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 .
DETAILED ACTION
Status of the Claims
1. Claims 1-38 are the original claims filed on 1/18/2023. In the Preliminary Amendment of 10/6/2023, claims 1-38 are canceled and new claims 39-42 are added. In the Response of 10/15/2025, claims 39 is amended and claims 40-42 are canceled.
2. Applicants have not identified support in the specification for the claim amendments. Support for claim amendments requires showing the amendment has a basis in the original application, such as in the specification, drawings, or description. In the interest of compact prosecution, support for the claim amendments is discussed herein below.
3. Claim 39 is the claim under examination. This Office Action is final.
Priority
4. USAN 18/155,740, filed 01/18/2023, is a Divisional of 16/312,743, filed 07/22/2019, now U.S. Patent # 11613572 and having 2 RCE-type filing therein,
16/312,743 is a National Stage entry of PCT/US2017/038373, International Filing Date: 06/20/2017, PCT/US2017/038373 Claims Priority from Provisional Application 62/352,698, filed 06/21/2016, PCT/US2017/038373 Claims Priority from Provisional Application 62/394,360, filed 09/14/2016, PCT/US2017/038373 Claims Priority from Provisional Application 62/491,908, filed 04/28/2017.
Information Disclosure Statement
5. As of 11/29/2025, a total of seven (7) IDS are filed: 4/18/2023; 10/6/2023; 8/28/2024; 8/28/2024; 8/28/2024; and 10/15/2025.
Withdrawal of Objections
Specification
6. The objections to the disclosure because of informalities is withdrawn.
a) The amended specification rectifies the improper use of the term, i.e., nanobodies, GENOVAC, DART, BiTE, which is a trade name or a mark used in commerce.
Claim Objections
7. The objections to Claims 39-42 because of informalities is moot for canceled claims 40-42 and are withdrawn for the pending(s):
a) Claim(s) 39thereof.” See [0040-0041] in the specification.
b) Claim(s) 39
c) Claim(s) 39
Rejections Maintained
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.
Written Description
8. The rejection of Claim(s) 39
Claim construction/ interpretation/ CLAIM MAP
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Claim 39 is amended to replace CD3 with CD3δε without explanation in the Response of 10/15/2025.
See [0188] OmniFlic rats were immunized with human and cynomolgus CD3-epsilon/delta constructs at Aldevron, Inc. (Fargo, ND) using the GENOVAC Antibody Technology. Draining lymph nodes were harvested after the final boost and RNA isolated. Following cDNA synthesis, the IgH heavy chain antibody repertoire was characterized by Next Generation Sequencing and our proprietary in-house software. Candidate antigen-specific VH sequences showing evidence of antigen-specific positive selection were selected. Several hundred VH sequences encoding FlicAbs were selected for gene assembly and cloned into an expression vector. Subsequently, fully human FlicAb IgG1 antibodies were expressed in HEK cells for analysis by Flow and ELISA. Human FlicAbs were tested for binding to primary human T cells and Jurkat cells by flow. In addition, human FlicAbs were tested using recombinant CD36s proteins in ELISA. All FlicAbs with positive binding for human T cells are listed in FIG. 1. Selected sequences were further characterized in T cell activation assays.
Claim 39 is amended without explanation in the Response of 10/15/2025 to replace the negative proviso with a positive recitation for “a pathogen antigen” that incorporates, inter alia, the subject matter of canceled claim 41. See
[0041] In some embodiments, a method is provided for treatment of infectious disease, the method comprising administering to an individual in need thereof an effective dose of a mono-specific, bi-specific, etc. antibody of the invention. Where the antibody is bispecific, a second antigen-binding site may specifically bind a pathogen antigen, e.g. bacteria, viruses or parasites.
The claimed method requires treating/preventing any pathogen infection in a subject using a bispecific antibody comprising a 1st polypeptide with a binding moiety (anti-CD3 δε) with a common/fixed VL region (SEQ ID NO: 69) and a CL domain; a 2nd polypeptide comprising a binding moiety (anti-CD3 δε or any one of a VH domain (SEQ ID NO: 1, 6, 13, 18 or 39)) with a CH1, hinge, CH2 and CH3 domain, wherein the 1st and 2nd polypeptide form the anti-CD3 δε binding portion of the bispecific antibody, and a 3rd polypeptide comprising a VH domain in single or tandem configuration with specific binding for a pathogen antigen with a hinge, CH2 and CH3 domain but no CH1 domain.
A) Applicants allege Example 5-6 and Figures 3-12D support the invention and that “one of skill in the art,…would understand how to make additional multispecific anti-CD3 antibodies and how to use the claimed method of treatment.”
Response to Arguments
i) Claim 39 is amended to recite CD3δε instead of what Applicants assert to be “CD3” in the Response of 10/15/2025.
ii) AS regards the alleged support for treating (therapeutic) a pathogen infection:
Example 5 teaches treating a HDLM2 is a multiple Myeloma cell line.
[0190] A bispecific FlicAb with one arm reacting with CD3 (ID 304703) and the other with human PD-L1 was produced and was shown to activate human CD8+ T cells only in the presence of PD-L1 positive tumor cells (FIG. 3). HDLM2 is a Multiple Myeloma cell line, which expresses PD-L1 on the surface. Ramos is a Burkitt's lymphoma cell line, which is negative for PD-L1. CD69 expression was used as a read-out. Bispecific antibody was used at the indicated concentrations.
[0191] As shown in FIG. 4, tumor cells (HDLM2, which express PD-L1 on the cell surface) were incubated with purified human CD8+ T cells and bispecific antibodies. HDLM2 cells do not express CD20 and co-culture with an α-CD3/α-CD20 bispecific FlicAb did not lead to killing of HDLM2 cells. Only co-culture of human CD8+ T cells and HDLM2 with an α-CD3/α-PD-L1 bispecific FlicAb led to significant killing.
Example 6 teaches killing activity and cytokine release from a U266 BCMA+ tumor cell line. See
[0193] Shown in FIG. 6, four αCD3_fam1:aBCMA bispecific antibodies, each with a unique anti-CD3 arm (as indicated) and a common anti-BCMA arm, were tested for the ability to kill U266 BCMA+ tumor cells through redirection of activated primary T cells. In this experiment U266 cells that express BCMA were mixed with activated pan T-cells in a 10:1 E:T ratio along with the addition of bispecific antibody. The x-axis shows the concentration of antibody used and the y-axis shows the % lysis of tumor cells 6 hours after addition of antibody. The killing activity was correlated with IL-2 release (FIG. 7); with IFN-γ release (FIG. 8) and with CD3 binding affinity (FIG. 9). The correlation between IL-2 production and U266 tumor cell lysis is R.sup.2=0.37. The correlation between IFN-γ production and U266 tumor cell lysis is R.sup.2=0.53. The correlation between U266 killing EC50 and protein binding affinity is R.sup.2=0.93.
Figure 3: bispecific FlicAb with one arm reacting with CD3 (ID 304703) and the other with human PD-L1 was produced and was shown to activate human CD8+ T cells only in the presence of PD-L1 positive tumor cells (FIG. 3).
Figure 4: bispecific FlicAb with one arm reacting with CD3 (ID 304703) and the other with human PD-L1 was produced and was shown to activate human CD8+ T cells only in the presence of PD-L1 positive tumor cells (FIG. 3).
Figure 5: summarizes data for antibodies in monospecific and bispecific format. Column 1 shows the sequence ID for the anti-CD3 VH sequence ID NO:304703 (SEQ ID NO:39), 314171 (SEQ ID NO:13), 313306 (SEQ ID NO:1), 313329 (SEQ ID NO:6) and 313283 (SEQ ID NO:18). Column 2 shows the MFI value for Jurkat cell binding of the parental monospecific anti-CD3. Column 3 shows the MFI value for cyno T-cell binding of the parental monospecific anti-CD3. Column 5 shows the picograms of IL-2 released by pan T-cells stimulated by the bispecific antibody binding the BCMA protein coated on plastic at the dose indicated. Column 6 shows the picograms of IL-6 released by pan T-cells stimulated by the bispecific antibody binding the BCMA protein coated on plastic at the dose indicated. Column 7 shows the picograms of IL-10 released by pan T-cells stimulated by the bispecific antibody binding the BCMA protein coated on plastic at the dose indicated. Column 8 shows the picograms of IFN-γ released by pan T-cells stimulated by the bispecific antibody binding the BCMA protein coated on plastic at the dose indicated. Column 9 shows the picograms of TNFα released by pan T-cells stimulated by the bispecific antibody binding the BCMA protein coated on plastic at the dose indicated. Column 10 shows the EC50 of bispecific antibody-mediated U266 tumor cell lysis in presence of human pan T-cells. Column 11 shows the percent lysis of U266 tumor cells in the presence of bispecific antibody and human pan T-cells at a dose of 333 ng/mL of bispecific antibody. Column 12 shows the protein binding affinity of the anti-CD3 arm of the bispecific antibody measured by Octet. Column 13 shows the MFI value for Jurkat cell binding of the bispecific antibody.
Figure 6: four αCD3_fam1:aBCMA bispecific antibodies, each with a unique anti-CD3 arm (as indicated) and a common anti-BCMA arm, were tested for the ability to kill U266 BCMA+ tumor cells through redirection of activated primary T cells. In this experiment U266 cells that express BCMA were mixed with activated pan T-cells in a 10:1 E:T ratio along with the addition of bispecific antibody.
Figure 7: The killing activity was correlated with IL-2 release.
Figure 8: The killing activity was correlated with IFN-γ release.
Figure 9: The killing activity was correlated with CD3 binding affinity.
Figure 10: FIG. 10A shows killing of RPMI-8226 cells, FIG. 10B shows killing of NCI-H929 cells, panel C shows killing of U-266 cells, and FIG. 10D shows killing of K562 cells, a negative control. The x-axis shows the concentration of antibody used and the y-axis shows the % lysis of tumor cells 6 hours after addition of antibody.
Figure 11: the level of IL-2 cytokine release was measured after resting human T cells were cultured with various tumor cell lines and increasing doses of αCD3_F1F:aBCMA bispecific antibody (as in FIG. 10). FIG. 11A shows IL-2 release stimulated by RPMI-8226 cells, FIG. 11B shows IL-2 release stimulated by NCI-H929 cells, FIG. 11C shows IL-2 release stimulated by U-266 cells, and FIG. 11D shows IL-2 release stimulated by K562 cells, a negative control.
Figure 12D: FIG. 12A shows IFN-γ release stimulated by RPMI-8226 cells, FIG. 12B shows IFN-γ release stimulated by NCI-H929 cells, FIG. 12C shows IFN-γ release stimulated by U-266 cells, and FIG. 12D shows IFN-γ release stimulated by K562 cells, a negative control.
Applicant’s specification fully discloses two examples, Example 5-6, testing the FlicAb in a bispecific format (Figure 2). Notably, the species of FlicAb tested in the limited number of experiments are focused on affecting cancer cells, in vitro. There are NO data to support the treatment effective endpoint required of the claimed invention for treating just any pathogen infection, in vivo.
“therapeutically effective dose”: Applicants have not identified a therapeutic effective dose for a pathogen infection:
[0168] Effective doses of the compositions of the present invention for the treatment of disease vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but nonhuman mammals may also be treated, e.g. companion animals such as dogs, cats, horses, etc., laboratory mammals such as rabbits, mice, rats, etc., and the like. Treatment dosages can be titrated to optimize safety and efficacy.
[0169] Dosage levels can be readily determined by the ordinarily skilled clinician, and can be modified as required, e.g., as required to modify a subject's response to therapy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient. In some embodiments, the therapeutic dosage the agent may range from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight. For example dosages can be 1 mg/kg body weight or 10 mg/kg body weight or within the range of 1-10 mg/kg. An exemplary treatment regime entails administration once every two weeks or once a month or once every 3 to 6 months. Therapeutic entities of the present invention are usually administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring blood levels of the therapeutic entity in the patient. Alternatively, therapeutic entities of the present invention can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the polypeptide in the patient.
[0178] The compositions can be administered for therapeutic treatment. Compositions are administered to a patient in an amount sufficient to substantially ablate targeted cells, as described above. An amount adequate to accomplish this is defined as a “therapeutically effective dose.”, which may provide for an improvement in overall survival rates. Single or multiple administrations of the compositions may be administered depending on the dosage and frequency as required and tolerated by the patient. The particular dose required for a treatment will depend upon the medical condition and history of the mammal, as well as other factors such as age, weight, gender, administration route, efficiency, etc.
Here the specification defines "therapeutically effective dose" in treating any undefined pathogen infection where the scope is not commensurate with the disclosure in the application at the time of filing.
ii) AS regards the alleged support for preventing (prophylactic) a pathogen infection: there are NO data showing FlicAb bispecific antibodies having a prophylactic effect, in vivo, for just any pathogen infection.
“prophylactic effective dose”; Applicants have not identified a prophylactic effective dose for a pathogen infection:
[0168] Effective doses of the compositions of the present invention for the treatment of disease vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but nonhuman mammals may also be treated, e.g. companion animals such as dogs, cats, horses, etc., laboratory mammals such as rabbits, mice, rats, etc., and the like. Treatment dosages can be titrated to optimize safety and efficacy.
[0170] In prophylactic applications, a relatively low dosage may be administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In other therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patent can be administered a prophylactic regime.
MPEP § 2163 states
“…the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics) or through a sufficient description of a representative number of species.”
Because applicant seeks patent protection for all such functionalized bispecific antibodies, the genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Here the specification defines "prophylactic effective dose" in treating any undefined pathogen infection where the scope is not commensurate with the disclosure in the application at the time of filing.
The rejection is maintained.
Conclusion
9. No claims are allowed.
10. 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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643