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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7-14-26 has been entered.
The prior election of species requirements have been withdrawn in view of applicant’s claim amendments.
Claims 56, 58-66, 74, 79-81, 84, and 85 are pending and under examination.
The prior obviousness-type double patenting rejections have been withdrawn in view of applicant’s claim amendments.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 56, 58-66, 74, 80 and 81 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 16 and 17 of U.S. Patent No. 11485796 (cited on an IDS) in view of Neijseen et al. (WO2012143524A2, cited on an IDS) as evidenced by, Nezu et al. (WO2012073985A1, cited on an IDS, the national stage entry under 35 U.S.C. § 371 of the ‘985 application into the USA corresponds to 20140112914 (also cited on an IDS)), Dixit et al. (WO2015006749, of record), Bargou et al. (Science, 2008, Vol 321, pages 974-977, of record).
The reference claims are set forth below:
Reference claim 9 is drawn to:
“A method of treating a disease comprising administering to a subject in need thereof an effective amount of a protein comprising a first polypeptide and a second polypeptide, wherein said first polypeptide and second polypeptide each comprises at least a hinge region, a CH2 region, and a CH3 region of an immunoglobulin heavy chain, wherein in at least one of said first polypeptide and second polypeptide, the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively, and wherein the amino acids are numbered according to the EU Index (clm 1), wherein said first polypeptide and second polypeptide further comprise a first binding region and a second binding region, respectively (clm 4), wherein both said first binding region and second binding region bind to CD3 (clm 7), and wherein at least said first binding region is selected from the group consisting of:
a. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12;
b. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12; and
c. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 (clm 9).”
Note that reference SEQ ID NOs: 6, 8, 9 and 12 of claim 9 are identical to SEQ ID NOs: 6, 8, 9 and 12 of the instant claims.
Reference claim 16 is drawn to:
“A method of treating a disease comprising administering to a subject in need thereof an effective amount of a protein comprising a first polypeptide and a second polypeptide, wherein said first polypeptide and second polypeptide each comprises at least a hinge region, a CH2 region, and a CH3 region of an immunoglobulin heavy chain, wherein in at least one of said first polypeptide and second polypeptide, the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively, and wherein the amino acids are numbered according to the EU Index (clm 1), wherein said first polypeptide and second polypeptide further comprise a first binding region and a second binding region, respectively (clm 4), wherein in both said first polypeptide and second polypeptide, the amino acids in the positions corresponding to L234, L235 and D265 in a human IgG1 heavy chain are F, E, and A, respectively, said first binding region binds CD3, and said second binding region binds a cancer-specific target (clm 16).”
Reference claim 17 specifies that the disease treated by base claim 1 is “cancer.”
However, the reference claims do not explicitly set forth the invention of instant claim 56 wherein cancer is being treated with a bispecific antibody comprising a first antigen binding domain that binds to human CD3 and comprises, e.g., VH and VL regions of SEQ ID NOs: 6 and 12; SEQ ID NOs: 8 and 12; or SEQ ID NOs: 9 and 12, and wherein the second antigen binding region binds to a cancer-specific target, a target that is overexpressed in cancer, or a target associated with cancer.
Neijseen taught intact, bispecific antibodies comprising a Her2 binding domain, a CD3 binding domain, and a modified Fc region, wherein the modified Fc region (i) promotes dimerization of one Her2 binding domain with one CD3 binding domain, and (ii) is effector-function deficient with respect binding Fcγ receptor expressing accessory cells such as neutrophils, monocytes/
macrophage, DC and NK cells (see, e.g., Examples 20-21, Example 27).
More particularly, Neijseen taught:
(i) the Fc-domain can be made effector-function deficient, e.g., by an N297Q mutation, or
(ii) in the alternative “residual Fc activity was further removed” by mutagenizing the Fc domains as follows: L234F, L235E, D265A, N297Q and P331S, thereby creating a variant referred to as “LFLEDANQPS.”
(see page 132-33 bridging paragraph).
Neijseen further shows effector-function deficient, bispecific anti-Her2/anti-CD3 antibodies having either the N297Q or the LFLEDANQPS mutations were capable of activating T-cell cytokine production in the presence of Her2-expressing target cells (see Figs. 20, 23, and text at Example 30). Moreover, while the bispecific anti-Her2/anti-CD3 antibody having an N297Q mutation exhibited some Fc-mediated activation of T-cells in assays comprising PBMC alone, the bispecific version having the LFLEDANQPS mutations did not show any significant Fc-mediated activation of T-cells in the same assay (see page 142, penultimate paragraph, page 144, 1st full paragraph, Figs. 17 and 21). Likewise, an effector-function deficient, bispecific anti-Her2/anti-CD3 antibody having the N297Q mutation (Her2 x huCLB-T3/4 N297Q) was able to treat a Her2-expressing cancer in vivo (see Figs. 33A and B).
The ability of bispecific anti-CD3 x anti-TAA antibody having diminished ability to bind Fcγ receptor to nonetheless activate the cytotoxic activity of CD3-expressing T cells in the presence of TAA-expressing target cells described by Neijseen was consistent with several other prior art (prior to 1-9-14) teachings.
For example, Nezu taught and exemplified an intact, Fc “silent” bispecific anti-GPC3 x anti-CD3 antibody (“GPC3 ERY8-2”) which is fully capable of mediating tumor cell killing in vivo (see paragraphs 325, 326, 332 and SEQ ID NO: 42, which is the GPC3 ERY8-2 having the Fc silencing mutations L234A, L235A and N297A).
As yet another example, Dixit showed a bispecific anti-CD3 x anti-CD19 antibody having certain Fc mutations that diminish FcγR-binding (see clone 6754 in Fig. 2 having L234A and L235A) depletes B-cell from the peripheral blood, bone marrow and spleen of NSG mice containing a CD34+ humanized immune system (see Example 16 and paragraph 333). This reference also describes how the 6754 clone and another FcγR knockout anti-CD3 x anti-CD19 bispecific, the 1661 clone, effectively deplete human B-cell cancers in the NSG mouse model (see Figs. 9 and 16), as well as depleting human B-cell in a whole blood assay (see Fig. 7A).
Likewise, Bargou taught a bispecific antibody comprising tandem anti-CD3 and anti-CD19 scFvs, said bispecific antibody lacking an Fc domain, was capable of depleting B-cells in human patients, see, e.g., Fig. 1A of Science, 2008, Vol 321, pages 974-977.
Thus, the ordinarily skilled artisan was well aware prior to applicant’s effective priority date that bispecific anti-TAA x anti-CD3 antibodies, such as the anti-Her2 x anti-CD3 antibodies of Neijseen, do not require fully intact Fc effector function to be activated by, and, in turn, to lyse TAA-expressing target cells.
Given the knowledge in the art set forth above, it would have been obvious to the ordinarily skilled artisan that Fcγ receptor-binding activity of bispecific molecules that bind the Her2 and CD3 antigens, i.e., Her2 x CD3, or that bind the CD19 and CD3 antigens, i.e., CD19 x CD3, can be diminished while retaining effective tumor target cell-dependent T-cell activation.
Thus, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to treat cancer by administering to a cancer patient, such as a Her2-expressing breast cancer patient in need thereof, or a CD19-expressing, indolent or aggressive B-cell lymphoma patient, an effective amount of a protein comprising a first polypeptide and a second polypeptide, wherein said first polypeptide and second polypeptide each comprises at least a hinge region, a CH2 region, and a CH3 region of an immunoglobulin heavy chain, wherein in at least one of said first polypeptide and second polypeptide, the amino acids in the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, respectively, and wherein the amino acids are numbered according to the EU Index (reference clm 1), wherein said first polypeptide and second polypeptide further comprise a first binding region and a second binding region, respectively (reference clm 4), wherein in both said first polypeptide and second polypeptide, the amino acids in the positions corresponding to L234, L235 and D265 in a human IgG1 heavy chain are F, E, and A, respectively, said first binding region binds CD3, and said second binding region binds a cancer-specific target (reference clm 16), such as the breast cancer antigen Her2 or the B-cell lymphoma antigen CD19.
As to the particular “first binding region binds CD3” it would have been obvious to one of ordinary skill in the art to make use of the bispecific antibodies comprising a first binding region selected from the group consisting of a. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 6 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12;
b. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 8 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12; and
c. a binding region comprising a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 (as recited in reference claim 9) since such bispecific antibodies are also claimed in the context of treating disease as recited in reference claim 1.
In so doing the ordinarily skilled artisan would be practicing a method of treatment that reads on claims 56, 58-61 and 63-66.
Moreover, given that SEQ ID NO: 8 of the reference patent is equivalent to SEQ ID NO: 7 of instant claims with a single conservative amino acid substitution (SEQ ID NO: 7 with N87S), in practicing the methods of treatment described above the ordinarily skilled artisan would likewise be practicing the inventions of instant claims 74, 80 and 81.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
No claims are allowed.
However, claims 79, 84 and 85 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Note in this regard that the antibodies “which collectively have 1 conservative amino acid substitution relative to the reference VH and VL region sequences selected from the group consisting of: a) SEQ ID NOs: 6 and 10, respectively…” are understood to be limited to those species of antibodies having a single “conservative amino acid substitution” as set forth in the specification at page 25, 1st full paragraph through the Table on page 25.
Considering the permissible conservative amino acid substitutions set forth in the Table on specification page 25 in the context of the CDR sequences of the heavy and light chain variable domains of SEQ ID NOs: 6-9 and 10-12 as displayed in Table 1 at pages 78-79, a rough estimate of the genus of human CD3-binding variants having 1 conservative amino acid substitution relative to the reference VH and VL region sequences is ≈ 150-170 species. Of these ≈ 150-170 species it would be expected by the skilled artisan that a majority will continue to bind human CD3 with sufficient affinity to be useful in the claimed method of treating cancer.
A reason such single conservative amino acid substitutions would have been expected by the ordinarily skilled artisan to retain their ability to treat cancer as claimed was because, as taught by Bortoletto et al. (Eur. J. Immunol. 2002. 32: 3102–3107, cited herewith), even when certain substitutions in the Vh CDR3 residues of the “TR66” antibody decreased its affinity for CD3, a bispecific antibody comprising the mutant TR66 x M79 (wherein M79 binds to EpCAM), was still capable of mediating killing of EpCAM-expressing target cells in vitro, even when the antibody was present at lower concentrations (see Table 1, e.g., “M13” versus “M76,” which were assessed for CD3 binding affinity in Figs 2A-B and for EpCAM killing ability in Figs 4A-B).
Consistent with the teachings of Bortoletto, List et al. (mAbs 4:6, 775–783; November/
December 2012, cited herewith) teaches: “Our results show the impact of Kd on the targeting performance of a bispecific antibody in a setting where a relatively high Kd for the CD3 binding interaction (200 ± 78 nM) is permissive to a good antibody accumulation at the tumor site in vivo.” (see page 779, right col., 1st full paragraph).
Further similar to the teachings of Bortoletto and List, see also Brischwein et al. (J Immunother 2007;30:798–807, cited herewith) describing how while BiTE-type bispecific antibodies have Kd = 10-7 M affinity for binding to CD3 expressing T-cells, this low CD3 affinity is a desirable feature of BiTE-type bispecific antibodies (see page 804-805 bridging paragraph and page 805, last full paragraph).
Thus, despite the possibility that some singular, conservative amino acid substitutions in a CDR residue of the recited Vh and Vl variable domains may diminish CD3 binding affinity to a limited extent, and in some instances completely (see, e.g., Bortoletto at Table 1, mutant “M3” where a single Y->F mutation in the Vh CDR3 of TR6 ablated CD3 binding), it is the opinion of the undersigned that given the knowledge of the prior art the ordinarily skilled artisan would more likely that not expect a moderate, and even perhaps a lower affinity CD3 binding domain to still have a reasonable ability to mediate treatment of cancer in a subject in need thereof. As such, especially when considering the limited breadth of the claimed genus (≈ 150-170 species), it is the opinion of the undersigned that a preponderance of the evidence supports the patentability of the claimed methods with respect to 35 USC § 112(a), written description and enablement.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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