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 .
Priority
The instant application, filed 04/14/2023, is a 371 filing of PCT/US21/54979, filed PCT/US21/54979, which claims domestic priority to U.S. provisional application number 63/092,972, filed 10/16/2020.
Amendments and Claim Status
The amendment filed on 09/21/2023 is acknowledged and entered.
Claims 3-7, 12, 14, and 20 are amended;
Claims 8-11, 13, and 15-19 are cancelled;
Claims 1-7, 12, 14, and 20-23 are pending and are under prosecution.
Information Disclosure Statement
The Information Disclosure Statement filed on 05/08/2023, 09/27/2024, 02/24/2025, and 07/25/2025 are acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the information disclosure statements are considered.
Restriction/Election
Applicant’s election with traverse of Group I in the reply filed on 10/27/2025 is acknowledged. Applicant’s arguments are found not persuasive; however, Applicant’s arguments are moot in view of the withdrawal of the restriction requirement as detailed below.
The traversal is on the grounds that Examiner has not provided a rationale as to why a person of ordinary skill in the art would have selected the prior art compound from among the hundreds of compounds disclosed by the prior art, as a starting point for modification.
This is not found persuasive because the claims lack unity of invention because the shared technical feature of the claims is not considered a special technical feature in light of the teachings detailed in the requirement for restriction office action, filed 08/27/2025. That is, there need not be a rationale as to why a person of ordinary skill in the art would have selected the prior art compound. The simple fact that the prior art compound exists and shares a common core structure with the compounds of the instant claims is enough to determine that the shared technical feature of the claims does not make a contribution over the prior art of record. Therefore, since this application is a national stage application and lacks unity of invention because the technical feature is not a special technical feature due to a lack of novelty, the restriction as set forth in the prior office action is proper.
The requirement for restriction is deemed proper. However, in view of allowability of the instantly claimed subject matter, the restriction requirement is hereby withdrawn.
In accordance with the MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
As per MPEP § 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species (Figure 1) makes a contribution over the prior art of record. Therefore, according to MPEP § 803.02: should the elected species appear allowable, the search of the Markush-type claim will be extended. The Markush-type claim shall be rejected and claims to the nonelected invention held withdrawn from further consideration. It has been determined that the entire scope claimed is not patentable.
Figure 1. Elected Species
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Figure 1. Example 25, Applicant’s elected species
Status of Claims
Claims 1-7, 12, 14, and 20-23 are pending in the instant application. Claims 1-6, 12, and 14 make a contribution over the prior art. Thus, the restriction requirement between Group I, a compound of Formula (I); Group II, a method of preparing a compound of Formula (I) ; and Group III, a method of treatment or prophylaxis of a disease comprising the administration of a compound of Formula (I); as set forth in the Office action mailed on 08/27/2025, has been reconsidered in view of the allowability of claims to the elected claims pursuant to MPEP § 821.04(a). Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between Groups I-III as set forth in the Office action mailed on 08/27/2025, is hereby withdrawn and claims 7 and 20-23 are hereby rejoined and fully examined for patentability under 37 CFR § 1.104. In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Objections
Claim 6 is objected to for the following informalities:
The use of curly brackets within the following compound name is improper. The curly brackets should be replaced with parentheses in order for the name to properly compile and create a 2D structure with use of chemical name to structure conversion software. That is,
6-Cyclopropyl-N-{(2-[(2,2-difluorocyclopropyl)methoxy)-5-isopropylphenyl]sulfonyl}-4-fluorobenzofuran-2-carboxamide
should be corrected to
6-Cyclopropyl-N-((2-[(2,2-difluorocyclopropyl)methoxy)-5-isopropylphenyl]sulfonyl)-4-fluorobenzofuran-2-carboxamide
If properly amended to overcome the objection, claim 6 would be allowable.
Claim Rejections - 35 U.S.C. § 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.
Claims 20-23 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 the treatment of specific breast and lung cancers, it does not reasonably provide enablement for treatment and/or prophylaxis of diseases, hyperproliferative diseases, or cancer generally, including bladder cancer, uterine cancer, endometrial cancer, prostate cancer, and the leukemia. The specification does not provide sufficient information to support the claimed invention to the full scope of cancers recited in the claims.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 20-23 of the instant application are drawn to a method of treating cancer by administering a compound of Formula (I). The claims encompass treating of diseases, hyperproliferative diseases, and cancer broadly, without limitation to specific cancer types, subtypes, or molecular contexts.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. While the specification provides functional data sufficient to support treatment of specific breast cancers and lung cancers, the rejected claims are not limited to those specific cancer types. Instead, the claims encompass treatment and/or prophylaxis of diseases, hyperproliferative diseases, and cancer generally. Applicant claims that the disclosed compounds can be used to treat cancer broadly, such that the claims read on numerous distinct cancers with different etiologies, molecular drivers, and therapeutic requirements. This includes cancers for which the specification provides no experimental data or mechanistic guidance. Accordingly, the scope of the claims far exceeds the guidance provided in the specification.
State of the Prior Art: There are no art recognized methods that could be used to establish that the instantly claimed diseases can be commonly addressed using the claimed therapeutic method. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method using the claimed agents. Additionally, there are no art recognized methods that could be used to identify subjects who would have predictably developed the broad spectrum of the aforementioned diseases in order to determine that the diseases were treated using the claimed methods.
Regarding common disease mechanisms and biomarkers, McKean et al. (Biomarkers in precision cancer immunotherapy: Promise and challenges. American Society of Clinical Oncology – Educational Book (2020), 40, p.e275-e291), hereinafter McKean, teach that although ongoing studies and trials investigate the use of multiple biomarkers predictive of patient response or harm, none of these are comprehensive in predicting potential benefit (of treatment). This unmet need for validated biomarkers is largely secondary to a prohibitive complexity within tumor parenchyma and microenvironment, dynamic clonal and proteomic changes to therapy, heterogenous host immune defects, and varied standardization among sample preparation and reporting (abstract). McKean also teach that treatment failures occur even in ICI patient cohorts, despite respective prescreening with biomarkers such as PD-L1 tumor proportion scores (p.e275). Regarding gene expression profiles specifically, McKean teaches that an important concept within gene expression profiles is that the predictive utility of such algorithms may be dependent on individual therapy plans. Data suggest that signaling and transcriptomic patterns may correlate only with response to therapy of directly related targets (p.e280). Unrelated immune pathways may require separate and individualized gene expression assays for different therapies (p.e280). Therefore, the selection of a particular therapy for any specific type of cancer is unpredictable, and requires individualized assays that are fully described to achieve correlation.
Predictability/Unpredictability in the Art: The pharmaceutical arts, particularly the treatment of cancer, are well-recognized as highly unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. The courts have upheld that in unpredictable arts, a greater degree of specificity is required to satisfy the enablement requirement. Cancer comprises a heterogeneous group diseases the distinct molecular drivers, signaling pathways, and therapeutic responses. As such, a person of ordinary skill in the art would recognize the inhibition of cancer- implicated enzymes in vitro, do not reliably predict therapeutic efficacy across different cancers, cancer subtypes, or patient populations. The translation of enzyme inhibition or cell line activity into effective cancer treatment depends on numerous factors, including tumor biology, compensatory signaling mechanisms, tissue specific effects, toxicity, and therapeutic window, none of which are addressed in a comprehensive or predictive manner in the instant specification.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of Formula (I) inhibit the enzymatic activity of the histone acetyltransferases KAT6A and KAT6B, as demonstrated by biochemical assays measuring acetylation and corresponding IC50 values (Table 2, pages 223-226). The specification further teaches that inhibition of KAT6A and KAT6B results in downstream cellular effects in select in vitro systems, including repression of ESR1-dependent transcription (page 226). The specification further teaches reduced proliferation in certain cancer derived cell lines, such as a specific breast cancer and lung cancer cell lines (pages 227-230). This data demonstrates cancer target engagement and limited cellular activity in selected experimental models. However, the specification does not teach or demonstrate treatment of cancer as a disease state, does not include in vivo tumor models, and does not provide evidence of tumor regression, disease control, or clinical efficacy across different cancer types. Rather, the disclosure is limited to enzyme inhibition and cellular pathway modulation in narrowly defined experimental contexts. Thus, the specification fails to provide sufficient evidence in support of the broad treatment of all disorders and diseases related to Eph receptor tyrosine kinase as recited in the instant claims.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the large range of diseases, hyperproliferative diseases, and cancers can be treated by the administration of the compounds claimed. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome. Such experimentation would necessarily include cancer specific validation of therapeutic efficacy, optimization of dosing regimens, assessment of toxicity and side effect profiles, and identification of responsive versus nonresponsive cancer subtypes. The specification provides only limited in vitro data demonstrating activity in to the numerous additional cancers recited in the claims. Accordingly, determining which cancers may be effectively treated would require extensive, individualized experimentation, amounting to undue burden.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. Accordingly, a method comprising administering a compound of Formula (I) to a subject in order to treat or prevent all the diseases, hyperproliferative diseases, and cancers encompassed by the claims is not enabled by the instant specification.
Claims 20-23 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 the treatment of specific breast and lung cancers, it does not reasonably provide enablement for the prophylaxis of any disease, and specifically not cancer. The specification does not provide sufficient information to support the claimed invention to the extent the claims encompass prevention of cancer.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 20-23 of the instant application are drawn to a method of prophylaxis of a disease, hyperproliferative disease, and cancer. The claims are drawn to prophylaxis of diseases, hyperproliferative diseases, and cancers in subjects having, suspected of having, or at risk of developing cancer, and thus, the instant claims encompass preventing disorders such as cancer using the compounds instantly claimed.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims encompass preventing cancer without limitation to any specific cancer type, molecular marker, or risk stratification applicant claims that administration of a compound of Formula (I) may be used to prevent a wide range of diseases, including cancer, such that the claims read on prophylaxis across numerous biologically distinct cancers and pre-disease states. The specification, however, provides no experimental data, mechanistic guidance, or predictive framework for preventing cancer, rendering the scope of the claims substantially broader than the disclosure. Thus, the cited claims are deemed very broad since these claims read on essentially preventing any cancer comprising the administration of a compound of Formula (I).
State of the Prior Art: While the state of the art with regard to the treatment of cancer is relatively advanced, the state of the art with regard to the prevention of cancer is underdeveloped. Cancer prevention presents unique challenges because it is not possible to determine whether cancer would have developed in a subject absent treatment. As a result, prophylactic efficacy cannot be reliably inferred from in vitro enzyme inhibition, or cancer cell line activity. Prevention requires long-term, population level studies that are not disclosed or suggested in the specification.
Regarding prevention of cancer, the American Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention. https://www.cancer.org/cancer/risk-prevention.html).
Predictability/Unpredictability in the Art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity in preventing diseases. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses the prophylaxis of cancer and other diseases and treating subjects at risk of developing cancer or other diseases. Thus, the skilled artisan would view that the prevention of all disorders/diseases encompassed by the claims, by administering a compound of Formula (I), is highly unpredictable.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that compounds of Formula (I) may inhibit specific proteins found in breast or lung cancer cells. (pages 223-229) Thus, the specification fails to provide sufficient evidence in support of prophylaxis of a disease, hyperproliferative disease, or any cancer as recited in the instant claims.
Additionally, the examples provided do not demonstrate the prevention of any diseases. Furthermore, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that recurrence of diseases/disorders was prevented using the claimed agents as there is no disclosed method to determine that recurrence of cancer or any diseases would have predictably occurred without treatment.
The Quantitation of Experimentation Required: In order to practice Applicants invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed compounds could be administered to a subject at risk of developing cancer. The population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome.
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. Prophylaxis of a disease, hyperproliferative disease, or any type of cancer is not enabled by the instant specification.
Allowable Subject Matter
Claims 1-5, 7, 12, and 14 are allowed.
The following is an examiner’s statement for reasons of allowance:
The instant claims are drawn to compounds of Formula (I) and a pharmaceutical composition thereof, wherein the compounds comprise a benzofuran ring substituted at the two position with a specific linker -C(O)-NH-SO2-connected to an aromatic or heteroaryl dramatic ring.
Searches of the prior art have identified several references which disclose compounds similar to those of the instant claims. While these references disclose compounds used in the treatment of cancer, none of the references, alone or in combination with the principles of bioisosteric replacement known to person of ordinary skill in the art, disclose or suggest the specific benzofuran substitution pattern and linker arrangement required by the instant claims. The following is a statement of the teachings of the closest prior art, and how the instant claims are distinguishable over said teachings.
The prior art by Harvey (WO 2018102419 A1, published June 7, 2018, cited on IDS filed 05/08/2023) discloses compounds of Formula (I),
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(claim 1), comprising a sulfonic group at linker position L (claim 4), connecting two rings (A and B) as KAT inhibitors. However, Harvey does not teach or suggest a benzofuran ring substituted at the linker, as required by the instant claims, nor any of the compounds herein claimed. Furthermore, a person of ordinary skill in the art would not have any motivation to modify the teachings of Harvey to arrive at any of the instantly claimed species.
Further searches identified Voss et al. (WO 2016198507 A1, published December 15, 2016, cited on IDS filed 05/08/2023), hereinafter Voss, who teaches a compound of Formula (I),
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, and disclose aryl sulfonohydrazide compounds for the treatment of cancer (claims 1 and 19). Firstly, the linker in a compound of Formula (I) (-C(O)-NH-NH-SO2-), is distinct from that of the instant claims (-C(O)-NH-SO2-). Furthermore, there is no disclosure of a benzofuran ring substituted at the linker, as required by the instant claims. Finally, a person of ordinary skill in the art would not have been motivated to modify the teachings of Voss to arrive at any of the compounds of the instant claims.
A similar linker moiety to that of Voss was identified in a disclosure by Harvey et al. (WO 2019108824 A1, published June 6, 2019, cited on IDS filed 05/08/2023), hereinafter Harvey’19, who teaches a compound of Formula (I),
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in a disclosure of histone acetyltransferase inhibitors (Title, Abstract, claim 1). As with the compounds in the previous disclosures, the teachings of Harvey’19 fail to disclose or suggest a benzofuran ring is required by the instant claims.
Finally, in the closest prior art by Bouche et al (US 12357603 B2, effectively filed April 25, 2019, for the purpose of 102 (a)(2)), hereinafter Bouche, teaches a compound of
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, which bears similarity to that of the instant claims. However, the published patent teaches an amino substitution on the core benzofuran ring, which does not overlap with the substitution at position R2 in the instantly claimed compound of Formula (I),
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, claimed to be a carbon atom in a number of variations (cyano, alkyl, aromatic, amide, etc.). There is no motivation for a person of ordinary skill in the art to modify the compounds taught by Bouche at the R2 position to arrive at the compounds of the instant claims.
As such, none of the identified references encompass the scope of the instantly claimed compounds, which are novel and nonobvious over the prior art at the inclusion of a benzofuran ring with the specific substituents, linked by (-C(O)-NH-SO2-). to a phenyl or heteroaryl group. These references lack identical or obvious limitations of the claims.
With regard to claim seven, directed to a method of preparing the compound of Formula (I), the specification adequately describes an enabling disclosure of the claimed preparation method, including suitable intermediates, coupling partners, and reaction conditions, such that a person of ordinary skill in the art would be able to practice the claimed method without undue experimentation. Additionally, because the prior art of record does not disclose or suggest the compounds of Formula (I), nor methods for preparing such compounds, the claimed method is deemed allowable.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should clearly be labeled, “Comments on Statement of Reasons for Allowance.”
Conclusion
Claim 6 is objected to.
Claims 20-23 are rejected.
Claims 1-5, 7, 12, and 14 are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sophia P. Hirakis whose telephone number is +1 (571) 272-0118. The examiner can normally be reached within the hours of 5:00 am to 5:00pm EST, Monday through Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached on +1 (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is +1 (571) 273-8300.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623