FINAL ACTION
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 responsive to the Amendment and Response filed 17 December 2025. Claims 83-87 and 91-92 have been amended, claims 89-90 and 93-94 have been canceled, and claims 95-104 have been added. The specification has also been amended; while applicant’s amendments to the specification (which address and overcome objections made in the prior Office action), Applicant’s attention is directed to their inclusion of paragraph 170 in the amendments, as no apparent changes are illustrated or have made been to that paragraph (thus, Applicant may want to re-review the paragraph to determine if it was included in the amendments in error, or if an intended amendment was inadvertently not made, etc.). All prior rejections of claims 89-90 and 93-94 are moot in view of the cancelation of those claims.
Claims 83-88, 91-92, and 95-104 are now pending and under consideration. Applicant’s amendments and arguments have been thoroughly reviewed, and have overcome the following objections/rejections set forth in the prior Office action:
The objections to the specification, in view of Applicant’s corrective amendments;
The prior rejections of claims under 35 USC 112(b) in view of Applicant’s claim amendments (although it is noted that the claims remain indefinite for the reasons given below);
The rejection of independent claim 83 and claims dependent therefrom under 35 USC 102(a)(1) and 35 USC 102(a)(2) as being anticipated by Taylor et al, in view of Applicant’s amendments to that claim; and
The rejection of independent claim 83 and claims dependent therefrom under 35 USC 101, in view of Applicant’s amendments to that claim (such that the claim now recites a combination of three active/manipulative method steps and no longer recites “determining if” a signature is detected, etc.)
Claims 83-88, 91-92, and 95-104 remain/are rejected for the reasons given below, which include new grounds of rejection necessitated by Applicant’s amendment. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Comment Regarding Basis for Amended Claim Language
It is noted that independent claim 83 has been amended to recite obtaining from a subject a “biological sample comprising cell-free” DNA, and isolating cfDNA from the “biological sample” (see (a) and (b) of claim 83). While the application as filed does not provide literal basis for the limitation ‘biological sample comprising cell-free” DNA, it is noted that Example 2 (pages 78-79) describes the use of cfDNA, including cfDNA “purified from plasma or serum”, and also refers to cfDNA “extracted from a tissue sample”, referring to blood, urine, saliva, and stool as examples of a “tissue sample” (see in particular paragraph 166; see also the disclosure in paragraph 48 of cfDNA originating from a “tissue sample” including bodily fluid or tissue). Additionally, the application includes more general references to a “patient sample” from which cell free DNA may be isolated via “isolation methods” (see paragraph 152), and the type of “subject” required by the claims is a subject “suspected of having liver cancer” (i.e., a type of “patient”). Accordingly, the application as filed provides basis for the new language of (a) and (b) of claim 83 (however, please see the new matter rejection below regarding other new limitations in the claims).
Election/Restrictions
Applicant’s election without traverse of SEQ ID NO: 98 and the corresponding gene SDK1 in the reply filed on May 7, 2025 is acknowledged.
Claims 83-88, 91-92, and 95-104 remain/are under consideration as directed to the elected species (and it is noted that the prior art continues to apply against the claims as directed to the elected species; see prior art rejections below).
Claim Rejections - 35 USC § 112(b)/second paragraph
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS AMENDMENTS TO THE CLAIMS:
Claims 83-88, 91-92, and 95-104 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 83-88, 91, and 95-104 are indefinite over the recitation in line 8 of independent claim 83 of the limitation “the nucleic acids”. As the claim no longer contains a prior reference to “nucleic acids” (as a result of the amendment to claim a method requiring cfDNA), clear antecedent basis for the term “the nucleic acids” is lacking, and it is unclear what “nucleic acids” are being referenced. In particular, it is unclear as to whether this a reference to any nucleic acids of “the biological sample”, to the cfDNA of (b), etc. Accordingly, further clarification is required.
Claims 83-88, 91, and 95-104 are indefinite over the recitation at lines 10-11 of independent claim 83 of the limitation “a DNA methylation probe comprising at least 5 nucleotides configured to bind a nucleotide sequence of…”. First, it is noted that the language “configured to bind a nucleotide sequence..” is not employed in the Application as filed (see also the new matter rejection below), and it is not clear what sequences/structures would (and would not) be encompassed by the language “at least 5 nucleotides configured to bind a nucleotide sequence” as recited in the claim. In particular, it is not clear whether this language might require, e.g., 5 (or more) nucleotides exactly complementary to a binding target, or whether this language might more broadly encompass anything “capable of binding” to a target (corresponding to a type of probe actually disclosed in the application, but the binding of which would be expected to vary based on binding conditions), etc. Additionally, while the application as filed does disclose/reference a “DNA methylation probe designed to bind to and quantify the degree of methylation a specific sequence” (see paragraph 69), given that a variety of different probe types could be considered as having been so “designed” – as well as the fact that the application references “developing DNA methylation probes” for both “a methylated state” and “an unmethylated state” (see paragraph 163) - it is unclear how the language “DNA methylation probe” might further limit what is claimed. As the motivation for designing a probe would be expected to differ from artisan to artisan, reliance on the purpose for designing a probe does not provide clear boundaries for what is being claimed (particularly as it pertains to a structure such as a DNA probe, which could simply be defined by disclosure of required structure, as well as the fact that this terminology appears to encompass probes for detection of either a methylated or an unmethylated state). Clarification is therefore required.
Regarding claim 99 (dependent from claim 83), which recites “performing methylation-specific polymerase chain reaction (PCR) amplification of the nucleic acids”, it is noted that because it is unclear what it encompassed by the term “the nucleic acids” in claim 83, claim 99 is indefinite with regard to what “nucleic acids” must be amplified to meet the requirements of this claim. Thus, clarification of both claim 83 and claim 99 is required to ensure that the meaning and boundaries of claim 99 are clear.
Claim 100, also dependent from claim 83, is indefinite over the recitation of the limitation “sequencing the nucleic acids or derivatives thereof”. First, the limitation “the nucleic acids or derivatives thereof” lacks clear antecedent basis, as there is no prior reference in the claims to “nucleic acids or derivatives thereof”. Second, as claim 83 is unclear with regard to what is encompassed by the limitation “the nucleic acids”, it is also unclear what is to be sequenced to meet the limitations of claim 100. Thus,
clarification of both claim 83 and claim 100 is required to ensure that the meaning and boundaries of claim 100 are clear.
Independent claim 92 is indefinite over the recitation of the limitations “a DNA methylation probe capable of binding to one or more differentially methylated regions in one or more of” a recited group of genes (with the elected species corresponding to SDK1) and “wherein the DNA methylation probe comprises at least 5 nucleotides configured to bind to a nucleotide sequence of any one of” a group of recited SEQ ID NOS (with the elected species being SEQ ID NO: 98). First, as was noted with regard to similar language in independent claim 83, the language “configured to bind a nucleotide sequence..” is not employed in the Application as filed (see also the new matter rejection below), and it is not clear what sequences/structures would (and would not) be encompassed by the language “at least 5 nucleotides configured to bind a nucleotide sequence” as recited in the claim. In particular, it is not clear whether this language might require, e.g., 5 (or more) nucleotides exactly complementary to a binding target, or whether this language might more broadly encompass anything “capable of binding” to a target (corresponding to a type of probe actually disclosed in the application, but the binding of which would be expected to vary based on binding conditions), etc. Additionally, while the application as filed does disclose/reference a “DNA methylation probe designed to bind to and quantify the degree of methylation a specific sequence” (see paragraph 69), given that a variety of different probe types could be considered as having been so “designed” – as well as the fact that the application references “developing DNA methylation probes” for both “a methylated state” and “an unmethylated state” (see paragraph 163) - it is unclear how the language “DNA methylation probe” might further limit what is claimed. As the motivation for designing a probe would be expected to differ from artisan to artisan, reliance on the purpose for designing a probe does not provide clear boundaries for what is being claimed (particularly as it pertains to a structure such as a DNA probe, which could simply be defined by disclosure of required structure, as well as the fact that this terminology appears to encompass probes for detection of either a methylated or an unmethylated state). Further, while the language “capable of binding to one or more differentially methylated regions” is noted, the term “differentially methylated” is a relative term – i.e., this could potentially encompass any nucleotide sequence differing in any way as compared to any other sequence with regard to methylation (or potentially could be an attempt to require something more particular/specific) – and an ordinary artisan would also expect probes of different structures to be “capable of binding” to different targets in a manner that depends upon binding conditions. Thus, that the manner in which this language may further limit what is claimed is unclear, and further clarification is required.
Claim Rejections - 35 USC § 112(a)/first paragraph
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS AMENDMENTS TO THE CLAIMS:
Claims 83-88, 91-92, and 95-104 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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. This is a new matter rejection.
Independent claim 83 (from which claims 84-88, 91, and 95-104 depend) has been amended to recite the limitation “a DNA methylation probe comprising at least 5 nucleotides configured to bind a nucleotide sequence of” a recited SEQ ID NO (with SEQ ID NO: 98 being under consideration herein), and independent claim 92 have been amended to recite the similar limitation “the DNA methylation probe comprises at least 5 nucleotides configured to bind a nucleotide sequence of…”; however the application as filed does not provide basis for a probe (including a “DNA methylation probe”) of this particular type. While the application as filed discloses probes “capable of binding” to recited nucleotide sequences (see, e.g., paragraphs 45 and 73), and methylation probes… “designed to bind…” to a sequence (paragraph 69), the language “configured to bind to” is not employed in the application as filed, nor would a person of ordinary skill in the art necessarily interpret “configured to bind” – which suggests some type of specific/fixed configuration – as equivalent/interchangeable with the terminology “capable of binding” (which merely requires a capability, rather than any particular configuration, structure, etc.) or “designed to bind” (which suggests a motivation/ intention in designing a probe a particular way, as opposed to a requirement limiting the structure/configuration of a probe). As probes corresponding to the language now recited in the amended claims were not expressly, implicitly, or inherently disclosed in the application as filed, the amendment of 17 December 2025 adds new matter to the claims.
Claim Rejections - 35 USC § 112(d)/fourth paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS’ AMENDMENTS TO THE CLAIMS:
Claim 84 and 86 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph for failing to “contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed”. In particular, the claims as amended depend from following claims (claims 103-104), rather than claims “previously set forth” (such that this requirement of 35 USC 112(d) is not met).
Claim Rejections - 35 USC § 102
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS’ AMENDMENTS TO THE CLAIMS:
Claim(s) 92 remains rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Taylor et al (US 2018/0066320 A1 [18 March 2018]; cited herein), as evidenced by the specification.
Taylor et al disclose methods and kits for detection of hepatocellular carcinoma (see entire reference). Taylor et al disclose that their invention “provides novel methylated DNA markers that discriminate HCC from normal controls (controls with and without cirrhosis”), providing technology for HCC screening and detection (see paragraphs 8 and 12). Taylor et al disclose that their markers comprise “one or more differentially methylated regions (DMR) as discussed herein, e.g., as provided in Tables 1 and 4”, with a variety of different techniques being available for detection/evaluation of methylation state (see paragraphs 15-18, as well as paragraphs 35-37 and 131-137); it is noted that Table 1 includes 4 DMRs corresponding to regions of the elected gene SDK1 (see Table 1 at page 21, right column, DMRs 232-235).
Regarding the requirements of amended claim 92 for a “DNA methylation probe capable of binding to one or more differentially methylated regions” in the elected SDK1 gene, “wherein the DNA methylation probe comprises at least 5 nucleotides configured to bind to a nucleotide sequence of” SEQ ID NO: 98, it is reiterated that this language is indefinite (as discussed above); however, at least one reasonable interpretation of this claim language encompasses nucleic acids identical to or complementary to SEQ ID NO: 98 over at least a length of 5 nucleotides (as such nucleic acids share a region of complete identity or complementarity over the length specified in the claim with respect to the specified sequence SEQ ID NO: 98, which is disclosed/defined in the specification as meeting the requirement of being a differentially methylated region of SDK1). As evidenced by Applicant’s specification at page 51, instant SEQ ID NO: 98 corresponds to chr7:3340400-3340600, such that instant SEQ ID NO: 98 overlaps by over 50 contiguous nucleotides with DMR233 of Taylor et al (see again Table 1 of Taylor et al at page 21, right column noting that DMR233 is disclosed at having the position chr7 3340543-3340635). Thus, based on at least one reasonable interpretation of the present claim language, Taylor et al disclose a DMR comprising “at least 5 nucleotides configured to bind to” SEQ ID NO: 98 (based on the shared identity of the sequence of Taylor et al with Applicant’s SEQ ID NO: 98 over more than 50 contiguous nucleotides, as described in and evidenced by the specification; it is also noted that Applicant’s arguments at page 12 [Reply of 17 December 2025] acknowledge this inherent property of instant SEQ ID NO: 98). As Taylor et al disclose kits comprising a variety of reagents/materials for use in their methods, inclusive of kits comprising nucleic acids comprising or consisting of any DMR of Table 1 (of which the above noted DMR 233 is one), Taylor et al anticipate claim 92 (see in particular paragraphs 38-40; see also paragraphs 18 and 127).
The Reply of 17 December 2025 traverses the prior rejection of claim 92 under 35 USC 102 on the following grounds. Applicant argues that Taylor “fails to disclose at least ‘a DNA methylation probe comprising at least 5 nucleotides configured to bind a nucleotide sequence of any one of SEQ ID Nos: 1-100’ (emphasis added)”, as required by the claims (Reply page 12). Applicant refers to Table 1 of Taylor et al, particularly referencing the four SDK1 gene DMRs (DMRs 232-235), and urging that these do not constitute a disclosure of what is required by the amended claims, referring to the genomic coordinates of instant SEQ ID NO: 98 (chr7:3340400-3340600) (Reply page 12). This argument has been thoroughly considered, but is not persuasive with regard to the product of claim 92, given what is currently embraced by the claims and actually disclosed by Taylor et al as evidenced by the specification (as discussed in the revised rejection above). In particular, the current language of claim 92, to the extent that it is presently understood, embraces products disclosed by Taylor et al, such that Taylor et al anticipate what is claimed.
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.
THE FOLLOWING ARE NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS’ AMENDMENTS TO THE CLAIMS:
Claim(s) 83-88, 91, and 95-104 is/are rejected under 35 U.S.C. 103 as being unpatentable over Taylor et al (US 2018/0066320 A1 [18 March 2018]; previously cited) in view of Reeve et al (WO9947706A1 [Sept. 1999]; cited herein), as evidenced by the specification.
Independent claim 83 as amended is drawn to a method of “detecting a hepatocellular carcinoma (HCC)-specific methylation signature in a subject suspected of having liver cancer” comprising obtaining a biological sample comprising cfDNA from the subject, isolated cfDNA therefrom, and “detecting the HCC-specific methylation signature in the biological sample, wherein the detecting comprises contacting the nucleic acids with an HCC-specific methylation signature detection molecule, wherein the HCC-specific methylation signature detection molecule is a DNA methylation probe comprise at least 5 nucleotides configured to bind to a nucleotide sequence of” SEQ ID NO: 98 (which is the elected target sequence). It is reiterated that multiple limitations of the claim (including the reference to “the nucleic acids” and the nature of the “DNA methylation probe”) are indefinite as discussed above, however the amended claim appears to require contacting target nucleic acids with a probe complementary to (i.e., “configured to bind to”), e.g., at least 5 nucleotides of elected SEQ ID NO: 98 (which is disclosed/defined in the specification as meeting the requirement of being a differentially methylated region of SDK1; see, e.g., page 51). Given the references in the claims to cfDNA, for purposes of comparing the claims to the prior art, claim 83 has been interpreted as referencing a contacting of the recited probe with cfDNA (although again, the boundaries of the instant claims are unclear); it is noted that dependent claim 85 teaches plasma, serum, and urine are preferred “biological samples” meeting the requirements of the claims.
Taylor et al disclose methods and kits for detection of hepatocellular carcinoma (see entire reference). Regarding the recitation of a subject “suspected of having liver cancer” (or not diagnosed with liver cancer, as in dependent claim 87) and the use of a biological sample therefrom, Taylor et al teach preferred embodiments of a subject with cirrhosis (see, e.g., paragraph 11, noting that this preferred subject type is recited in dependent claim 86), and also make clear that one application of their method is “screening for HCC” and employing their method in “identifying” a subject as having HCC/a neoplasm/etc., or detecting the presence of HCC (see, e.g., paragraph 31, 42, 45, 119, 128, 132, 137, 184, and 193-198, noting in particular the disclosure in paragraph 137 of the use of methods employing DMRs meeting the requirements of the claims in identifying the presence of HCC, and the disclosure at paragraphs 193-198 of subjects having risk for HCC). Taylor et al disclose that their invention “provides novel methylated DNA markers that discriminate HCC from normal controls (controls with and without cirrhosis”), providing technology for HCC screening and detection (see paragraphs 8 and 12). Taylor et al disclose that their markers comprise “one or more differentially methylated regions (DMR) as discussed herein, e.g., as provided in Tables 1 and 4”, with a variety of different techniques being available for detection/evaluation of methylation state (see paragraphs 15-18, as well as paragraphs 35-37 and 131-137). It is noted that Table 1 of Taylor et al includes 4 DMRs corresponding to regions of the elected gene SDK1 (see Table 1 at page 21, right column, DMRs 232-235). As evidenced by Applicant’s specification (again at page 51), instant SEQ ID NO: 98 corresponds to chr7:3340400-3340600, such that instant SEQ ID NO: 98 overlaps by over 50 contiguous nucleotides with DMR233 of Taylor et al (see again Table 1 of Taylor et al at page 21, right column noting that DMR233 is disclosed at having the position chr7 3340543-3340635). Thus, based on at least one reasonable interpretation of the present claim language, Taylor et al disclose a DMR comprising “at least 5 nucleotides configured to bind to” SEQ ID NO: 98 (based on the shared identity of the sequence of Taylor et al with Applicant’s SEQ ID NO: 98 over more than 50 contiguous nucleotides, as described in and evidenced by the specification; it is also noted that Applicant’s arguments at page 12 [Reply of 17 December 2025] acknowledge this inherent property of instant SEQ ID NO: 98). Further, Taylor et al also discloses such DMRs as targets of detection by a variety of methods, including nucleic acid sequencing (see again see paragraphs 15-18, as well as paragraphs 35-37 and 131-137, and particularly paragraph 35 regarding sequencing), and Taylor et al also disclose that such target nucleic acids may be present in “cell free” samples, as well as preferred samples specified in the instant claims as being sources of cfDNA, e.g., the preferred samples of plasma, serum, and urine as set forth in dependent claim 85 (see in particular paragraphs 34, 176, and 181-183). Thus, Taylor et al disclose methods meeting all requirements of the present claims other than the performance of a “detecting” employing a probe “configured” as specified of c) of claim 83 with respect to cfDNA; more particularly, while Taylor et al suggest detection in various sample types (including “cell free” samples, plasma, serum, etc.) of a target DMR overlapping instant SEQ ID NO: 98 (and thus clearly detectable by probes as set forth in the claims) - and further suggest that a variety of methods (including sequencing) may be employed in detecting such targets - Taylor et al do not disclose actually performing such a method, and thus fail to anticipate the claims.
Reeve et al teach compositions, including arrays, comprising all possible “N mer” oligonucleotides or subsets thereof “where N is preferably from 5 to 10, particularly 8 or 9” (see entire reference, particularly pages 4-5; quotation from page 5, lines 10-11). Reeve et al teach that their N mers may be DNA, RNA, PNA or “mimetics or mixtures thereof” (see page 5, lines 12-13), and state that the molecules may be in solution (page 4) or "immobilised at a spaced location on a surface of a support” (page 5). Given the structural requirements of the probe compositions taught by Reeve et al, these compositions inherently include numerous “DNA methylation probes” that are “configured to bind” throughout instant SEQ ID NO: 98 (and thus which meet the requirements of c) of instant claim 83). Reeve et al disclose the use of their reagents in sequencing by hybridization (see entire reference, particularly, e.g., pages 2-3), i.e. a type of nucleic acid sequencing. The method disclosed by Reeve et al comprises incubating together "under hybridisation conditions" target nucleic acid obtained from a sample and an oligomer composition of Reeve et al to determine the nucleic acid sequence of a target (see pages 2-7). Thus, use of sequencing as taught by Reeve et al as the preferred sequencing type in methods as taught by Taylor et al would result in a ”detecting” meeting the requirements of claim 83.
In view of the teachings of Taylor et al and Reeve et al, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to have modified the methods of Taylor et al as directed to detection of DMR233 (i.e., the DMR target overlapping instant SEQ ID NO: 98) so as to have performed those methods with regard to a biological sample comprising cfDNA, and using the sequencing method of Reeve et al as the sequencing taught and suggested by Taylor et al, and thereby to have performed a method meeting the requirements of independent claim 83. First, with regard to cfDNA and samples comprising such cfDNA, an ordinary artisan would have been motivated to have employed such cfDNA/samples in the methods taught by Taylor et al because Taylor et al state that such samples – including plasma, serum, urine, and “cell free” samples – are preferred samples for testing via their methods/analysis of HCC (see above, and in particular see again paragraphs 182-183). Second, as Taylor et al teach that sequencing is one methodology that may be employed in performance of their methods, and recite various particular types of sequencing that may be used, an ordinary artisan would have recognized the use of sequencing as taught by Reeve et al as simply one possible specific methodology that could be employed to successfully implement the methods of Taylor et al, and/or (with regard to any of the specific types of sequencing referenced by Taylor et al) as the simple substitution of one prior art technique for another to achieve the predictable result of sequencing targeting nucleic acid (including cfDNA) of interest.
Regarding claim 85 and its dependent claims 95-97, samples meeting the requirements of the claims are also addressed above.
Regarding dependent claim 87, it is reiterated that Taylor et al disclose types of subjects meeting the requirement of having “not been diagnosed with liver cancer”, such as those with cirrhosis (see again paragraph 11).
Regarding claim 88, as the methodology suggested by Taylor et al in view of Reeve et al when performed would be sufficient to detect any or all of preferred SEQ ID NO: 98 (the elected species), and includes all steps required by the claims, the teachings of Taylor et al in view of Reeve et al meet the requirements of the claim to the extent that it is understood (and it is noted that Taylor et al also disclose detecting multiple other DMRs in the SDK1 gene, and that it is clear from the teachings of Taylor et al that their methods are sufficient to detect/differentiate methylated CpG marker sites/CpG islands, including with regard to their disclosed DMRs; see, e.g., paragraphs 96-97, 134-135, and throughout the disclosure).
Regarding claim 91, the elected gene SDK1 has been addressed above.
Regarding claim 98, as Reeve et al teach probes including all possible “N mer” oligonucleotides or subsets thereof “where N is preferably from 5 to 10” (see above), the combined teachings of Taylor et al and Reeve et al suggest embodiments employing “at least 10 nucleotides configured to bind” to SEQ ID NO: 98.
Regarding claims 99-101, which require methods “further comprising” use of additional techniques for methylation detection, it is noted that methods including various further techniques are taught by Taylor et al; see, e.g., paragraphs 49 and 140-168, noting in particular the disclosures of methylation specific PCR (see, e.g., paragraphs 49 and 144) and various types of sequencing (see, e.g., paragraph 49 and 144-145).
Regarding claim 102, it is reiterated that Reeve et al teach that their sequencing methods may be implemented using a solid phase/array, which is sufficient to meet the requirements of the present claims (see, e.g., the Abstract and pages 1-3).
Regarding dependent claims 103-104, 84, and 86, all of which require measurement of a concentration of a methylation signature (see claim 103), Taylor et al disclose the practice of quantitative methods allowing for determination of concentration of nucleic acids (see, e.g., paragraphs 91-93, 134, and 191-197 regarding methylation concentration and 146-163 regarding preferred techniques for quantitation), and report that a variety of different “methylation values” may be used as quantitative indicators of methylation status (see in particular paragraphs 91-93, disclosing frequency, percent methylation, relative concentration, absolute concentration, etc.). Thus, absent a showing of an unexpected benefit providing by a particular value/measure as an indicator, the use of “copies per mL” would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention given the teachings of Taylor et al and Reeve. Further, with regard to claims 84 and 86, the number of copies measured in a particular sample from a particular subject when tested in the manner suggested by Taylor et al in view of Reeve et al would be expected to vary from subject to subject, and is an inherent characteristic of the tested sample. Thus, in suggesting the methods as claimed, including the use of samples of the preferred type set forth in the claims, obtained from subjects meeting the requirements of the claims (including, e.g., subjects with cirrhosis, as noted above), Taylor et al and Reeve et al suggest methods meeting the requirements of the claims (as the teachings of the cited art suggest performing methods including all required limitations, regardless of the outcome of those methods, including with regard to the concentration of target present in the tested sample(s)).
Accordingly, the teachings of Taylor et al in view of Reeve et al suggest the methods of claims 83-88, 91, and 95-104.
Claim Rejections - 35 USC § 101
THE FOLLOWING INCLUDES NEW GROUNDS OF REJECTION NECESSITATED BY APPLICANTS’ AMENDMENTS TO THE CLAIMS:
Claim 92 remains rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon/law of nature without significantly more.
Claim 92 as amended recites “at least one HCC-specific methylation signature detection molecules, wherein the HDCC-specific methylation signature detection molecule is a DNA methylation probe capable of binding to one or more differentially methylated regions in one or more” genes (with the elected species being an SDK1 gene), “wherein the DNA methylation probe comprises at least 5 nucleotides configured to bind to a nucleotide sequence of” SEQ ID NO: 98 (with the claim being indefinite, as discussed above, and with at least one reasonable interpretation of the claim reading on a molecule/probe including or complementary to any 5 contiguous nucleotides of SEQ ID NO: 98). This claim (to the extent that it is understood) thus continues to encompass a variety of naturally occurring nucleic acid fragments including any 5 naturally occurring nucleotides (and it is noted that such fragments are inherently “capable of binding” to corresponding target sequences, although the present claim language is unclear). Such nucleic acid fragments are products of nature that fall under the law of nature/natural phenomenon judicial exception, and the present claim language does not include anything imparting on the claimed molecule/probe any marked difference relative to corresponding naturally occurring nucleic acids. While the claim does require a kit comprising the molecule/probe, placing such a product into a generic kit/container does not add a meaningful limitation as it is merely a nominal or extra-solution component of the claim, and is nothing more than an attempt to generally link the product of nature to a particular technological environment. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the packaging of such molecules/probes into kits was clearly well-known, routine, and conventional as of the effective filing date of applicant’s invention (as exemplified by, e.g., Taylor et al, cited above). Thus, claim 92 is not directed to patent eligible subject matter.
The Reply of 17 December 2025 traverses the rejection on the following grounds. Applicant notes that claim 92 as amended recites “a DNA methylation probe capable of binding to one or more differentially methylated regions….[and] comprises at least 5 nucleotides configured to bind to a nucleotide sequence of any one of SEQ ID Nos: 1-100”, such that “claim 92 does not encompass naturally occurring nucleic acid fragments that are products of nature and hence does not fall under the law of nature/natural phenomenon judicial exception” (Reply page 11). This argument has been thoroughly considered but is not persuasive. As discussed above, claim 92 as amended is indefinite, and the nature of what is required by the relied upon “configured to bind’ language is not known. At present, there is nothing clearly required by the claim language that may be relied upon as necessarily differentiating what is claimed from a product of nature. Additionally, even to the extent that the claim may embrace some patent eligible embodiments (for example, some types of nucleic acids/probes containing modifications rendering them markedly different from naturally-occurring nucleic acids), a claim whose broadest reasonable interpretation covers both statutory and non-statutory embodiments “embraces subject matter that is not eligible for patent protection and therefore is directed to non-statutory subject matter” (MPEP 2106.03(II)). Accordingly, Applicant’s arguments are non-persuasive.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682