DETAILED ACTION
This action is in reply to papers filed 03/16/2026.
Claims 1, 3, 10, 13, 19-23, and 25-29 are pending and examined herein.
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 .
Election/Restrictions
Applicant previously elected Group 2, drawn to claims 1, 3, 7, 9, 10, 13, 17, and 19-29, without traverse in the reply filed on 10/08/2025.
Claims 4 and 6 are withdrawn from consideration as being drawn to a non-election invention.
Withdrawn Objection(s) and Rejection(s)
The objection to the disclosure is withdrawn in light of the substitute specification, which inserts the required incorporation-by-reference paragraph and deletes the embedded hyperlink and/or other form of browser-executable code.
The objections to claims 1 and 22 regarding minor informalities are withdrawn in light of the amendment to the claims.
The rejection of claims 20 and 23 under 35 U.S.C. 112(b) regarding the recitation of the phrase “administering one or more different therapies” is withdrawn in light of the amendment to the claims to strike said phrase.
The rejection of claim 29, which depends from claim 1, under 35 U.S.C. 112(b) regarding a lack of antecedent basis for the limitation "the ASMC" is withdrawn in light of the amendment to claim 1.
The rejection of claims 1, 3, 10, 13, 22, and 25-29 are rejected under 35 U.S.C. 103 over Lande (WO 2018/049073 A1) is withdrawn in light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17.
The rejection of claim 19 under 35 U.S.C. 103 over Lande (WO 2018/049073 A1), in view of Sanborn (PNAS, 2015, 112(47): E6456-E6465), is withdrawn in light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17.
The rejection of claim 20 under 35 U.S.C. 103 over Lande (WO 2018/049073 A1), in view of Sanborn (PNAS, 2015, 112(47): E6456-E6465) and Ahituv (WO 2018/148256 A1), is withdrawn in light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17.
The rejection of claim 23 under 35 U.S.C. 103 over Lande (WO 2018/049073 A1), in view of Ahituv (WO 2018/148256 A1), is withdrawn in light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17.
The rejection of claim 24 under 35 U.S.C. 103 over Lande (WO 2018/049073 A1), in view of Zhao (Cell Reports, 2016, 14(2): 2872-2888), is withdrawn in light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17.
The cancellation of claims 7, 9, 17, and 24 renders any rejections thereof moot.
Claim Interpretation
The term “disrupting agent” is not defined in the specification. The specification does recite that “In general, a modulating (e.g., disrupting) agent as described herein interacts with its target component of a genomic complex” (p 60, lines 22-23). In the absence of a definition, “disrupting agent” is given its broadest reasonable interpretation, which in the context of claim 1, is a composition that disrupts a genomic complex.
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 1, 3, 7, 9, 10, 13, 17, and 19-29 remain 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 1 recites the phrase “wherein the genomic complex has an integrity index (IntIndi) calculated by Formula 2” (lines 5-6). This phrase does not recite an active step, and therefore it is unclear whether the calculation of IntIndi is meant to be performed as part of the method of claim 1, or whether the IntIndi value is merely imposing a structural limitation on the genomic complex.
Furthermore, in the equation set forth in Formula 2 (line 7 of claim 1), it is unclear what is meant by “95th percentile frequency of all genomic complexes within cell sample” in the denominator. The specification recites that “In some embodiments, the normalization factor is the 95th percentile frequency of incidence of all genomic complexes (e.g., ASMCs) in the cell population (e.g., as seen in Formula 2 and measured by the method of Example 2)” (p 49, lines 26-28). However, Example 2 utilizes Formula 3 to obtain IntIndi (p 190, starting at line 25). The specification recites that “Formula 3 is similar to formula 2 above, but uses the base-2 logarithm of the number of PETs [paired end tags] supporting the loop, and uses a normalization factor that is the 99th percentile of the base-2 logarithm of the number of PETs supporting any single loop” (p 191, lines 11-13). Even in light of this description, it is unclear how one obtains a “95th percentile frequency of all AMSCs within cell sample” as required by claim 1, as opposed to, for example, a 95th percentile of paired-end tags from a sequencing library as demonstrated in Example 2.
Therefore, the metes and bounds of claim 1 remain unclear. Claims 3, 10, 13, 19-23, and 25-29 depend from claim 1, and therefore inherit its deficiencies.
Claim 21, which depends from claim 1, recites the limitation “the IntIndi calculated by Formula 2 in a cell of the subject” (lines 2-3). Amended claim 1 recites “wherein the genomic complex has an integrity index (IntIndi) calculated by Formula 2” (lines 5-6), implying that the integrity index is a property of a genomic complex, not a cell as a whole. Therefore, the metes and bounds of claim 21 are unclear.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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.
Examiner’s note: Claims 17 and 21 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. In light of the amendment to claim 1 to incorporate the limitations of cancelled claim 17, the rejection is now applied to claim 21 and claim 1 and its dependent claims, as set forth below.
Claims 1, 3, 10, 13, 19-23, and 25-29 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
The Nature of the Invention: The inventive concept in the instant application is a method of disrupting a genomic complex in a mammalian subject by administration of a disrupting agent targeted to the genomic complex, wherein the genomic complex has an IntIndi as measured by Formula 2 of between 0.5-1, and: wherein the administration of the disrupting agent reduces the IntIndi in a cell of the subject by at least 0.1 (claim 1) or, wherein one or more additional doses of the disrupting agent is administered to the subject until the IntIndi is less than 0.4, 0.3, 0.2, or 0.1 (claim 21).
Amount of Direction Provided by Inventor/Working Examples: The specification discloses three examples, but none of the examples teach a method of disrupting a genomic complex in a mammalian subject by administering to the mammalian subject a disrupting agent targeted to the genomic complex, as required by the instant claims. Example 1 shows the calculation of specificity index in a panel of cell lines (p 138-189), Example 2 shows the calculation of specificity index (p 189-194), and Example 3 shows the calculation of integrity index of selected genes (p 194-195).
There are several issues to note. First, none of these examples teaches the claimed invention, which is drawn to a method of disrupting a genomic complex in a mammalian subject by administering a disrupting agent to the genomic complex, let alone the reduction of the integrity index of the genomic complex as a result of administering the disrupting agent. As the claims require a specific effect (i.e., reduction of the integrity index by the presence of the disrupting agent), evidence showing this effect is required. Furthermore, although Examples 2 and 3 show the calculation of specificity index, these examples use Formula 3, not Formula 2 as claimed, to arrive at the specificity index.
Second, all descriptions pertaining to the method of reducing the integrity index of a genomic complex are recitations of embodiments, not working examples. For example, the specification states that “In some embodiments, a modulating agent (e.g., disrupting agent) decreases the integrity index of a targeted genomic complex (e.g., ASMC) by at least 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, or 0.9 (and optionally less than 1, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, or 0.5)” (p 63, para 1), but does not teach how this effect is achieved. This is problematic as Applicant is claiming a method of decreasing the integrity index of a targeted genomic complex by administration of a disrupting agent.
Furthermore, there is no guidance in the specification as to how different species of disrupting agents may differ in reducing the integrity index of the targeted genomic complex. The specification also lacks guidance on experimental conditions that may affect the reduction in the value of the integrity index. For example, no guidance is provided as to whether the magnitude of the change in integrity index depends on the type of disrupting agent used, mode of delivery, or dosage used.
The State of the Prior Art: The closet prior art, Lande (WO 2018/049073 A1), teaches site-specific disrupting agents that disrupt and/or modify anchor-sequence mediated conjunctions (ASMC; reads on genomic complex), by physical, genetic, or epigenetic means (p 1, Summary, para 1), and methods of delivering a site-specific disrupting agent to a mammalian cell (p 2, para 2 – p 4, para 3; p 118 - 165). However, Lande is silent regarding the integrity index of the targeted ASMCs. Furthermore, Lande does not exemplify or reduce to practice administering a genomic complex to a mammalian subject. Therefore, Lande cannot be relied upon to determine how the reagents and conditions disclosed therein should be adjusted to achieve the claimed effects of instant claims 1 and 21.
The level of Predictability in the Art/Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the large quantity of experimentation necessary to determine the effect of the administration of a disrupting agent on the integrity index of the genomic complex, including the type of disrupting agent used and species of mammalian subject, the state of the art which establishes a lack of effect of a disrupting agent delivered in vivo on the integrity index of a genomic complex, and the lack of guidance or evidence in the specification in achieving the claimed effect by the administering of a disrupting agent to a genomic complex, it would have required undue experimentation for one skilled in the art at the time of the invention to carry out the claimed invention. Therefore, the methods of claims 1 and 21 are not enabled. Claims 3, 10, 13, 19-23, and 25-29 are included in the rejection because they depend from claim 1, and therefore inherit its deficiencies.
Response to Arguments
Rejections under 35 U.S. C § 112(b)
Regarding the phrase “wherein the genomic complex has, or is identified as having, an Intlndi measured by Formula 2” in claim 1:
Applicant argues: Without assenting to the propriety of the rejection, and solely to expedite prosecution, Applicant has amended claim 1 to remove the recitation of "is identified as having" in the claim. Thus, amended claim 1 now recites, in pertinent part, "wherein the genomic complex has an integrity index" (emphasis added). Thus, the claim is clear in defining how the integrity index is related to the genomic complex. Further, Applicant has amended claim 1 to recite, in pertinent part, that the Intlndi is "calculated by Formula 2". The skilled artisan would thus clearly understand how Formula 2 is used to identify Intlndi in amended claim 1 and would further recognize that the Intlndi of the genomic complex imposes a limitation on what genomic complexes may be targeted by a disrupting agent according to the claimed method.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Although the relationship between the genomic complex and integrity index is clear in amended claim 1 (i.e., that the integrity index is an inherent property of the genomic complex), the phrase “wherein the genomic complex has an integrity index (IntIndi) calculated by Formula 2” (lines 5-6 of claim 1) does not recite an active step but does recite a passive verb (“calculated by Formula 2”), and therefore, it is unclear whether the calculation of IntIndi is meant to be performed as part of the method of claim 1, or whether the IntIndi value is merely imposing a structural limitation on the genomic complex.
Regarding the phrase “95th percentile frequency of all genomic complexes (e.g., ASMCs) within cell sample” in claim 1:
Applicant argues: Without assenting to the propriety of the rejection, and solely to expedite prosecution, Applicant has amended claim 1 to recite, in the denominator of Formula 2, "95th percentile
frequency of all ASMCs within cell sample". The specification as filed provides clear guidance to the skilled artisan in how to calculate the integrity index according to Formula 2. On page 49, lines 21-26, of the specification as filed, it is stated that "[i]n some embodiments, the integrity index of a target genomic complex ( e.g., ASMC) is the lower of: i) a ratio of the frequency of incidence of a target genomic complex (e.g., ASMC) in a cell population to a normalization factor; or ii) 1, where that normalization factor is a high percentile value (e.g., 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99th percentile) of the frequency of incidence of all genomic complexes ( e.g., ASMCs) in the cell population (e.g., the integrity index as determined by Formula 2)." The specification further provides examples of experimental techniques to measure the frequency of incidence of a genomic complex (e.g., ASMC). The specification further states, at page 50, lines 1-3, that "[t]he frequency of incidence of a genomic complex (e.g., ASMC) in a cell population may be measured, e.g., by an experimental technique such as ChIA-PET, HiChIP, HiC, or 4C-seq." Thus, the specification provides details on how to experimentally measure the values used in Formula 2 and explains how to use them in Formula 2. Based on at least the descriptions in the specification as well as common knowledge in the art at the time of filing, the skilled artisan would have no trouble understanding the metes and bounds of the claim.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Although the specification does recite "[i]n some embodiments, the integrity index of a target genomic complex ( e.g., ASMC) is the lower of: i) a ratio of the frequency of incidence of a target genomic complex (e.g., ASMC) in a cell population to a normalization factor; or ii) 1, where that normalization factor is a high percentile value (e.g., 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99th percentile) of the frequency of incidence of all genomic complexes ( e.g., ASMCs) in the cell population (e.g., the integrity index as determined by Formula 2)" on page 49, lines 21-26, it is still unclear how said normalization factor (i.e., the denominator in Formula 2 of claim 1) is calculated. Furthermore, although the specification further states, at page 50, lines 1-3, that "[t]he frequency of incidence of a genomic complex (e.g., ASMC) in a cell population may be measured, e.g., by an experimental technique such as ChIA-PET, HiChIP, HiC, or 4C-seq,” it remains unclear how a “95th percentile frequency of all AMSCs within cell sample” is calculated from the dataset of the aforementioned experimental techniques. It is noted that the basis of the rejection is not over the recitation of Formula 2, per se, but specifically regarding the phrase “95th percentile frequency of all ASMCs within cell sample” in the denominator of Formula 2.
Rejections under 35 U.S. C § 112(a)
Applicant argues: First, with respect to the Examiner's contention that "none of [the] examples teaches the claimed invention," and "[a]s the claims require a specific effect, evidence showing this effect is required", Applicant respectfully notes that a working example is not required to satisfy the enablement requirement. As stated in MPEP § 2164.02, "[t]he specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation." Here, the specification provides extensive guidance enabling the preparation and selection of suitable disrupting agents to achieve the claimed effect in a mammalian subject. For example, the specification describes various exemplary targeting moieties, including CRISPR/Cas molecules (see, e.g., pages 73-76 of the specification as filed), TAL effector molecules (see, e.g., pages 76-79 of the specification as filed), and Zn Finger molecules (see, e.g., pages 79-82 of the specification as filed). The specification as filed additionally provides ample description of various effector moieties, including genetic moieties and epigenetic modifying moieties as well as their uses and mechanisms (see, e.g., pages 82-101). Based at least on the teachings in the specification as filed and common knowledge in the art at the time of filing, a person of skill in the art would have no difficulty
selecting an appropriate disrupting agent for use within the claimed scope without undue experimentation.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). In the instant case, undue experimentation is required to carry out the method of claims 1 and 21, as set forth in the body of the rejection above.
Applicant argues: Further, the specification as filed provides extensive description explaining how to measure an integrity index as well as how disrupting agents reduce the integrity index of an ASMC. For example, the specification states that, "[i]n some embodiments, a modulating agent (e.g., disrupting agent) decreases the integrity index of a targeted genomic complex (e.g., ASMC) by at least 0.01 ... or 0.9." Examples 2 and 3 in the application demonstrate how to calculate integrity index of seven
different genes in the Gm 12878 cell line, using Formula 3 together with ChIA-PET and Hi-ChIP methodologies as representative methodologies. Additionally, information on how dosing and modes of delivery may be selected is provided at, for example, pages 113 and 114 of the specification as filed. These disclosures, in combination with general knowledge in the art, would sufficiently enable the skilled artisan to practice the claimed method without undue experimentation.
In response: Applicant’s arguments have been fully considered, but are not persuasive. Although the specification does state that "[i]n some embodiments, a modulating agent (e.g., disrupting agent) decreases the integrity index of a targeted genomic complex (e.g., ASMC) by at least 0.01 ... or 0.9,” as asserted by Applicant, undue experimentation is required to carry out this embodiment or the method of claim 1. Furthermore, pages 113 and 114 of the specification provide information on examples of pharmaceutically acceptable carriers, salts, excipients, and preparations. The specification does not provide information on how to select dosing and modes of delivery to achieve the effect of reducing the integrity index of the AMSC by at least 0.1, as required by instant claim 1, or to reduce the integrity index to less than 0.4, 0.3, 0.2, or 0.1, as required by instant claim 21.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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, Peter Paras can be reached at (571) 272-4517. 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.
/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
Prosecution Insights