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 November 13, 2025. Currently, claims 1-2, 16-19, 22, 24-26, 48-55 are pending. Claims 2, 17-18, 22 are withdrawn as not directed to elected subject matter.
Election/Restrictions
Applicant's election without traverse of Group I and SEQ ID NO: 83 (cg19688250), Claims 1, 2, 16-19, 24-26, 48-55 in the paper filed November 13, 2025 is acknowledged.
Claims 2, 17-18, 22 are withdrawn as not directed to elected subject matter.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application is a 371 of PCT/GB 2021/051537, filed June 17, 2021 and claims priority to UK 2009225.0 and 2107421.6, filed June 17, 2020 and May 25, 2025, respectively.
Drawings
The drawings are acceptable.
Claim Objections
Claims 1, 16, 19, 24-26, 52-55 are objected to because the claim contains more than one period (see 609.01(m)). Periods may not be used elsewhere in the claims except for abbreviations. For example, a. b. i. ii. Iii. Iv. contains a period and the end of the claim contains a period. This objection may be overcome by amending i. to read i) (see MPEP 608.01(m)).
Improper Markush Rejection
Claims 1, 16, 19, 24-26, 52-55 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 methylation CpGs and combinations of the CpGs.
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different CpG that could be detected is itself located in a separate region of the genome and has its own structure, as evidenced by the distinct SEQ ID NO:s. The CpGs recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different 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 CIN3 or cervical cancer. Accordingly, while the different markers are asserted to have the property of being expressed in CIN3 or cervical 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 CpGs 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 CIN3 or cervical 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 CIN3 or cervical 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.
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 25, 26, 52 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 25 is directed to “a method for …stratifying the individual according to their risk of having CIN3 and/or cervical cancer or their risk of CIN3 and/or cervical cancer development”.
Claims 26, 52 is directed to treating or preventing CIN3 and/or cervical cancer by administering one or more treatments to “the individual determined to have CIN3 and/or cervical cancer”.
Claims 25-26, 52 are directed to a process that involves the judicial exceptions of an abstract idea (i.e. the abstract steps of “stratifying an individual according to the risk of having CIN3 and/or cervical cancer”) and a law of nature/natural phenomenon (i.e. the natural correlation between the methylation and CIN3 and/or cervical cancer).
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 25 involves the patent-ineligible concept of an abstract process. Claim 25 requires performing the step of “stratifying an individual” according to risk of having CIN3 or cervical cancer. Neither the specification nor the claims set forth a limiting definition for "stratifying" and the claims do not set forth how “stratifying” is accomplished. As broadly recited the stratifying step may be accomplished mentally by thinking about a subject’s methylation state and assessing a group or stratification for the individual. Thus, the determining step constitutes an abstract process idea.
A correlation that preexists in the human is an unpatentable phenomenon. The association between methylation status such as cg19688250, SEQ ID NO: 83 methylation state and risk of CIN3 or cervical cancer is a law of nature/natural phenomenon. The limitations which tells users of the process to predict CIN3 or cervical cancer in the sample, amounts to no more than an "instruction to apply the natural law". This limitation is no more than a mental step. Even if the limitation 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 limitation does not require the process user to do anything in light of the correlation. The limitation step 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 assaying for methylation status, 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.
Claim 26 is directed to treating or preventing CIN3 and/or cervical cancer by administering one or more treatments to the individual. While the claim recites administering one or more treatments to the subject, this is not an integration of the exception into a practical application. The limitation does not indicate how the patient is to be treated, or what the treatment is but instead covers any possible treatment that a doctor decides to administer to the patient. The claim does not require the treatment is related to CIN3 or cervical cancer, but could instead be a treatment for sleep deprivation or diabetes. Even more the limitation is recited at such a high level of generality, making the limitation’s inclusion in the claim at best nominal. The administering one or more treatments to the subject limitation fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception.
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 assaying for mutation status is 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 methylation status without further specification as to how the sample should be analyzed. The claim does not recite a new, innovative method for such determination. The assaying step essentially tells users to determine the methylation through whatever known processes they wish to use.
The step of determining the mutation status was well known in the art at the time the invention was made. The prior art teaches that 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 methylation analysis to determine the 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 any method available to people skilled in the art for genome wide bisulfite sequences such as NGBS, Illumina 450K and Epic microarrays may be used (para 25).
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- 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 26, 48-52, 55 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.
Claims 48-51 are indefinite as being both incomplete, by its dependence on a cancelled claim; and for lack of antecedent basis for its limitation (“The composition …”) which is not present in cancelled base claim 9. Amending claims 48-51 to refer to a claim which recites a method, or deleting the claim, would obviate the rejection.
Claims 26 and 52 are indefinite over the recitation “the individual determined to have CIN3 and/or cervical cancer”. The individual lacks proper antecedent basis. Claim 1 does not refer to an individual determined to have CIN3 or cervical cancer. Correction is required.
Claim 55 is indefinite over the recitation “preferably”. The phrase "preferable" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed 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, 16, 19, 24-25, 55 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Farkas et al. (Epigenetics, Vol. 8, No. 11, pages 1213-1225, November 2013).
The instant specification notes the elected SEQ ID NO: 83, cg19688250, CpG site may be determined on the Illumina 450K array. Thus, assaying the 450K array inherently assays for SEQ ID NO: 83, cg19688250.
Farkas teaches genome-wide DNA methylation assay for analysis of biomarkers in cervical cancer. Farkas teaches the Illumina Infinium Human Methylation 450 Bead chip method was used to identify genome-wide DNA methylation changes in CpG islands (abstract). Farkas identifies differential methylation sites in cervical cancer compared with the CIN3 or normal cervical tissues (abstract).
With respect to Claim 24, the assay is performed by hybridizing DNA to an array (page 1221, col. 2).
With respect to Claim 25, Farkas teaches stratifying individuals by the risk of CIN3, cervical cancer and normal tissues using unsupervised clustering analysis (see Figure 1 and page 1222, col. 2).
With respect to Claim 55, Farkas samples cervical samples (page 1221, col. 2).
Claim(s) 1, 16, 19, 24-26, 55 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Szyf et al. (WO2020/115728, published June 11, 2020).
Claim(s) 1, 16, 19, 24-26, 55 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Szyf et al. (US2022/0073994, provisional filed December 4, 2018).
Claim(s) 1, 16, 19, 24-26, 55 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Szyf et al. (US Pat. 12,480,164, provisional filed December 4, 2018).
Each of the disclosures for the WO, US Publication and US Patent are identical but the disclosures have different publication dates. The numbering used in the rejection refers to the US Patent.
Szyf teaches DNA methylation biomarkers for early detection of cervical cancer. Szyf identifies cg19688250 (SEQ ID NO: 51) as biomarkers that were progressively methylated CGIDs with an average increase in methylation of 10% or decrease of more than 10% during transition from CIN1 to CIN3 stages (col. 12, lines 44-50 and col 19)
With respect to Claim 24, the assay is performed by hybridizing DNA to an array (col 6, lines 4-5).
With respect to Claim 25, Szyf teaches classifying or stratifying individuals by the risk of CIN3, cervical cancer and normal tissues (see col 12, lines 15-17). Szyf teaches samples above thresholds may be classified as cancer.
With respect to Claim 26, Szyf teaches using the DNA methylation biomarkers identified to provide a highly accurate, specific and sensitive assessment of risk that can guide early intervention and treatment of cervical cancer even in women at asymptomatic and precancerous stages (col. 5, lines 12-16).
With respect to Claim 55, Szyf samples cervical samples (col 12, lines 1-5).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 52-54 are rejected under 35 U.S.C. 103 as being unpatentable over Szyf et al. (US Pat. 12,480,164, provisional filed December 4, 2018) in view of Gross et al. (US 2021/0238693, provisional September 27, 2018).
Szyf teaches DNA methylation biomarkers for early detection of cervical cancer. Szyf identifies cg19688250 (SEQ ID NO: 51) as biomarkers that were progressively methylated CGIDs with an average increase in methylation of 10% or decrease of more than 10% during transition from CIN1 to CIN3 stages (col. 12, lines 44-50 and col 19).
Szyf does not teaches providing treatments repeatedly or assaying the CpG site at multiple time points.
However, Gross teaches analysis of methylation markers using the same 450K BeadChip and assess the likelihood or probability score at different time points such as before or after treatment to monitor disease progress or monitor treatment effectiveness (col 57, lines 50-60). Gross teaches obtaining a first sample from a cancer patient at a first time point and obtaining a second teat sample from the cancer patient at a second time point. Gross teaches the samples can be obtained over any desired set of time points and analyzed to monitor a cancer state. The time points may be 15 minutes up to 30 years (col. 58, lines 30-35).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention to have analyzed known cervical cancer detection methos, as taught by Szyf and administered treatments repeatedly to monitor treatment response and to have assayed methylation at multiple time point to monitor cancer state of the patient, as taught by Gross. The ordinary artisan would have been motivated to monitor cancer state and/or cancer treatment with multiple analysis over time to determine if the treatment is success and if the cancer is progressing.
Conclusion
No claims allowable over the art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
CN113423843A, filed February 4, 2020, teaches DNA methylation biomarkers for early detection of cervical cancer using the Illumina 450K/805K chip. CN113423843A teaches categorizing DNA methylation alteration in 3 stages of lesions (cervical intraepithelial neoplasia (CIN)). SEQ ID NO: 50 of CN113423843A is the cg19688250 methylation site.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached on (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEANINE A GOLDBERG/Primary Examiner, Art Unit 1682
December 31, 2025