DETAILED ACTION
This Office Action details a final action on the merits for the above referenced application No. Claims. 1-19 are pending in this application.
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 of Claims
Claims 1-19 are original.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 17 Sep. 2026 has been considered by the examiner.
Response to Amendment
The amendments filed on 4 Sep. 2026 have been entered.
Response to Arguments
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) 1-3, and 8-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Belhabib et al. (Cancers; published 11 Jul. 2021), in view of Palti et al. (US 2005/0209642 A1; published 22 Sep. 2005) for the reasons cited in the Office action filed on 5 Jun. 2026.
Belhabib et al. teach extracellular matrices and cancer associated fibroblasts: targets for cancer diagnosis and therapy (see title). Belhabib et al. teach that stroma modifications such as fibroblast activation into cancer associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling are now recognized as critical events for cancer progression and as potential therapeutic and diagnostic targets (see abstract). Fibroblasts become activated into CAFs under cancer stimulation, and favor cancer development (pg. 2). Belhabib et al. teach therapeutic targeting of the microenvironment and combination therapies (pgs. 14-15). FAP+ CAF depletion disrupts a CAF/cancer cell dialog through CXCR4/CXCL12 pathway inhibition restoring immune control of tumor growth. In addition to FAP another CAF marker, α-SMA has been targeted (pg. 15). FAP and PGDFRb are markers (pg. 2 table 1). Belhabib et al. teach LRRC15 as a marker (table 1, ref. 47). Belhabib et al. teach that glioblastoma-, breast cancer-, fibrosarcoma- and melanoma-derived exosomes contain and release MMP-2 activators such as Hsp90 that enhance cancer cell invasion by degrading collagens (pg. 12). Inhibition of lysyl oxidase, proteins responsible for collagen crosslinking and stabilization has showed mitigated results. LOX inhibitor (through BAPN) not only reduced collagen crosslinking and fibronectin assembly but also increased drug penetration and resensitized tumors to doxorubicin treatment in breast cancer and enhanced sensitivity to radiotherapy (pg. 19; scheme 2). In human hepatocellular carcinoma, the level of LOXL2 is highly increased and correlates with metastasis occurrence (pg. 11). Belhabib et al. teach preventing tumor progression (pg. 19) and intra-tumoral therapy (pg. 6).
Belhabib et al. do not teach the claimed methods of treating a subject, reducing or preventing CAF activation, and reducing CAF signaling comprising a step of applying alternating electric fields to a target site in a patient or to a population of cells comprising one or more fibroblasts optionally wherein the electric field has a frequency between 50 kHZ and 1 MHz or about 150 or 250 kHz and optionally wherein the electric field has a field strength of between 0.5 and 10 V/cm RMS or about 0.9 V/cm RMS.
Palti et al. teach treating a tumor or the like with electric fields at different orientations (see title). Palti et al. teach that cells in late anaphase or telophase stages of cell division are vulnerable to damage by AC electric fields that have specific frequency and field strength characteristics. The selective destruction of rapidly dividing cells can therefore be accomplished by imposing AC electric field in target region for a time. This selectively damages dividing cells like tumor cells but does not harm normal cells (abstract). Palti et al. teach methods for destroying cells that do not rely on chemotherapy alone ([0008]). Palti et al. teach the efficiency of cell destruction as a function of field strength for melanoma and glioma with frequency ranging from 50 kHz to 300 kHz and field strengths ranging from 1 to 2.5 V/cm (Figs. 29A, 29B, 30A, and 30B). The desired filed strength is between 0.1 and about 10 V/cm ([0090]). Frequencies are in the range of 50 kHz to about 500 kHz ([0071]). Palti et al. teach that undesirable fibroblast proliferation associated with wound healing, leading to scar and keloid formation after surgery or injury can be inhibited by application of the electric field according to the inhibited by application of an electric field in accordance with the invention ([0158]-[0160]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Belhabib et al. (methods of treating a subject and reducing or preventing CAF activation or reducing CAF signaling comprising administering optionally intratumorally or contacting a CAF inhibitor, a CAF activation inhibitor or a CAF signaling inhibitor such as a FAP inhibitor or a lox inhibitor that prevents collagen cross linking and elastin in ECM) by applying an alternating electric field to a target site of the subject in need thereof or to a population of cells before, after, or simultaneously as taught by Palti et al. because the application of the electric field would have been expected to advantageously enable tumor treatment and prevention of fibroblasts from becoming activated into CAFs preventing the formation of abnormal ECM that represents a breeding ground of cancer cells. The frequency and electric field strength of the alternating electric field are result effective variables that a person of ordinary skill in the art would have been motivated to optimize at the time of invention.
MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a frequency between 50 kHz and 1 MHz or about 150 or 250 kHz through routine experimentation in order to arrive order to arrive at an optimal frequency for preventing undesirable fibroblast proliferation and for treating tumor cells. A person of ordinary skill in the art would have arrived at a field strength of between 0.5 and 10 V/cm RMS or about 0.9 V/cm RMS through routine experimentation in order to arrive at an optimal field strength of for preventing undesirable fibroblast proliferation and for treating tumor cells.
Applicants’ Arguments
Applicants assert that Belhabib teaches that a combination therapy, namely treatment with a LOX inhibitor in combination with gemcitabine did not improved clinical outcomes. A person of ordinary skill would not have been motivated to combine a CAF inhibitor with any cancer therapeutic and one of ordinary skill would not have had a reasonable expectation that any combination would be successful. Simply inhibiting fibroblast proliferation associated with would healing with an electric field would not have provided the motivations to combine an alternating electric field with a CAF inhibitor since CAFs have nothing to do with wound healing and would not have provided one of ordinary skill a expectation that such a combination, namely anticancer therapy could be successfully used in combination with a wound healing therapy as taught by Palti. Neither Belhabib nor Palti understood the negative effect an electric field had on CAFs and would not have found it obvious to combine a CAF inhibitor with an alternating electric field. The current specification teaches that because alternating electric fields can increase CAFS one would want to inhibit CAFs so as to treat with an alternating field can continue without negative consequences.
Applicants’ arguments filed 4 Sep. 2024 have been fully considered but they are not persuasive.
In response to applicant's argument that the specification teaches that alternating electric fields can increase CAFs and thus, the fact that the inventor has recognized another reason for applying an alternating electric field to the target site of a subject cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Belhabib and Palti provide adequate reason and motivation for treating a subject in need thereof wherein the subject is undergoing therapy that includes administration of a CAF inhibitor to further treat the subject by applying an alternating electric field to the target site.
At pg. 2, Balhabib teaches that fibroblasts are the major components for the tumor microenvironment in most solid tumors and become activated into CAFs under cancer cell stimulation and in turn favor cancer development via secretion of ECM and soluble factors. During tumorgenesis, quiescent fibroblasts are activated in response to various stimuli including oxidative stress and growth factors such as PDGF, EGF, FGF, and SHH. CAFs have been shown to deposit fibronectin. This creates in the case of wound healing a positive feedback loop that keeps the fibroblasts in activated state in which YAP is translocated to the nucleus and α-SMA overexpressed. At [0158], Palti teaches that undesirable fibroblasts associated with wound healing can be inhibited by application of an electric field. At for example title, Palti teaches treating tumors.
Regarding treatment of the subject by administering to the subject a CAF inhibitor such as a FAP inhibitor, at pgs. 14-15, Belhabib teaches that the administration of a FAP inhibitor kills CAFs in restores immune control in tumor growth. While Belhabib teaches that some combinations therapies in some cases did not improve survival outcome, Belhabib does not teach that a combination therapy that includes and application of alternating electric fields as claimed and Belhabib stresses a need to better identify patients that would respond to therapy. In the case of treating a subject by administering FAP inhibitor to kill CAFs, a person of ordinary skill in the art in view of Palti would have understood it to be beneficial to additionally apply an alternating electric field at the tumor site because the application of the alternating electric fiekd would have been expected to prevent the positive feedback loop that keeps fibroblast in activated state and prevents the recruitment of additional fibroblast and because the application would have been expected to weaken the ECM. While the administration of a FAP inhibitor alone may reduce a CAF population, the administration of FAP inhibitor alone would not prevent activation of new fibroblasts. A recognized advantage is the strongest reason to combine.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the methods of Behabib (methods that treat a subject in need thereof comprising administering a CAF inhibitor to the subject optionally together with another therapy resulting in a combination therapy) so that the method further applies an alternating electric field to the target site of the subject in need thereof as taught by Belhabib and Palti because the applying would have been expected to prevent the positive feedback loop that keeps fibroblasts in an activated state whereby weaking the ECM, a breeding ground of cancer cells, and preventing the recruitment and activation of additional fibroblasts.
Claim(s) 1-5, and 7-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Belhabib et al. (Cancers; published 11 Jul. 2021), in view of Palti et al. (US 2005/0209642 A1; published 22 Sep. 2005), in further view of Sunami et al. (Cancers; published 9 Feb. 2021) and Dzobo et al. (OMICS A J. Int. Biol.; published 2020) for the reasons cited in the Office action filed on 5 Jun. 2026.
Belhabib et al. teach as discussed above.
Belhabib et al. do not further a FAP inhibitor that is talabostat, or an LRRC15 inhibitor that is ABBV-085 antibody or a PDGFGRβ inhibitor that is CP-673451.
Palti et al. teach as discussed above.
Sunami et al. teach targeting and reprogramming cancer associated fibroblasts and the tumor microenvironment in pancreatic cancer (see title). Sunami et al. teach that talabostat is an inhibitor of FAP and clinical trials targeting FAP using talabostat (see table 1). Sunami et al. teach clinical trials targeting LRRC15 using ABBV-085 (table 1) that inhibits cancer cells tumor xenograft growth (pg. 6).
Dzobo et al. teach broadening drug design and targets to tumor microenvironment (see title). Dzobo et al. teach that several studies demonstrated that inhibiting CAFs from expressing several markers, including PDGFR-β can prevent cancer growth (pg. 348). Dzobo et al. teach that inhibition of PDGFR by cp-673451 induces apoptosis (pg. 351).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Belhabib et al. so that the subject in need of treatment gets administered a FAP inhibitor wherein the FAP inhibitor is talabostat, a LRRC15 inhibitor wherein the LRRC15 inhibitor is ABBV-085, and/or a PDGFGRβ wherein the inhibitor is CP-673451 as taught by Sunami et al. and Dzobo et al. because those inhibitors would have been expected to advantageously enable concurrent treatment of CAF associated cancers.
Applicants’ Arguments
Applicants assert that Sunami and Dzobo fail to teach any motivations for combining the teachings of Belhabib and Palti.
Applicants’ arguments filed 4 Sep. 2024 have been fully considered but they are not persuasive. Belhabib and Palti were found to be sufficient for the reasons discussed above. Sunami and Dzobo teaches and motivates therapeutic treatment using CAF inhibitors such as talabostat, ABBV-085, and CP-673451.
Claim(s) 1-3, 6, and 8-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Belhabib et al. (Cancers; published 11 Jul. 2021), in view of Palti et al. (US 2005/0209642 A1; published 22 Sep. 2005), in further view of Sontake et al. (JCI Insight; published 2017) for the reasons cited in the Office action filed on 5 Jun. 2026.
Belhabib et al. teach as discussed above.
Belhabib et al. do not further teach a Hsp90 inhibitor that is 17-AAG.
Palti et al. teach as discussed above.
Sontake et al. teach Hsp90 regulation of fibroblast activation in pulmonary fibrosis (see title). Sontake et al. teach that in vivo therapy with 17-AAG attenuated progression of established and ongoing fibrosis (see abstract). Several studies have demonstrated that inhibition of Hsp-90 activity significantly impacts migration and invasion of cancer cells. An inhibitor of Hsp-90 17-AAG exerts antitumor effects. Inhibition of Hsp90 by 17-AAG repressed ECM production in murine renal and liver fibrosis models (see pg. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Belhabib et al. so that the CAF inhibitor is a Hsp90 inhibitor that is 17AAG as taught by Belhabib et al. and Sontake et al. because the Hsp90 inhibitor that is 17-AAG would have been expected to advantageously enable concurrent treatment of cancer and a reduction of a ECM breeding ground.
Applicants’ Arguments
Applicants assert that Sontake fails to teach or suggest any motivation for combining the teachings of Belhabib and Palti.
Applicants’ arguments filed 4 Sep. 2024 have been fully considered but they are not persuasive. Belhabib and Palti were found to be sufficient for the reasons discussed above. Sontak teaches and motivates therapeutic treatment using the 17-AAG CAF inhibitor.
Conclusion
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.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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