs. None of the positions share a common structure such as being located within the same gene or even within the same chromosomes. The recited methylation positions are located at distinct locations throughout the entire human genome and do not share a single structural similarity other than being a CG however in order to determine their position additional nucleotide regions are needed. The claims are not directed to only a CG but a CG in context of a specific location within the human genome, of which none of the positions are common. With respect to PTAB decisions, these are not precedential but they will be addressed. Ex part Buyyarapu each of the nucleic acid sequences had a common structure of being in close physical proximity to RN resistant locus of chromosome 21. Here none of the cytosines in the claims have a common structure, function or located in the same gene or chromosome region. Regarding Ex parte Narva the claims were directed to ROP nucleic acids wherein the nucleic acids were from different insects or comprise different portions of ROP sequence and share a common function of silencing the same ROP proteins. Here the recited cytosines are not from different species such as human and mice nor do the positions comprise fragments of the same nucleotides sequence. The recited methylated positions are located at distinct locations throughout the entire human genome and do not share a single structural similarity other than being a cytosine nucleotides however in order to determine their position additional nucleotide regions are needed. The claims are not directed to only a cytosine but a cytosine in context of a specific location within the human genome, of which none of the positions are common. Applicant is directed to similar fact pattern of PTAB decision of Ex Parte Chettier herein the Markush group consisted of SNPs and association with a disease and was determined that the recited SNPs were improper Markush rejection. This fact pattern is similarity to the instant claims in that it is a claimed SNP position with an associated disease and the single nucleotide position were in fact an improper Markush rejection. As such the species requirement is proper.
The requirement is still deemed proper and is therefore made FINAL.
Claims 27-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/26/2025. It is noted applicant elected the first 200 DMPs listed in table 1. Claim 27 requires all of the DMPs of table 1 as such the only claim that reads on the first 200 DMPs listed in table 1 is Claim 26, which is under examination.
Claims 8, 15-16, 20, 23, 25-26, 37 are under examination with respect to pre-invasive lesion that will progress to cancer, first 200 DMP of table 1 for claim 26, or a lesion that will progress to cancer.
New Grounds of Rejection
Claim Rejections - 35 USC § 112 (b)
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 26 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 26 recites comprising the DMPs identified in any one of Tables 1-10. The recitation of tables 1-10 renders the claim indefinite because it is unclear what limitation in tables 1-10 are part of the claimed invention. The metes and bounds of the claims are indefinite, it is unclear what is required from tables 1-10. Each of the tables has many different features and DMPs, even within the elected species and is it not clear from the tables the limitations required for the claims. Additionally claims are to be complete in themselves and incorporation by reference to a specific table is permitted only in exceptional circumstances where there is no practical way to define the invention in words. In the instant case, applicant can define the DMPs in words as recited within the tables.
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 8, 15-16, are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 8, 15-16 depend from claim 20. A claim in dependent form shall contain reference to a claim previously set forth. In the instant case, claims 8, 15-16 do not depend from a previous claim in that claims 8, 15-16 depend from a latter presented claim, claim 20.
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.
Improper Markush Rejection
Claim 26 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of DMPs identified in any of Tables 1-10 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Here each distinct element as part of the claimed method is a different methylation marker associated with a different gene pathway, or a different marker identified by a cg identification (or any combinations thereof). Each CG site is located at a distinct location within the genome and within different genes is relevant because this is how the CG position is identified, described and located. The CG locations recited within the claim do not have a common structure or function other than that which is shared with all CGs. None of the positions share a common structure such as being located within the same gene or even within the same chromosomes. The recited methylation positions are located at distinct locations throughout the entire human genome and do not share a single structural similarity other than being a CG however in order to determine their position additional nucleotide regions are needed. The claims are not directed to only a CG but a CG in context of a specific location within the human genome, of which none of the positions are common.
The recited alternative species do not share a single structural similarity as each methylation marker has a different chemical structure that consists of different sequence of nucleotides giving the context/content required to perform any analysis of the individual marker. Each locus has a different biological activity, each has a different specificity of hybridization and may have methylation associated with a specific role or biological function in a cell or tissue, for example alteration of expression of particular gene. Thus the different markers as recited in the claims do not share a single structural similarity or biological activity, the only structural similarity present is that all of the markers are nucleic acids. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleic acid alone is not essential to the activity of being related to lung cancer.
Here it is clear that the asserted common use of the methylation markers related to liver cancer (as asserted by the teachings in the specification) does not flow from any broadly ascribed common structure (See MPEP 706.03(y)). Note that when the Markush grouping is for alternative of chemical compound, the alternatives are regarded as being of a similar nature where the following criteria are filled:
(A) All alternatives have a common property or activity; AND
(B) (1) a common structure is present, that is a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
The phrase “significant structural elements is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In the present situation, there is no evidence of record to establish that it is clear from their very nature that the different methylation markers which are nucleic acids associated with any differential methylation associated with liver cancer. Following this analysis, the claims are properly rejected as containing an improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Maintained Rejections
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 8, 15-16, 20, 23, 25-26, 37 are rejected under 35 U.S.C. 101 because the claimed invention is directed to law of nature/natural phenomenon and an abstract idea without significantly more. The claims recite the judicial exception of a law of nature and abstract idea including mental process. This 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. This rejection was previously presented and has been rewritten to address the amendment to the claims.
The following inquiries are used to determine whether a claim is drawn to patent-eligible subject matter.
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 a naturally occurring thing or natural phenomena which is a natural principle: an asserted correlation between methylation status and pre-invasive lesion that will progression to cancer. This conclusion is supported by the claims requiring administering a cancer therapy to an individual that has a preinvasive lesion that will progression to lung cancer wherein the individual has a first population of DNA molecules having methylation presence or absence in a CG of each of the at least 200 DMPs and a second population of DNA molecules which is differentially methylated at substantial proportion of the last 200 DMPs as compared to the first population of DNA molecules. The recited relationship is a natural phenomenon that exists apart from any human action. This type of correlation is a consequence of natural processes.
The claims also recite the judicial exception of an abstract idea and particularly mental processes. Claim 20 recites identifies the presence or absence of methylation in CG of each of the at least 200 DMP. Neither the specification or the claims set forth limiting definition for identifying and the claims do not set forth how identifying is accomplished. The broadest reasonable interpretation of the identifying step is a step that can be accomplished mentally by evaluating data and critical thinking process. Such “identifying” encompasses process that may be performed mentally and this is an abstract idea.
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.
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.
It is noted that claim 20 recites a step of treating a pre-invasive lesion that will progress to cancer and “administering a cancer therapy to the individual, optionally wherein the therapy comprises surgical intervention”.
As mentioned above, 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.
The steps of “administering” a cancer therapy to the individual are 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 cancer therapies, including surgery, chemotherapy, radiation therapy, hormonal therapy, immunotherapy, targeted therapy, hyperthermia, and watch and wait. Additionally the treatment limitations do not appear to have a significant relationship to the exception. The claims do not set forth how MHI relates to the treatment. For these reasons the administering step does not integrate the judicial exceptions into a practical application.
In addition to the judicial exceptions the claims recite methylation analysis (claim 15-16), DNA sample (claim 17, 23, and 25) and DMPS location (claim 26). 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.
Step 2B - Does the claim recite additional elements that amount to significantly more than the judicial exception? No.
Herein the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than well-understood, routine, and conventional activities in the art and do not add something “significantly more” so as to render the claims patent-eligible. The step of providing a DNA sample and performing an assay to determine the methylation status, for at least 200 different differentially methylated positions merely instructs a scientist to use well established, routine and conventional nucleic acid techniques to gather samples for diagnostic analysis. The specification further teaches methylation analysis are well-known in the art (see pg. 23-31) and teaches using commercially available array system, Illumina HumanMethylation450 Bead Chip to assay DMPS (see pg. 28)
The step of performing an assay to determine the methylation status in the DNA sample constitutes a data gathering step required to apply the law of nature/natural phenomenon. The claims do not recite particular DMPs, even arguendo the claims recited specific DMPs, the claims do not require a particular, non-conventional primer or probe consisting of or comprising a specific nucleotide sequence or any other specific reagent that is used to accomplish such assaying such that the claims would recite significantly more than the judicial exception. The targets to be detected are part of the judicial exception and thereby the naming of the targets does not add something “significantly more” to the recited judicial exceptions.
The additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide inventive concept necessary to render the claims patient eligible. There is no combination of elements in this step that distinguishes it from well-understood, routine and conventional data gathering activity engaged in by scientists prior to applicant’s invention and at the time the application was filed. Many cited prior art references in this record demonstrate that these techniques were conventional at the time of the invention. The prior art of Lo (US2014/0080715A1, cited on IDS) demonstrates performing assay to determine methylation status at different methylation positions to identify cancer development (see para 52, 57, 127-139). Fan (WO2013/09666A1, cited on IDS) teaches methylation marker selection for identifying the presence of ovarian cancer by obtaining a DNA sample, assaying for differential methylated positions of at least 100 CpG sites (see abstract and claim 1 of Fan). Teschendorff et al. (JAMA Oncol, 2015, 1(4):476-485) teaches determining methylation status value of more than 200 differentially methylated positions in a DNA from preinvasive lung lesions to identify preinvasive lung lesions that will progression to cancer. Thus the prior art and specification demonstrates it was routine, well-known and conventional in the art to perform an assay to determine methylation status of at least 200 differentially methylated positions in a DNA sample. Claim 15-16 recite generically methylation assays. Claim 17, 23, and 25 further limit the sample. The dependent claims do not provide significantly more to the claims outside of the judicial exception as they encompass conventional techniques as described in the instant specification as noted above.
Response to Arguments
The response traverses the rejection on page 9 of the remarks mailed 07/09/2025. The response asserts that the claims are not directed to a law of nature and exclude the language for encompasses an abstract idea. This response has been reviewed but not found persuasive. Initially the response asserts that presently submitted claim 20 provides a nexus between the individual to be treated with one having a sample measured to have a high degree of methylation heterogeneity. This is a law of nature, a high degree of methylation heterogeneity in a sample related to regressive samples (See pg. 8 of the remarks). Because a high degree of methylation heterogeneity is related to regressive sample and identifying the methylation heterogeneity, the claims still encompass both an abstract idea and a law of nature. The claims require the mental analysis of determining methylation heterogeneity from a sample and treating a subject, as such the claims are not patent eligible as the claims encompass both a law of nature and an abstract idea. For these reasons and reasons of record the rejection is 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 8, 15-16, 20, 23, 25-26, 37 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 method of identifying increased risk of LUSC by (a) providing a DNA sample which has been taken from the individual; (b) performing an assay to determine the methylation status of at least 200 different differentially methylated positions (DMPs) in the DNA sample; (c) determining a methylation heterogeneity index (MHI) for the DNA sample, wherein the MHI is defined as the proportion of the assayed DMPs which have a β value between 1 and 0; and (c) identifying a MHI of a β value between .26 and .88 to identify increased risk of LUSC cancer, does not reasonably provide enablement for measuring in a lung sample at least 200 different differentially methylated positions wherein the DMPS are selected from a panel comprising at least 200 DMPs that are substantially randomly distributed across the genome and wherein measuring identifies the presence of absence of methylation and administer a cancer therapy to an individual that has a pre-invasive lesion that will progression to lung cancer wherein the individual has a first population of DNA molecules having methylation present or absence in CG of each of the least 200 DMPs and a second population of DNA molecules which are differentially methylation. 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 and use the invention commensurate in scope with these claims. This rejection was previously presented and ahs been rewritten to address the amendment to the claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to methods of treating of a preinvasive lesion that will progress to cancer, consistent with the elected species. The claims encompass identifying a preinvasive lesion that will progress to cancer by analysis of differentially methylated positions (DMPs) with and administering a cancer therapy to the individual. The claims encompass being able to predict preinvasive lesion that will progress to cancer and able to treat the preinvasive lesion from progression to cancer by any treatment method in any cancer. (i.e., radiation, surgery, alkylating agents, anti-metabolites, topoisomerase inhibitors, hormone treatments, immunotherapy, etc.).
The claims encompass providing a DNA sample and determining, the methylation status at least 200 DMPs (consistent with the elected species) The claims encompass determining the methylation status of any CpG site within the human genome, identifying a methylation status and determining preinvasive lesion progressing to cancer.
The nature of the invention requires a reliable correlation between the methylation status of at least 200 DMPs and the presence of a preinvasive lesion progressing to lung cancer. Further the nature of the invention requires a reliable correlation between the methylation status of at least 200 DMPs that will identify preinvasive lesion and the response to any type of therapy (i.e., radiation, surgery, alkylating agents, anti-metabolites, topoisomerase inhibitors, hormone treatments, immunotherapy, etc.) to administer a therapy to treat and prevent preinvasion lesion from progressing to cancer.
Teachings in the Specification and Examples
The specification teaches obtaining preinvasive squamous airway lesions obtained from patients. The patients were managed conservatively, undergoing surveillance and CT scanning with definitive cancer treatment only performed at the earliest pathological evidence of progression to invasive tumor (see ex 1 and 2).
The specification discloses CIS lesions were analyzed by whole genome sequencing (ex 3). The specification teaches differential methylation profiles on a discovery set of 26 progressive, 11 regressive and 23 control samples. The specification teaches methylation data showed a clear distinction between progressive and regressive subgroups (see pg. 60).
The specification teaches that MHI is predictive of CIS outcomes and presence of LUSC. The specification asserts an increased number of methylation probes with intermediate methylation was observed for LUSC samples compared to controls. The specification teaches that a β value between .26 and .88 is predictive of preinvasive lesion progressing to cancer. However the specification only demonstrates progression of preinvasive lesion progressing to cancer in LUSC. The specification asserts that increased heterogeneity may be genome-wide process rather than specific to functional pathways.
The specification provides no analysis other than LUSC. The specification provides no analysis of treatment of preinvasive lesions progressing to lung cancer. The specification provides no therapy of preinvasive lesions.
In the instant case it is highly unpredictable if it is possible to determine preinvasive lesion progressing to cancer in lung cancer, identifying the preinvasive lesion that will progress and determining therapy and treating or preventing the cancer in any cancer. While the specification identifies a HMI that may be predictive of CIS progressing to LUSC, there is no other cancers that are analyzed and there is no therapy or prevention methods that are disclosed that prevent CIS from progressing to LUSC. Thus, in the absence of evidence to the contrary, it is highly unpredictable if methylation of the disclosed HMI is diagnostic of any preinvasive lesion progressing to any type of lung cancer or any preinvasive lesion progressing to any type of cancer. It is further unpredictable to treat or prevent a preinvasive lesion progressing to cancer.
The instant specification provides a general overview of method of treatment of cancers (See pg. 51-54). However the specification provides no guidance on what therapy should be administer for prevention of preinvasive lesion progressing to cancer. The specification provides a list of therapies however there is no guidance on what MHI value is required for identifying a representative number of preinvasive lesions progressing to cancer and which therapies would be appropriate for preventing or treating preinvasive lesion progression to cancer in a representative number of cancers. There is no guidance on any cancer other LUSC and there is no guidance on what therapies are effective for treating preinvasive lesions that would progress to LUSC, much less other types of cancer as is broadly encompassed. It is highly unpredictable that a therapy that would treat a cancer would prevent a preinvasive lesion from progressing to therapy. While the specification asserts that any known treatment or procedure known in the art can be used, this treatment or procedure might be very aggressive for a preinvasive lesion. There is no guidance on how to determine which therapies would be appropriate for a preinvasive lesion that has been identified to progress to cancer. Additionally it is unpredictable to use the range disclosed in the instant specification to identify preinvasive lesions in any type of cancer. There is not a representative number of preinvasive lesions discloses that predictably are identified using the MHI taught in the instant specification.
State of the Art and the Unpredictability of the Art
While methods of measuring the methylation status of CpG sites in a DMR are known in the art, correlating the methylation status of CpG sites with the presence of cancer or response to therapy for cancer are highly unpredictable. The unpredictability will be discussed below.
Widschwendter et al. (Nature Reviews, Vol 15, pg. 292-309) teaches several challenges exist for genome wide DNA methylation correlation. Widschwendter teaches the need for the correct choice of easy to access surrogate tissue. Widschwendter teaches the easily modifiable nature of epigenetic markers creates difficulties in discriminating between cause and consequence and must, therefore be taken into account when considering timing of sample collection in relation to the manifestation of disease.
Chen (Cancer Prevention Research, 2023, 16, 439-48) teaches heterogeneity among cells, specimens and patients is a substantial obstacle for understanding and treating cancer. For tumor progression, variability from individual specimens or patients within a stage can dampen the differential signals across the stages. In additional many do not progress, leading to false signals when pooled together with progressing lesions (see pg. 444, 2nd column). Chen teaches this is tremendously challenging for large scale studies given patient compliance, unpredictability of disease progression and long time scale for cancer development. In the majority of cases precancers are completely removed to prevent cancer development leading to even less change for additional sampling from the same lesion over time.
Post filing date art, Hu (Nature Communications, 2021, 12:687, 1-13) teaches that methylation aberrations in precancers are poorly defined, largely due to lack of appropriate specimens. Hu teaches that many critical questions regarding methylation evolution during early carcinogenesis were not addressed (see pg. 8, 1st column). Hu addresses DNA methylome of lung preinvasive ADC and invasive ADC. Hu teaches DNA methylation aberrations are less complex in precancers and preinvasive lung cancer than invasive cancer and asserts that reprogramming the immune microenvironment and targeting aberrant methylation may have potential for treating precancer and preinvasive cancers to prevent invasive lung cancer and points to a clinical trial that was launched. Hu teaches that no known therapy to treat preinvasive cancer to prevent invasive lung cancer. (see pg. 10, 1st column). Hu teaches that neoplastic progression requires specimens obtained over the course of disease progression (see pg. 10, 2nd column).
Post filing date art, Malone (Genome Medicine, 2020, 12, 8, pp. 1-19) teaches epigenetic targeting as a precision medicine strategy is complex and requires prospective clinical evaluation, the accumulating knowledge in this area will increase its therapeutic potential over time (see pg. 8, 2nd column). Malone teaches that mutations signatures, RNA based gene expression profiling, immunophenotyping and TMB determine have proved to be useful prognostic and predictive biomarkers of response to anticancer therapies but whether this will lead to increase in treatment opportunities in unclear (see pg. 9, 1st column). Malone teaches limitations of full implementation of precision medicine in routine practice include complexity of molecule information generated and uncertainty surrounding clinical utility of information (see pg. 9, 2nd column). Malone teaches that many omics based test remain unproven on many fronts (see pg. 12, 2nd column).
Thus the post filing date art demonstrates the unpredictability of using methylation change to predict preinvasive lesion progressing to cancer and further treating any preinvasive cancer with any therapy. Further it is highly unpredictable to prevent ANY cancer by administering ANY cancer therapy based on the methylation status of 200 DMPs. The unpredictability which is demonstrated in the art. As discussed above the claims encompass being able to prevent progression of preinvasive lesions or treat preinvasive lesions to diverse types of cancer therapies such as radiation, surgery, alkylating agents, anti-metabolites, topoisomerase inhibitors, hormone treatments, immunotherapy, etc. in diverse cancer types. This breadth is not supported by the teachings in the specification. The specification does not teach a single therapy correlated to identification of preinvasive lesion of DMPs with the disclosed MHI. The specification has only provides an invitation for further experimentation.
Quantity of Experimentation:
The quantity of experimentation necessary is great, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to determine the presence of any cancer or preventing cancer by treating preinvasive lesion of any cancer using any therapeutic.
In order to practice the claimed invention one of skill in the art would first have to identify differentially methylated status between subjects with many different cancer types including analysis of preinvasive lesions and healthy subjects with the ability to monitor the progression of the preinvasive lesion to determine which methylation changes are associated with progression to cancer in a large genus of cancer. Then additional experimentation would need to be conducted to determine the MHI necessary for the DMPs in different types of cancer to determine if the preinvasive lesion developed to cancer. Additionally experimentation would be needed to determine therapy and prevention of each of the identified preinvasive lesions. Additional experimentation would need to be performed on subjects with a representative number of different types of lung cancer and include additional cancer types. Additionally one of skill in the art would have to perform experimentation with a representative number of different cancer therapies in order to determine a HMI and if HMI is predictive of progressing to cancer as well as which therapies would prevent and treat cancer. Finally experimentation should include the analysis of different types of biological samples. The specification has merely provided an invitation for further experimentation.
Conclusion:
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the guidance presented in the specification and the working examples, the skill of those in the art and the unpredictability of the art, and the quantity of experimentation necessary, it is the conclusion that an undue amount of experimentation would be required to make and use the invention.
Response to Arguments
The response traverses the rejection on page 9-10 of the remarks mailed 07/09/2025. The response asserts the claims encompass measuring methylation status for at least 200 different differentially methylated positions by identifying the presence or absence of methylation in CG of each of the at least 200 DMPs. The response asserts that measuring methylation at CG site is wholly routine the art and not much guidance would be required for a person of skill in the art. This response has bene reviewed but not found persuasive. While measuring methylation at CG sties of 200 DMPs is routine in the art and would not require much guidance, the claims are not directed to measuring CG sites of DMPs in a sample. The claims recite a method comprising measuring 200 DMPs and administering a cancer therapy to an individual that has a preinvasive lesion that will progress to a lung cancer wherein the individual has a first population of DNA molecules having methylation presence or absence in CG of each of the at least 200 DMPs, thus the claims require administer a cancer therapy to an individual that has a preinvasive lesion that will progression to lung cancer. The specification does not provide guidance on how to treat an individual with preinvasive lesion that will progression to lung cancer with the required 200 DMPs methylation. It is unpredictable to administer a cancer therapy to an individual that has a pre-invasive lesion that will progression to lung cancer, the specification does not provide guidance to what therapy would treat an individual that has a preinvasive lesion. There is no guidance on treating a subject with a preinvasive lesion. The specification does not provide guidance on the administering step and therefore there is an undue amount of experimentation would be required to make and use the invention. 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.
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/SARAE L BAUSCH/Primary Examiner, Art Unit 1699