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 .
Priority
Claims 1, 10, 17, and 29, from which all claims depend, recites an anti-CD45 antibody drug conjugate wherein the drug conjugate is selected from a group that includes an indolinobenzodiazepine pseudodimer. Provisional Applications 62/789,462 and 62/845,829 disclose antibody conjugates comprising “indolinobenzodiazepine, an indolinobenzodiazepine dimer, or a variant thereof”, but not an indolinobenzodiazepine pseudodimer; see 62/789,462 page 49 line 15 and 62/845,829 page 50 line 15, for example. Further, neither provisional application discloses the figures claimed in claims 61 and 62. Thus, the application is examined with priority date of the PCT filing, January 7, 2020.
Should Applicant disagree with the analysis above, he/she may point to the specific page and line within Provisional Applications 62/789,462 and 62/845,829 where an indolinobenzodiazepine pseudodimer or the figures in claim 61 and 62 are disclosed.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17, 18, and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites a method comprising administering an anti-CD45 ADC prior to the administration of CAR T cells. Claim 17 does not comprise a step of administering CAR T cells, but has been amended to recite a result (the absence of severe neutropenia) following administration of both the anti-CD45 ADC and CAR T cells. Since the claim recites the intended result of administering both the anti-CD45 ADC and CAR T cells, it is unclear whether the claim requires administering CAR T cells.
Claims 18 and 20 depend from claim 17 and fail to remedy the indefiniteness.
Claim Rejections - 35 USC § 103
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.
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, notwithareing 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 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62 are rejected under 35 U.S.C. 103 as being unpatentable over Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017) in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Regarding claims 1 and 25-29, Nixon et al. teaches a method of depleting a population of CD45+ cells in a human patient by administering a CD45 antibody conjugated to a cytotoxin (anti-CD45 ADC), wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, including those species specified in claims 25-29; see claims 1-5, 39-43 and page 58 lines 25-39, and page 59 lines 1-10. Claims 61 and 62 are also rejected for further limiting the indolinobenzodiazepine pseudodimer recited in the alternative with RNA polymerase inhibitor in claim 1, from which claims 61 and 62 depend.
Further, regarding claims 1 and 39, Nixon et al. teaches various conditions, both cancer and autoimmune, where the anti-CD45 ADC may be administered as a lymphodepleting agent prior to hematopoietic stem cell (HSC) transplant and/or CAR-T therapy; see page 40 lines 21-39 and page 41 lines 1-31. Moreover, regarding claims 40 and 41, Nixon et al. teaches that the anti-CD45 ADC may be administered in an amount sufficient to reduce the endogenous HSCs by 10%, 20%, or 30% or more; see page 78 lines 12-22.
While Nixon et al. does briefly reference use in CAR-T cell therapy, the primary focus of the lymphodepletion regimen taught is in preparation for HSC transplant. Additionally, Nixon et al. does not teach the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that CRS-cytokines which would not be substantially increased.
Regarding the use of a CD45-targeting antibody-drug conjugate in place of lymphodepleting chemotherapy prior to administration of a CAR-expressing immune cell as in claims 1, 5, 7, 17, 18, and 20, Ludwig et al. teaches the potential of using an anti-CD45 ADC as a preparative regimen prior to autologous or allogeneic CAR-T cell transfer. Ludwig et al. teaches that the anti-CD45 ADC may be administered in a single dose as an alternative to the high dose chemotherapy which is commonly employed for lymphodepletion. Regarding claims 57 and 58, Ludwig et al. teaches that the use of the anti-CD45 ADC induced expression of immune homeostatic cytokines, including IL-15. Regarding claims 59 and 60, Ludwig et al. teaches that targeted lymphodepletion may result in a more suitable immune homeostatic environment for the reception of adoptive cell therapies, and possibly reduce the incidence of cytokine release syndrome (CRS).
Ludwig et al. does not teach an anti-CD45 ADC wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or a RNA polymerase inhibitor, the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that the CD45 ADC does not result in a substantial increase in one or more CRS cytokines.
Regarding claims 1, 34, 36, and 37, Brogdon et al. teaches an anti-CD19 CAR-T cell wherein the CD19 binding domain is a scFv and the CAR-T cell further comprises a transmembrane domain, an intracellular signaling domain, and a costimulatory domain such as OX40 or 4-1BB; see claims 40, 46, and 57. Regarding claims 8, 10, and 11, Brogdon et al. teaches that the therapeutically effective dose of CAR-T cells 104 to 109 cells/kg; see paragraph 0346. Regarding the cancers of claim 39, Brogdon et al. teaches treating several cancers with the anti-CD19 CAR-T cells; see claim 90. And, regarding claims 59 and 60, Brogdon et al. teaches that cytokine release syndrome (CRS) is a side effect associated with administration of CAR-expressing cells and cytokines, including IFN-γ and IL-6, may be elevated in the patient; see paragraph 0338.
Nixon et al., Ludwig et al., Brogdon et al. teach that the anti-CD45 ADC prior to CAR T cell therapy does not result in neutropenia or severe neutropenia
Palchaudhuri et al. (2016) teaches that the use of a CD45-targeting antibody conjugated to a protein-based immunotoxin could be used for lymphodepletion without inducing neutropenia as seen with conventional conditioning and anti-CD45 radioimmunotherapy; see page 743 right column.
While Palchaudhuri et al. (2016) teaches about the potential of avoiding neutropenia by using an anti-CD45 ADC with a protein-based immunotoxin such as that instantly claimed, the reference does not teach what neutrophil levels are indicative of neutropenia or severe neutropenia.
Lustberg teaches that neutropenia is a condition commonly developed among cancer patients often due to chemotherapy. Lustberg teaches that neutropenia is defined as less than 1,500 cells/mm3 and severe neutropenia is defined as fewer than 500 cells/mm3; see page 1. Lustberg teaches that febrile neutropenia is considered an oncologic emergency associated with a high risk of mortality.
Given that Nixon et al. teaches an anti-CD45-targeting antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, which can be used for lymphodepletion primarily with HSC transplant, but also with CAR-T therapy and that Ludwig et al. teaches the potential use of a similar anti-CD45 ADC, which is currently being used as a conditioning treatment for HST, as a lymphodepleting regimen prior to CAR-T therapy, it would have been obvious to one of ordinary skill in the art to use the anti-CD45 ADC taught by Nixon et al. as a lymphodepleting preconditioning treatment for CAR-T cell therapy in a manner similar to that taught by Ludwig et al. One would be motivated to use the anti-CD45 ADC taught by Nixon et al. as a conditioning regimen for CAR-T cell therapy because Ludwig et al. teaches that CD45-targeted lymphodepletion may result in a more homeostatic environment for the reception of adoptive T cell therapy and reduce the incidence of CRS, a known side effect of CAR-expressing cell therapy as taught by Brogdon et al. One would have a reasonable expectation of success using the anti-CD45 ADC taught by Nixon et al. with the CD19-targeting CAR-T cell therapy taught by Brogdon et al. because both Nixon et al. and Ludwig et al. support the use of anti-CD45 ADCs as lymphodepleting regimens prior to CAR-T cell therapy, the administration of the anti-CD45 ADC taught by Nixon et al. is taught to be tailorable such that it may not deplete the majority of endogenous HSCs, Ludwig et al. teaches that in preclinical studies of CAR-T cell preconditioning with CD45-targeting ADCs expression of the T cell engrafting cytokine, IL-15, was induced, and both Nixon et al. and Brogdon et al. recite use in the treatment of overlapping cancers.
Further, it would have been obvious to one of ordinary skill in the art that using an anti-CD45 ADC with a protein-based immunotoxin for the purpose of lymphodepletion prior to CAR-T therapy as taught by Nixon et al., Ludwig et al., and Brogdon et al. and that using such an anti-CD45 ADC could reduce the risk of cancer patients developing the potentially life-threatening complication of neutropenia. The development of neutropenia is a common side effect of the CAR-T cell therapy and is likely associated with the chemotherapy-based lymphodepletion regimens. One would have had a reasonable expectation of success in avoiding the onset of neutropenia by substituting the anti-CD45 ADC conjugated to a protein-based immunotoxin in place of the usual chemotherapy regimens as supported by the teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., and Palchaudhuri et al. (2016).
Indeed, the fact that the subject treated with the method of claims 1, 10, and 17 does not develop severe neutropenia necessarily flows from the claimed method of administering the anti-CD45 ADC in lieu of lymphodepleting chemotherapy – the latter being associated with neutropenia – prior to CAR T cell therapy. Moreover, the court noted that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)); see MPEP 2111.04.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017) in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), ), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
The teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., Palchaudhuri et al., and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62, from which these claims depend are given previously in this Office action and are fully incorporated here.
While the teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg support using the anti-CD45 ADC in place of lymphodepleting chemotherapy regimens for a more targeted lymphodepletion, the references do not teach which chemotherapy regimens are currently used in CAR-expressing conditioning regimens.
Brudno et al. teaches that lymphodepleting chemotherapy may include cyclophosphamide, fludarabine, bendamustine, and pentostatin. Brudno et al. teaches that while lymphodepleting regimens boost CAR-T cell persistence and response rates, there use may increase the risk of CRS and neurotoxicity.
Thus, one would have been motivated to use an anti-CD45 ADC for lymphodepletion in place of the commonly used cyclophosphamide, fludarabine, bendamustine, and pentostatin-based regimens in order to reduce treatment toxicity while still increasing CAR-T cell persistence and response rates. Given that Ludwig et al. teaches that an anti-CD45 ADC is currently in clinical trials for lymphodepletion prior to hematopoietic stem cell transplant and that Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg together teach the use of a CD45 antibody conjugated to a cytotoxin for selective lymphodepletion prior to CAR-T administration, one would have a reasonable expectation of success and predictability.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017) in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), ), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017)
The teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., Palchaudhuri et al., and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach using a N-beta-maleimidopropyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB) linker between the anti-CD45 antibody and the immunotoxin.
Lutz et al. teaches the synthesis of immunotoxin molecule (HDP 30.2115) comprising the cleavable linker (BMP-Val-Ala-PAB); see Example 3. Figures 9-12 demonstrate that the HDP 30.2115 conjugated antibody is highly stabile with little to no loss of cytotoxicity in plasma and a non-enzymatic environments. Paragraph 0070 teaches that cleavable linkers such as BMP-Val-Ala-PAB are desirable for delivering the amatoxin payload because they are cleaved by lysosomal peptidases following the internalization of the ADC.
Given that Nixon et al. teaches that the anti-CD45 ADC can be internalized (see claim 58) and that Lutz et al. teaches the BMP-Val-Ala-PAB linker is stable until internalized, it would have been obvious to one of ordinary skill in the art to use the enzymatically cleavable linker. Paragraph 007 of Lutz et al. teaches that amatoxins are known to be particularly toxic for liver cells and that plasma stability Is of the utmost importance when using amatoxin conjugates for tumor therapy. One would have been motivated to use the cleavable linker for its demonstrated stability in plasma which could be attributed to reduced off-target toxicity. One would have had a reasonable expectation of success in using the BMP-Val-Ala-PAB because Lutz et al. teaches using it to conjugate amatoxins to antibodies and Figure 10 demonstrates the high stability of the amatoxin conjugate comprising BMP-Val-Ala-PAB in human plasma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017) in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), ), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62 above, and further in view of Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
The teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., Palchaudhuri et al., and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Nixon et al., Ludwig et al., Brogdon et al., Palchaudhuri et al. (2016), nor Lustberg teach that the anti-CD45 ADC has a half-life of 3 days or less.
Palchaudhuri et al. (2018) teaches that as bone marrow transplant (BMT) will likely require fast clearing ADCs to avoid depleting the incoming graft, we also created fast-half-life anti-CD45-AM variants with a t½ of 8-15 hours in mice; see Results.
One of ordinary skill in the art would have been motivated to use an anti-CD45 ADC with a short half-life as taught by Palchaudhuri et al. (2018) for the same reason – so as to not deplete the incoming CAR-expressing cells. Given that Ludwig et al., Nixon et al., and Brogdon et al. teach using an anti-CD45 ADC for lymphodepletion prior to CAR-expressing cell administration and Palchaudhari et al. (2018) teaches using an anti-CD45 ADC with a short half-life for lymphodepletion prior BMT was well tolerated in preclinical studies, one would have a reasonable expectation of success in using an anti-CD45 ADC with a short half-life as a lymphodepleting regimen for CAR-T therapy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 21 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017) in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), ), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62 above, and further in view of Palchaudhuri et al. (WO 2020/092654 A1; Effectively Filed: October 30, 2018).
The teachings of Nixon et al. in view of Ludwig et al., Brogdon et al., Palchaudhuri et al., and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 13, 14, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-62, from which these claims depend are given previously in this Office action and are fully incorporated here.
Neither Nixon et al., Ludwig et al., Brogdon et al., Palchaudhuri et al. (2016), nor Lustberg teach that the CDRs of the anti-CD45 ADC.
Palchaudhuri et al. teaches an anti-CD45 antibody, identified as AbA, which comprises CDRs of SEQ ID NOs: 2-4 and 6-8 which are 100% identical to instant SEQ ID NOs: 1-6, respectively; see claim 1.
Palchaudhuri et al. teaches that antibody AbA is able to internalize into CD45+ cells; see page 105 lines 28-29.
Further, claims 23-30 teach the anti-CD45 antibody conjugated to an RNA polymerase inhibitor (such as amanitin) a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, an indolinobenzodiazepine, and an indolinobenzodiazepine dimer.
Given that Palchaudhuri et al. teaches that the anti-CD45 antibody is capable of internalization, can be conjugated to the same cytotoxins, and is used in methods of depleting CD45+ cells prior to cell transfer and can be used in a subject in need of CAR T therapy (see page 24 line 8), it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success using the anti-CD45 ADC taught by Palchaudhuri et al. for the method of depleting CD45+ cells prior to CAR T therapy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
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, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69, 73, 75, 77, 78, 83, 85, 86, and 90-101 of copending Application No. 17/452,028 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 13, 15, 17, 19, 20, 22, 23, 26-28, 32, 33, 39, 47-49, 60, 61, 63, 78, 81, and 84 of copending Application No. 17/508,641 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 48-51, 54, 56, and 59-62 of copending Application No. 17/820,540 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Regarding instant claims 1 and 25-29, the copending claims teach a method of depleting a population of CD45+ cells in a human patient by administering a CD45 antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, including those species specified in claims 25-29; see copending claims 69, 73, 75, 77, 78, 83, 85, 86, and 90-101 of 17/452,028, copending claims 1-9, 12, 13, 15, 17, 19, 20, 22, 23, 26-28, 32, 33, 39, 47-49, 60, 61, 63, 78, 81, and 84 of 17/508,641, copending claims 1-3, 13, 48-51, 54, 56, and 59-62 of 17/820,540. Note that saponin in claim 54 and 60 of 17/820,540 is a ribosome inactivating protein. The construction of claims 25-27, and 29 do not require that the cytotoxin be one of those specified in claims 25-27 and 29. Additionally, Figure 4 of 17/452,028 demonstrates that cell internalization is an inherent property of the claimed anti-CD45 ADC. 17/508,641 recites anti-CD45 ADCs without specifying the sequence; however, page 37 lines 6-10 disclose an anti-CD45 internalizing antibody allowing the cytotoxin to reach the internal target. Regarding instant claim 61, copending claims 95 and 101 of 17/452,028 teach the same drug conjugate. Regarding instant claims 61 and 62, copending claims 12-15 and 60-63 of 17/508,641 teach the same drug conjugate and linker.
Further, regarding instant claims 1 and 39, the copending claims teach various conditions, both cancer and autoimmune, where the anti-CD45 ADC may be administered as a lymphodepleting agent prior to hematopoietic stem cell (HSC) transplant and/or CAR-T therapy; see copending claims 73, 75, 77, 78, 83, 85, and 86 of 17/452,028 and copending claims 27, 28, 33, 39, 47, 48, 76, 78, 81, and 84 of 17/508,641.
The claims of copending Application Nos. 17/452,028, 17/508,641, or 17/820,540 do not teach the use of the anti-CD45 ADC for lymphodepletion prior to CAR-T cell therapy, the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor the CRS-cytokines which would not be substantially increased.
Regarding the use of a CD45-targeting antibody-drug conjugate in place of lymphodepleting chemotherapy prior to administration of a CAR-expressing immune cell as in instant claims 1, 2, 5, 7, 17, 18, and 20, Ludwig et al. teaches the potential of using an anti-CD45 ADC as a preparative regimen prior to autologous or allogeneic CAR-T cell transfer. Ludwig et al. teaches that the anti-CD45 ADC may be administered in a single dose as an alternative to the high dose chemotherapy which is commonly employed for lymphodepletion. Regarding instant claims 57 and 58, Ludwig et al. teaches that the use of the anti-CD45 ADC induced expression of immune homeostatic cytokines, including IL-15. Regarding instant claims 59 and 60, Ludwig et al. teaches that targeted lymphodepletion may result in a more suitable immune homeostatic environment for the reception of adoptive cell therapies, and possibly reduce the incidence of cytokine release syndrome (CRS).
Ludwig et al. does not teach an anti-CD45 ADC wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or a RNA polymerase inhibitor, the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that the anti-CD45 ADC does not result in a substantial increase in one or more CRS cytokines.
Regarding instant claims 1 and 24-29, Nixon et al. teaches a method of depleting a population of CD45+ cells in a human patient by administering a CD45 antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, including those species specified in claims 25-29; see claims 1-5, 39-43 and page 58 lines 25-39, and page 59 lines 1-10. This particularly applies to the rejection of instant claims 25-28 over the claims of 17/508,641. Further, regarding instant claims 1 and 39, Nixon et al. teaches various conditions, both cancer and autoimmune, where the anti-CD45 ADC may be administered as a lymphodepleting agent prior to hematopoietic stem cell (HSC) transplant and/or CAR-T therapy; see page 40 lines 21-39 and page 41 lines 1-31. Moreover, regarding instant claims 40 and 41, Nixon et al. teaches that the anti-CD45 ADC may be administered in an amount sufficient to reduce the endogenous HSCs by 10%, 20%, or 30% or more; see page 78 lines 12-22. Regarding instant claim 22, Nixon et al. teaches that the antibody comprises a human IgG1; see claim 25.
Nixon et al. does not teach the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that the anti-CD45 ADC does not result in a substantial increase in one or more CRS cytokines.
Regarding instant claims 1, 34, 36, and 37, Brogdon et al. teaches an anti-CD19 CAR-T cell wherein the CD19 binding domain is a scFv and the CAR-T cell further comprises a transmembrane domain, an intracellular signaling domain, and a costimulatory domain such as OX40 or 4-1BB; see claims 40, 46, and 57. Regarding instant claims 8, 10, and 11, Brogdon et al. teaches that the therapeutically effective dose of CAR-T cells 104 to 109 cells/kg; see paragraph 0346. Regarding the cancers of instant claim 39, Brogdon et al. teaches treating several cancers with the anti-CD19 CAR-T cells; see claim 90. And, regarding instant claims 59 and 60, Brogdon et al. teaches that cytokine release syndrome (CRS) is a side effect associated with administration of CAR-expressing cells and cytokines, including IFN-γ and IL-6, may be elevated in the patient; see paragraph 0338.
Neither the claims of copending Application Nos. 17/452,028, 17/508,641, or 17/820,540, Ludwig et al., Nixon et al., nor Brogdon et al. teach that administration of the anti-CD45 ADC and CAR T cell therapy does or does not result in severe neutropenia.
While Palchaudhuri et al. (2016) teaches about the potential of avoiding neutropenia by using an anti-CD45 ADC with a protein-based immunotoxin such as that instantly claimed, the reference does not teach what neutrophil levels are indicative of neutropenia or severe neutropenia.
Lustberg teaches that neutropenia is a condition commonly developed among cancer patients often due to chemotherapy. Lustberg teaches that neutropenia is defined as less than 1,500 cells/mm3 and severe neutropenia is defined as fewer than 500 cells/mm3; see page 1. Lustberg teaches that febrile neutropenia is considered an oncologic emergency associated with a high risk of mortality.
Given that copending Application Nos. 17/452,028, 17/508,641, or 17/820,540 teach a CD45-targeting antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, which can be used for lymphodepletion primarily with HSC transplant and that Ludwig et al. teaches the potential use of a similar anti-CD45 ADC, which is currently being used as a conditioning treatment for HST, as a lymphodepleting regimen prior to CAR-T therapy, it would have been obvious to one of ordinary skill in the art to use the anti-CD45 ADC taught by copending Application Nos. 17/452,028, 17/508,641, or 17/820,540 as a lymphodepleting preconditioning treatment for CAR-T cell therapy as taught by Ludwig et al. One would be motivated to use the anti-CD45 ADC taught copending Application Nos. 17/452,028, 17/508,641, or 17/820,540 as a conditioning regimen for CAR-T cell therapy because Ludwig et al. teaches that CD45-targeted lymphodepletion may result in a more homeostatic environment for the reception of adoptive T cell therapy and reduce the incidence of CRS, a known side effect of CAR-expressing cell therapy as taught by Brogdon et al. One would have a reasonable expectation of success using the anti-CD45 ADC taught by 17/452,028, 17/508,641, or 17/820,540 with the CD19-targeting CAR-T cell therapy taught by Brogdon et al. because both Nixon et al. and Ludwig et al. support the use of anti-CD45 ADCs as lymphodepleting regimens prior to CAR-T cell therapy, the administration of the anti-CD45 ADC taught by Nixon et al. is taught to be tailorable such that it may not deplete the majority of endogenous HSCs, Ludwig et al. teaches that preclinical studies of CD45-targeting ADCs for CAR-T cell preconditioning demonstrated induction of the T cell engrafting cytokine, IL-15, and copending Application Nos. 17/452,028, 17/508,641, Nixon et al. and Brogdon et al. recite use in the treatment of overlapping cancers.
Further, it would have been obvious to one of ordinary skill in the art that using an anti-CD45 ADC with a protein-based immunotoxin for the purpose of lymphodepletion prior to CAR-T therapy as taught by Nixon et al., Ludwig et al., and Brogdon et al. and that using such an anti-CD45 ADC could reduce the risk of cancer patients developing the potentially life-threatening complication of neutropenia. The development of neutropenia is a common side effect of the CAR-T cell therapy and is likely associated with the chemotherapy-based lymphodepletion regimens. One would have had a reasonable expectation of success in avoiding the onset of neutropenia by substituting the anti-CD45 ADC conjugated to a protein-based immunotoxin in place of the usual chemotherapy regimens as supported by the teachings of copending Application Nos. 17/452,028, 17/508,641, or 17/820,540, Ludwig et al., Nixon et al., Brogdon et al., and Palchaudhuri et al. (2016).
Indeed, the fact that the subject treated with the method of claims 1, 10, and 17 does not develop severe neutropenia necessarily flows from the claimed method of administering the anti-CD45 ADC in lieu of lymphodepleting chemotherapy – the latter being associated with neutropenia – prior to CAR T cell therapy. Moreover, the court noted that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)); see MPEP 2111.04.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 5, 7, 8, 10, 11, 17, 18, 20-22, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 15-20, and 23-25 of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012).
Regarding instant claims 1 and 29, the issued claims teach a CD45 antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent or RNA polymerase inhibitor; see U.S. 12,209,135 B2 issued claims 1-22 and U.S. 12,291,576 B2 issued claims 1, 2, and 15-20. US 12,291,576 B2 teaches that the anti-CD45 antibodies can internalize into cells expressing CD45; see column 124 lines 60-63. US 12,209,135 B2 teaches that the anti-CD45 antibodies can internalize into cells expressing CD45; see Figure 16. Regarding instant claims 21 and 22, copending Application No. 17/244,856 teaches an anti-CD45 ADC comprising the CDRs of SEQ ID NOs: 2-4 and 6-8 which is 100% identical to instant SEQ ID NOs: 1-6, respectively, and wherein the antibody is an IgG; see copending claims 1, 17, and 21. U.S. 12,209,135 B2 issued claims 8, 12, and 16 teach the drug conjugate.
While issued claims 23-25 of U.S. 12,291,576 B2 teach that the anti-CD45 ADC can be used as a depleting regimen for HSCT, the issued claims of U.S. 12,209,135 B2 and U.S. 12,291,576 B2 do not teach the use of the anti-CD45 ADC for lymphodepletion prior to CAR-T cell therapy, the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor the CRS-cytokines which would not be substantially increased.
Regarding the use of a CD45-targeting antibody-drug conjugate in place of lymphodepleting chemotherapy prior to administration of a CAR-expressing immune cell as in instant claims 1, 5, 7, 11, 17, 18, and 20, Ludwig et al. teaches the potential of using an anti-CD45 ADC as a preparative regimen prior to autologous or allogeneic CAR-T cell transfer. Ludwig et al. teaches that the anti-CD45 ADC may be administered in a single dose as an alternative to the high dose chemotherapy which is commonly employed for lymphodepletion. Regarding instant claims 57 and 58, Ludwig et al. teaches that the use of the CD45 ADC induced expression of immune homeostatic cytokines, including IL-15. Regarding instant claims 59 and 60, Ludwig et al. teaches that targeted lymphodepletion may result in a more suitable immune homeostatic environment for the reception of adoptive cell therapies, and possibly reduce the incidence of cytokine release syndrome (CRS).
Ludwig et al. does not teach an anti-CD45 ADC wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or a RNA polymerase inhibitor, the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that the anti-CD45 ADC does not result in a substantial increase in one or more CRS cytokines.
Regarding instant claims 1 and 25-29, Nixon et al. teaches a method of depleting a population of CD45+ cells in a human patient by administering a CD45 antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent, a ribosome inactivating protein, or an RNA polymerase inhibitor, including those species specified in claims 25-29; see claims 1-5, 39-43 and page 58 lines 25-39, and page 59 lines 1-10. Further, regarding instant claims 1 and 39, Nixon et al. teaches various conditions, both cancer and autoimmune, where the anti-CD45 ADC may be administered as a lymphodepleting agent prior to hematopoietic stem cell (HSC) transplant and/or CAR-T therapy; see page 40 lines 21-39 and page 41 lines 1-31. Moreover, regarding instant claims 40 and 41, Nixon et al. teaches that the anti-CD45 ADC may be administered in an amount sufficient to reduce the endogenous HSCs by 10%, 20%, or 30% or more; see page 78 lines 12-22.
Nixon et al. does not teach the domains of the CAR-T cell, the therapeutic dose of CAR-T cells, the cancers for which the CAR-T cells are administered, the use of a T cell depleting agent, nor that the anti-CD45 ADC does not result in a substantial increase in one or more CRS cytokines.
Regarding claims 1, 34, 36, and 37, Brogdon et al. teaches an anti-CD19 CAR-T cell wherein the CD19 binding domain is a scFv and the CAR-T cell further comprises a transmembrane domain, an intracellular signaling domain, and a costimulatory domain such as OX40 or 4-1BB; see claims 40, 46, and 57. Regarding claims 8, 10, and 11, Brogdon et al. teaches that the therapeutically effective dose of CAR-T cells 104 to 109 cells/kg; see paragraph 0346. Regarding the cancers of claim 39, Brogdon et al. teaches treating several cancers with the anti-CD19 CAR-T cells; see claim 90. And, regarding claims 59 and 60, Brogdon et al. teaches that cytokine release syndrome (CRS) is a side effect associated with administration of CAR-expressing cells and cytokines, including IFN-γ and IL-6, may be elevated in the patient; see paragraph 0338.
Neither the claims of U.S. 12,291,576 B2 or U.S. 12,209,135 B2, Ludwig et al., Nixon et al., nor Brogdon et al. teach that administration of the anti-CD45 ADC and CAR T cell therapy does or does not result in severe neutropenia.
While Palchaudhuri et al. (2016) teaches about the potential of avoiding neutropenia by using an anti-CD45 ADC with a protein-based immunotoxin such as that instantly claimed, the reference does not teach what neutrophil levels are indicative of neutropenia or severe neutropenia.
Lustberg teaches that neutropenia is a condition commonly developed among cancer patients often due to chemotherapy. Lustberg teaches that neutropenia is defined as less than 1,500 cells/mm3 and severe neutropenia is defined as fewer than 500 cells/mm3; see page 1. Lustberg teaches that febrile neutropenia is considered an oncologic emergency associated with a high risk of mortality.
Given that U.S. 12,291,576 B2 and U.S. 12,209,135 B2 teach a CD45-targeting antibody conjugated to a cytotoxin, wherein the cytotoxin is an antimitotic agent and that Ludwig et al. teaches the potential use of a similar anti-CD45 ADC, which is currently being used as a conditioning treatment for HST, as a lymphodepleting regimen prior to CAR-T therapy, it would have been obvious to one of ordinary skill in the art to use the anti-CD45 ADC taught by U.S. 12,291,576 B2 or U.S. 12,209,135 B2 as a lymphodepleting preconditioning treatment for CAR-T cell therapy as taught by Ludwig et al. One would be motivated to use the anti-CD45 ADC taught U.S. 12,291,576 B2 or U.S. 12,209,135 B2 as a conditioning regimen for CAR-T cell therapy because Ludwig et al. teaches that CD45-targeted lymphodepletion may result in a more homeostatic environment for the reception of adoptive T cell therapy and reduce the incidence of CRS, a known side effect of CAR-expressing cell therapy as taught by Brogdon et al. One would have a reasonable expectation of success using the anti-CD45 ADC taught by U.S. 12,291,576 B2 or U.S. 12,209,135 B2 with the CD19-targeting CAR-T cell therapy taught by Brogdon et al. because both Nixon et al. and Ludwig et al. support the use of anti-CD45 ADCs as lymphodepleting regimens prior to CAR-T cell therapy, the administration of the anti-CD45 ADC taught by Nixon et al. is taught to be tailorable such that it may not deplete the majority of endogenous HSCs, Ludwig et al. teaches that preclinical studies of CD45-targeting ADCs for CAR-T cell preconditioning was demonstrated to induce expressing of the T cell engrafting cytokine, IL-15, and copending Application No. 18/598,342, Nixon et al. and Brogdon et al. recite use in the treatment of overlapping cancers.
Further, it would have been obvious to one of ordinary skill in the art that using an anti-CD45 ADC with a protein-based immunotoxin for the purpose of lymphodepletion prior to CAR-T therapy as taught by Nixon et al., Ludwig et al., and Brogdon et al. and that using such an anti-CD45 ADC could reduce the risk of cancer patients developing the potentially life-threatening complication of neutropenia. The development of neutropenia is a common side effect of the CAR-T cell therapy and is likely associated with the chemotherapy-based lymphodepletion regimens. One would have had a reasonable expectation of success in avoiding the onset of neutropenia by substituting the anti-CD45 ADC conjugated to a protein-based immunotoxin in place of the usual chemotherapy regimens as supported by the teachings of copending Application Nos. 17/452,028, 17/508,641, or 17/820,540, Ludwig et al., Nixon et al., Brogdon et al., and Palchaudhuri et al. (2016).
Indeed, the fact that the subject treated with the method of claims 1, 10, and 17 does not develop severe neutropenia necessarily flows from the claimed method of administering the anti-CD45 ADC in lieu of lymphodepleting chemotherapy – the latter being associated with neutropenia – prior to CAR T cell therapy. Moreover, the court noted that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)); see MPEP 2111.04.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69, 73, 75, 77, 78, 83, 85, 86, and 90-101 of copending Application No. 17/452,028 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/452,028 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 13, 15, 17, 19, 20, 22, 23, 26-28, 32, 33, 39, 47-49, 60, 61, 63, 78, 81, and 84 of copending Application No. 17/508,641 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/508,641 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 48-51, 54, 56, and 59-62 of copending Application No. 17/820,540 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/820,540 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 15-20, and 23-25 of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
The teachings of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Brudno et al. (Blood Reviews. 34: 45-55; Published Online: Nov 14, 2018).
The teachings of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
While the teachings of copending Application Nos. 17/452,028, 17/508,641, or 17/820,540; or U.S. Patent No. 12,291,576 B2 or 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg support using the CD45 ADC in place of lymphodepleting chemotherapy regimens for a more targeted lymphodepletion, the references do not teach which chemotherapy regimens are currently used in CAR-expressing conditioning regimens.
Brudno et al. teaches that lymphodepleting chemotherapy may include cyclophosphamide, fludarabine, bendamustine, and pentostatin. Brudno et al. teaches that while lymphodepleting regimens boost CAR-T cell persistence and response rates, there use may increase the risk of CRS and neurotoxicity.
Thus, one would have been motivated to use an anti-CD45 ADC for lymphodepletion in place of the commonly used cyclophosphamide, fludarabine, bendamustine, and pentostatin-based regimens in order to reduce treatment toxicity while still increasing CAR-T cell persistence and response rates. Given that Ludwig et al. teaches that an anti-CD45 ADC is currently in clinical trials for lymphodepletion prior to hematopoietic stem cell transplant and that copending Application Nos. 17/452,028, 17/508,641, or 17/820,540; or U.S. Patent No. 12,291,576 B2 or 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg together teach the use of a CD45 antibody conjugated to a cytotoxin for selective lymphodepletion prior to CAR-T administration, one would have a reasonable expectation of success and predictability.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69, 73, 75, 77, 78, 83, 85, 86, and 90-101 of copending Application No. 17/452,028 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/452,028 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 13, 15, 17, 19, 20, 22, 23, 26-28, 32, 33, 39, 47-49, 60, 61, 63, 78, 81, and 84 of copending Application No. 17/508,641 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/508,641 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 32 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 48-51, 54, 56, and 59-62 of copending Application No. 17/820,540 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/820,540 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 15-20, and 23-25 of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017).
The teachings of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 32 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Lutz et al. (WO 2017/149077 A1; Published: Sep 8, 2017).
The teachings of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach using a N-beta-maleimidopropyl-Val-Ala-para-aminobenzyl (BMP-Val-Ala-PAB) linker between the anti-CD45 antibody and the immunotoxin.
Lutz et al. teaches the synthesis of immunotoxin molecule (HDP 30.2115) comprising the cleavable linker (BMP-Val-Ala-PAB); see Example 3. Figures 9-12 demonstrate that the HDP 30.2115 conjugated antibody is highly stabile with little to no loss of cytotoxicity in plasma and a non-enzymatic environments. Paragraph 0070 teaches that cleavable linkers such as BMP-Val-Ala-PAB are desirable for delivering the amatoxin payload because they are cleaved by lysosomal peptidases following the internalization of the ADC.
Given that Nixon et al. teaches that the anti-CD45 ADC can be internalized (see claim 58) and that Lutz et al. teaches the high stability of the BMP-Val-Ala-PAB linker allowing for payload delivery only once internalized, it would have been obvious to one of ordinary skill in the art to use the enzymatically cleavable linker. Paragraph 007 of Lutz et al. teaches that amatoxins are known to be particularly toxic for liver cells and that plasma stability Is of the utmost importance when using amatoxin conjugates for tumor therapy. One would have been motivated to use the cleavable linker for its demonstrated stability in plasma which could be attributed to reduced off-target toxicity. One would have had a reasonable expectation of success in using the BMP-Val-Ala-PAB because Lutz et al. teaches using it to conjugate amatoxins to antibodies and Figure 10 demonstrates the high stability of the amatoxin conjugate comprising BMP-Val-Ala-PAB in human plasma.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69, 73, 75, 77, 78, 83, 85, 86, and 90-101 of copending Application No. 17/452,028 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/452,028 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 12, 13, 15, 17, 19, 20, 22, 23, 26-28, 32, 33, 39, 47-49, 60, 61, 63, 78, 81, and 84 of copending Application No. 17/508,641 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/508,641 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 33 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 13, 48-51, 54, 56, and 59-62 of copending Application No. 17/820,540 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
This is a provisional nonstatutory double patenting rejection.
The teachings of copending Application Nos. 17/820,540 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 33 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 15-20, and 23-25 of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
The teachings of U.S. Patent No. 12,291,576 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
Claim 33 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al. (Blood. 132 (Supplement 1): 5682; Published: Nov 29, 2018), Nixon et al. (WO 2017/219025 A1; Published: Dec 21, 2017), Brogdon et al. (US 2014/0271635 A1; Published: Sep 18, 2014), Palchaudhuri et al. (Nature Biotechnology. 34(7): 738-745; Published: Jun 6, 2016) and Lustberg (Clinical Advances in Hematology & Oncology. 10(12): 825-826; Published: Dec 2012) as applied to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60 above, and further in view of Palchaudhuri et al. (Blood. 132 (Supplement 1): 4526; Published: Nov 29, 2018).
The teachings of U.S. Patent No. 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg as related to claims 1, 5, 7, 8, 10, 11, 17, 18, 20, 25-29, 34, 36, 37, 39, 40, 41, and 57-60, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach that the anti-CD45 ADC has a half-life of 3 days or less.
Palchaudhuri et al. (2018) teaches that as bone marrow transplant (BMT) will likely require fast clearing ADCs to avoid depleting the incoming graft, we also created fast-half-life anti-CD45-AM variants with a t½ of 8-15 hours in mice; see Results.
One of ordinary skill in the art would have been motivated to use an anti-CD45 ADC with a short half-life as taught by Palchaudhuri et al. (2018) for the same reason – so as to not deplete the incoming CAR-expressing cells. Given that copending Application Nos. 17/452,028, 17/508,641, or 17/820,540; or U.S. Patent No. 12,291,576 B2 or 12,209,135 B2 in view of Ludwig et al., Nixon et al., Brogdon et al., Palchaudhuri et al. (2016), and Lustberg teach using an anti-CD45 ADC for lymphodepletion prior to CAR-expressing cell administration and Palchaudhari et al. (2018) teaches using an anti-CD45 ADC with a short half-life for lymphodepletion prior BMT was well tolerated in preclinical studies, one would have a reasonable expectation of success in using the ADC with a short half-life as a lymphodepleting regimen for CAR-T therapy.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Response to Arguments
Applicant’s amendments filed October 3, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Regarding the rejections under 35 U.S.C. 103, Applicant argues that Palchaudhuri et al. (2016) does not suggest that the claimed anti-CD45 ADC could be used as a conditioning agent for CAR T cell therapy and successfully prevent neutropenia because the saponin conjugate of Palchaudhuri et al. (2016) being a different class of cytotoxin than instantly claimed.
Examiner disagrees. The anti-CD45 ADC taught by Palchaudhuri et al. (2016) works by a similar mechanism of action as the anti-CD45 ADC instantly claimed – both are internalizing anti-CD45 antibodies conjugated to a cytotoxin. One would have expected both the anti-CD45 ADC of Palchaudhuri et al. (2016) and that of Nixon et al. – the same anti-CD45 ADC as instantly claimed – both function as lymphodepletion agents without risk of neutropenia.
Applicant points to Lustberg page 3 in which Lustberg states that “[n]eutropenia with certain drug regimens is not preventable.” Applicant appears to be applying the phrase “certain drug regimens” too liberally and without the context of the full paragraph. The drug regimens to which Lustberg is referring are lymphodepleting chemotherapy regimens. The full paragraph is reproduced below for context.
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Applicant argues that neither Palchaudhuri et al. (2016) nor Lustberg teach neutropenia in the context of CAR T cell therapy.
It is true that neither Palchaudhuri et al. (2016) nor Lustberg teach neutropenia in the context of CAR T cell therapy. Applicant’s interpretation of how the skilled artisan would have interpreted Palchaudhuri et al. (2016) and Lustberg is directly contradicted by Fried et al. (Bone Marrow Transplantation. 54(10): 1643-1650; Published Online: February 26, 2019) and Zavras et al. (OncoTargets and Therapy. 12: 4543-4554; Published: June 11, 2019) who teach that the art understood that lymphodepleting chemotherapy in CAR T cell regimens is associated with neutropenia.
Applicant argues that Palchaudhuri et al. (2016) and Lustberg acknowledging that neutropenia is a known side effect does not lead one of ordinary skill in the art to conclude that the claimed ADC can be used in the absence of a lymphodepleting agent to prevent severe neutropenia.
Examiner disagrees. As stated previously, one of ordinary skill in the art would conclude that using the claimed anti-CD45 ADC would not result in neutropenia because Palchaudhuri et al. (2016) teaches that an anti-CD45 ADC with a similar mechanism of action does not result in neutropenia.
It is noted that the limitation “wherein the human subject does not develop severe neutropenia” naturally flows from the claimed method. Notably, no additional steps are necessary to bring about this result.
Moreover, the court noted that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)); see MPEP 2111.04.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Kovtun et al. (WO 2017/004026 A1; Published: January 5, 2017) teaches an antibody drug conjugate comprising the indolinobenzodiazepine pseudodimer of claims 61 and 62, including with the linker shown in claim 62; see page 99. Sampson et al. (Clinical Cancer Research. 20(4): 972-984; Published: February 15, 2014) teaches a CAR-T cell pre-treatment comprising 5 Gy total body irradiation (TBI) immediately before T-cell transfer and that lymphodepletion with TBI is shown to be a critical factor in promoting the efficacy of CAR-modified T cells against tumors in the CNS; see page 974 right column and page 976 right column.
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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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682