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 .
Claim Status
Claims 1, 2, 4, 8, 11, 13, 20, 25 and 97-103, wherein Claims 97-103 are newly added. Claims 2, 11, 13, 20 and 98-103 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
Therefore, Claims 1, 4, 8, 25 and 97 are under examination.
Election/Restrictions
Applicant elected BI-9564 as the bromodomain 9 (BRD9) inhibitor species without traverse during an interview on 9/3/2025.
Newly amended Claim 2, is now drawn to a selective BRD9-degrading PROTAC inhibitor which is a nonelected BRD9 inhibitor species because neither the elected inhibitor, BI-9564, nor the inhibitor examined after expanding the examination to another species, bromosporine, is a PROTAC.
New Claims 2 and 98-103 are drawn to nonelected BRD9 inhibitor species, e.g., BI-7273, LP-99,TP-472, etc. Claims 2 and 98-103 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/23/2025.
Priority
This application is a 371 national stage application of PCT/US2021/026223 filed April 07, 2021, which claims the priority benefit of U.S. provisional application no. 63/007,161, filed April 8, 2020.
Information Disclosure Statement
The Information Disclosure Statement filed 12/23/2025 has been considered by the Examiner. The submission is in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Joint Inventor
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Treatment of HD with the elected species is free of the prior art
The use of the elected BRD9 inhibitor species (BI-9564) for treating Huntington’s disease (HD) is free of the prior art. Therefore, the search and consideration has been expanded to a different BRD9 inhibitor species, particularly bromosporine (see 0014).
Withdrawn Objections/Rejections
The objection to the specification has been overcome by amending claim 2 to remove the “degron” limitation and by amending par. 0030 of the specification to delete the term “and” after the term “patient”.
Claim 2 was objected to but has been overcome by amending claim 2 to remove the “degron” limitation and the duplicate recitation of “wherein the”.
Therefore, the above objections are hereby withdrawn.
Claims 1-4, 8, and 25 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph because the claims recited or encompassed the term “subject” which the specification was not clear about what additional limitation to “subject” or “patient” was intended by the definition provided in paragraph 0030. Because the specification has been amended to delete the ambiguous language, the rejection was overcome.
Claim 2 was rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The rejection has been overcome by amending claim 2 to remove the “degron” limitation.
Therefore, the rejection is hereby withdrawn.
Claim Rejections - 35 USC § 112 – Indefiniteness
New rejection, necessitated by amendment
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, 4, 8, 25, and 97 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.
1. Claim 1 recites “a therapeutically effective amount” of a BRD9 inhibitor “wherein the therapeutically effective amount corresponds to a concentration effective to reverse the expansion of the PAX6 neural rosette area induced by CAG expansion in neuroloids expressing the HTT gene”. Thus, the claims require: administering a therapeutically effective amount wherein the amount corresponds to a concentration in an in vitro neuroloid assay. It is unclear because neither the claims nor specification define how the in vitro concentration correlates with the administered dose amount in vivo. Because the claim relies on a concentration defined in an in vitro cellular system without explaining how this concentration corresponds to the administered amount in a subject, the scope of the claimed “therapeutically effective amount” is unclear.
2. Claim 1 recites “reverse the expansion of the PAX6 neural rosette area”. The claim does not define what constitutes reversal of expansion of PAX6 neural rosette area. A POSA would not know whether this constitute slowing down or merely halting expansion of the rosette area or whether it requires the rosette area to contract, whether contracting to some baseline rosette area or to a smaller area than the baseline in order to be considered “reversed”?
3. Claim 1 recites “PAX6 neural rosette area” as a measurement used to determine whether the claimed method is effective. However, the claim does not specify how the rosette area is to be measured, including the assay conditions, methodology, age/time point, protocol, seeding density, etc. used to determine the rosette area. Because the different protocols may produce different measurements of neural rosette area, the scope of the claim cannot be determined with reasonable certainty.
4. Claim 1 recites “neuroloids expressing the HTT gene”. However, neuroloids normally express the HTT gene. The phrase does not clearly define a disease-associated condition, because expression of the HTT gene occurs in normal cells as well as cells containing a mutant HTT allele. Accordingly, it is unclear what specific biological system or condition this phrase is intended to modify in the claim; and a POSA would not be able to determine the scope of the claim with reasonable certainty.
One of ordinary skill in the art is not apprised of the metes and bounds of the claimed invention.
Claim Rejections - 35 USC § 112 – Scope of Enablement
Rejection maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 8, 25, and 97 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being:
enabling for alleviating Huntington’s Diseases (HD) in a subject suffering from HD, does not reasonably provide enablement for treating HD as defined by the specification.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement requires a determination of whether the 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. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, the breadth of the claims, state and predictability of the art, and relative skill level:
The invention is based on inhibiting bromodomain 9 (BRD9) in a subject afflicted with Huntington’s disease (HD) by administering a BRD9 inhibitor and, thereby, treating HD in the subject. The specification defines the terms "treatment", "treat", and "treating" as referring to, inter alia, reversing a disease described therein, including HD. See 0031-0032. Given this broad definition, the breadth of the invention is broad enough to encompass “reversing HD”, which is not predictable. The specification does not enable reversal of Huntington’s disease (HD) in a subject, which falls within the scope of the claimed method because the specification defines “treating” to include reversal. In this regard, it is unpredictable whether a drug can be used to reverse HD because the state of the art after the filing of the current patent application is such that HD cannot be reversed. For example, with regard to reversing HD, the more recent art states the following:
eMentalHealth.ca (“Dementia.” The eMentalHealth.ca Team and Editorial Board, Dr. Tim Lau, Geriatric Psychiatrist, Royal Ottawa Mental Health Centre, and Assistant Professor, University of Ottawa (2016). https://primarycare.ementalhealth.ca/Simcoe-County/La-demence/index.php?m=article&ID=8921&r=ns-western) teaches “[h]untington's disease cannot be reversed; thus, the person with these conditions will gradually lose more and more mental functions.” See p. 3.
Brain Research UK (“Huntington’s disease.” Brain Research UK (2020);
https://web.archive.org/web/20200806215510/https://www.brainresearchuk.org.uk/neurological-conditions/huntingtons-disease) teaches that there is no cure for Huntington's and its progress cannot be reversed. See p. 2.
Reilmann et al. (“Pridopidine in early-stage manifest Huntington’s disease: a phase 3 trial.” Nat Med (2025). https://doi.org/10.1038/s41591-025-03920-3) teaches that available therapies are only symptomatic or investigational and no clinical trial has demonstrated restoration of loss of neuronal function. This Phase 3 PROOF-HD trial confirmed that “only symptomatic treatments are available” for HD. See abstract.
Therefore, the current state of the art contradicts the validity of the claim of reversing HD. As a result of such difficulties, HD “treatment” as broadly defined by the instant specification is unpredictable.
2. The amount of direction or guidance provided and the presence or absence of working examples:
The specification provides guidance for in vitro testing and results using organoid assays for HD. See Examples 1-8. No working examples demonstrating reversal of HD in a subject have been provided.
3. The quantity of experimentation necessary:
Because of the known unpredictability of the art, and in the absence of sufficient experimental evidence, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to reverse (i.e., “treat” as defined) HD as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that the specification provides enabling disclosure because the Examples demonstrate reversal of the HD phenotype in the neuroloid modes and because inhibition of BRD9 restores the toward wild-type phenotype in these in vitro cellular systems. Applicant further asserts that the fact that prior art methods may not have successfully reversed HD does not render the present invention non-enabled.
Due to the definition for the term “treating” in the specification, the claims encompass embodiments comprising reversing HD in a subject. However, the specification does not provide disclosure demonstrating reversal of HD in a subject. Instead, the specification provides data from in vitro neuroloid assays, including experiments measuring expansion of PAX6 neural rosette area in neuroloids expressing mutant HTT. While these experiments may show that certain BRD9 inhibitors affect cellular phenotypes in a neuroloid model, such data do not demonstrate reversal of HD in a subject. HD is a complex neurodegenerative disorder involving progressive neuronal loss and neurological dysfunction. Translating an observed effect in a cellular model to reversal of the disease in a subject would require substantial additional research and experimentation. The specification does not provide guidance enabling a POSA to achieve such outcomes across the full scope of the claims. Regarding Applicant’s argument that the lack of prior success in reversing HD does not render the invention non-enabled is not persuasive because the issue here is not whether prior art methods succeeded, but whether the specification enables the full scope of the claimed inventio, which includes reversing HD in a subject. The specification does not provide data demonstrating reversal of HD in a subject and the claims are not commensurate in scope with the data proffered to show enabling disclosure.
Claim Rejections - 35 USC § 103
Rejection maintained
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1, 4, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Olzscha et al. (Cell Chemical Biology (2017); 24:9–23. http://dx.doi.org/10.1016/j.chembiol.2016.11.009 - 10/6/2022 IDS) in view of ATM inhibitor (“ATMi”) (“Bromosporine.” ATM inhibitor (6/7/2017); https://www.atminhibitor.com/2017/06/07/Bromosporine/) and Sdelci et al. (US 20190117641 A1).
Claimed invention
A method of treating a subject having Huntington's Disease (HD), comprising administering to the subject a therapeutically effective amount of a bromodomain 9 (BRD9) inhibitor.
Prior art
Olzscha studied the effect of bromodomain inhibitors (BDIs) on the aggregation of a pathologically relevant form of huntingtin protein (“Htt”) involved in Huntington’s disease (HD). See abstract and p. 17. Olzscha demonstrates that certain BDIs such as bromosporine (a “BRD9 inhibitor” – see ATMi’s IC50 teachings and the instant specification’s broad definition for selective inhibitors at 0047) and especially compound 33 (i.e., a p300/CBP inhibitor) reduce Htt-96Q aggregation in Huntington’s disease cellular models, suggesting utility in HD:
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336
306
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Greyscale
(C) U2OS cells expressing HA-Htt-96Q or HA-Htt-20Q were treated with the respective BDI (2.5 mM), then fixed, permeabilized, and stained with Proteostat and DAPI as a nuclear counterstain. The number of Proteostat-positive aggregates was then quantified with an IN Cell Analyzer 1000. The data were derived from at least three independent experiments each in triplicates, and for each condition at least 1,500 cells were analyzed relative to 20Q, which was given an arbitrary value of 1. Level of statistical significance is indicated (*p % 0.05). Error bars denote SD. The sample expressing HA-Htt-20Q is depicted in black, and HA-Htt96Q-expressing cells are depicted in red. BSP, bromosporine; 33, compound 33; (+)-J, (+)-JQ1.
See Figure 7C and its caption at pp. 20 and 21, respectively. Emphasis added.
While Olzscha teaches that bromosporine reduces aggregation of pathological Htt involved in HD, Olzscha does not expressly teach administration of bromosporine to a subject for treating HD.
However, Olzscha further suggests treating Huntington's disease and related pathologies based on the results using certain BDIs. See p. 19, 2nd col. Sdelci teaches that bromosporine can suitably be used in a pharmaceutical composition and administered to a subject for therapeutic purposes. See Sdelci, Claims 1, 33 and 34.
A person of ordinary skill in the art (POSA) would have found it obvious to treat HD in a subject by administering a therapeutically effective amount of a bromodomain inhibitor (BDI) such as bromosporine (a BRD9 inhibitor) because Olzscha teaches that bromosporine reduced aggregation of pathological Htt and suggest the use of BDIs may be useful for treating Huntington’s disease. The POSA would have had a reasonable expectation of success that bromosporine would provide inhibitory activity against aggregation of pathogenic Htt in a subject with HD, and thereby providing beneficial effect to the HD patient.
Claim 4 limits claim 1, wherein the BRD9 inhibitor is a selective BRD9 inhibitor.
ATMi teaches bromosporine is an inhibitor against bromodomains with the following IC50 profile:
Bromodomain
Bromosporine IC50
Bromosporine inhibits BRD9 vs other bromodomain
BRD2
0.41 μM
3.3 times more potent against BRD9 than BRD2
BRD4
0.29 μM
2.3 times more potent against BRD9 than BRD4
BRD9
0.122 μM
n/a
CECR2
0.017 μM
less potent against BRD9
However, the specification states that a “selective BRD9 inhibitor can have at least two-fold, at least five-fold or at least ten-fold greater % inhibition against BRD9 vs. one, two, or three other bromodomain-containing proteins, such as, but not limited to, BRD2, BRD3, BRD4, or any combination of the foregoing.” See specification at 0047. Given that bromosporine have at least two-fold greater inhibition against BRD9 vs. BRD2 and BRD4, it meets the definition of a selective BRD9 inhibitor.
Claim 25 limits claim 1, wherein the BRD9 inhibitor is administered to the subject with a carrier. Sdelci teaches bromosporine can be administered with other agents for therapeutic purpose and formulated as a medicament comprising one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and/or solubility enhancers. See 0122; see also Claim 1, 33 and 34.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues Olzscha allegedly teaches away from using bromosporine or other BDIs for treating HD. In particular, Applicant asserts that Olzscha reports that bromosporine showed little effect on aggregation and negatively affected cell viability, and therefore, a POSA would have been discouraged from using bromosporine or related BDIs to treat HD. This is not persuasive because Olzscha teaches bromodomain proteins play an important role in the aggregation behavior of mutant huntingtin protein and bromodomain inhibition can modulate aggregation processes associated with HD. Thus, Olzscha identifies bromodomain proteins as relevant targets in HD and demonstrates that chemical inhibition of bromodomains can influence HD-related cellular phenotypes. Given these teachings would suggest investigation of bromodomain inhibition using a known BDI such as bromosporine as a therapeutic strategy for HD. Furthermore, the fact that a particular compound exhibited limited or mixed results in certain experimental conditions does not constitute a teaching away from the broader approach of targeting bromodomain proteins described by Olzscha. The reference does not discourage the use of bromodomain inhibitors generally; indeed, it demonstrates that bromodomain inhibition can influence mutant huntingtin protein aggregation and provides the relevance of bromodomain biological activity in HD.
Conclusion
No claims are allowed.
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 CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622