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 .
Applicant’s response filed 05/12/2026 has been received and entered into the case. All arguments and amendments have been considered.
Claims 1-10, 14-17 are pending and have been considered on the merits herein.
New objection and rejection necessitated by amendment
Claim Objections
Claim 1 is objected to because of the following informalities: the last line of claim 1 should have an “of” between “inhibition CDK4/6…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-10, 14-17 are 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. Specifically, the amendment to claim 1 stating “…administering an E2F inhibitor to the cancer cells to cause a synergistic increase in the inhibition of the one or the E2F family of transcription factors ” introduces new matter, which is not described in the specification as originally filed. Applicants’ specification does not demonstrate a synergistic increase in the inhibition of transcription factors when administering E2F and TTF to cancer cells. Applicants do not provide any data or a showing of synergy regarding transcription factors. The change in transcription factors is only demonstrated when applying TTF’s (see for example Fig. 3), but no data for when the combination of TTF and E2F inhibitors are applied/administered to demonstrate synergy. Applicants’ specification demonstrates a synergistic effect in the reduction of cancer cells (measured in cell survival and clonogenic survival assays) when TTF is applied for 72hours, in combination with 20 µM of E2F inhibitor HLM006474 and 0.5 µM of the CDK4/6 inhibitor abemaciclib (see Fig. 7A and B and Fig. 10, parag. 0071, 0076); however, the specification does not provide any data supporting the synergistic increase in inhibition of transcription factors with E2F inhibitor (with TTF). Therefore, the amendment changes the scope of the claims and applicants’ invention for which no support is provided. This is a new matter rejection.
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.
Claim 1 and dependent claims 2-10, 14-17 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.
Applicants have amended claim 1 to include the limitation of “to cause dysregulation of a CDK-RB-E2F axis within the cancer cells, the dysregulation comprising an inhibition of one or more transcriptional activators of the E2F family of transcription factors and an increase of one or more repressors of the E2F family of transcription factors…”. While applicants have verbatim support for this limitation in the specification, it is not clear what the activators and repressors of the transcription factors refer to. The scope of this limitation is interpreted in light of the specification, which teaches that transcriptional activators and repressors are inhibited and activated by TTF, which is measured in E2F target expression assays, which measures E2F target genes seen in Fig. 3A-D. Thus, for examination purposes, a teaching of dysregulation of E2F target genes is taken to meet the claimed limitation.
New rejection amended in light of applicants amendments
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.
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) 1-7, 10, 14-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krex et al. (US20190307781, IDS) in view of Karanam et al (Cell Death and Disease, 2017), Kent et al. (Nature, 6/2019, p. 326-338, IDS), WO2009/117484 (IDS) (to Cress et al.) Militello et al. (Front. Oncol., 2019, p. 1-7, IDS) supported by Giladi et al. (Seminars in Oncol., 2014, p.S35-S41, IDS) and Kirson et al. (BMC, Med. Phys. 2009, p. 1-13, IDS).
Regarding claims 1, 4, Krex teaches reducing survival of and killing cancer cells (0033) in a subject by applying alternating electric fields (Tumor Treating Fields (TTFields) with a frequency between 100-300 kHz to the cancer cells (abstract, 0002). The TTFields is administered with a therapeutic agent for treating cancer, specifically glioblastoma multiforme brain tumors (0002, 0004-0007).
Regarding claim 16 , the cancer cells are glioblastoma cells (0004, 0015, 0044).
Regarding claim 2, the at least a portion of the applying step is performed simultaneously with at least a portion of the administering step (0008).
Regarding claim 3 , the applying alternating electric fields step has a duration of at least 72 hours (0008).
Regarding claim 4, the frequency of the alternating electric field is between 180-220 kHz (0009).
Regarding claim 5, the alternating electric field has a field strength of at least 1 V/cm in at least some of the cancer cells (0010).
Regarding claim 17, Krex teaches that the combination treatment led to a 50% reduction in the number of cells (0054-0057, 0066-0072, Fig. 5-8).
While Krex does not specifically teach applicants newly added amendment to claim 1, drawn to applying alternating electric fields to cancer cells at a frequency “to cause a dysregulation of a CDK-RB-E2F axis within cancer cells, the dysregulation comprising inhibition of …and increase of … E2F family transcription factors”, this limitation is taken to necessarily happen as a result of applying the alternating electric field at the claimed frequency and for the claimed duration, as taught by Krex.
Further, support is provided by Karanam who teach applying TTF’s to cancer cells at a frequency of between 100-300kHz for up to 72 hours (p. 2, Results section TTfields reduce section). TTF target cancer cells though the exploitation of cell proliferation, inducing apoptosis in cancer cells, prevention of formation of the mitotic spindle, leads to microtubule depolymerization disrupting cytokinesis, thus exhibiting antiproliferative effects and cytotoxicity. When combined with chemotherapeutic drugs, TTF also enhance the efficacy of the drugs as well as radiation when combined with radiation treatment (p. 1, last parag.-p. 2, 1st parag., p. 3, 1st parag.). Karanam treat cancer cell lines with TTF to determine if the TTF’s induce additional mechanisms leading to cell death by performing gene expression analysis to determine the perturbation of genes. The reference finds that there was a significant association of expressed genes in the BRCA1 pathway when treated with TTF’s, thereby suggesting mechanisms involving DNA repair and replication beyond the abortive mitosis cell death mechanism known. When cancer cells are treated with TTF’s at a frequency of between 100-300kHz for up to 72 hours, genes in the BRCA1 pathway were inhibited such genes including BRCA1, FANCD2 and FANCA (these genes are disclosed by applicant to be “E2F transcriptional activators and repressors”, see Fig. 3A, 3C and 3D) (p. 3, BCA1 pathway section-p. 4, 1st parag., Fig. 4, Discussion section p. 6, last parag.-p. 7, whole page).
Krex does not teach administering CDK4/6 inhibitors and a E2F inhibitor as the therapeutic agents, with the TTFields (according to claims 1, 10, 14, 15) or the limitations of claims 6, 7.
Kent teaches E2F dysfunctions in cancer as well as the CDK-RB-E2F axis, which forms the core transcriptional machinery driving cell cycle progression (abstract, p. 326-328, p. 331, 2nd col.). E2F genes are major transcriptional regulators of cells cycle dependent gene expression and Kent teaches that high E2F transcriptional activity observed in virtually all cancers is most commonly a result of perturbation of the CDK-RB-E2F axis, by inactivation of its regulator RB, overexpression of CDK’s or inactivation of CDK inhibitors (abstract, p. 326-328, p. 328, 2nd col. 3rd full parag., p. 331, 2nd col.). Kent teaches that targeting the CDK-RB-E2F axis has become a key strategy in cancer treatment and CDK4/6 inhibitors including abemaciclib which led to stable cell cycle arrest in G1, limit tumor growth and induce tumor cell death have been approved for treating breast cancer, due to decreased expression of E2F target genes (p. 334, Targeting CDK-RB-E2F section and Box 1). Kent additionally suggests that E2Fs and their targets could play a role in sensitivity to CDK4/6 inhibition and while CDK4/6 inhibition is effective to suppress tumorigenesis, blocking E2F activity also limits tumor cell proliferation and viability (p. 335, 1st parag.). Kent teaches that HLM006474 effectively inhibits E2F activity by inhibiting multiple E2F’s and has been shown to have anti-proliferative and pro-apoptotic activity in multiple cancer cell lines and reduces tumor growth (p. 335, Small molecule inhibition section). When tested in combination with CDK4/6 inhibitors, HLM006474 has a synergistic effect in reducing proliferation of lung cancer cells in vitro (p. 335, whole 1st col.) and that targeted inhibition of E2F in combination with CDK4/6 inhibition may be the ideal treatment option, increasing CDK4/6 inhibitors and prevent resistance (p. 335, col. 2, 1st and 2nd parag.).
WO2009/117484 teaches HLM006474 to be a small molecule inhibitor of E2F activity having therapeutic efficacy in cancer, specifically cancers including non-small cell lung cancer, breast cancer, ovarian cancer, renal cancer, melanoma (skin) cancer, for example (p. 9, lines 13-18) by promoting or inhibiting cellular function including gene expression, protein expression, protein activity, cell growth, proliferation, apoptosis and the like (p. 9, lines 23-25). A therapeutically effective amount administered reduces size of a tumor, inhibits or stops tumor metastasis, inhibit or stops tumor growth, inhibits or stops cellular proliferation, inhibits or stops expression and activity of members of the E2F family (p. 9, lines 26-35) including E2F1 (Fig. 17, Ex. X, for example).
Regarding claims 6, 7, WO484 teaches administering at a dose of 40µM (p. 11, lines 24-30, Ex. II, p. 15, see Ex. II-VII, IX, X). The compound produces 50% inhibition of growth of cell lines treated with HLM006474 (Ex. IV, p. 16-17).
Militello teaches the mechanism and use of CDK4/6 inhibitors in BRCA-mutated breast cancers. They teach that palbociclib, ribociclib and abemaciclib are three CDK4/6 inhibitors used for treating BRCA-associated breast cancers (background section). Wild-type BRCA is involved in G1 cell cycle arrest. BRCA1 binds to hypophosphorylated RB, which interacts with the E2F transcription factor to block transcription and inhibit cell proliferation. In the presence of BRCA1 mutations, this antiproliferative control fails. However, in those cases, CDK4/6 inhibitors may restore the G1 arrest, preventing the cell from entering mitosis (p. 3, 2nd col., see entire document), thus inhibiting cell cycle expression.
Thus, before the effective filing date of the claimed invention, E2F inhibitor HLM006474 and CDK4/6 inhibitors including abemaciclib, palbociclib and ribociclib were known to be used for effectively reducing and killing cancer cells, and used as chemotherapeutic agents in patients having lung cancer, breast cancers, glioblastoma and melanoma. Additionally, Kent suggests that the combination of E2F inhibitors with the specific CDK4/6 inhibitors has a synergistic effect in reducing proliferation of lung cancer cells in vitro (p. 335, whole 1st col.) and that targeted inhibition of E2F in combination with CDK4/6 inhibition may be the ideal treatment option, increasing CDK4/6 inhibitors and prevent resistance. Thus, Kent, WO484 and Militello teach that the E2F and CDK4/6 inhibitors function as claimed. Therefore, a POSITA would have had a reasonable expectation of successfully using both an E2F and CDK4/6 inhibitor for reducing and killing cancer cells in the method of Krex.
In addition, methods of applying TTFields (alternating electric fields) in combination with chemotherapeutic agents to reduce and kill cancer cells was known in the art before the effective filing date as demonstrated by Krex. However, additive and synergistic effects when combined with chemotherapeutic agents is suggested by Giladi and Kirson.
Giladi teaches applying alternating electric fields (TTFields) to NSCLC cells in combination with chemotherapeutic agents and find that the addition of TTFields at a frequency of 150 kHz for 72 hours resulted in enhanced treatment efficacy across all cell lines tested, thus providing an additive efficacy benefit in treating NSCLC and reducing the survival of cancer cells by at least 20 fold compared to controls not receiving TTFields and chemotherapeutic agents (abstract, p. S36, whole page, S37, Results and discussion section-p. S39, Fig. 1-3).
Kirson teach the combined therapy of TTFields with chemotherapeutic agents when applied to breast cancer and glioma cell lines and also find that TTFields increases chemotherapeutic efficacy and sensitivity without increasing treatment related toxicities (abstract). Kirson applied alternating electric fields at 150 and 200 kHz, having a field strength of at least 1 V/cm to cancer cells for 72 hrs in combination with chemotherapeutic agents (p. 2, whole page, Methods section, TTFields treatment section, p. 4, Results section, Fig. 1, p. 5, whole page, Fig. 2-3, p. 8) and observe irreversible and complete inhibition of cell proliferation. Kirson finds both an additive and synergistic effect (p. 8, Analysis of combination efficacy). Kirson concludes that TTFields can be used as an anti-proliferative agent but also as an effective sensitizer of chemotherapeutic agents and combinations provide a greater therapeutic efficacy with lower drug concentrations (p. 11, conclusion).
Thus, before the effective filing date of the claimed invention, the combined therapy of TTFields with known chemotherapeutic agents was effectively used for reducing and killing cancer cells. The combined therapies were also taught to provide enhanced additive and synergistic effects to already used chemotherapeutic agents.
Therefore, a POSITA would have been motivated by the teachings of Krex, Giladi and Kirson to apply alternating electric fields as claimed to cancer cells in combination with known chemotherapeutic agents including E2F and CDK4/6 inhibitors taught by the prior art of record to successfully reduce and kill cancers when used in combination, with a reasonable expectation of successfully reducing and killing cancer cells as claimed.
Regarding applicants newly added limitations to claim 1, drawn to alternating electric fields frequency “to cause a dysregulation of a CDK-RB-E2F axis within cancer cells, the dysregulation comprising inhibition of …and increase of … E2F family transcription factors”, as well as administering an E2F and CDK4/6 inhibitors “to cause an increase in the inhibition of one of the E2F family transcription factors and to cause inhibition in CDK4/6 activity and cell cycle expression”, respectively; these limitations are taken to be necessarily occurring as a result of applying the electric field at the claimed frequency and duration (taught by the prior art of record, Krex, Giladi, Kirson) and administering the claimed effective concentrations of the inhibitors (also taught by the prior art or record, WO484 and Knudsen(see below)). Further, Kent, WO484 and Militello teaches that the E2F and CDK4/6 inhibitors function as claimed. These are intended results of the process steps of applying the electric field to cancer cells at the claimed frequency and duration and administering the concentrations of inhibitors. The combined prior art references teach the claimed method steps for reducing or killing cancer cells. Thus, it is the Examiners position that these results are inherent to the methods steps taught by the prior art. One would necessarily expect to achieve the same results when practicing the method of the art, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent . "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
The invention as a whole is prima facie obvious in view of the prior art or record.
Claim(s) 8, 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krex et al. US20190307781 (IDS) in view of Karanam et al (Cell Death and Disease, 2017), Kent et al. (Nature, 6/2019, p. 326-338, IDS), WO2009/117484 (IDS), Militello et al. (Front. Oncol., 2019, p. 1-7, IDS) supported by Giladi et al. (Seminars in Oncol., 2014, p. S35-S41, IDS) and Kirson et al. (BMC, Med. Phys. 2009, p. 1-13, IDS) as applied to claims 1-7, 10, 14-17 above, and further in view of Knudsen et al., (Oncotarget, 2017, p. 43678-43691, IDS).
The references do not teach the limitations of claims 8, 9.
Knudsen teaches that treating cancer cell lines with concentrations of 250 nM to 1 µM of abemaciclib is cytotoxically effective to inhibit cell growth and tumor growth in cancer cell lines (abstract, p. 43679 Results section, Fig. 1, 5, Discussion section p. 43687).
Therefore, it would have been within the purview of one of ordinary skill in the art to have pursued known options, i.e., concentrations disclosed to inhibit cell growth, to be used in the method of the prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, 10, 14, 15, 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-14 of copending Application No. 17693108 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to treating a tumor, i.e., a cancer cell comprising applying tumor treating fields at frequencies between 100-200 kHz and administering at least an E2F inhibitor and a CDK4/6 inhibitor, wherein the E2F inhibitor is HLM006474 and the CDK4/6 inhibitors are selected from abemaciclib, palbociclib and ribociclib. The examined claims differ from those of copending application 17693108 in that ‘108 claims additionally require delivering an ATR inhibitor; however, the method of the instant examined claims contain the transitional phrase “comprising” and thus, the method would not exclude the administration of an additional inhibitor. Thus, the examined claims would be anticipated by the reference claims .
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 10, 14, 15, 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, 18 of U.S. Patent No. 12420113. Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to treating a tumor, i.e., a cancer cell comprising applying tumor treating fields at frequencies between 100-200 kHz and administering at least an E2F inhibitor and a CDK4/6 inhibitor, wherein the E2F inhibitor is HLM006474. The examined claims differ from those of US’113 in that ‘113 claims additionally require delivering radiotherapy and the claims generically claim CDK4/6 inhibitors. The method of the instant examined claims contain the transitional phrase “comprising” and thus, the method would not exclude delivering radiotherapy. Thus, the examined claims would be obvious over the reference claims .
Claims 1, 4, 10, 14, 15, 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 20 of copending Application No. 19313279 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to treating a tumor, i.e., a cancer cell comprising applying tumor treating fields and administering at least an E2F inhibitor and a CDK4/6 inhibitor, wherein the E2F inhibitor is HLM006474. The examined claims differ from those of copending application 19313279 in that ‘279 claims additionally require delivering radiotherapy and the claims generically claim CDK4/6 inhibitors. The method of the instant examined claims contain the transitional phrase “comprising” and thus, the method would not exclude delivering radiotherapy. Thus, the examined claims would be obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 5/12/2026 have been fully considered but they are not persuasive.
Regarding the 103 rejections of Krex, WO484, Militello, Giladi and Kirson, applicant argues that the references do not teach the limitations of to cause a dysregulation of a CDK-RB-E2F axis within cancer cells, the dysregulation comprising inhibition of …and increase of … E2F family transcription factors”, as well as administering an E2F and CDK4/6 inhibitors “to cause an increase in the inhibition of one of the E2F family transcription factors and to cause inhibition in CDK4/6 activity and cell cycle expression”. As stated above in the rejection, these limitations are taken to be necessarily occurring as a result of applying the electric field at the claimed frequency and duration (taught by the prior art of record, Krex, Giladi, Kirson) and administering the claimed effective concentrations of the inhibitors (also taught by the prior art or record, WO484 and Knudsen).
Further, new reference Karanam teaches that TTF’s dysregulate BRCA1, and FANCD2, which are demonstrated by applicant to be E2F activators and repressors, i.e. E2F target genes.
Further, Kent, WO484 and Militello teach the inhibitors to function as claimed, but these are intended results of the process steps of applying the electric field to cancer cells at the claimed frequency and duration and administering the concentrations of inhibitors. The combined prior art references teach the claimed method steps for reducing or killing cancer cells. Thus, it is the Examiners position that these results are inherent to the methods steps taught by the prior art. One would necessarily expect to achieve the same results when practicing the method of the art, which is the same as applicants claimed method.
Further, regarding Krex, applicants argue that the reference teaches a different application/purpose for applying TTFields to tumor cells, i.e. mitotic arrest or delay) and a different type of drug, i.e. Aurora Kinase inhibitors to be used with TTFields for a different purpose.
The purpose of applying TTFields of Krex is the same as applicants, to reduce cancer cell viability, i.e. to reduce survival of cancer cells. TTFields are taught by Krex to be an anti-neoplastic treatment, wherein the TTFields are applied at a frequency between 100-300 kHz for 72 hours (0005, 0008, 0009, for example). Thus, Krex teaches that TTFields can be used together with chemotherapeutic drugs to reduce survival of cancer cells and/or kill cancer cells. While the drugs of Krex are not the same as those claimed, secondary references teaching the claimed E2F and CDK4/6 inhibitors known to be used alone and together to target the CDK-RB-E2F axis and reduce survival of cancer cells and/or kill cancer cells are applied (see Kent, WO484 to Cress, and Militello).
Applicant argues that the secondary references do not teach using TTFields with the drugs to target and weaken the CDK-RB-E2F axis, and that the teachings of Giladi and Kirson (teaching additive and synergistic effects when chemotherapeutic agents are combined with TTFields); however, the TTF are applied for a different purpose and the chemotherapeutic agents are not the same as those claimed, thus having a different mechanism of action.
Applicants argue the different stages of the cell cycle and that the specification teaches “combination therapeutics using TTFields combines TTFields with E2F and/or CDK 4/6 inhibitors to downregulate E2F1 and E2F2 of the CDK-RB-E2F axis." Specification, [0031]. "TTFields dysregulate the E2F family of transcription factors and render tumor cells susceptible to agents targeting the RB-E2F-CDK4/6 axis, thus substantially increasing the tumoricidal effects of TTFields alone or with agents that target DNA repair, replication stress, and other pathways regulated by the RB-E2F-CDK4/6 axis." Id. at [0032]. The Specification also notes that this is an entirely different application of TTFields than conventional techniques that use them to inhibit cytokinesis: "The CDK-Rb-E2F axis is druggable, indeed it is now a major drug target in cancer treatment, and in doing so, targeting this axis would change how TTFields could be used going forward including becoming an integral therapy that would enhance conventional radiation and chemotherapies that target DNA repair, cell cycle checkpoint or proliferation and survival pathways." Id. at [0104] (emphasis added)”.
It is the Examiners position that, new reference Karanam teaches that TTF not only functions by the exploitation of cell proliferation, inducing apoptosis in cancer cells, prevention of formation of the mitotic spindle, leads to microtubule depolymerization disrupting cytokinesis, but also TTF’s induce additional mechanisms leading to cell death, thereby suggesting mechanisms involving DNA repair and replication beyond the abortive mitosis cell death mechanism known.
Further, secondary references teach that E2F inhibitor HLM006474 and CDK4/6 inhibitors including abemaciclib were known to be used for effectively reducing and killing cancer cells, and used as chemotherapeutic agents in patients having lung cancer, breast cancers, glioblastoma and melanoma. Additionally, Kent suggests that the combination of E2F inhibitors with the specific CDK4/6 inhibitors has a synergistic effect in reducing proliferation of lung cancer cells in vitro (p. 335, whole 1st col.) and that targeted inhibition of E2F in combination with CDK4/6 inhibition may be the ideal treatment option, increasing CDK4/6 inhibitors and prevent resistance. Further, secondary references Giladi and Kirson each teach that when used in combination with chemotherapeutic agents, TTFields was found to have an additive with a tendency towards synergism effect, which increases chemotherapeutic efficacy and sensitivity without treatment related toxicity and allowing for the possibility of dose reduction.
Kirson test 72-hour application of TTFields with (different concentrations of) chemotherapeutic agents (Fig. 1) and find that the combination results in irreversible and complete inhibition of cell proliferation (p. 5-6). Kirson teaches that the mechanism involved is the sensitization of tumor cells to TTfields by the chemotherapeutic agent. Similar to the teachings of the other chemotherapeutics of Kirson, which act at the G and S phase of the cell cycle, Kent teaches that targeting the CDK-RB-E2F axis has become a key strategy in cancer treatment and CDK4/6 inhibitors including ribociclib and abemaciclib lead to stable cell cycle arrest in G1. Since TTfields act in the M-phase, a completely different stage of the cell cycle of the agents, at the least the additivity is expected between the agents and TTfields (see Kirson, Fig. 7, p. 11, whole page). Kirson concludes that TTFields can be used as an anti-proliferative agent but also as an effective sensitizer of chemotherapeutic agents and combinations provide a greater therapeutic efficacy with lower drug concentrations (p. 11, conclusion).
Giladi teaches applying alternating electric fields (TTFields) to NSCLC cells in combination with chemotherapeutic agents and find that the addition of TTFields at a frequency of 150 kHz for 72 hours resulted in enhanced treatment efficacy across all cell lines tested, thus providing an additive efficacy benefit in treating NSCLC and reducing the survival of cancer cells by at least 20 fold compared to controls not receiving TTFields and chemotherapeutic agents (abstract, p. S36, whole page, S37, Results and discussion section-p. S39, Fig. 1-3).
While the specific combination of TTFields with the claimed agents is not taught, the art teaches that TTFields with known chemotherapeutic agents adds at least an additive and enhanced treatment and thus a posita would have been motivated by the teachings of the art to add TTFields treatment to known cancer treating agents, i.e. the combination of CDK4/6 inhibitors and E2F inhibitors. TTFields has demonstrated to be effective when added to chemotherapeutic agents of all types to reduce the survival of different types of cancer cells, therefore, the combination would be expected to provide a multi-faceted approach having an anti-proliferative effect on cancer cells.
Therefore, given the combined teachings of the prior art references, a posita could have pursued known potential solutions with a reasonable expectation of successfully reducing survival of cancer cells.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
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 TIFFANY MAUREEN GOUGH whose telephone number is (571)272-0697. The examiner can normally be reached M-Thu 8-5.
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/TIFFANY M GOUGH/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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