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 .
Response to Amendment
The Amendment filed 07/13/2026 has been entered.
Claims 1, 2 and 5 have thereby been amended.
Claims 1-2, 5, and 7-23 are being examined in this office action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 2, 5, 7, 8, 12, 13, 16-18 and 20-23 in the alternative, as well as claim 19, are rejected under 35 U.S.C. 103 as being unpatentable over Zeevi (US 20200269041) (embodiment of Example 16) in view of Cheng (US 20200069958) in further view of Donovan (US 104444235).
Regarding claim 1, in the alternative, Zeevi discloses a method of treating a subject resistant to trastuzumab comprising: b) applying an alternating electric field, at a frequency for a period of time, to a target site of the subject (page 15, para. [209], sentences 3-4; page 2, para. [0047]); and c) administering trastuzumab to the target site of the subject (page 14, para. [0192]; page 15, para. [209], sentence 4). Although Zeevi does not explicitly disclose that the alternating electric field sensitizes the subject to the trastuzumab, the recitations of this limitation is an intended result limitation for the intended outcome of the claimed method, and as such is given no patentable weight, as the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (see MPEP 2112.I.).
Zeevi, in this interpretation, fails to explicitly disclose that the subject receiving the method of treatment is a subject who is resistant to trastuzumab. Cheng teaches an analogous method of treating breast cancer patients with trastuzumab in which trastuzumab is administered with cold plasma therapy in order to treat patients who are resistant to trastuzumab but still require treatment of the drug (para. [0011]). With this motivation of applying a dual-trastuzumab treatment to patients with trastuzumab resistance, provided by Cheng, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination method of treatment disclosed by Zeevi such that it is administered to subjects who have resistance to trastuzumab, as taught by Cheng, in order to effectively administer the needed trastuzumab treatment to patients that cannot receive the trastuzumab by traditional administration of it alone (para. [0011]). However, although Cheng explicitly teaches that patients with resistance to trastuzumab should receive the alternative treatment steps, being the Zeevi treatment method according to the combination, neither Zeevi nor Cheng explicitly teach the step of identifying which patients are resistant to trastuzumab.
Donovan teaches an analogous method of assessing and treating patients with trastuzumab-resistant tumors, and explicitly teaches the method step of a) identifying a subject as being resistant to trastuzumab (claim 9; col. 4, lines 59-62). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Zeevi-Cheng method by incorporating the specific step taught by Donovan or determining if the subject has trastuzumab resistance, in order to accurately monitor the treatment progression of the patient to assess their response to the treatment to provide them the most effective treatment for their specific condition.
Regarding claim 2, in the alternative, Zeevi in view of Cheng teaches a method of increasing accumulation of trastuzumab at a target site of a subject comprising: b) applying an alternating electric field, at a frequency for a period of time, to the target site of the subject (page 15, para. [209], sentences 3-4; page 2, para. [0047]); and c) administering trastuzumab to the target site of the subject (page 14, para. [0192]; page 15, para. [209], sentence 4). Although Zeevi does not explicitly disclose that the method results in increased accumulation of the trastuzumab at the target site compared to administering the trastuzumab at the target site without applying an alternating electric field, the recitations of this limitation is an intended result limitation for the intended outcome of the claimed method, and as such is given no patentable weight, as the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (see MPEP 2112.I.).
Zeevi, in this interpretation, fails to explicitly disclose that the subject receiving the method of treatment is a subject who is resistant to trastuzumab. Cheng teaches an analogous method of treating breast cancer patients with trastuzumab in which trastuzumab is administered with cold plasma therapy in order to treat patients who are resistant to trastuzumab but still require treatment of the drug (para. [0011]). With this motivation of applying a dual-trastuzumab treatment to patients with trastuzumab resistance, provided by Cheng, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination method of treatment disclosed by Zeevi such that it is administered to subjects who have resistance to trastuzumab, as taught by Cheng, in order to effectively administer the needed trastuzumab treatment to patients that cannot receive the trastuzumab by traditional administration of it alone (para. [0011]). However, although Cheng explicitly teaches that patients with resistance to trastuzumab should receive the alternative treatment steps, being the Zeevi treatment method according to the combination, neither Zeevi nor Cheng explicitly teach the step of identifying which patients are resistant to trastuzumab.
Donovan teaches an analogous method of assessing and treating patients with trastuzumab-resistant tumors, and explicitly teaches the method step of a) identifying a subject as being resistant to trastuzumab (claim 9; col. 4, lines 59-62). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Zeevi-Cheng method by incorporating the specific step taught by Donovan or determining if the subject has trastuzumab resistance, in order to accurately monitor the treatment progression of the patient to assess their response to the treatment to provide them the most effective treatment for their specific condition.
Regarding claim 5, in the alternative, Zeevi in view of Cheng teaches a method of increasing apoptosis of breast or stomach cancer cells at a target site of a subject comprising: b) applying an alternating electric field, at a frequency for a period of time, to the target site of the subject (page 15, para. [209], sentences 3-4; page 2, para. [0047]); and c) administering trastuzumab to the target site of the subject (page 14, para. [0192]; page 15, para. [209], sentence 4). Although Zeevi does not explicitly disclose that apoptosis of the cancer cells is increased when the method of administering alternating electric field therapy and trastuzumab is applied, the recitations of this limitation is an intended result limitation for the intended outcome of the claimed method, and as such is given no patentable weight, as the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (see MPEP 2112.I.).
Zeevi, in this interpretation, fails to explicitly disclose that the subject receiving the method of treatment is a subject who is resistant to trastuzumab. Cheng teaches an analogous method of treating breast cancer patients with trastuzumab in which trastuzumab is administered with cold plasma therapy in order to treat patients who are resistant to trastuzumab but still require treatment of the drug (para. [0011]). With this motivation of applying a dual-trastuzumab treatment to patients with trastuzumab resistance, provided by Cheng, it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination method of treatment disclosed by Zeevi such that it is administered to subjects who have resistance to trastuzumab, as taught by Cheng, in order to effectively administer the needed trastuzumab treatment to patients that cannot receive the trastuzumab by traditional administration of it alone (para. [0011]). However, although Cheng explicitly teaches that patients with resistance to trastuzumab should receive the alternative treatment steps, being the Zeevi treatment method according to the combination, neither Zeevi nor Cheng explicitly teach the step of identifying which patients are resistant to trastuzumab.
Donovan teaches an analogous method of assessing and treating patients with trastuzumab-resistant tumors, and explicitly teaches the method step of a) identifying a subject as being resistant to trastuzumab (claim 9; col. 4, lines 59-62). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the Zeevi-Cheng method by incorporating the specific step taught by Donovan or determining if the subject has trastuzumab resistance, in order to accurately monitor the treatment progression of the patient to assess their response to the treatment to provide them the most effective treatment for their specific condition.
Regarding claim 7, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the target site comprises one or more breast or stomach cancer cells (Zeevi: page 2, para. [0047], sentence 1; gastric cancer).
Regarding claim 8, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the alternating electric field is applied before, after, or simultaneously with administering trastuzumab (Zeevi: page 15, para. [209], sentences 3-4; the administration of the drug and delivery of the electric fields are at least partially simultaneous).
Regarding claim 12, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the frequency of the alternating electric field is between 100 kHz and 1 MHz (Zeevi: page 14, para. [0183]; 150 kHz).
Regarding claim 13, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the frequency of the alternating electric field is between 100 kHz and 500 kHz (Zeevi: page 14, para. [0183]; 150 kHz).
Regarding claim 16, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the trastuzumab is administered intratumorally, intracranially, intraventricularly, intrathecally, epidurally, intradurally, intravascularly, intravenously (targeted or non- targeted), intraarterially, intramuscularly, subcutaneously, intraperitoneally, orally, intranasally, via intratumor injection or via inhalation (Zeevi: page 14, para. [0192]; administered intravenously via IV drip).
Regarding claim 17, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the trastuzumab is administered in a pharmaceutical composition (Zeevi: page 14, para. [0192]; administered in pharmaceutical composition in IV regiment).
Regarding claim 18, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the subject has a cancer selected from breast or stomach cancer (Zeevi: page 2, para. [0047], sentence 1; gastric cancer).
Regarding claim 19, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 18, as described above, wherein the cancer (Cheng: para. [0011]) is breast cancer and the subject has trastuzumab resistance (Cheng: para. [0011]).
It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combination method of treatment disclosed by Zeevi such that it is administered to subjects who have breast cancer and the subject has resistance to trastuzumab, as taught by Cheng, in order to effectively administer the needed trastuzumab treatment in order to effectively administer the needed trastuzumab treatment to a wider range of patients (para. [0011]).
Regarding claim 20, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 18, as described above, wherein the cancer is a HER2 positive cancer (Zeevi: page 14, para. [0189]).
Regarding claim 21, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 18, as described above. Although Zeevi in view of Cheng does not explicitly teach that pAKT, pERK, and pHER2 expression is reduced, the recitation of this limitation is an intended result limitation for the intended outcome of the claimed method, and as such is given no patentable weight, as the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable (see MPEP 2112.I.).
Regarding claim 22, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, wherein the trastuzumab is administered prior to, simultaneous with or after applying the alternating electric field (Zeevi: page 15, para. [209], sentences 3-4; the administration of the drug and delivery of the electric fields are at least partially simultaneous).
Regarding claim 23, in the alternative, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, further comprising administering to a chemotherapeutic agent to the subject (Zeevi: page 14, paras. [0186] and [0189]).
Claim 9, in the alternative, is rejected under 35 U.S.C. 103 as being unpatentable over Zeevi (US 20200269041) (embodiment of Example 16) in view of Cheng (US 20200069958) in further view of Donovan (US 104444235) and in further view of Schmidt (US 20200330758).
Regarding claim 9, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, in the alternative as described above, but fails to explicitly teach that the application of the electric field therapy begins at least one hour before the administration of the trastuzumab drug.
Schmidt teaches an analogous method of treating cancer cells with both electric field therapy paired with a cancer drug, wherein the step of applying the alternating electric field begins at least one hour before administering trastuzumab (Fig. 9: the application of the electric fields starts at 902, before the administration of the cancer drug at 906; paras. [0070]-[0071], the cancer drug may be administered at least an hour after the electric fields have begun to be applied). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Zeevi in view of Cheng in view of Donovan, which teaches a general overlapping application of electric fields and administration of the cancer drug, by incorporating the teaching of Schmidt to being the application of the electric fields at least an hour prior to the administration of the drug, in order to induce apoptosis of some of the cancer cells before the trastuzumab is administered to the remaining cells (Schmidt: para. [0049], sentences 1-5).
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Zeevi (US 20200269041) (embodiment of Example 16) in view of Cheng (US 20200069958) and in further view of Anwar (US 20190000320).
Regarding claim 10, Zeevi in view of Cheng teaches the method of claim 1, as described above, but fails to disclose that the trastuzumab is tagged or labeled.
Anwar teaches an analogous method for HER-2 positive breast cancer treatment and imaging with trastuzumab, wherein the trastuzumab comprises a detectable agent (page 6, para. [0129], sentences 1-2). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the trastuzumab used in the method taught by Zeevi in view of Cheng with the fluorescently-labeled trastuzumab taught by Anwar, in order to allow for the targeted tumor cells to be visualized in vivo for tumor monitoring or surgical guidance (pages 4-5, para. [0121], last two sentences, and para. [0122], sentences 1-2).
Regarding claim 11, Zeevi in view of Cheng in further view of Anwar teaches the method of claim 10, as described above, wherein the detectable agent is a fluorophore (Anwar: page 5, para. [0123], sentence 7).
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Zeevi (US 20200269041) (embodiment of Example 16) in view of Cheng (US 20200069958) in further view of Donovan (US 104444235) in further view of Zeevi (US 20200269041) (embodiment of Example 3).
Regarding claim 14, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, but the method disclosed in Example 16 applied to patients fails to explicitly disclose the RMS of the alternating electric field therapy (TTFields) used.
In Example 3, Zeevi discloses an embodiment applied to cells wherein the alternating electric field has a field strength of between 0.5 and 4 V/cm RMS (page 4, para. [0091]). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the specific RMS intensity of the TTFields disclosed in Example 3 into the method of treatment with TTFields of Example 16 in view of Cheng, in order to maintain an effective intensity of the electric fields, which has already been optimized to imitate the parameters of TTFields for patient use (Zeevi: page 4, para. [0091], last sentence).
Regarding claim 15, Zeevi in view of Cheng in further view of Donovan teaches the method of claim 1, as described above, but the method disclosed in Example 16 for the application to patients fails to explicitly disclose the RMS of the alternating electric field therapy (TTFields) used.
In Example 3, Zeevi discloses an embodiment applied to cells wherein the alternating electric field has a field strength of at least 0.9 V/cm RMS (page 4, para. [0091]). It would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have incorporated the specific RMS intensity of the TTFields disclosed in Example 3 into the method of treatment with TTFields of Example 16 in view of Cheng, in order to maintain an effective intensity of the electric fields, which has already been optimized to imitate the parameters of TTFields for patient use (Zeevi: page 4, para. [0091], last sentence).
Response to Arguments
In light of the amendments filed 07/13/2026 that change the scope of independent claims 1, 2 and 5, Applicant's arguments, filed 07/13/2026, regarding the USC § 102 rejections, are persuasive, and the claims are now rejected only under USC § 103.
Applicant’s arguments regarding Zeevi-Cheng’s failure to teach the step of “identifying a subject as being resistant to trastuzumab” are considered moot, as independent claims 1, 2 and 5 no longer solely rely upon Zeevi in view of Cheng, but now rely upon Donovan to teach said step.
Applicant further argues that it would not have been obvious to combine Zeevi and Cheng to teach the Zeevi treatment method applied to patients with trastuzumab resistance. However, these arguments are not persuasive. The claims state that the method should be applied to a subject resistant to trastuzumab. Zeevi does not teach away from this, as it teaches the method applied to a general population (which is understood to contain a range of people not resistant and resistant to trastuzumab). Cheng is merely incorporated to teach a motivation of applying a combination treatment with trastuzumab to patients who have resistance in an attempt to make them more sensitive to the trastuzumab treatment. Cheng does not serve to motivate using an alternating electric field with trastuzumab in a patient, as Applicant asserts. Rather, Zeevi teaches that method for administration to patients in general, and Cheng serves to motivate specifying patient treatment to also include those with trastuzumab resistance. In other words, Cheng serves to motivate applying Zeevi’s treatment method, even to patients with trastuzumab resistance, as Cheng teaches methods and motivations for achieving efficacy of trastuzumab within patients that have a resistance to it. Additionally, Examiner is not asserting that alternating electric fields and cold atmospheric plasma are “interchangeable” treatments, as Applicant argues. Examiner maintains that Cheng is analogous to Zeevi within the scope of it teaching combination treatments with trastuzumab to increase its effectiveness. Therefore, Examiner maintains that Cheng serves to motivate applying Zeevi’s treatment method, even to patients with trastuzumab resistance in order to achieve success in the tumor treatment who have trastuzumab resistance.
For these reasons, claims 1-2, 5, and 7-23 stand rejected as recited above.
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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/K.A.W./Examiner, Art Unit 3783
/NATHAN R PRICE/Primary Examiner, Art Unit 3783
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