CORRECTED
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 supersedes the previously mailed Non-Final June 3, 2025 and August 1, 2025.
This action is in response to the papers filed May 16, 2025. Currently, claims 1-5 are pending.
Election/Restrictions
Applicant's election without traverse of SEQ ID NO: 2 in the paper filed May 16, 2025 is acknowledged.
Priority
This application is a 371 of PCT/KR2020/013290, September 29, 2020 and claims priority to KR 10-2019-0124549, October 8, 2019.
It is noted that a translation of the foreign document has not been received. Thus, the claims enjoy priority of September 29, 2020.
Drawings
The drawings are acceptable.
Specification
The use of the term MethyLight PCR, EpiTYPER, for example, which are trade names or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-8 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 a law of nature and a natural phenomenon.
Claims 1-5 are directed to providing or confirming the biological sample as liver sample when the methylation level is higher than a control sample not originated from liver. Claims 4-5 are also directed to providing and confirming.
Claims 6-7 are directed to “a method for detecting liver tissue-derived DNA”. These claims describe a relationship between origin of liver tissue and methylation.
Herein, the claims involves the patent-ineligible concept of an abstract process. Claims 4-5, 8 recites a comparison between the methylation level and a normal control that is deemed an abstract idea (see MPEP 2106.04(a)(2)(III)(A); • claims to “comparing BRCA sequences and determining the existence of alterations,” where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014)).
A correlation that preexists in the human is an unpatentable phenomenon. The claims are also directed to providing or confirming a biological sample is a liver sample. The association between methylation states such as SEQ ID NO: 2 methylation state and origin of the tissue from liver tissue is a law of nature/natural phenomenon. The claims tell users of the process to predict the origin of the tissue, amounts to no more than an "instruction to apply the natural law". This preamble is no more than a mental step. Even if the preamble 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 separating DNA and measuring methylation, 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.
Accordingly, the claims are directed to judicial exceptions.
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 methylation 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 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 measuring step essentially tells users to determine the methylation through whatever known processes they wish to use.
The step of determining the methylation levels 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 CpG sites. 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.
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 1-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for determining the methylation levels of SEQ ID NO:2 (cg12137206), does not reasonably provide enablement for determining the methylation indicates the sample originates from liver tissue. 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
The claims are drawn to method for determining whether a biological sample originates from liver tissue and compositions for determining whether a biological sample originates from liver tissue.
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 SEQ ID NO: 1 and 2 are methylated in tissues other than liver tissue.
Firestein et al. (US 2013/0129668, May 23, 2013) teaches SEQ ID NO: 2 is associated with arthritis. In particular Firestein teaches analysis of methylation loci including SEQ ID NO: 2 in cells such as fibroblast, synoviocyte, fibroblast-like synoviocyte, macrophage and peripheral blood cell. Thus, these are not liver tissue and as such provide evidence the mere presence of SEQ ID NO: 2 does not inform of the origin of tissue as liver tissue.
Venn et al. (US 2022/0090207, March 24, 2022) teaches SEQ ID NO: 222,325 is SEQ ID NO: 2 of the instant application. Venn teaches analyzing the cancer tissue of origin however Venn does not provide any guidance SEQ ID NO: 222,325 is associated with liver cancer.
Alexander (AJCN, Vol. 105, No.l 4, pages 991-1000, April 2017) teaches cg03792768 is within BDH1 is increased in subcutaneous adipose tissue in response to seven weeks PUFA overfeeding (page 134/291 online supplemental material). Thus, cg03792768 is detected in adipose tissue.
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Guidance in the Specification.
The specification provides no evidence that the methylation levels of SEQ ID NO:2 (cg12137206) are live tissue specific. The specification states the methylation levels of SEQ ID NO:2 (cg12137206) are high in normal liver tissue and liver cancer tissue samples and has low methylation level in other tissues including blood (page 3).
Figure 4 illustrates that methylation of SEQ ID NO:2 (cg12137206) in liver cancer tissue is both high and low. There mere detection of low methylation does not indicate non-liver tissue or the mere detection of high methylation does not indicate liver tissue.
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Figure 7 also illustrates the presence of high levels of methylation in whole blood as well as liver. Therefore, the presence of high level of methylation does not determine a biological sample originates from liver tissue. 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 skilled artisan to determine whether a biological sample originates from liver tissue. The specification illustrates that high levels of methylation are present in whole blood as well as liver tissue. The art teaches there is methylation of
SEQ ID NO: 2 in cells such as adipose, fibroblast, synoviocyte, fibroblast-like synoviocyte, macrophage and peripheral blood cell. Thus, these are not liver tissue and as such provide evidence the mere presence of SEQ ID NO: 2 does not inform of the origin of tissue as liver tissue. 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 1-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 1-8 are indefinite over the recitation “sequences represented by SEQ ID NO: 1 and 2”. It is unclear what it means for a sequence to be represented by SEQ ID NO: 1 and2. It is unclear whether the sequence merely comprises ATCG’s or whether there is some closer representation. If Applicant intends to require comprising or consisting of SEQ ID NO: 1 and 2, these terms are conventional terms of art and well understood.
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 of providing a liver sample. Claim 6 is directed to a method for detecting liver tissue-derived DNA in a biological sample. However, the claim only provides for comprising measuring the methylation levels of SEQ ID NO: 1 and 2. Thus it is not clear if applicant intends to cover any method for measuring the methylation levels of SEQ ID NO: 1 and 2, 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 2-5, 7 are similarly indefinite
Claims 3 and 7 contain trademark/trade names to different methods, such as MethyLight and EpiTYPER. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe methods and, accordingly, the identification/description is indefinite.
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) 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al. (US 2018/0274039, September 17, 2018).
Zhang teaches methylation markers for diagnosing hepatocellular carcinoma. Zhang teaches separating DNA from a biological sample and measuring methylation of CpG site of SEQ ID NO: 1 (cg03792768) and SEQ ID NO:2 (cg12137206). Table 6 lists both SEQ ID NO: 1 (cg03792768) and SEQ ID NO:2 (cg12137206). Table 6 shows markers used in HCC vs. Lung analysis, i.e. determining whether a biological sample originates from liver tissue. Zhang teaches the biological sample may be blood, biopsy, circulating tumor cells (see para 91-93, 132). Zhang teaches the methylation profile of selected CpG sites is determined using MethylLight (para 142).
With respect to Claims 4-5 the claims are conditional because they state “when” the methylation level is higher. Thus, if the level is not higher, the providing or confirming is not required.
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
August 4, 2025