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 .
Claims 1-22 are pending and examined on the merits.
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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Claims 1, 2, 6-16 and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No.10,751,430 in view of Weichert et al (U.S. 2014/0030187). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are either anticipated by, or obvious over the claims of the ‘430 patent.
Claims 12 and 13 of the patent disclose a method of treating a metastatic cancer in a subject comprising administering to a subject comprising determining an immunomodulatory dose of a phospholipid chelate compounds comprising administering to a subject a detection -facilitating dose of the radioactive chelate compound of
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which meets the limitations of instant claim 1(a) and (b). Claim 15 discloses that the immunomodulatory dose of the radioactive phospholipid meta chelate is calculated from the strength of the signals originating from the one or more malignant solid tumors within the subject, wherein the metal is Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Ga-67, In-111 and Tc-99m which meets the limitation of instant claim 1(c) for the determination of the immunomodulatory dose that is differentially taken up and retained by the malignant solid tumors by an alpha, beta , auger or gamma-emitting metal isotope and the limitations of claims 2 and 6-12. Claim 12(b) discloses the administration of the immunomodulatory dose to the subject, which meets the limitation of instant claim 1(d).
Claim 12(b) of the patent teaches that in situ tumor vaccination in the subject is carried out with one or more agents capable of stimulating specific immune cells within the tumor microenvironment wherein the concomitant immune tolerance cause by the metastatic tumors is prevented and the metastatic cancer is treated in the subject, which meets the limitations of instant claim 16.
Claims 1 and 2 of the patent teach that the immunomodulatory dose of the radioactive phospholipid chelate provides a radiation dose of 2 to 8 Gy or 2 to 5 Gy to the metastatic tumors, which meets the limitations of instant claims 14 and 15. Claim 4(b) of ‘430 teaches that the one or more agents capable of stimulating specific immune cells within the tumor microenvironment include an anti-GD2immunostimulatory antibody which meets the limitations of instant claims 18 and 19.
The claims of ‘430 do not specifically teach that the detection facilitating dose of the radioactive phospholipid chelate of the above formula is differentially taken up by and retained within malignant solid tumor tissue. Weichert et al provide evidence that the phospholipid ether analog of
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is retained at a higher level in areas of cancer or metastases than the surrounding regions (paragraphs [0023] and [0025]), and thus is differentially taken up by and retained within malignant solid tumor tissue meeting that limitation in claim 1(a).
The claims of ‘430 fail to teach the specific metal of the metal chelate compound of claim 1 part (c) and claim 13. The claims of ‘430 fail to teach that either of the first or second phospholipid compound are administered intravenously, the subject of claim 1 or the types of metastatic cancer listed in claim 22..
Section 804 II(b) of the M.P.E.P.states:
The specification can be used as a dictionary to learn the meaning of a term in the patent
claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d
1065, 1067 (Fed. Cir. 1999).
In the instant case, the ‘430 specification teaches that for providing a immunostimulating dose of the phospholipid metal chelate metal isotopes which emit ionizing radiation in a form that would result in immunostimulation include Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, and Th-227.
Thus, the immunomodulatory dose comprising the phospholipid metal chelates of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, and Th-227 are encompassed in claim 12(b) of the patent, rendering obvious instant claim 13.
The ‘430 specification defines the metastatic cancers that can be treated with the inventive method as:
melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, soft tissue sarcomas, Ewing’s sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, Wilms’ tumor, or pediatric brain tumors.
Thus, these cancers are encompassed in the genus of metastatic cancers to be treated in claim 12 of ‘430, and because all of said metastatic cancer occur in humans, it would be obvious to treat a human, thus rendering obvious instant claims 21 and 22.
Regarding claim 20, Weichert et al teach that the related radioactive phospholipid, NM404:
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, is intravenously infused (paragraph [0374]).
It would have been prima facie obvious to intravenously infuse both the first and second inventive phospholipid chelate compounds. One of skill in the art would have been motivated to do so because Weichert et al uses intravenous infusion for the related radioactive phospholipid. One of skill in the art would understand that intravenous administration of the radioactive chelates of the ‘430 patent allows for access of the radioactive phospholipid chelates to all metastatic tumors in the patient because metastatic lesions are dependent on the blood supply One of skill in the art would be motivated to provide an appropriate dose for all the metastatic tumors, thus is would be obvious to administer both the first and the second radioactive phospholipid chelate compound intravenously.
Claims 1, 2, 6-16 and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,751,430 as evidenced by Weichert et al (U.S. 2014/0030187) in view of Shen et al (U.S. 2015/0202335). The claims of the ‘430 patent as evidence by Weichert render obvious instant claims 1, 2, 6-16 and 18-22 for the reasons set forth above. The claims of the patent do not specifically teach the chelating agents or the chelating agents chelated to a metal atom of instant claims 3 and 4
Shen et al teach combinations of commonly used isotopes with chelating agents (Table 2) including the DOTA-R derivative (page 8, second column) which accommodates both the diagnostic and therapeutic Y-86 and Y-90, respectively and meets the limitations of claim, 3 for DOTA and its derivatives, claim 4, first structure and also renders obvious instant claim 5, first structure, based on the structure of claim 13 of ‘430 wherein m is 0 and n is 18.
It would have been prima facie obvious at the time prior o the effective filing date to use the DOTA derivative of DOTA-R as the chelating agent of the radioactive phospholipid chelate of claims 12 and 13 of the ‘430 patent. One of skill in the art would have been motivated to do so based on the teachings of Shen et al regarding commonly used chelating agent for in vivo imaging. Further one of skill n the art would have been motivated to select DOTA-R in order to accommodate the Y-86 for determining the immunomodulatory dose of the same radioactive chelate accommodating the Y-90 beta emitter. One of skill in the art would have been motivated to do so in order to use the same chelate phospholipid construct for determining the immunomodulatory dosage using the Y-86 positron emitter and providing the immunomodulatory dose using the Y-90 beta emitter.
Claims 1-5, 7-16, 18, and 20-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 19/053,084 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the application anticipate or render obvious the instant claims.
Claim 1(b) and (c) of ‘084 meets the limitations of instant claims 1(b) and 2, and the structural limitations of the chelate in instant claims 3-5. Claims 5 meets the limitation of subject who has metastatic disease. Claim 6 meets the limitations of a metal isotope that is a positron emitter or a single-photon emitter in instant claim 1(a) and Y-86 in claim 12. Claims 7-9 meet the limitations of radiometal isotopes which are beta and alpha emitters in instant claim 1(c) and claims 13.. Claims 11 and 12 meet the limitation of instant claims 14 and 15. Claim 18 meets the limitation of instant claims 16 and 18 requiring an agent capable of stimulating specific immune cells within the tumor microenvironment and an immunostimulatory mAb, respectively.
Section 804 II(b) of the M.P.E.P.states:
The specification can be used as a dictionary to learn the meaning of a term in the patent
claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d
1065, 1067 (Fed. Cir. 1999).
In the instant case, the ‘084 application defines the cancer treatable by the inventive methods as including:
melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer of the skin or head and neck, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, soft tissue sarcomas, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, , Wilms' tumor, or pediatric brain tumors.
Thus, said cancers are encompassed in claim 1 of ‘084, rendering obvious instant claim 22. Further because all of the above cancers are cancer which occur in humans, claim 21, requiring the treatment of a human subject, is obvious.
Regarding claim 20, it would have been prima facie obvious to administer both radioactive phospholipid metal chelates by the intravenous route. One of skill n the art would have been motivated to do so to access all metastatic lesions through the blood supply. One of skill in the art would have been motivated to do so in order to effectively treat metastatic tumors.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-5, and 7-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 and 18 of copending Application No. 19/053,084 in view of Vanpouille-Box et al (Vaccine, 2015, Vol. 33, pp. 7415-7422).
The claims of the ‘084 application teach or anticipate instant claims 1-5, 7-16, 18, and 20-22 for the reasons set forth above. Claim 13 of the ‘084 application taches that the immunostimulatory agent is a checkpoint inhibitor; claim 14 teaches that the checkpoint inhibitor of claim 13 is a CTLA-4 inhibitor. Claim 18 requires that the immunostimulatory agent is a immunostimulatory monoclonal antibody. The claims of the ‘084 application do not teach external beam radiation as an agent which induced in situ tumor vaccination, or the combination of external beam radiation and an anti-CTLA-4 antibody to treat metastatic disease.
Vanpouille-Box et al teach that ionizing radiation has proinflammatory effects that facilitate tumor rejection (abstract). Vanpouille-Box et al teach that radiation alters the tumor to enhance the concentration of effector T cells by induction of chemokines, cytokines and adhesion molecules and induce immunogenic cell death of cancer cells leading to cross-presentation of tumor antigens by dendritic cells to T cells (abstract).
Vanpouille-Box et al summarize the current clinical trials combining ipilimumab and a radiation treatment including NCT01689974 wherein metastatic melanoma is treated with the anti-CTLA4 antibody ipilimumab, in combination with radiation therapy; NCT01703507 where tumors metastatic to the brain are treated with ipilimumab and whole-brain radiation therapy; NCT02115139 wherein melanoma brain metastases are treated with ipilimumab ab whole brin radiation therapy and NCT02406183, wherein metastatic melanoma is treated with ipilimumab and stereotactic body irradiation.
It would have been prima facie obvious at the time of the effective filing date to combine ipilimumab as the CTLA4 inhibitor with external beam irradiation in the method of claim 14 of the ‘084 application, thus rendering obvious instant claim 19 directed to an anti-CTLA4 antibody in claim 19. One of skill in the art would have been motivated to do so based on claim 14 of the ‘084 application directed to a CTLA4 inhibitor as the immunostimulatory agent of claim 1, and the teachings of Vanpouille-Box et al of the treatment of metastatic cancer wherein ipilimumab is combined with radiation therapy, including external beam radiation therapy.
This is a provisional nonstatutory double patenting rejection.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643
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