DETAILED ACTION
1. The present application is being examined under the pre-AIA first to invent provisions.
2. 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 3-9 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 bendamustine 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 claim. The independent claim 1 is drawn to a synergistic combination of the anti-CD19 antibody and bendamiustine; 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 DSM# ACC497 (see page 17 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 1-11 and 13-19 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The following written description rejection is set forth herein.
Claims 1-9 are drawn to a synergistic combination of an anti-CD19 antibody that cross-competes with an antibody with the recited six CDRs and bendamustine for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia.
Independent claim 10 and dependent claims thereof are drawn to a method for treating, e.g. non-Hodgkin’s lymphoma, by administering bedamustine and an anti-CD19 antibody comprising the recited six CDRs. Dependent claim 11 further recites the VH and VL amino acid sequences of the antibody. Dependent claim 13 recites the constant region sequence of the VL.
Dependent claims (e.g. claim 2) recite that the anti-CD19 antibody in the synergistic combination to be an anti-CD19 antibody that binds the same epitope as an antibody comprising the six recited CDRs sequences.
Dependent claims (e.g. claim 3) encompass the anti-CD19 antibody with the specific six CDR sequences; dependent claims (e.g. claim 4) further recite amino acid sequences for the variable heavy chain and the variable light chain.
The specification discloses that anti-CD19 antibody MOR00208 and bendamustine in combination shows synergistic effect in the specific killing of MEC-1 cells (chronic B-cell leukemia cell line) as compared to the antibody and bendamustine alone (e.g. see page 15-18).
Further, the specification discloses that while the anti-CD19 antibody and bendamustine administered together did not show synergy over monotherapies in SCID mice subcutaneously implanted with human Burkitt's lymphoma cells RAMOS (e.g. see pages 19-20), the combination shows synergistic effect in the Non-hodgkin's RAMOS orthotopic tumor survival model as compared to the antibody and bendamustine alone (e.g. see pages 20-25).
It appears that the instant specification discloses example of anti-CD19 antibody MOR00208 is a humanized and affinity-optimized anti-CD19 antibody XmAb5574 (with S239D/I332E amino acid substitutions in the Fc region) that 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).
However, there is insufficient written description in the specification as-filed of the claimed genus of synergistic combination of an anti-CD19 antibody and bendamustine, 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 bendamustine for use in the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and/or acute lymphoblastic leukemia; dependent claims 3 and 4 recite amino acid sequences for the six CDRs, and VL and VL, respectively.
The claims lack the framework regions 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 bendamustine 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 bendamustine.
For example, Vajdos et al. (J. Mol. Biol. 320: 415-428, 2002) 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) 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) teach anti-CD19 antibody XmAb5574 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 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 bendamustine 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 MOR00208 consisting of S239D/I332E substitutions 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.
“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. Logically, if applicant was not in possession of atni-CD19 antibody which is being administered for the method of treating diseases such as non-Hodgkin’s lymphoma as recited in claims 10, 11, and 13-19, , applicant also was not in possession of methods of administering the antibody at the time the instant application was filed.
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 (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 of this title, 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.
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) and Bernett et al. (US 8,524,867, reference on IDS), as evidenced by Woyach et al. (Blood 2014, 124;24:3553-3560) and Examples in page 15 of the instant specification, in view of Weidmann et al (Annals of Oncology 2002, 13:1285-1289) or Herting et al. (US 2011/0165151).
Horton et al. teach in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody XmAb5574, a humanized and affinity-optimized anti-CD19 antibody. Specifically, 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 left column in page 8049). Horton et al. teach XmAb5574 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 control IgG1 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 displayed no or minimal levels of ADCC, emphasize the importance of Fc engineering for enhanced in vivo efficacy (e.g. see page 8056).
Horton et al. further teach the humanized and affinity-optimized anti-CD19 antibody XmAb5574 consisting of 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 MOR0208, the prior art antibody would inherently have the same amino acid sequences and functions (e.g. cross-compete) as the instantly claimed antibody.
Horton et al. discloses that while anti-CD20 antibody has been used successfully in treating non-Hodgkin’s lymphoma and some B cell leukemias, anti-CD19 antibodies may be more efficacious against early B-cell malignancies and other CD20- tumors (e.g. see right column in page 8049).
As evidenced by Woyach et al., XmAb5574 is MOR00208; as further evidenced by the disclosure, MOR00208 is anti-CD19 antibody in the working examples disclosed in the instant specification (e.g. see Examples in page 15). Thus, anti-CD19 antibody XmAb5574 disclosed by Horton et al. would inherently have the same amino acid sequences including six CDRs, VH, VL, and CH, and CL as recited in the instant claims.
Similarly, Bernett et al. teach that ADCC is a cell-mediated reaction wherein nonspecific cytotoxic effector cells (e.g. human peripheral blood monocytes) expressing FcγRIIIa recognize the Fc region of an antibody bound on a target cells (e.g. CD19 expressing lymphoma cells) and subsequently cause lysis of the target cells (e.g. see lines 40-51 in column 12 and Example 3 in columns 73-74).
Bernett et al. teach an anti-CD19 antibody having identical amino acids sequences (six CDRs, VH, VL region, CH, and CL as well as the Fc region with the amino acid modifications) (e.g. see sequence alignments attached to this Office Action).
Bernett et al. teach that the anti-CD19 antibody can be co-administered with a chemotherapeutic agent [e.g. see (230)]. 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 (223)].
Bernett et al. teach anti-CD19 clone 4G7 L1.155 that has heavy chain that is identical to the instant SEQ ID NO:12.
Bernett et al. teach following comparison of the anti-CD19 antibody with S239E/I332D substitutions with anti-CD20 antibody Rituximab:
In Example 6 (columns 76), the anti-CD19 antibody with S239D/I332E substitutions shows stronger anti-proliferation effect than unmodified anti-CD19 antibody and anti-CD20 antibody on Raji lymphoma cells (also see FIG. 20);
In Example 9, the anti-CD19 antibody with S239D/I332E substitutions shows better performance in both potency and efficacy when compared to anti-CD19 antibody without Fc modification or anti-CD20 antibody rituximab.
Bernett et al. further teach that the ADCC effect of the anti-CD19 antibody with S239D/I332E substitutions can be further enhanced by reducing the fucose content of the antibody (e.g. see Example 12 in column 79 and claims 1-32).
As such, both Horton and Bennett teach method of treating B cell malignancy such as non-Hodgkin’s lymphoma by administering the same anti-CD19 antibody as recited in the instant application.
The reference teachings differ from the instant invention by not describing a synergistic combination of the anti-CD19 antibody with bendamustine.
Weidmann et al. teach bendamustine (an alkylating nitrogen mustard group and a purine-like benzimidazol compound) is effective in inducing apoptosis in lymphoma cell (e.g. see right column in page 1285) and treating relapsed or refractory aggressive non-Hodgkin’s lymphoma (e.g. see page 1288). Weidmann et al. further teach that bendamustine is synergistic with cladribine on apoptosis of lymphoma cells (e.g. see right column in page 1288).
Weidmann et al. further teach that rituximab (anti-CD20 antibody) can sensitize lymphoma cells for bendamustine-induced apoptosis and concludes that “by combining bendamustine with other chemotherapeutic agents or antibody therapy, the anti-lymphoma effect may be further increased" (e.g. see right column in page 1288). Thus, Weidmann et al. teach combination therapy of bendamustine and antibody.
Herting et al. teach afucosylated anti-CD20 antibody exhibits enhanced dependent cellular cytotoxicity (ADCC) as compared to the anti-CD20 antibody that have no reduced fucose (e.g. see [0046]).
Herting et al further observed that combination of bendamustine with ADCC enhanced afucosylated anti-CD20 antibody showed synergistic anti-proliferative effects against non-Hodgkin’s lymphoma compared to the combination of fucosylated anti-CD20 antibody (not ADCC enhanced) rituximab (e.g. see claims 1-16). Herting et al. discloses detailed protocols of administering the anti-CD20 antibody and bendamustine, where the two agents were administered separately (e.g. see paragraph [0139]).
Herting et al. discloses detailed protocols of administering the anti-CD20 antibody and bendamustine, where the two agents were administered separately (e.g. see paragraph [0139]). Herting et al. teach that the afucosylated anti-CD20 antibody and bendamustine are formulated in two separate formulations (e.g. see [0102]). Herting et al. also teach co-administration of the afucosylated anti-CD20 antibody and bendamustine as one single formulation or as two separate formulations (e.g. see [0077]).
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 bendamustine disclosed by Weidmann et al. and Herting et al. One of ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, because both compounds are known to be therapeutic effective in treating lymphomas such as non-Hodgkin's lymphoma.
Further, give that Herting et al. teach that ADCC enhanced anti-CD20 antibody were shown to have synergistic effect in killing lymphoma cell line when combined with bendamustine, the ADCC enhanced anti-CD19 antibody XmAb5574 when combined with bendamustine (also showing inducing apoptosis against lymphoma cells) would be expected to inherently/intrinsically have synergistic effect capable of killing MEC-1 cell by ADCC at least two-fold better than bendamustine alone. 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 them 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 bendamustine 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.
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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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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