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 . 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.
Priority
The instant application is a 371 of PCT/US21/48868 filed on 09/02/2021, which claims domestic benefit to US provisional application no. 63/073,770 filed on 09/02/2020.
Status of the Claims
The claim amendments and remarks filed on 11/03/2025 is acknowledged. Claims 1, 6, 8, and 10 are amended. Claims 4-5 and 11-17 are cancelled. Claim 21 is newly added.
Accordingly, claims 1-3, 6-10, and 18-21 are pending and being examined on the merits herein
Withdrawn Objections/Rejections
The objection to the specification is withdrawn in view of the specification amendment filed on 11/03/2025 providing sufficient resolution of the structures.
The objection to the drawings is withdrawn in view of the replacement drawings filed on 11/03/2025.
The objection to claim 5 is withdrawn in view of claim 5 being cancelled.
The 35 USC 112(b) rejections for claims 1-9 are withdrawn. Claim 5 is cancelled, and claims 1 and 6 have been amended to remove the “such as” phrases.
The 35 USC 102 rejection over Francesconi for claims 6 and 8-10 are withdrawn in view of the removal of the compound “etoposide” in claim 6 and claim 10 now requiring at least two of the recited compounds, which has also narrowed the scope of the claims.
The 35 USC 103 rejection over Marks for claims 6 and 9-10 and over Marks in view of Boddy and Yang for claim 7 are withdrawn in view of the removal of the compound “etoposide” in claim 6 and claim 10 now requiring at least two of the recited compounds, which has also narrowed the scope of the claims.
The 35 USC 103 rejection over Moore in view of Folle and Rubin for claims 1-5, 10, and 18-20 is withdrawn in view of claims 4-5 being cancelled, the removal of the compound “etoposide” in claim 1, and claim 10 now requiring at least two of the recited compounds, which has narrowed the scope of the claims.
Claim Objections
Claim 6 is objected to because of the following informalities:
Claim 6 recites “ … (c) propantheline and/or an analog thereof;.” The semicolon at the end of the recited (c) group should be removed.
Appropriate correction is required.
The following grounds of rejections are new as necessitated by Applicant’s amendment to the claims.
Claim Rejections - 35 USC § 112
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 10 and 18-20 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.
Claim 10 recites “A pharmaceutical composition comprising; (a) … (b) … (c) … (d) … (e) … (f)…”.
Claim 10 is indefinite because a conjunction is missing between the recited groups, making it unclear if the groups are alternatives or all required.
For purposes of examinations, claim 10 is being interpreted as the recited groups being alternatives based on these groups being recited as alternatives in the previous claim set.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 6, 9-10, and 18-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Heinrich et al. (US20050032724A1 in PTO-892).
Heinrich teaches the use of irinotecan or derivative thereof for the preparation of a pharmaceutical composition for treating cancer, especially, colorectal cancer, cervical cancer, gastric cancer, lung cancer, malignant glioma, ovarian cancer, and pancreatic cancer in a patient having a genotype with a variant allele (see Abstract).
Heinrich teaches a method of treating cancer in a patient having one or more variant alleles of the MRP1 gene which indicates resistance or predisposition to resistance to irinotecan which comprises administering to the patient an increased amount of irinotecan (claim 18). Heinrich further teaches that for this method, patients that have a variant allele that indicates resistance or predisposition to resistance are treated with an MRP1 inhibitor such as quinidine and among others (claims 19-20). Here, the combination of irinotecan and quinidine in the method of Heinrich described above meets the alternative group (a) recited in instant claim 10.
Therefore, instant claims 6, 9-10, and 21 are anticipated.
In regards to instant claims 18-20, Heinrich teaches that their pharmaceutical compositions comprising the compounds can be conveniently administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation (see paragraph 0024).
Therefore, instant claims 18-20 are anticipated.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Moore et al. (WO2011115804A1 in PTO-892 dated 08/01/2025) in view of Folle et al. (Journal of Pharmacology and Experimental Therapeutics, 1966 in PTO-892 dated 08/01/2025), and as evidenced by MedlinePlus (in PTO-892 dated 08/01/2025).
Moore et al. discloses sGC stimulator compounds and their use, alone or in combination with one or more additional agent, for treating various diseases (see paragraph 002). Moore et al. discloses their compositions can be formulated for oral, parenteral, and nasal administration (see paragraphs 00156-00157). Moore et al. discloses that their compounds can be used to treat peripheral or cardiac vascular disorders/conditions which can benefit from sGC stimulation and includes pulmonary arterial hypertension and idiopathic pulmonary hypertensions and among other types (see paragraph 00187) as well as diseases related to high blood pressure such as arrythmias and among others (see paragraph 00187). Moore et al. discloses combination therapies which include the sGC stimulator compounds and one or more additional therapeutic agents for treatment a disease or disorder mediated, regulated, or influenced by sGC, cGMP, and/or NO (see paragraphs 00198 and 00201-00205). Moore et al. discloses examples of other therapeutic agents that can be combined, which include calcium channel blockers (see list number (9) in paragraph 00208), endothelin receptor antagonists such as bosentan (see list number (10) in paragraph 00208), and antiarrhythmic agents such as Type I (sodium channel blockers) which include quinidine (see list number (18) in paragraph 00208), and among several other listed agents.
Although Moore et al. suggests the combination of a sGC stimulator compound and several additional agents including bosentan and quinidine, Moore et al. does not expressly teach the combination of their sGC stimulator compound and quinidine for treating pulmonary hypertension.
Folle et al. disclose the cardiopulmonary effects of quinidine and procainamide (see Abstract). Folle et al. discloses in anesthetized dogs, the intravenous injection of quinidine consistently induced a fall in systemic blood pressure but a biphasic rise and fall in pulmonary arterial pressure (see Abstract). Folle et al. demonstrates in Fig. 3 and Fig. 7 that intravenous administration of quinidine resulted in an initial rise and delayed fall in pulmonary arterial pressure. Folle et al. discloses that the consistent pulmonary vasodilation initiated by both quinidine and procainamide is desirable when these drugs are used to treat arrhythmias associated with chronic cor pulmonale (see left column on page 102). Folle et al. discloses that this vasodilation would mean a reduction in pulmonary arterial pressure and in work load to the failing right ventricle (see left column on page 102). Here, as evidenced by MedlinePlus, cor pulmonale is a condition that causes the right side of the heart to fail due to certain conditions including pulmonary hypertension.
It would have been prima facie obvious to combine Moore et al. with Folle et al. before the effective filing date of the claimed invention by selecting quinidine for the combination therapy with the sGC stimulator compounds disclosed in Moore et al. for treating pulmonary hypertensions such as pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make these selections with a reasonable expectation of success because Moore et al. establishes combination therapies for treating various peripheral or cardiac vascular disorders/conditions which include pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension as well as related blood pressure conditions such as arrythmias. Furthermore, Folle et al. provides guidance that quinidine induces pulmonary vasodilation and may reduce pulmonary arterial pressure and can be beneficial for treating arrhythmias associated with chronic cor pulmonale, which is also a related blood pressure condition.
Claim(s) 6 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Ru et al. (International Journal of Oncology, 2015 in PTO-892).
Ru investigated the effect and mechanisms of quinidine, a commonly used voltage‑gated K+ channel blocker, on cell proliferation and apoptosis of U87‑MG cells (human glioblastoma cell line) (see Abstract). Ru demonstrates in Figure 1 on page 836 that quinidine significantly inhibited the proliferation of U87‑MG cells and induced apoptosis in a dose‑dependent manner. Ru further discloses that the anti‑proliferative and pro‑apoptosis effect of voltage‑gated K+ channel blocker quinidine in human glioma cells was mediated at least partly through regulating expression of miRNAs, and provided further support for the mechanisms of voltage‑gated K+ channels in mediating cell proliferation and apoptosis (see Abstract).
Even though Ru does not disclose administering an effective amount of quinidine to a subject in need thereof, it would have been prima facie obvious before the effective filing date of the claimed invention to have administered quinidine to a subject for treating glioblastoma. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Ru demonstrates that quinidine inhibited proliferation and induced apoptosis of human glioblastoma cancer cells in a dose-dependent manner.
Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ru et al. (International Journal of Oncology, 2015 in PTO-892), as applied to claim 6 above, and further in view of Li et al. (Cancer Cell, 2009 in PTO-892).
The teachings of Ru are as described above and teach the method of claim 6 as discussed above.
The difference between Ru and the claimed invention is that Ru does not teach a cancer that is characterized by an increased expression or activity of HIF-2alpha.
Li teaches that glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs) and further disclose that hypoxia-inducible factor HIF2α and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors (see Abstract). Li demonstrates in Figure 8 that elevated HIF2A expression is associated with poor survival of glioma patients.
It would have been prima facie obvious before the effective filing date of the claimed invention to have administered the quinidine disclosed in Ru to treat a glioblastoma patient with elevated HIF-2alpha expression as disclosed in Li to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to make this modification because Li teaches that elevated HIF2A expression is associated with poor survival of glioma patients. Furthermore, one of ordinary skill in the art would have made this modification with a reasonable expectation of success because Ru demonstrates that quinidine inhibited proliferation and induced apoptosis of human glioblastoma cancer cells in a dose-dependent manner.
Claim(s) 9-10 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Ru et al. (International Journal of Oncology, 2015 in PTO-892), as applied to claim 6 above, and further in view of Vredenburgh et al. (Neuro Oncol. 2009 in PTO-892)
The teachings of Ru are as described above and teach the method of claim 6 as discussed above.
The difference between Ru and the claimed invention is that Ru does not teach further administering one or more additional therapeutic agent such as irinotecan.
Vredenburgh teaches the use of irinotecan for the treatment of malignant glioma (see Abstract). Vredenburgh teaches that malignant glioma is the most commonly occurring primary malignant brain tumor and is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course (see Abstract). Vredenburgh teaches that chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival (see Abstract). Vredenburgh teaches that novel agents and new approaches to therapy are required to improve clinical outcomes and further discloses that irinotecan is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription, and can cross the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts (see Abstract). Vredenburgh teaches that its antitumor activity has also been demonstrated against glioblastoma cells with multi-drug resistance, and studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Vredenburgh teaches that irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results, and its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents (see Abstract).
It would have been prima facie obvious before the effective filing date of the claimed invention to have combined the quinidine disclosed in Ru with the irinotecan disclosed in Vredenburgh for treating a glioblastoma patient. One of ordinary skill in the art would have made this combination because both Ru and Vredenburgh teach that their respective agents are useful for the same purpose of treating glioblastomas. See In re Kerkhoven, MPEP 2144.06 section I.
Response to Arguments
Applicant’s arguments filed on 11/03/2025 have been fully considered in so far as they apply to
the rejections of the instant office action, but were not persuasive.
Applicant states that Moore in view of Folle and Rubin fail to teach or suggest a method of treating PAH comprising administering an effective amount of the compounds recited in instant claim 1 or 10. Applicant states that Moore does not teach administering quinidine to treat PAH, and that the sole mention of quinidine in Moore relates to its use as an antiarrhythmic agent. Applicant further states that Folle fails to remedy this defect because Applicant states that while Folle may investigate the effect of quinidine on pulmonary artery pressure, Applicant states this reference does not teach or suggest quinidine can effectively treat PAH. Applicant states that Folle reports “a complex action on pulmonary blood vessels”, characterized by an initial increase in pulmonary artery pressure, followed by a small and transient decrease in pressure (page 94 left column in Folle). Applicant states that in view of this teaching, a skilled artisan would not have considered quinidine, nor would have a reasonable expectation of success to treat PAH, and instead would expect that the undesirable increase in pulmonary artery pressure, coupled with negligible transient pressure decrease and lack of proportional dose-response, to render quinidine unsuitable for treating PAH.
Applicant’s arguments above were not found persuasive because while Folle teaches a biphasic rise and fall in pulmonary arterial pressure, Folle concludes and establishes that quinidine induces consistent pulmonary vasodilation (e.g. see Fig. 4 and 5) and can be beneficial for treating arrhythmias associated with chronic cor pulmonale, which is also a related pulmonary blood pressure condition. Furthermore, Folle provides guidance that this pulmonary vasodilation would mean a reduction in pulmonary arterial pressure and in work load to the failing right ventricle. Additionally, Moore et al. establishes combination therapies of sGC stimulator compounds along with additional agents, which include quinidine and bosentan, for treating various peripheral or cardiac vascular disorders/conditions such as pulmonary arterial hypertension and idiopathic pulmonary arterial hypertension as well as arrythmias.
Therefore, an ordinary skilled artisan, when viewing the combined teachings of Moore and Folle, could have predictably selected quinidine for the combination therapy with the sGC stimulator compounds as disclosed in Moore et al. for treating pulmonary hypertensions with a reasonable expectation of success.
Applicant states that Moore does not teach or suggest that quinidine alone can be used to treat PAH. Applicant states that the references also do not teach HEAQ, propantheline, ethacridine, or irinotecan and their uses for treating PAH.
Applicant’s arguments above were not found persuasive because the method in instant claim 1 recites the open-ended phrase “comprising”. See MPEP 2111.03 I. Therefore, any additional agents such as the sGC stimulator compounds in Moore are within scope of these claims. Furthermore, it is noted that the method in instant claim 1 only requires one of either quinidine, HEAQ, propantheline, ethacridine, or irinotecan for the treatment of PAH, which means the prior art does not need to teach all of the recited compounds and/or their use for treating PAH. Therefore, the rejection over Moore in view of Folle meets this limitation as described above.
Conclusion
No claim is found allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format.
For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693