DETAILED CORRESPONDENCE
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 .
This action is in response to the papers filed December 18, 2025. Currently, claims 1-17 are pending.
Election/Restrictions
Applicant's election without traverse of ZSCAN12 species in the paper filed December 18, 2025 is acknowledged.
Priority
This application is a 371 of PCT/EP2022/051512, filed January 24, 2022 and claims priority to EPO 21305086.7, filed January 25, 2021 and EPO 21306344.9, filed September 28, 2021.
Drawings
The drawings are acceptable.
Improper Markush Rejection
Claims 1-17 are 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.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
Here each species is considered to each of the genes. OXT and ZSCAN12 are located on different chromosomes and have different structures. Figure 2 illustrates different methylation patterns.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different gene that could be detected is itself located in a separate region of the genome and has its own structure. The genes recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different expression and methylation patterns. The only structural similarity present is that all detected positions are part of nucleic acid molecules. 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 nucleotide alone is not essential to the common activity of being correlated with colorectal cancer. Accordingly, while the different markers are asserted to have the property of being expressed in colorectal cancer, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “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. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the genes will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited genes would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited genes possess the common property of being associated with endometrial or ovarian cancer.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with endometrial or ovarian cancer.
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.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 1-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106, part II.
Based upon consideration of the claims as a whole, as well as consideration of elements/steps recited in addition to the judicial exception, the present claims fail to meet the elements required for patent eligibility.
Question 1
The claimed invention is directed to a process that involves a natural principle and a judicial exception.
Question 2A Prong I
The claims are taken to be directed to an abstract idea, a law of nature and a natural phenomenon.
Claim 1 is directed to “an in vitro method for detecting or monitoring an endometrial carcinoma or an ovarian carcinoma in a human subject by detecting or determining the level, methylation of elected ZSCAN12 gene”.
Claims 9-14 are further directed to monitoring the impact of a therapeutic treatment, early diagnosis of a subject, assessing risk of relapse, assessing molecular residual disease, assessing therapeutic resistance in patients with metastasis.
Claim 1 is directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “detecting or monitoring an endometrial carcinoma or an ovarian carcinoma”) and a law of nature/natural phenomenon (i.e. the natural correlation between the level or methylation of ZSCAN12 and endometrial carcinoma or an ovarian carcinoma). Claims 9-14 which require uses of the level or methylation are also laws of nature.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Herein, claim 1 involves the patent-ineligible concept of an abstract process. Claim 1 requires performing the step of “detecting or monitoring an endometrial carcinoma or an ovarian carcinoma”. Neither the specification nor the claims set forth a limiting definition for "detecting or monitoring" and the claims do not set forth how “detecting or monitoring” is accomplished. As broadly recited the detecting or monitoring step may be accomplished mentally by thinking about a subject’s level or methylation of ZSCAN12 and assessing whether the subject has endometrial carcinoma. Alternatively, the claim encompasses obtaining information from a database to detecting the level or methylation of ZSCAN12. Thus, the detecting or monitoring step constitutes an abstract process idea.
A correlation that preexists in the human is an unpatentable phenomenon. The association between methylation states such as elected ZSCAN12 methylation state and risk of endometrial or ovarian cancer is a law of nature/natural phenomenon. The preamble and use steps which tells users to predict endometrial or ovarian cancer in the sample, amounts to no more than an "instruction to apply the natural law". This is no more than a mental step. Even if the step requires something more such as to verbalize the discovery of the natural law, this mere verbalization is not an application of the law of nature to a new and useful end. The preamble does not require the process user to do anything in light of the correlation. The preamble fails to provide the “practical assurance” sought by the Prometheus Court that the “process is more than a drafting effort designed to monopolize the law of nature itself.”
Question 2A Prong II
The exception is not integrated into a practical application of the exception. The claims do not recite any additional elements that integrate the exception into a practical application of the exception. While the claim recites obtaining a sample and determining methylation or level of ZSCAN12, this is not an integration of the exception into a practical application. Instead, these elements are data gathering required to perform the method. Thus, the claim is “directed to” the exception.
Claims 9, 13, 14 mention and allude to a treatment however the claim does not require any active treatment step, therefore, the claims are not an integration of a natural law.
Question 2B
The second step of Alice involves determining whether the remaining elements, either in isolation or combination with the other non patent ineligible elements, are sufficient to “’transform the nature of the claim’ into a patent eligible application” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
The claims are not sufficiently defined to provide a method which is significantly more from a statement of a natural principle for at least these reasons:
The claims do not include applying the judicial exception, or by use of, a particular machine. The claims do not tie the steps to a “particular machine" and therefore do not meet the machine or transformation test on these grounds. The use of machines generally does not impose a meaningful limit on claim scope.
The claims also do not add a specific limitation other than what is well-understood, routine and conventional in the field. The measuring expression level and methylation status are mere data gathering step that amounts to extra solution activity to the judicial exception. It merely tells the users of the method to determine the expression level or methylation of a sample without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The determining step essentially tells users to determine the markers through whatever known processes they wish to use.
The step of determining the expression levels and methylation was well known in the art at the time the invention was made. The prior art teaches that expression levels and methylation analysis using commercially available biochips and arrays that comprise the claimed genes. The steps are recited at a high level of generality. The claim merely instructs a scientist to use any expression analysis assay, mutation and promoter methylation analysis to determine the expression and methylation status. The claim does not require the use of any particular non-conventional reagents. 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 applicant’s invention and at the time the application was filed.
Additionally, the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements were well known. Specifically, the specification teaches SEQ ID NO: 2 is probe cg25060829 on the Illumina 450K BeadChip.
Further it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 112-Scope of Enablement
The following is a quotation 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.
Claims 1-17 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 a method of detecting SEQ ID NO: 2 in human subjects to detecting methylation, does not reasonably provide enablement for a method for detecting or monitoring any level of expression or methylation in ZSCAN12. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to 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 nature of the invention and breadth of claims
Claims are drawn to method for detecting or monitoring any level of expression or methylation in ZSCAN12.
Claims 9-14 are further directed to monitoring the impact of a therapeutic treatment, early diagnosis of a subject, assessing risk of relapse, assessing molecular residual disease, assessing therapeutic resistance in patients with metastasis.
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).
The unpredictability of the art and the state of the prior art
The art teaches methylation analysis of ZSCAN12 in swabs from symptomatic patients with endometrial cancer (see Herzog et al. (J. or Clinical Oncology, Vol. 40, pages 3828-3838, 2022)). Figure 1 illustrates cg25060829 in ZSCAN12 and demonstrates a single methylation peak at cg25060829 but no additional methylated markers in the region.
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Guidance in the Specification.
The specification provides no evidence that the broad scope of the claims are enabled. The specification teaches SEQ ID NO: 2 is 87 nucleotides in length. The specification states this is the cg25060829 probe on the Illumina 450K array.
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The post filing date art illustrates differentially expression only at the single cg25060829 methylation site.
The specification teaches the probe is hypermethylated in uterine corpus endometrial cancers, and hypomethylated in ovarian cancer.
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The guidance provided by the specification amounts to an invitation for the skilled artisan to try and follow the disclosed instructions to make and use the claimed invention.
Quantity of Experimentation
The quantity of experimentation in this area is extremely large since there is significant number of parameters which would have to be studied to enable the use of any CpG site in ZSCAN12 for detecting or monitoring endometrial or ovarian cancer. The post filing date art of Hertzog illustrates differentially expression only at the single cg25060829 methylation site. It would require further unpredictable experimentation to analyze each of the CpG sites in ZSCAN12 and determine whether they are differentially methylated in endometrial or ovarian cancers.
The specification does not provide any support for monitoring the impact of a therapeutic treatment, early diagnosis of a subject, assessing risk of relapse, assessing molecular residual disease, assessing therapeutic resistance in patients with metastasis. There is no assessment of when methylation may be used to detect diagnosis and whether this is “early”, whether residual disease or therapeutic resistance may be detected. The specification teaches that it is not predictable that methylation is associated with the same phenotype in the same manner. Figure 2 illustrates hypermethylation in endometrial cancers and hypomethylation in ovarian cancers. Therefore, the skilled artisan would be required to perform further unpredictable and undue experimentation to determine which phenotypes are associated with hyper and hypo methylation since the specification provides no guidance.
This would require significant inventive effort, with each of the many intervening steps, upon effective reduction to practice, not providing any guarantee of success in the succeeding steps.
Level of Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
Thus given the broad claims in an art whose nature is identified as 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, the absence of a working example 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 method of the claim as broadly written.
Claim Rejections - 35 USC § 112- Second Paragraph
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.
Claims 1-17 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 pre-AIA the applicant regards as the invention.
The claims are indefinite. It is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of Claim 1 is directed to a method for detecting or monitoring an endometrial carcinoma or an ovarian carcinoma. However, the claim only provides for detecting or determining the level of, methylation of ZSCAN12 gene in a biological sample. Thus, it is not clear if applicant intends to cover any method detecting or determining the level of, methylation of ZSCAN12 gene in a biological sample, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something
more, it is unclear what additional active process step the method requires and it appears that the claims are incomplete. The claims fail to provide any active steps that clearly accomplish the goal set for the by the preamble of the claims. Claims 2-17 are similarly indefinite
B) Regarding claim 4, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
C) Claim 5 is indefinite over the recitation of at least 90% sequence identity with SEQ ID NO: 2 and/or SEQ ID NO: 2. The claim is unclear how the method can have 90% sequence identify to SEQ ID NO: 2 and SEQ ID NO: 2. Clarification is required.
D) Claims 9-14 are indefinite because it is unclear what additional limitations the intended use limitations add to the claim. The claim does not add any additional active method steps so it is unclear what steps are required.
E) Claim 10 recited “an early diagnosis” however the specification does not define what “early diagnosis” encompasses. The term “early” in claim 10 is a relative term which renders the claim indefinite. The term “early” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
F) Claim 13 is indefinite over the phrase “especially” because it is unclear whether after treatment is a required element of the claim or whether this is an optional limitation. Clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim(s) 1, 3, 7-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tothill et al. (Clinical Cancer Research, Vol. 14, No. 16, pages 5198-5208, 2008)
Tothill teaches a method for determining gene-level expression data from validation cohorts using the Affymetrix Human Genome U133 Plus 2.0 array for Ovarian cancer patients (page 24, para 80). ZSCAN 12 probes are on the U133 array and would detecting expression level of ZSCAN12 in a biological sample.
With respect to Claim 7, Tothill teaches the samples were serial tissue sections.
With respect to Claims 8 and 15, the claim merely limits the methylation detection and does not limit the level of expression limitation.
With respect to Claims 9-14, the claims are merely directed to intended use. The claim does not require any methods steps in addition to the detecting level of expression. The method of Tothill may be used for any of these uses.
Claim(s) 1-2, 7-15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Risinger et al. (Front Oncol. Vol. 3, No. 139, June 17, 2013).
Risinger teaches gene expression of early-stage endometrial cancers using the Affymetrix U133 array. ZSCAN 12 probes are on the U133 array and would detecting expression level of ZSCAN12 in a biological sample.
With respect to Claim 7, Risinger teaches the samples were tissue sections.
With respect to Claims 8 and 15, the claim merely limits the methylation detection and does not limit the level of expression limitation.
With respect to Claims 9-14, the claims are merely directed to intended use. The claim does not require any methods steps in addition to the detecting level of expression. The method of Risinger may be used for any of these uses.
Claim(s) 1, 3-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ahn et al. (US 2016/0265061, September 15, 2016).
The specification teaches SEQ ID NO: 2 is a probe on the Illumina 450K methylation array.
Ahn teaches methods for diagnosing ovarian cancer using CpG methylation. Ahn teaches performing DNA methylation microarray using an Infinium Human Methylation 450K BeadChip. Thus, Ahn inherently teaches detecting and determining methylation of ZSCAN12 gene in ovarian cancer (para 119).
With respect to Claim 7, Ahn teaches genomic DNAs were extracted from the tumor tissues (para 126).
With respect to Claims 8 and 15, the claim merely limits the methylation detection and does not limit the level of expression limitation.
With respect to Claims 9-14, the claims are merely directed to intended use. The claim does not require any methods steps in addition to the detecting level of expression. The method of Risinger may be used for any of these uses.
With respect to Claims 6 and 16, Ahn teaches the sample may be blood, serum, plasma, saliva, urine (para 99). When the DNA sample is in the serum or plasma, the DNA comprises circulating tumor DNA.
Claim(s) 1-2, 4-5, 7-15, 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (BMC Genomics, Vol. 15, No. 868, 2014).
The specification teaches SEQ ID NO: 2 is a probe on the Illumina 450K methylation array.
Zhang teaches methods for diagnosing endometrial cancer using CpG methylation. Zhang teaches analyzing DNA methylation microarray data from an Infinium Human Methylation 450K BeadChip. Zhang teaches TCGA Infinium 450K data was obtained (page 16, col. 2). Thus, Zhang inherently teaches detecting and determining methylation of ZSCAN12 gene in endometrial cancer (para 119).
With respect to Claim 7, Zhang teaches genomic DNAs were extracted from the tumor tissues (para 126).
With respect to Claims 8 and 15, the claim merely limits the methylation detection and does not limit the level of expression limitation.
With respect to Claims 9-14, the claims are merely directed to intended use. The claim does not require any methods steps in addition to the detecting level of expression. The method of Zhang may be used for any of these uses.
Conclusion
No claims allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEANINE ANNE GOLDBERG whose telephone number is (571)272-0743. The examiner can normally be reached Monday-Friday 6am-3:30pm.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
February 2, 2026