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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/30/2025 has been entered.
This Office Action is in reply to Applicants’ correspondence of 06/30/2025.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put this application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is NON-FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
in the reply filed on 05/09/2023 Applicants elected, without traverse, the invention of Group II (claims 23-26, directed to nucleic acid arrays).
Applicants further elected (with regard to the species election as set forth on page 4 of the Requirement of 12/09/2022), with traverse, the particular combination that is ICR NOs: 17, 20, 39, 54, 55, 67, 78, 88, 89, 92, 93, 94, 106, 114, 125, 140, 145, 165, 191, 197, 200, 225, 275, 286, 289, 295, 308, 310, 312, 313, 320, 324, 354, 374, 383, 395, 399, 403, 408, 416, 447, 457, 459, 460, 468, 508, 526, 527, 552, 560, 584, 585, 589, 620, 623, 635, 644, 656, 659, 663, 682, 699, 707, 748, 752, 753, 767, 768, 769, 778, 787, 797, 802, 803, 805, 815, 819, 827, 830, 832, 845, 938, 950, 964, 968, 972, 999, 1005, 1029, 1034, 1042, 1048, 1076, 1085, 1087, 1088, 1113, 1128, 1184, 1195, 1200, 1213, 1231, 1234, 1242, 1245, 1252, 1294, 1306, 1309, 1329, 1358, 1361, 1363, 1366, 1368, 1376, 1382, 1410, and 1477 (Applicants have noted that each ICR is provided in the sequence listing with the same SEQ ID NO).
Claims 7-22 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 3 of the Office Action of 08/23/2023.
Election was made without traverse in the reply filed on 05/09/2023.
Claim Rejections - 35 USC § 112 – New Matter
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.
Claims 24-26 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.
The instant rejection of claims is relevant to the limitation in the amended claim which requires that the claimed array is suitable to “permit simultaneous identification of the DNA methylation status of” the 120 recites ICRs (where each ICR number is the same SEQ ID NO: from the sequence listing). But the Application as originally filed does not provide for the particular “simultaneous identification” of DNA methylation status, as provided by a particular array of target probes. The rejection is relevant in light of the arguments set forth in Applicants’ Remarks of 06/30/2025, and the Declaration of Catherine Hoyo provided with the response of 06/30/2025, which set forth that some particular oligonucleotide structures are required for the recited functionality of the claims. But the application as originally filed does not set forth any aspects related to the simultaneous identification of particular imprint control regions. The only portion of the specification that may be related to such a limitation is set forth on pages 29-30 of the specification as filed:
In some embodiments, a pattern of methylation of ICRs that is associated with a disease such as autism, early onset liver cancer or other subtype, e.g., hepatocellular- or cholangiocarcinoma, can be developed into a panel. Such a panel of methylation patterns can then be multiplexed and used to detect the presence/absence of disease, or prognosis, for example, if a certain threshold of the number of differentially methylated regions is reached.
But the disclosure of multiplexing a “panel of patterns”, as recited in the specification, is not the same as requiring some array of probes for simultaneous identification of methylation status of the recited imprint control regions. Additionally, the disclosure of the specification makes it clear that any pattern of methylation that is multiplexed into a panel patterns is associated with some particular disease phenotype, and there is no particular disclosure in the application as filed which indicates that the SEQ ID NOs:/ICRs recited in the claims are specifically associated with a disease phenotype.
The requirement for simultaneous identification of the DNA methylation status of the ICRs is further relevant to the claimed array as it may include the probes of part (a) of claim 24, or the probes of part (b) of claim 24. The claims are amended to include the different probes in the alternative, thus the claim do not require the probes of (b) which are “complementary to nucleic acid sequences that are specific for each of (the recited SEQ ID NOs) subsequent to exposing the target probes to a bisulfite converting treatment”. While this limitation is itself new matter (as detailed in the next paragraph), it appears to make the claims directed to an array that includes only probes directed toward natural DNA sequences (i.e.: the array does not require probes that hybridize to bisulfite treated sequences, which would be required to make a determination about methylation).
As noted in the paragraph above, the claims recite, in part (b) of claim 24, “target probes that are complementary to nucleic acid sequences that are specific for each of (the recited SEQ ID NOs) subsequent to exposing the target probes to a bisulfite converting treatment”. But the application as filed (e.g.: p4) makes it clear that the probes are complementary to genomic DNA that has been subjected to a bisulfite converting treatment (i.e.: it is the genomic DNA, not any target probes, that are exposed to a bisulfite converting treatment).
As such the rejection of claims under 112(a) as encompassing subject matter not envisioned by the application as originally filed is appropriate.
New Claim Rejections - 35 USC § 112 - Indefiniteness
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24-26 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.
Claim 24-26 are unclear over the required structures of the target probes of the claimed nucleic acid arrays. In the instant case it is unclear what is intended to be required or encompassed by the probes because the claims recite, for example as set forth in part (a) of claim 24: target probes that are complementary to nucleic acid sequences that are specific for each of SEQ ID NOs: (recited SEQ ID NOs of the election). In this case the sequence of each SEQ ID NO is defined in the sequence listing, but the sequences of the “target probes” are not the defined SEQ ID NOs, nor the complement of the defined SEQ ID NOs. The “target probes” of the claims are complementary to “to nucleic acid sequences that are specific for” the defined SEQ ID NOs. But the application as filed does not set forth any limiting definition of what is required for any sequence to be “specific for” any other different sequence. So, in the instant case the claims are directed to arrays comprising “target probes”, and while the “target probes” are complementary to sequences, the skilled artisan does not know what sequences the target probes are complementary to because there is no clear definition of what those sequences in fact are because they are only defined as “specific for” the recited SEQ ID NOs. Here it is noted that while the specification provides a definition for “hybridizing specifically to” (p.13 of the specificity), it is not this defined phrase that appears in the claims. This is especially relevant where the specification teaches that the invention may encompass probes with mismatches as compared to a hybridization partner.
Claim 26 is unclear over the recitation of the limitation that “the plurality of interrogatable nucleotide molecules correspond to at least 100, 250, 500, 1000, or all of ICRs 1-1611 and/or the genomic regions associated with SEQ ID NOs: 1612-1816”. In the instant case the election was directed to the 120 ICR sequences that are recited in claim 24. It is unclear how the 120 recited ICR sequences are intended to “correspond to” 250, 500, 1000 or all of the ICRS 1-1611, because the 120 particular ICRs are particular genomic sequences that do not “correspond” to other different sequences. Additionally, the specification asserts (p.7) that:
SEQ ID NOs: 1612-1816 are the nucleotide sequences of human genomic sequences that were identified in whole genome methylation analyses in Alzheimer's patients but that did not align with any of the ICRs corresponding to SEQ ID NOs: 1-1611.
So it is unclear how the array directed to the 120 recited ICRs includes the genomic regions that are recited as SEQ ID NOs: 1612-1816.
Withdrawn Claim Rejection – Improper Markush Group
The rejection of Claims 24, 25, and 26 under the judicially approved "improper Markush grouping" doctrine is withdrawn. Though amendments to the claims appear to be direct the claimed subject matter to the combination of ICRs consonant with the election.
Maintained Claim Rejections - 35 USC § 102
Modified as Necessitated by Claim Amendments
Claim(s) 24-26 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fodor et al (US 2001/0053519 A1).
It is noted that several aspects of the claims have been addressed previously in this Office Action under 35 USC 112(b) as being unclear. Here the claims are rejected in view of the cited prior art where the cited prior art appears to teach an array of oligonucleotides the structure of which is encompassed by the claims, which meets the broad functional limitations of the claims.
Fodor et al exemplifies (e.g.: Figs 2-5; p.10, para 101) a comprehensive nucleic acid array comprising every possible 10-mer probe sequence. Because of the comprehensive nature of the array of Fodor et al, where the array includes every possible 10-mer sequence, such an array includes nucleic acids that meet the broad structural limitations required by the claims, and can perform the required function of the claims. For example, the array of Fodor et al includes probes consisting of the sequences : 5’-ACTCCGTCTC -3’ (the reverse complement of positions 283-274 bisulfite treated SEQ ID NO: 17 where the cytosine at position 278 is methylated and remains a C with base pairs with G) and 5’-ACTCCATCTC -3’ (the reverse complement of positions 283-274 bisulfite treated SEQ ID NO: 17 where the cytosine at position 278 is unmethylated is converted to a U which base pairs with A), which could be used to detect the methylation of the cytosine at position 278 of SEQ ID NO: 17 in bisulfite treated human genomic DNA.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 102 as anticipated by the cited prior art. Applicants’ arguments (p.8-11 of the Remarks of 06/30/2025) have been fully considered but are not persuasive to withdraw the rejection. The Declaration of Cathrine Hoyo, PhD, under 37 CFR 1.132 filed 06/30/2025 is insufficient to overcome the rejection of claims based upon the cited prior art as maintained above for the reasons as detailed below.
Applicants’ remarks have argued “the arrays of Fodor could not be employed for identified methylation statuses of particularly recited sequences because the length of the probes on the arrays”. Applicants’ argument in this regard is based on the number of times any 10-mer sequence would be expected to occur in a human genome, leading Applicants to the conclusion that using a 10mer probe would make it impossible to determine if any detected hybridization is in fact between a 10-mer probe and its intended target in the ICR or some other non-intended gene locus. This argument is not persuasive because it appears to require some particular methodology (e.g.: the entirety of a human genome as a single sample is applied to the claimed array), but fails to consider that the claim is directed to a product (i.e.: a nucleic acid array) and not to any method. The MPEP provides guidance on the analysis of claimed products, and the comparing of the claims to the prior art. As set forth in MPEP 2114(II), the manner of operating a claimed device does not differentiate the claimed apparatus from the prior art:
“[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). A claim containing a "recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus" if the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987)
The MPEP in 2111.02 further addresses statements of intended use with regard to claimed products and provides:
If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)
In the instant case, Applicants’ arguments fail take into account that the only structures of the claimed array are broadly recited as, for example, “probes that are complementary to nucleic acids sequences that are specific for each of” the recited SEQ ID NOs. And while these limitations have been addressed earlier in this Office Action under 35 USC 112(b) as unclear, the Examiner maintains that the array of Fodor, as cited in the rejection, meets the required structural limitations of the claims.
Turning back to Applicants’ argument (i.e.: that the human genome is too complex to for the particular ICR loci of the claim to be analyzed by the array of Fodor), this argument is no persuasive because it is not commensurate in scope with the claims. The claims are directed to a product (i.e.: an array of nucleic acids on a solid support), and recite the functional limitation/intended use of “identification of the DNA methylation status of Imprint Control Regions (ICRs)”. Applicants’ argument about the complexity of the entire human genome does not reflect the limitations of the claim which require only the analysis of 120 ICR loci (as identified by SEQ ID NO in the claim). Furthermore, the argument does not consider the ways in which the complexity of the entire genome may be reduced for analysis of the array of the prior art. While there may be a plurality of 10-mer sequence in the human genome complementary to, for example, 5’-ACTCCGTCTC -3’ and/or 5’-ACTCCATCTC -3’ (relevant to detecting methylation of the cytosine at position 278 of SEQ ID NO: 17 in bisulfite treated human genomic DNA), the particular loci of interest can be detected after target enrichment, for example by target capture hybridization using a complementary capture probe, or amplification of the target locus using labeled primers specific for the region of interest and hybridization of the labeled amplicon to the array. As such, Applicants’ argument that “Fodor's arrays cannot [target particular ICRs] because any particular binding event could not possibly be attributed to any particular genetic sequence because the sequences on the array occur thousands of times in the genome” is not persuasive to withdrawn the rejection. And while Applicants assert that these the use of the prior art array of Fodor in some particular methodology envisioned by the Applicants requires an “additional procedural step” that “is not a feature of the Fodor arrays per se”, and that in order to properly anticipate the claim “the Fodor arrays would be required to permit identification of the DNA methylation status of the recited directly” because “this is clearly the intent of the present claims and would be recognized as such by one of ordinary skill in the art upon consideration of the application as a whole”, The Examiner maintains that the cited prior art teaches all of the required structures of the array as claimed, and could be used to perform the intended use of the claimed array as recited in the claims.
Applicants have provided a Declaration under 1.132 (made by Cathrine Hoyo, PhD, 06/30/2025) asserted to provide evidence that the array of Fodor does not meet the limitations of the claims. The assertions of the declaration are directed to the intended use of the claimed array in a particular methods of methylation detection/analysis. As detailed above, the claims are directed to a product, not to any particular methods, and where the prior art product may be used to perform the broadly recited intended use of the claimed product, the Examiner maintains the rejection is appropriate. The Declaration asserts (e.g.: parts 4-11) that the complexity of the human genome would prevent the analysis the recited ICRs using the 10-mer array of Fodor. This assertion has been addressed above in this response to Remarks. Here it is additionally noted that the use of comprehensive arrays in the analysis of complex samples, such as transcriptomes, was know in the prior art as taught by van Dam et al (2002). Furthermore, as noted above, the claims are directed to an array that is relevant to only 120 loci, and the prior art teaches that software for the analysis of bisulfite treated sequences, for purposes of designing primers and probes, was known in the prior art (e.g.: Li et al (2002)). Consider for example the MethPrimer results for instant SEQ ID NO: 17 and 20, which are included in the claims, where the results allow the skilled artisan to design primers for specific amplification of particular CG containing dinucleotides in each locus, and the identification of probes that would allow for the detection of methylated or unmethylated cytosines in the relevant amplicons.
The Declaration asserts (at part 14) “the CpG sites targeted by the presently claimed Imprint Control Region (ICR) arrays are largely missing from Fodor's arrays, with less than 6% overlap.” It is unclear how this assertion is being applied to the probes of the Fodor array. The Fodor array includes every possible 10-mer nucleic acid. In so far as any CpG in any ICR is contained with some particular 10-mer context, there is a probe on the Fodor array that will hybridize to that 10-mer context; it is further relevant to point out that the claims are directed to 120 particular ICR loci, not every possible ICR locus in the human genome. And where each ICR locus may have multiple CpG dinucleotides in different 10-mer contexts, with multiple 10-mer windows of sequences overlapping any CpG dinucleotide, and where different CpG dinucleotides in any ICR locus may be expected to be comethylated (e.g.: Illumina Methylation BeadChips achieve breadth of coverage using two Infinium™ Chemistries – Technical Note (2022)), the 10-mer array of Fodor et al includes probes suitable for identification of methylation in the 120 ICRs recited in the claims.
Requirement for Information
Applicant and the assignee of this application are required under 37 CFR 1.105 to provide the following information that the examiner has determined is reasonably necessary to the examination of this application.
The Examiner has identified the following citation/reference that is relevant to the instantly claimed subject matter:
Natalia Carreras-Gallo, Varun B. Dwaraka, Dereje D. Jima, David A. Skaar, Tavis L. Mendez, Antonio Planchart, Wanding Zhou, Randy L. Jirtle, Ryan Smith & Cathrine Hoyo. Creation and validation of the first infinium DNA methylation array for the human imprintome. Epigenetics Communications (2024) 4:5.
The authorship of the cited reference includes inventors of the instant application, and appears to be an array of oligonucleotides similar to the instantly claimed array. The Imprintome array of the reference includes probes directed to CpGs in asserted ICRs that are the same as probes in other prior art arrays directed to methylation analysis and are relevant to CpGs disclosed in the instant application. For example, Table S3 of the cited reference discloses an Imprintome probe directed to cg09414948 (chr1:16164296), which is also included the Illumina 850k EPIC Methylation Array, and is the CpG located at position 273-274 of SEQ ID NO: 22 of the instant application.
The Examiner requires additional information in order to make further determinations about the patentability to the instant claims. In response to this requirement, please provide answers and relevant information to each of the following:
1. Of the 120 recited ICR loci in claim 24, which of those loci have CpG dinucleotides that are represented on commercially available methylation detection arrays. Applicants should provide an identification of CpG dinucleotides using cg# indetifiers.
2. Of the 120 recited ICR loci in claim 24, which of those loci have CpG dinucleotides that are not represented on commercially available methylation detection arrays.
The fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to this requirement. This waiver extends only to those documents within the scope of this requirement under 37 CFR 1.105 that are included in the applicant’s first complete communication responding to this requirement.
Any supplemental replies subsequent to the first communication responding to this requirement and any information disclosures beyond the scope of this requirement under 37 CFR 1.105 are subject to the fee and certification requirements of 37 CFR 1.97.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.58. Where the applicant does not have or cannot readily obtain an item of required information, a statement that the item is unknown or cannot be readily obtained may be accepted as a complete reply to the requirement for that item.
This requirement is an attachment of the enclosed Office action. A complete reply to the enclosed Office action must include a complete reply to this requirement. The time period for reply to this requirement coincides with the time period for reply to the enclosed Office action.
Conclusion
No claim is allowed.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. Carreras-Gallo et al (2024) teaches an array of oligonucleotides for analysis of DNA methylation at genomic sites related to monoallelic expression of imprinted genes. The reference provides particular probes used in an assay similar to the arguments provided by Applicants in traversal of the rejection of claims provided in the instant Office Action. It is suggested that Applications may wish to amend the claims to include structural limitation of the claimed probes such that they are similar to the array of the reference and consonant with the teachings of the specification. For example, the specification (e.g. p. 14 and 19 of the specification as filed) appears to provide for 50-mer probe pairs where one member of the pair is the sequence, or complementary to the sequence, of a bisulfite converted ICR assuming the presence of one or more C5-methylated cytosines, and the second member of the pair includes the same nucleotide sequence by with one or more guanosines replaced with adenosines.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683