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 .
DETAILED ACTION
The Amendment filed August 7, 2025 in response to the Office Action of March 7, 2025 is acknowledged and has been entered.
The Declaration of Dr. Xiankai Sun filed August 7, 2025 is acknowledged and has been considered.
Claim 36 has been amended.
Claims 5, 13-15, 17-19, 34, and 36-43 are pending.
Claim 13, 14, 17-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Accordingly, claims 5, 15, 34, and 36-43 are pending and under consideration.
Information Disclosure Statement
Information Disclosure Statement (IDS) filed August 7, 2025 has been entered and considered.
MAINTAINED/MODIFIED REJECTIONS
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 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.
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.
Claim(s) 5, 15, 34 and 36-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen (Chen et al., Nature, vol. 539, 112-117, Publication Date: 2016-11-03, with Extended Data, of record) and in view of Donnelly (Donnelly, Seminars in Nuclear Medicine, 47:454-460, Publication Year: 2017, of record).
Chen teaches that clear cell renal cell carcinoma (ccRCC) is characterized by
inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. See page 112, col. 1, para. 1.
Chen teaches that HIF-2α has a 280 Å cavity within the PAS-B domain. PT2399 and PT2385 are specific HIF-2α inhibitors (antagonist) that bind the cavity and dissociated HIF-2α from HIF-1β. See page 112, col. 1, para. 2.
Chen teaches that immunoprecipitation of the HIF-1β subunit, which is shared by both HIF-2α and HIF-1α, showed that PT2399 specifically disassembled HIF-2 but not HIF-1 complexes (Fig. 2a). Akin to engineered mutations, a glutamate side chain would prevent PT2399 access. Consistent with this notion, PT2399 failed to dissociate HIF-2 complexes in mutant tumors (Fig. 4e).
Chen teaches that PT2399 decreased tumor growth by 60% across all tumor grafts evaluated (P<0.001). Among ccRCC tumorgrafts, 56% (10/18) were sensitive. Unexpectedly, four ccRCCs were resistant to PT2399. See page 112, col. 2, para. 3; Fig. 1.
Chen teaches that HIF-2α protein was expressed in 83% of cells in sensitive tumors compared to 23% resistant tumors (P<0.0001, Fig. 3a, b and Extended Data Fig. 4a). Lower, and at times undetectable, HIF-2α levels in resistant tumors may explain why PT2399 does not affect gene expression in this group. See page 115, col. 1, para. 3.
Chen teaches that ccRCC can be classified into HIF-2α-dependent and HIF-2α-independent tumors, and these tumors differ in HIF-2α (and possibly HIF-1α) levels and in their base gene expression. See page 115, col. 2, para. 2.
Chen teaches that sensitive tumors could acquire resistance to prolonged treatment (>120 days) with PT2399, which is associated with a mutation preventing PT2399 access. See the bridging paragraph of pages 115-116; and Fig. 4a-4e.
Chen teaches that a metastatic ccRCC patient remained free of progression on PT2385 for more than 11 months, despite extensive pretreatment. See the bridging paragraph of pages 116-117.
Chen teaches that taken together, these data validate HIF-2 as a target for ccRCC, provide insight into HIF-2-mediated tumorigenesis, establish variable tumor dependence on HIF-2 identifying different ccRCC subtypes and associated biomarkers that may be incorporated in future clinical trials, showcase the specificity of PT2399, and anticipate mechanisms of resistance. See the bridging paragraph of pages 116-117.
Chen teaches method of PET/CT scan, comprising two rounds PECT/CT scan to assess tumor response. See § Methods-PET/CT.
Chen teaches as set forth above. However, Chen does not teach using a HIF-2α-specific radioactive tracer comprising an HIF-2α-specific inhibitor and a radioactive label to detect HIF-2α expression with a PET scan, and determine whether the tumor is HIF-2α inhibitor resistant, thereby distinguishing tumors with differential expression of HIF-2α.
Donnelly teaches that PET is a translational, noninvasive imaging technique that provides quantitative information about a potential drug candidate and its target at the molecular level. See Abstract.
Donnelly teaches that molecular imaging techniques such as PET can significantly impact productivity and lower development costs by ensuring a new drug has target engagement, proper receptor occupancy, and guides dose selection in a more rapid timeframe. See 454, col. 1, para. 1.
Donnelly teaches that generally, there are three main approaches for the use of PET tracers. The first is using a radiolabeled candidate to evaluate the distribution and pharmacokinetics of the drug candidate. For small molecules PET tracers, direct labeling with short-lived PET radionuclides such as replacing a native carbon (C-12) with carbon-11 (20-minute half-life) or a native fluorine (F19) with fluorine-18 (109.5 minute half-life) is important to keep the physiochemical properties of the molecule the same. Recent advancements in PET radiochemistry have helped make this process more feasible. The second approach is to use a radioligand with known affinity for the molecular target of interest to evaluate the PD properties of the drug candidate. Finally, a small molecule PET tracer is used as an imaging biomarker of a known biochemical, metabolic, or physiological process (such as FDG) to evaluate efficacy of a candidate drug. See page 455, § PET within Drug Discovery and Development.
Donnelly teaches that PET tracers can be used in both preclinical animal models to confirm a drug’s target engagement, receptor occupancy, dose selection, and dose ranges to provide information to plan focused human studies in early development. See page 456, col. 2, para. 3.
Donnelly teaches various ways to make small molecule PET tracers and many small molecule PET tracers (table on page 459).
Donnelly teaches that small molecule PET tracers can be used in late-phase clinical development as surrogate markers of response and to show pharmacologic differentiation of an asset from a drug already on the market. Additional PET can show differentiation when a new competitor drug comes to the market. Patient selection, using PET to select the proper patient population that will benefit from the drug candidate, is a powerful technique used during full clinical development of a drug candidate. This is a personalized medicine approach and allows researchers to ask mechanism-based questions within patient populations. This approach can determine if a drug is relevant within a disease population which is key to the proposed mode of action of a drug. See page 458, § PET within Full Clinical Development.
Based on the teaching of Chen, one of ordinary skill in the art would have added a step to check HIF-2α expression in ccRCC patients, and to identify the patients with high HIF-2α expression as suitable patients for a HIF-2α inhibitor therapy, e.g. PT2399 or PT2385 and to identify the patients with low/no HIF-2α expression as the patients who are HIF-2α inhibitor resistant (distinguishing tumors with differential expression of HIF-2α) because Chen teaches that HIF-2α protein was expressed in 83% of cells in PT2399 sensitive tumors compared to 23% in PT2399 resistant tumors. It would have been prima facie obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teachings of Chen and Donnelly, to develop a radioactive PET tracer e.g. PT2399 or PT2385 labeled with 18F, to test HIF-2α expression, because Donnelly teaches 1) PET scan can provide quantitative information about drug target (e.g. HIF-2α, a target of PT2399 and PT2385) at molecular level; 2) PET scan is non-invasive; 3) PET scan with radioactive tracer is widely used in clinical settings; 4) the binding of PT2399 and PT2385 to HIF-2α is specific and well-understood; 5) direct labeling with short-lived PET radionuclides e.g. 18F, is important to keep the physiochemical properties of the molecule the same; 6) PET scan can be used to screen patients suitable for a therapy. One of ordinary skill in the art would have been motivated to expand the application of PT2399 or PT2385, and identify the best patient population for a HIF-2α inhibitor therapy. Because PT2385/PT2399, radioactive labeling method, and PET scan are well known in the art, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed method.
Regarding to claims 37-40, a HIF-2α-expressing tumor would be likely sensitive to a HIF-2α inhibitor treatment, as taught by Chen. Thus, one ordinary skill in the art would have added a treatment step with a HIF-2α inhibitor, such as PT2399 or PT2385, to these patients.
Regarding to claim 41, Chen teaches that PT2385 is effective for metastatic ccRCC. See the bridging paragraph of pages 116-117.
Regarding to claim 42, Chen teaches that sensitive tumors could acquire resistance to PT2399 with prolonged treatment. One of ordinary skill in the art would have wanted to identify the patients who might develop drug-resistance during the treatment and would add a step to check HIF-2α expression after certain period of HIF-2α inhibitor treatment, and would identify the patients with lowered HIF-2α expression as patients with decreased sensitivity to a HIF-2α inhibitor therapy.
Regarding to claim 43, as set forth above, one of ordinary skill in the art would have added a step to check HIF-2α expression in ccRCC patients, and to identify the patients with high HIF-2α expression as suitable patients for a HIF-2α inhibitor therapy, e.g. PT2399 or PT2385. One of ordinary skilled would have known that the first amount of the HIF-2α-specific radioactive tracer in the tumor would indicate the amount of binding of HIF-2α-specific radioactive tracer (e.g PT2399) to HIF-2α the tumor. Thus, the first amount of the HIF-2α-specific radioactive tracer would reflect the HIF-2α expression in the tumor.
Response to Arguments
For the rejection of claims 5, 15, 34 and 36-43 under 35 U.S.C. 103 applicant argues:
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Applicant’s arguments have been fully considered but they are not persuasive.
Regarding to the limitation “distinguishing tumors with differential expression of HIF-2α”, Chen teaches HIF-2α protein was expressed in 83% of cells in sensitive tumors compared to 23% resistant tumors (P<0.0001, Fig. 3a, b and Extended Data Fig. 4a). Lower, and at times undetectable, HIF-2α levels in resistant tumors may explain why PT2399 does not affect gene expression in this group. Thus, one of ordinary skilled in the art would have known and been motivated to distinguish tumors (sensitive tumor or resistant tumor) with differential expression of HIF-2α.
In the Remarks filed August 7, 2025 and Declaration of Dr. Su filed August, 2025, applicant first argues that a skilled person would not have a reasonable expectation that HIF-2α could be targeted by PET at the time of filing and the cited references do not teach HIF-2α can be a viable PET target.
First, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
As set forth above, Chen teaches that HIF-2α protein were detectable in ccRCC tumor tissue (Fig. 3a, b and Extended Data Fig. 4a). Chen teaches that HIF-2α has a 280 Å cavity within the PAS-B domain. PT2399 and PT2385 are specific HIF-2α inhibitors (antagonist) that bind the cavity (page 112, col. 1, para. 2). Chen teaches that PT2399 decreases tumor growth by 60% across all tumor grafts evaluated (P < 0.001) (page 112, col. 2, para. 3; Fig. 1). Tumor sensitivity to PT2399 is correlated to the expression of HIF-2α (Fig. 3a, b and Extended Data Fig. 4a). Thus, one of ordinary skill in the art would have expected that HIF-2α can be targeted/bound by PT2399 in vivo. Donnelly teaches various ways to make small molecule PET tracers and many small molecule PET tracers (table on page 459). Taken together, as set forth above, one of ordinary would have had a reasonable expectation that a PET tracer based on PT2399 would be able to detect HIF-2α in ccRCC, because HIF-2α protein expression is high in PT23pp sensitive tumor tissue, PT2399 can specifically bind HIF-2α and show activity associated with HIF-2α expression in vivo. In addition, using the administration method well-known in the art for PET scan, as evidenced by Leide-Svegborn (Radiation Protection Dosimetry, 2010, Vol. 139, No. 1-3, pp. 208-213, Publication Date: 02/18/2010), one of ordinary skill in the art would have a reasonable expectation that the PET-tracer can reach the area of tumor quickly, as the drug travels through the bloodstream and the binding between the PET tracer and HIF-2α would occur before degradation of radioactivity.
Applicant pointed out that the uncertainty is high (para. 7 of Declaration), difference between in vivo and in vitro assays, and an ideal PET target would have certain properties (such as (a) to (d) of para. 5 of Declaration). However, uncertainty does not equate patentability since the expectation of success need only be reasonable not absolute. Thus, given all the HIF-2α expression data in ccRCC tumor, PT2399 binding specificity to HIF-2α, as set forth above, one of ordinary skill in the art would have had a reasonable expectation of success to reach the claimed invention.
In addition, in the field of biological technology, no invention has absolute certainty of success before experimental tests. For example, the data shown in the specification and Declaration were related to detection of HIF-2α in ccRCC with PT2385 and PT2977. No data have been provided for detecting HIF-2α expression in any tumor with a PT2399 PET tracer. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to develop the claimed method. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed invention.
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Applicant further argues that the specification showed surprising results that HIF-2α could be a viable PET target. As set forth above, the combination of recited references teaches a method of detecting HIF-2α expression in a subject with ccRCC by determining a PET tracer (such as compound based on PT2399) targeting HIF-2α. Thus, HIF-2α is used as a target for PET tracer is not essentially surprising.
In addition, the results provided by the specification and declaration are the data shown in the specification and Declaration were related to detection of HIF-2α in RCC with high HIF-2α expressing tumor with PT2385 and PT2977. No data have been provided for detecting HIF-2α expression with a PT2399-based PET tracer, or in other tumors with various HIF-2α expression levels.
“Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.)”. MPEP 716.02(d)
In this case, the claimed method encompasses PET tracers derived from PT2385 and PT2399, and encompasses broad genus of tumors with different HIF-2α expression levels. However, the specification and Declaration only provide PET tracers derived from PT2385 and RCC tumors with high HIF-2α expression. Accordingly, the data is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention.
Additionally, for the evidence of the Declaration to show the non-obviousness of the claimed invention the presented evidence must show unexpected results. See MPEP716.02(a) I-IV. However, the evidence presented in the Declaration simply shows that PT2977 and PT2385 function as claimed. The Declaration does not provide any evidence that the claimed method is superior or unexpected compared to the methods known in the art.
Further a declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See MPEP 716.02(e). The declaration did not explicitly compare the claimed subject matter with the closest prior art.
Thus, Applicant’s arguments and the Declaration of Dr. Xiankai Sun are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
Conclusion
No claims are allowed.
All other rejection set forth in the previous Office Action of March 7, 2025 are hereby withdrawn in view of the claim amendments and Applicant’s arguments.
THIS ACTION IS MADE FINAL. 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 CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646