Detailed Action
The present office action is in response to the amendments filed on 19 Nov 2025.
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 .
Status
Claims 1, 14, 32, 66, and 72-79 of the pending application have been examined on the merits. Claims 20, 24-25, and 67-71 of the pending application remain withdrawn. Acknowledgement is made of the amendments filed 19 Nov 2025. Acknowledgement is made of the cancelation of claims 2-13, 15-19, 21-23, 26-31, and 33-65.
Priority
Applicants identify the instant application, Serial #: 17/440,591, filed 17 Sep 2021, as a National Stage Entry of International Patent Application #: PCT/US20/23265, filed 18 Mar 2020, which claims priority from U.S. Provisional Application #: 62/820,059, filed 18 Mar 2019.
Response to Applicant Arguments
Examiner acknowledges the amendments filed 19 Nov 2025.
The objection to claim 79 is rendered moot following applicant amendments.
Regarding the rejection of claims 1, 14, 32, 66, and 72-79 under 35 U.S.C. § 103 over Lu et al. (J Clin Endocrinol Metab, 2017, 102:2825-2835; provided in IDS 09/17/2021), hereinafter Lu, further in view of Qian et al. (Clin Cancer Res, 2012, 18:4104-4113; provided in the office action mailed 03 Dec 2024), hereinafter Qian, and Pivonello et al. (Endocrine Rev, 2015, 36:385-486; provided in the office action mailed 03 Dec 2024), hereinafter Pivonello, have been fully considered but they are not persuasive.
Applicant argues that Lu is silent regarding a dual inhibitor of HDAC and PI3K, or the use thereof for treatment of Cushing's disease, let alone by administering the compound for more than 12 months (Remarks, pg. 9). Applicant argues that Qian does not cure the defects of Lu. Applicant argues that because Qian discloses pharmacokinetic and pharmacodynamic data of CUDC-907 in cancer cell lines instead of a pituitary gland adenoma, the reference is not relevant and does not predict the success of treating Cushing's disease with CUDC-907 (Remarks, pgs. 9-10).
Examiner notes the correction provided by applicant that Cushing's disease is a non-cancerous tumor and examiner has amended the 103 rejection accordingly (see below). However, Qian is also relied on to teach that vorinostat has a low oral bioavailability and short half-life in plasma whereas CUDC-907 has an oral bioavailability approximately 2-fold higher than vorinostat and a higher accumulation in tumor tissue which may result in improved clinical activity (pg. 4112, column 1). Examiner maintains that Qian is relevant for teaching CUDC-907 has benefits over vorinostat that would have been recognized by a person of ordinary skill in the art.
Applicant argues that Pivonello fails to cure the defects of the combination of Lu or Qian. Applicant argues that that the only small molecule treatments taught by Pivonello are not dual HDAC/PI3K inhibitors and that the treatments have declining or inconsistent efficacy problems and adverse effects (Remarks, pg. 10). Applicant further argues that Pivonello would counsel the one of ordinary skill in the art away from the claimed invention because Pivonello discloses that small molecule therapies for the treatment of Cushing's disease have declining efficacy over long periods of time (Remarks, pg. 10).
This is not persuasive. Pivonello is relied on for teaching that clinical trials for the medical treatment of Cushing's disease in a patient can last longer than 36 months, and this would be within the expected course of experimentation to continue treatments for long periods of time to measure control and remission of the drug on cortisol levels in patients (see the office action mailed 19 May 2025 and the amended rejection under 35 U.S.C. § 103 below). Pivonello further teaches that several small molecules are considered effective for treating Cushing’s disease, including ketoconazole (pg. 433, column 2), metyrapone (pg. 435, column 1), etomidate (pg. 437, column 1), mitotane (pg. 440, column 1), cabergoline (pg. 446, column 1), and pasireotide (pg. 451, column 1). Together, the references teach the artisan to apply CUDC-907 to the treatment of Cushing's disease in place of vorinostat and that it would be within the normal course of experimentation to continue clinical trials for up to and beyond 36 months (see the office action mailed 19 May 2025 and the amended rejection under 35 U.S.C. § 103 below).
Applicant argues that examiner made contradictory statements regarding the presentation of applicant's evidence showing that existing methods for treating Cushing's disease may become ineffective over time (Remarks, pgs. 10-11). Applicant argues that multiple references, including Pivonello, demonstrate that the current standard of care is rarely effective for treating Cushing's disease long term and that one of ordinary skill in the art would not have had a reasonable expectation of success that the now-claimed therapy would remain effective for 12 months or more (Remarks, pg. 11).
Examiner thanks for applicant for pointing out contradictory statements and correcting the record, however, the evidence and arguments presented are not persuasive. Pivonello is relied on for teaching that clinical trials for the medical treatment of Cushing's disease in a patient can last longer than 36 months and this would be within the expected course of experimentation to continue treatments for long periods of time to measure control and remission of the drug on cortisol levels in patients (see the office action mailed 19 May 2025 and the amended rejection under 35 U.S.C. § 103 below).
Applicant argues that the artisan would not have been motivated to administer a dual inhibitor of HDAC and PI3K with the reasonable expectation that said inhibitor would be effective at treating Cushing's disease for 12 months or more based on the failings of the cited combination of references and the high level of unpredictability associated with the art (Remarks, pg. 12).
This is not persuasive. See the office action mailed 19 May 2025 and the amended rejection under 35 U.S.C. § 103 below. Briefly, based on the teachings of Lu, Qian, and Pivonello, a person of ordinary skill in the art would have treated tumors derived from surgical extirpation with CUDC-907 in place of vorinostat because of the higher intratumoral accumulation, higher oral bioavailability, and higher plasma half-life that CUDC-907 has compared to vorinostat. The artisan would further have understood that clinical trials lasting for periods greater than 36 months would be an expected course of experimentation for patients with Cushing's disease to measure control and remission of the drug on cortisol levels in patients (see below).
Applicant further argues that there unexpected results associated with the claimed methods. Applicant argues that dual HDAC and PI3K inhibitors possess surprising synergy for treating Cushing's disease. Applicant points to Fig. 1B and 1D in particular to show it is surprising that multiple dual inhibitors of HDAC and PI3K disclosed and tested inhibit ACTH at 100 nM (Remarks, pgs. 12-13). Applicant argues that further experiments that determined the IC50 of CUDC-907 as seen in Fig. 3C show dual HDAC and PI3K inhibition show favorable phenotypic outcomes for treating Cushing's disease (Remarks, pg. 13). Applicant also argues that mouse models demonstrate that CUDC-907 potently reduces volume of tumors, tumor weight, and circulating ACTH levels in Fig. 4B, 4C, and 4D, respectively (Remarks, pg. 13).
These arguments are not considered persuasive because Figs 1B and 1D do not single out HDAC and PI3K inhibitors only, but show that they also have an effect along with multi-CDK inhibitors, PI3K/mTOR inhibitors, PLK-1 inhibitors, and PAK inhibitors. A single HDAC/PI3K inhibitor was instead singled out by these experiments. Furthermore, based on Lu, it would be obvious to a person having ordinary skill in the art that the HDAC inhibiting activity of CUDC-907 would inhibit ACTH expression. Fig. 3C does not have the proper controls to compare CUDC-907 effects against other HDAC or PI3K inhibitors to determine if this effect is surprising. Figs. 4B, 4C, and 4D also do not include controls such as HDAC inhibitors or PI3K inhibitors that would lend weight to the claims of unexpected results. As such, it is unconvincing that CUDC-907 reduces tumor weight, tumor volume, and circulation of ACHT in an unexpected fashion.
Finally, applicant argues that combining a PI3K inhibitor (Panabinostat) with an HDAC inhibitor (Burparlisib) increases inhibition of ACTH secretion and proliferation versus either agent along, indicating synergistic pharmacology and points to Figs. 6B and 6C as evidence (Remarks, pg. 13). Applicant further that Fig. 6B shows dual inhibition through CUDC-907 delivers the effects of PI3K/HDAC inhibition in a single agent providing superior antiproliferative potency (Remarks, pg. 13). Applicant argues that Fig. 6C shows that PI3K inhibitors are 200 times less potent at reducing cell proliferation of AtT20 cells (Remarks, pg. 13). Applicant also argues that Fig. 6D shows that CUDC-907 suppresses POMC mRNA significantly more than either a HDAC inhibitor or PI3K inhibitor administered alone (Remarks, pg. 13).
This is not persuasive. Examiner respectfully notes that Figs. 6B and 6C are directed towards comparisons between PI3K and HDAC inhibitors when measuring ACTH secretion and proliferation rates of the tumors and do not contain data about co-administering PI3K inhibitors and HDAC inhibitors. Example 4 indicates that Figs. 6F-I compare the effects of either a PI3K inhibitor alone or co-administration of a PI3K inhibitor and a HDAC inhibitor. With this in mind, the data of Figs. 6F-I do not have the proper controls to make the claim that co-administration with a PI3K inhibitor and an HDAC inhibitor show synergy. The graphs compare administration of Burparlisib alone with co-administration of Burparlisib and Panabinostat. However, there is no data showing administration of Panabinostat alone, making the claim that Example 4 proves synergy unconvincing. It is further unconvincing that Fig. 6B shows that CUDC-907 has superior antiproliferative effects when only relative ACTH secretion rate is being measured and there is no mention of proliferation being measured. As for Figs. 6C and 6D, while the PI3K inhibitors have less antiproliferative activity than CUDC-907, it would have been obvious to the person of ordinary skill in the art, based on Lu, that the HDAC inhibiting activity of CUDC-907 would have the effects of reducing proliferation rate, arrested cell growth, suppressing POMC mRNA, and increased cell death in pituitary adenoma-derived cells.
In light of the discussion above, the rejection of claims 1, 14, 32, 66, and 72-79 under 35 U.S.C. § 103, as obvious over Lu, Qian, and Pivonello is amended for the reasons of record found below.
Claim Rejections - 35 USC § 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.
Claim 79 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. In the amendments filed 19 Nov 2025, applicant amended claim 79 to read, “the method of claim 1, wherein the method reduces POMC mRNA concentration in the subject by at least 20% as compared to a reference subject suffering from Cushing’s disease, hypercortisolism, Itsenko-Cushing syndrome, or hyperadrenocorticism.” While reducing POMC mRNA concentration in a subject by at least 20% is supported by the instant disclosure, applicant has not pointed out where the amended claim is supported, nor does there appear to be a written description of the claim limitation, “as compared to a reference subject suffering from Cushing’s disease, hypercortisolism, Itsenko-Cushing syndrome, or hyperadrenocorticism.” Applicant may overcome this rejection by amending the claim or pointing how the specification supports the amended claim.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 1, 14, 32, 66, and 72-79 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lu and further in view of Qian and Pivonello.
Lu teaches that HDAC inhibitors are antitumor drugs approved for clinical use with the potential to affect adrenocorticotropin hormone (ACTH) hypersecretion by inhibiting pro-opiomelanacortin (POMC) transcription (pg. 2825, “Context” section). Lu also teaches that the SAHA (i.e., vorinostat) is an oral pan-HDAC inhibitor approved by the FDA and induced growth arrect and increased cell death in pituitary adenoma-derived cells using clinically achievable concentrations (pg. 2826, column 1). Additionally, Lu teaches SAHA significantly decreased human pituitary corticotroph tumor (hCtT) survival and ACTH secretion in tumors derived from surgical extirpation in eight patients with Cushing’s disease (pg. 2828, column 2 and Figures 1(f) and 2(f)). However, Lu does not teach treating hCtTs derived from tumors removed from Cushing’s disease patients with CUDC-907.
Qian teaches CUDC-907 is a novel dual inhibitor of PI3K and HDAC (pg. 4104, column 2) which integrates HDAC inhibitory functionality into a core structure scaffold shared by several PI3K inhibitors (pg. 4105, column 2 and Figure 1). Qian teaches administering CUDC-907 orally to rats (pg. 105, column 2). Additionally, Qian teaches that SAHA (vorinostat) has low oral bioavailability and short half-life in plasma whereas mouse pharmacokinetic studies show that CUDC-907 has an oral bioavailability approximately 2-fold higher than SAHA (pg. 4112, column 1). Qian also teaches that CUDC-907 tends to accumulate in tumor tissue with an AUC (area under the plasma concentration time curve) approximately 2-fold greater than in plasma and that these results suggest that the higher intratumoral accumulation and antitumor activity of CUDC-907 compared with other HDAC inhibitors may potentially result in improved clinical activity (pg. 4112, column 1).
Pivonello teaches the historically, medical therapy has played a secondary role in the management of Cushing’s disease (pg. 426, column 2). Pivonello also teaches that medical therapy is presently considered in the following situations:
1) before surgery, as preoperative treatment, especially in patients with severe disease, in order to control cortisol excess and improve the clinical picture before surgical intervention; 2) after surgery as adjuvant treatment in patients with surgical failure or partial success, due to incomplete removal of the pituitary tumor, while awaiting for the decision of a definitive therapeutic approach, including repeat pituitary surgery, pituitary radiotherapy, or adrenal surgery; 3) before, during, and after pituitary radiotherapy as a bridging treatment, while waiting for the complete effectiveness of radiotherapy; and 4) as first-line treatment, mainly in patients without a clear indication for surgery, due to a pituitary tumor that is nonvisible or with an extrasellar expansion or an unfavorable location, or that is invasive of the surrounding tissue, in case of the lack of availability of an expert pituitary surgeon, in addition to patients who display contraindications for surgery or refuse surgery (pg. 427, column 1).
Additionally, Pivonello teaches clinical trials done for medical treatments of Cushing’s disease. For instance, studies that evaluate outcomes of ketoconazole (200 to 1200 mg/day) and metyrapone (500 to 6000 mg/day) in Cushing’s disease are listed in Table 9 on pg. 431. In the compilation of studies for ketoconazole, patient follow up was done between 0.03-156 months and follow up for metyrapone was done between 0.25-66 months (pg. 431, Table 9). Furthermore, Pivonello teaches that pituitary-directed drugs, including cabergoline, pasireotide, and retinoic acid, have been studied in clinical trials for longer than 24 months (pg. 443, Table 11). Pivonello teaches that in a combination of clinical trials for cabergoline patient follow-up was performed between 6-60 months, in a combination of clinical trials for pasierotide patient follow-up was between 0.03-37.8 months, and in a combination of clinical trials for retinoic acid patient follow-up was between 6-12 months.
It would be obvious to one of ordinary skill in the art to combine the teaching of Lu that the HDAC inhibitor vorinostat is a promising treatment of Cushing’s disease with the teaching of Qian that CUDC-907 is an HDAC inhibitor with higher intratumoral accumulation, higher oral bioavailability, and higher plasma half-life than vorinostat. It is obvious to the skilled artisan that treating Cushing’s disease with CUDC-907 has advantages over vorinostat and the artisan would have a reasonable expectation of success that CUDC-907 would work to treat Cushing’s disease. See In re Sernaker, 702 F.2d 989, 994-95 (Fed. Cir. 1983) (“The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”)
A person having ordinary skill in the art would be motivated to use CUDC-907 in place of vorinostat to treat tumors derived from surgical extirpation in eight patients with Cushing’s disease because CUDC-907 exhibits higher intratumoral accumulation, an oral availability 2-fold higher than vorinostat, and better antitumor activity than vorinostat and thus CUDC-907 would have potentially improved clinical activity than vorinostat.
It would be obvious to a person having ordinary skill in the art to perform clinical trials lasting longer than 36 months for medical treatment for patients with Cushing’s disease. It would be an expected course of experimentation to continue treatments for long periods of time to measure control and remission of the drug on cortisol levels in the patients. It would further be expected to treat patients with Cushing’s disease with daily administrations of the drug as taught by Pivonello. Thus, by combining the teachings of Lu with Qian and Pivonello, one having ordinary skill in the art would treat patients having Cushing’s disease with CUDC-907 for longer than 36 months with daily oral dosages.
The limitations of reducing ACTH concentrations in a subject by at least 30% and 60% (instant claims 76 and 77, respectively), reducing tumor growth in a subject by at least 50% (instant claim 78), and reducing POMC mRNA concentration in a subject by at least 20% (instant claim 79) are the outcomes of steps performed in the administration of CUDC-907 to treat Cushing’s disease. Qian, Lu, and Pivonello teach the steps for administering CUDC-907 to treat Cushing’s disease and, therefore, must necessarily have the same outcomes as instant claims 76-79.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jonathan D. Mahlum whose telephone number is (703)756-4691. The examiner can normally be reached 8:30 AM - 5:00 PM ET, M-F.
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/J.D.M./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625