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 .
DETAILED ACTION
The amendment filed November 13, 2025 in response to the Office Action of May 14, 2025 is acknowledged and has been entered.
Claims 1, 15, 18, 21, and 24 have been amended.
Claim 3-6, 8-13, 16, 17, 19, 20, 22, 23, 25-27, 29-31, 36 and 37 were previously canceled.
Claims 1, 2, 7, 14, 15, 18, 21, 24, 28, 32-35, and 38-41 are pending.
Claims 2, 35, 39 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 7, 14, 15, 18, 21, 24, 28, 32-34, 38 and 40 are currently under consideration as drawn to the elected invention.
MAINTAINED/MODIFIED REJECTION
Claim Rejections - 35 USC § 112
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.
Claims 1, 7, 14, 15, 18, 21, 24, 28, 32-34, 38 and 40 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. This is a WRITTEN DESCRIPTION rejection.
All rejected claims are drawn to a broad genus of a heterodimeric multispecific antibodies: The heterodimeric multispecific antibodies of claim 1 (1+1+2 Lo, see Figure 1b and Figure 1c) and its dependent claims comprise four polypeptide chains: the first polypeptide chain comprises components for binding to a first epitope and second epitope; the second polypeptide chain comprises components for binding to a first epitope; the third polypeptide chain comprises components for binding to a third epitope; the fourth polypeptide chain comprises components for binding to a third epitope and a second epitope. Claim 1 also recites sequences of light chain variable domains and heavy chain variable domains for the first epitope. Claim 1 further recites a broad genus of epitopes on a cancer cell bound by the third immunoglobulin and a broad genus of epitopes on a white cell, a lymphocyte, a macrophage , a T cell, or a NKT cell bound by the second immunoglobulin and the fourth immunoglobulin, however no sequences/structure for the second immunoglobulin, the third immunoglobulin and the fourth immunoglobulin are provided. Thus, given Broadest Reasonable Interpretation (BRI), claim 1 would encompasses all potential immunoglobulins (known or yet to be discovered) bind to all possible tumor antigens/epitopes (known or yet to be discovered) on all types of cancer cells, and all potential immunoglobulins (known or yet to be discovered) bind to all possible epitopes (known or yet to be discovered) on all types of white cells, lymphocytes, macrophages, T cells and NKT cells.
There is insufficient written description in the specification as-filed of a heterodimeric multispecific antibody as claimed.
Vas-Gath, Inc. v" Mahurkar, 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed".
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of afunctional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., binding to antigen, high affinity, neutralization activity, competing with a reference antibody for binding), “[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
In the instant case, the claim encompasses a broad genus of heterodimeric multispecific antibodies to a broad genus of epitope combinations. The specification only discloses three heterodimeric multispecific antibodies in 1+1+2Lo format comprising SEQ ID NO: 1321 and 1325 as claimed ([0063], Figure 23 and Examples 11 and 12). By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff (Rudikoff et al., Proc Natl Acad Sci USA 1982, 79(6) 1979-1983, Publication Year:1982, of record). Rudikoff teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding. Even if the antibody is limited to antibody which can bind to tumor associated antigens, Riemer (Riemer et al. Mol Immunol, 2005 42(9): 1121-1124, Publication Date: 2005-01-08, of record) teaches that antibodies binding the same antigens have been shown to both ameliorate and aggravate disease symptoms (entire document, particular page 1123, column 1), indicating unpredictability of therapeutic outcomes. Thus, the specific antibodies disclosed by the specification (e.g. Table 1) would not tell structure of other antibodies with similar properties to all the antigens for the second, the third and fourth immunoglobulin recited by claim 1.
In view of above, the specification teaches only a few heterodimeric multispecific antibodies as summarized in Fig. 23 ([0063]). In total, the specification teaches only 3 heterodimeric multispecific antibodies in format of 1+1+2Lo comprising SEQ ID NOs: 1325 and 1321.
HDTVS
Type
Fab1
VH&VL
SEQ ID NOs
Fab2
VH&VL
SEQ ID NOs
scFv1
VH&VL
SEQ ID NOs
scFv2
VH&VL
SEQ ID NOs
Ag1
Ag2
Ag3
Ag4
1+1+2Lo
Hu3F8
1325
1321
huM195
2395
2394
huOKT3
2391
2390
huOKT3
2391
2390
GD2
CD33
CD3
CD3
1+1+2Lo
Hu3F8
1325
1321
Hu4D5H
91A
1421
1417
huOKT3
2391
2390
huOKT3
2391
2390
GD2
HER2
CD3
CD3
1+1+2Lo
Hu3F8
1325
1321
Hu8H9
621
617
huOKT3
2391
2390
huOKT3
2391
2390
GD2
B7H3
CD3
CD3
Example 12 describes one more specific heterodimeric multispecific antibody encompassed by the amended claim 1: Lo1(GD2)+1(L1CAM)+2(CD3) (the elected antigen combination) without disclosing the sequence information. Taken together, all heterodimeric multispecific antibodies described in the specification as shown above have: 1) the same anti-CD3 scFv1 and scFv2 corresponding to the second immunoglobulin and the fourth immunoglobulin of the claim 1; 2) only four different options for the third immunoglobulin (CD33, HER2, L1CAM and B7H3). However, claim 1 encompasses unlimited number of the third immunoglobulins which can bind a cancer cell, and encompasses unlimited number of the second immunoglobulins and the fourth immunoglobulins to a broad genus of antigens on all white blood cells, all lymphocytes, all macrophages, all T cells, and all NKT cells. As acknowledged by the specification, the biological activity of the tri- and tetra-specific variants of the HDTVS platform is dependent on the antigen/epitope combination, as well as the relative binding affinities to each target antigen. The Lo1+1+2 HDTVS require its Fab domains to bind to two distinct tumor antigens that are within a proximity of 60-120 angstroms from each other. Several unexpected results were observed (see [0069] of the instant publication 2022/0098329 A1). In addition, biophysical properties such as orientation (cis or trans), valency and target affinity had a unpredictable impact on the functionality of the HDTVS variants (see [0070] of the instant publication) Thus, the limited exemplary heterodimeric multispecific antibodies disclosed by the specification do not provide structure of other epitopes/antigens encompassed by the claim, or structure of other the second immunoglobulin, the third immunoglobulins and the fourth immunoglobulin encompassed by the claim, or the property and function of all other heterodimeric multispecific antibodies encompassed by the claim.
In addition, the claims identify the immunoglobulins by function, where the function is:
the third immunoglobulin binds to its respective epitope with a monovalent affinity or an effective affinity between about 100 nM or about 100 pM;
the third immunoglobulin binds to an epitope of cancer cell;
the second and fourth immunoglobulins bind to an epitope on a blood cell, a lymphocyte, a macrophage, a T cell, or a NKT cell;
the first immunoglobulin and the third immunoglobulin bind to cell surface epitopes simultaneously (see claim 24).
However, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the immunoglobulins. The specification does not show monovalent affinity or an effective affinity for the third immunoglobulins recited by claim 1; or other combination of the first immunoglobulin and the third immunoglobulin which can bind to cell surface epitopes simultaneously. Based on the Specification and prior art, one of ordinary skilled in the art would not be able to “visualize or recognize” a member of the genus encompassed by claim 1 with the functions recited above.
Although Applicants may argue that it is possible to screen for antibodies that bind and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... '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." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171 ). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed.
The instant specification fails to describe structural features common to the members of the genus, which features constitute a substantial portion of the genus because the instant specification discloses structurally unrelated heterodimeric multispecific antibodies that do not share the same sequence structure and binding function, and may or may not function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody or antigen-binding portion thereof do, rather than what they are.
Claim 7 recites VH sequences for VH-2 and VH-4; and/or VL sequences for VL-2 and VL-4. Thus, the claims encompassed second immunoglobulins and fourth immunoglobulins with partial CDRs. In addition, it still encompass a broad genus of the third immunoglobulins and a broad genus of combinations of different immunoglobulins which may or may not have the required properties and functions.
Claims 14 and 21 recite complete VH and VL sequences for the second and fourth immunoglobulins. claim 22 recites antigens for the second and fourth immunoglobulins. However, as set forth above, they still encompass a broad genus of the third immunoglobulins and a broad genus (unlimited) of combinations of different immunoglobulins which may or may not have the required properties and functions. In addition, the structure of antigen does not tell the structure of immunoglobulins which bind to the antigen. Thus, one of ordinary skill in the art would not be able to readily recognize/visualize the structure of the second immunoglobulins or immunoglobulins with required properties.
Claims 15 recites antigens for the third immunoglobulin. As set forth above, claim 15 still encompasses a broad genus of the second and the fourth immunoglobulins and a broad genus (unlimited) of combinations of different immunoglobulins which may or may not have the required properties and functions. In addition, the structure of antigen does not tell the structure of immunoglobulins which bind to the antigen.
Taken together, the instant specification has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between functions and the structure of the heterodimeric multispecific antibody by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of heterodimeric multispecific antibodies broadly encompassed by the claimed invention. Thus, claims 1, 7, 14, 15, 18, 21, 24, 28, 32-34, 38 and 40 are properly rejected.
Response to Arguments
For the 112(a) Written Description rejection, Applicant argues:
As an initial matter, Applicant respectfully disagrees with the Office's assertion that the claims encompass "unlimited heterodimeric multi specific antibodies," and the Office's reliance on Vas-Gath, Centocor, and other similar case law is misplaced. Those cases dealt with antibodies defined solely by functionality (i.e. binding epitope). In contrast, present claim 1 structurally defines multiple components of the claimed constructs and functionally limits the same including by reciting (i) the SEQ ID NOs corresponding to the first immunoglobulin that binds to GD2 (i.e. an anti-GD2 hu3F8 VH and VL sequences) and has a binding affinity of "about 100 nM to about 100 pM,"1; (ii) the binding target of the third immunoglobulin (i.e. a
tumor antigen), wherein the VH and VL sequences of the third immunoglobulin have a binding affinity thereof of "about 100 nM to about 100 pM," specific structural examples of which are identified by the SEQ ID NO combinations recited in amended claim 15; (iii) the orientation of
the first, second, third, and fourth immunoglobulins; (iv) the second and fourth immunoglobulins
having identical VH and VL sequences that bind to epitopes of a limited subset of immune cells;
and (v) the reduced GD2-mediated binding affinity of the claimed HeteroDimeric Tetra Valency
and Specificity (HDTVS) construct to GD-2 expressing healthy cells as compared to anti-GD2
bivalent immunoglobulin constructs having the same VH and VL sequences as the first
immunoglobulin (i.e. hu3F8 VH and VL sequences). Accordingly, the instant claims recite
numerous, detailed structural and functional limitations and are thus not analogous to the
claimed antibodies described in Vas-Gath or Centocor line of cases, and is compliant with the
MPEP 216311.A.3.(a).
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to applicant’s argument, the claims do not recite the detailed structural for the claimed heterodimeric multispecific antibodies. For example, the independent claim 1 only recites the format of the antibodies and the structure (VL-1 and VH-1 sequences) of the first immunoglobulin (VL-1 and VH-1), however, the structures of other three immunoglobulins are not defined.
It is acknowledged that the claims define the functions/properties of the second, the third and the fourth immunoglobulins. However, the instant specification has not provided a sufficient description about the correlation between the recited functions and the structure of the immunoglobulins. As set forth above, the examples disclosed in the specification do not teach the structure of other immunoglobulins which would have the same functions/properties as the ones disclosed in the examples.
Without knowing the structures (e.g. VL and VH) of the other three immunoglobulins, one of ordinary skill in the art would not be able to visualize/recognize the claimed heterodimeric multispecific antibodies.
Applicant argues the examples disclose that the specification described several heterodimeric multispecific antibodies which have claimed functions and properties. And Applicants further argues:
Furthermore, Applicant respectfully asserts that the Office has mischaracterized the contents of paragraph [0069]. These statement regarding the "unpredictable impact" of orientation, valency, and target affinity on HDTVS variant functionality relate to the fact that the claimed HDTVS constructs possessed enhanced therapeutic efficacy when compared to homodimeric antibodies, despite having dramatically lower binding affinity to target cells in in vitro assays. For example, while the 1 + 1 +2Lo anti-GD2 HDTVS constructs in Figures 13 and 15 had dramatically lower binding affinities to GD2-positive cells compared to homodimeric GD2 constructs, the 1 + 1 +2Lo anti-GD2 HDTVS construct in Figure 16 had nearly identical cytotoxic activity to a homodimeric GD2 construct.
Applicant’s arguments have been fully considered but they are not persuasive. It is acknowledged that the heterodimeric multispecific antibodies with written description support in the specification have: 1) the same anti-CD3 scFv1 and scFv2 corresponding to the second immunoglobulin and the fourth immunoglobulin of the claim 1; 2) Fig. 13 and Fig 15 shows results for only two specific constructs with specific sequences (GD2+HER2+CD3, GD2+L1CAM+CD3); and 3) the first immunoglobulin has a VL and VH sequence of SEQ ID NO: 1321 and SEQ ID NO: 1325, respectively. However, claim 1 encompasses unlimited number of the third immunoglobulins which can bind any cancer antigen/epitope, and encompasses unlimited number of the second immunoglobulins and the fourth immunoglobulins to a broad genus of antigens on all white blood cells, all lymphocytes, all macrophages, all T cells, and all NKT cells. The limited examples disclosed by the specification do not teach other the immunoglobulins encompassed by the instant claims. For example, claim 1 recites that the third immunoglobulin bind to its epitope with a monovalent affinity or an effective affinity between about 100 nM to about 100 pM. However, the specification has not established a correlation between the recited function and the structure of antibodies. One of ordinary skill in the art would not be able to visualize/recognize immunoglobulins with such functions.
In addition, contrary to Applicant’s argument, Examiner correctly pointed out that the biological activity of the tri- and tetra-specific variants of the HDTVS platform is dependent on the antigen/epitope combination, as well as the relative binding affinities to each target antigen, as evidenced by paragraph [0069] of the instant publication. Paragraph [0070] also states: “biophysical properties such as orientation (cis vs trans), valency (mono- vs bi-valent) and target affinity (KD ~nM or <pM) had an unpredictable impact on the functionality of the HDTVS variants”. Thus, the properties for each of immunoglobulins are critical for the function of the claimed antibodies. As set forth above, the specification has not established the correlation between the function and structure for the second immunoglobulin, the third immunoglobulin and the fourth globulin. Given that the claims encompass unlimited number (known and yet to be discovered) of the third immunoglobulins which can bind a cancer cell, and encompasses unlimited number (known and yet to be discovered) of the second immunoglobulins and the fourth immunoglobulins to a broad genus of antigens on all white blood cells, all lymphocytes, all macrophages, all T cells, and all NKT cells, the specification fails to convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the claimed invention.
Thus, the rejection is maintained for the reasons of record.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1, 7, 14, 15, 18, 21, 28, 32-34, 38 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Brinkmann (Brinkmann et al., MABS, 2017, vol. 9, NO. 2, 182-212, Publication Date: 2017-01-10, cited in IDS of 08/22/2022, of record), in view of Cheung2013 (Cheung et al., US 2013/0216528 A1, Publication Date: 2013-08-22, of record), Cheung2016 (Cheung et al., WO 2016/014942 A1, Publication Date: 2016-01-28, of record), Bramson (Bramson et al., US 2016/0368964 A1, Publication Date: 2016-12-22, of record), Jensen (Jensen, US 7,070,995 B2, Publication Date: 2006-07-04, of record), and Reckamp (Reckamp et al., Cancer Res (2008) 68 (9_Supplement): 4620, Publication Date: 2008-05-01, of record).
Brinkmann teaches various heterodimeric multispecific antibodies having the structure: scFv appended at the C-terminus of IgG light chain, as recited in instant claim 1 (see Figure 2, box 11; col. 2, page 195).
Brinkmann teaches that fusing scFv to the C-terminus of either the heavy or light chain keeps the IgG binding site unaffected (bottom para., col. 2 on page 195).
Brinkmann teaches that such fusion maintained high expression level, thermostability, and protease resistance. They also maintained Fc effector functions and half-life similar to parental IgG antibodies. Fusion of an scFv to the C-terminus of an IgG light chain also results in functional bispecific antibodies, many of which are stable and behave in the same manner as regular IgGs. Each of the termini of light and heavy chain of an IgG can be utilized. One can further imagine that multivalent molecules, including tri- or multispecific antibodies, can be produced by fusing scFv molecules of the same of different specificity to the N- or C-terminus of the light or heavy chain of an antibody (page 195, col. 2, para. 2).
Brinkmann teaches that typical linkers used for IgG-scFv fusion proteins are composed of 2 or 3 repeats of G4S (lines 1-2, col. 1 on page196).
Binkmann teaches that different heavy chains and light chains can be generated by genetic means. This allows use of heavy and light chains of defined composition, e.g. certain human isotypes, and implementation of mutated sequences, to either force correct assembly between the two heavy chains and cognate heavy and light chains (page 189, col. 1, para. 1).
Brinkmann teaches that using Fab arm exchanging method (e.g. CrossMab) can generate antibodies with various combinations of heavy chain-light chain pairs, including asymmetric IgGs with heavy and light chains from two different antibodies. The concept was further evolved to generate tetravalent, tetraspecific four-in-1 antibodies by applying a knobs-into-holes Fc region and the CrossMab technology to two-in-1 Fab arms (Fig. 2, box 7; page 193, col. 2, para. 2). It’s obvious to one ordinary skill in the art, the format comprises two immunoglobulins bind to their respective epitope with a monovalent affinity (e.g. Fig. 2-box 7-CrossMab (IgG-klh)).
Brinkmann teaches genetic engineering to force heterodimerization of heavy chains (Table 1 and Fig. 4), including “knobs-into-holes” model: a CH3 interface favoring heterodimeric assembly by replacing small side chains on one CH3 interface with larger ones to generate a knob, and replacing large side chains on the other CH3 domain with smaller ones to generate a hole (distinct heterodimerization domains) (page 189, col. 2, para. 3). The knobs-into-holes was widely adopted, and now forms a versatile basis of producing bispecific IgG molecules (page 190, col. 1, para. 2).
Brinkmann teaches that approaches have been developed to allow the correct pairing of cognate heavy and light chains (summarized in Table 2) in combination with Fc-modified heavy chains (summarized in Table 1).
Brinkmann teaches that there is no “one best format”, and format variability is essential to serve diverse antibody applications (page 202, col. 1, paras 3-4).
Brinkmann teaches tandem scFv (taFV) that binds GD2 and CD3. See p. 199-left column-1st full paragraph.
Brinkmann teaches as set forth above. Brinkmann does not teaches the specific linker sequence (GGGGS)6, the specific combination of antigens e.g. GD2, CD3, and L1CAM (the elected species), or specific CDRs recited.
Cheung2013 teaches that GD2 is a disialoganglioside abundant on tumors of neuroectodermal origin, including neuroblastoma and melanoma with highly restricted expression in normal tissues. And GD2 antibody shows therapeutic activity to neuroblastoma (NB) and melanoma ([0004]).
Cheung2013 teaches a humanized anti-GD2 antibody hu3F8-H1L1-IgG1 comprises heavy chain variable domain of SEQ ID NO: 4 and light chain variable domain of SEQ ID NO: 5 ([0014], claim 1), which are identical to SEQ ID NO: 1325 and 1321 of the instant application, respectively (the elected species).
Seq ID NO: 1325 vs. SEQ ID NO: 4 of Cheung:
US-13-702-319-4
Query Match 100.0%; Score 638; Length 448;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYN 60
Qy 61 SAFMSRLTISKDNSKNTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SAFMSRLTISKDNSKNTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSS 119
Seq ID NO: 1321 vs. SEQ ID NO: 5 of Cheung:
US-13-702-319-5
Query Match 100.0%; Score 534; Length 211;
Best Local Similarity 100.0%;
Matches 104; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPA 60
Qy 61 RFSGSGYGTEFTFTISSVQSEDFAVYFCQQDYSSFGQGTKLEIK 104
||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGYGTEFTFTISSVQSEDFAVYFCQQDYSSFGQGTKLEIK 104
Given that the anti-GD2 antibody hu3F8-H1L1-IgG1 of Cheung 2013 comprises the same VH and VL domain as claimed antibody, the anti-GD2 antibody hu3F8-H1L1-IgG1 would have the same affinity to GD2, the first epitope, as the claimed antibody.
Cheung2013 teaches multispecific antibodies and bispecific antibodies, comprising GD2 binding arm ([0065], [0066]).
Cheung2013 teaches for bispecific fusion protein, scFv can be connected to the constant region of the light chain of another humanized antibody ([0068]).
Cheung2013 teaches that the anti-GD2 antibodies can be used to treat various malignant diseases, such as multiple myeloma, leukemia, lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, renal cell carcinoma, pancreatic carcinoma, prostatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, sarcomas, malignant melanoma ([0213]).
Cheung2013 teaches that hu3F8-H1L1-IgG1 shows cytotoxicity to neuroblastoma LAN-1 cells (Table 4, Example 5); and therapeutic activity in Xenografts model ([0292] and Example 8).
Cheung2013 teaches CD4+ T cells can become activated when their surface CD3 is cross linked by antibodies ([0335]). Arming of polyclonally activated T cells with anti-CD3 x anti-TAA combines the targeting specificity of MoAB (e.g. hu3F8 where TAA is GD2) can be used to arm ex vivo expanded activated T cells before infusion into a patient ([0336]).
Cheung2013 teaches that bifunctional antibodies targeting CD3 and a tumor antigen have demonstrated capacity to link cytotoxic T-cells to tumor cells ([0338]).
Cheung2013 teaches a bispecific anti-GD2 and anti-CD3 antibody, with a first antigen binding site derived from humanized 3F8 antibody (claims 22 and 25).
Cheung2013 teaches multivalent, multispecific antibody or fragment thereof comprising the anti-GD2 antibody (e.g. 3F8). The 3F8 antibody is humanized ([0027]).
Cheung2013 teaches that hu3F8-H1L1-IgG1 has binding affinity of 11±3 nM (Table 2).
Cheung2016 teaches that an scFv comprises a fusion protein of the variable regions of the VH and VL of an immunoglobulin. The VH is fused to the VL via a peptide linker ([0066]). In certain embodiments, the scFv peptide linker is a linker of SEQ ID NO: 41, which is (G4S)6 ([0067] and [00112] Table 1).
Cheung2016 teaches fusing an scFv fragment binding to CD3 fused to C-terminus of light chain of HER2 antibody (trastuzumab), see Fig. 1A and claims 1 and 34.
Bramson teaches scFV to CD3 ([0080]) and an antibody binds to CD3 of SEQ ID NO: 14 ([0081], also called as UCHT1) which comprises VH and VL of SEQ ID NO: 701 and 697.
Seq ID NO: 697 vs. SEQ ID NO: 14 of Bramson:
RESULT 17
US-15-117-173-14
Query Match 100.0%; Score 560; Length 250;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPS 61
Qy 61 KFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 62 KFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIK 108
Seq ID NO: 701 vs. SEQ ID NO: 14 of Bramson:
RESULT 9
US-15-117-173-14
Query Match 100.0%; Score 655; Length 250;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 129 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTY 188
Qy 61 NQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 189 NQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTV 248
Qy 121 FS 122
||
Db 249 FS 250
Given that the anti- CD3 antibody UCHT1 of Bramson comprises the same VH and VL domain as claimed antibody, the UCHT1 would have the same affinity to CD3, a third epitope, as the claimed antibody
Bramson teaches that single chain UCHT1 binds to CD3 ([0146], [0150], Fig. 3).
Bramson teaches that single chain UCHT1 is a CD3 binding scFv moiety ([0152] and Fig. 1).
Bramson teaches variants of UCHT1 (claim 32).
Both Cheung and Bramson teaches that CD3 scFv can be used in making multispecific binding molecules.
Jensen teaches VH and VL chains of a single chain monoclonal antibody to CE7 linked with Fc regions and CE7-specific redirected immune cells comprising a receptor for CE7, which can be used to treat CE7+ neuroblastoma (see Abstract). As evidenced by Reckamp, CE7 is an epitope of L1CAM (see Title and Abstract).
Jensen teaches CE7R chimeric receptor comprises SEQ ID NO: 2 (see Fig. 2A, the bridging paragraph of cols. 12-13, claim 1). As shown below, SEQ ID NO: 2 of Jensen comprises SEQ ID NO: 1881 and 1885 of the instant application (the elected species):
US-10-120-198B-2
Query Match 100.0%; Score 559; Length 631;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPRLLISGATNLVTGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 158 DIQMTQSSSSFSVSLGDRVTITCKANEDINNRLAWYQQTPGNSPRLLISGATNLVTGVPS 217
Qy 61 RFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 218 RFSGSGSGKDYTLTITSLQAEDFATYYCQQYWSTPFTFGSGTELEIK 264
US-10-120-198B-2
Query Match 100.0%; Score 651; Length 631;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 23 QVQLQQPGAELVKPGASVKLSCKASGYTFTGYWMHWVKQRPGHGLEWIGEINPSNGRTNY 82
Qy 61 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 83 NERFKSKATLTVDKSSTTAFMQLSGLTSEDSAVYFCARDYYGTSYNFDYWGQGTTLTVSS 142
Given that the anti-CE7 antibody of Jensen comprises the same VH and VL domain as claimed antibody, the antibody of Jensen would have the same affinity to CE7, a third epitope, as the claimed antibody
Jensen teaches that both GD2 targeted therapy and CE7 targeted therapy can be used to treat neuroblastoma (col. 2, lines 21-37, 66-67; and col. 4, lines 13-35; and col. 11, lines 50-67).
Jensen teaches the CE7 targeting therapy (with the CE7 binding domain comprising SEQ ID NO: 2) is effective in treating neuroblastoma (see Figs 1 and 2, Example 9).
Reckamp teaches that L1CAM has been shown to be overexpressed in multiple tumors such as SCLC and NSCLC, and associated with invasive/metastatic tumor biology (see Abstract).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make trispecific or multispecific antibodies using the formats, e.g. i) a format in Fig. 2 box 7-CrossMab, wherein the antibody comprises different heavy-light chain pairs and each heavy chain comprises heterodimerization domains is incapable of forming a stable homodimer with a stable homodimer and can form a heterodimer, and further append a same scFv at each C-terminus of light chains of the bispecific antibody to form a trispecific antibody (claim 1 format), as taught by Brinkman (including tri- or multispecific antibodies, can be produced by fusing scFv molecules of the same of different specificity to the N- or C-terminus of the light or heavy chain of an antibody (page 193, col. 2, para. 2; and Fig. 2), and to use the linker (G4S)6 taught by Cheung2016 to make scFv, and to use the antibody combination targeting CD3, GD2, and L1CAM, and use the sequence as elected as taught by Cheung2013, Bramson and Jensen, because Cheung2016 teaches making bispecific antibody comprising a scFv comprising the linker (G4S)6, Cheung2013 teaches the GD2 antibody with elected sequence has therapeutic activity to neuroblastoma, and can be combined with CD3 to make bispecific antibody to treat various diseases including cancers; Bramson teaches that single chain UCHT1 (comprising the elected sequences) binds to CD3 which shows good binding activity to CD3, Reckamp further teach that L1CAM is overexpressed in multiple tumors such as SCLC and NSCLC, and associated with invasive/metastatic tumor biology (see Abstract), and Jensen teaches the anti-L1CAM antigen-binding fragment comprising the elected sequences which have been used in treating neuroblastoma patients. Because Brinkmann teaches that different formats can be used with different antibodies, different antigens and for different purposes, and prior arts has established that the properties of a multispecific antibodies are generally unpredictable, one of ordinary skill in the art would have been motivated to develop various formats with various antibody combinations. Given that the method of making multispecific antibodies are well known in the art, one of ordinary skilled in the art would have had a reasonable expectation of success to make multispecific antibodies in different formats as claimed (such as anti-GD2 x CD3 x L1CAM antibody) and that the trispecific antibody targeting GD2 and CD3 and L1CAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients. The motivation would have been to develop a better antibody for neuroblastoma treatment.
Regarding the claimed “the first immunoglobulin and the third immunoglobulin binds to its respective epitope with a monovalent affinity or an effective affinity between about 100 nM or about 100 pM”, as set forth above, Cheung2013 teaches the same VH and VL (SEQ ID NOs: 13121+1325) as the first immunoglobulin, and Jensen teaches the same VH and VL (SEQ ID NOs: 1881+18850), thus, heterodimeric multispecific antibody taught by the combined references would have the same first and third immunoglobulins. Same first and third immunoglobulins would have the same affinity to their respective epitopes as recited by claim 1.
Regarding to the limitation of “wherein the heterodimeric multispecific antibody shows reduced GD2-mediated binding to GD2-expressing healthy cells compared to an anti-GD2 bivalent immunoglobulin comprising a VL amino acid sequence and a VH amino acid sequence of SEQ ID NO: 1321 and SEQ ID NO: 1325”, because the heterodimeric multispecific antibody taught by the references is monovalent for GD2-mediated binding, one of ordinary skill in the art would have had a reasonable expectation that the antibody with bivalent GD2-binding and the same binding domain would have higher GD-2 binding than the monovalent antibody.
Regarding claim 18, Cheung2013 teaches a humanized anti-GD2 antibody hu3F8-H1L1-IgG1 comprises heavy chain variable domain of SEQ ID NO: 4 and light chain variable domain of SEQ ID NO: 5 ([0014], claim 1), which are identical to SEQ ID NO: 1325 and 1321 of the instant application, respectively (the elected species). Thus, the antibody taught by the combined references would be considered as a humanized antibody.
Regarding claim 28, Brinkmann teaches the “knobs-into-holes” model: a CH3 interface favoring heterodimeric assembly by replacing small side chains on one CH3 interface with larger ones to generate a knob, and replacing large side chains on the other CH3 domain with smaller ones to generate a hole (distinct heterodimerization domains) (page 189, col. 2, para. 3). The knobs-into-holes was widely adopted, and now forms a versatile basis of producing bispecific IgG molecules (page 190, col. 1, para. 2). Brinkmann also teaches other IgG1 or IgG2 heterodimerization domains in CH3 domain (see Table 1).
Regarding claim 32, Cheung 2013 a polynucleotide encoding an antibody and the method of generating the polynucleotide ([0101] and [0102]).
Regarding claim 33, Cheung 2013 a vector comprises the polynucleotide encoding an antibody ([0108]- [0113]).
Regarding claim 34, Cheung teaches a pharmaceutical composition comprising an antibody (e.g. chimeric or humanized anti-GD2 antibody) and pharmaceutically acceptable carrier ([0043]).
Regarding claim 38, Cheung2013 teach a kit comprising at least one chimeric or humanized anti-GD2 antibody or fragment ([0045]), and packaging material such as instructions for use ([0206]).
Response to Arguments
For the 103 rejection, Applicant argues:
Brinkmann fails to teach or suggest heterodimeric multispecific antibodies having the IgG-scFv-LC configuration, wherein the first immunoglobulin comprises the anti-GD2 hu3F8 VH and VL sequences and wherein the first immunoglobulin and the third immunoglobulin bind to their respective epitopes with a monovalent affinity or an effective affinity between about 100 nM to about 100 pM Nor does Brinkmann provide any guidance as to what multispecific antibody configuration would reduce GD2-mediated binding to with GD2- expressing healthy cells compared to any bivalent anti-GD2 immunoglobulin, let alone an antiGD2 immunoglobulin comprising a VL amino acid sequence and a VH amino acid sequence of SEQ ID NO: 1321 and SEQ ID NO: 1325 (hu3F8). Moreover, Brinkmann fails to provide the
skilled artisan with a reason to expect that adjusting the monovalent affinity or effective affinity
of the antigen binding domains of the IgG within the IgG-[L ]-scFv antibody configuration would
confer any advantages, let alone reduce GD2-mediated binding with GD2-expressing healthy
cells. Indeed, the Office itself states that "prior arts has established that the properties of a
multispecific antibodies are generally unpredictable," Office Action, page 28 ( emphasis added), further bolstering Applicant's assertion that the skilled artisan would lack the motivation to generate the specific claimed anti-GD2 1 + 1 +2Lo HDTV s constructs in view of Brinkmann, absent some specific teaching or suggestion to generate a heterodimeric, multispecific antibodies having the 1+1+2Lo design. Accordingly, Brinkmann fails to provide the skilled artisan with a motivation to modify the heterodimeric multispecific antibody formats disclosed therein in the manner claimed.
Cheung2013, Bramson and Jensen, which are solely relied upon as teaching specific VH and VL amino acid sequences of the anti-GD2 antibody hu3F8-HlLl-lgGl, the CD3 scFv, and
the monoclonal antibody to CE7, respectively, Cheung2016, which merely teaches the use of a
(GGGGS)6 linker to fuse anti-CD3 scFv fragments to the C-terminus of a light chain of the
HER2 antibody trastuzumab, and Reckamp, which merely discloses that LlCAM is overexpressed in multiple tumors such as SCLC and NSCLC, fail to remedy the aforementioned deficiencies of Brinkmann.
The Office asserts that the skilled artisan would have a reasonable expectation that
"multispecific antibody would improve antibody specificity to some cancers which express
multiple cancer-associated antigens." Office Action, page 28. However, the novel and inventive design of the claimed anti-GD2 HDTVS constructs permits improved therapeutic index ( or safety) when the target antigens are NOT unique to tumors, where each target antigen (but never both) is shared to some extent by normal cells. As discussed in paragraph [00310] of the published specification "[w]hile a standard BsAb or 2+2 design would harm normal tissues, this Lo1+1+2 design should spare normal tissues that express only one of the two targeted antigens, while maintaining the full potency against a tumor cell that expresses both antigens."
Applicant’s arguments have been fully considered but they are not persuasive. It is noted that claim 1 is drawn a heterodimeric multispecific antibody of 1+1+2Lo format. As set forth above, Brinkermann teaches methods of making trispecific or multispecific antibodies of format 1+1+2; Cheung2013, Bramson and Jensen teach antibodies (immunoglobulins) with the claimed VH and VL sequences thus the antibodies would have affinities in the claimed range because the antibodies have the same structures. In addition, Brinkmann teaches that different formats can be used with different antibodies, different antigens and for different purposes, and prior arts has established that the properties of a multispecific antibodies are generally unpredictable, one of ordinary skill in the art would have been motivated to develop various formats with various antibody combinations for various conditions (e.g. cancers with different antigen expression levels). Given that the method of making multispecific antibodies are well known in the art, one of ordinary skilled in the art would have had a reasonable expectation of success to make multispecific antibodies in different formats as claimed (such as anti-GD2 x CD3 x L1CAM antibody) and that the tri-specific antibody targeting GD2 and CD3 and L1CAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients. The motivation would have been to develop a better antibody for neuroblastoma treatment.
Although GD2 expressed in some normal tissues, Cheung2013 teaches anti-GD2 antibody comprising the same VH and VL; teaches making multispecific antibody comprising GD2 binding arm; teaches anti-GD2 antibody for treating cancers; teaches that the specific anti-GD2 antibody shows cytotoxicity to neuroblastoma LAN-cells and therapeutic activity in xenografts model. Thus, one of ordinary skill in the art would use and keep improve the treatment based on anti-GD2 antibody. One of ordinary skill in the art would have reasonable expectation that multispecific antibody would improve antibody specificity to some cancers which express multiple cancer-associated antigens. Since the combined references teach the same multispecific antibodies as instantly claimed, e.g. anti-GD2 x CD3 x L1CAM antibody, the antibodies would have the same properties as claimed, including lowered GD-2 mediated binding to GD-2 expressing health cells compared to bivalent GD-2 antibody comprising the same GD-2 binding domain.
In the field of biological technology, no invention has absolute certainty of success before experimental tests (empirical evidence) and unpredictability would not prevent skilled ones in the art to develop new antibodies for cancer treatment, as evidenced by recited references. Thus, only a reasonable expectation of success (not absolute) would have motivated an artisan to make the heterodimeric multispecific antibody. Given the teachings from references, an ordinary skilled in the art would have would have had a reasonable expectation of success in producing the claimed antibody (e.g. GD2+L1CAM+CD3).
Applicant further argues:
The Office's assertion regarding Figures 13 and 15 that "the binding affinity for these
two 1 + 1 +2 low affinity HDTVS is about the average of two homodimeric antibodies," is incorrect. Office Action, page 33. Figures 13 and 15 of the instant application actually show a
greater than additive reduction in 1+1+2Lo construct binding affinity compared to bivalent
anti-GD2 immunoglobulins comprising a VL amino acid sequence and a VH amino acid
sequence of SEQ ID NO: 1321 and SEQ ID NO: 1325 (hu3F8).
Surprisingly, despite the decreased binding affinity of the 1 + 1+2Lo anti-GD2 HDTVS
constructs compared to homodimeric controls, Figure 16 shows an anti-GD2 1+1+2Lo HDTVS
construct with nearly identical therapeutical cytotoxicity efficacy to a homodimeric (bivalent) anti-GD2 (hu3F8) antibody.
The skilled artisan could not have reasonably expected that the presently claimed 1 + 1 +2Lo anti-GD2 HDTVS constructs could both display (a) decreased binding in in vitro assays as compared to homodimeric antibody controls and (b) retain equal or improved anti-tumor activity.
Applicant’s argues that the results for 1+1+2 low affinity anti-GD2 HDTVs are superior and unexpected. Applicant’s arguments have been fully considered but they are not persuasive. As recognized by paragraphs [0069] the biological activity of the tri- and tetra-specific variants of the HDTVS platform is dependent on the antigen/epitope combination, as well as the relative binding affinities to each target antigen. The evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d).
In this case, the claims are very broad, encompass a broad genus of third immunoglobulins and/or a broad genus of second and fourth immunoglobulins to many antigens. Only a couple of specific epitope combinations and specific immunoglobulin combinations have been tested in the instant application. Thus the evidence provided by Figs. 13, 15 or 16 is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Accordingly, Applicant’s arguments are not found persuasive for the reasons set forth above and the rejection is maintained for the reasons of record.
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.
Patent No. US 9,315,585
Claims 1, 7, 14, 15, 18, 21, 28, 32-34, 38 and 40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-35 of U.S. Patent No. US 9,315,585 B2 (hereinafter Pat. 585, corresponding application: 13/702,319 which is corresponding to Cheung2013 cited below), in view of Brinkmann (Brinkmann et al., MABS, 2017, vol. 9, NO. 2, 182-212, Publication Date: 2017-01-10, cited in IDS of 08/22/2022, of record), Cheung2016 (Cheung et al., WO 2016/014942 A1, Publication Date: 2016-01-28, of record), Cheung2013 (Cheung et al., US 2013/0216528 A1, Publication Date: 2013-08-22, of record), Bramson (Bramson et al., US 2016/0368964 A1, Publication Date: 2016-12-22, of record), Jensen (Jensen, US 7,070,995 B2, Publication Date: 2006-07-04, of record), and Reckamp (Reckamp et al., Cancer Res (2008) 68 (9_Supplement): 4620, Publication Date: 2008-05-01, of record).
The claims of Pat. 585 teach:
1. A humanized or chimeric antibody or fragment thereof capable of binding to GD2, wherein the antibody or fragment thereof comprises any of the following:…
(iii) a variable heavy chain domain of SEQ ID NO:4 and a variable light chain domain of SEQ ID NO:5; …. As set forth in 103 rejection, heavy chain variable domain of SEQ ID NO: 4 and light chain variable domain of SEQ ID NO: 5 are identical to SEQ ID NO: 1325 and 1321 of the instant application, respectively (the elected species).
3. A pharmaceutical composition comprising the humanized or chimeric antibody or fragment thereof of claim 1, and further comprising a pharmaceutically acceptable carrier or diluent.
5. A bispecific antibody having first and second antigen binding sites, one of which comprises antigen binding sequences of a light chain and a heavy chain of a humanized 3F8 antibody.
6. The bispecific antibody of claim 5 wherein the second antigen binding site is selected from the group consisting of scFv, scFab, Fab, and Fv.
8. The bispecific antibody of claim 5 wherein the second antigen binding site is specific for CD3.
30. The humanized or chimeric antibody or fragment thereof of claim 1, wherein the humanized or chimeric antibody comprises a variant Fc region.
Thus, the claims of Pat. 585 teach anti-GD2 antibody with the elected VH and VL sequences, and bispecific antibody targeting GD2 and CD3. However, the claims of Pat. 585 do not teach, the specific format as claimed (e.g. heterodimization domains in heavy chain or specific linkers), the trispecific combination of antigens e.g. GD2, CD3, and L1CAM (the elected species), or specific CDRs recited for CD3 and L1CAM.
Brinkmann, Cheung2016, Cheung2013, Bramson, Jensen, and Reckamp teach as set forth above.
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to make a bispecifc antibody such as anti-GD2 and anti-CD3 bispecific antibody, as taught by the claims of Pat. 585, and to further develop trispecific or multispecific antibodies using the formats, e.g i) a format in Fig. 2 box 7-CrossMab, wherein the antibody comprises different heavy-light chain pairs and each heavy chain comprises heterodimerization domains is incapable of forming a stable homodimer with a stable homodimer and can form a heterodimer, and further append a same scFv at each C-terminus of light chains of the bispecific antibody to form a trispecific antibody (claim 1 format), as taught by Brinkman (including tri- or multispecific antibodies, can be produced by fusing scFv molecules of the same of different specificity to the N- or C-terminus of the light or heavy chain of an antibody (page 193, col. 2, para. 2; and Fig. 2), and to use the linker (G4S)6 taught by Cheung2016 to make scFv, and to use the antibody combination targeting CD3, GD2, and L1CAM, and use the sequence as elected as taught by Cheung2013, Bramson and Jensen, because Cheung2016 teaches making bispecific antibody comprising a scFv comprising the linker (G4S)6, Cheung2013 teaches the GD2 antibody with elected sequence has therapeutic activity to neuroblastoma, and can be combined with CD3 to make bispecific antibody to treat various diseases including cancers; Bramson teaches that single chain UCHT1 (comprising the elected sequences) binds to CD3 which shows good binding activity to CD3, Reckamp further teach that L1CAM is overexpressed in multiple tumors such as SCLC and NSCLC, and associated with invasive/metastatic tumor biology (see Abstract), and Jensen teaches the anti-L1CAM antigen-binding fragment comprising the elected sequences which have been used in treating neuroblastoma patients. Because Brinkmann teaches that different formats can be used with different antibodies, different antigens and for different purposes, and prior arts has established that the properties of a multispecific antibodies are generally unpredictable, one of ordinary skill in the art would have been motivated to develop various formats with various antibody combinations. Given that the method of making multispecific antibodies are well known in the art, one of ordinary skilled in the art would have had a reasonable expectation of success to make multispecific antibodies in different formats as claimed (such as anti-GD2 x CD3 x L1CAM antibody) and that the trispecific antibody targeting GD2 and CD3 and L1CAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients. The motivation would have been to develop a better antibody for neuroblastoma treatment.
Response to Arguments
For the Double Patenting rejection, Applicant argues:
The claims of the instant application are patentably distinct from the claims of the '585 patent because the claimed heterodimeric tri-specific antibodies show reduced GD2-mediated binding to GD2-expressing healthy cells compared to an anti-GD2 bivalent immunoglobulin comprising a VL amino acid sequence and a VH amino acid sequence of SEQ ID NO: 1321 and SEQ ID NO: 1325 (hu3F8). Likewise, the combined teachings of Brinkmann, Cheung2013, Cheung2016, Bramson, Jensen, and Reckamp do not provide any guidance as to what multispecific antibody configuration would have reduced GD2-mediated binding to GD2-expressing healthy cells compared to any anti-GD2 immunoglobulin, let alone the anti-GD2 immunoglobulins (i.e., hu3F8) claimed in the '585 patent. Nor do the cited references provide the skilled artisan with a reason to expect that adjusting the monovalent affinity or effective affinity of the antigen binding domains of the IgG within the bi specific anti-GD2 antibodies claimed in the '585 patent would confer any of the unexpected functional properties discussed above.
Applicant’s arguments have been fully considered but they are not persuasive. As set forth above, Pat. 585 teach anti-GD2 antibody with the elected VH and VL sequences, and bispecific antibody targeting GD2 and CD3. Brinkmann, Cheung2016, Cheung2013, Bramson, Jensen, and Reckamp further teaches the multispecific antibody format and antibody sequences recited by the instant claims. Based on the teachings from references, one of ordinary skill in the art would have expected that tri-specific antibody targeting GD2 and CD3 and L1CAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients. One of ordinary skill in the art would have been motivated to develop various formats with various antibody combinations.
Regarding unexpected functional properties, as recognized by paragraphs [0069] of the instant specification and common knowledge in the field, the biological activity of the tri- and tetra-specific variants of the HDTVS platform is dependent on the antigen/epitope combination, as well as the relative binding affinities to each target antigen. The evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d).
In this case, the claims are very broad, encompass a broad genus of third immunoglobulins and/or a broad genus of second and fourth immunoglobulins to many antigens. Only a couple of specific epitope combinations and specific immunoglobulin combinations have been tested in the instant application. Thus the evidence provided by Figs. 13, 15 or 16 is not commensurate in scope with the claimed invention and does not demonstrate the non-obviousness of the claimed invention. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Applicant further argues:
In response to prior arguments, the Office asserts that "one of ordinary skill in the art would have expected that trispecific antibody targeting GD2 and CD3 and LlCAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients." Office Action, page 39. Yet, this proposition is directly contradicted by the Office's own assertion that "prior arts has established that the properties of a multispecific antibodies are generally unpredictable." Office Action, page 28 (emphasis added). Further, the Office's presumption that "the binding affinity for these two 1 + 1 +2 low affinity HDTVS is about the average of two homodimeric antibodies," is directly undermined by the data of the instant application.
Applicant’s arguments have been fully considered but they are not persuasive. Contrary to applicant’s argument, "one of ordinary skill in the art would have expected that trispecific antibody targeting GD2 and CD3 and LlCAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients" is not contradicted by the "prior arts has established that the properties of a multispecific antibodies are generally unpredictable.". Unpredictability would not prevent a skilled in the art to develop new antibodies for cancer treatment and only a reasonable expectation of success is needed for a skilled person to do so. As set forth above, Cheung2013 teaches the GD2 antibody with elected sequence has therapeutic activity to neuroblastoma, and can be combined with CD3 to make bispecific antibody to treat various diseases including cancers; Bramson teaches that single chain UCHT1 (comprising the elected sequences) binds to CD3 which shows good binding activity to CD3, Reckamp further teach that L1CAM is overexpressed in multiple tumors such as SCLC and NSCLC, and associated with invasive/metastatic tumor biology (see Abstract), and Jensen teaches the anti-L1CAM antigen-binding fragment comprising the elected sequences which have been used in treating neuroblastoma patients. Because Brinkmann teaches that different formats can be used with different antibodies, different antigens and for different purposes, and prior arts has established that the properties of a multispecific antibodies are generally unpredictable, one of ordinary skill in the art would have been motivated to develop various formats with various antibody combinations. Thus, one of ordinary skill in the art would have a reasonable expectation that tri-specific antibody targeting GD2 and CD3 and L1CAM would have enhanced specificity to neuroblastoma cells and improved therapeutic activity to neuroblastoma patients, because the tri-specific antibody target two antigens on neuroblastoma cells simultaneously.
Thus, the rejection is maintained for the reasons of record.
Conclusion
No claims are allowed.
All other objection and rejections set forth in the previous Office Action of May 14, 2025 are hereby withdrawn in view of the claim amendments and Applicant’s arguments.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/ Examiner, Art Unit 1642
/PETER J REDDIG/ Primary Examiner, Art Unit 1646