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 Office Action is in reply to Applicants’ correspondence of 06/29/2026.
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. No new grounds of rejection are presented in this Office Action. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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 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Claims 7-22 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 3 of the Office Action of 08/23/2023.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.
Maintained Claim Rejections - 35 USC § 112 – New Matter
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.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 for including new matter as maintained above. Applicants’ arguments (p.6-7 of the Remarks of 06/29/2026) have been considered but are not persuasive to withdraw the rejection.
Applicants have argued that the limitation to thereby permit “simultaneous identification” of methylation status of ICRs is provided to clarify the inherent operation of the disclosed array, and thus does not introduce any new matter. Applicants further provide that “a nucleic acid array comprising probes directed to multiple imprinting control regions necessarily permits analysis of those multiple targets within the same assay.” The argument is not persuasive because it is contradicted by the traversal of the rejection of claims in view of the prior art where Applicants have argued that a 10-mer array, which includes probes specific to the recited SEQ ID NOs, is not encompassed by the claims because “the claims are not directed merely to the presence of isolated probe sequences on a solid support” and requires “molecules that are designed … to permit simultaneous identification of the DNA methylation status of the recited ICRs”. Thus, Applicants appear to intend that there are some structural requirements of the probes of the claims which allow for “simultaneous identification” of the ICRs, but the application as originally filed does not in fact describe the particular structures of the probe combinations nor does the application as originally filed provide for the particle intended use of “simultaneous identification”. Thus, arguing that “one of ordinary skill in the art would readily understand that the instantly claimed arrays enable concurrent evaluation of multiple targets” is not sufficient to conclude that the application as originally filed is directed to some particular combination of probes that is required for the intended use that is presented in the amended claims. In this regard it is noted that the written description requirement is distinct from an analysis that might render some aspect of the claims obvious. While Applicants’ intended use of “simultaneous identification” might be obvious in light of array technology related art, it is not a particular aspect of the array (e.g.: what sequence elements or probe lengths of the combinations of probes are required for use in simultaneous identification of ICR methylation) that is disclosed in, or envisioned by, the application as filed. Finally, it is noted that the rejection identifies the limitation “exposing the target probes to a bisulfite converting treatment” as an element of new matter, and this aspect of the rejection is not traversed by the arguments of the response.
New Claim Rejections - 35 USC § 112 - Indefiniteness
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 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” 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.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 for being indefinite as maintained above. Applicants’ arguments (p.7-8 of the Remarks of 06/29/2026) have been considered but are not persuasive to withdraw the rejection.
Applicants have argued that “in the context of nucleic acid probe technology, a person of ordinary skill in the art would readily understand a sequence that is "specific for" a recited target sequence to be a sequence capable of specifically hybridizing to that target sequence under appropriate conditions.” This argument is not persuasive because, as detailed in the rejection, there are several layers of elements in the claims that lead to a lack of clarity of what is required for the claims. The claims are directed to an array comprising “target probes”. But the “target probes” are themselves not defined by any particular structure; the “target probes” of the claims are “complementary to nucleic acid sequences”. This recitation does not require any particular amount of complementarity (e.g.: over a specific length of the probe as compared to the sequence). And the “nucleic acid sequences” to which the “target probes” are complementary are not themselves clearly defined as requiring any sequence. The claims recite “nucleic acid sequences that are specific for each of [the elected sequences]”, but as noted in the rejection there is nothing in the specification that provides what is required for any “nucleic acid sequences” to be “specific for” the recited SEQ ID NOs. Thus, while Applicants argue that:
… a person of ordinary skill in the art would readily understand a sequence that is "specific for" a recited target sequence to be a sequence capable of specifically hybridizing to that target sequence under appropriate conditions. The application as filed expressly describes and defines specific hybridization, thereby providing objective guidance as to the meaning of sequence specificity in the context of the claimed invention.
the Examiner maintains that where it is the array of “target probes” that is being claimed, there is no clear definition of what is required by, or encompassed by, the nucleic acids sequences (where it is the ‘nucleic acids sequences’ that the probes are complementary to) such that they are ‘specific for’ the recited ICR sequences. There are no ‘appropriate conditions’ set forth in the claims, or set forth as a definition in the specification such that the claim is informed, making the structure of the ‘nucleic acid sequences’ unclear. Where the ‘nucleic acid sequences’ are unclear the ‘tareget probes’ which are claimed as complementary to the ‘nucleic acid sequences’ are also unclear. Where Applicants argue:
… probes containing one or more mismatches … reflects the well-established principle that nucleic acid probes may retain sequence specificity despite less than perfect complementarity.
the Examiner maintains that it is not clear how much “less than perfect complementarity” is intended to be encompassed by the claims, and thus it is unclear what structures of “target probes” are required by and encompassed by the claims.
Maintained Claim Rejections - 35 USC § 102
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.8-10 of the Remarks of 06/30/2025) have been fully considered but are not persuasive to withdraw the rejection.
Applicants’ remarks have argued that Fodor does not disclose an array configured for interrogation of the recited ICR loci because the prior art discloses a universal array containing every possible 10-mer sequence “without regard to any particular genomic locus, imprint control region, methylation target, or collection of methylation targets”. The argument is not persuasive because it is directed to a possible intended use of the claimed array of “target probes”, but does not provide an indication of the distinction between the structure of the array of the prior art and the structure of the arrays encompassed by the claims. As noted in the rejection, the Examiner maintains that the array of Fodor includes probes that can be used for the identification of DNA methylation status of ICRs. Even where Applicants have maintained the argument that “the ability to identify methylation status at those loci depends upon the relationship between the probes and the targeted ICR sequences”, such an argument is not persuasive where the detection of any nucleic acid content (such as in a sample where cytosines are converted (unmethylated) or unconverted (methylated) by bisulfite treatment) is dependent upon the sequence of the probes of the array. Where the array of Fodor exemplifies 1,048,576 probes (i.e.: 410; every possible 10-mer probe), the Examiner maintains that the array of Fodor comprises target probes to nucleic acid sequence that are specific to each of the recited SEQ ID NOs. Where the prior art structure can perform the intended use of the claims, the prior art meets the claims. Thus while Applicants argue that:
Fodor neither describes nor suggests an array designed for interrogation of the recited ICRs, nor does Fodor disclose an array configured to permit simultaneous identification of methylation status across the specifically recited ICR loci.
This argument is not persuasive. The structural limitations of the broadly claimed array is met by the array exemplified by the cited prior art. While the prior art may demonstrate the use of the array in a different analysis, where the array could be used for the broad intended use of the claims (i.e.: identification of methylation), the rejection is appropriately maintained.
While Applicants may have some particular embodiment of the claims (i.e.: particular sense and antisense probes of specific sequences directed to a particular combination of CG positions in each of the recited ICS sequences) that has been constructed and used in the analysis of genomic material (e.g.: the “Human Imprintome array” from Carreras-Gallo et al (2024) (cited on the PTO-892 of 12/29/2025)), the claims are not particularly directed to any such specific combination of specific probes.
Requirement for Information
Applicants’ reply of 06/29/2026 has provided the information requested in the Requirement of 12/29/2025.
Conclusion
No claim is allowed.
The art made of record and not relied upon is considered pertinent to applicant's disclosure. Gunderson et al (1998) provides a 9-mer array and the use of the array in sequencing targets with >99.9% accuracy.
THIS ACTION IS MADE FINAL. 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.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights