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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/02/2026 has been entered.
Claim Status
Applicant’s reply filed on 06/02/2026 is acknowledged. Claims 1, 9, 12, and 14 have been amended. Claims 23 and 24 are newly added.
Claims 1-24 are pending and under examination.
Rejections Withdrawn
All rejection from the Office Action dated 12/03/2025 are herein withdrawn.
New Grounds of Rejection
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating EGFRvIII-positive brain cancer comprising intravenous administration of a small-format, non-Fc anti-EGFRvIII agent comprising the binding regions set forth in SEQ ID NO: 9, 10, 102, and 103, does not reasonably provide enablement for treating EGFRvIII-positive brain cancer comprising intravenous or subcutaneous administration of any size or any format anti-EGFRvIII agent comprising the binding regions set forth in SEQ ID NO: 9, 10, 102, 103. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention
With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method is that EGFRvIII-positive brain tumors can be treated by either intravenous or subcutaneous administration of an EGFRvIII/CD3 bispecific antibody of any format or size.
The state of the relevant art
The art enables the treatment of brain tumors comprising small-format bispecific antibodies administered intravenously. Razpotnik (Front Immunol. 2017 Sep 25;8:1181, PTO-892 12/03/2025) teaches small antibody formats such as Fab or scFv have improved tissue penetration, and the lack of an Fc region circumvent FcRn-dependent efflux from the brain and lack effector functions such as antibody-dependent cellular cytotoxicity (Pg. 3, Left column, Alternative forms of Ab, Lines 1-11). To this end, Choi (Proc Natl Acad Sci USA. 2013 Jan 2;110(1):270-5, IDS filed 06/02/2026) teaches that daily intravenous administration of a small-format EGFRvIIIxCD3 antibody (shown in Fig. 1A) can potently activate T cells in vivo to achieve significant antitumor effects against EGFRvIII-expressing tumors in the CNS of murine glioblastoma models (Data in Fig. 5).
Pertaining to the bispecific antibody format of the instant disclosure, the relevant pre- and post-filing art teach intravenous administration of an EGFRvIII BiTE ® can be used to treat brain tumors in preclinical and clinical settings. Pertaining to preclinical data, Sternjak (Mol Cancer Ther. 2021 May;20(5):925-933, IDS filed 04/03/2024) teaches intravenous administration of the EGFRvIII BiTE® AMG 596 antibody demonstrated high anti-tumor activity as monotherapy against established glioblastoma tumor in NOD/SCID mice (Fig. 5). Pertaining to clinical administration of an EGFRvIII BiTE ®, Clinical Trial NCT03296696 is directed to a dose escalation study of AMG 596 monotherapy in patients with EGFRvIII-positive glioblastoma. NCT03296696 discloses continuous intravenous infusion at varying dosages and schedules in patients diagnosed with grade 4 glioblastoma or lower grade malignant glioma with EGFRvIII positive tumor (Pg. 9, Inclusion Criteria, bullet point 3 and Pg. 15, Arm/Group Description).
The art does not teach subcutaneous administration of bispecific antibodies for treatment of brain tumors. The art also does not teach the ability for large-format, Fc-containing bispecific antibodies to pass through the blood-brain barrier in clinically relevant amounts required for treating tumors in the brain.
The amount of direction provided by the inventor and the existence of working examples
What is enabled by the working examples is narrow in comparison to the breadth of the claims. The working examples provided in the instant specification are all directed to methods of treating brain cancer comprising administration of AMG 596 by continuous intravenous administration (See Examples 1-8 starting on Specification Pg. 32). The instant disclosure does not provide examples of subcutaneous administration of an anti-EGFRvIII agent and does not distill to practice treatment of brain cancer using an anti-EGFRvIII in a format other than the BiTE® format of AMG 596.
In view of the lack of the predictability of the art to which the invention pertains, the lack of guidance and direction provided by applicant, and the absence of appropriate working examples commensurate with the scope of the claims, undue experimentation would be required to use the claimed invention.
The quantity of experimentation needed to make or use the invention
The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating metabolic disorders. Therefore, claim 1 and dependent claims are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement.
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 1-19 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Raum (US2017/0029512A1, published 02/02/2017, PTO-892 04/21/2025) in view of Topp (Lancet Oncol. 2015 Jan;16(1):57-66).
The disclosure of Raum is directed to a bispecific antibody construct comprising a first binding domain which binds to EGFRvIII on the surface of a target cell and a second binding domain that binds to CD3 on the surface of a T cell and provides for the use of the bispecific construct in the treatment of cancer (see Abstract). Raum discloses the bispecific construct of the instant disclosure.
Regarding claims 1 and 2, pertaining to a method for treating EGFRvIII-positive brain cancer, comprising administering to a subject in need thereof intravenously an anti-EGFRvII agent, at an initial dose of from 500pg/day to 12000 pg/day, for at least 14 days, wherein said anti-EGFRvII agent comprises the amino acid sequence of SEQ ID Nos. 9, 10, 102, and 103 (claim 1) and wherein the EGFR-positive cancer is glioblastoma (claim 2), Raum discloses the following:
A bispecific antibody construct comprising an EGFRvIII binding domain and an CD3 binding domain (Pg. 171, claim 1).
The EGFRvIII binding domain comprises SEQ ID NO: 157 and 158, identical to instant SEQ ID NO: 9 and 10 (Pg. 171, claim 1).
The CD3 binding region comprises SEQ ID NO: 26 and 90, identical to instant SEQ ID NO: 102 and 103 (Pg. 172, claim 4).
A method for treating glioblastoma comprising administering to a person a need comprising a step of administering an effective amount of the antibody construct of the disclosure (Pg. 173, claims 12 and 13).
A typical dosage may range from about 0.1 μg/kg to up to about 30mg/kg ([0371], Lines 1-2).
The bispecific antibodies of the disclosure were validated for therapeutic efficacy using in vitro assays directed toward EGFRvIII-positive human glioblastoma cell lines. See for example, Fig. 8 which shows the bispecific antibodies are able to redirect stimulated human CD8+ effector T cells against EGFRvIII-positive cells.
Regarding claim 3-4 and 24, wherein said anti-EGFRvIII agents of claim 1 comprises the amino acid sequence of SEQ ID NOs: 11 and 104 (claim 3) and wherein said anti-EGFRvIII agent comprises the amino acid sequence or SEQ ID NO: 12 or 13 (claims 4 and 24), Raum discloses the EGFRvIII scFv set forth in SEQ ID NO:159 and identical to instant SEQ ID NO: 11, the CD3 scFv set forth in SEQ ID NO: 100 and identical to SEQ ID NO: 104, and the EGFRvIII-CD3 bispecific molecule set forth in SEQ ID NO: 160 and identical to instant SEQ ID NO: 12.
The table below shows the corresponding sequences between the instant invention and Raum. The sequence alignments are shown in the Office Actions dated 04/21/2025 and 12/03/2025.
Instant
Raum (US2017/0029512A1)
EGFRvIII binding domain VH
SEQ ID NO: 9
SEQ ID NO: 157
EGFRvIII binding domain VL
SEQ ID NO: 10
SEQ ID NO: 158
CD3 binding domain VH (I2C)
SEQ ID NO: 102
SEQ ID NO: 26
CD3 binding domain VL (I2C)
SEQ ID NO: 103
SEQ ID NO: 90
EGFRvIII binding domain scFv
SEQ ID NO: 11
SEQ ID NO: 159
CD3 binding domain scFv
SEQ ID NO: 104
SEQ ID NO: 100
EGFRvIII-CD3 bispecific molecule
SEQ ID NO:12
SEQ ID NO: 160
Regarding claims 5-7, wherein said anti-EGFR agent is administered at an initial dose of from 1000 μg/day to 6000 μg/day (claim 5), 1500 μg/day to 6000 μg/day (claim 6), or 3000 μg/day to 6000 μg/day (claim 7), Raum teaches a typical dosage range from about 0.1 μg/kg to up to about 30 mg/kg ([0371], Lines 1-2), which corresponds to a dosage range of 7 μg to 2100 mg in a 70 kg subject.
Raum does not teach: (1) the claimed treatment schedule or (2) further administration of an anti-inflammatory agent to the subject.
These deficiencies are taught by Topp.
The disclosure of Topp is directed to a clinical trial confirming the activity and safety profile of blinatumomab, a CD19-targeting bispecific T-cell engager antibody construct. The disclosure of Topp is cited herein for providing for the general strategy for clinically relevant administration of a bispecific T cell engager antibody.
Regarding claim 8, wherein said anti-EGFRvIII agent is administered by continuous intravenous infusion, Topp teaches patients received blinatumomab as continuous intravenous infusion with a portable pump (Pg. 59, Left column, Lines 3-4).
Regarding claims 9-11 and 23, wherein said anti-EGFRvIII agent is administered for at least 28 days at the dose from 500 μg/day to 12000 μg/day (claim 9), 1500 μg/day to 6000 μg/day (claim 10), 3000 μg/day to 6000 μg/day (claim 11) or 1000 μg/day to 6000 μg/day, Raum teaches the dosage range as taught above and Topp teaches patients received blinatumomab as continuous intravenous infusion in 4-week (28-day) cycles (Pg. 59, Left column, Lines 3-5).
Regarding claims 12-15, wherein the method of claim 1 further comprises administering to the subject one or more subsequent doses of the anti-EGFRvIII agent for at least 14 days at a dose of 500 μg/day to 12000 μg/day (claim 12), 3000 μg/day to 6000 μg/day (claim 13), and 500 μg/day to 12000 (claim 14) or 3000 μg/day to 6000 μg/day for at least 28 days (claim 15), Topp further teaches blinatumomab is administered in multiple 28-day treatment cycles (Pg. 59, Left column, Lines 3-6).
Regarding claims 16, wherein said one or more subsequent doses according to the method of claim 12 are dosed at least one week after the previous dose, Topp teaches each treatment cycle is followed by two treatment-free weeks (Pg. 59, Left column, Lines 3-6).
Regarding claim 17, wherein said ERGFRvIII agent according to the method of claim 1 is administered at a 14-day on/14-day off cycle or a 28-day on/14 day-off cycle, Topp teaches each 4-week (28 day) treatment cycle is followed by two treatment-free weeks (Pg. 59, Left column, Lines 3-6).
Regarding claims 18-19, wherein the method of claim 1 further comprises administering an anti-inflammatory agent to said subject (claim 18), wherein said anti-inflammatory agent is a corticosteroid (claim 19), Topp teaches subjects received dexamethasone premedication within 1 hour before treatment initiation in each cycle and before the dose step in cycle one to minimize infusion reactions (Pg. 59, Left column, Lines 9-13).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the treatment method of Raum comprising administration of an EGFR/CD3 bispecific antibody by (1) using the treatment schedule of Topp and (2) administration of an anti-inflammatory agent as taught by Topp. One would have been motivated to do so because Topp provides a continuous intravenous method comprising 28-day cycles for a bispecific T cell engager, and this method could readily be used for treatment comprising the EGFR/CD3 bispecific T cell engager of Raum. Raum specifically teaches a major challenge in the development of drugs is the predictable modulation of pharmacokinetics profiles such as the drug half-life ([0346], Lines 1-10). This challenge as it relates to treatment with small antibody formats such as that of Raum is mediated by the administration route and schedule of Topp. There would be an expectation of success in using the administration schedule of Topp with the bispecific T cell engager of Raum because Topp teaches their method using a bispecific T cell engager produces clinically relevant and safe results in patients.
Claims 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over Raum (US2017/0029512A1, published 02/02/2017) in view of Topp (Lancet Oncol. 2015 Jan;16(1):57-66) as applied to claims 1-19 and 23-24 above, and further in view of Pirker (Lancet Oncol. 2012 Jan;13(1):33-42).
The combined teachings of Raum and Topp teach a method of treating EGFRvIII-positive brain cancer comprising administering to a subject in need thereof an anti-EGFRvIII agent comprising the anti-EGFRvIII and anti-CD3 binding domains of the instant invention.
The combined teachings of Raum and Topp do not teach: (1) obtaining a biological sample from said subject and detecting the presence of EGFRvIII in said samples, or (2) assessing said subject for EGFRvIII-positivity, wherein said assessment is immunohistochemistry (IHC) H-score.
These deficiencies are taught by Pirker.
The disclosure of Pirker is directed to the use of EGFR immunohistochemistry scoring to characterize EGFR expression in NSCLC patients who received anti-EGFR cetuximab treatment. They found EGFR expression correlated with overall survival in response to anti-EGFR treatment (Abstract, Findings). They concluded that the correlation between survival and EGFR expression as characterized by their novel scoring method is underscored by the principal that a high level of EGFR expression likely indicates tumor dependency on EGFR signaling and subsequent sensitivity to anti-EGFR cetuximab therapy (Pg. 40, Left column, Discussion, Lines 1-10). Of note, Pirker details the scoring method used (Pg. 34, Right column, Full paragraph 2, Lines 1-9), but does not use the term “H-score”. The instant specification identifies the scoring method as detailed in Pirker as the H-score method (Specification, Pg. 28, paragraph 63).
Regarding claims 20-22, wherein the method of claim 1 further comprises obtaining a biological sample and detecting the presence of EGFRvIII expression level in said sample (claim 20), wherein said subject according to claim 1 has been assessed for EGFRvIII-positivity, wherein said assessment is IHC H-score (claim 21), and wherein said H-score of a biological sample of the subject in need of treatment is from 8 to 280 (claim 22), Pirker teaches scoring tumor tissues based on immunohistochemical staining intensity of the target antigen, which in their case was EGFR (Pg. 34, Right column, Procedures, Lines 1-9). Pirker teaches the scoring method resulted in a score of 0-300 and used a score of 200 as the treatment threshold. This threshold falls within the instantly claimed range for EGFRvIII.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to use immunohistochemistry H-score as taught by Pirker to assess EGFRvIII-positiviity as part of a method of assessing a subject in need of anti-EGFRvIII for the treatment taught in the combined teachings of Raum and Topp. One would have been motivated to do so because Pirker teaches positive EGFR H-score correlated with responsiveness to anti-EGFR treatment. Though the antigen of Pirker is different than Raum and Topp (EGFR vs EGFRvIII) the disclosure of Pirker is relied on primarily for teaching the H-score method, a semi-quantitative means of reporting the protein expression of a tissue based on immunohistochemistry. Pirker confirmed that their scoring method could reliably predict responsiveness to treatment with an agent that targets the quantified antigen. There would be an expectation of success because one can readily perform immunohistochemistry comprising the use of EGFRvIII-specific antibodies to determine positivity of EGFRvIII in the biological sample.
Response to Applicant’s Remarks
The following references cited in the reply 06/02/2026 have been considered: Syversen et al., Yarden, Kuchimanchi et al., Strohl and Naso, and von Stackelberg et al.
Applicant's arguments filed 06/02/2026 have been fully considered but they are not persuasive. The arguments pertaining to the current rejections will be addressed below:
The Applicant argues the previously applied prior art references pertaining to dosing regimen fail to render the instant invention obvious for the following reasons: (1) unpredictable dosing based on structural differences and BBB penetration and (2) unpredictable dosing based on potency and (3) unexpected results from the instantly claimed dosing regimen. (Remarks, Pg. 6-9)
In response, all of the arguments provided pertaining to unpredictable dosing and unexpected results are in the context of an anti-EGFVRvIII BiTE® antibody administered intravenously to humans. The scope of the claims is not commensurate with the data provided for at least the following reasons: (1) the independent claim does not claim a BiTE® antibody format or a structural equivalent, and (2) the independent claim recites both intravenous and subcutaneous routes of administration.
Claim 1 is directed to an “anti-EGFRvIII agent” which comprises the amino acid sequence of SEQ ID NO: 9, 10, 102, and 103, said sequences corresponding to EGFRvIII and CD3 binding domains. The instant specification defines “anti-EGFRvIII agents” as recombinant protein constructs comprising two binding domains, each domain derived from an antigen-binding fragment of a full-length antibody. While the prior art applied in the rejection above (Raum) discloses the BiTE® of the instant specification, the claims as currently written do not exclude any other formats, including larger bispecific formats that include Fc regions that would not readily cross the BBB. The finding of unexpected results would be considered if the claim scope was limited to a small-format, non-Fc bispecific antibody that encompasses the disclosed BiTE® antibody format and structural equivalents.
Importantly, claim 1 recites the anti-EGFRvIII agent is administered intravenously or subcutaneously. The different administration modes require vastly different amounts of agent for therapeutic efficacy. The disclosure does not provide examples of subcutaneous administration of the BiTE ® of the disclosure or how the administration route correlates to therapeutic efficacy of the claimed dosage. Therefore, the applied prior art that teaches a range that encompasses the claimed range is still appropriate as it would be reflective of the different routes of administration.
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 1-19 and 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,155,629 in view of Raum (US2017/0029512A1, published 02/02/2017) and Topp (Lancet Oncol. 2015 Jan;16(1):57-66).
Regarding claims 1-2 and 8, pertaining to a method for treating EGFRvIII-positive brain cancer, comprising administering to a subject in need thereof intravenously an anti-EGFRvII agent, at an initial dose of from 500 μg/day to 12000 μg/day, for at least 14 days, wherein said anti-EGFRvII agent comprises the amino acid sequence of SEQ ID Nos. 9, 10, 102, and 103 (claim 1), wherein the EGFR-positive cancer is glioblastoma (claim 2), and wherein said anti-EGFRvIII agent is administered by continuous intravenous infusion (claim 8), ‘629 discloses the following:
A method for treating glioblastoma or glioma comprising administering to a subject in need an effective amount of a bispecific antibody construct, said antibody construct comprises a first binding domain which binds to EGFRvIII and a second binding domain which binds to CD3 (claim 1).
The polypeptide is administered by continuous intravenous administration (claim 20).
The EGFRvIII binding domain comprises SEQ ID NO:157 and 158, identical to instant SEQ ID NO: 9 and 10 (claim 1).
The CD3 binding region comprises SEQ ID NO: 98 and 99, identical to instant SEQ ID NO: 102 and 103 (claim 1).
Regarding claims 3-4 and 24, wherein said anti-EGFRvIII agents of claim 1 comprises the amino acid sequence of SEQ ID NOs: 11 and 104 (claim 3) and or wherein said anti-EGFRvIII agent comprises the amino acid sequence or SEQ ID NO: 12 or 13 (claims 4 and 24), ‘629 discloses the EGFRvIII scFv set forth in SEQ ID NO: 159 and identical to instant SEQ ID NO: 11 (claim 4), the CD3 scFv set forth in SEQ ID NO: 100 and identical to SEQ ID NO: 104 (claim 4), and the EGFRvIII-CD3 bispecific molecule set forth in SEQ ID NO: 160 and identical to instant SEQ ID NO: 12 (claim 5).
The table below shows the corresponding sequences between the instant invention and ‘629. The sequence alignments are shown in the Office Actions dated 04/21/2025 and 12/03/2025.
Instant
US. Pat. No. 11,155,629
EGFRvIII binding domain VH
SEQ ID NO: 9
SEQ ID NO: 157
EGFRvIII binding domain VL
SEQ ID NO: 10
SEQ ID NO: 158
CD3 binding domain VH (I2C)
SEQ ID NO: 102
SEQ ID NO: 98
CD3 binding domain VL (I2C)
SEQ ID NO: 103
SEQ ID NO: 99
EGFRvIII binding domain scFv
SEQ ID NO: 11
SEQ ID NO: 159
CD3 binding domain scFv
SEQ ID NO: 104
SEQ ID NO: 100
EGFRvIII-CD3 bispecific molecule
SEQ ID NO:12
SEQ ID NO: 160
‘629 does not teach: (1) the claimed treatment dosages, (2) the claimed treatment schedule, or (3) further administration of an anti-inflammatory agent to the subject.
These deficiencies are taught by Raum and Topp.
Raum:
The disclosure of Raum is directed to a bispecific antibody construct comprising a first binding domain which binds to EGFRvIII on the surface of a target cell and a second binding domain that binds to CD3 on the surface of a T cell and provides for the use of the bispecific construct in the treatment of cancer (see Abstract).
Regarding claims 5-7, wherein said anti-EGFR agent is administered at an initial dose of from 1000 μg/day to 6000 μg/day (claim 5), 1500 μg/day to 6000 μg/day (claim 6), or 3000 μg/day to 6000 μg/day (claim 7), Raum teaches a typical dosage range from about 0.1 μg/kg to up to about 30 mg/kg ([0371], Lines 1-2), which corresponds to a dosage range of 7 μg to 2100 mg in a 70 kg subject.
Topp:
The disclosure of Topp is directed to a clinical trial confirming the activity and safety profile of blinatumomab, a CD19-targeting bispecific T-cell engager antibody construct. The teachings of Topp are provided herein pertaining to its teachings regarding a strategy for the administration of a bispecific T cell engager.
Regarding claims 9-11 and 23, wherein said anti-EGFRvIII agent is administered for at least 28 days at the dose from 500 μg/day to 12000 μg/day (claim 9), 1500 μg/day to 6000 μg/day (claim 10), 3000 μg/day to 6000 μg/day (claim 11) or 1000 μg/day to 6000 μg/day, Raum teaches the dosage range as taught above and Topp teaches patients received blinatumomab as continuous intravenous infusion in 4-week cycles (Pg. 59, Left column, Lines 3-5).
Regarding claims 12-15, wherein the method of claim 1 further comprises administering to the subject one or more subsequent doses of the anti-EGFRvIII agent for at least 14 days at a dose of 500 μg/day to 12000 μg/day (claim 12), 3000 μg/day to 6000 μg/day (claim 13), and 500 μg/day to 12000 (claim 14) or 3000 μg/day to 6000 μg/day for at least 28 days (claim 15), Topp further teaches blinatumomab multiple 28-day treatment cycles (Pg. 59, Left column, Lines 3-6).
Regarding claims 16, wherein said one or more subsequent doses according to the method of claim 12 are dosed at least one week after the previous dose, Topp teaches each treatment cycle is followed by two treatment free weeks (Pg. 59, Left column, Lines 3-6).
Regarding claim 17, wherein said ERGFRvIII agent according to the method of claim 1 is administered at a 14-day on/14-day off cycle or a 28-day on/14 day-off cycle, Topp teaches each 4 week (28 day) treatment cycle is followed by two treatment free weeks (Pg. 59, Left column, Lines 3-6).
Regarding claims 18-19, wherein the method of claim 1 further comprises administering an anti-inflammatory agent to said subject (claim 18), wherein said anti-inflammatory agent is a corticosteroid (claim 19), Topp teaches subjects received dexamethasone premedication within 1 hour before treatment initiation in each cycle and before the dose step in cycle one to minimize infusion reactions (Pg. 59, Left column, Lines 9-13).
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to modify the treatment method of ‘629 comprising administration of an EGFR/CD3 bispecific antibody by using (1) the dosages of Raum, (2) the treatment schedule of Topp, (3) and administration of anti-inflammatory agent as taught by Topp. One would have been motivated to do so because Raum is directed to the same bispecific agents as ‘629 and provides the dosages ranges in contemplation of administration of those bispecific agents and Topp provides a continuous intravenous method comprising 28-day cycles for a bispecific T cell engager. There would be an expectation of success in using the dosages of Raum and administration schedule of Topp with the bispecific T cell engager of ‘629 because optimization of dosages and administration schedules is routinely performed in the art and Topp specifically teaches their administration schedule using a bispecific T cell engager produces clinically relevant and safe results in patients.
Claims 1-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11,155,629 in view of Raum (US2017/0029512A1, published 02/02/2017) and Topp (Lancet Oncol. 2015 Jan;16(1):57-66) as applied to claims 1-19 and 23-24 above and further in view of Pirker (Lancet Oncol. 2012 Jan;13(1):33-42).
The combined teachings of ‘629, Raum and Topp teach a method of treating EGFRvIII-positive brain cancer comprising administering to a subject in need thereof an anti-EGFRvIII agent comprising the anti-EGFRvIII and anti-CD3 binding domains of the instant invention.
The combined teachings of ‘629, Raum, and Topp do not teach: (1) obtaining a biological sample from said subject and detecting the presence of EGFRvIII in said samples, or (2) assessing said subject for EGFRvIII-positivity, wherein said assessment is immunohistochemistry (IHC) H-score.
These deficiencies are taught by Pirker.
The disclosure of Pirker is directed to the use of EGFR IHC H-score to characterize EGFR expression in NSCLC patients who received anti-EGFR cetuximab treatment and correlated EGFR expression with longer survival (Abstract, Findings).
Regarding claim 20, wherein the method of claim 1 further comprises obtaining a biological sample and detecting the presence of EGFRvIII expression level in said sample,
Regarding claims 20-22, wherein the method of claim 1 further comprises obtaining a biological sample and detecting the presence of EGFRvIII expression level in said sample (claim 20), wherein said subject according to claim 1 has been assessed for EGFRvIII-positivity, wherein said assessment is IHC H-score (claim 21), and wherein said H-score of a biological sample of the subject in need of treatment is from 8 to 280 (claim 22), Pirker teaches scoring tumor tissues based on immunohistochemical staining intensity of the target antigen, which in their case was EGFR (Pg. 34, Right column, Procedures, Lines 1-9). Pirker teaches the scoring method resulted in a score of 0-300 and used a score of 200 as the treatment threshold. This threshold falls within the instantly claimed range for EGFRvIII.
It would have been prima facie obvious to one having ordinary skill in the art at the time of filing to use immunohistochemistry H-score as taught by Pirker to assess EGFRvIII-positiviity as part of a method of assessing a subject in need of anti-EGFRvIII for the treatment taught in the combined teachings of’629, Raum and Topp. One would have been motivated to do so because Pirker teaches positive EGFR H-score correlated with responsiveness to anti-EGFR treatment. Though the antigen of Pirker is different than ‘629 (EGFR vs EGFRvIII) the disclosure of Pirker is relied on primarily for teaching the H-score method, a semi-quantitative means of reporting the protein expression of a tissue based on immunohistochemistry. Pirker confirmed that their scoring method could reliably predict responsiveness to treatment with an agent that targets the quantified antigen. There would be an expectation of success because one can readily perform immunohistochemistry comprising the use of EGFRvIII-specific antibodies to determine positivity of EGFRvIII in the biological sample.
Conclusion
No claims are allowed.
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/CAROL ANN CHASE/Examiner, Art Unit 1646
/HONG SANG/Primary Examiner, Art Unit 1646
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