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 .
Claim Status
Applicant’s reply filed on 11/07/2025 is acknowledged. Claims 1, 21, 24, 36, 45 are amended. Claims 8, 9, 20, 23, 77, 78, 80, 83, 84, 86, 89, 92, 93, 95, 96, and 98-100 are cancelled.
Restriction/Election
Applicant’s election without traverse of following species in the reply filed 03/25/2025 is acknowledged: (1) MPDL3280A (atezolizumab) as the PD-1 axis binding antagonist; and (2) a HER2-positive breast cancer as the HER2-positive cancer.
Claims 1-2, 6, 10, 12, 14, 16, 21, 24, 26-28, 31, 36-41, 45-47, 51-53, 55, 58-59, 61, 64, 67-68, 70-71, 73-76, 101-106, 112-113, 115 are pending and under examination.
Rejections Withdrawn
The following rejections are withdrawn in view of amendments filed 11/07/2025:
The rejection of claims 1, 2, 6, 8-10, 12, 14, 16, 20, 21, 23, 24, 26-28, 31, 36, 37, 39-41, 45-47, 51-53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-78, 80, 83, 84, 86, 89, 92, 93, 95, 96, 98-106, 112, 113, and 115 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 rejection of claims 80, 83, 84, 86, 89, 92, 93, 95, 96, and 98-100 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26) in view of Dedrick (published 12/04/2003) as evidenced by the National Center for Health Statistics Anthropometric Reference Data for Children and Adults.
New Grounds of Rejection Necessitated by Amendment
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.
Claims 1, 2, 6, 10, 12, 14, 21, 24, 26-28, 31, 36-39, 102, 112, 113, and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26, PTO 892 06/23/2025) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) as evidenced by LenioBio “Rapid Production of a bispecific antibody”, FDA Runimotamab entry, PTO 892 06/23/2025.
Clinical Trial NCT034448042 is directed to a phase I, open-label, dose escalation study of the safety and pharmacokinetics of BTRC4017A/runimotamab, the HER2 TDB of the instant invention. (Pg. 6, Official Title).
Regarding claim 1, pertaining to a method of treating or delaying the progression of a HER2-positive cancer comprising administering to the subject a treatment regimen comprising a HER2 antibody and a HER2 T cell-dependent bispecific antibody (TDB), the HER2 TDB comprising an anti-HER2 arm and an anti-CD3 arm, wherein the HER2 antibody and the HER2 TDB both bind domain IV of HER2, Clinical Trial NCT03448042 teaches the administration of the HER2 TDB of the instant disclosure BTRC4017A/runimotamab in subjects with locally advanced or metastatic HER2-expressing cancers (see Title). Clinical Trial NCT03448042 discloses a treatment group that has received prior HER2 antibody trastuzumab therapy (the HER2 antibody of the instant disclosure) (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria), which broadly but reasonably anticipates the method wherein the subject is administered a HER2 antibody and HER2 TDB that bind the same target because the claim does not specify the interval between administration of the two antibodies.
Regarding claim 1, wherein the HER2 TDB and the HER2 antibody bind competitively to domain IV of HER2, Clinical Trial NCT03448042 discloses administration of the HER2 antibody trastuzumab and HER2 TDB runimotamab (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria). The instant specification teaches that HER2-binding site of BTRC4017A/runimotamab is derived from trastuzumab and binds the same epitope in domain IV of HER2 thereby competitively binding (Specification, Pg. 43, Lines 26-32).
Regarding claims 1, 10, 12, 14, pertaining to the identity of the HER2 antibody, wherein the HER2 antibody is trastuzumab, Clinical Trial NCT03448042 discloses administration of the HER2 antibody trastuzumab (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria).
Regarding claims 1, 21, 24, and 26, which define the HER2 TDB binding arms, the claimed antibody pertains to BTRC4017A/runimotamab disclosed in Clinical Trial NCT03448042.
Regarding claims 27, 28, 31, wherein the HER2 TDB is a full- length antibody comprising a modified Fc region (claim 27), wherein the modified Fc region comprises one or more substitution mutations that reduces effector function of the HER2 TDB (claim 28), and wherein the one or more substitution mutations comprise an aglycosylation mutation (claim 31), the Fc region of the HER TDB antibody runimotamab is aglycosylated as evidenced by LenioBio (Pg. 2, paragraph 3).
Regarding claims 36 and 37, wherein the HER2 TDB comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from the CH11, CH21, CH31 and CH12, CH22, and CH32 domains (claim 36) and wherein the CH31 and CH32 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH31 domain is positionable in the cavity or protuberance, respectively, in the CH32 domain, the Fc region of the HER TDB antibody runimotamab comprises CH1, CH2, and CH3 domains as evidenced by the FDA “Runimotamab” entry (Pg. 3 of the PDF) and the Fc region are connected by a knob-in-hole mutation as evidenced by LenBio (Pg. 2, paragraph 2) which corresponds to the instantly claimed “protuberance cavity.”
Regarding claim 38, pertaining to a method of delaying the progression of a HER2-positive cancer in a subject, the method comprising administering trastuzumab and a HER2 TDB with sequences corresponding to runimotamab, Clinical Trial NCT03448042 discloses a treatment group that has received prior trastuzumab therapy (the HER2 antibody of the instant disclosure) (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria).
Regarding claim 39, wherein the HER2 antibody is administered prior to administration of the HER2 TDB, Clinical Trial NCT03448042 discloses a treatment group that has received prior trastuzumab therapy (the HER2 antibody of the instant disclosure) (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria), which broadly but reasonably anticipates the method wherein the subject is administered a HER2 antibody and HER2 TDB that bind the same target because the claim does not specify the interval between administration of the two antibodies.
Regarding claim 102, wherein the HER2 antibody or the HER2 TDB are administered by intravenous infusion, Clinical Trial NCT03448042 teaches that the HER2 TDB is administered via IV infusion (Pg. 8, Arms and Interventions, right column).
Regarding claim 112, wherein the subject has been administered trastuzumab in a previous treatment regimen, Clinical Trial NCT03448042 discloses a treatment group that has received prior trastuzumab therapy (the HER2 antibody of the instant disclosure) (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria).
Regarding claims 113 and 115, wherein the HER2-positive cancer is a HER2-positive solid tumor or a locally advanced or metastatic HER2-positive cancer (claim 113) and wherein the HER2-positive cancer is selected from the list disclosed in claim 115, Clinical Trial NCT03448042 discloses treatment of HER2-expressing gastric/gastroesophageal cancer (Pg. 10, HER2-Expressing Gastric/Gastroesophageal (GEJ) Cancer-Specific Inclusion Criteria). Clinical Trial NCT03448042 does not disclose trastuzumab and runimotamab administered within the same regimen.
This deficiency is taught by Chang.
The disclosure of Chang is directed to optimizing CAR T immunotherapy and teaches the administration of the CAR T cell is preceded by “predosing” with an antibody that binds to the same disease-associated antigen (Abstract, Lines 13-16). Chang teaches that the predosing protocol is designed to reduce off-tumor, on-target toxicity by normal tissues by saturating normal tissues with lower antigen expression levels while still allowing a cytotoxic effect against the higher antigen levels found in tumor cells ([0013], Lines 6-10, 27-31). Chang teaches the goal of the disclosed predosing method was to reduce the risk of a “cytokine storm” ([0010], Lines 8-19).
Regarding claim 1, 2, and 6, wherein the treatment regimen results in an increased therapeutic index of the HER2 TDB as compared to treatment with the HER TDB in the absence of the HER2 antibody, this is an intended result of the treatment method and does not add to or modify the active method steps of the claimed method.
It would have been obvious to one having ordinary skill in the art to modify the HER2 TDB treatment method of Clinical Trial NCT03448042 with the teachings of Chang, by predosing with a monoclonal antibody of the same specificity. It would have been obvious to do so because Chang teaches predosing with an antibody against the same target as the T-cell mediated immunotherapy reduces off-tumor/on-target toxicity against normal tissues. There is an expectation of success in applying the predosing methodology to the methods of Clinical Trial NCT03448042 because although Chang is directed to predosing for CAR T cell therapy, the clinical trial and Chang are analogous art because they are both directed to T cell-mediated immunotherapy and Chang provides evidence that predosing with a corresponding antibody does not diminish anti-tumor effects of subsequent immunotherapy ([00013], Lines 17-20).
Claims 1, 2, 6, 10, 12, 14, 16, 21, 24, 26-28, 31, 36-39, 102, 112, 113, and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26, PTO 892 06/23/2025) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) as applied to claims 1, 2, 6, 10, 12, 14, 21, 24, 26-28, 31, 36-39, 102, 112, 113, and 115 above, and further in view of Lo (J Biol Chem. 2017 Mar 3;292(9):3900-3908, PTO 892 06/23/2025).
The combined teachings of Clinical Trial NCT03448042 and Chang teach administration of the HER2 trastuzumab and the HER2 TDB BTRC4017A/runimotamab resulting in an increased therapeutic index.
The combined teachings of Clinical Trial NCT03448042 and Chang do not teach wherein the trastuzumab is an Fc-modified variant comprising one or more amino acid modifications that reduces effector function.
This deficiency is taught by Lo.
The disclosure of Lo is directed to the generation of an “effector-less” antibody with a L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-γ-dependent, antibody-dependent, cell-mediated cytotoxicity in human IgG1 (Abstract, Lines 16-19).
Regarding claim 16, wherein the Fc-modified trastuzumab variant comprises one or more amino acid modifications that reduces effector function, Lo teaches that the LALA-PG mutation eliminates IgG1 effector functions while maintaining typical pharmacokinetics and thermostability, enabling knob-into-hole bispecific antibody production (Abstract, Lines 21-27 and Fig. 2).
It would have been obvious to one having ordinary skill in the art to modify the trastuzumab used in the combined method of Clinical Trial NCT03448042 and Chang with one or more amino acid modifications that reduces effector functions. One would have been motivated to do so because Lo teaches that LALA-PG substitutions improve the safety of bispecific antibodies (Pg. 3902, Left column, Full paragraph 2) in keeping with the goal of the methods of Clinical Trial NCT03448042 and Chang which is to reduce non-tumor specific immunotoxicity. There would be an expectation of success in modifying the trastuzumab in the method of Clinical Trial NCT03448042 and Chang with mutations that reduce effector functions because Lo provides an exemplary modification that reduces effector function in bispecific antibodies without affecting antibody stability.
Claims 1, 2, 6, 10, 12, 14, 21, 24, 26-28, 31, 36-41, 102, 112, 113, and 115 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26, PTO 892 06/23/2025) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) as applied to claims 1, 2, 6, 10, 12, 14, 21, 24, 26-28, 31, 36-39, 102, 112, 113, and 115 above, and further in view of Piccart-Gebhart (N Engl J Med. 2005 Oct 20;353(16):1659-72, PTO 892 06/23/2025). (Citation corrected herein)
The combined teachings of Clinical Trial NCT03448042 and Chang teach administration of the HER2 trastuzumab and the HER2 TDB BTRC4017A/runimotamab resulting in an increased therapeutic index.
The combined teachings of Clinical Trial NCT03448042 and Chang do not teach that (1) the HER2 antibody is administered at a dose of 5 mg/kg to 10 mg/kg or (2) wherein the HER2 antibody is administered about once every three weeks.
This deficiency is taught by Piccart-Gebhart.
The disclosure of Piccart-Gebhart is directed to investigating the efficacy and safety of the HER2 recombinant monoclonal antibody trastuzumab, reporting the one-year results of an international, multicenter trial of patients with advanced breast cancer that overexpresses HER (Abstract Background and Results).
Regarding claims 40 and 41, wherein the HER2 antibody is administered at a dose of 5 mg/kg to 10 mg/kg (claim 40) and wherein the HER2 antibody is administered about once every three weeks (claim 41), Piccart-Gebhart teaches administration of trastuzumab at an initial dose of 8 mg/kg of body weight, followed by maintenance doses of 6 mg/kg every three weeks for two years (Pg. 1660, Study Design, Lines 15-21).
It would have been obvious to one having ordinary skill in the art to administer the HER2 antibody trastuzumab of Clinical Trial NCT03448042 and Chang at 6 mg/kg every three weeks according to the guidelines provided by Piccart-Gebhart. It would have been obvious to do so because Clinical Trial NCT03448042 and Chang teach the administration of trastuzumab, but do not provide guidelines for administration dose or timing, and Piccart-Gebhart provides an exemplary dosage schedule supported by human clinical trial data. There would have been an expectation of success in administering the trastuzumab of Clinical Trial NCT03448042 and Chang the dosage of Piccart-Gebhart because Piccart-Gebhart provides evidence of the safety of trastuzumab administered at that dose and timing schedule.
Claims 45, 46, 53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-76, 101 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26, PTO 892 06/23/2025) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) and Dedrick (published 12/04/2003, PTO 892 06/23/2025) as evidenced by National Center for Health Statistics Anthropometric Reference Data for Children and Adults.
Clinical Trial NCT034448042 is directed to a phase I, open-label, dose escalation study of the safety and pharmacokinetics of BTRC4017A/runimotamab, the HER2 TDB of the instant invention. (Pg. 6, Official Title).
Clinical Trial NCT03448042 does not teach (1) administration of a HER2 antibody prior to the HER2 TDB treatment or (2) the fractionated, dose-escalated regimen of the instant disclosure.
These deficiencies are taught by Chang and Dedrick.
The disclosure of Chang is directed to optimizing CAR T immunotherapy and teaches the administration of the CAR T cell is preceded by “predosing” with an antibody that binds to the same disease-associated antigen (Abstract, Lines 13-16).
The disclosure of Dedrick is directed to methods of administering a method of reducing negative side effects of immunotherapy comprising in general, a first conditioning dose of the therapeutic compound followed by administration of a second therapeutic dose wherein the second dose is higher than the first (see entire Abstract).
Regarding claim 45, wherein the method regimen comprises a first dose of the HER2 antibody followed by an escalating first dose cycle and a second dose of HER2 antibody and another dose of HER2 TDB equivalent to the highest dose of the first cycle, the references teach the following:
Chang teaches cyclical administration of the immunotherapy regimen ([01790], full paragraph) and teaches a predosing a subject with uncongjuagted monoclonal antibody against the disease associated antigen prior to administration of T-cell mediated immunotherapy (Pg. 49, Chang claim 1) and teaches that the administration of the predose is repeated (Pg. 51, Chang claim 31).
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Dedrick teaches dose escalation variations including several embodiments that anticipate the claimed dose escalation methods. For example, Table 4 (Pg. 12) teaches a first dose of 0.7 mg/kg followed by an escalated dose of 1.0 mg/kg or 2.0 mg/kg.
Regarding claim 46, wherein the first dose of the HER2 antibody is administered one day prior to the C1D1, and wherein the subject is monitored for a period of 30 minutes to 24 hours between the first dose of the HER2 antibody and the first does of the HER2 TDB, Chang teaches that the predose antibody is administered 1 day prior to administration of the T cell-based immunotherapy (Pg. 51, Chang claim 28). Chang provides an example wherein mice received a predose of unconjugated monoclonal antibody on day prior to administration of immunotherapy, and implicit within the method is the monitoring of the murine subjects between dosages (Pg. 29, Example 12).
Regarding claims 53 and 61, wherein the second dose of the HER2 TDB is at least two-fold of the first dose (claim 53) or two-fold to ten-fold the first dose (claim 61), Dedrick provides an embodiment where the first dose is 0.7 mg/kg and the second dose is 2.0 mg/kg (See above Table 4, High dose).
Regarding claim 55 and 64, wherein the first dose is from 0.003 mg to 50 mg (claim 55) or wherein the first dose is 0.01 to 20 mg (claim 64), the claimed doses correspond to 3.8x105 mg/kg to 0.6 mg/kg using the average female weight of 77kg (as evidenced by the National Center for Health Statistics Anthropometric Reference Data for Children and Adults, Pg 7, Table 3). In an exemplary intravenous dosage embodiment, Dedrick teaches a first “conditioning” dose of 0.3 mg/kg (Pg. 12, Table 3, Group A and B).
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Regarding claim 58, wherein the first cycle further comprises a third dose of the HER2 TDB, wherein the third dose is greater than the second dose, Dedrick teaches an exemplary three dose escalation regimen (Pg. 12, Table 3, Group B).
Regarding claim 59, wherein the C1D1, the C1D2, and the C1D3 are cumulatively greater than a highest cleared dose of the HER2 TDB in a first dosing cycle of a one-step fractionation, dose- escalation dosing regimen, this claim is interpreted to mean the addition of the three doses is higher than the highest individual dose which is anticipated by the dosing schema see in Dedrick Table 3.
Regarding clam 67, wherein the method comprises administering to the subject the three HER2 TDB doses on about Days 1, 8, and 15, respectively, Dedrick teaches administration of the doses every 7 days, labelled on Table 3 as Days 0, 7, and 14.
Regarding claims 68, 70, 71, and 73, wherein the length of the cycles are 21 days (claim 68), wherein the subject is administered a first dose on day one of cycle 2 (claim 70), wherein the treatment regimen comprises one or more additional dosing cycles (claim 71) and wherein the length of each of the additional dosing cycles is 21 days (claim 73), Chang teaches administration of the immunotherapy on three week treatment cycle, starting with a once-weekly infusion for the first two week and a rest of one week, with the cycles repeated as tolerated ([0246], Lines 1-4).
Regarding claims 74-76, wherein each of the one or more additional dosing cycles comprises a single dose of the HER2 antibody and a single dose of the HER2 TDB (claim 74), wherein the method comprises administering the HER2 antibody and the HER2 TDB on Day 1 of each of the one or more additional dosing cycles (claim 75), and wherein the HER2 antibody is administered prior to the HER2 TDB on Day 1 of each of the one or more additional dosing cycles (claim 76), the claims are dependent on claim 71 and 45, which do not define the length of the treatment cycle, therefore the methods are anticipated by the treatment methods of Dedrick, such as those seen in Tables 3 or 4 above.
Regarding claim 101, wherein he treatment regimen of claim 45 results in an increased therapeutic index of the HER2 TDB as compared to a control treatment regimen, , this property is an intended result of the claimed methods.
It would have been obvious to one having ordinary skill in the art to modify the method of Clinical Trial NCT03448042 by (1) administering a HER2 antibody prior to the HER2 TDB treatment or (2) dosing the subjects using the the fractionated, dose-escalated regimen of the instant disclosure. One would have been motivated to do so because (1) Chang teaches predosing with an antibody against the same target as the T-cell mediated immunotherapy reduces off-tumor/on-target toxicity against normal tissues and (2) Dedrick provides exemplary dosage schedules for antibody immunotherapy suitable for adaptation in the current methods. There is an expectation of success in applying the teaching of Chang and Dedrick to the methods of Clinical Trial NCT03448042 because Chang and Dedrick are analogous art because they are both directed to T cell-mediated immunotherapy and Chang provides evidence of their methods distilled to practice within their respective disclosures.
Claims 45-47, 51-53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-76, 101 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) and Dedrick (published 12/04/2003, PTO 892 06/23/2025) as applied to claims 45, 46, 53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-76, 101 above, and further in view of Piccart-Gebhart (N Engl J Med. 2005 Oct 20;353(16):1659-72, PTO 892 06/23/2025).
The combined teaching of Clinical Trial NCT03448042, Chang, and Dedrick teach administration of a HER2-specific antibody and a HER2 TDB on a dose-escalating cycle.
The combined teachings of Clinical Trial NCT03448042, Chang, and Dedrick do not teach (1) the first dose of the HER2 antibody is from 5 mg/kg, (2) wherein the first or second dose of the HER2 antibody is administered by infusion over a period of at least 30 minutes.
This deficiency is taught by Piccart-Gebhart.
The disclosure of Piccart-Gebhart is directed to investigating the efficacy and safety of the HER2 recombinant monoclonal antibody trastuzumab, providing a report of the one-year results of an international, multicenter trial of patients with advanced breast cancer that overexpresses HER (Abstract Background and Results).
Regarding claims 47 and 51, wherein the first dose of the HER2 antibody is from 5 mg/kg to 10 mg/kg (claim 47) and wherein the dose is administered by infusion over a period of at least 30 minutes (claim 51), Piccart-Gebhart teaches administration of HER2 antibody trastuzumab at 6 mg/kg or 8 mg/kg doses administered intravenously over a 90-minute period (Pg. 1661, Right column, Administration of Trastuzumab, Lines 1 and 2).
It would have been obvious to one having ordinary skill in the art to administer the HER2 antibody trastuzumab of Clinical Trial NCT03448042, Chang and Dedrick wherein (1) the first dose of the HER2 antibody is from 5 mg/kg, (2) the first or second dose of the HER2 antibody is administered by infusion over a period of at least 30 minutes according to the guidelines provided by Piccart-Gebhart. It would have been obvious to do so because Clinical Trial NCT03448042, Chang, and Dedrick teach the administration of trastuzumab, but do not provide guidelines for amount or mode of administration, and Piccart-Gebhart provide an exemplary dosage method for the disclosed antibody. There would have been an expectation of success in administering the trastuzumab of Clinical Trial NCT03448042, Chang, and Dedrick using the dosage methods of Piccart-Gebhart because Piccart-Gebhart provides evidence of the safety of trastuzumab administered at that dose.
Claims 45, 46, 53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-76, 101, 103-106 are rejected under 35 U.S.C. 103 as being unpatentable over Clinical Trial NCT034448042 (version 2018-02-26, PTO 892 06/23/2025) in view of Chang (US2016/0361360A1, published 12/15/2016, PTO 892 06/23/2025) and Dedrick (published 12/04/2003, PTO 892 06/23/2025) as applied to claims 45, 46, 53, 55, 58, 59, 61, 64, 67, 68, 70, 71, 73-76, 101 above, and further in view of Chui (WO2017/087280A1, published 05/26/2017, PTO 892 06/23/2025).
The combined teaching of Clinical Trial NCT03448042, Chang, and Dedrick teach administration of a HER2-specific antibody and a HER2 TDB on a dose-escalating cycle.
The combined teachings of Clinical Trial NCT03448042, Chang, and Dedrick do not teach the method further comprises administration of one or more additional therapeutic agents.
This deficiency is taught by Chui.
The disclosure of Chui is directed to method of treating patients having HER2-positive cancer and discloses the use of PD-L1 binding antagonist administered in combination with the HER2 antibody trastuzumab (Abstract).
Regarding claims 103-106, wherein the method according to claim 1 further comprises administering one or more additional therapeutic agents (103), wherein the additional therapeutic agent is a PD-1 axis agonist (claim 104), wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist (claim 105), and wherein the PD-L1 binding antagonist is MPDL3280A/atezolizumab (claim 106), Chui teaches co-administration of HER2 antagonist trastuzumab and PD-L1 antagonist atezolizumab (see for example, Fig. 3). Chui teaches PD-L1 is a target for immunotherapy because it is overexpressed in tumors and binding it’s ligands results in T cell deactivation ([0024], Lines 1-6).
It would have been obvious to one having ordinary skill in the art to add atezolizumab to the anti-HER2 treatment methods of Clinical Trial NCT03448042, Chang, and Dedrick. One would have been motivated to do so because Chui provides an exemplary combination therapy for the treatment of HER2 positive breast cancer ([00117], Lines 10-12) targeting two important tumor-related targets. There would be an expectation of success in adding atezolizumab to the methods of Clinical Trial NCT03448042, Chang, and Dedrick because atezolizumab was a routinely administered immunotherapy administered at the time of filing.
Applicant’s Arguments
Applicant's arguments filed 11/07/2025 have been fully considered but they are not persuasive.
The applicant traverses the 35 U.S.C. 103 rejections on the following grounds:
I. Applicant submits that among the cited references, only the ClinicalTrial and Chang describe any administration of two different agents that target HER2. The remaining references were cited to supplement various deficiencies in ClinicalTrial and Chang but are entirely silent with respect to administration of two different agents that target HER2. (Remarks, Pg. 14)
In response, additional references are provided to modify the base prior art under 35 U.S.C. 103 and appropriate KSR obviousness rationales and explanation of reasonable expectation of success are provided herein.
II. The presently claimed methods are directed to a combination therapy regimen comprising administering the HER2 antibody and the HER2 TDB as part of the same treatment regimen, rather than administering the HER2 antibody solely as a pretreatment for the HER2 TDB. (Remarks, Pg. 14)
In response, the rationale for a combination therapy comprising administering a competing antibody prior to immunotherapy is provided by Chang. Chang teaches “pre-dosing with unconjugated antibody against the same disease-associated antigen may saturate normal tissues with lower antigen expression levels, while still allowing cytotoxic effect against the higher antigen levels found in tumor cells” ([0013], Lines 27-32). Chang additionally teaches that the predose may be repeated ([0013], Lines 10-11) indicating that administration of the antibody is incorporated within the treatment regimen rather than solely for pretreatment.
III. A skilled artisan would understand that the HER2 antibody has to be administered within a reasonable amount of time relative to the administration of the HER2 TDB in order to increase the therapeutic index of the HER2 TDB, e.g., by reducing the risk of on-target/off-tumor toxicity. In particular, because antibodies have a relatively short half-life, in order for the HER2 antibody to cross compete with the HER2 TDB to saturate HER2 epitopes in low HER2-expressing normal cells, the presence of the HER2 antibody and the HER2 TDB must temporally overlap. Therefore, the ClinicalTrial fails to provide any teaching or motivation of the presently claimed combination treatment regimen, e.g., comprising trastuzumab and runimotamab. (Remarks, Pg. 15)
In response, this interpretation requires reading limitations from the specification into the claims, as the claim 1 does not claim a required time separation between administration of the two products. The disclosure of Chang teaches the rationale for the claimed treatment method and does provide a temporal relationship between administration of predose and immunotherapy treatment.
IV. With respect to Chang, the Office's citation of Applicant's own disclosure to demonstrate inherency is improper: inherency derives from prior art, not from the Applicant's disclosure (M.P.E.P. § 2112 and M.P.E.P. § 2144). If the Office desires to establish an inherent claim limitation, it must do so from the prior art, providing a rationale or evidence for the determination that the allegedly inherent characteristic necessarily flows from the teaching of the applied prior art" (Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990), see also M.P.E.P. § 2112, (IV)) (underlining emphasis in original, italicized emphasis added). (Remarks, Pg. 15)
In response, the examiner wishes to clarify that the limitations pertaining to an increased therapeutic index are recitations of an intended result of the claimed method and are not given patentable weight independent from the active method steps. The intended results flow from the active method steps of the claims and do not add additional limitations to the methods. MPEP 2111.04 I. states “…the court noted that a ‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’ Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).”
Unless it is the applicant’s assertion that the claimed method would not necessarily result in an increased therapeutic index or that there are embodiments of the claimed method that would not produce an increased therapeutic effect, then these intended results are provided for in the prior art rejection that renders obvious the claimed methods.
V. The Office's citation of Chang, particularly the characterization of Chang as analogous art,
is improper. Chang is directed to the use of CAR-T cell therapy in treating cancers (disclosing
specifically CEACAM5 CAR-T cell therapy for treating CEACAM5-positive cancers), and describes that
predosing with an unconjugated antibody does not inhibit antitumor activity of antibody-drug conjugates (ADCs), CAR-T cells, or CAR-natural killer (NK) cells that target the same antigen, e.g., CEACAM5. Applicant respectfully disagrees that Chang is analogous prior art and that a skilled artisan would look to Chang to solve dosing/toxicity problems for a CD3 bispecific antibody. CAR-T cell therapies are administered with intent that they will persist in the patient for years, whereas antibodies are mostly dosed multiple times for oncology indications because antibodies have a relatively short half-life and are cleared by the body at rates much quicker than CAR-T cells. A person of ordinary skill would not address toxicity issues arising from administering CD3 bispecific antibodies by considering techniques used to address CAR-T therapies because of the entirely different pharmacokinetics. Therefore, a skilled artisan would lack motivation to look to combine the entirely unrelated teachings of ClinicalTrial and Chang; they are not analogous art (Remarks, Pgs. 15-16)
In response, the office does not concede that the disclosure of Chang is not analogous art. Chang seeks to solve a problem that is relevant to the claimed T cell-engaging, antibody-based immunotherapy (i.e. a cytokine storm associated with intense antitumor responses mediated by large numbers of activated T cells, Chang [0010]) and has provided a method that can readily be translated to the instant case. In Fig. 3, Chang specifically demonstrates the “predose” methodology applied as a means to prevent adverse effects of antibody drug conjugate IMMU-130. Chang describes the methodology in a manner that is neutral to the type of immunotherapy by stating “that predosing of the parental antibody does not diminish the subsequent targeting of agents recognizing the same antigen on tumor or other diseased cells (FIG. 3)” ([0013], Lines 17-20, emphasis added).
To this end, the teaching of predosing a patient with an antibody that competes with a therapeutic and/or diagnostic antibody is reported in several instances in that art. Boswell (J Nucl Med. 2012 Sep;53(9):1454-61) evaluated a predosing strategy with unconjugated antibody to block ADC uptake in target-expressing tissues while preserving tumor uptake and efficacy (Abstract, Lines 8-11). Boswell concludes efficacy in ADC therapy can be maintained after a predose of unconjugated antibody to block undesirable uptake in non-malignant tissues, providing a viable alternative to conventional dosing strategies and potential for improved safety profiles for ADC regimens (Pg. 1460, Conclusion).
See also Buschbaum (Cancer Res. 1992 Feb 1;52(3):637-42) who teaches that unlabeled specific antibody predosing can substantially enhance tumor binding by radiolabeled anti-B1 antibody and decrease antibody uptake in normal tissues (Pg. 641, Right column, Last paragraph) and Sharkey (Cancer. 2010 Feb 15;116(4 Suppl):1134-45) who teaches pretargeting methods are recognized for their ability to improve radionuclide targeting with reduced hematological toxicity, making these procedures very promising in an environment where the current chemotherapeutic agents are associated with major hematopoietic toxicity (Pg. 1142, Left column).
Thus, in the instant case, the therapeutic agents are known in the prior art and the antibody pre-dosing methodology for reducing off-tumor effects is also obvious over the prior art.
Conclusion
No claims are allowed.
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.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646