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 .
Applicant’s amendments to the claims dated 9/30/2024 are acknowledged. Claims 1-65 are cancelled. Claims 66-105 are new. Prosecution on the merits commences for claims 66-105.
PRIORITY
The instant application, 6/7/24, is a CONTINUATION of US Patent No. 12,029,784, filed 10/23/20, which is a CONTINUATION of US Patent No. 11,633,463, filed 04/01/2020, which is a CONTINUATION of US Patent No. 10,646,558, filed 07/08/2019, which is a CONTINUATION of US Patent No. 10,383,929 filed 06/12/2017, which is a 371 National Stage Application of PCT/US2015/064269, filed 12/07/2015; which claims priority to US Provisional Application No. 62/200,505, filed 08/03/2015; and US Provisional Application No. 62/091,419, filed 12/12/2014. Thus, the earliest possible priority for the instant Application is 12/12/2014.
CLAIMS
Independent claims 66, 75, 88, 99 and 105 methods of treating B-cell malignancies, comprising administering recombinant immune effector cells encoding and/or expressing a chimeric antigen receptor (CAR), wherein the CAR comprises amino acids 22-493 of the amino acid sequence set forth as SEQ ID NO: 9.
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CLAIM INTERPRETATION
SEQ ID NO:9 comprises the amino acid sequence of a CAR targeting BCMA, comprising anti-BCMA binding regions (amino acids 22-270), a CD8 hinge and CD8 transmembrane domain (amino acids 271-339), an intracellular 4-1BB domain (amino acids 340-381), and an intracellular CD3ζ (amino acids 382-493), as diagrammed below:
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As written, claims 66, 75 and 99 only require amino acids 22-493, comprising the sequences encoding the CD8 hinge, CD8 transmembrane domain, and intracellular 4-1BB and CD3ζ domain:
whereas claim 105 only requires amino acids 271-493 of SEQ ID NO:9, comprising the sequences encoding the CD8 hinge, CD8 transmembrane domain, and intracellular 4-1BB and CD3ζ domain, and allows for any CAR binding sequences.
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Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 66-68, 71-77, 80-87, 99-101, and 103-105 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, cited on Applicant’s IDS dated 10/15/2024, further in view of WO2013/059593 to Orentas, and WO2013/061273 to Dominici.
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With regard to clams 66, 75, 99 and 105, Kochenderfer discloses methods of treating B-cell malignancies comprising administering recombinant human immune effector cells comprising BCMA-targeted CARs (Abstract, paragraphs [0007], [0023], [0027]-[0030], [0074]). Kochenderfer discloses the anti-bcma2-BB CAR, encoded by SEQ ID NO: 10 therein, which comprises comprise a CD8a signal sequence, a BCMA-binding region operably linked to a CD8 hinge, a CD8 transmembrane domain, a 4-1BB intracellular domain, and a CD3ζ intracellular domain (Table 1, paragraphs [0027]-[0030], [0032]-[0034], [0090]), the structure of which can be visualized accordingly:
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Amino acids 1-270, 281-349 and 359-512 of Kochenderfer’s SEQ ID NO: 10 are identical to SEQ ID NO 9’s amino acids 1-270, 271-339, and 340-493; however, Kochenderfer’s sequence comprises two insertions (boxed sequences below):
Kochenderfer discloses the hinge and transmembrane domains, including from CD8, can be derived from any suitable sequence or molecule (paragraphs [0032]-[0033]). Kochenderfer does not identify the specific amino acids within the CARs that encode the BCMA binding region, the CD8 TM region, the 4-1BB region or the CD3ζ region. Thus, while Kochenderfer discloses a CAR receptor that comprises 100% identity to amino acids 1-270, 271-339, and 340-493 of instantly claimed SEQ ID NO: 9, the specific boundaries of the domains within the CAR of Kochenderfer are not disclosed:
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As such, Kochenderfer does not disclose wherein the anti-BCMA CAR comprises amino acids 22-493 or 271-493 of SEQ ID NO:9 as required by claims 66, 75, 99 or 105.
Orentas discloses second-generation chimeric antigen receptors (CARs) targeting HA22, wherein the CARs comprise a HA22 binding domain operably linked to a CD8 transmembrane domain, a 4-1BB (CD137) signaling domain, and a CD3ζ signaling domain (abstract, paragraphs [0022], [0033]-[0038], [0065], [0126], Table 1).
Orentas discloses the CD8 transmembrane domain can be encoded by SEQ ID NO: 10 or 33, the 4-1BB domain can be encoded by SEQ ID NO: 13 or 34, and the CD3ζ domain can be encoded by SEQ ID NO: 14 or 15 ([0033],[0034]):
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CD8: SEQ ID NO: 33 is a smaller fragment of SEQ ID NO: 10
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4-1BB: SEQ ID NO: 34 is a smaller fragment of SEQ ID NO: 13:
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CD3ζ: SEQ ID NO: 14 and 35 differ by a single amino acid at position 14:
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Orentas’ disclosed amino acid sequences for the individual CD8, 4-1BB and CD3ζ domains establishes the domain boundaries in Kochenderfer:
Orentas’ SEQ ID NOs. 10 (CD8 TM), 13 (4-1BB) and 14 (CD3ζ) produces a 243 amino acid protein:
FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
The 243 amino acid protein generated from the combination of Orentas’ SEQ ID NOs 10, 13 and 14 is 99.6% identical to amino acids 271-512 of Kochenderfer, differing only by the insertion of a single amino acid (boxed below):
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As such, the disclosure of Orentas establishes the domain boundaries in the anti-BCMA CAR SEQ ID NO: 10 of Kochenderfer, wherein the CD8 hinge and TM comprise amino acids 271-354, the 4-1BB domain comprises amino acids 355-400, and the CD3ζ domain comprises amino acids 401-512. A skilled artisan would recognize amino acids 1-270 comprise sequences encoding the BCMA binding region:
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Thus, Kochenderfer’s SEQ ID NO: 10, in light of Orentas, establishes wherein Kochenderfer’s amino acids 1-270, comprising the anti-BCMA sequences, have 100% identity to amino acids 1-270 of claimed SEQ ID NO: 9; and amino acids 271-512, encoding the CD8 hinge, CD8 TM, 4-1BB domain and CD3ζ domain, have 99.6 % identity to amino acids 271-493 of claimed SEQ ID NO: 9:
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Dominici discloses CARs targeted to GD2, wherein the GD2 binding domains are operably linked a CD8 hinge domain, a CD8 transmembrane domain, a 4-1BB signaling domain and a CD3ζ signaling domain (page 8, lines 15-22, page 9, line 27- page 10, line 2; page 13, lines 21-26; FIG. 1). Nucleic Acid SEQ ID NO: 1 of Dominici encodes the anti-GD2 CAR, wherein nucleotides 89-880 encode at least the GD2 binding domains and nucleotides 881-1612 encode the CD8 regions (hinge and transmembrane domain), the 4-1BB domain and the CD3ζ domain (page 10, lines 5-9; FIGs. 1-2). Translation of SEQ ID NO: 1, results in a 487 amino acid CAR, wherein nucleotides 89-880 correspond to amino acids 1-264, and nucleotides 881-1612 correspond to amino acids 265-487 of the CAR:
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Amino acids 265-487 of the anti-GD2 CAR are 100% identical to amino acids 271-493 (encoding the CD8 hinge, CD8 TM, 4-1BB domain and CD3ζ domain) of SEQ ID NO:9:
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Dominici’s CAR comprising amino acids 265-487 aligned with amino acids 271-493 of claimed SEQ ID NO:9 can be visualized accordingly:
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Thus, Dominici establishes the amino acid sequences encoding the CD8 hinge, CD8TM, 4-1BB domain and the CD3ζ domain of SEQ ID NO: 9 were known.
In addition, Orentas’ disclosed amino acid sequences for the individual CD8, 4-1BB and CD3ζ domains confirm the domains exemplified in Dominici:
Orentas’ SEQ ID NOs. 33 (CD8 TM), 34 (4-1BB) and 14 (CD3ζ) produces a 223 amino acid protein:
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
The 243 amino acid protein generated from the combination of Orentas SEQ ID NOs 33, 34 and 14 is 100% identical to amino acids 265-487 of Dominici:
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Thus, Orentas confirms the amino acid sequences that encode individual CD8 hinge/transmembrane, 4-1BB and CD3ζ domains used in Dominici, that are identical to amino acids 271-493 of claimed SEQ ID NO: 9, were known.
It would have been obvious to combine Kochenderfer’s methods of treating B-cell malignancies, comprising administering an anti-BCMA CAR comprising a CD8 hinge, CD8 transmembrane domain, a 4-1BB signaling domain and a CD3ζ signaling domain, further with Orentas and Dominici. Kochenderfer’s anti-BCMA CAR, encoded by SEQ ID NO: 10, in view of Orentas, establish the BCMA binding sequences are within amino acids 1-270; and that the CD8 hinge, CD8 transmembrane domain, 4-1BB signaling domain and the CD3ζ signaling domain are encompassed by amino acids 271-512:
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Amino acids 1-270 of Kochenderfer’s SEQ ID NO: 10, in view of Orentas, (comprising amino acids 22-270) are 100% identical to amino acids 1-270 of instantly claimed SEQ ID NO: 9:
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It would have been obvious to substitute the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain, comprising amino acids 271-512 of Kochenderfer’s SEQ ID NO: 10, with the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain, comprising amino acids 265-487 of SEQ ID NO: 1 of Dominici. Both the amino acids encoded from Kochenderfer 271-512 and amino acids 265-487 are known for coding the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain in chimeric antigen receptors.
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Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
The substitution of Dominici’s amino acids 265-487 for Kochenderfer’s amino acids 271-512 results in an anti-BCMA CAR comprising 493 amino acids, that is 100% identical to claimed SEQ ID NO: 9:
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As such, Kochenderfer in view of Orentas and Dominici render obvious methods of treating a B-cell malignancy, or multiple myeloma (MM) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least,
a CAR comprising b) amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9; or
a CAR comprising: a) means for binding B-cell maturation antigen (BCMA) and;
b) amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO: 9, as required by instant claims 66, 75, 99 or 105.
With regard to claims 67, 68, 76 and 77 and 100, Kochenderfer discloses wherein the B-cell malignancy is multiple myeloma (MM), and wherein the patent exhibits symptoms (paragraphs [0006], [0061]-[0062], [0072]), which reads on overt multiple myeloma absent evidence to the contrary.
With regard to claims 71, 72 and 80-81 Kochenderfer discloses the immune effector cells comprise T cells or NK cells (paragraphs [0064]-[0065], [0057]-[0059]).
With regard to claims 73-74, 86-87, and 103-104, Kochenderfer discloses the immune effector cells are administered parenterally or intravenously (paragraphs [0069], [0076]).
With regard to claims 82-85 and 101, Kochenderfer discloses the CAR is encoded on a vector, and the vector is an episomal vector, or a viral vector, including a retroviral or lentiviral vector (paragraphs [0048], and [0053]-[0055]).
Claims 69-70, 78-79 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, further in view of WO2013/059593 to Orentas, and WO2013/061273 to Dominici, as applied to claims 66-68, 71-77, 80-87, 99-101, and 103-105 above, and further in view of WO2010/104949 to Kalled, of record, cited on Applicant’s IDS dated 10/15/2024. Claims 69-70, 78-79 are directed to embodiments wherein the B-cell malignancy is non-Hodgkin's lymphoma (NHL), including Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma.
The disclosures of Kochenderfer, Orentas and Dominici are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Kochenderfer, Orentas and Dominici combine to render obvious a method of treating a B-cell malignancy, or multiple myeloma (MM), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR comprising b) amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9. Kochenderfer discloses wherein the B-cell malignancy is multiple myeloma (MM) (paragraphs [0006], [0061]-[0062], [0072]), or other lymphomas based on the surface expression of BCMA on the B-cells (paragraph [0063]).
Kochenderfer discloses the CAR-T cells function by expressing BCMA-binding proteins (anti-BCMA) which direct the recombinant CAR T-cell to malignant cells expressing BCMA (paragraph [0026]). Kochenderfer discloses the antigen binding domains targeting BCMA can be any BCMA antigen binding protein, including those derived from the anti-BCMA antibodies disclosed in WO2010/104949 to Kalled (paragraphs [0027]-[0029], [0030]).
However, none of Kochenderfer, Orentas or Dominici disclose wherein a CAR targeting BCMA can be used to treat the non-Hodgkin’s lymphomas as claimed.
Kalled discloses BCMA is a target for B-cell related diseases (paragraphs [005]). Kalled discloses anti-BCMA antibodies which bind and target malignant B-cells with BCMA expression in order to treat the malignant B-cell disorder (paragraph [044]-[045]). Kalled discloses the anti-BCMA antibodies can be used to target B-cell lymphomas, including multiple myeloma, as well as follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and immunoblastic lymphoma (paragraph [046]).
It would have been obvious to combine the method of treating a B-cell malignancy, including multiple myeloma (MM), or other lymphomas, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR according to Kochenderfer, Orentas and Dominici, further with the disclosure of Kalled. Kochenderfer discloses the anti-BCMA CARs can be used to treat multiple myeloma, or other lymphomas with BCMA expression, and refers to antibodies disclosed in Kalled. Kalled discloses the anti-BCMA antibodies disclosed therein can be used to target B-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and immunoblastic lymphoma. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention because using anti-BCMA antibodies to target B-cell lymphomas, including the lymphomas claimed, was known at the time of the invention.
Claim 102 is rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, further in view of WO2013/059593 to Orentas, and WO2013/061273 to Dominici, as applied to claims 66-68, 71-77, 80-87, 99-101, and 103-105 above, and further in view of WO2012/170911 to Denaro, of record, cited on Applicant’s IDS dated 10/15/2024. Claim 102 is directed to an embodiment wherein the anti-BCMA CAR is encoded on a lentiviral vector comprising a left (5') lentiviral LTR wherein the promoter of the 5' LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; a right (3') lentiviral self- inactivating (SIN) LTR; and a heterologous polyadenylation sequence.
The disclosures of Kochenderfer, Orentas and Dominici are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Kochenderfer, Orentas and Dominici combine to render obvious a method of treating a B-cell malignancy, or multiple myeloma (MM), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR comprising b) amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9. Kochenderfer discloses wherein the CAR is encoded on a lentiviral vector (paragraphs [0055], [0093]).
However, none of Kochenderfer, Orentas or Dominici disclose wherein the lentivirus comprises the specific features as claimed.
Denaro discloses lentiviral vectors encoding heterologous genes, wherein the lentiviral vector comprises a left (5') lentiviral LTR wherein the promoter of the 5' LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the heterologous gene; a right (3') lentiviral self- inactivating (SIN) LTR; and a heterologous polyadenylation sequence (page 3, line 20 – page 5, line 15; page 10, line 13 – page 14, line 9; page 15, lines 6-17; page 16, lines 1-9; page 19, lines 1-11).
Denaro discloses each structure within the lentiviral vector either performs a specific function, enhances expression of the heterologous transgene, or increases safety of the vector (page 30, line 25 – page 31, line 11; page 32, lines 13-22):
Replacing the promoter of the 5' LTR is replaced with a CMV promoter drives transcription of the viral genome in a tat-independent manner, and reduces the possibility of recombination resulting in replication-competent viruses (page 13, lines 6-15);
A Psi (Ψ) packaging signal is required for insertion of viral RNA into the viral capsid or particle (page 12, lines 11-18);
A cPPT/FLAP element may act as a cis-active determinant of lentiviral genome nuclear import and/or increase viral titer, thus increasing transduction and transgene expression (page 13, line 27 – page 14, line 9, page 30, lines 27-39);
A Rev response element (RRE) is an RNA export element that regulates the transport of an RNA transcript from the nucleus to the cytoplasm, thus increasing transgene expression (page 14, lines 10-18; page 30, lines 27-29);
A myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the heterologous gene, provides enhanced transcription of the heterologous gene (page 19, lines 1-11);
A right (3') lentiviral self- inactivating (SIN) LTR results in replication defective viruses, which improves safety. A 3’ SIN LTR deletes or modifies the 3’ U3 LTR sequences, which prevents viral transcription beyond the first round of viral replication (page 12, line 27 - page 13, line 5); and
A heterologous polyadenylation sequence increases stability of the transcript (page 15, lines 6-17).
Denaro discloses cells transfected or infected with the lentiviral vector encoding the heterologous gene can be administered to a subject in need of therapy (page 24, lines 13-17; page 28, lines 1-4).
It would have been obvious to combine the method of treating a B-cell malignancy, including multiple myeloma (MM), or other lymphomas, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR, wherein the anti-BCMA CAR is encoded on a lentiviral vector according to Kochenderfer, Orentas and Dominici, further with the disclosure of Denaro. A skilled artisan would have been motivated to use the lentiviral vector of Denaro when generating the anti-BCMA CAR T-cells of Kochenderfer, Orentas and Dominici in order to increase the safety and expression of the anti-CAR proteins encoded on lentiviral vectors in transduced T-cells. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as lentiviruses comprising the claimed structures were known in the art at the time of the invention.
Claims 88-90, 92-95, and 98 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, further in view of WO2013/059593 to Orentas, WO2013/061273 to Dominici and WO2012/170911 to Denaro, of record.
Independent claim 88 is directed to a method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, a CAR comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9; and wherein the anti-BCMA CAR is encoded on a lentiviral vector comprising a left (5') lentiviral LTR wherein the promoter of the 5' LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; a right (3') lentiviral self- inactivating (SIN) LTR; and a heterologous polyadenylation sequence.
With regard to claim 88, Kochenderfer discloses methods of treating B-cell malignancies comprising administering recombinant human immune effector cells comprising BCMA-targeted CARs (Abstract, paragraphs [0007], [0023], [0027]-[0030], [0074]). Kochenderfer discloses wherein the CAR is encoded on a lentiviral vector (paragraphs [0055], [0093]). Kochenderfer discloses the anti-BCMA CARs are formulated as a composition comprising a physiologically acceptable excipient (paragraphs [0065]-[0068]) and administered in therapeutically effective amounts ([0072]).
Kochenderfer discloses the anti-bcma2-BB CAR, encoded by SEQ ID NO: 10 therein, which comprises comprise a CD8a signal sequence, a BCMA-binding region operably linked to a CD8 hinge, a CD8 transmembrane domain, a 4-1BB intracellular domain, and a CD3ζ intracellular domain (Table 1, paragraphs [0027]-[0030], [0032]-[0034], [0090]).
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Amino acids 1-270, 281-349 and 359-512 of Kochenderfer’s SEQ ID NO: 10 are identical to SEQ ID NO 9’s amino acids 1-270, 271-339, and 340-493; however, Kochenderfer’s sequence comprises two insertions (boxed sequences below):
Kochenderfer discloses the hinge and transmembrane domains, including from CD8, can be derived from any suitable sequence or molecule (paragraphs [0032]-[0033]). Kochenderfer does not identify the specific amino acids within the CARs that encode the BCMA binding region, the CD8 TM region, the 4-1BB region or the CD3ζ region. Thus, while Kochenderfer discloses a CAR receptor that comprises 100% identity to amino acids 1-270, 271-339, and 340-493 of instantly claimed SEQ ID NO: 9, the specific boundaries of the domains within the CAR of Kochenderfer are not disclosed:
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However, Kochenderfer does not disclose wherein the anti-BCMA CAR comprises amino acids 22-493 of SEQ ID NO:9, nor wherein the lentiviral encoding the anti-BCMS CAR comprises the structures as required by claim 88.
Orentas discloses second-generation chimeric antigen receptors (CARs) targeting HA22, wherein the CARs comprise a HA22 binding domain operably linked to a CD8 transmembrane domain, a 4-1BB (CD137) signaling domain, and a CD3ζ signaling domain (abstract, paragraphs [0022], [0033]-[0038], [0065], [0126], Table 1).
Orentas discloses the CD8 transmembrane domain can be encoded by SEQ ID NO: 10 or 33, the 4-1BB domain can be encoded by SEQ ID NO: 13 or 34, and the CD3ζ domain can be encoded by SEQ ID NO: 14 or 15 ([0033],[0034]):
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CD8: SEQ ID NO: 33 is a smaller fragment of SEQ ID NO: 10
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4-1BB: SEQ ID NO: 34 is a smaller fragment of SEQ ID NO: 13:
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CD3ζ: SEQ ID NO: 14 and 35 differ by a single amino acid at position 14:
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Orentas’ disclosed amino acid sequences for the individual CD8, 4-1BB and CD3ζ domains establishes the domain boundaries in Kochenderfer:
Orentas’ SEQ ID NOs. 10 (CD8 TM), 13 (4-1BB) and 14 (CD3ζ) produces a 243 amino acid protein:
FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNRRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
The 243 amino acid protein generated from the combination of Orentas’ SEQ ID NOs 10, 13 and 14 is 99.6% identical to amino acids 271-512 of Kochenderfer, differing only by the insertion of a single amino acid (boxed below):
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As such, the disclosure of Orentas establishes the domain boundaries in the anti-BCMA CAR SEQ ID NO: 10 of Kochenderfer, wherein the CD8 hinge and TM comprise amino acids 271-354, the 4-1BB domain comprises amino acids 355-400, and the CD3ζ domain comprises amino acids 401-512. A skilled artisan would recognize amino acids 1-270 comprise sequences encoding the BCMA binding region:
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Thus, Kochenderfer’s SEQ ID NO: 10, in light of Orentas, establishes wherein Kochenderfer’s amino acids 1-270, comprising the anti-BCMA sequences, have 100% identity to amino acids 1-270 of claimed SEQ ID NO: 9; and amino acids 271-512, encoding the CD8 hinge, CD8 TM, 4-1BB domain and CD3ζ domain, have 99.6 % identity to amino acids 271-493 of claimed SEQ ID NO: 9:
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Dominici discloses CARs targeted to GD2, wherein the GD2 binding domains are operably linked a CD8 hinge domain, a CD8 transmembrane domain, a 4-1BB signaling domain and a CD3ζ signaling domain (page 8, lines 15-22, page 9, line 27- page 10, line 2; page 13, lines 21-26; FIG. 1). Nucleic Acid SEQ ID NO: 1 of Dominici encodes the anti-GD2 CAR, wherein nucleotides 89-880 encode at least the GD2 binding domains and nucleotides 881-1612 encode the CD8 regions (hinge and transmembrane domain), the 4-1BB domain and the CD3ζ domain (page 10, lines 5-9; FIGs. 1-2). Translation of SEQ ID NO: 1, results in a 487 amino acid CAR, wherein nucleotides 89-880 correspond to amino acids 1-264, and nucleotides 881-1612 correspond to amino acids 265-487 of the CAR:
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Amino acids 265-487 of the anti-GD2 CAR are 100% identical to amino acids 271-493 (encoding the CD8 hinge, CD8 TM, 4-1BB domain and CD3ζ domain) of SEQ ID NO:9:
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Dominici’s CAR comprising amino acids 265-487 aligned with amino acids 271-493 of claimed SEQ ID NO:9 can be visualized accordingly:
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Thus, Dominici establishes the amino acid sequences encoding the CD8 hinge, CD8TM, 4-1BB domain and the CD3ζ domain of SEQ ID NO: 9 were known.
In addition, Orentas’ disclosed amino acid sequences for the individual CD8, 4-1BB and CD3ζ domains confirm the domains exemplified in Dominici:
Orentas’ SEQ ID NOs. 33 (CD8 TM), 34 (4-1BB) and 14 (CD3ζ) produces a 223 amino acid protein:
TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
The 243 amino acid protein generated from the combination of Orentas SEQ ID NOs 33, 34 and 14 is 100% identical to amino acids 265-487 of Dominici:
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Thus, Orentas confirms the amino acid sequences that encode individual CD8 hinge/transmembrane, 4-1BB and CD3ζ domains used in Dominici, that are identical to amino acids 271-493 of claimed SEQ ID NO: 9, were known.
Denaro discloses lentiviral vectors encoding heterologous genes, wherein the lentiviral vector comprises a left (5') lentiviral LTR wherein the promoter of the 5' LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the heterologous gene; a right (3') lentiviral self- inactivating (SIN) LTR; and a heterologous polyadenylation sequence (page 3, line 20 – page 5, line 15; page 10, line 13 – page 14, line 9; page 15, lines 6-17; page 16, lines 1-9; page 19, lines 1-11).
Denaro discloses each structure within the lentiviral vector either performs a specific function, enhances expression of the heterologous transgene, or increases safety of the vector (page 30, line 25 – page 31, line 11; page 32, lines 13-22):
Replacing the promoter of the 5' LTR is replaced with a CMV promoter drives transcription of the viral genome in a tat-independent manner, and reduces the possibility of recombination resulting in replication-competent viruses (page 13, lines 6-15);
A Psi (Ψ) packaging signal is required for insertion of viral RNA into the viral capsid or particle (page 12, lines 11-18);
A cPPT/FLAP element may act as a cis-active determinant of lentiviral genome nuclear import and/or increase viral titer, thus increasing transduction and transgene expression (page 13, line 27 – page 14, line 9, page 30, lines 27-39);
A Rev response element (RRE) is an RNA export element that regulates the transport of an RNA transcript from the nucleus to the cytoplasm, thus increasing transgene expression (page 14, lines 10-18; page 30, lines 27-29);
A myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to the heterologous gene, provides enhanced transcription of the heterologous gene (page 19, lines 1-11);
A right (3') lentiviral self- inactivating (SIN) LTR results in replication defective viruses, which improves safety. A 3’ SIN LTR deletes or modifies the 3’ U3 LTR sequences, which prevents viral transcription beyond the first round of viral replication (page 12, line 27 - page 13, line 5); and
A heterologous polyadenylation sequence increases stability of the transcript (page 15, lines 6-17).
Denaro discloses cells transfected or infected with the lentiviral vector encoding the heterologous gene can be administered to a subject in need of therapy (page 24, lines 13-17; page 28, lines 1-4).
It would have been obvious to combine Kochenderfer’s methods of treating B-cell malignancies, comprising administering an anti-BCMA CAR comprising a CD8 hinge, CD8 transmembrane domain, a 4-1BB signaling domain and a CD3ζ signaling domain, further with Orentas, Dominici and Denaro.
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With regard to the claimed requirement wherein the CAR comprises amino acids 22-493 of SEQ ID NO: 9, Kochenderfer’s anti-BCMA CAR, encoded by SEQ ID NO: 10, in view of Orentas, establish the BCMA binding sequences are within amino acids 1-270; and that the CD8 hinge, CD8 transmembrane domain, 4-1BB signaling domain and the CD3ζ signaling domain are encompassed by amino acids 271-512:
Amino acids 1-270 of Kochenderfer’s SEQ ID NO: 10, in view of Orentas, (comprising amino acids 22-270) are 100% identical to amino acids 1-270 of instantly claimed SEQ ID NO: 9:
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It would have been obvious to substitute the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain, comprising amino acids 271-512 of Kochenderfer’s SEQ ID NO: 10, with the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain, comprising amino acids 265-487 of SEQ ID NO: 1 of Dominici. Both the amino acids encoded from Kochenderfer 271-512 and amino acids 265-487 are known for coding the CD8 hinge, CD8 transmembrane domain, the 4-1BB signaling domain and the CD3ζ signaling domain in chimeric antigen receptors.
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Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
The substitution of Dominici’s amino acids 265-487 for Kochenderfer’s amino acids 271-512 results in an anti-BCMA CAR comprising 493 amino acids, that is 100% identical to claimed SEQ ID NO: 9:
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As such, Kochenderfer in view of Orentas and Dominici render obvious methods of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising human immune effector cells and a pharmaceutically acceptable excipient, wherein the cells comprise, at least, a lentiviral vector encoding an anti-BCMA CAR, wherein the CAR comprises b) amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9.
With regard to the claimed requirement wherein the lentiviral vector encoding the anti-BCMA CAR comprises specific structures in claim 88, it would have been obvious to combine Kochenderfer, Orentas and Dominici, further with the disclosure of Denaro. A skilled artisan would have been motivated to use the lentiviral vector of Denaro when generating the anti-BCMA CAR T-cells of Kochenderfer, Orentas and Dominici in order to increase the safety and expression of the anti-CAR proteins encoded on lentiviral vectors in transduced T-cells. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as lentiviruses comprising the claimed structures were known in the art at the time of the invention.
With regard to claims 89-90, Kochenderfer discloses the immune effector cells comprise T cells or NK cells (paragraphs [0064]-[0065], [0057]-[0059]).
With regard to claims 92-93, Kochenderfer discloses the CAR is encoded on a lentiviral vector derived from HIV-1 (paragraphs [0055] and [0093]). In addition, Denaro discloses the lentiviral vectors encoding the heterologous genes are derived from HIV-1 (page 10, lines 13-20, page 13, line 16 – page 14, line 18, page 16, lines 1-2, page 32, lines 4-7).
With regard to claims 94-95, and 98 Kochenderfer discloses wherein the B-cell malignancy is multiple myeloma (MM), and wherein the patent exhibits symptoms (paragraphs [0006], [0061]-[0062], [0072]), which reads on overt multiple myeloma absent evidence to the contrary. Multiple myeloma is a plasma cell malignancy (paragraphs [0005], [0019]-[0021], [0026], [0061], [0082]-[0083]).
Claims 96 and 97 are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, WO2013/059593 to Orentas, and WO2013/061273 to Dominici and WO2012/170911 to Denaro, of record as applied to claims 88-90, 92-95, and 98 above, and further in view of WO2010/104949 to Kalled, of record. Claims 96-97 are directed to embodiments wherein the B-cell malignancy is non-Hodgkin's lymphoma (NHL), including Burkitt lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle cell lymphoma.
The disclosures of Kochenderfer, Orentas, Dominici and Denaro are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Kochenderfer, Orentas and Dominici combine to render obvious a method of treating a B-cell malignancy, or multiple myeloma (MM), in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising human immune effector cells and a pharmaceutically acceptable excipient, wherein the cells comprise, at least, an anti-BCMA CAR encoded on a lentiviral vector, wherein the CAR comprises b) amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9. Kochenderfer discloses wherein the B-cell malignancy is multiple myeloma (MM) (paragraphs [0006], [0061]-[0062], [0072]), or other lymphomas based on the surface expression of BCMA on the B-cells (paragraph [0063]).
Kochenderfer discloses the CAR-T cells function by expressing BCMA-binding proteins (anti-BCMA) which direct the recombinant CAR T-cell to malignant cells expressing BCMA (paragraph [0026]). Kochenderfer discloses the antigen binding domains targeting BCMA can be any BCMA antigen binding protein, including those derived from the anti-BCMA antibodies disclosed in WO2010/104949 to Kalled (paragraphs [0027]-[0029], [0030]).
However, none of Kochenderfer, Orentas, Dominici or Denaro disclose wherein a CAR targeting BCMA can be used to treat the non-Hodgkin’s lymphomas as claimed.
Kalled discloses BCMA is a target for B-cell related diseases (paragraphs [005]). Kalled discloses anti-BCMA antibodies which bind and target malignant B-cells with BCMA expression in order to treat the malignant B-cell disorder (paragraph [044]-[045]). Kalled discloses the anti-BCMA antibodies can be used to target B-cell lymphomas, including multiple myeloma, as well as follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and immunoblastic lymphoma (paragraph [046]).
It would have been obvious to combine the method of treating a B-cell malignancy, including multiple myeloma (MM), or other lymphomas, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR according to Kochenderfer, Orentas, Dominici and Denaro, further with the disclosure of Kalled. Kochenderfer discloses the anti-BCMA CARs can be used to treat multiple myeloma, or other lymphomas with BCMA expression, and refers to antibodies disclosed in Kalled. Kalled discloses the anti-BCMA antibodies disclosed therein can be used to target B-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, and immunoblastic lymphoma. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention because using anti-BCMA antibodies to target B-cell lymphomas, including the lymphomas claimed, was known at the time of the invention.
Claim 91 is rejected under 35 U.S.C. 103 as being unpatentable over WO2013/154760 to Kochenderfer, of record, WO2013/059593 to Orentas, and WO2013/061273 to Dominici and WO2012/170911 to Denaro, of record, as applied to claims 88-90, 92-95, and 98 above, and further in view of US Patent Application Publication No. 2013/0288368 to June, of record, cited on Applicant’s IDS dated 10/15/2024. Claim 91 is directed to embodiments wherein composition comprising the anti-BCMA CAR T-cell comprises a cryoprotective agent.
The disclosures of Kochenderfer, Orentas, Dominici and Denaro are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Kochenderfer, Orentas and Dominici combine to render obvious a method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising human immune effector cells and a pharmaceutically acceptable excipient, wherein the cells comprise, at least, an anti-BCMA CAR encoded on a lentiviral vector, wherein the CAR comprises amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9. Kochenderfer discloses wherein the pharmaceutical composition is formulated with excipients, buffer and/or preservatives (paragraphs [0065]-[0068]), and may be stored prior to administration (paragraph [0064]).
However, none of Kochenderfer, Orentas, Dominici or Denaro disclose wherein the anti-BCMA CAR T-cells are formulated with a cryoprotective agent as required by claim 91.
June discloses pharmaceutical compositions comprising CAR-T cells comprising antigen binding domains targeted to antigens expressed on tumors including B-cell malignancies (Abstract, paragraphs [0003]-[0010], [0016], [0019]-[0022], [0099], [0122]-[0123], [0130]-[0134], [0200]-[0215]). June discloses CARs comprise a CD8 signal domain, an antigen binding domain, a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain (paragraphs [0053]-[0057], [0140]-[0141], [0150]-[0153], Table 5). June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11).
It would have been obvious to combine the method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of human immune effector cells comprising, at least, an anti-BCMA CAR according to Kochenderfer, Orentas, Dominici and Denaro, further with the disclosure of June. Kochenderfer discloses the anti-BCMA CARs can be stored prior to use, and June discloses pharmaceutical compositions comprising CAR T-cells formulated with cryopreservative agents that are administered to subjects with B-cell malignancies. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention because formulating CAR T-cells with cryopreservative agents was known at the time of the invention.
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.
The following non-statutory double patenting rejections are made over U.S. Patent No. 12,029,784, U.S. Patent No. 11,351,236, U.S. Patent No. 10,646,558; U.S. Patent No. 11,633,463; U.S. Patent No. 11,382,965; U.S. Patent No. 11,020,466; U.S. Patent No. 10,639,358; U.S. Patent No. 10,383,929; U.S. Patent No. 10,639,359; and U.S. Patent No. 10,624,960.
Each of the cited patents are related, share the same inventive entity, and the same effective filing date, and have the same specifications. Many of the cited patents are directed to compositions, and the instant claims are directed to methods of using the compositions.
When construing claims under prosecution directed to a method of using a composition, against patented claims to the composition itself, it is proper to use a composition claim to reject a method of use claim where that method of use is disclosed in the specification of the application claiming the composition.
MPEP 804 (B)(1):
When considering whether the invention defined in a claim of an application would have been anticipated by or is an obvious variation of the invention defined in the claim of a patent or copending application, no part of the reference patent or application may be used as if it were prior art. General Foods Corp. v. Studiengesellschaft Kohle mbH, 972 F.2d 1272, 1281, 23 USPQ2d 1839, 1846 (Fed. Cir. 1992) ("Our precedent makes clear that the disclosure of a patent cited in support of a double patenting rejection cannot be used as though it were prior art, even where the disclosure is found in the claims"). This does not mean that one is precluded from all use of the reference patent or application disclosure to understand the meaning of the reference claims.
In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
The rejections may also be made when taken in light of:
US Patent Application Publication No. 2013/0288368 to June, of record
June discloses pharmaceutical compositions comprising CAR-T cells comprising antigen binding domains targeted to antigens expressed on tumors including B-cell malignancies (Abstract, paragraphs [0003]-[0010], [0016], [0019]-[0022], [0099], [0122]-[0123], [0130]-[0134], [0200]-[0215]). June discloses CARs comprise an antigen binding domain, a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain (paragraphs [0053]-[0057], [0140]-[0141], [0150]-[0153]). June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11).
June discloses the CARs comprise an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain, wherein
CD8 signal peptide:
SEQ ID NO: 19 = MALPVTALLLPLALLLHAARP, 21 amino acids;
CD8 hinge:
SEQ ID NO: 21 = TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIY, 47 amino acids;
CD8 transmembrane domain:
SEQ ID NO: 22 = IWAPLAGTCGVLLLSLVITLYC, 22 amino acids;
4-1BB domain
SEQ ID NO: 23 = KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL, 42 amino acids; and
CD3ζ domain
SEQ ID NO: 24 = RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYN
ELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR, 112 amino acids.
Instant SEQ ID NO:9 comprises the amino acid sequence of a CAR targeting BCMA, comprising CD8 signal peptide (amino acids 1-21), anti-BCMA binding regions (amino acids 22-270), a CD8 hinge and CD8 transmembrane domain (amino acids 271-339), an intracellular 4-1BB domain (amino acids 340-381), and an intracellular CD3ζ (amino acids 382-493), as diagrammed below:
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The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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WO2013/154760 to Kochenderfer, of record
Kochenderfer discloses methods of treating B-cell malignancies comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065]). Kochenderfer discloses the anti-BCMA CARs are encoded on polynucleotides in lentiviral based vectors (paragraphs [0055], [0093]). Kochenderfer discloses vectors encoding the anti-BCMA CARs are introduced into human immune effector cells, including T-cell and NK cells, and expressed (paragraphs [0057]-[0059]). Kochenderfer discloses the B-cell malignancies treated with the anti-CART cells include multiple myeloma, (paragraphs [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-50 of U.S. Patent No. 12,029,784 taken in view of US Patent Application Publication No. 2013/0288368 to June. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious variants of the patented claims.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claims 1, 11, 19, 31 and 42 of the ‘784 patent are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that comprise or express an anti-BCMA chimeric antigen receptor encoded by the amino acid comprising (1)/consisting of (11, 19, 31 and 42) sequence set forth in SEQ ID NO:9. Independent claims 19 and 31 require the CAR is encoded on a vector, with claim 31 requiring wherein the anti-BCMA is encoded on a lentivirus with specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
The claims of the ‘784 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
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the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
It would have been obvious to modify the claims of the cited patent by selecting a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-10, 12-18, 20-30, 32-41 and 43-50, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy;
wherein the cells are formulated with a cryoprotectant;
wherein the cells are administered parenterally or intravenously.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-39 of U.S. Patent No. 11,351,236 taken in view of US Patent Application Publication No. 2013/0288368 to June. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious variants of the patented claims in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claims 1, 12, and 23 of the ‘236 patent are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor encoded by the nucleic acid sequence set forth in SEQ ID NO:10. Independent claim 12 further requires wherein the anti-BCMA is encoded on a lentivirus with specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence. The translation of the nucleic acid sequence SEQ ID NO:10 recited in the cited patent results in an amino acid sequence with 100% identity to instantly claimed SEQ ID NO:9.
The claims of the ‘784 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprise an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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It would have been obvious to modify the claims of the cited patent by translating the nucleic acid, and selecting a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-11, 13-22, and 24-39, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy;
wherein the cells are formulated with a cryoprotectant;
wherein the cells are administered parenterally or intravenously.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,646,558, taken in view of US Patent Application Publication No. 2013/0288368 to June and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘558 patent is directed to a chimeric antigen receptor (CAR) comprising the amino acid sequence set forth in SEQ ID NO: 9 encoded by the polynucleotide sequence set forth in SEQ ID NO: 10. Translation of the nucleic acid sequence SEQ ID NO:10 recited in the cited patent results in an amino acid sequence with 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘558 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 38-45; column 44, lines 43-64; column 63, lines 34-39; column 67 line 36 – column 68, line 34).
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
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the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
Thus, it would have been obvious to the skilled artisan to use the nucleic acids set forth as SEQ ID NO: 10, encoding an amino acid encoding an anti-BCMA CAR as set forth as SEQ ID NO:9, and select a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains, and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-30, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, taken in light of the teachings of the ‘558 patent at column 9, lines 38-45; column 44, lines 43-64; column 63, lines 34-39; column 67 line 36 – column 68, line 34;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,633,463, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘463 patent is directed to a nucleic acid comprising a polynucleotide encoding a chimeric antigen receptor (CAR) comprising the amino acid sequence in SEQ ID NO: 9. The amino acid SEQ ID NO:9 claimed in the cited patent has 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘463 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 39-46; column 44, lines 45-50; column 63, lines 56-61; column 67, line 26 – column 68, line 58).
The claims of the ‘463 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
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the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
Thus, it would have been obvious to the skilled artisan to use the nucleic acids encoding an amino acid encoding an anti-BCMA CAR as set forth as SEQ ID NO:9, and select a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘463 patent.
Claims 2-7, and 13-19 of the ‘463 patent require wherein the nucleic acid encoding amino acid SEQ ID NO:9 are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-21, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, taken in light of the teachings of the ‘463 patent at column 9, lines 39-46; column 44, lines 45-50; column 63, lines 56-61; column 67, line 26 – column 68, line 58;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 11,382,965, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘965 patent is directed to a chimeric antigen receptor (CAR) comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO: 9. The amino acid SEQ ID NO:9 recited in the cited patent has 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘965 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 44-51; column 44, lines 58-64; column 64, lines 4-9; column 67, line 42 – column 69, line 8).
The claims of the ‘965 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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Thus, it would have been obvious to the skilled artisan to select a subset of amino acids encoded on SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘965 patent.
Claims 4-15 of the ‘965 patent require wherein the nucleic acid encoding amino acid SEQ ID NO:9 are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-30, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, taken in light of the teachings of the ‘965 patent at column 9, lines 44-51; column 44, lines 58-64; column 64, lines 4-9; column 67, line 42 – column 69, line 8;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11,020,466, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘466 patent is directed to a chimeric antigen receptor (CAR) consisting essentially of the amino acid sequence set forth in SEQ ID NO: 9. The amino acid SEQ ID NO:9 recited in the cited patent has 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘466 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 48-51; column 45, lines 15-21; column 64, lines 35-41; column 68, line 7 – column 69, line 40).
The claims of the ‘466 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
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the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
Thus, it would have been obvious to the skilled artisan to select a subset of amino acids encoded on SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains, and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘466 patent.
Claims 11-23 of the ‘466 patent require wherein the nucleic acid encoding amino acid SEQ ID NO:9 are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-27, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, in light of the teachings of the ‘466 patent at column 9, lines 48-51; column 45, lines 15-21; column 64, lines 35-41; column 68, line 7 – column 69, line 40;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of U.S. Patent No. 10,639,358, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘358 patent is directed to a chimeric antigen receptor (CAR), wherein the CAR is encoded by the polynucleotide sequence set forth in SEQ ID NO: 10. Translation of the nucleic acid sequence of SEQ ID NO:10 recited in the cited patent results in an amino acid with 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘358 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 43-44; column 44, lines 61-67; column 64, lines 5-11; column 67, line 42 – column 69, line 8).
The claims of the ‘358 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
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the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
Thus, it would have been obvious to the skilled artisan to select a subset of amino acids encoded on SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘358 patent.
Claims 7-18 of the ‘358 patent require wherein the nucleic acid encoding amino acid SEQ ID NO:9 are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-30, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, in light of the teachings of the ‘358 patent at column 9, lines 43-44; column 44, lines 61-67; column 64, lines 5-11; column 67, line 42 – column 69, line 8;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,383,929, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘929 patent is directed to a polynucleotide encoding a chimeric antigen receptor (CAR) comprising the polynucleotide sequence set forth in SEQ ID NO: 10. Translation of the nucleic acid sequence of SEQ ID NO:10 recited in the cited patent results in an amino acid with 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘929 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 41-44; column 44, lines 60-65; column 63, line 66 -column 64, line 4; column 67, line 34 – column 68, line 67).
The claims of the ‘929 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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Thus, it would have been obvious to the skilled artisan to use the nucleic acids encoding an amino acid encoding an anti-BCMA CAR as set forth as SEQ ID NO:9, and select a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains, and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘929 patent.
Claims 2, 7-18 of the ‘929 patent require wherein the nucleic acid comprising SEQ ID NO 10, are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-21, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, in light of the teachings of the ‘929 patent at column 9, lines 41-44; column 44, lines 60-65; column 63, line 66 -column 64, line 4; column 67, line 34 – column 68, line 67;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,639,359, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘359 patent is directed to a population of cells comprising T cells, wherein the T cells comprise a lentiviral vector comprising a left (5′) lentiviral LTR; a Psi (Ψ) packaging signal; a central polypurine tract/DNA flap (cPPT/FLAP); a retroviral export element; a promoter operably linked to a polynucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the polynucleotide sequence is set forth in SEQ ID NO: 10; and a right (3′) lentiviral LTR. Translation of the nucleic acid sequence of SEQ ID NO:10 recited in the cited patent results in an amino acid with 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘359 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 42-45; column 44, lines 24-27; column 63, lines 34-39; column 67, line 1 – column 68, line 34).
The claims of the ‘359 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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Thus, it would have been obvious to the skilled artisan to use the nucleic acids set forth as SEQ ID NO: 10, encoding an amino acid encoding an anti-BCMA CAR as set forth as SEQ ID NO:9, and select a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of instant claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, these claim is obvious from the claims of the ‘359 patent.
Claims 1-12 of the ‘359 patent require wherein the nucleic acid comprising SEQ ID NO 10, are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-21, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, in light of the teachings of the ‘359 patent at column 9, lines 42-45; column 44, lines 24-27; column 63, lines 34-39; column 67, line 1 – column 68, line 34.
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Claims 66-105 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10,624,960, taken in view of US Patent Application Publication No. 2013/0288368 to June, and WO2013/154760 to Kochenderfer. Although the claims at issue are not identical, they are not patentably distinct from each other because they are not patentably distinct and/or are obvious variants of the claimed invention in light of the cited art.
Independent claims 66, 75, 88, 99 and 105 are drawn to methods of treating a B-cell malignancy, including multiple myeloma, comprising administering recombinant immune effector cells that express an anti-BCMA chimeric antigen receptor comprising amino acids 22-493 of the amino acid sequence set forth in SEQ ID NO:9 (Claims 66, 75, 88 and 99); or wherein the BCMA chimeric antigen receptor comprises “a means for” binding BCMA and amino acids 271-493 of the amino acid sequence set forth in SEQ ID NO:9 (claim 105).
Independent claims 66 and 99 are directed to methods wherein the immune cells express the CAR receptor; Independent claims 75 and 88 are directed to methods wherein the immune cells encode the CAR receptor on a vector, including a lentiviral vector, wherein the lentiviral vector the specific structure comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Independent claim 1 of the ‘960 patent is directed to A lentiviral vector comprising a left (5′) lentiviral LTR wherein the promoter of the 5′ LTR is replaced with a CMV promoter; a Psi (Ψ) packaging signal; a cPPT/FLAP; a Rev response element (RRE); a myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted (MND) promoter operably linked to a polynucleotide sequence encoding a chimeric antigen receptor (CAR), wherein the polynucleotide sequence is set forth in SEQ ID NO: 10; a right (3′) lentiviral self-inactivating (SIN) LTR; and a heterologous polyadenylation sequence. Translation of the nucleic acid sequence of SEQ ID NO:10 recited in the cited patent results in an amino acid with 100% identity to instantly claimed SEQ ID NO:9.
The specification of the ‘960 patent discloses the nucleic acids and amino acids encoding anti-BCMA CARs disclosed therein can be used to generate human immune cells which are used in methods of treating B-cell malignancies (column 9, lines 43-46; column 44, lines60-67; column 64, lines 6-9; column 67, line 42 – column 69, line 8).
The claims of the ‘960 patent do not require wherein the CAR comprises amino acids 22-493 or 271-493 as presently claimed.
June discloses CARs targeted to tumor antigens in B-cell malignancies, wherein the CAR comprises an antigen binding domain, CD8 signal peptide (leader sequence), a CD8 hinge, a CD8 transmembrane domain, a 4-1BB domain, and a CD3ζ domain defined by SEQ ID NO therein.
The CD8 signal peptide, CD8 hinge, CD8 transmembrane domain, and 4-1BB domain disclosed in June are 100% identical to the corresponding amino acid sequences in SEQ ID NO: 9; and
the CD3ζ domain disclosed in June is 99% identical to the corresponding CD3ζ domain in SEQ ID NO: 9:
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Thus, it would have been obvious to the skilled artisan to use the nucleic acids set forth as SEQ ID NO: 10, encoding an amino acid encoding an anti-BCMA CAR as set forth as SEQ ID NO:9, and select a subset of amino acids encoded by SEQ ID NO: 9, as selecting 22-493 excludes the CD8 signal peptide, and selecting 271-493 excludes the CD8 signal peptide and BCMA binding domains and encode and express the CAR in human effector immune cells in methods of treating B-cell malignancies, according to instantly claimed 66, 75, 88, 99 and 105.
Further with regard to the requirement of instant claim 88, wherein the nucleic acid encoding the anti-BCMA CAR is encoded on a vector, including a lentiviral vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence, this claim is obvious from the claims of the ‘960 patent.
Claims 1-3 of the ‘960 patent require wherein the nucleic acid comprising SEQ ID NO 10, are encoded on vectors, including lentiviral vectors vector comprising a left (5′) retroviral LTR, a Psi (Ψ ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a REV response element; a dl587rev primer-binding site substituted (MND) promoter operably linked to the polynucleotide encoding the CAR; and a right (3′) a self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Instant claims 67-74, 76-87, 89-98, and 100-104 are obvious variants or similar in scope to patented claims 2-21, relating to:
wherein the human immune effector cells are T cells or NK cells;
wherein the human immune effector cells are formulated with pharmaceutical composition comprising a physiological acceptable excipient;
wherein the vector is an episomal vector, a viral vector, or a retroviral vector;
wherein B-cell malignancy that is treated includes multiple myeloma, non-Hodgkin’s lymphoma or a plasma cell malignancy, the ‘960 patent at column 9, lines 43-46; column 44, lines60-67; column 64, lines 6-9; column 67, line 42 – column 69, line 8;
wherein the cells are formulated with a cryoprotectant, when taken in light of June. June discloses the CAR T-cells are formulated as pharmaceutical compositions with cryopreservative agents (paragraphs [0222], [0315]-[0319], [0323], Fig 11); and
wherein the cells are administered parenterally or intravenously, when taken in light of Kochenderfer. Kochenderfer discloses methods of treating B-cell malignancies, including multiple myeloma, comprising administering immune effector cells expressing CAR receptors directed towards BCMA to patients in need thereof, wherein the cells are formulated in pharmaceutically acceptable carriers (paragraphs [0058], [0061]-[0063], [0065], [0072]). Kochenderfer discloses the CAR-T cells are administered parenterally or intravenously (paragraph [0076]).
Thus, it would have been obvious to administer CAR-T cells expressing an anti-BCMA CAR parenterally or intravenously, as these methods of administration were known for administering CAR-T cells for therapeutic purposes at the time of the invention.
Conclusion
No claims are allowed.
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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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