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 05/16/2022, is a national stage entry of PCT/US2020/063000, filed 12/03/2020, which claims domestic priority to U.S. provisional application no. 62/943,632, filed 12/04/2019.
Continued Examination Under 37 CFR § 1.114
A request for continued examination under 37 CFR § 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR § 1.114, and the fee set forth in 37 CFR § 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR § 1.114. Applicant's submission filed on 02/06/2026 has been entered.
Amendments and Claim Status
The amendment filed on 02/06/2026 is acknowledged and entered.
Claims 1, 7, 8, 9, 11, and 13 are amended;
Claims 2-6, 12, 14, 16-24, 28, 33, and 36-44 are cancelled;
Claims 1, 7-11, 13, 15, 25-27, 29-32, 34, and 35 are pending.
Information Disclosure Statement
An Information Disclosure Statement has not been submitted.
Response to arguments
Applicant’s arguments filed 02/06/2026 with respect to the claim objections and claim rejections under 35 U.S.C. § 102 (a) (1) have been fully considered.
With respect to the objection to claim 8, the inclusion of the line break is sufficient to overcome the objection.
With respect to the objection to claims 7, 11, 13, 15, and 26, the amendment to claim 1 is sufficient to overcome the objection.
With respect to the rejection of claims 1 and 8 under 35 U.S.C. § 102 (a) (1) as being anticipated by Anthony et al. (WO 2008076225 A2, published June 26, 2006), hereinafter Anthony, the amendment filed to claim 1, specifically the amendment to the substituents of R3 is sufficient to overcome the rejection.
Status of Claims
Claims 1, 7-11, 13, 15, 25-27, 29-32, 34, and 35 are pending in the instant application. Claims 9, 10, 27, 29-32, 34, and 35 were previously withdrawn from further consideration pursuant to 37 CFR §1.142 (B), as being drawn to a nonelected invention or species. Upon examination, it has been determined that claims 1, 7, 8, 11, 13, 15, 25, and 26 make a contribution over the prior art. Thus, the restriction requirement between Group I, a compound of Formula (I), and Group II, a method of treatment comprising the administration of a compound of Formula (I), as set forth in the Office action, filed 02/12/2025, has been reconsidered in view of the allowability of claims to the elected invention pursuant to MPEP § 821.04(a). Pursuant to the procedures set forth in MPEP § 821.04(a), the restriction requirement between Groups I and II as set forth in the Office action mailed on 02/12/2025, is hereby withdrawn and claims 9, 10, 27, 29-32, 34, and 35 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.
Therefore, claims 1, 7-11, 13, 15, 25-27, 29-32, 34, and 35 are under consideration in the instant application, and are being examined on the merits as such.
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 27, 29-32, 34, and 35 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 a method of inhibiting HIF2a, it does not reasonably provide enablement for a method of treating a disease, disorder, or condition, mediated at least in part by HIF2a comprising administering to a subject in need thereof the compound or pharmaceutically acceptable salt thereof of Formula (I). The specification does not provide sufficient information to support 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:
The following factors are considered in determining whether undue experimentation is required to practice the invention:
(1) Nature of the invention;
(2) Breadth of the claims;
(3) State of prior art;
(4) Level of ordinary skill in the art;
(5) Level of predictability in the art;
(6) Amount of direction provided;
(7) Presence of working examples; and
(8) Quantity of experimentation required to make or use the invention.
In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988).
Nature of the invention: Claims 27, 29-32, 34, and 35 of the instant application are drawn to a method of treating a disease, disorder, or condition, mediated at least in part by HIF2a comprising administering to a subject in need thereof the compound or pharmaceutically acceptable salt thereof of Formula (I).
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. Applicant claims that the claimed compounds can be used to treat disease, disorder, or condition, mediated at least in part by HIF2a. Accordingly the cited claims are deemed very broad since these claims read on treating essentially any disease, disorder, or condition in which HIF2a is implicated, whether directly or indirectly.
Furthermore, the claims are deemed very broad with respect to patient group (i.e., newly diagnosed or remission, cytogenetic risk, transplant eligibility), biomarker status, disease stage, routes of administration, duration of treatment, and dosing schedules of a compound of claim 1.
State of the Art: There are no art recognized methods that could be used to establish that the instantly claimed method can be used to treat a disease, disorder, or condition, mediated at least in part by HIF2a. Additionally, there are no examples provided to demonstrate the use of the claimed compositions in a broad range of diseases, disorders, or conditions, mediated at least in part by HIF2a as there is no disclosed common mechanism or structural feature that links HIF2a to all of the claimed diseases, disorders, or conditions provided in the instant specification, nor within in the art.
Regarding the variability of the role of HIF2a biology in disease contexts, Patel and Simon (Cell Death and Differentiation, Volume 15, pg. 628-634, published February 15, 2008) teach that HIF2a biology is complex, pleiotropic, and context-dependent (pages 628 and 629). Patel and Simon teach that HIF2a is expressed across multiple organs and cell types and is involved in wide-ranging physiological processes. Its involvement is not limited to a narrow or predictable therapeutic setting. The art further teaches that a binding of an inhibitor to HIF2a is not sufficient for target gene activation, and specificity depends on additional protein regions and cooperating factors, which underscores mechanistic complexity and limits predictability across disease contexts (page 629). The disclosure also reports cell type dependent effects for HIF2a in cancer biology, and notes unresolved and conflicting findings regarding apoptosis and tumor growth (pages 631 and 632). This demonstrates that therapeutic outcomes cannot be generalized by merely implicating HIF2a. Therefore a method of treatment centered on HIF2a is not a straightforward process, but one that depends on the mechanism of action of the specific context of HIF2a in a particular disease, disorder, or condition.
Regarding compounds which are similar in structure, such as those taught by Anthony (WO 2008076225 A2, published June 26, 2006), the compounds are taught to be useful as HIV reverse transcriptase inhibitors (Abstract). There is no evidence that the instantly claimed compounds, which are distinguishable over the prior art of Anthony, would be capable of being useful in treating any disease, disorder, or condition, mediated at least in part by HIF2a.
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 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 includes treating any disease mediated at least in part by HIF2a kinases. Thus, the skilled artisan would view that successfully targeting the large number of diseases, disorders, or conditions mediated at least in part by HIF2a encompassed by the claims comprising the administration of the compounds, is highly unpredictable, as there are a large number of HIF2a kinase inhibitors, as demonstrated in the teachings of Patel and Simon, above.
Moreover, one of skill in the art would recognize that it is highly unpredictable in regard to therapeutic effects, side effects and toxicity generated by administering a singular class of compounds for treating all the disorders and diseases encompassed by the claims.
Guidance of the Specification/Working Examples: Applicant has only provided working examples of binding of the instantly claimed compounds to HIF2a (Table 1). Thus, the specification fails to provide sufficient evidence in support the broad use of the claimed compounds for treating any disease, disorder, or condition, mediated at least in part by HIF2a as instantly claimed.
Additionally, none of the examples provided demonstrate the testing of the claimed methods against the large number of diseases, disorders, or conditions mediated by HIF2a as instantly claimed. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could commonly target all said diseases, disorders, or conditions, as there is no disclosed recognized common link between the instantly claimed therapeutic contexts.
The MPEP at § 2164.02 states that a single working example in the specification for a claimed invention is enough to preclude a rejection stating nothing is enabled, since at least that embodiment would be enabled. However, in these cases a rejection stating that enablement is limited to a particular scope may continue to be appropriate. The Court in In re Brana is instructive with regard to working examples in the pharmaceutical setting. In essence, the Court found a pharmaceutical invention enabled where the animal model (in vitro or in vivo) correlates to the claimed use and the claimed compounds compared favorably with compounds known to have the same therapeutic effect. In re Brana, 51 F.3d 1560, 1566; 34 USPQ2d 1436, 1441 (Fed. Cir. 1995).
The MPEP at § 2164.02 is instructive regarding animal models and states that an in vitro or in vivo animal model example in the specification constitutes a "working example" if that example "correlates" with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute "working examples." In this regard, the issue of "correlation" is also dependent on the state of the prior art. If the art is such that a particular model is recognized as correlating to a specific condition, it should be accepted as correlating unless the examiner has evidence that the model does not correlate. In re Brana at 51 F.3d 1566; 34 USPQ2d 1441 (Fed. Cir. 1995).
Patent applications claiming new methods of treatment usually find support in test results, however, human trials cannot be required for a therapeutic invention to be patentable. Janssen Pharmaceutica N.V. v. Teva Pharms. USA, Inc., 583 F.3d 1317, 1324 [92 USPQ2d 1385] (Fed. Cir. 2009). Results from animal tests or in vitro experiments may suffice to satisfy the utility requirement. Id. Under the appropriate circumstances, in vitro testing alone may establish a practical utility for the compound in question. For example, in Janssen Pharmaceutica, the Federal Circuit noted its own previous findings with regard to in vitro test results,
We noted in Cross v. Iizuka that “[w]e perceive no insurmountable difficulty, under appropriate circumstances, in finding that the first link in the screening chain, in vitro testing, may establish a practical utility for the [pharmaceutical] compound in question” in order for a patent to issue. 753 F.2d 1040, 1051 [224 USPQ 739] (Fed. Cir. 1985). We concluded that in vitro test results for a claimed pharmaceutical compound, combined with animal test results for a structurally similar compound, showed “a reasonable correlation between the disclosed in vitro utility and an in vivo activity. Id. at 1327.
In this case, no working examples are presented demonstrating the claimed processes.
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 used to treat any disease, disorder, or condition, mediated at least in part by HIF2a. 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”. A method for treating any disease, disorder, or condition, mediated at least in part by HIF2a comprising administering the compounds as claimed is not enabled by the instant specification.
Claim Rejections - 35 U.S.C. § 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 27, 29-32, 34, and 35 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.
Claims 27, 29-32, 34, and 35 of the instant application claim a method of treating a disease, disorder, or condition, mediated at least in part by HIF2a comprising administering to a subject in need thereof the compound or pharmaceutically acceptable salt thereof of Formula (I).
It is unclear what “mediated at least in part by HIF2a” refers to and how to determine if a disease is mediated at least in part by HIF2a. The term “mediated at least in part by HIF2a” in claims 27, 29, 30- 32, 34, and 35 is a relative term which renders the claim indefinite. The term is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define how to determine if a disease is mediated at least in part by HIF2a. Thus it is unclear what would be considered mediated at least in part by HIF2a by a person of ordinary skill in the art. There are a large number of diseases that could be considered mediated at least in part by HIF2a. These diseases can range from pulmonary hypertension (Shimoda et al. (Curr Op Phys, Volume 7, pages 33-40, published January 7, 2019), cited on applicant IDS filed 12/16/2022) to cancer (Murugesan et al. (Drug Discovery Today, Volume 23, Issue 7, published July 2018), cited on applicant IDS filed 12/16/2022). Moreover, there are diseases that could result from HIF2a dysfunction that do not directly have HIF2a at the center of the disease morphology. The claims, as written, do not define the way in which the disease, disorder, or condition is mediated by HIF2a—whether directly implicating HIF2a dysfunction or whether the disease, disorder, or condition which develop as a result of diseases, conditions, or disorders that implicate HIF2a dysfunction. Thus an ordinary skilled artisan cannot ascertain the metes and bounds of the claimed invention and thus the claims are properly rejected as being indefinite.
Allowable Subject Matter
Claims 1, 7-11, 13, 15, 25 and 26 are allowable.
The following is a statement of reasons for the indication of allowable subject matter:
Claims 1, 7-11, 13, 15, 25 and 26 are drawn to a compound represented by Formula (I) which has been found to be allowable over the prior art of record. The closest related prior art are Anthony (see earlier citation) which teach structurally similar compounds. Although the chemical core of the compounds taught in the prior art are structurally similar to the instantly claimed compounds, the compounds of the instant claims have specific substituents which distinguish them from the prior art. More specifically, the prior art by Anthony does not detail wherein:
R3 is -S(O)2Ra.
Y is NH or O in combination with the rest of the claimed substituents
X1, X2, and X3 are N in combination with the rest of the claimed substituents
X1, X2, and X3 are N in combination with the rest of the claimed substituents
The teachings of Anthony do encompass the scope of the instantly claimed compounds. The reference lacks identical or obvious limitations of the claims. Furthermore, there is no teaching or suggestion that would serve as a motivation for a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to modify the prior art to arrive at the instantly claimed compounds. Thus, the cited claims of the instant application are novel and nonobvious over the closest related prior art.
Conclusion
Claims 1, 7-11, 13, 15, 25, and 26 are allowed.
Claims 27, 29-32, 34, and 35 are rejected.
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.
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/SOPHIA P HIRAKIS/Examiner, Art Unit 1623
/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623