The examiner of this application in the PTO has changed. To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Peter Johansen, Group Art Unit 1644, Technology Center 1600.
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 .
Election/Restrictions
Applicant's reply to the Restriction Requirement, dated August 26, 2025, has been received. By way of this reply, Applicant has elected, without traverse, the species of B-Cell Acute Lymphoblastic Leukemia (B-ALL), DOMP as chemotherapy, and Revised Management Guidelines of claim 27.
Claims 9, 11, 18, and 23-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 26, 2025.
Claims 1-8, 10, 12-16, 19, 20-22, and 26-28 are therefore under examination before the Office.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at page 93. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 (i.e., changing from AIA to pre-AIA ) 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.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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.
Claims 1-6, 13, and 15-16 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by June (US20150283178A1, cited previously).
June teaches a method of treating a B cell malignancy, comprising administering T cells expressing an anti-CD19 chimeric antigen receptor (CAR) (para. 0006). June further teaches that the B cell malignancy may be B-cell acute lymphoid leukemia (B-ALL) (para. 0008), and that the cells administered are autologous (para. 0030 and 0034), which is pertinent to claim 1.
June further teaches that the patient has relapsed after one or more other therapies, such as the BTK inhibitor ibunitib (para. 0062), which is pertinent to claims 2-5. June also teaches patients who are relapsed may have had 1-4 prior cancer therapies (para. 0545).
June further teaches administering a CD19-target CAR-T therapy 12 months or less after a first line therapy (para. 0072), which is pertinent to claim 6.
June further teaches that the patient may undergo leukapheresis prior to chemotherapy (para. 0734).
June further teaches lymphodepletion with cyclophosphamide and/or fludarabine (para. 0058). June also teaches dosages of fludarabine at 10-50 mg/m2 intravenously (para. 0607).
June further teaches that T cells for CART-19 manufacturing are purified from peripheral blood mononuclear cells (PBMC)(para. 0826).
June further teaches enrichment of cells for CD4+ and CD8+ T cells by positive selection with anti-CD3 and anti-CD28 and IL-2, and depletion of circulating cancer cells (para. 0452-0456), which is pertinent to claim 13. June also teaches transduction with a nucleic acid encoding a CAR (para. 0098 and 0285).
While June does not explicitly teach that the T cell product comprises fewer cancer cells than a T cell product comprising T cells from a leukapheresis product that has not been positively selected for CD4+ and CD8+ T cells, or other superior product attributes recited in claim 16, the method of June is identical to the instantly claimed method and would therefore result in a product with identical features. June therefore inherently anticipates the subject matter of claims 15 and 16. MPEP 2112.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). It is noted that, if the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada, 911 F.2d 705, 709, 15 USPQ2d.
June further teaches that the patient is assessed for cytokine release syndrome after T cell administration (para. 1010).
June further teaches administration of tocilizumab and corticosteroids for treatment of side effects resulting from CAR-T cell administration (para. 0636).
June further teaches administration of methylprednisolone for Grade 3 or 4 toxicity (para. 0868).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7-8, 10, 12, 14, 19, 20-22, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over June as applied to claim 1 above, and further in view of Gore (Blood Cancer J. 2018 Aug 22;8(9):80), Kasagra (Bone Marrow Transplant. 2019 Nov;54(11):1868-1880), Paul (Symposium on neoplastic hematology and medical oncology, Volume 91, Issue 11 p1645-1666 November 2016), and Better (US20150344844A1).
The teachings of June have been discussed supra. However, June does not teach blinatumomab, bridging therapy after leukapheresis and before conditioning/lymphodepleting chemotherapy, DOMP chemotherapy, or FMC63-28Z.
Gore teaches CAR-T cell treatment with tisagenlecleucel, an anti-CD19 CAR-T cell treatment, in CD19-positive patients with B-cell ALL after prior treatment with blinatumomab (page 6, right column, third paragraph).
Kansagra teaches bridging chemotherapy after T-cell collection by leukapheresis and prior to lymphodepleting chemotherapy, prior to anti-CD19 therapy for patients with B-cell ALL (page 1871).
Kansagra further teaches lymphodepleting chemotherapy of fludarabine and cyclophosphamide (page 1872, left column, first paragraph), which is pertinent to claim 10.
Paul teaches combinations of 6-mercaptopurine, methotrexate, vincristine and dexamethasone for treatment of B-cell ALL (page 1649, right column, third paragraph).
Better teaches an anti-CD19 CAR made with FMC63-28Z and the retroviral vector MSGV, which is replication incompetent (para. 0004 and 0026).
Better further teaches activating CAR-T cells with anti-CD3 antibodies, anti-CD28 antibodies, and IL-2 (para. 0034).
Better further teaches administering one or more doses of the cells to the subject (para. 0007 and 0134).
Better also teaches that an attending physician can determine appropriate dosages of treatments suitable for treatment (para. 0132 and 0309).
Better further teaches that a complete response to treatment can be measured by the Lugano criteria (para. 0030 and 0171), which is pertinent to claim 19.
Better further teaches that treatment with CAR-T cells may result in cytokine release syndrome and neurotoxicity (i.e., neurologic toxicity) within a week (para. 0177-0178), which is pertinent to claims 20 and 21.
Better further teaches that cytokine release syndrome may present as fever, chills, fatigue, tachycardia, nausea, hypoxia, and hypotension, and neurological complications include seizure, encephalopathy, aphasia (i.e., speech disorders), delirium (i.e., confusion), and seizure-like activity (i.e. tremors)(para. 0183), which is pertinent to claim 22.
Better further teaches tocilizumab for treatment of cytokine release syndrome (para. 0181).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the teachings of June, Gore, Kansagra, Paul, and Better to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since all of the references are concerned with treatment for B-cell ALL. Starting from the treatment of June, additional features of suitable treatment such as prior treatment with blinatumomab, bridging chemotherapy, DOMP, and treatment of neurotoxicity were also known according to Gore, Kasagra, Paul, and Better, respectively. The features of Gore, Kasagra, Paul, and Better for the treatment of B-cell ALL could be applied to the treatment of June through known methods, with each component of the combination performing its known, usula function, and the combination would have yielded nothing more than predictable results.
The difference between the claimed invention and the prior art is the schedules and dosages of the treatments. However, it is noted that determination of dosage is routinely determined by the ordinary artisan as of the effective filing date of the claimed invention, and was known as a result effective variable that depends on the conditions of the patients. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). This is especially true as Better teaches that an attending physician can determine appropriate dosages of treatments suitable for treatment (para. 0132 and 0309). One of ordinary skill in the art would appreciate the timing or dosage of the therapy could be adjusted to achieve optimum therapeutic efficacy.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, 10, 12-16, 19, 20-22, and 26-28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 12,156,887 in view of June, Gore, Kansagra, Paul, and Better.
The '887 patent claims a method of treating a malignancy by administering an effective dose of anti-CD19 chimeric antigen receptor (CAR)-T cells to the patient (claim 1).
The '887 patent further claims the malignancy is B-cell acute lymphoid leukemia (B-ALL)(claim 5).
However, the '887 patent does not claim autologous cells, blinatumomab, bridging therapy after leukapheresis and before conditioning/lymphodepleting chemotherapy, DOMP chemotherapy, or FMC63-28Z.
June teaches a method of treating a B cell malignancy, comprising administering T cells expressing an anti-CD19 chimeric antigen receptor (CAR) (para. 0006). June further teaches that the B cell malignancy may be B-cell acute lymphoid leukemia (B-ALL) (para. 0008), and that the cells administered are autologous (para. 0030 and 0034), which is pertinent to claim 1.
June further teaches that the patient has relapsed after one or more other therapies, such as the BTK inhibitor ibunitib (para. 0062), which is pertinent to claims 2-5. June also teaches patients who are relapsed may have had 1-4 prior cancer therapies (para. 0545).
June further teaches administering a CD19-target CAR-T therapy 12 months or less after a first line therapy (para. 0072), which is pertinent to claim 6.
June further teaches that the patient may undergo leukapheresis prior to chemotherapy (para. 0734).
June further teaches lymphodepletion with cyclophosphamide and/or fludarabine (para. 0058). June also teaches dosages of fludarabine at 10-50 mg/m2 intravenously (para. 0607).
June further teaches that T cells for CART-19 manufacturing are purified from peripheral blood mononuclear cells (PBMC)(para. 0826).
June further teaches enrichment of cells for CD4+ and CD8+ T cells by positive selection with anti-CD3 and anti-CD28 and IL-2, and depletion of circulating cancer cells (para. 0452-0456), which is pertinent to claim 13. June also teaches transduction with a nucleic acid encoding a CAR (para. 0098 and 0285).
While June does not explicitly teach that the T cell product comprises fewer cancer cells than a T cell product comprising T cells from a leukapheresis product that has not been positively selected for CD4+ and CD8+ T cells, or other superior product attributes recited in claim 16, the method of June is identical to the instantly claimed method and would therefore result in a product with identical features. June therefore inherently anticipates the subject matter of claims 15 and 16. MPEP 2112.
It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). It is noted that, if the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada, 911 F.2d 705, 709, 15 USPQ2d.
June further teaches that the patient is assessed for cytokine release syndrome after T cell administration (para. 1010).
June further teaches administration of tocilizumab and corticosteroids for treatment of side effects resulting from CAR-T cell administration (para. 0636).
June further teaches administration of methylprednisolone for Grade 3 or 4 toxicity (para. 0868).
Gore teaches CAR-T cell treatment with tisagenlecleucel, an anti-CD19 CAR-T cell treatment, in CD19-positive patients with B-cell ALL after prior treatment with blinatumomab (page 6, right column, third paragraph).
Kansagra teaches bridging chemotherapy after T-cell collection by leukapheresis and prior to lymphodepleting chemotherapy, prior to anti-CD19 therapy for patients with B-cell ALL (page 1871).
Kansagra further teaches lymphodepleting chemotherapy of fludarabine and cyclophosphamide (page 1872, left column, first paragraph), which is pertinent to claim 10.
Paul teaches combinations of 6-mercaptopurine, methotrexate, vincristine and dexamethasone for treatment of B-cell ALL (page 1649, right column, third paragraph).
Better teaches an anti-CD19 CAR made with FMC63-28Z and the retroviral vector MSGV, which is replication incompetent (para. 0004 and 0026).
Better further teaches activating CAR-T cells with anti-CD3 antibodies, anti-CD28 antibodies, and IL-2 (para. 0034).
Better further teaches administering one or more doses of the cells to the subject (para. 0007 and 0134).
Better also teaches that an attending physician can determine appropriate dosages of treatments suitable for treatment (para. 0132 and 0309).
Better further teaches that a complete response to treatment can be measured by the Lugano criteria (para. 0030 and 0171), which is pertinent to claim 19.
Better further teaches that treatment with CAR-T cells may result in cytokine release syndrome and neurotoxicity (i.e., neurologic toxicity) within a week (para. 0177-0178), which is pertinent to claims 20 and 21.
Better further teaches that cytokine release syndrome may present as fever, chills, fatigue, tachycardia, nausea, hypoxia, and hypotension, and neurological complications include seizure, encephalopathy, aphasia (i.e., speech disorders), delirium (i.e., confusion), and seizure-like activity (i.e. tremors)(para. 0183), which is pertinent to claim 22.
Better further teaches tocilizumab for treatment of cytokine release syndrome (para. 0181).
It would have been prima facie obvious for a person of ordinary skill in the art as of the effective filing date to combine the '887 patent with teachings of June, Gore, Kansagra, Paul, and Better to arrive at the claimed invention. An ordinary artisan would have been motivated to do so, and have a reasonable expectation of success, since all of the references are concerned with treatment for B-cell ALL. Starting from the treatment of June, additional features of suitable treatment such as prior treatment with blinatumomab, bridging chemotherapy, DOMP, and treatment of neurotoxicity were also known according to Gore, Kasagra, Paul, and Better, respectively. The features of Gore, Kasagra, Paul, and Better for the treatment of B-cell ALL could be applied to the treatment of June through known methods, with each component of the combination performing its known, usual function, and the combination would have yielded nothing more than predictable results.
The difference between the claimed invention and the prior art is the schedules and dosages of the treatments. However, it is noted that determination of dosage is routinely determined by the ordinary artisan as of the effective filing date of the claimed invention, and was known as a result effective variable that depends on the conditions of the patients. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) (determination of suitable dosage amounts in diuretic compositions considered a matter of routine experimentation and therefore obvious). This is especially true as Better teaches that an attending physician can determine appropriate dosages of treatments suitable for treatment (para. 0132 and 0309). One of ordinary skill in the art would appreciate the timing or dosage of the therapy could be adjusted to achieve optimum therapeutic efficacy.
Claims 1-5 and 13-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-8, and 10 of copending Application No. 17/091,039 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they are drawn to identical methods.
The '039 application claims a method for treating relapsed or refractory mantle cell lymphoma (MCL), comprising administering to the subject a therapeutically effective amount of a composition which comprises autologous T cells expressing an anti-CD19 chimeric antigen receptor (CAR) wherein the T cells comprise CD4+ and CD8+ CAR T cells that are prepared from peripheral blood mononuclear cells (PBMCs) by positive enrichment and consequent partial or complete depletion of circulating cancer cells and wherein the anti-CD19 CAR comprises an anti-CD19 single-chain variable fragment (scFv) comprising the heavy chain and light chain variable regions of FMC63, a CD28 intracellular signaling region, and a CD3-zeta signaling domain (claim 1).
The '039 application further claims the MCL is refractory to, or has relapsed following, one or more of chemotherapy, radiotherapy, immunotherapy, an autologous stem cell transplant, or any combination thereof (claim 3).
The '039 application further claims the subject has received 1-5 prior treatments, such as the Bruton Tyrosine Kinase inhibitor (BTKi) ibrutinib (claims 4-5).
The '039 application further claims the subject receives a bridging therapy after leukapheresis to obtain the PBMCs and before the consequent partial or complete depletion of circulating cancer cells the subject receives a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 intravenously, both given on each of the fifth, fourth, and third days before T cell infusion (claim 7).
The '039 application further claims the PBMC are enriched for T cells by selection for CD4+ and CD8+ cells, activated with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, and then transduced with a replication-incompetent viral vector containing a polynucleotide encoding the anti-CD19 CAR (claim 10).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/PETER JOHANSEN/Examiner, Art Unit 1644