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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/12/2026 has been entered.
Election/Restrictions
Applicant’s election of Group (I) with the addition of compound 2250
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as the elected compound in the reply filed on 12/09/2024 is acknowledged and maintained.
Priority
This application is a 35 U.S.C. 371 National Phase Entry Application from PCT/IB2020/054852, filed May 21, 2020, which claims the benefit of U.S. Provisional Application No. 62/851 ,424 filed on May 22, 2019.
Claims Status
Claims 1, 4-5, 7-8, 12, and 30 are pending. Claims 2-3, 6, 9-11, and 13-29 are canceled. Claim 12 is withdrawn. Claims 1, 4, 5, 8, 12, and 30 are examined in accordance to the elected species.
Action Summary
Claims 1, 4, 5, 8, 12, and 30 rejected under 35 U.S.C. 103 as being unpatentable over Pfirrmann et al (US10,392,355 B2) in view of Reidenberg et al (WO2020/047113 A1) Salim (Neuroblastoma: Clinical Outcomes and Experimental Studies on Cell Signaling, University of Liverpool, August, 2010.), Jogi et al (PNAS, May 14, 2002, vol. 99, no. 10, 7021–7026), Rosenbaum et al (American Journal of Roentgenology, Volumne 201, Issue 1, June 21, 2013, pages 1-6), and Capozzi et al (Anticancer Research October 2016, 36 (10) 5025-5030), are maintained, but modified and revisited in light of the claim amendment.
Drawings
The drawings are objected to because Figures 7A and 7B are blurred and not clear enough. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Modified and revisited Rejection
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.
Claims 1, 4, 5, 8, 12, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Pfirrmann et al (US10,392,355 B2) in view of Salim (Neuroblastoma: clinical outcomes and experimental studies on cell signaling, University of Liverpool, August 2010), Jogi et al (PNAS, May 14, 2002, vol. 99, no. 10, 7021–7026), Rosenbaum et al (American Journal of Roentgenology, ) Volume 201, Issue 1, June 21, 2013, pages 1-6), and Capozzi et al (Anticancer Research October 2016, 36 (10) 5025-5030).
Pfirrmann teaches a method of treating a subject having pancreatic cancer comprising administering an oxathiazin-like compounds and derivative thereof such as compound 2250
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and/or taurolidine in combination with gemcitabine to the subject. (See claim 12.) Moreover, Pfirrmann teaches the oxathiazin-like compounds and derivatives thereof metabolize much slower in the bloodstream than taurolidine and taurultam. Accordingly, lower doses of such compounds can be administered to a patient to achieve similar effects. (See lines 10-14 of column 3.) Pfirmann also teaches it was unexpectedly found that within minutes of the exposure of taurolidine, tumor cells react by imitating the program of apoptotic cell death by increasing reactive oxygen species (ROS), and by the damage caused be elevated ROS to the mitochondria of the tumor cell results in the loss of their membrane potential and the release of apoptosis induce factor (AIF). (See lines 15-29.) Pfirrmann teaches the method can also treat neuroblastoma and pancreatic cancer among other cancer. (See lines 37-40.) Pfirrmann teaches the method kills tumor cells and/or CSCs, or inhibits their growth, by oxidative stress, apoptosis and/or inhibiting growth of new blood vessels at the tumor site (anti-angiogenesis and anti-tubulogenesis). A primary mechanism of action for killing tumor cells and/or CSCs is oxidative stress. (See lines 66-67 of column 2 bridging lines 1-4 of column 3.) Pfirrmann teaches the compounds can be administered by intravenous. (See lines 15-18.) Furthermore, Pfirrmann teaches oxathiazin-like compounds and derivatives thereof can also be used to treat skin cancer. (See lines 35-45.) Skin cancer is a skin disease, meeting the limitation of claim 12.
Pfirrmann does not specifically teach a subject having a pancratic neuroendocrine tumor in this case pancreatic neuroblastoma.
Salim teaches neuroblastoma is a neuroendocrine tumor arising from the sympathetic chain of the neural crest. (See Section 1.1 on page 8.)
Jogi teaches the hypoxic NB (neuroblastoma) cells increased the expression of TH and other hypoxia-inducible genes, such as VEGF, IGF-2, and GAPDH. (See last paragraph of the left column of page 7024.)
Capozzi teaches the positive results obtained by sunitinib, a multi-targeted tyrosine kinase receptor inhibitor of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR), c-kit, RET, colony stimulating factor-1 receptor (CSF-1R) and Fms-like tyrosine kinase 3 (FLT3), with direct antitumor and antiangiogenic effects, have highlighted the importance of tumor angiogenesis inhibition in controlling pancreatic neuroendocrine tumors (pNETS). (See Abstract.) Moreover, Capozzi teaches the role of angiogenesis in the malignant spread of pNET cells is finally supported by in vivo studies conducted on the RIP1Tag2 mouse model. (See first paragraph of the right column of page 5025.) Capozzi further teaches angiogenesis inhibitors to treat pNETs. (See Title of the second paragraph of the right column of page 5026.) Capozzi further teaches angiogenesis is the development of new blood vessels from pre-existing ones; it is crucial in wound healing, embryogenesis, and normal tissue growth. However, as cancer develops through the angiogenesis process, a tumor can grow only if it is able to build new vessels from the surrounding environment. This process works both in local development and in metastatic spread. Notably, pNETs are highly vascularized neoplasms. This characteristic is associated to the overexpression of both ligand and related receptor of vascular endothelial factor (VEGF). (See third paragraph of the left column of page 5026.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to use the method taught by Pfirrmann for treating pancreatic cancer and neuroblastoma which a pancreatic neuroendocrine tumor where the method exhibits antiangiogenetic inhibitory effect for treating pancreatic neuroblastoma or pancreatic endocrine tumor to give Applicant’s claimed method. One would have been motivated to do so, because not only Pfirrmann teaches GP2250 and gemcitabine can treat neuroblastoma and pancreatic cancer among other cancer, but also because Salim establishes that neuroblastoma is a neuroendocrine tumor, Jogi shows that hypoxia neuroblastoma cells increase VEGF express, underscoring the role of angiogenesis, Capozzi the highlights that inhibiting VEGFR, such as sunitinib, has a direct anti-angiogenic effect and is important for controlling pancreatic neuroendocrine tumors. Given this, a person of ordinary skill in the art would be motivated to apply the same combination to pancreatic neuroendocrine tumors and its associated symptoms, and increase production or localization of reactive oxygen species and its associated symptoms, expecting success, because VEGFR inhibition is recognized to control these tumors through anti-angiogenesis.
It would have further been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to employ the same combination taught by Pfirrmann-already known for treating both pancreatic cancer and neuroblastoma-toward treating pancreatic neuroblastoma or pancreatic endocrine tumors. Given the overlap in tumor types and the established effectiveness of the combination in both, one of ordinary skill in the art would have a reasonably expected success simply by extending that known treatment to this specific tumor subtype.
Applicant’s argument
Applicant argues that the amount of underlying technical analysis that is required to satisfy the standard of "articulated reasoning with rational underpinning" depends, at least in part, on the complexity of the technology. The claimed methods directed to a pancreatic neuroendocrine tumor (referred to as a "PNET" or "pNET") in a subject identified as having a pancreatic neuroendocrine tumor are both new and complex. In view of the amendments, as discussed during the interview, a person of ordinary skill in the art would not have been motivated to use compound 2250 in combination with gemcitabine in a method of treatinga subject identified as having a pancreatic neuroendocrine tumor with a reasonable expectation of success.
Examiner’s response
In response, Applicant’s argument is not persuasive. The prior art references establish a clear rational; Pfirrmann’s combination already treats both pancreatic cancer and neuroblastoma, and Capozzi highlights that inhibiting VEGFR is effective in controlling pNET. Since neuroblastoma is a neuroendocrine tumor (as Salim states), the prior art provides a logical bridge. Thus, the expectation of success is well-grounded and the claim complexity does not negate the clear teachings of the prior art.
Applicant’s argument
Applicant argues that the Office's reasoning that a skilled artisan would have had motivation to treat both PNETs and neuroblastoma and, thus, treating pancreatic neuroblastoma, reading on the claimed methods, has been rendered moot in view of amended claims 1, 4, 5, and 8. The amended claims are not directed to a method of treating pancreatic neuroblastoma. Rather, the claimed methods are directed to treating a subject identified as having a pancreatic neuroendocrine tumor comprising administering to the subject having the pancreatic neuroendocrine tumor compound 2250 in combination with gemcitabine is not disclosed or suggested in the cited references, alone or when viewed in combination.
Examiner’s response
In response, Applicant’s argument is not persuasive. The Examiner is still relying on the broader principle that a skilled artisan would look to analogous tumors. While Applicant amended the claims to focus specifically on pancreatic neuroendocrine tumors, the Examiner’s rationale still holds. The prior art (Pfirrmann, Salim, Jogi, and Capozzi) collectively show that both pNETs and neuroblastoma share significant biological overlap, particularly in their vascularization and VEGF dependence. Thus, a skilled artisan would still be motivated apply the known combination taught by Pfirrmann to the neuroendocrine context because these tumors respond similarly to angiogenesis inhibition. The complexity does not preclude obviousness since the prior art provides the basis for the extension.
Applicant’s argument
Applicant argues that the Office alleged that there would have been motivation to use Compound 2250 and gemcitabine from Pfirrmann based on its listing of neuroblastoma and pancreatic cancer with oxathiazin-like compounds and derivatives and/or taurolidine in combination with gemcitabine. See Office Action at pp. 4 and 7. However, Pfirrmann only mentions treatment with pancreatic tumor cells, including Panc Tu-1 (epithelioid carcinoma origin), BxPC-3 (adenocarcinoma origin), Mia Paca-2 (Pancreatic Ductal Adenocarcinoma origin), ASPC1 (Adenocarcinoma origin) and pancreatic primary tumor cells Bo80 (Pancreatic Ductal Adenocarcinoma origin). See Pfirrmann Example 9. There is no suggestion in Pfirrmann to use compound 2250 and gemcitabine to treat a patient identified as having pancreatic neuroendocrine tumors. In contrast, the specification of the subject application discloses the synergistic effect of 2250 and gemcitabine on QGP-1 and Bo99 pancreatic neuroendocrine tumor cell lines. See Figures 16B and 18. While the Office contended that Pfirrmann discloses neuroblastoma, which is not a PNET in the first place, there was no motivation to select one tumor type (neuroblastoma) out of a long laundry list of tumor types and then apply a combination treatment for a completely distinct tumor, which is not even mentioned, with a reasonable expectation of success.
Examiner’s response
In response, Applicant’s argument is not persuasive. While the experimental result of Example demonstrates synergy for an in vitro assay that utilizes GP-2250 200 µM and gemcitabine in the amount of 100 µM or 1000 µM, such experimental data is not commensurate in scope with the claim. Specifically, the claim broadly recites any amount of compound 2250 and any amount of gemcitabine. Additionally, the observed in vitro synergy with the in vitro concentration does not automatically translate to in vivo. The asserted experiment uses 200 µM GP-2250 and 100 µM or 1000 µM gemcitabine, whereas the claim involves actual administration step-implying in vivo complexity, such as absorption, metabolism, and systemic distribution. Since the claim is broad in scope and not restricted to these in vitro conditions, one of ordinary skill in the art would recognize that achieving the same synergy in a complex in vivo environment is not inherently obvious. Thus, the asserted experimental results asserted by applicant are not commensurate in scope with the claim’s full scope, reinforcing that success in the claimed method would not have been reasonably expected based on the cited experiment alone.
Conclusion
Claims 1, 4, 5, 8, 12, and 30 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628