DETAILED ACTION
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 .
Status of Claims
This office action is in response to Applicant's Response to Election / Restriction filed on August 19, 2025.
Claims 1-8 are pending, with claim 8 withdrawn.
Claims 1-7 are under examination. This is the first action on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/18/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant's election without traverse of Group I (claims 1-7) filed on August 19, 2025 is acknowledged.
Claim 8 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II).
Examination on the merits commences on claims 1-7.
Priority
The priority date of the instant claims 1-7 is 12/17/2021, filling date of the US provisional application NO. 63/290,949. The applicant also claims priority of Foreign Application CANADA 3,142,851, which has a filling date on 12/17/2021.
Claim Interpretation
In evaluating the patentability of the claims presented in this application, claim terms have been given their broadest reasonable interpretation (BRI) consistent with the specification, as understood by one of ordinary skill in the art, as outlined in MPEP§ 2111.
For the purpose of applying prior art, claim 1 recites the term "congenital BAV."
According to the specification in paragraph [0003], "BAV" is an abbreviation from "bicuspid aortic valve."
The specification further defines "BAV" as follows:
"[0031] As used herein the term BAV refers to any anatomical configuration in which two cusps are fused, irrespectively of the type of fusion. BAV can exist in isolation, but is often associated with other congenital cardiac lesions."
Therefore, the term "congenital BAV" is interpreted under BRI and in light of the specification as referring to the BAV condition, as defined by the specification, that is present from birth.
For the purpose of applying prior art, claim 1 recites the term "BAV- associated aortopathy." The application's disclosure does not explicitly define this term, but provides relevant definitions as follows:
"[0033] As used herein, the term "BAV disease" or "BAV associated disease" includes both valvular and vascular pathologies associated with the detection of BAV.
[0034] "BAV disease" and "BAV syndrome" encompass both of these pathologies
and may be used interchangeably.
[0035] The term "aortopathies" and "aortopathy", as used herein, refer to any
pathological condition of the aorta (for example dilatation, aneurysm, dissection, coarctation or simply dysfunction) whether determined by genetic diseases or having a sporadic onset. BAV disease can be a type of aortopathy."
Therefore, the term "BAV- associated aortopathy" is interpreted under BRI and in light of the specification to encompass any pathological condition of the aorta (e.g., dilatation, aneurysm, dissection, coarctation or simply dysfunction) that is associated with BAV.
Claim 1 recites the term "methylation marker," which is defined by the specification as follows:
" [0038] The term "methylation marker" as used herein refers to any suitable biomarker based on one or more methylated bases in a nucleotide sequence which functions as an objective indication of a medical state, e.g., BAV-associated aortopathy."
For the purpose of applying prior art, claim 1 recites:
"optionally comparing the level of methylation of the methylation maker in the sample of the subject with a comparator control,
wherein disproportionate hypomethylation of the methylation marker in the cfDNA sample would suggest that the subject is at risk of developing BAV- associated aortopathy."
These recitations are interpreted as not required by the claimed method, because the comparing step is optional, and the "wherein" clause describes a potential outcome of the optional step. Therefore, these claim languages do not further limit the scope of the claimed method.
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.
Claims 1-7 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites in the preamble "[a] method of determining the risk of a human subject with congenital BAV having BAV- associated aortopathy or developing BAV- associated aortopathy." However, the body of the claim does not include any step that determines such risks.
The claim recites an optional step of "comparing the level of methylation of the methylation maker in the sample of the subject with a comparator control," followed by a "wherein" clause stating that disproportionate hypomethylation "would suggest" the subject is at risk of developing BAV- associated aortopathy. However, this optional step does not determine, but only "suggests" risk of developing BAV- associated aortopathy, when certain condition is met. The method does not recite any step that address the risk of having BAV- associated aortopathy, as stated in the preamble.
Furthermore, the phrase "disproportionate hypomethylation" is indefinite. The application's disclosure does not define or describe what constitutes "disproportionate" or provide guidance as to how such disproportionate hypomethylation would be identified or measured. It is unclear what baseline or threshold is used for determining whether hypomethylation is "disproportionate."
Accordingly, it is unclear how the recited method steps achieve the determination of risks stated in the preamble.
Claims 2-7 are rejected for depending from claim 1 and not remedying the indefiniteness.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-7 are rejected under 35 U.S.C. 112(a), as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A) Claim 1 recites "[a] method of determining the risk of a human subject with congenital BAV having BAV- associated aortopathy or developing BAV- associated aortopathy."
Thus, claim 1 recites determining the risk of a human subject with congenital BAV having BAV- associated aortopathy; or determining the risk of a human subject with congenital BAV developing BAV- associated aortopathy.
However, the applicant's disclosure lacks sufficient detail to demonstrate possession of a method that performs such determinations, as required under 35 U.S.C. 112(a).
Accordingly to MPEP 2163 (written description requirement), the specification must clearly demonstrate that the inventor was in possession of the claimed invention at the time of filling.
In this instant case, the specification does not provide any description or guidance on how the determination of risks can be achieved. The only working example provided analyzes methylation markers in samples from patients with confirmed BAV-associated aortopathy that require surgical intervention (see, e.g., [0082], [0085]). These patients do not match the recited subject population in the claim ꟷ i.e., individuals with congenital BAV but with unknown risk status of either having or developing BAV- associated aortopathy.
Moreover, the specification itself states that the identified methylation markers in the working example do not correlate with BAV- associated aortopathy (e.g., aortic dilation), are not indicative of disease severity, and are not useful for estimating risk of aortic rupture ([00106]):
“[00106] Our candidate DMRs were also evaluated using plasma cfDNA obtained from patients with BAV-associated aortopathy undergoing surgery. The levels of both aorta-specific and total plasma cfDNA did not correlate with maximal aortic diameter which is consistent with numerous studies documenting that aortic dimensions (both absolute diameter and rate of progression) are insufficient for assessing the severity of aortopathy and in estimating the underlying risk for aortic rupture (12, 24-26). However, although our aorta-specific DMRs did not correlate with aortic dimension, three of them did correlate significantly with levels of cell death in the aorta. This encouraging result provides a rationale for cfDNA as a biomarker for aortic cell death which, as we have also shown, is associated with elevated regions of WSS. Although our candidate DMRs showed no significant correlation with several histological markers associated with elastin degradation and dysregulation of ECM proteins known to occur in aortopathy, the integrity of the aortic wall is impacted by many factors, including apoptosis that leads to the depletion of vascular smooth muscle cells (27-29). Regardless of the mechanism of cell death, DNA fragmentation and its release into the circulation is a common endpoint. Thus, the level of aorta-specific cfDNA is potentially an independent and end-stage measure of aortic cell death, regardless of mechanism. “ [emphasis added]
Therefore, the methylation markers identified in the example are not shown to be predictive or determinative of the risks recited in the claim. At most, the application's disclosure demonstrates identification of aorta-specific differentially methylated regions (DMRs) that correlate with aortic cell death, which is not sufficient to support a method of determining risks as recited in the claim.
Accordingly, the applicant's disclosure does not convey to those skilled in the art that the inventor had possession of the claimed invention at the time of filling, failing to meet the written description requirement of 35 U.S.C. 112(a).
B) Claim 1 recites "a methylation marker that is associated with BAV- associated aortopathy," by attempting to claim all methylation markers based on their association with a medical condition, without identifying any specific, shared feature or characteristics among all species in this genus, the claim extends beyond the disclosed invention, constituting a "reach-through claim." Such language improperly seeks to claim all methylation markers with known and unknown association with BAV- associated aortopathy at the time of the invention, thus failing to meet the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph.
Accordingly to MPEP 2163 (written description requirement), the specification must clearly demonstrate that the inventor was in possession of the claimed invention at the time of filling. A claim that encompass any and all methylation markers associated with BAV- associated aortopathy, without adequately describing any common structural features shared by these biomarkers fails to meet this requirement, because a person skilled in the art would not be able to ‘visualize or recognize’ the members of the genus 1. Thus, the specification does not provide sufficient written description support for a person skilled in the art to recognize that the inventor had possession of the broad genus claimed at the time of filling.
Claims 2-7 are rejected because they depend from claim 1 and inherit the deficiencies of the base claim.
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 1-5 and 7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
Independent claim 1 is drawn to a method comprising the following steps:
“obtaining a cell free DNA (cfDNA) sample from the subject,
measuring the level of methylation of a methylation marker that is associated with BAV- associated aortopathy in the cfDNA sample. “
Therefore, the claims are directed to steps to observe a methylation marker in a cell free DNA sample from a subject.
Following the analysis below the claims are not patent eligible under 35 U.S.C. 101.
Step 1 - Whether the Claim is to a Statutory Category : YES. The claims are drawn to a method, therefore to one of the four statutory categories.
Step 2A Prong 1 - Whether the Claim Recite an Abstract idea, Law of Nature, or Natural Phenomenon: Yes.
The claims relies on the natural correlation of a methylation marker and a subject having a physiological condition (i.e., BAV- associated aortopathy), which is a naturally occurring relationship. As stated in MPEP 2106.04(b)(I), laws of nature and natural phenomena, as identified by the courts, include naturally occurring principles/relations and nature-based products that are naturally occurring or that do not have markedly different characteristics compared to what occurs in nature. A subject naturally possesses a methylation pattern in their epigenome, and a methylation marker comprised by the subject's epigenome is classified as naturally occurring principles/relations.
Claim 1 is broadly written without specifying any sequences of region comprising the recited methylation marker or their genomic coordinates, thus it effectively seeks to monopolize the natural correlation between unspecified methylation markers and any human subject with congenital BAV, which is a judicial exception excluded from patentability because “monopolization of those tools through the grant of a patent might tend to impede innovation more than it would tend to promote it.” Alice Corp., 573 U.S. at 216, 110 USPQ2d at 1980 (quoting Myriad, 569 U.S. at 589, 106 USPQ2d at 1978 and Mayo Collaborative Servs. v. Prometheus Labs. Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012)).
In conclusion, the claims recite laws of nature and natural phenomena.
Step 2A Prong 2- Whether the Claim Recite Additional Elements that Integrate the Judicial Exception into a Practical Application: No. The claim does not integrate the judicial exception into a practical application.
While claim 1 broadly recites an obtaining step and a measuring step, the steps are recited at a high level of generality and reflect extra-solution activities for data gathering, without any additional elements that impose a meaningful limit on the judicial exception. See MPEP §2106.04(d). Thus, these method steps merely observe the judicial exception and do not integrate it into a practical application.
It is now well settled under Federal Circuit case law that the use of conventional techniques in a standard way to observe nucleic acids in a biological sample is not eligible for patentability under 35 U.S.C. § 101. CareDx, Inc. v. Natera, Inc., 40 F.4th 1371, 1377 (Fed. Cir. 2022). Therefore, to impose a meaningful limit, a claim must do more than simply apply the natural law with methods/approaches that are known in the art. For instance, a method claim could be patent eligible by reciting a specific, novel, and unconventional way of detecting a biomarker (e.g. using a combination of primers that are not known in the art).
Step 2B- Whether a Claim Amounts to Significantly More: No. In this instant case, the claims, when considered as a whole, do not recite any inventive concept with additional elements that amount to significantly more than the judicial exception.
Methods for observing methylation levels using standard approaches are well known and conventional in the field of biology, as indicated by Applicant's own disclosure (see specification in para.[0065-0067] for examples). And as recognized by the courts, "determining the level of a biomarker in blood by any means" is a well-understood, routine, conventional activity in the life science arts, see MPEP 2106.05.
The claims do not appear to add markedly different characteristics that significantly modify or use the naturally occurring correlation in a manner that is not naturally occurring. The dependent claims 2-5 and 7 do not recite additional elements that amount to significantly more than the judicial exception, as they either further describe the judicial exception or represent mere general linkage of the judicial exception to the additional elements in the claims (MPEP § 2106.05(h)).
In conclusion, the claims are not patent eligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by BAHADO-SINGH (WO2021108525A1 - Detecting congenital heart defects ; Published on 2021-06-03).
BAHADO-SINGH teaches minimally invasive methods of detecting, diagnosing, or predicting congenital heart defect (CHD), including Bicuspid A-V valve with dilated main pulmonary artery, by performing DNA methylation analysis of cell free DNA (entire document, see Abstract and [0094-0095] for examples).
Regarding claim 1, BAHADO-SINGH teaches a method comprising:
obtaining a cell free DNA (cfDNA) sample from the subject ([0094] ‘case of Bicuspid A-V valve with dilated main pulmonary artery’; [0097]” cfFDNA was extracted from maternal blood”),
measuring the level of methylation of a methylation marker that is associated with BAV- associated aortopathy in the cfDNA sample (([0094] ‘case of Bicuspid A-V valve with dilated main pulmonary artery’; [0097] “further bisulfite conversion and methylation profiling”; [00103]; [00106] lines 1-6; Table 1 ).
Regarding claim 2, BAHADO-SINGH teaches methylation marker comprises a differentially methylated region (DMR) on Chr 11(Table 1, page 27, “cg19125926” for example).
Regarding claim 4, BAHADO-SINGH teaches measuring the cfDNA for the presence of one or more methylation markers comprises sequencing the cfDNA([0041]).
Regarding claim 5, BAHADO-SINGH teaches bisulfite sequencing([0041]).
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over BAHADO-SINGH (WO2021108525A1 - Detecting congenital heart defects ; Published on 2021-06-03), in view of Litterst (Litterst et al. Droplet Digital™ PCR: Detection of DNA Methylation; published in 2014).
The teachings of BAHADO-SINGH are recited above and applied as for base claims 1 and 4-5.
Regarding claim 7, while BAHADO-SINGH teaches performing DNA methylation analysis using bisulfite sequencing([0041]), it does not explicitly teach the use of droplet digital PCR (ddPCR) for methylation detection.
Litterst discloses the use of ddPCR for detection of DNA methylation in bisulfite-converted DNA samples with "unprecedented sensitivity, linearity, and robustness of DNA methylation detection." (entire document, see Abstract for example)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply the ddPCR technique taught in Litterst to the method of cfDNA methylation analysis in BAHADO-SINGH, to further validate the cfDNA methylation markers identified in BAHADO-SINGH. The motivation would arise from the advantageous performance characteristics of ddPCR, as suggested by Litterst.
The person of ordinary skill would have had a reasonable expectation of success in combining the references' teachings because both are directed to DNA methylation analysis using compatible laboratory techniques. BAHADO-SINGH already teaches bisulfite treatment of cfDNA (e.g., [0041] "Bisulfite Conversion"), and Litterst teaches ddPCR on bisulfite-treated DNA samples.
Such combination would have been obvious as it represents the KSR principle of predictable use of prior art technique (i.e., ddPCR in Litterst) according to a known method (i.e., cfDNA methylation analysis in BAHADO-SINGH) to yield predictable results. (See MPEP §2143).
Conclusion
No claims are allowed.
No references were found teaching or suggesting claims 3 and 6, but they are rejected for reasons given above.
Claims 3 and 6 are objected to as being dependent upon rejected base claims 2/1 and 5/4/1, but would be allowable if rewritten to overcome the rejections under 35 U.S.C. 101, 35 U.S.C. 112(b) and 35 U.S.C. 112(a) set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
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/TIAN NMN YU/Examiner , Art Unit 1681 /AARON A PRIEST/Primary Examiner, Art Unit 1681
1 A “sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad Pharms., 598 F.3d at 1350.