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 .
Notice of New Examiner
This case has been transferred to a new examiner for continued examination. Any further communications regarding this case may be directed to the contact information included in the conclusion of this office action.
Status of Claims
Applicant’s amendment filed 10/29/2022 is acknowledged. Claims 1-16 have been amended. Claims 22-31 have been added. Claims 1-15 and 19-21 have been cancelled. 16-18 and 22-31 are pending in the instant application and the subject of this non-final office action.
Priority
The current application claims priority to 16/465,133 as a divisional.
The definition of a divisional, as set forth in MPEP 201.06 is: “A later application for an independent or distinct invention, carved out of a nonprovisional … , an international application designating the United States, or an international design application designating the United States and disclosing and claiming only subject matter disclosed in the earlier or parent application.” The section further notes that: “A continuation-in-part application should not be designated as a divisional application.”
No restriction was identified in the family, and the claims of the instant application overlap the invention of the patent stemming from 16/465,133 (US 11,560,597 B2), as discussed in the Double Patenting section below.
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.
In response to this requirement, please provide answers to each of the following interrogatories eliciting factual information:
For each of the co-pending applications and patents identified in the non-statutory double patenting rejection below, do any ligated sequences (i.e., paired genomic DNA ranges) corresponding to the interactions and/or probes corresponding to interactions claimed have a curvature propensity peak score of at least 5 degrees per helical turn as calculated in the instant application (e.g., Fig. 2-6) for:
the claimed sequence/interaction region (i.e., if a 60 nt sequence, the entire sequence)? If so, please provide the identity of the claimed interaction/probe/sequence with the highest peak score and its curvature propensity peak score.
a total of 800 nt, wherein the 800 nt is centered around the ligation site and/or interaction site and/or probe/sequence corresponding to an interaction? If so, please provide the identity of the claimed interaction/probe/sequence with the highest peak score and its curvature propensity peak score.
It is noted that if a claimed probe/set of claimed interaction regions is not centered about the ligation site within a probe/set of regions, and this is known to the Applicant, please center the calculation about the ligation site rather than the probe/set of regions.
The timing fee and certification requirements of 37 CFR 1.97 are waived for those documents submitted in reply to the 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 where appropriate.
The applicant is reminded that the reply to this requirement must be made with candor and good faith under 37 CFR 1.56. 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.
Specification
The use of terms including but not limited to “FAM”, “Texas Red”, “JOE”, and “HEX”, each which is a trade name or a mark used in commerce, has been noted in this application. Such terms should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or have been included on an IDS form, they have not been considered.
The Information Disclosure Statements filed July 18, 2023 and December 12, 2024 have been considered.
Claim Objections
Claims 24 and 26 are objected to because of the following informalities:
Claim 24: The claim recites “an epigenetic … interactions which is specific”; “interactions” should be singular.
Claim 26: The “-“ should be removed or replaced. They may be confused with negative signs.
Appropriate correction is required.
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.
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 18, 23, and 27-29 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.
Regarding claim 18, the claim recites “calculated for up to 20 to 400 bases upstream and/or downstream of the ligation site”. No definition of “ligation site” was identified in the specification. The term, as used in parent claim 16, must be interpreted broadly enough to encompass ligation sites of claim 18 and the corresponding section of the specification (pg. 18, para 1) that recite that the ligation site may encompass sequences of a restriction enzyme recognition sequence of a restriction enzyme used to cut the crosslinked nucleic acid, including those with cut sites (where ligation would occur) distal to the recognition sequence.
However, as claim 16 does not require use of a particular restriction enzyme or other cleavage/fragmentation means, the “ligation site” is not a defined point/region. Therefore, defining a further region based upon the ligation site is not clear because the metes and bounds cannot be established by one of skill in the art.
Regarding claim 23, first, the claim recites “the restriction enzyme recognition sequence of the restriction enzyme” and “said restriction enzyme is …”. There is insufficient antecedent basis for this limitation in the claim.
Second, the claim recites “preferably said restriction enzyme is TaqI”. The term “preferably” renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention.
Regarding claim 25, the claim recites “the subgroup”. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 27, the claim recites “said probe”. Claim 27 recites “a probe which binds the ligation site during the PCR reaction”. Claim 16 recites “a probe which is detectable upon activation during a PCR reaction”. It is unclear to which of the probes “said probe” refers. For this reason, there is insufficient antecedent basis for this limitation in the claim.
Claim 28 is indefinite for depending from claim 27 and not rectifying the deficiency.
Regarding claim 28, the claim recites “an oligonucleotide … and/or … a fluorophore … and/or … a quencher … and optionally said fluorophore is selected from HEX, Texas Red and FAM”.
First, the contains the trademark/trade name “HEX”, “Texas Red”, and “FAM”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe fluorophores and, accordingly, the identification/description is indefinite.
Second, the conjunctions are set up such that the artisan may choose a fluorophore and/or quencher that is required to covalently attach to “the oligonucleotide without selecting the oligonucleotide. This is unclear.
Third, the term “optionally” renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention.
Regarding claim 29, the claim recites “preferably a length of … bases”. The term “preferably” renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention.
Claim Rejections - 35 USC § 112(d)
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.
Claims 27-28 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Regarding claims 27-28, claim 27 recites “wherein said detecting comprises … qPCR … which uses … a probe which binds the ligation site during the PCR reaction, wherein said probe comprises sequence which is complementary to sequence from each of the chromosome regions …”. Claim 16, upon which claim 27 depends, recites “method for quantitatively detecting … using a probe which is detectable upon activation during a PCR reaction … wherein said method comprises contacting the ligated sequence with the probe … and detecting the extent of activation of the probe, and wherein said probe binds the ligation site”.
Claim 27 recites a new “a probe” that binds the ligation site during the PCR reaction, where the probe of claim 27 appears to replace the probe of claim 16. For this reason, claim 27 fails to include the limitation that the probe is detectable upon activation during a PCR reaction. Therefore, claim 27 and dependent claim 28 fail to comply with the requirements of 112(d).
Regarding claim 28, the claim recites “wherein said probe comprises an oligonucleotide which specifically binds to said ligated product … or”. Claim 27, on which claim 28 depends, recites “detecting comprises specific detection…by … qPCR … us[ing] … a probe which binds the ligation site … said probe comprises sequence which is complementary to sequence from each of the chromosome regions that have come together in the chromosome interaction”.
The probe of claim 27 requires binding the ligation site, sequence complementary to each of the chromosome regions flanking the ligation site, and being part of a specific detection in qPCR. The limitation that the probe comprise an oligonucleotide that specifically binds the ligated product is already required by the complementarity of the sequence of the probe. Any length implied by “oligonucleotide” is similarity already limited by the use in qPCR.
As claim 28 sets forth the limitation as one of multiple alternatives and the oligonucleotide limitation can be selected alone, claim 28 fails to comply with the requirements of 112(d) because it fails to further limit the subject matter of the claim upon which it depends.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 16 and 22-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Akoulitchev (US 2009/0186352 A1; published 07/23/2009) in view of Davis-Taber (Davis-Taber R, et al. Molecular characterization of human SUR2-containing K(ATP) channels. Gene. 2000 Oct 3;256(1-2):261-70) and Simonis (Simonis M, Kooren J, de Laat W. An evaluation of 3C-based methods to capture DNA interactions. Nat Methods. 2007 Nov;4(11):895-901), as evidenced by Sato (Sato S. A single cleavage of Simian virus 40 (SV40) DNA by a site specific endonuclease from Thermus aquaticus, Taq I. J Biochem. 1978 Feb;83(2):633-5).
Regarding claim 16, 22, 27-29, and 31, Akoulitchev teaches a method of detecting a ligated sequence wherein the ligated sequence is formed by a method comprising cross-linking DNA which has been brough into close proximity [i.e., two gene regions, see claim 3] (claim 5); subjecting the cross-linked DNA to a restriction digesting [i.e., an enzyme; see para (0120)] ligating the digested structure (instant claim 22); and detecting the presence of the ligated sequence using a PCR reaction (claim 9). See also Fig. 6.
Akoulitchev teaches that the method may be performed in a quantitative manner in order to determine the proportion of cells of the individual that have abnormal gene expression, which may aid in the determination of a stage of a disease (para [0039]; instant claim 16).
Akoulitchev teaches that the method is performed in vitro and that the state where regions of the genome are associated in the genome of the same are epigenetic chromosomal states (para [0028]; instant claim 22).
Akoulitchev teaches that the ligated sequence may be detected using a probe such as a polynucleotide probe that binds specifically to the ligated sequence (para [0034]). Akoulitchev teaches that the probe may be 20 or 30 bases long (para [0049]; instant claim 29).
Akoulitchev teaches a method of identifying a compound for treating abnormal expression comprising determining whether a candidate substance is capable of causing the chromosome structure of the gene to change from the abnormal structure which is adopted during abnormal expression to the normal structure, to thereby determine whether the candidate substance may be capable of treating abnormal expression (para [0053]), wherein the method may be carried out on a cell or tissue that comprises the gene (para [0054]) and by administering the candidate substance and determining whether the change occurs (para [0055]).
Akoulitchev teaches analyzing frozen tissue samples from patients (para [0195]) and applying the method of detecting to a sample of an individual (claim 1).
Akoulitchev teaches that abnormal expression may lead to a disease state and will typically lead to an impairing of the viability and/or functioning of the cell or tissue or organ in which the abnormal expression occurs (para [0017]).
However, Akoulitchev fails to explicitly teach 1) that the probe is utilized during the PCR reaction and the probe binds the ligation site (instant claim 16) and 2) that a compound is administered to an individual being in need to a therapeutic agent (instant claim 31).
Davis-Taber teaches a method of quantitative PCR using real-time Taqman PCR techniques [i.e., the extent of “activation” of the probe is detected] (pg. 262, col 2, para 1) using probes that both span and do not span a known junction of the DNA amplicons (Fig. 3; see also pg. 263, 2.2. Real-time Taqman polymerase chain reaction and pg. 265, 3.3. Quantitation of mRNA levels of SUR2 exon 17 variants, spanning pg. 266). Davis-Taber teaches that the junction-spanning probe has a length of 32 nt and the other probe has a length of 30 nt, and that the sets were designed based on the complementary DNA (Table 2; instant claim 29). It is noted that the length of a probe would be a matter of routine optimization based at least on the sequence constraints of the region. See MPEP 2144.05.
Davis-Taber teaches that the Taqman probes used 5’ FAM and a 3’ quencher (pg. 263, 2.2. Real-time Taqman polymerase chain reaction; instant claim 28)
Davis-Taber teaches that by utilizing real-time Taqman PCR to examine the levels of each variant quantitatively, they could obtain a more accurate representation of the data and utilize this method to compare the relative abundance of the variants in multiple tissues (pg. 269, col 1, para 2).
Motivating reference Simonis teaches that a meaningful 3C [i.e., crosslinking of proximal DNA, digesting with RE; ligation; and quantification by PCR; see pg. 895, Common principles, spanning pg. 896] analysis relies on accurate quantification of the different ligation products (pg. 897, Final steps: PCR in 3C). Simonis teaches that measurements have to be taken when each DNA amplification is in the linear range for each different ligation product, but that utilizing standard DNA template amounts and PCR cycles is only semiquantitative and prone to inaccuracies because measurements may be taken outside of the linear range, but that this can be addressed by using TaqMan probes to improve specificity (pg. 897, Final steps: PCR in 3C, spanning pg. 898).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize the TaqMan probes of Davis-Taber in the method of Akoulitchev, motivated by the desire to obtain a more accurate representation of data when comparing relative abundance, as taught by Davis-Taber. It further would have been obvious to utilize a probe spanning the ligation site (instant claim 27). The artisan would have been so motivated to utilize a junction-spanning probe by the desire to improve specificity and/or because it would have been obvious to try both junction-spanning and not junction-spanning probes in order to address the problem of inaccurate quantification recognized in the field, as detailed by Simonis, wherein the design and outcomes of such would have been predictable given the capabilities to design and test probe/primer sets before the effective filing date. There would have been a strong expectation for success as both Akoulitchev and Simonis are concerned with quantification of DNA amplicons to determine effects on expression in tissues utilizing probes and PCR, wherein design of probes and primers are routine skills within the art. It is noted that Akoulitchev is also concerned with alternative splicing (see, e.g., para [0103]).
It is further noted that claim 16 requires that the probe binds the ligation site. The ligation site is defined as being capable of comprising a restriction enzyme recognition sequence in claim 23. Thus, the ligation site is interpreted broadly to encompass regions adjacent to sticky/blunt ends comprising recognition sequence and any intervening sequence (e.g., for shifted cleave REs). Accordingly, it is noted that a probe binding to the ligation site of claim 16 may bind only to a recognition sequence, for example, downstream of any cut/fragmentation/etc. site. As such, the binding site is subject to routine optimization based at least on the sequence content and the choice of means of cleavage/fragmentation. See MPEP 2144.05.
If further would have been obvious to the artisan before the effective filing date of the claimed invention to further combine with the method of identifying a compound for treating abnormal expression of Akoulitchev given 1) the intended use of treating abnormal expression in that method and 2) the identification of a compound of being capable of treating such an abnormal chromosome structure identified in the method of detection. The artisan would have been so motivated in order to address the impaired viability and/or functioning of the cell/tissue/organ, as taught by Akoulitchev. There would have been a strong expectation of success as Akoulitchev teaches multiple classes of compounds and means of identifying suitable ones.
Regarding claim 23, in the method of Akoulitchev in view of Sato and Simonis, Akoulitchev teaches that the ligation site of the ligated sequence comprises the reconstructed restriction enzyme recognition sequence by teaching ligation results in DNA strand ends that were formed by digestion being ligated together (para [0032] and that the restriction enzyme is TaqI (para [0120]), evidenced by Sato. While Akoulitchev does not explicitly teach that the ligation site regenerates the restriction enzyme recognition sequence, it is inherently taught because TaqI has a palindromic recognition sequence below (Sato, pg. 633). Thus, it follows that ligation of the of the sticky ends would regenerate the same sequence (instant claim 23).
PNG
media_image1.png
71
158
media_image1.png
Greyscale
Regarding claim 24-25, in the method of Akoulitchev in view of Sato and Simonis,, Akoulitchev teaches that the method may be carried out to diagnose a genetic disorder or cancer [i.e., individuals who belong to a subgroup who have a particular genetic disorder or cancer] (claim 2; instant claim 24), wherein the individual may be human (para [0024]; instant claim 25).
Regarding claim 26, in the method of Akoulitchev in view of Sato and Simonis, Akoulitchev teaches that the PCR primers will bind within 500 base pairs of each other when binding the ligated product (para [0033]).
It is noted that claim 26 only requires that the ligated sequence comprise a nucleic acid sequence of the required length; there is no requirement as to the content of nucleic acid sequence. See also MPEP 2131.03(I) regarding the anticipation of ranges. Without any cited purpose of the sequence, it is also noted that such may be a matter of routine optimization. See MPEP 2144.05.
Regarding claim 30, in the method of Akoulitchev in view of Sato and Simonis, Akoulitchev teaches that the particular regions detected by the method are on the same chromosome and are typically less than 50,000 bases apart (para [0040]).
Claim(s) 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Akoulitchev (US 2009/0186352 A1; published 07/23/2009) in view of Davis-Taber (Davis-Taber R, et al. Molecular characterization of human SUR2-containing K(ATP) channels. Gene. 2000 Oct 3;256(1-2):261-70) and Simonis (Simonis M, Kooren J, de Laat W. An evaluation of 3C-based methods to capture DNA interactions. Nat Methods. 2007 Nov;4(11):895-901) as applied to claim 16 above, and further in view of Nagy (Nagy T, et al. bend.it Server [Internet]. Jedlik Laboratories; 2016 Nov 24 [cited 2026 Jan 31]. Available from: https://web.archive.org/web/20161124090029/http://pongor.itk.ppke.hu/dna/bend_it.html).
Regarding claims 17-18, in the method of Akoulitchev in view of Sato and Simonis, Akoulitchev teaches the detection is of a loop-like structure (entire document, e.g., para [0027] and Fig. 4) and that the regions participating in a chromosome conformation may be various distances apart, wherein the association of the sequences may cause a loop/loop-like/topologically closed structure to form (para [0040]).
Akoulitchev fails to teach a particular helical turn curvature/score or conditions for calculation of such a score.
Nagy rectifies this by teaching a method of predicting of DNA curvature based on DNA sequences, wherein experimentally tested straight motifs give values below 5 degrees/turn and curved motifs produces values of 5-25 degrees per turn (Introduction, pg. 1; claim 17), i.e., that 5 degrees is the threshold for “curved”/looped DNA. Nagy instructs that a maximum on a curvature-propensity plot produced by its method within said range corresponds to “belief” that the region may adopt a curved conformation and lack thereof is indicative of rigid segments (Evaluation, pg. 1). Nagy provides an exemplary range of 210 nucleotides that would form a circle given a curvature of 18 degrees (Theory, pg. 2) and provides a default window size for curvature of 31 nt, which is also stated to be the standard segment length (The Form, pg. 2 and Theory, pg. 2; instant claim 18).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed inventions to have calculated the curvature propensity peak score for the sequences upstream and/or downstream of the ligation site using the method of Nagy in the combined method, motivated by the desire to only design probes for those sequences that are curved and therefore would be likely to be capable of participating in the DNA loop structures of Akoulitchev. There would be a strong expectation of success as Nagy is also concerned with DNA curvature, i.e., looping.
It is further noted that the particular maximum chosen and the window for which the score is calculates are matters of routine optimization given the large range for the bases upstream and/or downstream and the range provided in Nagy for curvature. See also the teachings in Evaluation, pg. 1 regarding the variability of experimentally measured values and notes on use of predicted curvature properties alone, wherein the instant disclosure recites use of the same BEND algorithm (pg. 33, Example 3, para 2; Nagy, Introduction. pg. 1).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The following claims are rejected on the ground of nonstatutory double patenting as being unpatentable over the indicated claims of the listed co-pending Applications in view of Akoulitchev (US 2009/0186352 A1; published 07/23/2009), Davis-Taber (Davis-Taber R, et al. Molecular characterization of human SUR2-containing K(ATP) channels. Gene. 2000 Oct 3;256(1-2):261-70) and Nagy (Nagy T, et al. bend.it Server [Internet]. Jedlik Laboratories; 2016 Nov 24 [cited 2026 Jan 31]. Available from: https://web.archive.org/web/20161124090029/http://pongor.itk.ppke.hu/dna/bend_it.html), as evidenced by Sato (Sato S. A single cleavage of Simian virus 40 (SV40) DNA by a site specific endonuclease from Thermus aquaticus, Taq I. J Biochem. 1978 Feb;83(2):633-5).
Application:
Instant claims rejected:
Rejected over claims:
Fails to recite:
Other notes:
17/287092
16-18 and 22-31
1-18-19, 22, 26-27, and 31
• Probe length of 10-40 nt; • Curvature score; • Therapeutic agent; • Ligated seq length; • Enzymatic cleavage
• Subgroup is human suitable for sport/training;
Table 30.A3:
SEQ ID NO: 136 (>70% claimed as probe)
• 60 nt;
• Lig. regions ~100k nt apart;
• TaqI site @ mid-point
17/609273
16-18 and 22-31
1, 21, and 23
• Probe length; • Curvature score; • RE recognition sequence or enzyme
• Subgroup is human with prostate cancer;
• Interaction (d): Lig. regions ~96k bp apart and comprise 60 nt
18/000243
16-18 and 22-31
1-18
• Curvature score
• Subgroup is fibrosis and probes are directed to human chromosomes; • Tables claimed via “interaction”;
Table 1, #2 probe (>70% claimed): •Multiple lig. regions taught, including ~55k nt apart;
• TaqI site @ mid-point;
• Interaction comprises multiple regions, incl. at least 10 nt
18/247133
16-18 and 22-31
1-11
• Curvature score; • Enzymatic cleavage
• Subgroup is muscular atrophy and probes are directed to human chromosomes;
Table 1, #1 probe:
• Multiple lig. regions taught, including ~55k nt apart;
• TaqI site @ mid-point;
• Interaction comprises multiple regions, incl. at least 10 nt
18/259908
16-18 and 22-31
1-10 and 13-32
• Curvature score; • Enzymatic cleavage
• Subgroup is a prognosis/risk class of Covid-19 outcomes and probes are directed to human chromosomes;
Table 1, #1:
• Multiple lig. regions taught, including ~119k nt apart;
• TaqI site @ mid-point;
• Interaction comprises multiple regions, incl. at least 10 nt
18/547579
16-18 and 22-31
1-15
• Curvature score; • Enzymatic cleavage
• Subgroup is a response class and/or hyperprogressor class for immunotherapy and probes are directed to human chromosomes;
Table 2, #6:
• Multiple lig. regions taught, including ~58k nt apart;
• TaqI site @ mid-point;
• Interaction comprises multiple regions, incl. at least 10 nt
As cited and discussed in the 103 above, Akoulitchev teaches or suggests:
enzymatic digestion of ligated nucleic acids, including by TaqI (instant claim 22), wherein the TaqI site has a recognition sequence of TCGA, evidenced by Sato, which has been identified in probes/interactions above;
probe length (instant claim 29); and
administering a therapy based on the method (instant claim 31).
Additionally, Akoulitchev teaches that ligated product sizes may vary based on at least the restriction site chosen by the enzyme during digestion (para [0132]).
Akoulitchev teaches that its method enables detection or diagnosis of abnormal gene expression of an individual (para [0006]) and that it has identified several markers including a previously unknown one implicated in transcriptional regulation (para [0089]).
Akoulitchev teaches that abnormal expression may lead to a disease state and will typically lead to an impairing of the viability and/or functioning of the cell or tissue or organ in which the abnormal expression occurs (para [0017]).
As cited and discussed in the 103 above, Davis-Taber teaches:
quantitative PCR with probes spanning a junction (instant claims 16 and 27).
Davis-Taber teaches that by utilizing real-time Taqman PCR to examine the levels of each variant quantitatively, they could obtain a more accurate representation of the data and utilize this method to compare the relative abundance of the variants in multiple tissues (pg. 269, col 1, para 2).
As cited and discussed in the 103 above, Akoulitchev and Nagy teach:
chromosome interactions result from loop-like structures (instant claims 17-18); and
that curved DNA has a curvature propensity peak score of at least 5 degrees per helical turn and that such a score may be calculated for about 30 or about 200 nt (instant claims 17-18).
Nagy teaches that a maximum on a curvature-propensity plot produced by its method within said range corresponds to “belief” that the region may adopt a curved conformation and lack thereof is indicative of rigid segments (Evaluation, pg. 1).
Where enzymatic cleavage isn’t explicitly taught, utilizing enzymatic cleavage would have been obvious, at least in view of Akoulitchev. The artisan would have been so motivated by a desire to identify unknown transcriptional markers, as taught by Akoulitchev or because enzymatic cleavage is known and predictable species of cleavage. See MPEP 2144.08, Akoulitchev, and Sato. There would have been a strong expectation of success as the probes/interactions of the inventions each teach at least the restriction enzyme recognition sequence of TaqI, wherein it would such would be expected to be present in the ligation site to which a probe binds.
Where PCR, probes, and/or quantitative PCR using probes spanning ligation points is not explicitly taught, such would have been an obvious species of detection of the interactions claimed inventions and/or combined methods, at least in view of Davis-Taber. The artisan would have been so motivated by the desire to obtain a more accurate representation of the data and to enable the ability to compare relative abundance of the probes/interactions in multiple sample types/tissues/individuals, as taught by Davis-Taber. There would have been a strong expectation for success as the probes or sequences that have been defined as probes are taught by the claims of the inventions and the artisan would be able to further optimize for qPCR in view of Davis-Taber. It is noted that each of the probes described is interpreted given the defined probe name or explicitly defined in the tables of the specification to span a ligation point. MPEP 804(II)(B)(1) states that the specification may be used as a dictionary to learn the meaning of term and the scope of the reference claims in NSDP rejections; in this case, it was used to determine where the probes bind and/or the locations of the interactions claimed and the scope to the human genome.
Given the teachings of Akoulitchev and Nagy, it would be expected that each of ligated sequences represented by the probes/interactions of the claimed inventions and/or combined method above would have a curvature propensity peak score of at least 5 degrees per helical turn, indicating a curvature of the DNA, thereby enabling DNA looping rather than a rigid conformation, as taught by Nagy. If the Applicant answers in the affirmative to the Request for Information, such would also be a matter of an inherent property of the claimed probes/interactions. It would be obvious to calculate the score for regions of about 30 or about 200 bases, wherein such would also be a matter of routine optimization given the ability to change the window size, to choose different cleave means if optimizing for ability to participate in ligation instead, etc. There would have been a strong expectation of success as Nagy is directed toward circular DNA and the claims circularize DNA via cross-linking.
Where treatment with a therapeutic agent isn’t taught, such would have been obvious in the combined method in view of Akoulitchev given 1) the intended use of treating abnormal expression in that method and 2) the identification of a compound of being capable of treating such an abnormal chromosome structure identified in the method of detection. The artisan would have been so motivated in order to address the impaired viability and/or functioning of the cell/tissue/organ, as taught by Akoulitchev. There would have been a strong expectation of success as Akoulitchev teaches multiple classes of compounds and means of identifying suitable ones.
Further, given at least the teachings of Akoulitchev on RE cleavage, the nucleic acid encompassed by the ligated sequence is determined to be a matter of routine optimization based on the chosen means of cleavage, length of digestion, choice of enzyme, etc. See MPEP 2144.05.
Any additional limitations of the co-pending claims are encompassed by the open claim language “comprising” found in the instant claims.
The following claims are rejected on the ground of nonstatutory double patenting as being unpatentable over the indicated claims of the listed U.S. Patents in view of Akoulitchev (US 2009/0186352 A1; published 07/23/2009), Davis-Taber (Davis-Taber R, et al. Molecular characterization of human SUR2-containing K(ATP) channels. Gene. 2000 Oct 3;256(1-2):261-70) and Nagy (Nagy T, et al. bend.it Server [Internet]. Jedlik Laboratories; 2016 Nov 24 [cited 2026 Jan 31]. Available from: https://web.archive.org/web/20161124090029/http://pongor.itk.ppke.hu/dna/bend_it.html), as evidenced by Sato (Sato S. A single cleavage of Simian virus 40 (SV40) DNA by a site specific endonuclease from Thermus aquaticus, Taq I. J Biochem. 1978 Feb;83(2):633-5).
Patent:
Instant claims rejected:
Rejected over claims:
Fails to recite:
Other notes:
11,434,522 B1
16-18 and 22-31
1-5
• Probe length of 10-40 nt; • Curvature score
• Subgroup is a predisposition class for ALS;
• Treatment is human;
• PCR or probe;
Probe SEQ ID NO: 716 (>70% claimed):
• 60 nt;
c
• Lig. regions ~50k nt apart;
• TaqI site @ mid-point
11,535,893 B2
16-18 and 22-31
1
• Curvature score; • PCR or probes
• Subgroup is human in need of Alzheimer’s therapy
11,560,597 B2
16-18 and 22-31
1-6
• Curvature score
• Subgroup is chromosome interaction and/or classes of claim 4 and probes correspond to human chromosomes;
Table 4, SEQ ID NO: 26:
• Interaction regions ~920k apart
• TaqI site @ 7 nt;
• Amplicon defined by corresponding primers >10 nt
11,746,378 B2
16-18 and 22-31
1-3
• PCR (but teaches fluor and/or quencher on probe); • Curvature score; • Enzymatic cleavage
• Subgroup is human in need of breast cancer therapy;
Table of Fig. 22 C (3rd seq)/probe SEQ ID NO:109:
• 60 nt;
• Lig. regions ~45k nt apart;
• TaqI site @ mid-point
11,840,737 B2
16-18 and 22-31
1-4
• Curvature score; • Enzymatic cleavage
• Subgroup is class of human responsive to immunotherapy;
Table 4 probe SEQ ID NO: 362:
• 60 nt;
• Lig. regions ~58 nt apart;
• TaqI site @ mid-point
12,006,547 B2
16-18 and 22-31
1-2
• Curvature score; • Enzymatic cleavage
• Subgroup is human in need of therapy for ALS;
Table 1 probe SEQ ID NO: 2:
• 60 nt;
• Lig. regions ~117k nt apart;
• TaqI site @ mid-point
For ‘893, it is noted that the scope of detection in the claims encompasses detection by PCR (col 5, lines 28-34) and that the presence or absence can be represented by specific primers and/or probe sequences disclosed (col 9, para 3), wherein claimed SEQ ID NO: 8 is defined to be a probe in Table 2. Therefore, the detection of ‘893 encompasses the genus of detection with PCR using probe and such could have been claimed in ‘893. See further discussion below.
As cited and discussed in the 103 above, Akoulitchev teaches:
enzymatic digestion of ligated nucleic acids, including by TaqI (instant claim 22), wherein the TaqI site has a recognition sequence of TCGA, evidenced by Sato, which has been identified in probes/interactions above; and
probe length (instant claim 29).
Additionally, Akoulitchev teaches that ligated product sizes may vary based on at least the restriction site chosen by the enzyme during digestion (para [0132]).
Akoulitchev teaches that its method enables detection or diagnosis of abnormal gene expression of an individual (para [0006]) and that it has identified several markers including a previously unknown one implicated in transcriptional regulation (para [0089]).
As cited and discussed in the 103 above, Davis-Taber teaches:
quantitative PCR with probes spanning a junction (instant claims 16 and 27).
Davis-Taber teaches that by utilizing real-time Taqman PCR to examine the levels of each variant quantitatively, they could obtain a more accurate representation of the data and utilize this method to compare the relative abundance of the variants in multiple tissues (pg. 269, col 1, para 2).
As cited and discussed in the 103 above, Akoulitchev and Nagy teach:
chromosome interactions result from loop-like structures (instant claims 17-18); and
that curved DNA has a curvature propensity peak score of at least 5 degrees per helical turn and that such a score may be calculated for about 30 or about 200 nt (instant claims 17-18).
Nagy teaches that a maximum on a curvature-propensity plot produced by its method within said range corresponds to “belief” that the region may adopt a curved conformation and lack thereof is indicative of rigid segments (Evaluation, pg. 1).
Where enzymatic cleavage isn’t explicitly taught, utilizing enzymatic cleavage would have been obvious, at least in view of Akoulitchev. The artisan would have been so motivated by a desire to identify unknown transcriptional markers, as taught by Akoulitchev or because enzymatic cleavage is known and predictable species of cleavage. See MPEP 2144.08, Akoulitchev, and Sato. There would have been a strong expectation of success as the probes/interactions of the inventions each teach at least the restriction enzyme recognition sequence of TaqI, wherein it would such would be expected to be present in the ligation site to which a probe binds.
Where PCR, probes, and/or quantitative PCR using probes spanning ligation points is not explicitly taught, such would have been an obvious species of detection of the interactions claimed and/or combined methods, at least in view of Davis-Taber. The artisan would have been so motivated by the desire to obtain a more accurate representation of the data and to enable the ability to compare relative abundance of the probes/interactions in multiple sample types/tissues/individuals, as taught by Davis-Taber. There would have been a strong expectation for success as the probes or sequences that have been defined as probes are taught by the claims of the inventions and the artisan would be able to further optimize for qPCR in view of Davis-Taber. It is noted that each of the probes described is interpreted given the defined probe name or explicitly defined in the tables of the specification to span a ligation point. MPEP 804(II)(B)(1) states that the specification may be used as a dictionary to learn the meaning of term and the scope of the reference claims in NSDP rejections; in this case, it was used to determine where the probes bind and/or the locations of the interactions claimed and the scope to the human genome.
Given the teachings of Akoulitchev and Nagy, it would be expected that each of ligated sequences represented by the probes/interactions of the claimed inventions and/or combined methods would have a curvature propensity peak score of at least 5 degrees per helical turn, indicating a curvature of the DNA, thereby enabling DNA looping rather than a rigid conformation, as taught by Nagy. If the Applicant answers in the affirmative to the Request for Information, such would also be a matter of an inherent property of the claimed probes/interactions. It would be obvious to calculate the score for regions of about 30 or about 200 bases, wherein such would also be a matter of routine optimization given the ability to change the window size, to choose different cleave means if optimizing for ability to participate in ligation instead, etc. There would have been a strong expectation of success as Nagy is directed toward circular DNA and the claims circularize DNA via cross-linking.
Further, given at least the teachings of Akoulitchev on RE cleavage, the nucleic acid encompassed by the ligated sequence is determined to be a matter of routine optimization based on the chosen means of cleavage, length of digestion, choice of enzyme, etc. See MPEP 2144.05.
Any additional limitations of the reference patent claims are encompassed by the open claim language “comprising” found in the instant claims.
Conclusion
No claims are allowed.
This Office action has an attached requirement for information under 37 CFR 1.105. A complete reply to this Office action must include a complete reply to the requirement for information above. The time period for reply to the attached requirement coincides with the time period for reply to this Office action.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Lei (US 20090117076 A1; published 05/07/2009; as cited in the IDS dated 07/18/2023) teaches treating tumor cells with a targeted therapy in combination with an immunotherapy (Abstract), wherein targeted treatment is selected from antibodies (para [0007]).
It is noted that Akoulitchev teaches the candidates in the method of identifying treatments comprising antibody agents (para [0056]) and that the method may diagnose cancer (claim 1), i.e., the individual may have cancer.
De Laat (US 20070231817 A1; published 10/04/2007) teaches a method of providing a sample of cross-linked DNA; digesting the cross-linked DNA with a primary restriction enzyme; ligating the cross-linked nucleotide sequences; amplifying; and hybridizing the amplified sequence(s) to an array (Abstract). De Laat teaches a set of probes complementary in sequence to the nucleic acid sequence adjacent to each primary restriction enzyme recognition site in genomic DNA (claim 18; see also claim 23: 0 bp from each of the recognition site of a primary restriction enzyme) and wherein there may be two or more probes capable of hybridizing to the sequence (claim 24). Fig. 2c teaches a schematic of two probes adjacent to the ligation point, wherein it is taught that each probe analyzes a possible ligation partner (para [0110]).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Emma R Hoppe whose telephone number is (703)756-5550. The examiner can normally be reached Mon - Fri 11:00 am - 7:00 pm.
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.
/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636