DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-17 are pending and being examined.
Claim Objections
2. Claims 2-5 are objected to because of the following informalities: Claims 2-5 recite that the antibody “is” one of the listed proteins CTLA-4, PD-1, HVEM…PD-1, TIGIT, CTLA-4…OX40. The claims as currently constituted indicate the antibodies are the listed proteins themselves. However, it appears Applicants intended to recite that the antagonistic antibody and the agonistic antibody bind to a protein selected from the group consisting of CTLA-4, PD-1, HVEVM, PD-1, TIGIT, CTLA-4, OX40, etc. Appropriate correction is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
3. Claim(s) 1-17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2017/023749, Kadiyala et al, claiming priority to July 2015.
Kadiyala teaches conjugates attached to the surface of a nanoparticle ([110]; [119-122]; [124]; [128]; [178]; claims 1-12, 22-23, 25-27, 30, 34, 75-84), wherein the conjugate comprises at least one antagonist agent specific to a coinhibitory signal molecule and at least one agonist agent specific to a costimulatory signal molecule, wherein the antagonist agent of the conjugate can inhibit an immunosuppressive regulatory signal and the agonist agent in the same conjugate can activate an immuno-potentiating signal; the combined effect tips the balance of the immunoregulation towards a positive immune response ([343]; [346]).
Kadiyala teaches: “a conjugate comprising an antagonist agent specific to a coinhibitory molecule and a conjugate comprising an agonist agent specific to a costimulatory signal may be formulated into a single nanoparticle of the present invention to generate the same effect” ([343]), therefore, Kadiyala teaches separate conjugates, one comprising an antagonist and another comprising an agonist, that are not conjugated to each other, and are present on the same nanoparticle.
Kadiyala teaches the antagonist agent specific to a coinhibitory molecule includes antagonist antibodies to T-cell surface antigens: CTLA-4, PD-1, PD-L1 (B7-H1), TIM-3, LAG-3, BTLA or TIGIT that act as immune checkpoint inhibitors ([30]; [33-63]; [69-70]; [128]; [153-154]; [159]; [344]; Table 1; claims 1-12), including monoclonal anti-PD-1 antibodies nivolumab, pembrolizumab and pidilizumab (Table 1).
Kadiyala teaches the agonist agent specific to a costimulatory signal includes agonist antibodies to T-cell surface antigens CD28, 4-1BB, or OX40 and provides exemplary monoclonal antibodies ([29-30]; [69-70]; [106-108]; [343]; claims 22-23).
Kadiyala teaches utilizing click chemistry to attach the conjugates directly to the nanoparticle ([231]).
Kadiyala teaches a pharmaceutical composition comprising the nanoparticle in a pharmaceutically acceptable carrier ([209-243]; [335]; [396]; claim 85).
Kadiyala teaches a method for inhibiting an immunosuppressive signal to increase cancer-specific immune response in a subject; method for inducing T cell immune response; method for activating T cells; and method of treating cancer in a subject, the methods comprising administering a pharmaceutically effective amount of the conjugate nanoparticle ([13-15]; [28]; [30-34]; [71]; [348]; [355]; claim 86);
wherein the nanoparticle conjugate is administered via a route such as topical, intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, and subcutaneous) ([330-335]);
wherein the method further comprises administering chemotherapy and/or radiation therapy ([354]);
wherein the subject is diagnosed with cancer such as breast, colon, bladder, lung, ovarian, esophageal, pancreatic, and more ([355]); and
wherein the subject is a human patient ([332]; [355]).
4. Claim 1-6, 8-17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication 2019/0175755, Kosmides et al, claiming priority to August 2016.
Kosmides teaches a nanoparticle or microparticle comprising first and second different T-cell receptor targeting antibodies conjugated to the surface of the particle, wherein a first antibody functions as an immune checkpoint inhibitor including antagonistic anti-PD-L1 or anti-PD-1 antibody, and a second antibody functions as a T-cell co-stimulator including agonistic anti-OX40 antibody or anti-4-1BB antibody ([10-16]; [52]; [145-148]; [160-168]; [175]; [200-201]; claims 2-35);
wherein the antibody is monoclonal or a fragment such as scFv ([182]; [199]);
wherein the particle is in a composition comprising a pharmaceutically acceptable carrier ([231-233]; [258]); and
methods of administering the particle to a subject having cancer to bind and stimulate T-cells in the subject ([7-9]; [60-61]; [64-69]; claims 1-35), wherein the cancer includes colorectal and other cancers ([18]; [63]; [74-75]; claim 18); wherein the subject is human ([20]; [78]); the method further comprising administering chemotherapy and/or radiation therapy to the subject ([83-95]); and wherein the particle is administered intratumorally or intravenously ([21]; [233-235]).
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.
5. Claim 1-6, 8-17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2019/0175755, Kosmides et al, claiming priority to August 2016; in view of WO 2017/023749, Kadiyala et al, claiming priority to July 2015; Chen et al (Cellular Immunology, 2014, 287:91-99); and US Patent Application Publication 2015/0190506, Cheung et al, published July 2015.
Kosmides teaches a nanoparticle or microparticle comprising first and second different T-cell receptor targeting antibodies conjugated to the surface of the particle, wherein a first antibody functions as an immune checkpoint inhibitor including antagonistic anti-PD-L1 or anti-PD-1 antibody, and a second antibody functions as a T-cell co-stimulator including agonistic anti-OX40 antibody or anti-4-1BB antibody ([10-16]; [52]; [145-148]; [160-168]; [175]; [200-201]; claims 2-35); wherein the particle is organic and made of cellulose material ([132-133]); wherein the antibody is monoclonal or a fragment such as scFv ([182]; [199]); wherein the particle is in a composition comprising a pharmaceutically acceptable carrier ([231-233]; [258]); and methods of administering the particle to a subject having cancer to contact and bind T-cells in the subject ([7-9]; [60-61]; [64-69]; claims 1-35), wherein the cancer includes colorectal and other cancers ([18]; [63]; [74-75]; claim 18); wherein the subject is human ([20]; [78]); the method further comprising administering chemotherapy and/or radiation therapy to the subject ([83-95]); wherein the particle is administered intratumorally or intravenously ([21]; [233-235]).
Although Kosmides specifically suggests making and using a particle comprising a first antibody that functions as an immune checkpoint inhibitor such as antagonistic anti-PD-1 antibody, and a second antibody that functions as a T-cell co-stimulator such as agonistic anti-OX40 antibody, Kosmides does not exemplify utilizing the two antibodies together in the particle.
Kadiyala teaches as set forth above, and further teach utilizing PLGA nanoparticles ([185]; [213]; [259]; [274]; [288]; [291-297]).
Chen teaches that organic poly(lactic-co-glycolic acid) (PLGA) is one of the most successfully developed biodegradable nanoparticle carriers, and demonstrate successfully attaching anti-OX40 agonistic antibody to the surface of PLGA nanoparticles (Materials and Methods; p. 92, col. 1, first paragraph; Figure 1). Chen demonstrates successfully inducing cytotoxic T-cell (CTL) proliferation and enhancing CTL activation by contacting the anti-OXC40-PLGA-NP with T-cells (sections 3.4 to 3.5; Figures 5 and 6). Chen suggests administering the anti-OXC40-PLGA-NP clinically to activate CTL responses in cancer immunotherapy and conclude that PLGA-based nanoparticle formulation provides an efficient delivery system for antibody (abstract; p. 97, col. 1-2; p. 98, Conclusion in section 5).
Cheung teaches treating cancer in a patient, as well as enhancing anti-tumor immune response, with a combination of antibodies that antagonize and bind PD-1, and antibodies that agonize and bind OX40, in order to provide one antagonist specific to a coinhibitory signal molecule and at least one agonist specific to a costimulatory signal molecule to enhance T cell activation and enhance an antitumor immune response; wherein administration to the patient is intravenous; wherein the patient has breast, ovarian or lung cancer ([69]; [416-420]; [428]; [430-434]; [442]; [444-445]; [541]; Examples, claims); further comprising administering chemotherapy or radiation therapy ([84-91]; [93]; [429]). Cheung suggests the composition can comprise a nanoparticle ([414]). Cheung teaches known exemplary monoclonal antibodies that bind to and agonize OX40 and antagonize PD-1 for use together ([166-172]; [255-268]). Cheung teaches that administering a “PD-1 axis binding antagonist” (a PD-1/PD-L1 inhibitor) in combination with an OX40 agonist is synergistic in cancer treatment, reducing tumor size, enhancing T cell activation, and reducing intratumoral Foxp3+ Treg cells, as exemplified with administration of PD-L1 and OX40 antibodies to various cancer models ([163-166]; [541-555]).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to combine antagonist PD-1 antibodies with agonist OX40 antibodies on the nanoparticles of Kosmides for the treatment of cancer, enhancing anti-tumor immune responses, and activation of T cells. One would have been motivated to because Kosmides, Kadiyala and Cheung specifically suggest doing so for the same purpose. One of ordinary skill in the art would have a reasonable expectation of success given Kosmides, Kadiyala and Cheung teach known exemplary monoclonal antibodies that perform the PD-1 antagonistic and OX40 agonistic functions, and Cheung demonstrates successful synergistic results in reducing tumor size, enhancing T cell activation, and reducing intratumoral Foxp3+ Treg cells, when combining OX40 agonist antibodies with a PD-1 axis binding antagonist antibodies.
6. Claim(s) 7 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication 2019/0175755, Kosmides et al, claiming priority to August 2016; WO 2017/023749, Kadiyala et al, claiming priority to July 2015; Chen et al (Cellular Immunology, 2014, 287:91-99); and US Patent Application Publication 2015/0190506, Cheung et al, published July 2015, as applied to claims 1-6 and 8-17 above, and further in view of Werengowska-Ciecwierz et al (Advances in Condensed Matter Physics, 2015, p. 1-27); Shi et al (Journal of Materials Chemistry, 2009, 19:5485-5498); and Hassane et al (Bioconjugate Chem. 2006, 17:849-854).
Kosmides, Kadiyala, Chen, and Cheung (the combined references) teach a composition comprising a nanoparticle or microparticle comprising an anti-PD1 antagonistic antibody and an anti-OX40 agonistic antibody conjugated to the surface of the particle, as set forth above. Kosmides et al further suggest the antibodies can be conjugated to the particle by various means including any well-known methods in the art ([70]). Kadiyala further suggests utilizing click chemistry to attach the antibody conjugates directly to the particle, particularly to aliphatic polymers ([231]).
The combined references do not demonstrate the antibodies are conjugated to the particle by click chemistry.
Werengowska-Ciecwierz summarizes known methods of bioconjugation of particles to ligands or antibodies, particularly for targeted cancer therapy (section 4). Werengowska-Ciecwierz summarizes known and successful “click chemistry” methods for bioconjugation (parts (i)-(iv) and Schemes 5-11 on pages 10-12 and teach these reactions are characterized by high efficiency, stereospecificity, and harmless side products.
Shi also summarizes known methods of conjugation of ligands or antibodies to nanoparticles for therapeutic purposes and teach click chemistry by alkyne-azide reaction, wherein click chemistry provides high yields, is simple in product isolation, stereospecific, and compatible with organic and aqueous reaction conditions (section 4.5; Figure 12).
Hassane teaches conjugation of ligands to organic particles by click chemistry and teach it has the advantages of being highly regiospecific, chemoselective, and tolerant to a wide variety of other functional groups. It can also be performed almost quantitatively under mild conditions in aqueous buffers (p. 849, col. 2; abstract). Hassane demonstrates their efficient and convenient chemoselective conjugation method based on click chemistry for coupling ligands to liposomes (abstract; Scheme 1-3).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize click chemistry to conjugate the antibodies to the surface of the particles of the combined references. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Kosmides suggests the antibodies can be conjugated to the particle by various means including any well-known methods in the art ([70]) and Kadiyala suggests conjugation by click chemistry; (2) Werengowska-Ciecwierz, Shi, and Hassane teach the advantages of click chemistry to conjugate ligands to particles include high efficiency, produces high yields, is simple in product isolation, stereospecific, harmless side products, and compatible with organic and aqueous reaction conditions; and (3) Werengowska-Ciecwierz, Shi, and Hassane teach or demonstrate that bioconbjugation of ligands or antibodies to organic particles using click chemistry are known, successful, and well-established.
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.
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7. Claims 1-17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,884,738. Although the claims at issue are not identical, they are not patentably distinct from each other because the US Patent claims a microparticle or nanoparticle comprising an antagonistic anti-PD-1 antibody and agonist anti-OX40 antibody conjugated to the particle surface that is considered a species of the instantly claimed particles, therefore obviates the instantly claimed genus. The US patent further claims compositions and methods overlapping with, and rendering obvious the instant claims. The US Patent claims:
1. A particle, which can be a microparticle or nanoparticle, comprising two different targeting agents,
wherein each of the targeting agents is conjugated directly to the particle's surface,
wherein the two different targeting agents are not conjugated to each other,
wherein each of the targeting agents binds to a different protein receptor on a T cell surface, and
wherein the two different targeting agents are an antagonistic PD-1 antibody or active fragment thereof, and an agonistic OX40 antibody or active fragment thereof, respectively.
2. The particle of claim 1, wherein the antibody or active fragment thereof is selected from the group consisting of a monoclonal antibody, a Fab fragment, a Fab′-SH fragment, a FV fragment, a scFV fragment, a (Fab′)2 fragment, and any combination thereof.
3. A composition comprising the particle of claim 1 and a pharmaceutically acceptable carrier.
4. A method of activating a T cell, comprising contacting the T cell with the particle of claim 1 under conditions whereby each targeting agent can bind a different protein receptor on the T cell surface.
5. A method of inducing a T cell immune response, comprising contacting the T cell with the particle of claim 1 under conditions whereby each targeting agent can bind a different protein receptor on the surface of the same T cell.
6. A method of inducing a T cell immune response in a subject in need thereof, comprising administering to the subject an effective amount of the particle of claim 1 under conditions whereby each targeting agent can bind a different protein receptor on the surface of the same T cell.
7. A method of activating T cells in a subject in need thereof, comprising administering to the subject an effective amount of the particle of claim 1 under conditions whereby each targeting agent can bind a different protein receptor on the surface of the same T cell.
8. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the particle of claim 1 under conditions whereby each targeting agent can bind a different protein receptor on the surface of the same T cell.
9. The method of claim 8, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, uterine cancer, colon cancer, kidney cancer, esophageal cancer, prostate cancer, colorectal cancer, glioblastoma, neuroblastoma, liver cancer, skin cancer, blood cancer and any combination thereof.
10. The method of claim 8, wherein the subject has been diagnosed with cancer.
11. The method of claim 8, wherein the particle is administered via a route selected from the group consisting of intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intrathecally, intraventricularly, intraorbitally, intranasally, by implantation, by inhalation, by intratumoral, and any combination thereof.
12. The method of claim 8, further comprising a step of administering to the subject an effective amount of a chemotherapeutic agent and/or radiation therapy.
13. The method of claim 8, wherein the subject is a mammal.
14. The method of claim 13, wherein the mammal is a human.
15. The particle of claim 1, wherein the two different targeting agents are conjugated to the nanoparticle by click chemistry.
16. The particle of claim 1, wherein the targeting agent is antibody clone RMP1-14 and/or antibody clone OX-86.
8. Conclusion: No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/ Primary Examiner, Art Unit 1642
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