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 .
Claims 1-19 and 23-33 are pending.
Applicant’s election without traverse of Group IV that read on (A) SEQ ID NOs: 95, 96, and 98 as the species of HCDR1, HCDR2, and HCDR3, respectively, that binds to EGFR, (B) SEQ ID NO: 106, 107 and 133 as the HCDR1, HCDR2, and HCDR3, respectively, that binds to cMET, (C) SEQ ID NOs: 108, 109, and 110 as the species of LCDR1, LCDR2, and LCDR3, respectively, that binds to cMET, (D) the EGFR arm comprises a single domain heavy chain domain of SEQ ID NO: 10, (E) the cMET arm comprises a heavy chain of SEQ ID NO: 24 and a light chain of SEQ ID NO: 26, (F) SEQ ID NO: 126, 127 and 128 as the HCDR1, HCDR2, and HCDR3, respectively, that binds to VEGF and SEQ ID NO: 129, 132 and 131 as the species of LCDR1, LCDR2, and LCDR3, respectively, that binds to VEGF, (G) SEQ ID NO: 74 as the species of anti-VEGF scFv, in the reply filed on September 24, 2026 is acknowledged.
Claims 1-8, 19 and 26-33 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 10-18 and 23-25, drawn to a multispecific antibody that read on (A) SEQ ID NOs: 95, 96, and 98 as the species of HCDR1, HCDR2, and HCDR3, respectively, that binds to EGFR, (B) SEQ ID NO: 106, 107 and 133 as the HCDR1, HCDR2, and HCDR3, respectively, that binds to cMET, (C) SEQ ID NOs: 108, 109, and 110 as the species of LCDR1, LCDR2, and LCDR3, respectively, that binds to cMET, (D) the EGFR arm comprises a single domain heavy chain domain of SEQ ID NO: 10, (E) the cMET arm comprises a heavy chain of SEQ ID NO: 24 and a light chain of SEQ ID NO: 26, (F) SEQ ID NO: 126, 127 and 128 as the HCDR1, HCDR2, and HCDR3, respectively, that binds to VEGF and SEQ ID NO: 129, 132 and 131 as the species of LCDR1, LCDR2, and LCDR3, respectively, that binds to VEGF, (G) SEQ ID NO: 74 as the species of anti-VEGF scFv, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/256,705, filed Oct 18, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 15, 2024 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
The listing of references in the specification at pages 95-100 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on April 15, 2024 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claims 10-15, 18, and 23 are objected to because of the following informality “-“ should have been “to”.
Claim 10 is objected to because of the following informalities:
“the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 1-4” should have been “the EGFR arm comprises a light chain variable comprises SEQ ID NO: 2 and a heavy chain variable comprises SEQ ID NO: 1 or a light chain variable comprises SEQ ID NO: 4 and a heavy chain variable comprises SEQ ID NO: 3”.
“a single domain heavy chain sequences selected from” should have been “a single domain antibody selected from the group consisting of”.
“tandem single domain heavy chain sequences selected from” should have been “a tandem single domain antibody selected from the group consisting of”.
“cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23-40” should have been “cMET arm comprises a light chain sequence and a heavy chain sequence wherein the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37”.
“at least one single domain heavy chain domain selected from” at line 22 should have been “at least one single domain antibody selected from the group consisting of”.
Claim 11 is objected to because of the following informality: “at least one single domain heavy chain domain selected from” should have been “at least one single domain antibody selected from the group consisting of”.
Claim 12 is objected to because of the following informality: “tandem single domain heavy chains selected from” should have been “a tandem single domain antibody selected from the group consisting of”.
Claim 13 is objected to because of the following informality: “single domain heavy chain selected from SEQ ID NOs: 5-12; or tandem single domain heavy chain selected from SEQ ID NOs: 13-18” should have been “a single domain antibody selected from the group consisting of SEQ ID NO: 5 to 12; or a tandem single domain antibody selected from the group consisting of SEQ ID NO: 13 to 18”.
Claim 14 is objected to because of the following informality: “a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 23-40” should have been “a light chain sequence and a heavy chain sequence wherein the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37”.
Claim 16 is objected to because of the following informality: the word “heavy” is missing before “chain SEQ ID NO: 29 and light chain SEQ ID NO: 30;” at line 8.
Claim Rejections - 35 USC § 112
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.
Claims 10 and 25 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 applicant regards as the invention.
Regarding claim 10, the recitation of “the EGFR arm comprises a single domain heavy chain sequences selected from SEQ ID NOs: 5-12 or tandem single domain heavy chain sequences selected from SEQ ID NOs: 13-18” renders the claim indefinite because it is not clear a single domain heavy chain comprises how many sequences selected from SEQ ID NO: 5-12. Further, it is not clear how many tandem single domain heavy chain sequences are included in the EGFR arm encompassed by the claimed multispecific antibody. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Claim 25 recites the limitation "antigen-binding fragment" in claim 10. There is insufficient antecedent basis for this limitation in the claim.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 10-18 and 23-25 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 Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 10 encompasses a multispecific antibody comprising an EGFR arm that can bind EGFR and a cMet arm that can bind cMET, wherein: the EGFR arm comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 95, 96, and 97; SEQ ID NOs: 95, 96, and 98; SEQ ID NOs: 95, 96, and 105; SEQ ID NOs: 102, 100, and 101; and SEQ ID NOs: 102, 103, and 104; respectively, or
the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 1-4; a single domain heavy chain sequences selected from SEQ ID NOs: 5-12; or tandem single domain heavy chain sequences selected from SEQ ID NOs: 13-18; and
wherein: the cMET arm comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3,
wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 106, 107, and 133; SEQ ID NOs: 111, 112, and 113; SEQ ID NOs: 111, 114, and 113; SEQ ID NOs: 99, 118, and 119; SEQ ID NOs: 99, 120, and 119; SEQ ID NOs: 99, 121, and 119; SEQ ID NOs: 99, 122, and 119; respectively;
and wherein the LCDR1, LCDR2, and LCDR3 are selected from: SEQ ID NOs: 108, 109, and 110; SEQ ID NOs: 115, 116, and 117; and SEQ ID NOs: 123, 124, and 125; respectively, or
the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23-40 or at least one single domain heavy chain domain selected from SEQ IDNO: 41-44.
Claim 11 encompasses the multispecific antibody of claim 10, wherein the EGFR arm comprises at least one single domain heavy chain domain selected from SEQ ID NOs: 5-12.
Claim 12 encompasses the multispecific antibody of claim 10, wherein the EGFR arm comprises tandem single domain heavy chains selected from SEQ ID NOs: 13-18.
Claim 13 encompasses the multispecific antibody of claim 10, wherein the anti-EGFR arm comprises heavy chain SEQ ID NO: 1 and light chain SEQ ID NO: 2; heavy chain SEQ ID NO: 3 and light chain SEQ ID NO: 4; single domain heavy chain selected from SEQ ID NOs: 5-12; or tandem single domain heavy chain selected from SEQ ID NOs: 13-18.
Claim 14 encompasses the multispecific antibody of claim 10, wherein the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 23-40.
Claim 15 encompasses the multispecific antibody of claim 10, wherein the cMET arm comprises at least one single domain heavy chain domain selected from SEQ ID NOs: 41-44.
Claim 16 encompasses the multispecific antibody of claim 10, wherein the anti-cMET arm comprises heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 25; heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 26; heavy chain SEQ ID NO: 24 and light chain SEQ ID NO: 25; heavy chain SEQ ID NO: 24 and light chain SEQ ID NO: 26; heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 30; heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 31; heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 32; heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 30; heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 31; heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 32; chain SEQ ID NO: 29 and light chain SEQ ID NO: 30; heavy chain SEQ ID NO: 29 and light chain SEQ ID NO: 31; heavy chain SEQ ID NO: 29 and light chain SEQ ID NO: 32; heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 38; heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 39; heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 40; heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 38; heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 39; heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 40; heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 38; heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 39; heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 40; heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 38; heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 39; heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 40; heavy chain SEQ ID NO: 37 and light chain SEQ ID NO: 39; or heavy chain SEQ ID NO: 37 and light chain SEQ ID NO: 40.
Claim 17 encompasses the multispecific antibody of claim 10, further comprising an anti-VEGF antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 129, 130, and 131; and SEQ ID NOs: 129, 132, and 131; respectively; and wherein the LCDR1, LCDR2, and LCDR3 are SEQ ID NOs: 126, 127, and 128, respectively.
Claim 18 encompasses the multispecific antibody of claim 17, wherein the anti-VEGF antibody or antigen-binding fragment comprises an amino acid sequence having at least 85% identity to any one of SEQ ID NOs: 73-76.
Claim 23 encompasses the multispecific antibody of claim 10, wherein the multispecific antibody comprises amino acid sequences selected from SEQ ID NOs: 83-94.
Claim 24 encompasses the multispecific antibody of claim 23, wherein the multispecific antibody comprises amino acid sequences set forth in SEQ ID NO: 90, SEQ ID NO: 84, and SEQ ID NO: 85, respectively.
Claim 25 encompasses a pharmaceutical composition comprising the antibody or antigen- binding fragment of claim 10.
The specification discloses a multispecific antibody comprising a EGFR arm that binds to EGFR and a cMet arm that binds to cMET, wherein the EGFR arm comprises a single domain antibody (VHH) fused to an Fc wherein the single domain antibody (VHH) comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 5 to 10 or a tandem single domain antibody fused to an Fc wherein the tandem single domain antibody comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 13 to 18, and wherein the cMET arm comprises a heavy chain and a light chain wherein the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 and the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 or a single domain antibody fused to Fc wherein the single domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 41 to 44, see Fig. 5B, p. 44-47, 51-54, 71-74.
However, the term “EGFR binding arm” encompasses IgG antibody as well as VHH antibody. The specification does not describe EGFR arm comprises just heavy chain without the light chain CDRs 1-3 encompassed by the IgG antibody still maintains antigen binding (claim 10).
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). It is unlikely that EGFR binding arm as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function for EGFR. Note, amending claim 10, line 4 to recite “the EGFR arm comprises a single domain antibody (VHH) comprising a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 95, 96, and 97; SEQ ID NOs: 95, 96, and 98; SEQ ID NOs: 95, 96, and 105; SEQ ID NOs: 102, 100, and 101; and SEQ ID NOs: 102, 103, and 104; respectively” would obviate this rejection.
Regarding the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 1-4 (claim 10), the specification discloses two antibodies matuzumab and cetuximab wherein the matuzumab comprises a particular combination of a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 2; the cetuximab comprises a VH sequence of SEQ ID NO: 3 and a VL sequence of SEQ ID NO: 4, see p. 44 specification.
However, the specification does not describe random pairing of the VH sequence of SEQ ID NO: 1 from matuzumab with the VL sequence of SEQ ID NO: 4 from cetuximab or vice versa. The same issue applies to the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23-40 (claims 10 and 14), see p. 51-54.
Regarding claims 18 and 19, the specification does not describe where and what amino acid within the full-length sequence of any one of SEQ ID NO: 71-76 to be substituted, deleted, added or a combination thereof such that the modified antibody having just 85% sequence identity still maintains antigen binding to VEGF or PD-L1. Thus one of skill in the art cannot "visualize or recognize" most members of the genus.
The state of the art is such that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 79: 1979, 1982; PTO 892). Rudikoff et al 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.
Barrios et al (J Molecular Recognition 17: 332-338, 2004; PTO 892) teach the amino acid residues in the CDRs and the length of the antibody heavy chain complementarity determining region (CDR3) are critical for antigen specific binding site (see abstract, in particular). The length of the amino acid sequence that linked the CDRs of immunoglobulin light and heavy chains is important in maintaining their required conformation for binding and in vivo activity.
MacCallum et al (Mol. Biol 262: 732-745, 1996; PTO 892) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
Wu et al (J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. As such, the skilled artisan could not immediately envision the structure of those antibodies that bind an antigen on neoplastic cells and inhibit the growth of those neoplastic cells from antibodies that bind the antigen but lack therapeutic effect (e.g., promote the growth of neoplastic cells).
Regarding the multispecific antibody comprises amino acid sequences selected from SEQ ID NOs: 83-94 (claim 23), the plural “amino acid sequences” encompass more than one sequences. The specification discloses a particular combination of heavy chain sequences each comprising a knob or a hole and pair with a particular VL chain, see p. 71-74.
However, the specification does not teach multispecific antibody comprising all SEQ ID NO: 83 to 94 or random pairing of any two heavy chains without the light chain sequences.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only (1) a multispecific antibody comprising a EGFR arm that binds to EGFR and a cMet arm that binds to cMET, wherein the EGFR arm comprises a single domain antibody (VHH) fused to an Fc wherein the single domain antibody (VHH) comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 5 to 10 or a tandem single domain antibody fused to an Fc wherein the tandem single domain antibody comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 13 to 18, and wherein the cMET arm comprises a heavy chain and a light chain wherein the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 and the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 or a single domain antibody fused to Fc wherein the single domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 41 to 44, (2) the multispecific antibody above further comprises a scFv antibody that binds to VEGF wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 73 to 76, (3) the multispecific antibody above further comprises a scFv antibody that binds to PD-L1 wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 71 and 72, (4) the multispecific antibody above wherein the antibody comprises the amino acid sequences set forth in SEQ ID NO: 90, SQE ID NO: 84 and SEQ ID NO: 85, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph.
Claims 10-18 and 23-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a multispecific antibody comprising a EGFR arm that binds to EGFR and a cMet arm that binds to cMET, wherein the EGFR arm comprises a single domain antibody (VHH) fused to an Fc wherein the single domain antibody (VHH) comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 5 to 10 or a tandem single domain antibody fused to an Fc wherein the tandem single domain antibody comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 13 to 18, and wherein the cMET arm comprises a heavy chain and a light chain wherein the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 and the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 or a single domain antibody fused to Fc wherein the single domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 41 to 44, (2) the multispecific antibody above further comprises a scFv antibody that binds to VEGF wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 73 to 76, (3) the multispecific antibody above further comprises a scFv antibody that binds to PD-L1 wherein the scFv comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 71 and 72, (4) the multispecific antibody above wherein the antibody comprises the amino acid sequences set forth in SEQ ID NO: 90, SQE ID NO: 84 and SEQ ID NO: 85, does not reasonably provide enablement for ***. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. . In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 10 encompasses a multispecific antibody comprising an EGFR arm that can bind EGFR and a cMet arm that can bind cMET, wherein: the EGFR arm comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 95, 96, and 97; SEQ ID NOs: 95, 96, and 98; SEQ ID NOs: 95, 96, and 105; SEQ ID NOs: 102, 100, and 101; and SEQ ID NOs: 102, 103, and 104; respectively, or
the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 1-4; a single domain heavy chain sequences selected from SEQ ID NOs: 5-12; or tandem single domain heavy chain sequences selected from SEQ ID NOs: 13-18; and
wherein: the cMET arm comprises a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3,
wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 106, 107, and 133; SEQ ID NOs: 111, 112, and 113; SEQ ID NOs: 111, 114, and 113; SEQ ID NOs: 99, 118, and 119; SEQ ID NOs: 99, 120, and 119; SEQ ID NOs: 99, 121, and 119; SEQ ID NOs: 99, 122, and 119; respectively;
and wherein the LCDR1, LCDR2, and LCDR3 are selected from: SEQ ID NOs: 108, 109, and 110; SEQ ID NOs: 115, 116, and 117; and SEQ ID NOs: 123, 124, and 125; respectively, or
the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23-40 or at least one single domain heavy chain domain selected from SEQ IDNO: 41-44.
Claim 11 encompasses the multispecific antibody of claim 10, wherein the EGFR arm comprises at least one single domain heavy chain domain selected from SEQ ID NOs: 5-12.
Claim 12 encompasses the multispecific antibody of claim 10, wherein the EGFR arm comprises tandem single domain heavy chains selected from SEQ ID NOs: 13-18.
Claim 13 encompasses the multispecific antibody of claim 10, wherein the anti-EGFR arm comprises heavy chain SEQ ID NO: 1 and light chain SEQ ID NO: 2; heavy chain SEQ ID NO: 3 and light chain SEQ ID NO: 4; single domain heavy chain selected from SEQ ID NOs: 5-12; or tandem single domain heavy chain selected from SEQ ID NOs: 13-18.
Claim 14 encompasses the multispecific antibody of claim 10, wherein the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 23-40.
Claim 15 encompasses the multispecific antibody of claim 10, wherein the cMET arm comprises at least one single domain heavy chain domain selected from SEQ ID NOs: 41-44.
Claim 16 encompasses the multispecific antibody of claim 10, wherein the anti-cMET arm comprises
heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 25;
heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 26;
heavy chain SEQ ID NO: 24 and light chain SEQ ID NO: 25;
heavy chain SEQ ID NO: 24 and light chain SEQ ID NO: 26;
heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 30;
heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 31;
heavy chain SEQ ID NO: 27 and light chain SEQ ID NO: 32;
heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 30;
heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 31;
heavy chain SEQ ID NO: 28 and light chain SEQ ID NO: 32;
chain SEQ ID NO: 29 and light chain SEQ ID NO: 30;
heavy chain SEQ ID NO: 29 and light chain SEQ ID NO: 31;
heavy chain SEQ ID NO: 29 and light chain SEQ ID NO: 32;
heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 38;
heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 39;
heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 40;
heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 38;
heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 39;
heavy chain SEQ ID NO: 34 and light chain SEQ ID NO: 40;
heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 38;
heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 39;
heavy chain SEQ ID NO: 35 and light chain SEQ ID NO: 40;
heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 38;
heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 39;
heavy chain SEQ ID NO: 36 and light chain SEQ ID NO: 40;
heavy chain SEQ ID NO: 37 and light chain SEQ ID NO: 39; or
heavy chain SEQ ID NO: 37 and light chain SEQ ID NO: 40.
Claim 17 encompasses the multispecific antibody of claim 10, further comprising an anti-VEGF antibody or an antigen-binding fragment thereof comprising a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 129, 130, and 131; and SEQ ID NOs: 129, 132, and 131; respectively; and wherein the LCDR1, LCDR2, and LCDR3 are SEQ ID NOs: 126, 127, and 128, respectively.
Claim 18 encompasses the multispecific antibody of claim 17, wherein the anti-VEGF antibody or antigen-binding fragment comprises an amino acid sequence having at least 85% identity to any one of SEQ ID NOs: 73-76.
Claim 23 encompasses the multispecific antibody of claim 10, wherein the multispecific antibody comprises amino acid sequences selected from SEQ ID NOs: 83-94.
Claim 24 encompasses the multispecific antibody of claim 23, wherein the multispecific antibody comprises amino acid sequences set forth in SEQ ID NO: 90, SEQ ID NO: 84, and SEQ ID NO: 85, respectively.
Claim 25 encompasses a pharmaceutical composition comprising the antibody or antigen- binding fragment of claim 10.
The specification discloses a multispecific antibody comprising a EGFR arm that binds to EGFR and a cMet arm that binds to cMET, wherein the EGFR arm comprises a single domain antibody (VHH) fused to an Fc wherein the single domain antibody (VHH) comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 5 to 10 or a tandem single domain antibody fused to an Fc wherein the tandem single domain antibody comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 13 to 18, and wherein the cMET arm comprises a heavy chain and a light chain wherein the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 and the light chain sequence is selected from the group consisting of SEQ ID NO: 25, 26, 30, 31, 32, 38, 39 and 40, and the heavy chain sequence is selected from the group consisting of SEQ ID NO: 23, 24, 27, 28, 29, 33, 34, 35, 36 and 37 or a single domain antibody fused to Fc wherein the single domain comprises the amino acid sequence selected from the group consisting of SEQ ID NO: 41 to 44, see Fig. 5B, p. 44-47, 51-54, 71-74.
However, the term “EGFR binding arm” encompasses IgG antibody as well as VHH antibody. The specification does not teach EGFR arm comprises just heavy chain without the light chain CDRs 1-3 for IgG antibody still maintains antigen binding encompassed by the EGFR binding arm (claim 10).
Chiu et al (Antibodies 8: 55-80, 2019; PTO 892) teaches the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (see p. 4, in particular). It is unlikely that EGFR binding arm as defined by the claims, which may contain less than the full complement of CDRs from the heavy and light chain variable regions have the required binding function for EGFR. Amending claim 10, line 4 to recite “the EGFR arm comprises a single domain antibody (VHH) comprising a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3, wherein the HCDR1, HCDR2, and HCDR3 are selected from: SEQ ID NOs: 95, 96, and 97; SEQ ID NOs: 95, 96, and 98; SEQ ID NOs: 95, 96, and 105; SEQ ID NOs: 102, 100, and 101; and SEQ ID NOs: 102, 103, and 104; respectively” would obviate this rejection.
Regarding the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 1-4 (claim 10), the specification discloses just two antibodies matuzumab and cetuximab wherein the matuzumab comprises a particular combination of a VH sequence of SEQ ID NO: 1 and a VL sequence of SEQ ID NO: 2; the cetuximab comprises a VH sequence of SEQ ID NO: 3 and a VL sequence of SEQ ID NO: 4, see p. 44 specification.
However, the specification does not teach random pairing of the VH sequence of SEQ ID NO: 1 from matuzumab with the VL sequence of SEQ ID NO: 4 from cetuximab or vice versa. The same issue applies to the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23-40 (claims 10 and 14), see p. 51-54.
Regarding claims 18 and 19, the specification does not teach where and what amino acid within the full-length sequence of any one of SEQ ID NO: 71-76 to be substituted, deleted, added or a combination thereof such that the modified antibody having just 85% sequence identity still maintains antigen binding to VEGF or PD-L1.
The state of the art is such that even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may affect antigen-binding function as evidenced by Rudikoff et al. (Proc Natl Acad Sci USA 79: 1979, 1982; PTO 892). Rudikoff et al 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.
Barrios et al (J Molecular Recognition 17: 332-338, 2004; PTO 892) teach the amino acid residues in the CDRs and the length of the antibody heavy chain complementarity determining region (CDR3) are critical for antigen specific binding site (see abstract, in particular). The length of the amino acid sequence that linked the CDRs of immunoglobulin light and heavy chains is important in maintaining their required conformation for binding and in vivo activity.
MacCallum et al (Mol. Biol 262: 732-745, 1996; PTO 892) analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col.) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.).
Wu et al (J. Mol. Biol. 294: 151-162, 1999; PTO 892) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
Regarding the multispecific antibody comprises amino acid sequences selected from SEQ ID NOs: 83-94 (claim 23), the plural “amino acid sequences” encompass more than one sequences. The specification discloses a particular combination of heavy chain sequences each comprising a knob or a hole and pair with a particular VL chain, see p. 71-74.
However, the specification does not teach multispecific antibody comprising all SEQ ID NO: 83 to 94 or random pairing of any two heavy chains without the light chain sequences. As such, the skilled artisan could not immediately predict, recognize, or distinguish those antibodies that bind an antigen on neoplastic cells and inhibit the growth of those neoplastic cells from antibodies that bind the antigen but lack therapeutic effect (e.g., promote the growth of neoplastic cells).
There are insufficient in vivo working examples. It is unpredictable which multispecific antibody is effective to treat any and all cancer.
Therefore, one skilled in the art cannot practice the invention with a reasonable expectation of success without undue experimentation.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 10, 14, 16 and 25 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Bossenmaier et al (US20100254989, published Oct 7, 2010; PTO 892).
Claim 10 recites a multispecific antibody comprising an EGFR arm that can bind EGFR and a cMet arm that can bind cMET, wherein:
the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 3-4; and
wherein: the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 33 and 38.
Claim 14 recites the multispecific antibody of claim 10, wherein the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 33 and 38.
Claim 16 encompasses the multispecific antibody of claim 10, wherein the anti-cMET arm comprises heavy chain SEQ ID NO: 33 and light chain SEQ ID NO: 38.
Regarding claims 10, 14, 16, Bossenmaier teaches heterodimeric bivalent bispecific antibody having one arm that binds to human ErbB-1 (aka EGFR) and the other arm that binds to human c-Met, see entire document, para.[0022], [0028], [0097], Fig. 2a reproduced below for Applicant’s convenience.
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707
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The ErbB1 binding arm comprises a heavy chain amino acid sequence of SEQ ID NO: 1, which is identical to the claimed SEQ ID NO: 3, see sequence alignment below, para. [0028]:
ALIGNMENT:
Query Match 100.0%; Score 638; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYN 60
Qy 61 TPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 119
And a light chain amino acid sequence of SEQ ID NO: 2, which is identical to the claimed SEQ ID NO: 4, see sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 556; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPS 60
Qy 61 RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK 107
The c-Met binding arm comprises a heavy chain amino acid sequence of SEQ ID NO: 5, which is identical to the claimed SEQ ID NO: 33, see sequence alignment below, para. [0028]:
ALIGNMENT:
Query Match 100.0%; Score 640; Length 119;
Best Local Similarity 100.0%;
Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTFTSYWLHWVRQAPGKGLEWVGMIDPSNSDTRF 60
Qy 61 NPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSS 119
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NPNFKDRFTISADTSKNTAYLQMNSLRAEDTAVYYCATYRSYVTPLDYWGQGTLVTVSS 119
And a light chain amino acid sequence of SEQ ID NO: 6, which is identical to the claimed SEQ ID NO: 33, see sequence alignment below, para. [0028]:
ALIGNMENT:
Query Match 100.0%; Score 597; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCKSSQSLLYTSSQKNYLAWYQQKPGKAPKLLIYWASTR 60
Qy 61 ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIK 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYAYPWTFGQGTKVEIK 113
Regarding claim 25, Bossenmaier teaches a pharmaceutical composition comprising the reference antibody, see abstract, [0002], [0035], in particular.
Since the Patent Office does not have the facilities for examining and comparing the antibodies of the instant invention to those of the prior art, the burden is on applicant to show that the prior art antibody is different from the claimed antibody. See In re Best, 562 F2d 1252. 195 USPQ 430(CCPA 1977).
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 10, 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 11,235,063 (filed Oct 27, 2016; PTO 892) in view of US Patent No. 9,328,173 (issued May 3, 2016; PTO 892).
Claim 10 recites a multispecific antibody comprising an EGFR arm that can bind EGFR and a cMet arm that can bind cMET, wherein:
the EGFR arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 1-2; and
wherein: the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NO: 23 and 25.
Claim 14 recites the multispecific antibody of claim 10, wherein the cMET arm comprises a light chain sequence and a heavy chain sequence selected from SEQ ID NOs: 23 and 25.
Claim 16 encompasses the multispecific antibody of claim 10, wherein the anti-cMET arm comprises heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 25.
Regarding claim 10, the ‘063 patent teaches a heterodimeric bispecific antibody comprising one arm, e.g., Fab or scFv which specifically binds to EGFR and a second arm, e.g., Fab or scFv fragment which specifically binds to c-MET, see entire document, abstract, in particular. The reference EGFR arm comprises a heavy chain sequence and a light chain sequence wherein the heavy chain sequence comprises the amino acid sequence of SEQ ID NO: 14, which is identical to the claimed SEQ ID NO: 1, see sequence alignment below, col. 9, in particular:
OTHER INFORMATION: hu425 VH sequence
Query Match 100.0%; Score 654; Length 121;
Best Local Similarity 100.0%;
Matches 121; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSHWMHWVRQAPGQGLEWIGEFNPSNGRTNY 60
Qy 61 NEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDGRYFDYWGQGTLVTVS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKSKATMTVDTSTNTAYMELSSLRSEDTAVYYCASRDYDYDGRYFDYWGQGTLVTVS 120
Qy 121 S 121
|
Db 121 S 121
And the reference light chain comprises the amino acid sequence of SEQ ID NO: 13, which is identical to the claimed SEQ ID NO: 2, see sequence alignment below, col. 9, in particular:
OTHER INFORMATION: hu425 VL sequence
Query Match 100.0%; Score 554; Length 107;
Best Local Similarity 100.0%;
Matches 106; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASSSVTYMYWYQQKPGKAPKLLIYDTSNLASGVPSR 60
Qy 61 FSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIK 106
||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FSGSGSGTDYTFTISSLQPEDIATYYCQQWSSHIFTFGQGTKVEIK 106
The ‘063 patent teaches that the bispecific heterodimeric immunoglobulin molecule which binds to both EGFR and c-MET are effective in the treatment of EGFR and c-MET expressing tumors, see col. 3, line 16-19.
The ‘063 patent does not teach that the c-Met binding arm comprises heavy chain SEQ ID NO: 23 and light chain SEQ ID NO: 25 as per claims 10, 14, and 16.
However, the ‘173 patent teaches bispecific antibody that binds to EGFR and c-Met wherein the c-Met binding arm comprises a heavy chain amino acid sequence of SEQ ID NO: 21, which is identical to the claimed SEQ ID NO: 23, see entire document, see col. 20, line 60, sequence alignment below:
Query Match 100.0%; Score 619; Length 115;
Best Local Similarity 100.0%;
Matches 115; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGRVNPNRRGTTY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGRVNPNRRGTTY 60
Qy 61 NQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARANWLDYWGQGTTVTVSS 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARANWLDYWGQGTTVTVSS 115
The reference light chain amino acid sequence comprises SEQ ID NO: 22, which is identical to the claimed SEQ ID NO: 25, see sequence alignment below, col. 20, line 61, in particular:
ALIGNMENT:
Query Match 100.0%; Score 556; Length 108;
Best Local Similarity 100.0%;
Matches 108; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIYLHWYQQKPGKAPKLLIYSTSNLASGVP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSVSSSVSSIYLHWYQQKPGKAPKLLIYSTSNLASGVP 60
Qy 61 SRFSGSGSGTDFTLTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEIK 108
||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SRFSGSGSGTDFTLTISSLQPEDFATYYCQVYSGYPLTFGGGTKVEIK 108
The multifunctional antibody that binds to MET and EGFR is useful for treating EGFR and MET expressing cancer in human by blocking both MET and EGFR activation, see col. 27, line 17-19, Example 5, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute a known c-Met binding arm comprising a heavy chain and a light chain sequences in the bispecific heterodimeric immunoglobulin molecules which bind to both EGFR and c-MET of ‘063 patent for another, e.g., c-Met binding arm comprising a heavy chain and a light chain sequences as taught by the ‘173 patent with a reasonable expectation of success, e.g., bispecific antibody having one amr that binds to EGFR and the other arm that binds to c-MET for treating cancer expressing EGFR and c-MET.
One of ordinary skill in the art would have been motivated to do so because the ‘063 patent teaches that the bispecific heterodimeric immunoglobulin molecules which bind to both EGFR and c-MET are effective in the treatment of EGFR and c-MET expressing tumors (see col. 3, line 16-19) and the ‘173 patent teaches that that bispecific antibody that binds to MET and EGFR is useful for treating EGFR and MET expressing cancer in human by blocking both MET and EGFR activation, see col. 27, line 17-19, Example 5, in particular.
Further, simple substitution of one known element, e.g., VH and VL that binds to c-MET in one arm of the bispecific antibody that binds to EGFR and c-MET for another, e.g., another VH and VL that binds to c-MET would obtain predictable results, e.g., bispecific antibody having one arm that binds to EGFR and the other arm that binds to c-MET. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 11,235,063 (filed Oct 27, 2016; PTO 892) in view of US Patent No. 9,328,173 (issued May 3, 2016; PTO 892) as applied to claims 10, 14 and 16 mentioned above and further in view of Qu et al (US20190184012, published June 20, 2019; PTO 892) or US Patent No. 11,692,016 (filed July 2, 2020; PTO 892) or Laeremans et al (US20090252681, published Oct 8, 2009; PTO 892).
The combine teachings of the ‘063 patent and the ‘173 patent have been discussed supra.
The references above do not teach the multispecific antibody wherein the EGFR arm comprises a single domain antibody comprising the amino acid sequence of SEQ ID NO: 11 or SEQ ID NO: 12 as per claims 11 and 13.
However, Qu teaches nanobody (aka VHH or single domain antibody) that binds to EGFR (see para. [0039]) wherein the anti-EGFR nanobody comprising the amino acid sequence of SEQ ID NO: 5, which is identical to the claimed SEQ ID NO: 11, see para. [0046], sequence alignment below:
ORGANISM: Lama glama
Query Match 100.0%; Score 690; Length 138;
Best Local Similarity 100.0%;
Matches 130; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKQREFVAAIRWSGGYTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKQREFVAAIRWSGGYTYY 60
Qy 61 TDSVKGRFTISRDNAKTTVYLQMNSLKPEDTAVYYCAATYLSSDYSRYALPQRPLDYDYW 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TDSVKGRFTISRDNAKTTVYLQMNSLKPEDTAVYYCAATYLSSDYSRYALPQRPLDYDYW 120
Qy 121 GQGTQVTVSS 130
||||||||||
Db 121 GQGTQVTVSS 130
Qu teaches that nanobody, which has the advantages of being non-toxic, low cost, and convenient to use, and is particularly suitable for transdermal delivery, see para. [0015], in particular.
Likewise, the ‘016 patent teaches llama single domain Ab (sdAb), e.g., Ega1 (anti-EGFR) antibody comprising the amino acid sequence of SEQ ID NO: 1594, which is identical to the claimed SEQ ID NO: 11, see col. 181, line 13-20, col. 198, lines 24-35, Fig. 26, in particular.
Query Match 100.0%; Score 690; Length 132;
Best Local Similarity 100.0%;
Matches 130; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKQREFVAAIRWSGGYTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGGGLVQPGGSLRLSCAASGRTFSSYAMGWFRQAPGKQREFVAAIRWSGGYTYY 60
Qy 61 TDSVKGRFTISRDNAKTTVYLQMNSLKPEDTAVYYCAATYLSSDYSRYALPQRPLDYDYW 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TDSVKGRFTISRDNAKTTVYLQMNSLKPEDTAVYYCAATYLSSDYSRYALPQRPLDYDYW 120
Qy 121 GQGTQVTVSS 130
||||||||||
Db 121 GQGTQVTVSS 130
Likewise, Laeremans teach nanobody (aka single domain antibody) such as PMP9G9 that binds to EGFR wherein the antibody inhibits EGFR expressing tumor cells, see Example 9, in particular. The reference nanobody comprises the amino acid sequence of SEQ ID NO: 91, which is identical to the claimed SEQ ID NO: 12, see entire document, para. [0019], [0028], [0105] to [0108], sequence alignment below,
Query Match 100.0%; Score 674; Length 127;
Best Local Similarity 100.0%;
Matches 127; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQAGGSLRLSCAASGRTFSSYAMGWFRQAPGKEREFVVAINWSSGSTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQAGGSLRLSCAASGRTFSSYAMGWFRQAPGKEREFVVAINWSSGSTYY 60
Qy 61 ADSVKGRFTISRDNAKNTMYLQMNSLKPEDTAVYYCAAGYQINSGNYNFKDYEYDYWGQG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNAKNTMYLQMNSLKPEDTAVYYCAAGYQINSGNYNFKDYEYDYWGQG 120
Qy 121 TQVTVSS 127
|||||||
Db 121 TQVTVSS 127
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substitute a known EGFR binding arm in the bispecific heterodimeric immunoglobulin molecules which bind to both EGFR and c-MET of the ‘063 patent and ‘173 patent for another, e.g., EGFR binding arm from single domain antibody as taught by Qu or the ‘016 patent or Laeremans to arrive at the claimed invention with a reasonable expectation of success, e.g., bispecific antibody having one arm that binds to EGFR and the other arm that binds c-MET for treating cancer expressing EGFR and c-MET.
One of ordinary skill in the art would have been motivated to do so because Qu teaches that nanobody has the advantages of being non-toxic, low cost, and convenient to use, and is particularly suitable for transdermal delivery (see para. [0015], in particular) and Laeremans teach that nanobody (aka single domain antibody) such as PMP9G9 that binds to EGFR and inhibits EGFR expressing tumor cells, see Example 9, in particular.
Further, simple substitution of one known element, e.g., EGFR binding domain in one arm of the bispecific antibody for another, e.g., another EGFR binding domain would obtain predictable results, e.g., bispecific antibody having one arm that binds to EGFR and the other arm that binds to c-MET. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 11,235,063 (filed Oct 27, 2016; PTO 892) in view of US Patent No. 9,328,173 (issued May 3, 2016; PTO 892) as applied to claims 10, 14 and 16 mentioned above and further in view of Urech et al (US20170073415, published March 16, 2027; PTO 892) and WO2019232323 publication (published December 5, 2019; PTO 892) or US Patent No. 9,987,314 (issued June 5, 2018; PTO 892).
The combine teachings of the ‘063 patent and the ‘173 patent have been discussed supra.
The references above do not teach the multispecific antibody wherein the antibody further comprises an anti-VEGF antibody or an antigen binding fragment thereof as per claim 17, wherein the anti-VEGF antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% sequence identity to SEQ ID NO: 73 to 76 as per claim 18.
However, Urech multispecific molecule such as IgG-scFv (see para. [0130]) that binds to a target on the surface of a cell, e.g., EGFR, VEGF, see para. [0075]. Urech teaches that humanized anti-VEGF Rabbit Monoclonal Antibody Inhibits Angiogenesis and Blocks Tumor Growth in Xenograft Models, see para. [0115], in particular.
The ‘063 patent, the ‘173 patent, and Urech do not teach the anti-VEGF antibody or antigen-binding fragment thereof comprises an amino acid sequence at least 85% sequence identity to SEQ ID NO: 73 to 76.
However, the WO2019232323 publication teaches IgG-scFv bispecific antibody ([0069], [0080]) that binds to VEGF and EGFR (see para. [0085], [00129], [00168], claims in particular) wherein the scFv that binds to VEGF comprising a heavy chain variable region (VH) and light chain variable region (VL) and wherein the anti-VEGF scFv comprises the amino acid sequence of SEQ ID NO: 7 derived from bevacizumab, which is 90.8% sequence identity to the claimed SEQ ID NO: 73 as per claim 18, see Figs. 2A to D, sequence alignment below:
Query Match 90.8%; Score 1200; Length 700;
Best Local Similarity 89.8%;
Matches 220; Conservative 12; Mismatches 13; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKLEIKGGGGSGGGGSGGG 120
|||||||||||||||||||||||||||||||||||||||||||:||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEP 180
||:||||:|| | :|| |:::|| |||||||||||||||||||:||||:||||||||||
Db 121 GSEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEP 180
Qy 181 TYAQGFTGRFVFSLDTSVSTAYLQICSLKAEDTAVYFCAKYPHYYGSSHWYFDVWGQGTL 240
||| | || |||||| ||||||: ||:|||||||:|||||||||||||||||||||||
Db 181 TYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTL 240
Qy 241 VTVSS 245
|||||
Db 241 VTVSS 245
The WO2019232323 publication teaches bispecific antibody that binds to VEGF comprising a heavy chain variable region (VH) and light chain variable region (VL) wherein the anti-VEGF scFv comprises the amino acid sequence of SEQ ID NO: 7 derived from bevacizumab, which is 90.5% identity to the claimed SEQ ID NO: 74 as per claim 18, see sequence alignment below:
Query Match 90.5%; Score 1195; Length 700;
Best Local Similarity 88.2%;
Matches 216; Conservative 17; Mismatches 12; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
||||||||||||||||||||||| ||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPS 60
Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKLEIKGGGGSGGGGSGGG 120
|||||||||||||||||||||||||||||||||||||||||||:||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKGGGGSGGGGSGGG 120
Qy 121 GSQVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEP 180
||:||||:|| : :|| |:::|| |||||||||||||||||||:||||:||||||||||
Db 121 GSEVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEP 180
Qy 181 TYAQKFQGRFTFTADESTSTAYMELSSLRSEDTAVYYCAKYPHYYGSSHWYFDVWGQGTL 240
||| |: ||||: | | ||||::::|||:||||||||||||||||||||||||||||||
Db 181 TYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTL 240
Qy 241 VTVSS 245
|||||
Db 241 VTVSS 245
The WO2019232323 publication teaches that the antibody is useful for treating EGFR expressing cancers, see para. [00126] to [00127], in particular.
Likewise, the ‘314 patent teaches anti-VEGF scFv comprises the amino acid sequence of SEQ ID NO: 36, which is 90.8% identical to the claimed SEQ ID NO: 75, see col. 32, line 22-45, FIG. 7, sequence alignment below:
OTHER INFORMATION: anti-VEGF ScFv amino acid sequence
Query Match 90.8%; Score 1200; Length 265;
Best Local Similarity 89.8%;
Matches 220; Conservative 12; Mismatches 13; Indels 0; Gaps 0;
Qy 1 QVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTY 60
:||||:|| | :|| |:::|| |||||||||||||||||||:||||:||||||||||||
Db 20 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 79
Qy 61 AQGFTGRFVFSLDTSVSTAYLQICSLKAEDTAVYFCAKYPHYYGSSHWYFDVWGQGTLVT 120
| | || |||||| ||||||: ||:|||||||:|||||||||||||||||||||||||
Db 80 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 139
Qy 121 VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGK 180
||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||
Db 140 VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGK 199
Qy 181 APKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 200 APKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGT 259
Qy 241 KLEIK 245
|:|||
Db 260 KVEIK 264
The reference anti-VEGF scFv comprises the amino acid sequence of SEQ ID NO: 36, which has a 90.5 % sequence identity to the claimed SEQ ID NO: 76, see sequence alignment below:
OTHER INFORMATION: anti-VEGF ScFv amino acid sequence
Query Match 90.5%; Score 1195; Length 265;
Best Local Similarity 88.2%;
Matches 216; Conservative 17; Mismatches 12; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTY 60
:||||:|| : :|| |:::|| |||||||||||||||||||:||||:||||||||||||
Db 20 EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTY 79
Qy 61 AQKFQGRFTFTADESTSTAYMELSSLRSEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 120
| |: ||||: | | ||||::::|||:||||||||||||||||||||||||||||||||
Db 80 AADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVT 139
Qy 121 VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGK 180
||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||
Db 140 VSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGK 199
Qy 181 APKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGT 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 200 APKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGT 259
Qy 241 KLEIK 245
|:|||
Db 260 KVEIK 264
The ‘314 patent teaches that a wide range of different forms of antibody may be employed (see col. 27, line 30); antibodies for use may be obtained using any suitable method known in the art (see col. 28, line 5). Known antibodies or antibody-binding fragments can be employed to generate alternative antibody formats with the same CDRs or the same variable regions, for examples, a full-length antibody can readily be converted into a Fab, Fab’, or scFv fragment (see col. 27, line 25-29, in particular). The antibody is useful for treating various tumor, see col. 37, lines 40-55, in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to append the scFv antibody that binds to VEGF of WO2019232323 publication or the ‘314 patent to the bispecific IgG antibody of the WO2019232323 publication, just like that of Urech to arrive at the claimed invention with a reasonable expectation of success, e.g., multispecific IgG antibody comprising an EGFR arm that binds to EGFR and the arm that binds to cMet and further comprising scFv antibody that binds to VEGF at the N-terminus or C-terminus of IgG antibody.
One of ordinary skill in the art would have been motivated to do so because Urech teaches that humanized anti-VEGF antibody inhibits angiogenesis and blocks tumor growth in vivo (see para. [0115]); the WO2019232323 publication teaches that the antibody is useful for treating EGFR expressing cancers (see para. [00126] to [00127], in particular and the ‘314 patent teaches that antibody is useful for treating various tumor, see col. 37, lines 40-55, in particular.
One of ordinary skill in the art would have had a reasonable expectation of success in making and fusing any known anti-VEGF scFv to the bispecific IgG antibody that binds to EGFR and c-Met for treating cancer, because each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ... [T]he idea of combining them flows logically from their having being individually taught in the prior art" (see MPEP 2144.06).
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Allowable Subject Matter
SEQ ID NO: 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 24, 26, 28, 29, 31, 32, 34, 35, 36, 37, 39, 40, 42, 44, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93 and 94 are free of prior art.
Conclusion
Claim 24 is 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.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
