DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s amendment filed on August 9, 2024 is acknowledged.
Claims 10-19 have been added.
Claims 1-19 are pending and currently under consideration.
3. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
4. Claims 3- are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A) claims 3-9 are indefinite in the recitation of "the antibody" because the metes and the bounds of "the antibody” is unclear and ambiguous. It is not clear if "the antibody" is referring the antibody specific for CD19 in the preamble of independent claim 1 that cross-competes or the antibody comprising the six CDRs in the body of the claim 1.
For examination purposes, "the antibody" is read as the antibody comprising the six CDRs in the body of the independent claim 1 rather than the antibody specific for CD19 that cross-competes.
B) claim 6 and 7 recite the limitation of anti-CD19 antibody and fludarabine are "administered separately" or “administered prior to administration of the antibody specific for CD19”, respectively. There is insufficient antecedent basis for this limitation in the claims. Claims 6 and 7 are depended upon claim 1. Independent claim 1 is drawn to a synergistic combination of the anti-CD19 antibody and fludarabine; claim 1 does not encompass administration/administer.
5. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
6. Claim 8 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
It is apparent that the MEC-1 cell as recited is required to practice the claimed invention. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the cell which, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the cell has been deposited under the Budapest Treaty and that the cell will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the cell described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Further, amendment of the specification to disclose the date of deposit and the complete name and address of the depository (ATCC.10801 University Boulevard, Manassas, VA 20110-2209) is required as set forth in 37 C.F.R. 1.809(d).
It is noted that the specification disclosed the MEC-1 cells is a chronic B-cell leukemia cell line with DSMZ# ACC497 (see page 16 of the instant specification).
This rejection may be overcome by reciting the DSM number in the claim and amending the instant specification to disclose the name and address of the depository.
7. Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 and dependent claim thereof are drawn to a synergistic combination of an anti-CD19 antibody that cross-compete with an antibody comprising the recited six CDRs sequences and fludarabine for use in the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.
Dependent claim 2 further recite that the anti-CD19 antibody binds to the same epitope as the antibody comprising the six CDRs sequences.
Claims 1 and 2 do not recite the anti-CD19 antibody structure but rather relied on what the antibody binds, e.g. cross-compete with or binds the same epitope as the antibody having the six CDRs amino acid sequences.
Dependent claim 4 further limit the anti-CD19 antibody to have the amino acid sequences of VH and VL. Dependent claim 5 further recites the amino acid sequence of SEQ ID NO:12 of the heavy chain constant region.
The specification discloses that the antibody sequences recited in the instant claims are from the anti-CD19 antibody MOR208 as disclosed in USSN 12/377,251 (e.g. see page 10 of the specification as-filed).
The anti-CD19 antibody MOR208 is a humanized and affinity-optimized anti-CD19 antibody formerly known as XmAb5574 (see Kellner et al. Leukemia 2013, Letters to the Editor pages 1567-1614, Title in particular).
The XmAb5574 (with S239D/I332E amino acid substitutions in the Fc region) exhibits enhanced immune cell-mediated effector functions and increased apoptotic activity, thereby maximizing the chance for successful clinical applications of human lymphoma and leukemia (e.g. see page 8056 of Horton et al. Cancer Research 2008, 68;19:8049-8057).
Therefore, the anti-CD19 antibody disclosed in the specification, namely MOR208 (XmAb5574), is structurally defined by not only the six CDRs for antigen binding but also by the Fc sequence that contains two amino acid substitutions S239D/I332E that contribute the features of enhanced effector functions and increased apoptotic activity.
However, there is insufficient written description in the specification as-filed of the claimed genus of synergistic combination of an anti-CD19 antibody and fludarabine, wherein the anti-CD19 antibody cross-competes and/or binds to the same epitope as an antibody comprising the six CDRs or an antibody comprising the VH and VL sequences.
The claims recite a genus of anti-CD19 antibody in a synergistic composition with fludarabine for use in the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.
The claims lack antigen binding region sequences and the Fc region, specifically the two amino acid substitutions S239D/I332E in the Fc region that are important part of the structure for the anti-CD19 antibody that correlates the function of synergy with fludarabine for the use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or lymphoblastic leukemia.
It appears that the scope of the claims includes numerous structural variants, and the genus is highly variant (e.g. unidentified framework regions and the Fc region) because a significant number of structural differences between genus members is permitted. The specification does not describe the structure the anti-CD19 antibody other than the examples discussed above. The specification does not describe the particular physical or chemical characteristics for the anti-CD 19 antibodies nor does the specification disclose sufficient correlations between the structure of the anti-CD19 antibodies and the function of synergy when combined with fludarabine.
For example, Vajdos et al. (J. Mol. Biol. 320: 415-428, 2002, reference on IDS) state that while antigen binding is primarily mediated by the CDRs, more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations may also contact antigen (page 416, left col.).
Further, Ghetie et al. (Blood, 1994, 83;5:1329-1336, reference on IDS) teach anti-CD19 antibodies BU12, HD37, B43, and 4G7 have similar affinities to CD19 and recognizes the same or adjacent epitopes on the CD19 antigen, BU12 antibody has the highest affinity to CD19 and thus is more effective in inducing cell cycle arrest of the CD19+ lymphoma cells and B43 is ineffective (e.g. see right column in page 1332).
More importantly, Horton et al. (Cancer Research 2008, 68;19:8049-8057, reference on IDS) teach anti-CD19 antibody XmAb5574 (former name of MOR208) consists of two amino acid substitutions S239D/I332E (e.g. see Production of antibodies in left col. in page 8050). This antibody displays increased FcγRIIIa (100-fold) and FcγRIIa (10-fold) and markedly enhanced ADCC activity (significantly increased both efficacy and potency) relative to anti-CD19 IgG1 antibody analog (e.g. see pages 8051-8052). Horton et al. teach XmAb5574 not only increases ADCC but also increases ADCP and apoptosis against B cell tumors and enhances tumor inhibition in mouse xenograft models (e.g. see page 8055). The higher affinity for FcγRIIIa translates directly into substantially enhanced ADCC against a broad range of leukemia and lymphoma cell lines and primary tumor cells and the increased FcγR affinity of XmAb5574 is critical for maximal effectiveness because anti-CD19 IgG1 antibody analog without the S239D/I332E amino acid substitutions in the Fc region displayed no or minimal levels of ADCC, emphasize the importance of Fc engineering for enhanced in vivo efficacy (e.g. see page 8056).
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of the anti-CD19 antibody that competes or binds the same epitope broadly encompassed by the claimed invention.
A skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the genus that exhibit this functional property synergistic effect when combined with fludarabine based on cross-competing or binding the same epitope as the specific anti-CD19 antibody having the full structure of VH, VL and the Fc region disclosed in the instant specification.
It does not appear based upon the limited disclosure of specific anti-CD19 antibody MOR208 consisting of S239D/I332E substitutions in synergistic composition with fludarabine alone that Applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the limited number of species disclosed and the extensive variation permitted within the genus of the anti-CD19 antibody in a synergistic combination with fludarabine.
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claims. Id. 43 USPQ2d at 1406.
In the absence of disclosure of relevant, identifying characteristics of the anti-CD19 antibodies, there is insufficient written disclosure under 35 U.S.C. 112, first paragraph.
Therefore, there is insufficient written description for genera of the anti-CD19 antibodies, broadly encompassed by the claimed invention, other than the particular anti-CD19 antibody structurally defined by the description in the specification as filed under the written description provision of 35 USC 112, first paragraph.
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
9. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
10. Claims 1-19 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Horton et al. (Cancer Research 2008, 68;19:8049-8057, reference on IDS) and Bernett et al. (US 8,524,867, reference on IDS) in view of Bolognesi et al. (Leukemia 2004, 18:1215-1222) and Dreyling et al. (US 2011/0165152) as evidenced by Woyach et al. (Blood 2014, 124;24:3553-3560, reference on IDS) and Example in page 17 of the instant specification.
Horton et al. teach that anti-CD19 monoclonal antibody XmAb5574 containing S239D/I332E amino acid substitutions in the Fc region has potent in vitro and in vivo activity against lymphoma and leukemia (see Title, Abstract, and lines 6-9 of the 2nd paragraph in the left column in page 8050). Horton et al. teach that CD19 is an attractive target for cancers of lymphoid origin due to its high expression in most non-Hodgkin’s lymphomas, acute lymphoblastic leukemia, and chronic lymphocytic leukemia (e.g. see Introduction in left column in page 8049). Horton et al. teach that the Fc engineered XmAb5574 has high affinity to human CD19 and substantially increased affinity for human FcγRIIIa and FcγRIIa which directly translates to substantially enhanced ADCC and ADCP against a broad range of leukemia and lymphoma cell lines and primary tumor cells (e.g. see paragraph spanning pages 8055-8056). Horton et al. teach method of treating lymphoma in SCID mouse by administering XmAb5574 antibody (e.g. see last paragraph in left col. in page 8053).
As evidenced by Woyach et al., XmAb5574 is MOR208; as further evidenced by the disclosure, MOR208 is anti-CD19 antibody in the working examples disclosed in the instant specification (e.g. see Examples in page 17).
Horton et al. teach the humanized and affinity-optimized anti-CD19 antibody XmAb5574 (with S239D/I332E amino acid substitutions in the Fc region) exhibits enhanced immune cell-mediated effector functions and increased apoptotic activity, thereby maximizing the chance for successful clinical applications of human lymphoma and leukemia (e.g. see page 8056). Given that the anti-CD19 antibody XmAb5574 is the same as the instantly disclosed MOR208, the prior art antibody would inherently have the same amino acid sequences and functions (e.g. cross-compete) as the instantly claimed antibody. Also note that MOR00208 induces minimal internalization of the CD19 antigen and should not affect effector functions (e.g. see left column in page 8052 of Horton et al., Cancer Research 2008, 68;19:8049-8057).
Horton et al. teach that while anti-CD20 antibody is efficacious in approximately half of the patients suffering from B-cell malignancies, “CD19 is an attractive alternative target for the immunotherapy of lymphoproliferative disorders due to its expression on a wider range of lymphomas and leukemias, including some early B-cell malignancies that do not express CD20” (e.g. see Discussion in the right column in page 8055).
Horton et al. conclude that “the humanized and affinity-optimized anti-CD19 antibody XmAb5574 was Fc-engineered to enhance immune cell-mediated effector functions” and that it also “possesses increased apoptotic activity [], exhibits multiple modes of potent tumor cytotoxicity that are substantially increased relative to unmodified anti-CD19 antibodies” (e.g. see last paragraph in the right column in page 8056).
Similarly, Bernett et al. teach an anti-CD19 antibody having identical amino acids sequences (six CDRs, VH and VL region, as well as the Fc region with the amino acid substitutions S239D/I332E) (e.g. see attached sequence alignments for the claimed SEQ ID Nos: 10, 11, and 12); the anti-CD19 antibody can be administered to treat non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (e.g. see lines 20-25 in col. 56).
Bernett et al. teach that the most commonly used agents in treating non-Hodgkin’s lymphoma include fludarabine and was shown to fie superior response rates (e.g. see lines 4-8 in col. 3 and lines 55-60 in col. 3)
Bernett et al. teach that the anti-CD19 antibody can be co-administered with a chemotherapeutic agent including purine analogs fludarabine in a method of treating [e.g. see line 26 in col. 66). Bernett et al. teach that such combination administration can provide "a benefit that is increased versus treatment with only either the antibody or the agent alone” [e.g. see lines 19-35 in col. 63).
The reference teachings differ from the instant invention by not exemplifying the combination of the anti-CD19 antibody with fludarabine in a method of treating non-Hodgkin’s lymphoma.
Bolognesi et al. teach that anti-CD20 antibody immunoconjugate (designed for non-Hodgkin's lymphoma therapy) shows a specific cytotoxicity for CD20+ lymphoma cells from non-Hodgkin’s lymphoma patients and produces a synergistic effect with fludarabine used in clinic for treatment of many B-cell neoplasia and one of the most used drugs for low-grade non-Hodgkin's lymphoma therapy (e.g. see entire document, particularly page 1215 and right column in page 1221).
Dreyling et al. teach that fludarabine is a chemotherapy drug (a DNA precursors /antimetabolites) used in treatment of hematological malignancies (e.g. see [0008]). Dreyling et al. teach that combination of fludarabine with an afucosylated anti-CD20 antibody, known to have increased antibody-dependent cell mediated cytotoxicity (ADCC) effect over anti-CD20 antibody with fucose, showed synergistic therapeutic effect over non-Hodgkin's lymphoma (e.g. see claims 1-14 and paragraph [0052] in page 5 and paragraph [0011]).
Dreyling et al. teach detailed protocols of administering the anti-CD20 antibody and fludarabine where the two agents are administered separately (e.g. see paragraph [0133] in page 12). Dreyling et al. also teach that the effector function enhanced afucosylated anti-CD20 antibody and the fludarabine can be administered “as one single formulation or as two separate formulations. The co-administration can be simultaneous or sequential in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities” (see [0070]).
It would thus be obvious to one of ordinary skill in the art at the time the invention was made to combine the anti-CD19 antibody disclosed by Horton et al. and Bernett et al. with fludarabine disclosed by Bolognesi et al. and Dreyling et al. in a method for treating B-cell malignancies such as non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and/or acute lyphoblastic leukemia in a subject. One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, because both compounds (the anti-CD19 antibody with S239D and I332E amino acid substitutions in the Fc region and fludarabine) are known to be therapeutic effective in treating lymphomas such as non-Hodgkin's lymphoma.
As such, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. . . [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205USPQ 1069, 1072 (CCPA 1980) (see MPEP 2144.06).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to determine all operable mode of administration (administer fludarabine prior to the anti-CD19 antibody) because determination of administration order of the compounds is well within the purview of one of ordinary skill in the art at the time the invention was made.
Further, given that Dreyling et al. teach that effector function enhanced anti-CD20 antibody were shown to have synergistic effect with fludarabine in killing lymphoma cell line, it is reasonable to expect that the anti-CD19 antibody XmAb5574 (with S239D/I332E amino acid substitutions in the Fc region) exhibiting enhanced immune cell-mediated effector functions including ADCC and increased apoptosis when combined with fludarabine (also showing inducing apoptosis against lymphoma cells) would also have synergistic effect and capable of killing MEC-1 cell as recited in instant claims 8 and 11, which necessarily flows from the teachings of the applied prior art.
This is because both afucosylated anti-CD20 antibody and the Fc modified anti-CD19 antibody XmAb5574 and with reduced fucose share a common mechanism of action ---- enhanced ADCC activity in killing lymphoma cells. As such, the substitution of the known afucosylated anti-CD20 antibody for the Fc modified anti-CD19 antibody XmAb5574 would have yielded predictable result of synergistic effect in killing lymphoma cells.
11. No claim is allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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