DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/18/2025 has been entered.
Claims 2, 7-8, 16-18, 20, 35, and 37-55, of record 12/18/2025, are pending and subject to prosecution.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 2, 17-18, 20, 35, 37-38, and 41-55 under 35 U.S.C. 103 as being unpatentable over Morgan et al. (US 20180085444 A1) in view of Berdeja et al. (Blood, 2017), June et al. (US 20180044424 A1), Screen Captures from YouTube video clip entitled "BCMA-Targeted CAR T-Cell Therapy for Myeloma" (YouTube, 2018), Moreau et al. (Annals of Oncology, 2017), and Majithia et al. (Leukemia, 2016):
RE: Rejection of claims 2, 7-8, 16-18, 20, 35, and 37-55 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan et al. (US 20180085444 A1) in view of Berdeja et al. (Blood, 2017), June et al. (US 20180044424 A1), Screen Captures from YouTube video clip entitled "BCMA-Targeted CAR T-Cell Therapy for Myeloma" (YouTube, 2018), Moreau et al. (Annals of Oncology, 2017), and Majithia et al. (Leukemia, 2016), further in view of Gerecke et al. (Deutsches Ärzteblatt International, 2016):
The applicant asserts that one of ordinary skill in the art would not have been motivated to combine the teachings of the prior art references to arrive at the claimed invention (Applicant Remarks, page 9). The applicant asserts that June et al., YouTube, Majithia et al., and Gerecke et al. are silent on the treatment of a high-risk multiple myeloma population with anti-BCMA CAR-T cells (Applicant Remarks, page 10). The applicant asserts that the Office’s interpretation of the teachings of Berjeda et al., wherein a majority of anti-BCMA CAR-T cell-treated multiple myeloma patients had high-risk cytogenetics, as reading on “high-risk multiple myeloma” is incorrect (Applicant Remarks, page 10).
In light of the applicant’s arguments and upon further consideration, the rejections are withdrawn.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 43 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 43 requires the subject to have a serum beta-2 microglobulin level greater than or equal to 5.5mg/l. However, parent claim 2 requires the subject to have R-ISS stage III, for which ISS stage III (serum beta-2 microglobulin ≥ 5.5 mg/l) is a necessary criterion (See instant specification, table 4). Claim 43 therefore does not further limit claim 2.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 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.
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 2, 7-8, 16-18, 37-41, 43-44, and 46-55 are rejected under 35 U.S.C. 103 as being unpatentable over Alexander et al. (US 20190008852 A1) in view of Morgan et al. (US 20180085444 A1), of record.
Regarding claims 2, 7-8, 16, 38-41, 43-44, 46, 48-50, 53, and 55: Alexander et al. teach therapies comprising a fluorobenzonitrile small molecule drug for treating multiple myeloma (See Abstract). The multiple myeloma can be high-risk multiple myeloma, and it can be characterized by early progression (e.g., less than 12 months) following autologous stem cell transplant (which reads on “early relapse”) or by genetic abnormalities at one or more of del(17/17p) and t(14; 16)(q32;q32) (See ¶0031, 0177, 0181, and 0189). The multiple myeloma can be high-risk multiple myeloma that is relapsed or refractory to one, two, or three previous treatments (which reads on “the subject has received no more than two lines of prior therapy” and “no more than one of the lines of prior therapy”) (See ¶0181). The patient to be treated may have developed drug resistance to the therapy, such as resistance to one, two, or three anti-multiple myeloma therapies, wherein the therapies are selected from a CD38 monoclonal antibody (CD38 mAb, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example, thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide) (See ¶0205). The multiple myeloma can be refractory to lenalidomide or pomalidomide (which reads on “an immunomodulatory agent” and “lenalidomide alone”) (See ¶0189). Combination therapy can include immune cells, such as T cells, expressing a CAR (See ¶0268, 0281, and 0285). The CAR comprises an antigen-recognizing extracellular domain (such as an antibody or scFv), transmembrane domain, and intracellular signalling domain and can target BCMA (which reads on “an extracellular domain that binds to BCMA”) (See ¶0269-0270, 0277-0278 and 0285). The CAR intracellular signalling domain can be derived from CD3ζ, and co-stimulatory domains can be derived from CD28, CD134, and/or CD137 (See ¶0279).
Alexander et al. do not expressly teach treatment of a subject having the risk factor R-ISS stage III. Alexander et al. also do not teach a dosage for the CAR-T cells.
The instant specification discloses that ISS stage III (serum beta-2 microglobulin ≥ 5.5 mg/l) is a necessary criterion for R-ISS stage III (See instant specification, table 4).
Morgan et al. teach anti-BCMA CARs (See Abstract). The CARs can be expressed in T cells (which read on “immune cells”) for treating multiple myeloma (See ¶0068-0072 and 0456-0457). Subjects can be administered therapeutically effective amounts of the CAR-T cells, which can be dosages of at least 0.1 × 105 to 1 × 1010 cells (which reads on “300 x 106 cells to 600 x 106 cells” and “350 x 106 cells to 550 x 106 cells”) (See ¶0460 and 0468-0470).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al. to comprise administering a dosage of at least 0.1 × 105 to 1 × 1010 anti-BCMA CAR-T cells. One would be motivated to make this modification because Morgan et al. teach this dosage range as appropriate for treating B cell-related conditions such as multiple myeloma (See ¶0068-0072 and 0470). There would be a reasonable expectation of success in doing so because a CAR-T cell dose within this range could be readily administered to a subject in need thereof.
Regarding claim 17: Following the discussion of claims 2, 7-8, 16, 38-41, 43-44, 46, 48-50, 53, and 55, Alexander et al. teach that measurable disease in multiple myeloma can be defined as having serum M-protein quantities greater than or equal to 0.5 g/dl by sPEP or urine M-protein levels greater than or equal to 200 mg/24 h by uPEP (See ¶0499). One of ordinary skill could reasonably assume that the subject might exhibit either criterion.
Regarding claims 18 and 37: Following the discussion of claims 2, 7-8, 16-17, 38-41, 43-44, 46, 48-50, 53, and 55, Alexander et al. teach that the high-risk multiple myeloma can be multiple myeloma that is relapsed within twelve months of first treatment (which reads on “has achieved a response to at least one of the prior lines of therapy” and “the response is a minimal response or better”) (See ¶0181).
Regarding claim 47: Following the discussion of claims 2, 7-8, 16, 38-41, 43-44, 46, 48-50, 53, and 55, Alexander et al. teach that the CAR transmembrane domain can be derived from CD8 but do not expressly teach derivation from CD8α.
Morgan et al. teach that anti-BCMA CARs can comprise a CD8α transmembrane domain (See ¶0183).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al. to substitute a CD8α transmembrane domain, as taught by Morgan et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claims 51-52: Following the discussion of claims 2, 7-8, 16, 38-41, 43-44, 46, 48-50, 53, and 55, Alexander et al. do not teach antigen-binding amino acid sequences for the CAR.
Morgan et al. teach that the anti-BCMA binding moiety can comprise a VL sequence identical to instant SEQ ID NO 7 (See ¶0012, SEQ ID NO 7, and alignment below). This sequence also comprises CDRs with the sequences of instant SEQ ID NOs 1-3 (underlined) (See ¶0013).
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The anti-BCMA binding moiety can comprise a VH sequence identical to instant SEQ ID NO 8 (See ¶0014, SEQ ID NO 8, and alignment below). This sequence also comprises CDRs with the sequences of instant SEQ ID NOs 4-6 (underlined) (See ¶0015).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al. to substitute the BCMA-binding sequences taught by Morgan et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Regarding claim 54: Following the discussion of claims 2, 7-8, 16, 38-41, 43-44, 46, 48-50, 53, and 55, Alexander et al. do not expressly teach a nucleotide sequence for the CAR.
Morgan et al. teach that the CAR can comprise a polynucleotide sequence identical to instant SEQ ID NO 10 (See ¶0033-0034, SEQ ID NO 10, and alignment below (first 120 bp shown)).
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It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al. to substitute the anti-BCMA CAR nucleotide sequence taught by Morgan et al. Substitution of one known element for another known element is considered to be prima facie obvious, absent a showing that the substitution yields more than predictable results. See MPEP 2143(I)(B).
Claims 2, 7-8, 16-18, 37-44, and 46-55 are rejected under 35 U.S.C. 103 as being unpatentable over Alexander et al. (US 20190008852 A1) in view of Morgan et al. (US 20180085444 A1), of record, further in view of Rajkumar (American Journal of Hematology, 2016).
The teachings of Alexander et al. and Morgan et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 42: Following the discussion of claims 2, 7-8, 16-18, 37-41, 43-44, and 46-55, Alexander et al., modified by Morgan et al., render obvious the administration of a therapy comprising anti-BCMA CAR immune cells to a subject with high-risk multiple myeloma but do not teach prior therapy as comprising dexamethasone.
Rajkumar teaches that the recommended initial treatment for high-risk multiple myeloma comprises carfilzomib, lenalidomide, and dexamethasone (See fig. 1). Low-dose dexamethasone is preferred in most patients for initial therapy (See page 724, col. 2, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al., modified by Morgan et al., to administer the CAR cells to subjects whose prior therapy had included dexamethasone. One would have been motivated to make this modification because Rajkumar teaches that dexamethasone is recommended in the initial therapy for multiple myeloma, including high-risk multiple myeloma (See page 724, col. 2, ¶1 and fig. 1), and there would be a reasonable expectation of success in doing so.
Claims 2, 7-8, 16-18, 37-41, and 43-55 are rejected under 35 U.S.C. 103 as being unpatentable over Alexander et al. (US 20190008852 A1) in view of Morgan et al. (US 20180085444 A1), of record, further in view of Chan et al. (Current Hematologic Malignancy Reports, 2017).
The teachings of Alexander et al. and Morgan et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 45: Following the discussion of claims 2, 7-8, 16-18, 37-41, 43-44, and 46-55, Alexander et al., modified by Morgan et al., render obvious the administration of a therapy comprising anti-BCMA CAR immune cells to a subject with high-risk multiple myeloma but do not teach the subject as having high serum lactate dehydrogenase.
Chan et al. teach that R-ISS stage III encompasses ISS stage III and either adverse cytogenetics by FISH or high serum lactate dehydrogenase (See table 1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Alexander et al., modified by Morgan et al. to comprise therapeutic administration to high-risk multiple myeloma subjects having high serum lactate dehydrogenase levels. One would be motivated to make this modification because Chan et al. teach that high serum lactate dehydrogenase can be used in place of cytogenetic abnormalities for making an assessment of R-ISS stage III (See table 1), and there would be a reasonable expectation of success in doing so.
Allowable Subject Matter
Claims 20 and 35 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art do not teach or suggest progression-free survival of subjects having, specifically, high-risk multiple myeloma for at least six months following administration of anti-BCMA CAR immune cells at a dosage of 300 x 106 cells to 600 x 106 cells.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M Babic, can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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