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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/17/2025 has been entered.
Claims 1-10, 14-21, 24-29 are pending and have been considered on the merits herein.
It was previously indicated that claims 1-9, 16-20, 26-29 receive the earliest effective filing date of 3/22/2021 as the disclosure of the prior-filed application, Application No. 62/993603, failed to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. In light of applicants claim amendments, applicants receive the earliest effective filing date of 3/23/2020. Further, as indicated in the Advisory Action mailed 12/4/2025, applicants effectively invoked the prior art exception under 35 USC(b)(2)(C) demonstrating common ownership to overcome the 102(a)(2) rejection over the Story reference. The Declaration under 37 CFR 1.130(a) filed on 12/17/2025 is sufficient to overcome the rejection of claims 1-7, 10, 14-21, 24-28 based on Story et al. US20190298982 (IDS). applicants have effectively established that the disclosure was obtained directly or indirectly from the inventor or a joint inventor.
Thus, the rejection of Claim(s) 1-7, 10, 14-21, 24-28 rejected under 35 U.S.C. 103 as being unpatentable over Story et al. US20190298982 (IDS) in view of Kent et al. (Nature, 6/2019, p. 326-338, IDS), WO2009/117484 (IDS) and 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 Phys. 2009, p. 1-13, IDS) is withdrawn.
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 21 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: what the E2F inhibitor comprises.
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, 14-21, 24-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krex et al. US20190307781 (IDS) in view of Kent et al. (Nature, 6/2019, p. 326-338, IDS), WO2009/117484 (IDS) (to Cress et al.) and 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, 18, 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 claims 16 and 27, the cancer cells are glioblastoma cells (0004, 0015, 0044).
Regarding claims 2 and 19, the at least a portion of the applying step is performed simultaneously with at least a portion of the administering step (0008).
Regarding claims 3 and 20, the applying 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).
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, 18, 21, 24-25) or the limitations of claims 6, 7 and 28.
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.). 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 (abstract, p. 326-328, 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 lead 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). Kent additionally suggest 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 and has been shown to have anti-proliferative and pro-apoptotic activity in multiple cancer cell lines and reduces tumor growth. 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 and 28, 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).
The above references do not teach the limitations of claim 26.
Regarding claim 26, 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, 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. 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 claims 1 and 18, drawn to alternating electric fields frequency and duration “sufficient to cause a dysregulation of an E2F family transcription factors and render cells susceptible to agents targeting a CDK-RB-E2F axis”, as well as the therapeutically effective concentrations of an E2F and CDK4/6 inhibitors “sufficient to cause one or more of a downregulation of E2F1 and E2F2 and an upregulation of E2F6 of the CDK-RB-E2F axis”; 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)). 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).
lll. A REJECTION UNDER 35 U.S.C. 102/103 CAN BE MADE WHEN THE PRIOR
ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS
SILENT AS TO AN INHERENT CHARACTERISTIC
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103, expressed as a 102/103 rejection. “There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C.103 and for anticipation under 35. U.S.C. 102.” In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102/103 rejection is appropriate for these types of claims as well as for composition claims.
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, and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krex et al. US20190307781 (IDS) in view of Kent et al. (Nature, 6/2019, p. 326-338, IDS), WO2009/117484 (IDS) and 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, 14-21, 24-28 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 and 29.
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, 18, 21, 24, 25, 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-14, 19, 20 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, 18, 21, 24, 25, 27 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, 18, 21, 24, 25, 27 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 12/17/2025 have been fully considered but they are not persuasive.
Regarding the pending ODP rejections of record, applicants wish to hold the ODP rejections in abeyance until allowable subject matter is indicated.
Regarding the 103 rejections of Krex, WO484, Militello, Giladi and Kirson, applicant argues that the references do not teach the limitations of “for a duration sufficient to cause a dysregulation of an E2F family transcription factors and render cells susceptible to agents targeting a CDK-RB-E2F axis”, as well as the therapeutically effective concentrations of an E2F and CDK4/6 inhibitors “sufficient to cause one or more of a downregulation of E2F1 and E2F2 and an upregulation of E2F6 of the CDK-RB-E2F axis”.
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). 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).
lll. A REJECTION UNDER 35 U.S.C. 102/103 CAN BE MADE WHEN THE PRIOR
ART PRODUCT SEEMS TO BE IDENTICAL EXCEPT THAT THE PRIOR ART IS
SILENT AS TO AN INHERENT CHARACTERISTIC
Where applicant claims a composition in terms of a function, property or characteristic and the composition of the prior art is the same as that of the claim but the function is not explicitly disclosed by the reference, the examiner may make a rejection under both 35 U.S.C. 102 and 103, expressed as a 102/103 rejection. “There is nothing inconsistent in concurrent rejections for obviousness under 35 U.S.C.103 and for anticipation under 35. U.S.C. 102.” In re Best, 562 F.2d 1252, 1255 n.4, 195 USPQ 430, 433 n.4 (CCPA 1977). This same rationale should also apply to product, apparatus, and process claims claimed in terms of function, property or characteristic. Therefore, a 35 U.S.C. 102/103 rejection is appropriate for these types of claims as well as for composition claims.
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.").
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 and/or kill 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 chemotherapeutic agents are not the same as those claimed, thus having a different mechanism of action.
It is the Examiners position 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 (abstract, p. 10, discussion section). 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).
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
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.
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, Melenie Gordon can be reached at 571-272-8037. 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.
/TIFFANY M GOUGH/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651