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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
The amendments filed on 9/30/2025 which claims 1, 4, 16, and 34 were amended is acknowledged.
Claims 1-4, 6, 8-10, 12-14, 16, 20, 24, 26, 30-31, and 33-35 are pending in the instant application.
Priority
This application is a 371 of PCT/US2019/048954, filed on 8/30/2019.
Claim Interpretation
Claims 14 and 20 are drawn to antibodies comprising a particular set of CDRs or “a humanized form thereof”. The language of “a humanized form thereof” was interpreted to refer exclusively to the framework regions of the antibody being derived from a human and not the CDRs of the antibody. The instantly claimed CDRs as stated are derived from mice (instant spec, pg 38, para 1-pg 40, para 4), which can then be inserted into a human framework region in order to generate a humanized antibody.
Withdrawn Objections
The objection to claim 16 has been withdrawn, applicant nested the conjunctions appropriately.
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 1-4, 6, 8-10, 12-13, 24, 26, and 34-35 are 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
claim 1, 34
Claims 1 and 34 are drawn to the CPBP being 3E10 antibody fragment that has the function of (i) increasing DNA damage; and/or (ii) reducing DNA repair; and (iii) has the function “activates the cGAS/STING inflammatory pathway”. Applicant has failed to provide the core structure of that the 3E10 antibody fragment must possess in order to preserve these functions, thus applicant has failed to meet the written description. In order to claim the breadth of fragments appropriately, applicant must claim the fragment comprising one of the complete sets of six CDRs described in claim 16. Absent this core structure, the fragment does not possess the binding properties necessary for it to function. This core structure must be supplied because Applicant cannot meet the written description by supplying a representative number of species, due to the unpredictability of antibody structure. Even when provided with several related antibodies that have the desired function of binding the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity. Furthermore, note in the decision in Amgen v. Sanofi 2017, where the Court supported previous decisions (Centocor 2011; Abbvie 2014) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen.” Because applicant is incapable of meeting the written description requirement via describing a representative number of species, applicant must instead provide the core structure responsible for the function of “cell penetration” and “increasing DNA damage and/or reducing DNA repair” and “activates the cGAS/STING inflammatory pathway”. Dependent claims 2-4, 6, 8-10, 12-13, 24, 26, and 35 fail to cure these deficiencies, thus also fail to meet the written description 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6, 8-10, 12-14, 16, 20, 24, 26, 30, 31, and 33-35 are rejected under 35 U.S.C. 103 as being unpatentable over Hansen et al. (US20170291961) in view of Callahan et al. (doi: 10.1189/jlb.1212631), Wu et al. (doi: 10.1021/acs.bioconjchem.9b00245), Jillian et al. (WO2018094144), James et al. (US20150376279), Rattray et al. (WO2019152806), and Campbell et al. (WO2019018426).
claim 1, 8-9
Regarding claims 1, 8, and 9, Hansen teaches a method of treating cancer and viral infections comprising administering the antibody 3E10 (abstract) that penetrates cells, binds DNA, and inhibits DNA repair (pg 1, para 0005). Hansen teaches the 3E10 antibody and the D31N variant thereof, are selectively lethal to cancer cells deficient in DNA repair (pg 1, para 0011). Because the D31N variant of 3E10 is the same antibody used in the instantly claimed examples (instant Example 1 and 2), the properties of (1) can penetrate a cell without the aid of a conjugate or carrier, (2) is able to induce of DNA damage, (3) is able to bind DNA, and (4) activates the cGAS/STING inflammatory pathway, are inherent properties. MPEP 2112.01 (II) states:
“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Additionally, something which is old does not become patentable upon the discovery of a new property. See MPEP § 2112(I). Hansen teaches that the antibodies of the invention can be combined with other chemotherapeutic antibodies (pg 17, para 0189). Hansen teaches that antibodies targeting CTLA4 (a type of ICM) are FDA approved for treating tumors (pg 1, para 0004).
Hansen does not explicitly teach a combination therapy comprising the 3E10 antibody and an anti-PD1, anti-PD-L1, and/or anti-CTLA4 antibody.
Callahan teaches antibodies that block CTLA4, PD1, and PD-L1 are effective in treating cancer (abstract) via reactivating T cells to attack the cancer cells (pg 41, col 2, para 1). Callahan teaches these checkpoint-blocking antibodies have demonstrated clinical activity in a variety of tumor types, including melanoma, RCC, and NSCLC, displaying a distinct profile of antitumor activity and toxicity (pg 41, col 2, para 2). Callahan teaches a variety of combination therapies including these antibodies, dependent on the cancer type, such as ipilimumab (anti-CTLA4 antibody), gemcitabine (an antimetabolite), and cisplatin (DNA replication/repair inhibitor) for urothelial carcinoma (Table 4).
Wu teaches a combination therapy comprising a cell-penetrating CLIP6-OVA immune adjuvant in combination with an immune checkpoint blockade therapy, being an effective way of treating cancer (abstract). Wu teaches the combination is an effective therapeutic vaccine, wherein the immune checkpoint blockade antagonizes PD-1 (pg 2116, col 1, para 1).
It would have been obvious to combine the teachings of Hansen, Callahan, and Wu because (1) Hansen provides the 3E10 antibody and teaches it can be used in combination with another therapeutic monoclonal antibody known to treat cancer, such as anti-CTLA4 antibodies; (2) Callahan teaches combining immune checkpoint inhibiting antibodies with drugs such as cisplatin that disrupt DNA replication/repair, similar to 3E10; and (3) Wu teaches that immune checkpoint blockade of PD-1 is successful in treating cancer when combined with another cell-penetrating immunostimulant. One of skill in the art would have had a reasonable expectation of success because Hansen teaches combining the 3E10 antibody with other monoclonal antibodies known to treat cancer, and both Callahan and Wu teach using immune checkpoint inhibitors as an adjunct therapy for treating cancer in combination with DNA repair/replication inhibitors or cell-penetrating immunostimulants.
claim 2
Regarding claim 2, Hansen teaches the antibodies of the invention, when combined with another chemotherapeutic agent, such as a PARP inhibitor (a type of ICM), synergistically enhance a cell’s sensitivity to that chemotherapeutic agent (pg 17, para 0190). Hansen teaches that the antibodies of the invention can be used to enhance the radiosensitivity of a tumor to radiotherapy (pg 17, para 0186). Because synergistic enhancement requires the combination therapy has a greater effect than the sum of its’ parts, this also meets the limitation of the combination therapy having a greater effect than either therapy in isolation.
claim 3
Regarding claim 3, Hansen teaches the 3E10 antibody and the D31N variant thereof, are selectively lethal to cancer cells deficient in DNA repair (pg 1, para 0011).
!claim 4
Regarding claim 4, Hansen teaches that the di-scFv variant of the D31N 3E10 antibody, begins to reduce tumor volume over a period of 1-30 days (Fig. 4A; Example 3).
Hansen is silent on the length of time between the administration of the 3E10 antibody and the ICM.
Jillian teaches a method of treating cancer comprising administering a combination therapy comprising an immune checkpoint inhibitor and an anti-STn antibody (claim 19 and 20). Jillian teaches the immune checkpoint inhibitor can optionally target PD-1 or CTLA4 (pg 3, para 0010). Jillian teaches the combination therapy refers to a subject being simultaneously exposed to two or more agents administered at the same time or within an interval of time such that the subject is at some point in time simultaneously exposed to both and/or such that there may be an overlap in the effect of each agent on the patient; such as at least one dose of one or more agents is administered within about 24 hours, 12 hours, 6 hours, 3 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute of at least one dose of one or more other agents (pg 9, para 0042). The instantly claimed time-window of 1 hour to 4 weeks overlaps with the time window of 1 minute to 1 day described by Jillian. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. See MPEP § 2144.05(I).
It would have been obvious to combine the teachings of Hansen, Callahan, Wu, and Jillian because (1) Hansen teaches that the 3E10 antibody starts exhibiting a tumor-reducing effect within 1-30 days and that the 3E10 antibody can be combined with an immune checkpoint inhibitor; (2) Callahan teaches combining immune checkpoint inhibiting antibodies with drugs such as cisplatin that disrupt DNA replication/repair, similar to 3E10; and (3) Wu teaches that immune checkpoint blockade of PD-1 is successful in treating cancer when combined with another cell-penetrating immunostimulant; (4) Jillian teaches that immune checkpoint inhibitors can administered within 1 minute-24 hours of another antibody also known to treat cancer. One of skill in the art would have had a reasonable expectation of success because the 3E10 antibody and immune checkpoint inhibitor are known to have a synergistic effect when administered in a time window in which they can exert a biological effect simultaneously. Furthermore, differences in a dosage regimen will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such dosage regimen is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In the instant case, applicant has not provided any evidence of criticality, thus arriving at an optimal dosage window of 1 hour to 4 weeks, is considered a matter of routine experimentation. See MPEP § 2144.05(II)(A). Additionally, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C).
claim 6
Regarding claim 6, Hansen teaches that the antibodies of the invention can be combined with other chemotherapeutic agents (pg 17, para 0189), such as a PARP1 inhibitor or cisplatin (pg 2, para 0023-0024).
claim 10
Regarding claim 10, Hansen teaches the 3E10 antibody is a lupus autoantibody (pg 1, para 0005). Because the D31N variant of 3E10 is the same antibody used in the instantly claimed examples (instant Example 1 and 2), the property of being derived from a subject or animal model with “systemic lupus erythematous” is an inherent property. Something which is old does not become patentable upon the discovery of a new property. See MPEP § 2112(I).
claim 12
Regarding claim 12, Hansen teaches the same D31N variant of the 3E10 antibody as described in the instant examples (pg 1, para 0011). Because the D31N variant of 3E10 is the same antibody used in the instantly claimed examples (instant Example 1 and 2), the property inhibiting RAD51 is an inherent property. Something which is old does not become patentable upon the discovery of a new property. See MPEP § 2112(I).
claim 13
Regarding claim 13, Hansen teaches the scFv variants of the 3E10 antibody are also effective in treating cancer and infection (abstract).
claim 14, 16
Regarding claims 14 and 16, Hansen teaches the 3E10 antibody comprising 100% sequence similarity to the VH of instant SEQ ID NO: 7 (SEQ ID NO: 25), shown below with the CDRs of instant SEQ ID NOs: 30, 32, and 33 underlined.
instant_7 ---------------EVQLVESGGGLVKPGGSRKLSCAASGFTFSNYGMHWVRQAPEKGL 45
Hansen_25 GGGGSGGGGSGGGGSEVQLVESGGGLVKPGGSRKLSCAASGFTFSNYGMHWVRQAPEKGL 180
*********************************************
instant_7 EWVAYISSGSSTIYYADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARRGLLLDY 105
Hansen_25 EWVAYISSGSSTIYYADTVKGRFTISRDNAKNTLFLQMTSLRSEDTAMYYCARRGLLLDY 240
************************************************************
instant_7 WGQGTTLTVSS---------------------- 116
Hansen_25 WGQGTTLTVSSLEQKLISEEDLNSAVDHHHHHH 273
***********
Hansen also teaches 100% sequence identity to the VL of instant SEQ ID NO: 1 (SEQ ID NO: 3), shown below with the CDRs of instant SEQ ID NOs: 34, 36, and 37 underlined.
instant_1 DIVLTQSPASLAVSLGQRATISCRASKSVSTSSYSYMHWYQQKPGQPPKLLIKYASYLES 60
Hansen_3 DIVLTQSPASLAVSLGQRATISCRASKSVSTSSYSYMHWYQQKPGQPPKLLIKYASYLES 60
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instant_1 GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSREFPWTFGGGTKLEIK------ 111
Hansen_3 GVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHSREFPWTFGGGTKLEIKRADAAP 117
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!claim 20
Regarding claim 20, Hansen teaches a method of treating cancer and viral infections comprising administering the antibody 3E10 (abstract) that binds DNA and inhibits DNA repair (pg 1, para 0005).
Hansen does not teach the CPBP comprising the VH of instant SEQ ID NO: 16 nor the VL of instant SEQ ID NO: 12.
James teaches a cell penetrating antibody called 5C6 that binds DNA (pg 2, para 0024) and is effective in treating cancer (pg 1, para 00090-0011). James teaches the 5C6 antibody comprises 100% sequence identity to the VH of instant SEQ ID NO: 16 (SEQ ID NO: 5), shown below with the CDRs underlined.
instant_16 QLKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPAKRLEWVATISSGGGSTYY 60
James_5 QLKLVESGGGLVKPGGSLKLSCAASGFTFSSYTMSWVRQTPAKRLEWVATISSGGGSTYY 60
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instant_16 PDSVKGRFTISRDNARNTLYLQMSSLRSEDTAMYYCARRAYSKRGAMDYWGQGTSVTVSS 120
James_5 PDSVKGRFTISRDNARNTLYLQMSSLRSEDTAMYYCARRAYSKRGAMDYWGQGTSVTVSS 120
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James teaches 5C6 antibody comprises 100% sequence identity to the VL of instant SEQ ID NO: 12 (SEQ ID NO: 1), shown below with the CDRs underlined.
instant_12 DIVLTQSPASLAAVSLGERATISYRASKSVSTSGYSYMHWNQQKPGQAPRLLIYLVSNLE 60
James_1 DIVLTQSPASLAAVSLGERATISYRASKSVSTSGYSYMHWNQQKPGQAPRLLIYLVSNLE 60
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instant_12 SGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHIRELDTFFGGGTKLEIK 112
James_1 SGVPARFSGSGSGTDFTLNIHPVEEEDAATYYCQHIRELDTFFGGGTKLEIK 112
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It would have been obvious to combine the teachings of Hansen, Callahan, Wu, and James because (1) Hansen and James both teach antibodies that are capable of penetrating the cell and binding DNA are effective in treating cancer; and (2) James provides the amino acid sequence of the 5C6 antibody that is known to have these properties. One of skill in the art would have had a reasonable expectation of success because both antibodies operate by similar mechanisms and are known to treat cancer.
claim 24, 26
Regarding claims 24 and 26, Hansen teaches that the antibodies of the invention can be combined with other chemotherapeutic antibodies (pg 17, para 0189). Hansen teaches that antibodies targeting CTLA4 are FDA approved for treating tumors (pg 1, para 0004).
Hansen does not teach PD-1 or PD-L1 antagonists as being effective in treating cancer.
Callahan teaches antibodies that block CTLA4, PD1, and PD-L1 are effective in treating cancer (abstract) via reactivating T cells to attack the cancer cells (pg 41, col 2, para 1). Callahan teaches these checkpoint-blocking antibodies have demonstrated clinical activity in a variety of tumor types, including melanoma, RCC, and NSCLC, displaying a distinct profile of antitumor activity and toxicity (pg 41, col 2, para 2).
It would have been obvious to combine the teachings of Hansen, Callahan, and Wu because (1) Hansen provides the 3E10 antibody and teaches it can be used in combination with another therapeutic monoclonal antibody known to treat cancer, such as anti-CTLA4 antibodies; (2) Callahan teaches combining immune checkpoint inhibiting antibodies with drugs such as cisplatin that disrupt DNA replication/repair, similar to 3E10; and (3) Wu teaches that immune checkpoint blockade of PD-1 is successful in treating cancer when combined with another cell-penetrating immunostimulant. One of skill in the art would have had a reasonable expectation of success because Hansen teaches combining the 3E10 antibody with other monoclonal antibodies known to treat cancer, and Callahan and Wu both teach using immune checkpoint inhibitors targeting PD1 and/or PD-L1 as an adjunct therapy for treating cancer in combination with DNA repair/replication inhibitors or cell-penetrating immunostimulants.
!claim 30-31, 33
Regarding claims 30-31 and 33, Hansen teaches that the cell-penetrating antibodies of the invention can be combined with other chemotherapeutic antibodies (pg 17, para 0189). Hansen teaches that antibodies targeting CTLA4 are FDA approved for treating tumors (pg 1, para 0004).
Hansen does not teach a cell-penetrating anti-DNA binding protein comprising the set of six CDRs within instant SEQ ID NOs: 61-76, or 88, in that order. Hansen does not explicitly teach a combination therapy comprising the 3E10 antibody and an anti-PD1, anti-PD-L1, and/or anti-CTLA4 antibody. Hansen does not teach the cell-penetrating anti-DNA binding protein comprising the di-scFv of instant SEQ ID NO: 70.
Campbell teaches anti-DNA binding protein that is effective in treating cancer (abstract; pg 1, para 3-4), that is a variant of the 3E10 antibody (pg 9, L7). Campbell teaches this anti-DNA binding protein comprises 100% sequence identity to the di-scFv of instant SEQ ID NO: 70 (SEQ ID NO: 41), shown below with the LCDRs of instant SEQ ID NOs: 35, 36, and 37; and the HCDRs of instant SEQ ID NOs: 30, 32, and 33.
instant_70 DIQMTQSPSSLSASLGDRATITCRASKTVSTSSYSYMHWYQQKPGQPPKLLIKYASYLES 60
Campbell_41 DIQMTQSPSSLSASLGDRATITCRASKTVSTSSYSYMHWYQQKPGQPPKLLIKYASYLES 60
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instant_70 GVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQHSREFPWTFGGGTKVEIKRADAAPGGG 120
Campbell_41 GVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQHSREFPWTFGGGTKVEIKRADAAPGGG 120
************************************************************
instant_70 GSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWV 180
Campbell_41 GSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWV 180
************************************************************
instant_70 SYISSGSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGLLLDYWGQ 240
Campbell_41 SYISSGSSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGLLLDYWGQ 240
************************************************************
instant_70 GTTVTVSSASTKGPSVFPLAPLESSGSDIQMTQSPSSLSASLGDRATITCRASKTVSTSS 300
Campbell_41 GTTVTVSSASTKGPSVFPLAPLESSGSDIQMTQSPSSLSASLGDRATITCRASKTVSTSS 300
************************************************************
instant_70 YSYMHWYQQKPGQPPKLLIKYASYLESGVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQ 360
Campbell_41 YSYMHWYQQKPGQPPKLLIKYASYLESGVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQ 360
************************************************************
instant_70 HSREFPWTFGGGTKVEIKRADAAPGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLS 420
Campbell_41 HSREFPWTFGGGTKVEIKRADAAPGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLS 420
************************************************************
instant_70 CAASGFTFSNYGMHWVRQAPGKGLEWVSYISSGSSTIYYADSVKGRFTISRDNAKNSLYL 480
Campbell_41 CAASGFTFSNYGMHWVRQAPGKGLEWVSYISSGSSTIYYADSVKGRFTISRDNAKNSLYL 480
************************************************************
instant_70 QMNSLRAEDTAVYYCARRGLLLDYWGQGTTVTVSS 515
Campbell_41 QMNSLRAEDTAVYYCARRGLLLDYWGQGTTVTVSS 515
***********************************
Callahan teaches antibodies that block CTLA4, PD1, and PD-L1 are effective in treating cancer (abstract) via reactivating T cells to attack the cancer cells (pg 41, col 2, para 1). Callahan teaches these checkpoint-blocking antibodies have demonstrated clinical activity in a variety of tumor types, including melanoma, RCC, and NSCLC, displaying a distinct profile of antitumor activity and toxicity (pg 41, col 2, para 2). Callahan teaches a variety of combination therapies including these antibodies, dependent on the cancer type, such as ipilimumab (anti-CTLA4 antibody), gemcitabine (an antimetabolite), and cisplatin (DNA replication/repair inhibitor) for urothelial carcinoma (Table 4).
Wu teaches a combination therapy comprising a cell-penetrating CLIP6-OVA immune adjuvant in combination with an immune checkpoint blockade therapy, being an effective way of treating cancer (abstract). Wu teaches the combination is an effective therapeutic vaccine, wherein the immune checkpoint blockade antagonizes PD-1 (pg 2116, col 1, para 1).
It would have been obvious to combine the teachings of Hansen, Campbell, Callahan, and Wu because (1) Hansen provides the 3E10 antibody and teaches it can be used in combination with another therapeutic monoclonal antibody known to treat cancer, such as anti-CTLA4 antibodies; (2) Campbell provides the structure of a di-scFv 3E10 variant that is effective in treating cancer; (3) Callahan teaches combining immune checkpoint inhibiting antibodies with drugs such as cisplatin that disrupt DNA replication/repair, similar to 3E10; and (4) Wu teaches that immune checkpoint blockade of PD-1 is successful in treating cancer when combined with another cell-penetrating immunostimulant. One of skill in the art would have had a reasonable expectation of success because Hansen teaches combining the 3E10 antibody with other monoclonal antibodies known to treat cancer, wherein Campbell provides the exact structure of a functional 3E10 scFv variant demonstrated to be effective in treating cancer, whereas both Callahan and Wu teach using immune checkpoint inhibitors as an adjunct therapy for treating cancer in combination with DNA repair/replication inhibitors or cell-penetrating immunostimulants. One of skill in the art would have had a reasonable expectation of success because both antibodies share similar amino acid structures, operate by similar mechanisms, and are known to treat cancer.
claim 34, 35
Regarding claims 34 and 35, Hansen teaches a pharmaceutical composition comprising the cell-penetrating antibodies of the invention and other active ingredients (pg 11, para 0125). Hansen teaches that the antibodies of the invention can be combined with other chemotherapeutic antibodies (pg 17, para 0189). Hansen teaches that antibodies targeting CTLA4 (a type of ICM) are FDA approved for treating tumors (pg 1, para 0004). Hansen teaches the antibodies of the invention, when combined with another chemotherapeutic agent, such as a PARP inhibitor (a type of ICM), synergistically enhance a cell’s sensitivity to that chemotherapeutic agent (pg 17, para 0190). Because synergistic enhancement requires the combination therapy has a greater effect than the sum of its’ parts, this also meets the limitation of the combination therapy having a greater effect than either therapy in isolation. Hansen teaches that the antibodies of the invention can be used to enhance the radiosensitivity of a tumor to radiotherapy (pg 17, para 0186). Hansen teaches a method of treating cancer and viral infections comprising administering the antibody 3E10 (abstract) that penetrates cells, binds DNA, and inhibits DNA repair (pg 1, para 0005). Hansen teaches the 3E10 antibody and the D31N variant thereof, are selectively lethal to cancer cells deficient in DNA repair (pg 1, para 0011). Because the D31N variant of 3E10 is the same antibody used in the instantly claimed examples (instant Example 1 and 2), the properties of (1) can penetrate a cell without the aid of a conjugate or carrier, (2) is able to induce of DNA damage, (3) is able to bind DNA, and (4) activates the cGAS/STING inflammatory pathway, are inherent properties. MPEP 2112.01 (II) states:
“Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Additionally, something which is old does not become patentable upon the discovery of a new property. See MPEP § 2112(I). Hansen teaches that the antibodies of the invention can be combined with other chemotherapeutic antibodies (pg 17, para 0189). Hansen teaches that antibodies targeting CTLA4 (a type of ICM) are FDA approved for treating tumors (pg 1, para 0004).
Hansen does not explicitly teach a combination therapy comprising the 3E10 antibody and an anti-PD1, anti-PD-L1, and/or anti-CTLA4 antibody.
Callahan teaches antibodies that block CTLA4, PD1, and PD-L1 are effective in treating cancer (abstract) via reactivating T cells to attack the cancer cells (pg 41, col 2, para 1). Callahan teaches these checkpoint-blocking antibodies have demonstrated clinical activity in a variety of tumor types, including melanoma, RCC, and NSCLC, displaying a distinct profile of antitumor activity and toxicity (pg 41, col 2, para 2). Callahan teaches a variety of combination therapies including these antibodies, dependent on the cancer type, such as ipilimumab (anti-CTLA4 antibody), gemcitabine (an antimetabolite), and cisplatin (DNA replication/repair inhibitor) for urothelial carcinoma (Table 4).
Wu teaches a combination therapy comprising a cell-penetrating CLIP6-OVA immune adjuvant in combination with an immune checkpoint blockade therapy, being an effective way of treating cancer (abstract). Wu teaches the combination is an effective therapeutic vaccine, wherein the immune checkpoint blockade antagonizes PD-1 (pg 2116, col 1, para 1).
It would have been obvious to combine the teachings of Hansen, Callahan, and Wu because (1) Hansen provides the 3E10 antibody and teaches it can be used in combination with another therapeutic monoclonal antibody known to treat cancer, such as anti-CTLA4 antibodies, generating a synergistic effect; (2) Callahan teaches combining immune checkpoint inhibiting antibodies with drugs such as cisplatin that disrupt DNA replication/repair, similar to 3E10; and (3) Wu teaches that immune checkpoint blockade of PD-1 is successful in treating cancer when combined with another cell-penetrating immunostimulant. One of skill in the art would have had a reasonable expectation of success because Hansen teaches combining the 3E10 antibody with other monoclonal antibodies known to treat cancer, wherein the combination, is at a minimum, additive, and both Callahan and Wu teach using immune checkpoint inhibitors as an adjunct therapy for treating cancer in combination with DNA repair/replication inhibitors or cell-penetrating immunostimulants.
Response to Arguments
Applicant’s arguments filed on 9/30/2025 have been fully considered but they are not persuasive.
112(a); pg 8, para 4
Applicant argues that the claim amendment requiring the antibody be 3E10 antibody and exemplary fragments of this antibody satisfies the written description requirement. Applicant says this is possible because the antibodies used in the invention are not novel as they were in Abbvie. Applicant cites See Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d at 1384, 231 USPQ at 94; Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1085 (Fed. Cir. 2005), Vas-Cath, 935 F.2d at 1563, 19 USPQ2d at 1116; and Martin v. Johnson, 454 F.2d 746, 751, 172 USPQ 391, 395 (CCPA 1972) in support of not describing the antibody structure in detail.
The inclusion of the 3E10 antibody limitation supplied much needed clarity, however the structure of the fragments themselves is still found lacking as discussed in the modified 112(a) written description rejection above. Due to the unpredictability of antibody structure and binding, applicant cannot meet the written description requirement solely by describing exemplary species. Examiner recommends claiming the complete set of six CDRs for the 3E10 antibodies in the base claim to overcome this rejection. Dependent claims can thus be drawn to the 3E10 identity of the antibody and also to specific fragment types (e.g. scFv).
103; pg 11, para 3
Applicant cites re Hack, 245 F.2d 246,248, 114 USPQ 161, 163 (CCPA 1957) in support of a new use for an old structure might be patentable to the discoverer in a process of using. Applicant asserts their discovery of 3E10 antibodies being able to activate the cGAS/STING pathway was previously unknown, absent the knowledge of this newly discovered property, Applicant asserts that there was no motivation to combine the 3E10 antibody with an immune checkpoint inhibitor (e.g. PD-1 antagonists, PD-L1 antagonists, and CTLA4 antagonists). Applicant cites Kubin, 561 F.3d at 1359, 90 USPQ2d at 1423 in support of the existence of too many options to select from and that the rejection is based on improper hindsight. Applicant cites Id. (citing In re O'Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir.)), to support the assertion that the prior art only supplied general guidance as to the particular form of the claimed invention, but not enough information to arrive at the successful combination disclosed in the invention.
As described in the 103 rejection above, the motivation supplied to combine the 3E10 antibody with an immune checkpoint inhibitor is simply that both agents were known to be independently effective in treating cancer. Thus a person of skill in the art would have had a reasonable expectation of success of combining two known anti-cancer therapies in a method of treating cancer. Knowledge of the particular mechanism by which it achieves this (i.e. activates the cGAS/STING pathway) was not requisite knowledge in order to combine these two therapies into a combination therapy regime. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). It is recognized that the instant claims are drawn to broad genera of immune checkpoint inhibitors (e.g. PD-1 antagonists, PD-L1 antagonists, and CTLA4 antagonists), thus arriving at combination of the 3E10 antibody with one of these three genera fails to establish a selection requiring improper hindsight, as these genera are substantially broad and limited by function not structure. Furthermore, all of these genera have well-established anticancer activity.
103; pg 12, para 2
Applicant asserts a synergistic effect upon combining the 3E10 antibody with an immune checkpoint inhibitor: “The antitumor efficacy of cGAMP administered by i.t. injection into B16.F10 tumors was enhanced when combined with anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte associated-4 (CTLA-4) antibodies. studies, cyclic dinucleotides (CDNs) together with anti PD-1 incited much stronger antitumor effects than monotherapy in a mouse model of squamous cell carcinoma model as well as of melanoma. Luo et al. showed encouraging results by combining a STING-activating nanovaccine and an anti-PDl antibody, which lead to generation of long-term antitumor memory in TC-1 tumor model.”
While evidence of synergy provides a strong argument against a conclusion of obviousness as described in MPEP § 716.02(a)(I); evidence of this assertion could not be found in the instant specification, as there were no experiments describing the effect of combining the 3E10 antibody with an immune checkpoint inhibitor. MPEP § 2145 states “arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).” The citation of Luo appears to refer to doi: 10.1038/nnano.2017.52, an academic paper that shares no common author or institution with the instant application (citation retrieved from instant spec pg 3, para 1). The content of the paper predates the instant application (published in 4/24/2017), and would constitute prior art if it made the assertions applicant claims. However this publication discusses the synergy between an immune-stimulating nanoparticle and an anti-PD-1 antibody, and makes no reference to the 3E10 antibody. Thus it is unclear how this publication provides evidence of synergy for the instant application.
Conclusion
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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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675