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 .
Claims and Previous Objections/Rejections Status
Claims 353,355-371,373-376 and 378-388 are pending in the application. Claims 358-361 and 379-383 are withdrawn from consideration. Claim 388 is newly added in the amendment filed 12/23/25.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Maintained Rejections
Response to Arguments
Applicant's arguments filed 12/23/25 have been fully considered but they are not persuasive.
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 rejection of claims 353,355,371 and 385 provisionally rejected on the ground of
nonstatutory double patenting as being unpatentable over claims 34,41 and 48 of copending Application No. 18/038,943 is maintained.
Applicant requests that the nonstatutory double patenting rejection be held in abeyance until allowable subject matter is determined.
The rejection is not held in abeyance and is maintained.
The rejection of claims 353,355-357,362 and 378 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,2,5,7,19,20 and 61-63 of copending Application No. 17/761,545 is maintained.
Applicant requests that the nonstatutory double patenting rejection be held in abeyance until allowable subject matter is determined.
The rejection is not held in abeyance and is maintained.
Response to Arguments
Applicant’s arguments, see REMARKS, filed 12/23/25, with respect to the rejection(s) of claim(s) 353,355-357,369,376,378 and 386 under 35 U.S.C. 102(a)(1) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Monahan et al. (The EMBO Journal (2017) 36: 2951-2967) and a new ground(s) of rejection is made in view of Napoli et al. (The EMBO Journal (2009) 28, 1708-1719) in view of Sanders et al. (Biochim. Biophys Acta 1743 (2005) 141-150) and Mijatovic et al. (Mol Cancer Ther (2008) 7 (5): 1285-1296).
New Grounds of Rejection
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 353,355-357,364-367,373,375,378,386 and 388 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Monahan et al. (The EMBO Journal (2017) 36: 2951-2967).
Monahan et al. (The EMBO Journal (2017) 36: 2951-2967) teaches that FUS (RNA-binding
protein fused in sarcoma) comprises liquid droplets (p2956, left column, third paragraph).
Previous examination showed that the addition of stoichiometric amounts of RNA enhanced liquid-liquid phase separation (LLPS) of wild-type FUS. (p2956, left column, second paragraph).
The RNA anticipates the test agent, such as RNA of the instant claims.
The FUS liquid droplets LLPS anticipate the a condensate of the instant claims.
The FUS anticipates a component in a condensate of the instant claims and the signaling factor of the instant claim 355.
The enhanced LLPS anticipates the test agent alters or disrupts an interaction between a condensate and a second component of the condensate of the instant claim 364 as LLPS is where molecules self-segregate (demix) to form two co-existing liquids into which other molecules can
partition and localize their cellular functions (p2951, right column, last paragraph; p2952, left column,
first paragraph).
The LLPS of wild-type FUS anticipates the condensate component becomes sequestered in a
second condensate after contacting with the test agent of the instant claim 365 and changes the normal
location of the condensate component of the instant claim 373.
The addition of RNA to full length FUS 6E and 12E disrupted LLPS (p2956, left column, second paragraph).
The disruption of LLPS was observed by differential interference contrast (DIC) microscopy
(p2956, left column, second paragraph) that anticipates the microscopy of the instant claims.
The examination of the phase separation of full length FUS, 6E and 12E involved monitoring changes in morphology of protein assemblies over longer periods of time or with orbital agitation via
DIC microscopy with and without RNA (p2956, left column, third paragraph).
The FUS 6E and 12E anticipate the condensate component has a mutation of the instant claim
356.
The monitoring changes in morphology anticipates modulation of one or more properties, such as composition of the instant claims.
Monahan et al. further hypothesized that phosphorylation could disrupt FUS self-association and aggregation by altering the biophysical properties (p2954, Phosphorylation and phosphomimetic variants reduce FUS LC phase separation and aggregation; p2954, right column, second paragraph).
DNA-PK is able to phosphorylate all S/TQ positions in the FUS LC (p2952, FUS LC is multiply phosphorylated by DNA-PK; p2953, left column, first paragraph) that anticipates phosphorylation of the component in the condensate of the instant claim 386.
The DNA-PK anticipates the test agent, such as DNA of the instant claims.
The method involves evaluating the phase separation of wild-type FUS LC (with and without
DNA-PK treatment) and FUS LC 12E via DIC microscopy (p2954, right column, second paragraph) that anticipates microscopy of the instant claims.
The wild-type FUS LC incubated for 1 day undergoes LLPS to form round micron sized droplets (p2954, right column, second paragraph) that anticipates the condensate of the instant claims.
The FUS anticipates the component in a condensate of the instant claims and a signaling factor of the instant claim 355.
Dramatic morphological differences emerged within day 1 of incubation (p2956, left column, last paragraph) that anticipates the modulation of one or more properties, such as formation or composition of the instant claims.
The LLPS to form round micron sized droplets anticipates the test agent alters or disrupts an
interaction between a condensate and a second component of the condensate of the instant claim 364 as LLPS is where molecules self-segregate (demix) to form two co-existing liquids into which other molecules can partition and localize their cellular functions (p2951, right column, last paragraph; p2952, left column, first paragraph).
DIC of the LLPS of wild-type FUS LC anticipates assessing whether the wild-type version is
sequestered in the condensate of the instant claim 375.
Neuronal inclusion of aggregated RNA-binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes (abstract) and therefore the LLPS of wild-type FUS LC anticipates the condensate sequesters a component associated with a disease of the instant claim 366.
FUS subtypes of ALS are most often caused by mutations in the FUS nuclear localization signal (abstract; p2959, Phosphomimetic substitutions in FUS LC reduce aggregation propensity in cells) that
anticipates the mutation is associated with or characterizes a disease or condition of the instant claim
357 and the mutant version of a wild type protein of the instant claim 367.
The method of the disclosure further involves mapping in-cell phosphorylation sites
across FUS LC (abstract; p2953, left column) that anticipates contacting a cell of the instant claim 365 and imaging the cell of the instant claim 388.
DIC microscopy of FUS LC without DNA-PK treatment (p2954, right column, second paragraph) anticipates imaging a cell in the absence of the test agent of the instant claim 378.
Cytoplasmic FUS gain-of-function toxicity arises from sequestration of RNA into inclusions
(p2963, right column, first full paragraph) that anticipates a condensate component is sequestered of the instant claims.
Claim(s) 353,355,362-367,369-371,376,384 and 385 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Napoli et al. (The EMBO Journal (2009) 28, 1708-1719) in view of Sanders et al. (Biochim. Biophys Acta 1743 (2005) 141-150) and Mijatovic et al. (Mol Cancer Ther (2008) 7 (5): 1285-1296).
Napoli et al. (The EMBO Journal (2009) 28, 1708-1719) teaches that promoter-targeted siRNA inhibits transcription of the c-myc gene (abstract). The c-Myc is a transcription factor (p1708, right column, second paragraph).
The siRNA anticipates the test agent, such as RNA of the instant claims.
The c-Myc transcription factor anticipates the transcription factor Myc of the instant claims 362 and 363.
Sanders et al. (Biochim. Biophys Acta 1743 (2005) 141-150) teaches that c-Myc is largely
localized to the nucleolus and is present in nucleolar extracts (abstract). The nucleolus sequesters c-Myc
(abstract; p146, 3.2 and 3.3).
Mijatovic et al. (Mol Cancer Ther (2008) 7 (5): 1285-1296) teaches that several tumor suppressors and oncoproteins, such as MYC are sequestered in nucleoli of tumor cells and suggests a cancer-related role for nucleoli that goes beyond protein synthesis. Compounds that selectively target perturbations in the organization of nucleolar machinery represent new means of anticancer therapy (p1286, left column, first paragraph).
The Myc of Napoli et al. anticipates the component of a condensate of the instant claims as c-Myc is largely localized to the nucleolus (e.g. condensate) wherein the Myc is sequestered in the nucleoli
of tumor cells.
Napoli et al. teaches that c-Myc is one of the most frequently over-expressed genes in human cancers (p1709, Inhibition of c-myc expression by promoter-targeted siRNAs) and is an oncogenic transcription factor (p1709, Inhibition of c-myc expression by promoter-targeted siRNAs) that anticipates the transcription factor of the instant claim 355.
The Myc over-expressed genes in human cancers anticipates the disease or condition is cancer of the instant claim 376.
The over-expressed Myc anticipates the condensate component associated with a disease is a protein over-expressed in the disease of the instant claim 367.
The c-myc promoter-targeted siRNA interfered with transcription initiation blocking the assembly of the pre-initiation complex (abstract) that anticipates the modification of one or more properties of the condensate, such as formation or composition of the instant claims.
The method involves assessing the ability of siRNAs to block c-myc transcription (p1709, left
column, first paragraph) that anticipates the test agent modulates transcriptional activity associated
with the condensate of the instant claim 365 and assessing the transcriptional activity of a gene
associated with the condensate after contacting with a test agent of the instant claim 385.
The RNA-directed transcriptional interference may be a natural mechanism of transcriptional control and siRNAs target noncoding RNAs participating in this regulatory pathway (abstract) and anticipates the test agent alters or disrupts an interaction between the condensate component and a second component of the instant claim 364.
The method further includes transfecting PC3 prostate cancer cells with siRNAs and harvesting 72h later to measure c-myc mRNA and protein levels (p1709, Inhibition of c-myc expression by promoter-targeted siRNAs). Consistently, c-Myc protein level was reduced in cells treated with active siRNAs and not affected cells treated with control siRNAs (p1709, Inhibition of c-myc expression by promoter-targeted siRNAs).
Microscopy examination of siRNA-treated cells confirmed the absence of signs of apoptotic cell death but revealed morphological changes with the induction of a senescence-like process (p, left column) that anticipates the modification of one or more properties of the condensate of the instant claims.
The microscopy examination anticipates the microscopy of the instant claims.
To detect c-Myc, cells were incubated with anti-c-Myc antibody followed by incubation with FITC-labelled anti-mouse secondary antibody (p1717, Cell cycle, BrdU incorporation and apoptosis assays) that FITC anticipates the detectable tag, such as fluorescent tag and antibody of the instant claims 369-371.
The detection of c-Myc with FITC-labelled anti-mouse secondary antibody anticipates determining based on imaging whether the condensate sequesters a condensate component associated
with a disease.
The FITC-labelled anti-mouse secondary antibody anticipates the antibody comprises a detectable tag of the instant claim 384.
Response to Arguments
Applicant’s arguments, see REMARKS, filed 12/23/25, with respect to the rejection(s) of claim(s) 353,355-357,362-364,369,371,376,378 and 385-387 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Napoli et al. (The EMBO Journal (2009) 28, 1708-1719) in view of Sanders et al. (Biochim. Biophys Acta 1743 (2005) 141-150) and Mijatovic et al. (Mol Cancer Ther (2008) 7 (5): 1285-1296) and in further view of Vlach et al. (The EMBO Journal vol. 15 no. 23 pp. 6595-6604, 1996) and Kumar et al. (Cancer Informatics 2017, 16, 1-7).
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.
Claim(s) 353,355,362-367,369-371,376 and 384-387 is/are rejected under 35 U.S.C. 103 as being
unpatentable over Napoli et al. (The EMBO Journal (2009) 28, 1708-1719) in view of Sanders et al. (Biochim. Biophys Acta 1743 (2005) 141-150) and Mijatovic et al. (Mol Cancer Ther (2008) 7 (5): 1285-1296) and in further view of Vlach et al. (The EMBO Journal vol. 15 no. 23 pp. 6595-6604, 1996), Sears (Cell Cycle 3:9, 1133-1137; September 2004) and Kumar et al. (Cancer Informatics 2017, 16, 1-7).
Napoli et al. discloses that stated above.
Sanders et al. discloses that stated above.
Mijatovic et al. discloses that stated above.
Napoli et al. does not disclose that the sequestration of the condensate component modulates a secondary condensate by restricting access to a second condensate.
Vlach et al. (The EMBO Journal vol. 15 no. 23 pp. 6595-6604, 1996) discloses that the effect of Myc is mediated by a non-covalent sequestration of p27 and requires transcriptionally active Myc-Max dimers (abstract; p6596, left column, second paragraph). The Myc induced sequestration of p27 in a form unable to bind cyclin E/CKD2 (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the Myc of Napoli et al. sequesters p27 upon active Myc-Max dimer and therefore, modulates a secondary condensate component p27 so that it is unable to bind cyclin E/CKD2.
Napoli et al. does not disclose phosphorylation or dephosphorylation of a component of the condensate.
Sears (Cell Cycle 3:9, 1133-1137; September 2004) discloses the sophisticated and complex signaling pathway that controls the life cycle of c-Myc from protein synthesis to ubiquitin-mediated degradation. The pathway involves Ras-activated kinases, the Pin1 propyl isomerase, the PP2A phosphatase and a series of c-Myc phosphorylation and dephosphorylation events that control its stability. Doubly phosphorylated c-Myc is recognized by Pin 1 and PP2A can then dephosphorylate
Serine 62 (abstract; Figure 2; p1135, right column, first paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the life cycle of c-Myc of Napoli et al. involves doubly phosphorylation followed by dephosphorylation via PP2A of the c-Myc component of the condensate.
Napoli et al. does not disclose that Myc is an IDR.
Kumar et al. (Cancer Informatics 2017, 16, 1-7) discloses that cMyc oncoprotein has been
divided into structured and disordered domains. Intrinsically disordered proteins (IDPs) have been
implicated in several human diseases and should be considered as potential novel drug targets
(abstract).
c-Myc is an IDP which attains ordered structure only after binding to its disordered partner MAX protein (p3, right column, last paragraph) and the IDPs comprise regions called intrinsically disordered
regions (IDRs) (p1, Introduction) that encompasses the transcription factor comprising an IDR of the
instant claim 362.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that the Myc of Napoli et al. is an IDR as Kumar et al. teaches that c-Myc is an IDP comprising regions called intrinsically disordered regions (IDRs).
Conclusion
Claims 368 and 374 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The
examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618